INDEX

1. Perioperative fluid & electrolyte management

Dr. Rajdeep Singh
2. Synergistic Gangrene
Dr. Mayank Jayant
3. Deep Neck Space Infections
Dr. Ravi Meher
4. Early Breast Cancer
Dr. V Seenu
5. Locally Advanced Breast Cancer
Dr. PN Agarwal, Dr. Vivek Wadhawa
6. Metastatic Breast Cancer
Dr. Durgatosh Pandey, Dr. Jyoti Sharma, Dr. Paras Khanna, Dr. Ajay
Gogia
7. Management of Axillary nodes in Breast Cancer
Dr. Gaurav Agarwal, Dr. Sendhil Rajan
8. Diagnostic evaluation of a breast lump
Dr. PN Agarwal, Dr. Varun Jain
9. Triage
Dr. Gulshanjit Singh
10. Disaster Managemant
Dr. Ajit Sinha, Dr. RK Soni
11. Bullet Injuries
Dr. Vivek Agrawal, Dr. Mohit Kumar Joshi
12. Blast Injuries
Dr. SV Kumar
13. Prevention of Surgical Site Infections
Dr. VK Malik, Dr. Ashish Dey
14. Parenteral Nutrition
Dr. Amit Sachdeva
15. Ulcerative Colitis: Surgical Aspects
Dr. Sundeep Saluja, Dr. Saleem Naik
16. Retroperitoneal Tumours
Dr. Jainendra K. Arora
17. Malignant Melanoma
Dr. Ravi Kannan, Dr. Ritesh Tapkire, Dr. Rajeev Kumar
18. The Surgeon and Molecular knowledge
Dr. Ravi Kant, Dr. Bina Ravi
19. Periampullary carcinoma
Dr. Sundeep Singh Saluja, Dr. Sandip Chandrasekhar, Dr. John M
Manipadnam
20. Biliary Strictures
Dr. PK Mishra, Dr. Harsh Shah
21. Liver Abscess
Dr. Pradeep Garg
22. Choledochal Cyst
Dr. Shivendra Singh, Dr. Nikhil Gupta
23. Rationale of Investigations for work-up of a case of Obstructive
Jaundice
Air Cmde Aswini K Pujahari
24. Abdominal tuberculosis
Dr. Shaji Thomas
25. Asymptomatic Gallstones
Dr. RS Mohil, Dr. Shailendra Singh
26. Surgery in Acute Pancreatitis
Dr. Rajneesh K Singh, Dr. Rakesh K Singh
27. Gastric Outlet Obstruction
Dr. Manoj Andley
28. Bladder Outlet Obstruction
Dr. Kim Mammen, Dr. Navin Suthahar
29. Genitourinary Tuberculosis
Dr. Madhusudan Agrawal, Dr. Manoj Sharma
30. Renal Transplant
Dr. Sandeep Guleria
31. Rationale of Investigations for work-up of a patient of Renal Lump
Dr. Sanjay Gupta
32. Pheochromocytoma
Dr. Deepak Ghuliani
33. Endocrine tumours of the Pancreas
Dr. SK Mishra, Dr. Naval Bansal
34. Bone Tumours – Principles of management: an Overview
Dr. Sudhir K Kapoor
35. Hormonal Management of prostate cancer
Dr. Rishi Nayyar, Dr. Raman Tanwar
36. Solitary Thyroid Nodule
Dr. TK Thusoo
37. Multinodular Goitre
Dr. Arun K Kakar, Dr. Ashish Airen
38. Hyperthyroidism
Dr. Sunil Chumber, Dr. Pratyusha Priyadarshini
39. Well differentiated thyroid cancer
Dr. NK Shukla
40. Rationale of investigations for workup of a patient with thyroid
swelling
Dr. Anjali Mishra, Dr. Sunil Malla Bujar Barua
41. Buerger’s disease
Dr. MP Arora
42. Critical Limb Ischemia
Dr. CB Singh
43. Compartment syndrome
Dr. Sushanto Neogi
44. Atherosclerotic Peripheral Vascular Disease
Dr. NS Hadke, Dr. Ankit Jain

45. Robotic Surgery: Overview, Applications and Future Trends

Dr. Vivek Bindal
46. Radiofrequency Ablation in Surgical Practice
Dr. Anubhav Vindal, Dr. Bipin Singh
48. Scientific Basis of Symptoms, Signs, Investigations and Treatment
of Chronic Arterial Insufficiency
Dr. Pawanindra Lal
49. Reduced Port Surgery
Dr. Vinod K Malik, Dr. Ashish Dey, Dr. Vijay Singh
50. Fundoplication for GERD-Current Status
Dr. Pawanindra Lal, Dr. Anubhav Vindal
51. Current management of urolithiasis
Dr. R.C.M. Kaza
 CONTRIBUTORS

Disaster Management Parenteral Nutrition

Dr. Ajit Sinha Dr. Amit Sachdeva
Professor & Consultant Surgeon Senior Manager, Medical Affairs
Vardhman Mahavir Medical College & Assoc. Baxter
Safdarjung Hospital, Delhi
Delhi
Rationale of investigations for workup of a case Radiofrequency ablation in surgical practice
of thyroid swelling Dr. Anubhav Vindal
Dr. Anjali Mishra Assistant Professor Surgery,
Additional Professor, Endocrine & Breast Maulana Azad Medical College &
Surgery, Sanjay Gandhi Post Graduate Institute assoc. Lok Nayak Hospital, Delhi
of Medical Sciences, Lucknow
Multinodular Goitre Rationale of Investigations in a case of
Dr. Arun K. Kakar Obstructive Jaundice
Consultant Surgeon, Air Cmde Aswini K. Pujahari
Pushpanjali Croslay Hospital Professor & Head of Surgery
Delhi Armed Forces Medical College,
Pune
Critical Limb Ischaemia Pheochromocytoma
Dr. CB Singh Dr. Deepak Ghuliani
Associate Professor Surgery, Assistant Professor Surgery,
Maulana Azad Medical College & Maulana Azad Medical College &
assoc. Lok Nayak Hospital, Delhi assoc. Lok Nayak Hospital, Delhi

Metastatic Breast Cancer Management of axilla in breast cancer

Dr. Durgatosh Pandey Dr. Gaurav Agarwal
Assistant Professor Surgical Oncology, Professor, Endocrine & Breast Surgery
Dr BRA-IRCH, All India Institute of Medical Sanjay Gandhi Post Graduate Institute of
Sciences, Delhi Medical Sciences, Lucknow

Triage Retroperitoneal tumours

Dr. GulshanJit Singh Dr. Jainendra Arora
Consultant & Head of Surgery Assistant Professor Surgery,
Vardhman Mahavir Medical College & Assoc. Vardhman Mahavir Medical College and
Safdarjung Hospital, Delhi assoc. Safdarjung hospital, Delhi

Bladder outlet obstruction Genitourinary Tuberculosis

Dr. Kim Mammen Dr Madhusudan Agrawal
Professor & Head of Urology, Ex-Professor of Urology
Christian Medical College SN Medical College, Agra
Ludhiana Consultant Urologist, Agra

Gastric Outlet Obstruction Synergistic gangrene

Dr. Manoj Andley Dr. Mayank Jayant
Professor of Surgery, Assistant Professor,
Lady Hardinge Medical College & Government Medical College Hospital
assoc. Smt. Sucheta Kriplani Hospital, Delhi Chandigarh
Buerger’s Disease Atherosclerotic Peripheral vascular disease
Dr. M.P. Arora Dr. NS Hadke
Director-Professor in Surgery, Director-Professor of Surgery,
Lady Hardinge Medical College, Maulana Azad Medical College &
New Delhi assoc. Lok Nayak Hospital, Delhi

Well differentiated thyroid cancer Chronic Arterial Insufficiency

Dr. NK Shukla Fundoplication in GERD-Current Status
Professor & Head of Surgical Oncology, Dr. Pawanindra Lal
BRA-IRCH, All India Institute of Medical Professor of Surgery
Sciences, Delhi Maulana Azad Medical College &
assoc. Lok Nayak Hospital, Delhi
Biliary strictures Locally Advanced breast cancer
Dr. PK Mishra Diagnostic evaluation of a breast lump
Consultant GI Surgeon, Dr. PN Agarwal
Govind Ballabh Pant Hospital, Director-Professor & Head of Surgery,
Delhi Maulana Azad Medical College &
assoc. Lok Nayak Hospital, Delhi
Liver Abscess Perioperative Fluid & Electrolyte management
Dr. Pradeep Garg Dr. Rajdeep Singh
Professor of Surgery Associate Professor, Surgery,
Post graduate Institute of Medical Sciences Maulana Azad Medical College &
Rohtak, Haryana assoc. Lok Nayak Hospital, Delhi

Surgery in Acute Pancreatitis Deep Neck Space Infections

Dr Rajneesh K. Singh Dr Ravi Meher
Professor of GI Surgery, Associate Professor, ENT
Sanjay Gandhi Post Graduate Institute of Maulana Azad Medical College &
Medical Sciences, Lucknow assoc. Lok Nayak Hospital, Delhi

Malignant Melanoma The Surgeon and Molecular knowledge

Dr. Ravi Kannan Dr. Ravi Kant
Director & Consultant Surgical Oncologist, Professor & Head of Surgery,
Cachar Cancer Hospital and Research Centre, All India Institute of Medical Sciences,
Silchar, Assam Bhopal, MP

Penile cancer Homonal management of prostate cancer

Dr. RCM Kaza Dr Rishi Nayyar
Director Professor Surgery, Associate Professor, Urology
Maulana Azad Medical College & Dr RML Hospital & PGIMER,
assoc. Lok Nayak Hospital, Delhi New Delhi

Asymptomatic gallstones Renal transplantation

Dr. RS Mohil Dr Sandeep Guleria
Consultant Surgeon & Associate Professor Senior Consultant Surgeon,
Surgery, Vardhman Mahavir Medical College (General Surgery,GI Surgery and
and assoc. Safdarjung hospital, Delhi Transplantation)
Indraprastha Apollo Hospitals, New Delhi
Rationale for investigations for workup of a Abdominal tuberculosis
patient with renal lump Dr. Shaji Thomas
Dr. Sanjay Gupta Director Professor, Surgery,
Professor of Surgery, Lady Hardinge Medical College &
University College of Medical Sciences & assoc. Smt. Sucheta Kriplani Hospital, Delhi
assoc. Guru Teg Bahadur Hospital, Delhi
Choledochal Cyst Endocrine tumours of pancreas
Dr Shivendra Singh Dr. SK Mishra
Senior Consultant and Chief, Professor & Head, Endocrine and Breast
GI Oncosurgery and Liver transplantation Surgery, Sanjay Gandhi Post Graduate Institute
Rajiv Gandhi Cancer Institute of Medical Sciences, Lucknow
New Delhi
Bone tumours-Principles of management Hyperthyroidism
Dr Sudhir Kapoor Dr Sunil Chumber
Dean & Professor of Orthopaedics Professor of Surgery
ESI PGIMSR & Hospital All India Institute of Medical Sciences,
Basaidarapur, New Delhi New Delhi

Ulcerative Colitis-Surgical Aspects Compartment syndrome

Periampullary carcinoma Dr. Sushanto Neogi
Dr. Sundeep Saluja Associate Professor Surgery,
Professor of GI Surgery, Maulana Azad Medical College &
Govind Ballabh Pant hospital, assoc. Lok Nayak Hospital, Delhi
Delhi
Blast Injuries Solitary Thyroid Nodule
Dr. SV Kumar Dr. TK Thusoo
Principal & Head of Surgery Consultant Endocrine surgeon,
Andhra Medical College Max Hospitals,
Vishakhapatnam Delhi
Andhra Pradesh
Early breast cancer Bullet Injuries
Dr. V Seenu Dr. Vivek Agrawal
Professor of Surgery, Director Professor Surgery,
All India Institute of Medical Sciences, University College of Medical Sciences &
Delhi assoc. Guru Teg Bahadur Hospital, Delhi

Robotic Surgery Prevention of Surgical Site Infections

Dr. Vivek Bindal Reduced Port Surgery
Consultant Laparoscopic, Bariatric & Robotic Dr. VK Malik
Surgeon, Institute of Minimal Access, Metabolic Vice Chairman & Consultant, Surgery
and Bariatric Surgery (iMAS) & Institute of Sir Ganga Ram Hospital
Robotic Surgery (IRS), New Delhi
Sir Ganga Ram Hospital, New Delhi
 Perioperative Fluid Management
Rajdeep Singh

Water is essential for the body, and the homeostatic mechanisms for maintaining body water are so
effective that we do not commonly see the effects of water excess or deficit. Any surgical procedure is
a stress for the body, and it reacts accordingly. General surgery patients undergoing abdominal
surgery require particular care since most remain nil orally for a few days after surgery. A sub-group
of patients require preoperative fluid management also, such as peritonitis and intestinal obstruction.
In this article, normal requirements and mechanisms for fluid and electrolyte balance will be stressed,
followed by specific disease conditions.

Aims of Fluid Therapy

• Correction of shock and establish proper tissue perfusion
• Correct fluid deficit and ongoing losses
• To provide maintenance requirement of fluid electrolyte if needed
• Proper selection of fluid so as to correct electrolyte and acid base 
disorder simultaneously.

Normal requirements

Water
Fifty to 60% of body weight is composed of water in adults. The range is wide, because muscle has
75% water content whereas fat has 15% water content. Consequently, athletes and young adults
have more total body water compared to obese or elderly persons. Maintenance fluid requirements
generally work out to 30-35 ml/kg/day for an adult. An easy to remember formula for calculation of the
maintenance rate is the 4-2-1 rule:
 4ml/kg/hr for first 10 kg
 2ml/kg/hr for the next 10 kg
 1ml/kg/hr for each kg over 20kg

Therefore, a 53 kg man would require a maintenance rate of (4*10)+(2*10)+(1*(53-20))=93ml/hr,

which comes out to about 2.2 litres per day. To this are added expected fluid losses, to reach the
desired fluid volume to be infused in a day. E.g. a febrile person in a warm environment will require 1
litre extra, as will persons with ileostomy or fistula losses.
Water gain by body: Water losses:
Food 500-700 ml Urine 800-1500 ml
Water intake 800-1500 ml Sweat and respiration 600 ml
Metabolism 250 ml Faeces 250 ml

Body fluid is partitioned into the Intracellular (66%) and Extracellular (34%) compartments. The
extracellular compartment can be further subdivided into the Transcellular (GI secretions, CSF, bile,
etc), Intravascular (blood) and Extravascular (aka interstitial fluid) compartments. Water can move
freely between these compartments, so that whatever fluids are given intravenously move across
capillaries into the interstitial fluid and then into the cells without any restriction.

Various proteins present in the vessels and interstitial fluid exert osmotic pressure also. The osmotic
pressure in vessels is higher than in interstitium, which retains fluid in the intravascular compartment.
A decrease in intravascular osmotic pressure allows shift of fluid into the interstitium, with consequent
loss of circulating fluid volume. Conversely, if the colloid osmotic pressure in the vessels can be
increased, fluid shifts into the vessels, expanding the intravascular volume.

This is of particular importance in resuscitation of the shock patient. Since the interstitial and
intracellular compartments are big, infusion of iso-tonic fluids (eg Ringer’s Lactate) simply shift more
fluid into the interstitial fluid. It has been calculated that for 500ml increase in the intravascular
circulating volume, 2000ml of crystalloids need to be transfused. In contrast, if colloid solutions (eg
albumin, starch) are transfused, the larger particles of colloids exert a higher osmotic pressure, and
so retain fluid in the intravascular compartment. Therefore, 500ml of colloids will retain an equal
volume of circulating fluid in the vessels. Though debated, current opinion is in favour of using 4 times
crystalloid volume instead of colloids, especially for initial resuscitation.

When the serum proteins or sodium is low, they exert a low osmotic pressure and fluid diffuses into
the interstitial fluid. Similarly, if large volumes of crystalloids are transfused, more fluid enters the
interstitium. This manifests as tissue oedema, which is more if some degree of local inflammation is
present. The most obvious manifestation is pulmonary oedema, but it should be remembered that
oedema occurs at the site of anastomoses or bowel repairs also. The postoperative obligatory fasting
these patients undergo worsens the situation. Local oedema at anastomotic sites increases tissue
tension at the repair site and impairs tissue healing, leading to anastomotic leaks. This has been
proved in studies that compared a restricted fluid regimen versus conventional regimen on bowel
anastomotic healing after colectomies, and it was consistently found that a restricted fluid regimen
produces better outcomes than a liberal regimen.

Sodium
Sodium is the principal cation of plasma and interstitial fluid. Its value ranges from 135 to 145 mEq/L,
and is regulated chiefly by the action of aldosterone and anti-diuretic hormone. In general, sodium
and water move together, so that infusions of sodium containing fluids equilibrate between the
vascular and interstitial compartments.

Normal daily requirements of sodium are 1-2 mEq/kg/day, translating to 53-106 mEq/day for a 53 kg
person. Considering that most iv fluids contain more than this amount per litre, it stands to reason that
normally patients do not require more than 1-2 bottle/pack per day. This amount has to be increased
for most ongoing surgical losses, such as in fistulas, nasogastric aspirates and vomiting/ diarrhoea.
The ideal situation would be to measure the sodium concentration of fluid losses, and so replace
electrolytes accordingly. However this is not always feasible, so an estimate can be made based on
type of losses.

Table 1: Approximate electrolyte composition of various bodily fluids (mEq/L)

Approx daily volume
Source Na+ K+ Cl- HCO3- H+
(ml)
Salivary glands 50 20 40 30 100 - 1,000
Stomach (fasting) 100 10 140 30 1,000
Bile 140 5 100 60 500 - 1,000
Pancreas 140 5 75 100 1,000
Duodenum 140 5 80 100 - 2,000
Ileum 140 5 70 50 100 - 2,000
Colon 60 70 15 30

Therefore, most bowel losses have a sodium loss similar to plasma, so should be replaced by a
similar volume of sodium containing fluids. So, if there is 500ml of ileal losses, it should be replaced
by 500ml of Ringer’s Lactate or isotonic saline. Sweating in an acclimatised person usually does not
cause much sodium loss. However, an unacclimatised person can lose significant amount of sodium
while sweating.

The above restriction on sodium requirement is not applicable in a shock patient (non-cardiogenic),
where saline is preferred since it exerts osmotic pressure also and expands the vascular
compartment (refer to fluid in shock, above). Pure water fluids (like 5% Dextrose) are not used in
shock.
Estimation of serum sodium is usually accurate in estimating body losses, so replacement amount in
hyponatremia can be calculated according to the following equation:

Na deficit = 0.6 x wt(kg) x (desired Na (mEq/L) - Measured Na (mEq/L))

Half of the calculated deficit is replaced initially, with a rate of not more than 0.5 mEq/L/hr. This means
for a 55 kg person with a serum sodium of 120,
 the total requirement is 330mEq.
 total body water will be = 0.6x wt (kg)= 33L;
 desired rate of increase of body sodium = 0.5xbody water=0.5x33=16.5mEq/hr
 therefore time taken to correct deficit = 330/16.5 = 20 hours

Isotonic or hypertonic fluid can be used to correct the deficit. If isotonic saline is used, the rate of
infusion will be 100ml/hr for 20 hrs. However, isotonic saline provides water also, which will dilute the
sodium till it is removed by the kidneys. Therefore 3% hypertonic saline is commonly used, in which
case the rate of infusion will be lower (32ml/hr for 20 hrs)

Potassium
Potassium is the principal intracellular cation, with a plasma level of 3.5-5.2 mEq/L. Normal daily
requirement is 1-1.5 mEq/kg. Therefore, for a 55kg person, daily requirement is 55 – 80 mEq. Most iv
fluids do not contain this amount of potassium, so additional potassium has to be added to the iv fluid
for maintenance. The ampoule of KCl available in the market contains 1.5g of potassium, which is
equivalent to 20mEq of Potassium. Therefore, most patients require 3-4 ampoules added to iv fluids
daily. Further addition is required for ongoing losses; the table given above can be used to estimate
the amount of potassium lost with different types of fistulas. It should be remembered that potassium
is a cardioplegic – rapid administration of potassium containing fluids will cause cardiac arrest in
diastole. To avoid this, potassium should be administered in the ward at not more than 10mEq/hr, and
at 20mEq/hr with ECG monitoring. A near normal renal function (Creatinine ≤ 2.0 mg%) is presumed.
Potassium is also controlled by aldosterone levels. Due to its intracellular nature, serum levels do not
reflect the true body content of potassium. By the time serum levels decrease, the body has already
lost a lot of potassium. Therefore, potassium losses should be estimated and replaced before serum
levels decrease. The following formula can be used to estimate total body deficit of potassium, but is
not commonly used since potassium is not primarily an intravascular cation.

K deficit (mEq) = (K normal – K measured) x kg body weight x 0.4

It should be remembered that alkalosis can change serum potassium level (0.1 pH rise decreases K
by 0.6) as can many drugs, such as insulin and furosemide.

In the immediate postoperative period, the stress response of the body conserves potassium.
Therefore, no potassium supplementation is required in the first 24 hours after routine surgery.

Calcium and Magnesium

Though important for the body, especially in maintenance of normal cardiac contractility,
supplementation is normally not required in the perioperative period. Calcium is maintained by
mobilization from the bone, so hypocalcemia is uncommon unless due to parathyroid deficiency.
Supplementation is indicated if prolonged iv nutrition is being given, where it forms part of the TPN
protocol.

Magnesium deficiency can manifest on routine investigations as refractory hypokalemia. If serum

potassium does not rise after adequate replacement, consider getting magnesium levels estimated.

Composition of various intravenous fluids

5% Dextrose
The most common fluid for replacement therapy is 5% Dextrose. This contains 5g of glucose in 100ml
of water. Therefore, the energy provided is 170 kcal/L only (iv glucose on metabolism provides
3.4kcal/g). With infusion of 2.5 L of 5% Dextrose per day, a maximum of 425 kcal can be provided.
Therefore, it is clear that the only indication for 5% Dextrose is to provide free water to the body.
Addition of dextrose makes the solution isotonic, but the small amount of dextrose is rapidly
metabolised so free water is in effect produced. The small amount of dextrose also provides an
energy source to the RBCs and brain, which cannot use other sources of energy, but even then the
whole requirement is not met.

Normal Saline
Contains 154 mEq of Na and Cl each per litre. Therefore, each 500ml bottle has 72mEq of Na and Cl
each. Depending on the estimated requirement of Na per day, the dose of normal saline is calculated,
usually 1-2 bottles per day. This usually provides more chloride than is required, resulting in
hyperchloraemic metabolic acidosis. It does not make a difference in a person with normally
functioning kidneys; replacement with low chloride solutions such as Ringer’s is needed if it occurs.
Additives (eg potassium) can usually be safely added to normal saline.

Lactated Ringer’s solution

The ionic composition is as near to plasma as possible. Technically it is an acidic solution (pH 6.5),
but Lactate is added to the solution which is metabolized to bicarbonate in the liver and counteracts
metabolic acidosis. As such it is an alkalinizing solution. It is indicated as a general replacement fluid
for a wide variety of conditions, such as burns and shock.

Hartmann’s solution
Very similar to Lactated Ringer’s solution with some ionic differences. It is primarily in use in the
British isles.

Dextrose in saline
Commonly abbreviated to DNS, it is not a mixture of 5% dextrose and normal saline. Instead, it is 5g
of dextrose added to 100ml of saline. Therefore, it is a hypertonic solution, indicated for conditions like
head injury, meningitis, etc. Routine use in adult postoperative patients should not be done.

Isolyte – G, M
These were specific solutions introduced to replace specific losses from the body. E.g. Isolyte-G was
used to replace gastric losses (volume for volume), Isolyte-M for maintenance fluid, containing higher
concentrations of potassium, Isolyte-P for paediatric age group, Isolyte-S for general electrolyte
replacement and Isolyte-E for extracellular fluid replacement (provides magnesium also). These
solutions however have not caught on since the requirements can be met by conventional fluids also.
All isolytes are contraindicated in shock, hepatic failure, and some in renal failure.

Table 2: Concentration of electrolytes of some common iv fluids. (all in mEq/L unless specified)
Solution Na K Cl Lactate Dextrose Remarks
1. 5% dextrose - - - - 50g
2. Normal saline 154 - 154 - -
3. Dextrose in NS 154 - 154 - 50g
4. Lactated Ringer’s 130 4 109 28 - 1.5mmol of Ca also
5. Hartmann’s solution 131 5 111 29 - 2.0 mmol of Ca also
6. Isolyte G 65 17 150 - 50g 69mEq of Ammonia
7. Isolyte M 40 35 38 - 50 15mEq Phosphate; 20mEq
acetate

How to write fluid orders?

1. Assess previous days fluid balance. The balance has to be adjusted in the next day’s chart.
2. Calculate total fluid requirement, allowing for previous day’s balance, insensible losses and
visible losses. E.g 3000 ml of total fluid
3. Calculate sodium requirement for next 24 hours, and based on that calculate the amount of
normal saline to be administered. E.g 1000 ml of normal saline.
4. Subtract amount of saline from total fluids, to calculate free water required by the body. ie
3000-1000 = 2000 ml. This amount is replaced using 5% dextrose.
5. Calculate the amount of potassium required in next 24 hours e.g 60 mEq. Add 20mEq to 500
ml of fluid x 3 such bottles.
Therefore the final charting in this example would be:
 5% Dextrose with 20mEq of potassium
 Normal saline
 5% Dextrose with 20mEq of potassium
 5% Dextrose
 Normal saline with 20mEq of potassium
 5% Dextrose

Suggested reading
1. Handbook On Critical Care And Fluid Management by Pawanindra Lal. PeePee publishers, 2008.
th
2. Miller’s Anaesthesia. 7 Ed. Eds Miller RE. Churchill Livingstone Elsevier, 2009.
th
3. Schwartz’s Principles of Surgery. 9 Ed. Eds Brunicardi et al. McGraw Hill, 2010.
4. Pandya S. Fluid therapy in medical disorders. In: API textbook of Medicine. 605-608
 Synergistic Gangrene (Necrotizing Fasciitis)
Mayank Jayant

Historical Background
The description of skin and soft tissue infections, defined as an inflammatory microbial infection of
epidermis, dermis and subcutaneous tissue can be traced upto 5th century as done by Hippocartes. It
can inflict any part of the body but extremities, perineal area and operative sites are commonly
involved. This infective entity are been assigned various names till date with Necrotizing fasciitis (NF)
most commonly used. The term Necrotizing fasciitis was coined by Wilson in 1952. First description of
the similar entity was given by a confederate army surgeon during Civil war in 1871. Throughout the
th th
19 and 20 century, cases of NF occurred sporadically and were restricted to military hospitals
during wars with few reports affecting civilian population.

Nomenclature and Terminology

There is no paucity in literature regarding the various nomenclature used for this disease. Necrotizing
fasciitis has been referred by different names like Necrotizing erysipelas, acute non clostridial
crepitant cellulitis, Synergistic necrotizing cellulitis, phagedena, haemolytic streptococcal gangrene ,
meleney’s synergistic gangrene , Fournier’ gangrene etc. Skin and soft tissue infection (SSTI) have
been classified according to the layer of infection, severity and microbiological etiologies. FDA (Food
and Drug Authority) coined the term Complicated SSTI in 1998 which included Necrotizing fasciitis,
surgical site infections, infection associated with bite and animal contact, infections in
immunocompromised patients. This excluded non complicated skin conditions like erysipelas,
impetigo, cellulitis etc.

The revised guidelines issued by FDA in 2010, introduced a new classification known as Acute
bacterial skin and skin structure infection (ABSSSI).FDA designation of ABSSSI include extensive
cellulitis/erysipelas, wound infections, major cutaneous abscesses, infected burns accompanied by
redness, edema, and/or induration of a minimum surface area of 75 sq cm accompanied by lymph
node enlargement or systemic symptoms such as fever 38˚ or greater.

Necrotizing fasciitis (NF)

NF is a rare soft tissue infection involving subcutaneous tissue upto the fascia that cause rapid local
tissue necrosis and life threatening severe sepsis. It is commonly known as ‘Flesh eating disease’.

Pathogenesis
The pathogenesis includes a complex interplay between agent and host factors. Most of the patients
who develop NF have preexisting conditions that render them susceptible to infection, although it
does occur in young, previously healthy individual as well.

Risk Factors
1. Old age
2. Diabetes Mellitus
3. Alcoholism
4. Intravenous drug abuse
5. Chronic renal failure
6. Chronic liver failure
7. Peripheral vascular disease
8. Immunocompromised condition like HIV patient, Steroid user
9. Malnutrition
10. COPD and CHF

The infection is generally precipitated by some of injury or local pathological condition which include
trauma(blunt / penetrating), insect bite, dermatological disease like psoriasis, operation site infection,
burn ,ulcer or even after child birth. There are report of fulminant NF following minor abrasion,
tattooing and skin piercing. In approximately 36 % patients no preceding skin lesion or injury is found
and haematogenous inoculum of bacteria at site of infection is contemplated.
NF is generally a deep seated infection of subcutaneous tissue that results in progressive destruction
of fascia and fat and spares the skin initially. Muscles generally are unaffected. The pathological
events include:
 Extensive tissue destruction
 Thrombosis of blood vessels
 Abundant bacterial spreading along the fascial planes.
 Relatively few acute inflammatory cells although small collection of PMN leucocyte and
microabscesses have been described.

Subcutaneous tissue damage and systemic toxicity are related to the production and release of
bacterial toxins and endogenous cytokines which leads to activation of interleukins, TNF, Interferon α
and γ which are precursor molecule for capillary thrombosis leading to the necrotic event affecting
skin and subcutaneous tissue.

Microbiology
NF is caused by a variety of aerobes and facultative anaerobes including Group A Streptococcus
(GAS), Stap. aureus, Clostridia, Bacteroids , E.coli, H. influenza, Pseudomonas, Vibrio and fungi .
Based on the microbiological profile, NF is divided into four groups with first two being predominant.

Type I
This is seen in 80 % cases where the infections are polymicrobial and Synergism among bacteria
lead to fulminant infection. The bacteriology includes a mixture of anaerobe, aerobes and facultative
anaerobes (E.coli, pseudomonas and bacteroid spp). It is generally seen in patient who are
immunocompromised, children, those with underlying abdominal pathology , have undergone surgical
procedure, diabetics or patients with vascular diseases. The infection generally starts around the foot
and extends upto the legs along the fascial planes. In head and neck the infection presents as
Ludwig’s angina and post operatively as Meleney’s synergistic gangrene.

Type II
This contribute to 20% of NF and is usually caused by monomicrobial gram positive organism, the
most common being Group A Streptococcus (GAS) alone or occurring along with Stap. aureus. In
contrast to Type I, it affects all age groups without any complicated illness. Predisposing factors
include blunt trauma, muscle sprains, child birth, and intravenous drug abuse. The pathophysiology in
case of GAS is attributed to exotoxins A & B produced by it which can lead to Shock (Toxic shock
syndrome) and multiorgan failure.

Type III
This is a monomicrobial gram negative infection including marine related organisms. The most
common gram negative organism is Vibrio spp. Wound contamination with sea water accounts for 25
% cases. Virulence factors and digestive enzymes contribute to high mortality (25%) despite
aggressive therapy.

Type IV
These caused fungal infection and generally follows traumatic wounds and burns and isolation of
Aspergillus, Candida and Zygomycetes are seen.

Presentation
NF is difficult to diagnose in early stages due to the nonspecific signs. A high index of suspicion with
low threshold to prompt surgical intervention should be the dictum.
The clinical presentation of NF entails progressive skin changes with systemic features. Early on only
tenderness, erythema, swelling and warm skin is present. This is because the infection is deep seated
and generally spares the epidermis. It mimics non complicated skin conditions like cellulitis, impetigo
and erysipelas. The cardinal manifestation is severe pain out of proportion of the physical findings.
Lymphangitis and lymphadenitis are rare.
Soon the area becomes swollen with clear demarcation which progresses into skin changes i.e
bronzing of skin and induration followed by breakdown with purple bullae and blistering within 3-5
days.
In the later stage, the lesion turns black and form necrotic crusts with necrotic fascial tissue and
grayish secretions underneath. It is accompanied with hyposensitivity of the tissue and crepitation.
General physical findings
 Fever (> 38˚ C)
 Tachycardia
 Hypotension
 Tachyponea

Table 1. Clinical Stages of Necrotizing Fasciitis

Stage 1 Stage 2 Stage 3
Tenderness Blisters and bullae Tissue necrosis
formation
Erythema Hyposenstivity
Odema Anaesthesia
Warm skin Tissue crepitation
Fever Haemorrghic bullae

Laboratory Diagnostic Procedures

Multi organ dysfunction may reflect deranged liver and renal functions, coagulopathy and elevated
creatinine kinase due to severe sepsis. Hypocalcemia is seen in synergistic NF. Rapidly falling
hemoglobin with stable hematocrit signifies intravascular haemolysis.
Laboratory Risk Indicators for necrotizing Fasciitis (LRINEC)

LRINEC is a simple laboratory system to distinguish between NF and other soft tissue infections. It
includes
Table 2: LRINEC scoring system for NF
Variables Score
Hemoglobin (g/dl)
> 13.5 0
11-13.5 1
<11 2
Total leucocyte count (/mm3 )
<15 0
15-25 1
>25 2
Glucose (mmol/L)
<10 0
>10 1
C- reactive protein
<150 0
>150 4
Sodium (mmol/L)
>135 0
<135 2
Creatinine (µmol/L)
<141 0
>141 2
Score of more than 6 is highly suspicious of NF and more than 8 is diagnostic.

Surgical Diagnosis
The gold standard for detecting necrotizing soft tissue infection is tissue biopsy. The operative
findings include presence of dusky gray subcutaneous fat and fascia with scanty serosanguineous
discharge, lack of resistance to finger dissection and presence of dishwater foul smelling pus.

Management
The key aspect of management includes early diagnosis, resuscitation, and administration of broad
spectrum antibiotics followed by radical surgical debridement, intensive care support and finally
reconstruction.
Resuscitation, Antibiotic and Critical care
The degree of respiratory, hemodynamic, renal and Table 3. First line antimicrobial agents
metabolic compromise must be quicky assessed. Early Mixed Infection
resuscitation with I/V fluids or colloids should be initiated  Ampicillin – sulbactum or
and inotrope should be added if required. All patients Piperacillin – tazobactum
should be started with broad spectrum antibiotics to cover Plus
staphylococcus, streptococcus, gram negative rods and  Clindamycin and Ciprofloxacin
anaerobes.
 Imipenem
 Meropenem
Surgical treatment
Surgical debridement is the mainstay of the treatment of  Cefotaxime plus
NF and results are greatly improved with early Metronidazole or clindamycin
debridement as compared to delay in surgery. Early
Streptococcus infection
wound debridement should include excision of all
nonviable tissue, drainage of all abscesses and extensive Penicillin Plus Clindamycin
fasciotomy.Aggressive and extensive debridement should
S. aureus infection
be done until there is no further evidence of infection and
Cefazolin/Vancomycin/Clindamycin
if further debridement is required the patient should be
promptly taken up for it. Other forms of surgical procedure
Clostridium infection
which may be required are amputations and defunctioning
colostomy for perineal wounds. Clindamycin
Penicillin
Once the infection is controlled, dressing with alginate or hydrogel is done and skin cover should be
provided either with secondary suturing or split skin grafting.

Adjunct Measures
Hyperbaric oxygen therapy has been used with controversial status in literature. Some studies have
reported better survival benefit with this therapy especially in synergistic infections. It involves placing
patient in an environment with increased ambient pressure while breathing 100 % oxygen which leads
to enhanced oxygenation in blood and tissues. This prevents further necrosis and enhances healing.
Intravenous Immunoglobulin (IVIG) is reasonable and desirable option to neutralize streptococcal
toxins.

Negative Pressure Wound Therapy

Vaccum Assisted closure of wounds have been used and found effective in non healing limb wounds
after debridement.

Outcome
The moratlity rates for NF vary considerably from 10 to 75 %. The outcome is also region specific with
truncal (44%) and perineal (28%) having higher mortality as compared to limbs (22%).The factors
leading to higher mortality include delayed debridement, age >60 yr, female gender, hypotension,
acidosis, bacteremia, area involved more than 250 cm3 , renal failure , hyponatremia, elevated blood
lactate , peripheral vascular disease and number of comorbidities.

Fournier’s Gangrene

Fournier’s Gangrene (FG) is the necrotizing fasciitis of the perineum and the genital area which can
extend up to the abdominal wall. It was described by a French dermatologist Jean – Alfred Fournier in
1883 when he gave account of five young men with fulminant gangrene of scrotum and penis. It is a
type I Necrotizing fasciitis.

Epidemiology
Fournier’s Gangrene is a rare condition with an incidence of 1.6 cases pr 100,000 males representing
0.02 % of hospital admissions. It is note to occur in middle aged men ( mean age -50-60 years) to a
lesser extent among women and children.

Etiology and predisposing factors

Although originally described as idiopathic gangrene of the genitalia, Fournier’s gangrene has an
identifiable cause in approximately 95% of cases. The necrotizing process commonly originates from
an infection in the anorectum, urogenital tract, or skin of the genitalia
Trauma, recent surgery, and the presence of foreign bodies may also lead to the disease. Perianal,
perirectal and ischiorectal abscesses, anal fissures; colonic perforations, urethral strictures with
urinary extravasations; epididymoorchitis or hidradenitis may lead to the disease. Urethral
instrumentation, prosthetic penile implants, superficial soft-tissue injuries, intramuscular injections,
genital piercings, steroid enemas (used for the treatment of radiation proctitis), blunt thoracic trauma,
and penile self-injection with cocaine have been reported in the literature as causative factors.

In women, septic abortions, vulva or Bartholin gland abscesses, hysterectomy, andepisiotomy are
documented sources of sepsis. In men, anal intercourse may increase risk of perineal infection, either
from blunt trauma to the area or by spread of rectally carried microbes.

In children, strangulated inguinal hernia, circumcision, omphalitis, insect bites, trauma, urethral
instrumentation, peri-rectal abscesses, systemic infections, and burns have led to the disease.
Poor perineal hygiene or the presence of chronically indwelling catheters, such as in paraplegic
patients, poses an increased risk.

Pathophysiology
Because Fournier’s gangrene is predominantly an infectious process of the superficial anddeep
fascial planes, appreciating the anatomic relationship of the skin and subcutaneousstructures of the
perineum and abdominal wall is vital.

Scarpa’s fascia forms distinct layer deep to Camper fascia whoch is the superficial fascia of
abdominal wall. In the perineum, Scarpa’s fascia blends into Colles’ fascia (superficial perineal
fascia), and continuous with Dartos fascia of the penis and scrotum.

Several important anatomic relationships should be considered. A potential space between the
Scarpa’s fascia and the deep fascia of the anterior wall (external abdominal oblique) allows for the
extension of a perineal infection into the anterior abdominal wall. Superiorly, Scarpa’s and Camper’s
fasciae coalesce and attach to the clavicles, ultimately limiting the cephalad extension of an infection
that may have originated in the perineum. Colles’s fascia is attached to the pubic arch and the base of
the perineal membrane, and it is continuous with the superficial Dartos fascia of the scrotal wall. The
perineal membrane is also known as the inferior fascia of the urogenital diaphragm and, together with
Colles’ fascia, defines the superficial perineal space. The aetiological factors allow the portal of entry
of the microorganism into this superficial perineal space and fulminant infections spread along these
fascial envelopment of the genitalia throughout the perineum along the trunk , occasionally involves
and very rarely to chest.

Fournier’s gangrene is predominantly a polymicrobial infection. The responsible organism include

both aerobic and anaerobic strains: E.coli, Streptococcus, Staphylococcus, Enterobacter,
Bacteroids.The aerobes and anaerobes act synergistically and produce enzymes like collagenase,
heparinase, hylorunidase, streptokinase and streptodornase which promote rapid digestion of fascial
barriers, tissue destruction and necrosis.

Clinical Presentation
The most common presenting symptoms of FG include genital discomfort and pruritis in prodromal
phase followed by scrotal swelling, pain, hyperemia, erythema, induration, crepitus and fever which
may ultimately culminate into necrosis, foul discharge and gangrene. It is usually associates with
fever, tachycardia, dehydration, hypotension, leukocytosis, anaemia and thrombocytopenia.

Fournier’s Gangrene Severity Index (FGSI)

Laor etal developed the Fournier’s Gangrene Severity Index for prognostication and predicting
mortality. A score above 9 indicates 75 % mortality where as a score below 78 % has 78% survival
chances.
Treatment
Aggressive and extensive surgical debridement is the cornerstone for managing Fournier’s gangrene.
Broad spectrum antibiotics covering gram –ve, +ve aerobes and anaerobes should be constituted.
Generally care depending on the condition of the patient should be provided including fluid
resuscitation, nutrition, wound care and intensive care if required. Urinary diversion in form of
Suprapubic cystostomy or faecal diversion in form of Colostomy may be done in casees of extensive
penile or perineal involvement. Healthy surgical wound generally heal with secondary intention but
large defects may require local flaps or skin grafting for wound closure.

Meleney’s Synergistic gangrene

This is a rare form of TypeI Necrotizing Fasciitis seen in postoperative patients at operative site. It
was first described by Brewer and Meleney in 1926. Synergistic gangrene is a potentially fatal
polymicrobial soft tissue infection involving organisms creating synergistic virulence and is also known
as Postoperative Progressive synergistic gangrene.Most of the time it develops as a complication of
laparotomy wounds or colostomy sites or as a chronic ulcer in the extremity. It is a slowly expanding
lesion confined to the superficial fascia and usually results from a synergistic interaction between
Staph. aureus and microaerophilic streptococci. Inoculation occurs from a surgical incision or drain
site and conditions affecting the immune response are risk factors, especially diabetes and obesity. It
appears as a painful erythematous area, which later ulcerates progressing to gangrene. It is
characterized by spreading cellulitis followed by the formation of central ulcerated areas covered with
eschar and necrosis which grow relentlessly unless treated. By this time the patient will be toxic with
extensive tissue loss having already occurred. Early suspicion and prompt intervention results in
better outcome. As in other forms of Necrotizing fasciitis, antibiotic therapy together with surgical
debridement are the mainstay of treatment.

Suggested reading
1. M. E. Losa, et al. A rare case of Meleney’s Ulcer after partial chemical matricectomy. Rev Esp Quimioter 2013;26
(2):128-130.
2. Howse EA. Meleney’s synergistic gangrene: a case study. Crit Care Nurse 1995; 15:59-64.
3. Shiroff AM, Herlitz GN, Gracias VH. Necrotizing soft tissue infections. J Intensive Care Med 2012.
4. Puvanendran R, Huey JC, Pasupathy S. Necrotizing Fasciitis. Can Fam Physician. 2009;55(10):981-7.
5. Cheung JPY, Fung B, Tang WM, Ip WY. A review of necrotizing fasciitis of the extremities. Hong Kong Med J
2009;15:44-52.
6. Machado NO. Necrotizing Fasciitis: The importance of early diagnosis, prompt surgical debridement and adjuvant
therapy. North Am J Med Sci 2011;3:107-118.
7. De Tullio D, Rossi C, Bolzon S, Scagliarini L, Occhionorelli S. Necrotozing Fasciitis : a surgical emergency .
Update Surg 2010;62;83-87.
8. Morgan MS. Diagnosis and management of necrotizing fasciitis: a multiparametric approach. Review. J Hosp
Infect 2010;75 :249-257.
9. Shimizu T, Tokuda Y. Necrotizing Fasciitis. Inter Med 2010 ;49:1051-1057.
10. Arnoff DM , Bloch KC. Assessing the relationship between the use of nonsteroidal anti-inflammatory drugs and
necrotizing fasciitis caused by group A Streptococcus .Medicine 2003;82(4):225-235.
11. Myslinski W, Mosieovicz J, Kazubek M etal. Nonsteroidal antiinflammatory drugs over dosage – the cause or the
consequence of necrotizing fasciitis? J Eur Acad Dermmatol Venereol 2003;17:227-228.
12. Bross MH, Soch K, Morales R, Mitchell RB. Vibrio vulnificus infection: diagnosis ang treatment. Am Fam
Physician 2007;76:539-544.
13. Jain D, Kumar Y, Vasistha RK etal . Zygomycotic necrotizing fasciitis in immunocompetent patients: series of 18
cases. Mod Pathol 2006;19:1221-1226.
14. Banwell PE, Teot L. Topical negative pressure (TNP): the evolution of a novel wound therapy . J Wound Care
2003;12:122-128.
15. Su YC, Chen HW, Hong YC, Chen CT, Hsiao CT,Chen IC. Laboratory risk indicator for necrotizing fasciitis score
an the outcome . ANZ J Surg 2008;78:968-972.
16. Martínez-Rodríguez R [1] , Ponce de León J, Caparrós J, Villavicencio H: Fournier’s gangrene: a monographic
urology center experience with twenty patients. Urol Int 2009, 83, 323–328.
17. Yanar H, Taviloglu K, Ertekin C, Guloglu R, Zorba U, Cabioglu N etal I: Fournier’s gangrene: risk factors and
strategies for management. World J Surg 2006, 30, 1750–1754.
18. A, Hajji F, Ismail TO, Chafiqui J, Ghadouane M, Ameur A, Abbar M etal: Hyperbaric oxygen therapy adjunctive to
surgical debridement in management of Fournier’s gangrene: usefulness of a severity index score in predicting
disease gravity and patient survival. Actas Urol Esp. 2011, 35, 332–338.
19. Roje Z, Matić D, Librenjak D, Dokuzović S, Varvodić J: Necrotizing fasciitis: literature review of contemporary
strategies for diagnosing and management with three case reports: torso, abdominal wall, upper and lower limbs.
World J Emerg Surg 2011, 23, 6, 46.
20. Taviloglu K, Yanar H. Necrotizing fasciitis: strategies for diagnosis and management. World J Emerg Surg 2007;
2: 19-21.
21. Rajan S. Skin and soft tissue infection: Classifying and treating a spectrum. Cleveland Clin J Med 2012;79: 57-66.
22. Steven DL etal . Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections Clinical
Infectious Diseases 2005;41: 1373–406.
23. Liu C, Bayer A, Cosgrove SE, et al. Infectious Diseases Society of America. Clinical practice guidelines by the
Infectious Diseases Society of America for the treatment of methicillin resistant Staphylococcus aureus
infections in adults and children. Clin Infect Dis 2011;52(3):e18-55.
24. 2010 FDA Guidance. Guidance for industry: acute bacterial skin and skin structure infections: developing drugs
for treatment. Draft Guidance. Federal Register: 2010 Volume 75, Number 166.
25. Napolitano LM. Severe soft tissue infection. Infect Dis Clin North AM 2009;10:571-591.
26. Chang VCW, Chen C, Wu HH. Necrotizing Fasciitis. J Med Sci 2008 ;28(4):175-178.
 Deep Neck Space Infections
Ravi Meher

Anatomy of the Cervical Fascia

The fibrous connective tissue that constitutes the cervical fascia varies from loose areolar tissue to
dense fibrous bands. This fascia serves to envelope the muscles, nerves, vessels and viscera of the
neck, thereby forming planes and potential spaces that serve to divide the neck into functional units.
The cervical fascia functions to both direct and limit the spread of disease processes in the neck and
therefore a sound knowledge of the fascial layers is essential to understanding the presentation,
treatment and potential complications of infections in the neck. Infections are one of the most
commonly occurring head and neck pathologies. Mortality has decreased significantly in the
postantibiotic era, but resistant organisms are on the rise.

The cervical fascia was first described by Burns in 1811. Fascia is investing fibrous tissue related to
muscles and major neck structures. The neck has a superficial and deep fascia.

Superficial cervical fascia: This is a thin layer that invests the platysma muscle extends superiorly
in the face to cover the facial muscles. It is the equivalent of subcutaneous tissue elsewhere in the
body and forms a continuous sheet from the head and neck to the chest, shoulders and axilla.

Deep cervical fascia: The deep fascia has three layers

a) Superficial layer
b) Middle or visceral layer
c) Deep layer.

Superficial or Investing Layer

This arises from the ligamentum nuchae and the
spinous processes of the cervical vertebrae and
invests the entire neck, splitting to enclose the
trapezius and the sternocleidomastoid muscle. The
superior attachment is to the external occipital
protuberance, the superior nuchal lines, the mastoid
tip and the zygomatic arch. Inferiorly it attaches to
the acromium, the clavicle and the sternum. In the
midline, anteriorly it attaches to the hyoid and
continues superiorly to enclose the submandibular
and parotid glands. Here it also covers the anterior
bellies of the digastrics and the mylohyoid, thereby
forming the floor of the submandibular space. At the
mandible, the fascia splits into an internal layer,
which covers the medial surface of the medial pterygoid to the skull base and an outer layer that
covers the masseter and inserts on the zygomatic arch. It also forms the stylomandibular ligament.
The two spaces it forms are the space of the posterior triangle on either side of the neck and the
suprasternal space of Burns in the midline.

Middle Layer or Pretracheal or Visceral Fascia

This part of cervical fascia passes deep to the strap muscles and encircles the trachea, thyroid and
the oesophagus. The superiorly it attached to the hyoid and thyroid cartilage, inferiorly it inserts on
the sternum and clavicle. The visceral division passes inferior into the upper mediastinum where it is
continuous with the fibrous pericardium and covers the thoracic trachea and esophagus, while
posteriorly this fascia covers the buccinator and the pharyngeal constrictors to the skull base and this
portion is also called the buccopharyngeal fascia. Movement of the hyoid and strap muscles during
swallowing elevates the fascia so that thyroid lumps characteristically move on deglutition.

Deep Layer or Prevertebral Fascia

This arises from the ligamentum nuchae and the spinous processes of the cervical vertebrae. At the
transverse processes of the cervical vertebra, it divides into an anterior alar layer and a posterior
prevertebral layer. The alar fascia extends from the base of the skull to the second thoracic vertebra,
where it joins the visceral fascia. It lies between the visceral layer of the middle fascia and the
prevertebral layer. The prevertebral fascia lies just anterior to the vertebral bodies and extends the
entire length of the vertebral column. It travels circumferentially around the neck and covers the
vertebral muscles, the deep muscles of the posterior triangle of the neck and the scalene muscles.
This layer of fascia surrounds the brachial plexus and subclavian vessels and continues laterally as
the axillary sheath.

Carotid Sheath
The carotid sheath is a fascial layer that receives contributions from all three layers of deep cervical
fascia and contains the carotid artery, internal jugular vein and vagus nerve and 80 percent of the
lymph nodes of the neck. It continues from the skull base through the neck along the anterior surface
of the prevertebral fascia, and enters the chest behind the clavicle and it is potential route for direct
spread of infection from neck to mediastinum.

The various layers of cervical fascia, as they pass around and attach to structures in the neck, form
several potential spaces. The hyoid is the most important structure that limits the spread of infection
in the neck and is the most reliable landmark when performing surgery for deep neck abscesses.
Therefore, when studying these spaces, it is reasonable to group them according to their relationship
to the hyoid into three categories-spaces involving the entire length of the neck, suprahyoid spaces
and infrahyoid spaces.

Anatomy of the Neck Spaces

Superficial neck space - The superficial space is located

between the superficial fascia and the superficial layer of
the deep fascia. This potential space lies superficial and
deep to the platysma and contains loose areolar tissue,
lymph nodes, nerves and vessels—the most significant of
which is the external jugular vein. The loose areolar tissue
provides the dissection plane for raising subplatysmal skin
flaps. This space is most commonly involved with
superficial cellulitis of the neck, but if abscess formation
does occur, diagnosis is not difficult as this will present with
obvious fluctuance, erythema, warmth and tenderness. A
superficial space abscess can be approached with a
transverse incision within Langers lines in the area of
prominence, followed by evacuation of purulent material,
local wound care and appropriate antibiotic therapy.

Deep Neck Space

a) Spaces Spanning the Entire Length of the Neck
 Retropharyngeal space (space of Gillette) - also known as the posterior visceral space, the
retrovisceral space and the retroesophageal space. It occupies the space posterior to the
pharynx and esophagus. Its anterior wall is made up of the buccopharyngeal fascia
superiorly and the visceral division of the middle fascia inferiorly, the posterior wall is the alar
layer of the deep fascia, and the lateral boundary is the carotid sheath. This space extends
from the base of the skull to the level of the first and second thoracic vertebra, where the
fascial layers making up its walls join together. It contains lymph node of Rouvier and
connects to parapharyngeal space laterally above the hyoid. Infection can spread by
lymphatics from paranasal sinuses or nasopharyngeal region
 Danger space (of Grodnisky)- Posterior to the retropharyngeal space lies the danger space,
so named because it contains loose areolar tissue and offers little resistance to the spread of
infection. It is the space between the alar layer and prevertebral layer of the deep fascia and
runs from the skull base to the diaphragm.
 Prevertebral space - is limited anteriorly by the prevertebral fascia, laterally by the attachment
of this fascia to the transverse processes and posteriorly by the anterior longitudinal ligament,
the vertebral bodies and the deep musculature. It extends the entire length of the vertebral
column. Infection in this space tends to stay somewhat localized due to the dense fibrous
attachments between the fascia and the deep muscles.
  Visceral vascular space- is the potential space within the carotid sheath. Like the prevertebral
space the visceral vascular space is quite compact, contains little areolar tissue and is
resistant to the spread of infection. Therefore it was termed as the “Lincoln’s highway” of the
neck. It extends from the base of skull into the mediastinum and because it receives
contributions from all three layers of deep fascia it can become secondarily involved by
infection in any other deep neck space by direct spread.

b) Suprahyoid Spaces
 Submandibular space- The submandibular space is bounded by the mandible anteriorly and
laterally, the lingual mucosa superiorly, the hyoid postero-inferiorly and the superficial layer of
the deep cervical fascia inferiorly. The mylohyoid muscle divides this space into a superior
sublingual space and an inferior submaxillary (submylohyoid) space. The sublingual space
contains loose areolar tissue, the hypoglossal and lingual nerves, the sublingual gland and
Wharton’s duct. The submylohyoid space contains the anterior bellies of the digastrics and
the submandibular glands. These two subdivisions freely communicate around the posterior
border of the mylohyoid.
 Parapharyngeal space- The parapharyngeal space is also called the pharyngomaxillary
space, the lateral pharyngeal space and the peripharyngeal space. It has been described as
having the shape of an inverted cone, with the base at the base of the skull and the apex at
the hyoid. The boundaries of this space are the skull base superiorly (petrous portion of
temporal bone vs. sphenoid), the hyoid inferiorly, the pterygomandibular raphe anteriorly, the
prevertebral fascia posteriorly, the buccopharyngeal fascia medially and the superficial layer
of the deep fascia over the mandible, medial pterygoid and parotid laterally. The
parapharyngeal space communicates with several other deep neck spaces, including the
submandibular space, the retropharyngeal space, the parotid space and the masticator
space. This has important implications in the spread of infection in the neck. The
parapharyngeal space is subdivided by the styloid process into an anterior, muscular or
prestyloid compartment and a posterior, neurovascular or poststyloid compartment. The
prestyloid space contains fat, muscle, lymph nodes and connective tissue and is bounded by
the tonsillar fossa medially and the medial pterygoid laterally. The poststyloid space contains
the carotid sheath and cranial nerves IX, X and XII. The stylopharyngeal aponeurosis of
Zuckerkandel and Testus is formed by the intersection of the alar, buccopharyngeal and
stylomuscular fascia and acts as a barrier to the spread of infection from the prestyloid
compartment to the poststyloid compartment.
 Peritonsillar space- The peritonsillar space is formed by the capsule of the palatine tonsil
medially, the superior constrictor laterally, the anterior tonsillar pillar superiorly and the
posterior tonsillar pillar inferiorly. This space contains loose areolar tissue, primarily in the
area adjacent to the soft palate, which explains why the majority of peritonsillar abscesses will
localize to the superior pole of the tonsil.
 Masticator space- The masticator space is formed by the superficial layer of the deep cervical
fascia as it surrounds the masseter laterally and the pterygoid muscles medially. This space
contains these muscles as well as the body and ramus of the mandible, the inferior alveolar
nerves and vessels and the tendon of the temporalis muscle. The masticator space is in
direct communication with the temporal space superiorly deep to the zygoma. Infection may
spread through third molars
 Temporal space- The temporal space has as its lateral boundary the superficial layer of deep
fascia as it attaches to the zygoma and temporal ridge and its medial boundary the
periosteum of the temporal bone. It is subdivided into superficial and deep spaces by the
body of the temporalis muscle. This space contains the internal maxillary artery and the
mandibular nerve.
 Parotid space- The parotid space is surrounded by the superficial layer of the deep fascia that
sends dense connective tissue septa from the capsule into the gland. In addition to the
parotid gland, this space contains the parotid lymph nodes, the facial nerve and posterior
facial vein. The fascial envelope is deficient on the supero-medial surface of the gland,
facilitating direct communication between this space and the parapharyngeal space.

c) Infrahyoid Spaces
 The suprasternal space of Burns in the midline formed by splitting of the superficial layer of
deep cervical facsia.
 Another potential space below the hyoid is the anterior visceral space. This area is enclosed
 by the middle layer of the deep cervical fascia and contains the thyroid gland, esophagus and
trachea. This potential space runs from the thyroid cartilage into the anterior superior
mediastinum to the arch of the aorta. Below the level of the thyroid gland this space
communicates laterally with the retropharyngeal space

Etiology
 An odontogenic source is most common, although tonsillitis, pharyngitis, and even sinusitis
are occasionally identified as the initiating site of infection.
 Trauma- blunt trauma to the anterior aspect of the neck may result in laceration of the
pharyngeal mucosa or trauma due to sharp foreign body such as a fish or chicken bone in the
hypopharynx.
 Iatrogenic deep neck infection may develop after traumatic endotracheal intubation or
endoscopic evaluation.
 Use of the internal jugular vein for the intravenous administration of total parenteral nutrition
or illicit narcotics is associated with both deep neck infection and thrombosis of the internal
jugular vein

Microbiolgy
The most commonly involved organisms were S. aureus and Streptococcus species. Anaerobic
bacteria especially in odontogenic deep neck infection is commonly seen. Recent reports indicate an
increase in the incidence of methicillin-resistant S. aureus in community-acquired staphylococcal
infections.

Preoperative evaluation
 Contrast enhanced Computed tomography (CECT) - to localize the site and size of the lesion
and to determine whether the infection has progressed from local tissue sepsis (cellulitis) to
suppuration (frank abscess). A mass with a low-density center surrounded by a high-density
rim suggests central necrosis and abscess formation. Conversely, development of an
inflammatory mass that is homogeneous throughout may indicate that the infection is still in
the cellulitis phase.
 Gram staining and culture sensitivity testing before the administration of antibiotics. It is
recommended starting an antibiotic effective against β-lactamase, as well as an antibiotic
effective against anaerobic oral flora. Blood sugar and HIV status should be checked to rule
out diabetes mellitus and AIDS.
 The airway should be carefully monitored. If the patient is having difficulty handling
secretions, is drooling, or is frankly short of breath, an elective tracheotomy should be
performed immediately.
 When an odontogenic source of infection is identified, consultation with a dentist and drainage
of a periorbital abscess or tooth extraction may contribute greatly to subsequent control of
infection.

SURGICAL APPROACHES

Standard of therapy for the management of deep neck abscess is incision and drainage.

A neck cellulitis may respond to intravenous antibiotics alone whereas surgical drainage is required
for an abscess. This may be especially true in children. Failure to improve on intravenous antibiotics
is an indication to intervene surgically. A well-localized deep neck infection may by treated by needle
aspiration of the abscess and high-dose intravenous antibiotics. These techniques require close,
careful patient follow-up. Progression of disease is an indication to institute more aggressive therapy
consisting of open surgery and drainage. Any patient with airway compromise is not a good candidate
for needle aspiration therapy, one should proceed directly to establishing an airway and incision and
drainage under these circumstances.

 The submandibular space can be approached percutaneously or through the mouth.

Abscesses that develop superior to the mylohyoid sling may be adequately drained through
the floor of the mouth. Generally, however, an abscess that is posterior and inferior to the
mylohyoid muscle requires a transcervical incision placed in a submandibular skinfold. Care is
taken to avoid the marginal mandibular branch facial nerve. The abscess is opened bluntly.
 Finger dissection helps to fully evacuate all loculations, after which the wound is copiously
irrigated and a drain inserted.
 Access to the parapharyngeal space should be obtained percutaneously. Usually, a horizontal
incision made in an upper cervical skin crease at the level of hyoid(carotid bifurcation) offers
adequate exposure and results in postoperative cosmesis. This incision should ordinarily be
made at approximately the level of the. The sternocleidomastoid muscle is then reflected
posteriorly. The great vessels are reflected posteriorly and the abscess cavity entered. The
parapharyngeal space is most easily approached by passing just anterior to the posterior
belly of the digastrics muscle. Ligation of the facial artery with anterior displacement of the
submandibular gland may be required. The abscess cavity is digitally explored, with care
taken to break down all loculations. The wound is copiously irrigated and a drain inserted. The
parapharyngeal space should not be drained transorally inasmuch as such drainage does not
allow the surgeon to identify and protect important neurovascular structures. Limited, well-
localized abscesses that involve the superior aspect of the retropharyngeal space may be
drained transorally. The risk, of course, is that purulent debris will be aspirated. It is
recommended that patients be intubated and placed in the Trendelenburg position.
 A large retropharyngeal abscess should be drained transcutaneously. Posterior retraction of
the sternocleidomastoid muscle and the great vessels exposes the retropharyngeal space,
which is explored digitally with care taken to break down all loculations. The wound should be
copiously irrigated. Drains can be left in multiple sites in the retropharyngeal space to ensure
proper postoperative drainage. Parapharyngeal or retropharyngeal space abscess patients
should be carefully considered for tracheotomy if there is an airway compromise.

Necrotizing cervical fasciitis is a rarely encountered, potentially lethal infection caused by

polymicrobial organisms, including gram-positive cocci and anaerobic bacteria that synergistically
produce acute fulminant infection with tissue necrosis. There is subcutaneous emphysema because
of air-forming organisms. At the time of incision and drainage, frank purulent debris is not
encountered. Instead, exploration may reveal foul-smelling gray-brown tissue fluid with no localization
of infection. Muscle and fascia may be frankly necrotic. This is a potentially lethal situation. Incision
plus drainage is inadequate. The entire area of infection must be exposed in patients with necrotizing
fasciitis. Necrotic tissue should be repeatedly dedrided and the wound left open. Broad-spectrum
antibiotics should be administered, and the patient should be monitored in an intensive care setting.
Urgent initiation of hyperbaric oxygen therapy may be considered. The wound cannot be closed until
all necrotic tissue has been eliminated and the wound is actively granulating with healthy tissue.

Complications of Deep neck space abscess

 Airway obstruction – more common in infants because of excess of loose areolar tissue, small
and narrow larynx. Patients with paraphyangeal and retropharyngeal abscess may are more
prone to develop respiratory compromise. Any stridor or impending obstruction muse be dealt
with urgent trachesotomy.
 Aspiration pnuemonitis and lung abscess if an abscess bursts in the oropharynx.
 Horner’s syndrome may be present. Any associated neuropathy, the most common type of
which is injury to the vagus nerve or the cervical sympathetic chain, may resolve with
resolution of the infection. Neuropathy may be permanent in some case.
 Vascular complications
o Thrombophlebitis of the internal jugular vein may be heralded by a spiking febrile
course (Lemierre Syndrome)
CT can also identify the thrombosed vein as a characteristic ring caused by contrast
material on the wall of the vein and absence of contrast material within the lumen.
o Jugular vein thrombosis is most commonly associated with patients in whom deep
neck infection is caused by self-injection of illicit drugs directly into the jugular vein.
The surgeon should be especially aware of the possibility that the patient is infected
with methicillin-resistant S. aureus. At the time of incision and drainage, it is
appropriate to ligate and remove the thrombosed jugular vein.
o Carotid blow out- it’s a rare life threatening complication characterized by sentinel
bleed either from oral cavity or nose and may be some time from ear, protracted
clinical course (7-14 days) and hematoma of surrounding neck tissues with
hemodynamic collapse. Infective necrosis of carotid artery system may develop with
deep neck infection. Early recognition and proximal control of carotid is essential.
Sometimes it is possible to identify a branch of the external carotid artery that is
 affected and individually ligate that particular branch. In other circumstances, the
entire common carotid artery may need to be ligated. When the situation allows,
intraoperative arteriography may provide information that aids in making these
decisions. This may be encountered at the time of incision and drainage if a clot is
found in the neck, which should alert the surgical team immediately. A
pseudoaneurysm of the carotid or other affected vessel may be evident on a contrast-
enhanced CT scan and endovascular stenting or vessel occlusion or coiling of
psuedoaneurym may be attempted.
 Progression of deep neck infection to mediastinitis is a potential fatal complication. This
situation can be recognized clinically by the severity of the bedside situation as characterized
by fever, diaphoresis, shortness of breath, and sepsis. Localization of the infectious process
through CT scanning may facilitate appropriate drainage. Consultation with colleagues in
thoracic surgery is always appropriate.
 Other complications which can be there are septicemia, meningitis, abscess in other parts of
body, osteomyelitis of mandible, vertebrae and its subluxation.

Postoperative Management
Intravenous antibiotics are continued and modify antibiotics according to culture and sensitivity
information. A feeding tube is required for nutritional support and wound and drains are inspected
regularly. The drains may be advanced when drainage is scant and then removed. The incision is
allowed to heal by secondary intention. The tracheotomy tube is removed when resolving pain and
edema indicate a favorable clinical course.

Failure to adequately drain all loculations may result in persisting pain, fever, leukocytosis, and
dysfunction. Failure to demonstrate clear-cut clinical improvement indicates a possible persistent
undrained abscess. Repeat CT may be helpful in these circumstances. If a small loculation is
demonstrated, it may be possible to drain it with the gloved hand by re-exploring the wound.

Infected third or fourth bronchial cleft cysts may be manifested as a paratracheal abscess or unilateral
bacterial thyroiditis. In the acute setting, antibiotics should be administered. A barium esophagogram
may help identify a possible hypopharyngeal tract. Surgical exploration with excision of the tract and
closure of the pharyngeal fistula is indicated when the thyroid gland is involved by the tract; unilateral
thyroid lobectomy is required. Failure to recognize and adequately treat necrotizing fasciitis or jugular
vein thrombosis is a potentially lethal error of omission.

REFERENCES
th
1. Cummings Otolaryngology Head and Neck Surgery, 5 ed.
2. Lee KJ, Essential Otolaryngology Head and Neck Surgery
3. Pasha R, Otolaryngology Head and Neck Surgery Clinical Reference Guide.
4. Herr RD, Serious Soft Tissue Infections of the Head and Neck, American Family Physician, September 1991, Vol
44, no 3, 878-888
5. Hartmann RW Jr. Ludwig's angina in children. Am Fam Physician. 1999 Jul;60(1):109-12.
rd
6. Netter FH Atlas of Human Anatomy 3 Ed.
7. Singh I, Meher R, Agarwal S, Raj A. Carotid artery erosion in a 4-year child. Int J Pediatr Otorhinolaryngol.
2003 Sep;67(9):995-8.
8. Meher R, Jain A, Sabharwal A, Gupta B, Singh I, Agarwal AK. Deep neck abscess: a prospective study of
54 cases. J Laryngol Otol. 2005 Apr;119(4):299-302.
9. Meher R, Garg A, Malhotra V, Singh I. Pseudoaneurysm of the internal carotid artery in an infant aged 8
months. N Z Med J. 2006 Jan 27; 119(1228):U1815.
10. The masticator space: From anatomy to pathology, N. Faye et al, Journal of Neuroradiology Volume 36, 121-130
(June 2009).
11. http://www.utmb.edu/otoref/grnds/grndsindex.html
12. http://iris3.med.tufts.edu/headneck
13. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/allergy/rhino-sinusitis/
14. Scott-Brown: Otolaryngology. 7th Edition. Volume II. Nose and Head and Neck.
15. http://doctorcayoo.blogspot.com/2009/12/peritonsiler-abscess-pta-quinsy-1.html
16. http://iris3.med.tufts.edu/dentgross/labguide/Homepage.html
 Management of early breast cancer
V. Seenu

From the point of view of management, breast cancer is classified into early, locally advanced and
early breast cancer.

The term early breast cancer includes T1/ T2 tumors with N0/N1 lymph node status. The extent of
staging investigations used in these patients varies widely. Bilateral mammogram is mandatory to
look for multifocal disease (especially while planning breast conservation) and contralateral second
primary. US can be used for similar purpose in women with dense breasts. CEMRI is needed only in
select group of patients. Most investigators believe that it is sufficient to get chest X ray and
ultrasound abdomen to evaluate the lungs and liver in these patients. Bone scan is routinely not
recommended in these patients. PET scan for staging can be used as an investigational tool and is
not routinely recommended for staging of breast cancer.

Surgical treatment of primary tumor can be breast conservation surgery (wide local excision +
radiotherapy with or without boost)/ breast oncoplasty or mastectomy. The essential principle of WLE
is to obtain 1 cm tumor free margin 3 dimensionally leaving behind enough of breast tissue so as to
give good cosmesis. BCS should be offered to all patients who are suitable for conservation.
Absolute contraindication for BCS is multifocal tumor involving more than one quadrant of the breast.

Breast oncoplasty is a new terminology. It encompasses attempt at excellent cosmesis without

compromising survival. The surgical techniques commonly used for breast oncoplasty are BCS with
tisuue displacement or with pedicle based breast or modifies myocutaneous flaps. This term also
includes Skin sparing mastectomy with reconstruction (Implants- saline / silicon & myocutaneous
flaps- TRAM, DIEPM, LD), and lipomodelling of the breast.

Management of axilla in early breast cancer depends on whether axilla is clinically negative or has
metastasis. In clinically negative axilla, sentinel lymph node node biopsy is the standard of care.
Sentinel Node (SN) Concept (Sentinel = a guard, one who keeps watch or a sentry) is based on the
belief that Lymphatics from primary tumor drain to a first node in regional basin and this node
accurately depicts the status of entire nodal basin. The used for DLN biopsy are dye directed (Blue
dye), radiotracer directed (Hot node) or combination. Combination technique is the recommended
technique for SLN biopsy. As an alternative to SLN biopsy, some investigators have reported use of
4-node sampling or axillary sampling with equal success and morbidity rates as SLNB. In patients
with axillary lymph node metastasis, complete axillary lymph node dissection (ALND) is the surgical
procedure of choice.

Adjuvant systemic treatment in early breast cancer depends on the age of patients, menopausal
status and receptor status (ER, PR & Her2 Neu). In young premenopausal women who are ER-
ve,PR-ve and Her2Neu –ve, combination chemotherapy (CEF/ Taxol + epirubicin) is recommended.
In patients who are elderly, post menopausal and ER+, PR+, tamoxifen or aromatase inhibitors are
recommended. In patietns who are Her2Neu positive (Her2neu 3+), trastuzumab is recommended.
However, trastuzumab is expensive and most patients in Indian settings are unable to afford this
treatment.
 Locally Advanced Breast Cancer
P.N. Agarwal, Vivek Wadhawa

Locally advanced breast cancer (LABC) is defined by bulky primary breast tumors and/or extensive
adenopathy. This includes patients with T3 (>5 cm) or T4 tumors (chest wall fixation or skin ulceration
and/or satellitosis) and N2/N3 disease (matted axillary and/or internal mammary metastases) [1].
Recent studies demonstrate that prolonged survival can be achieved in patients with metastatic
[1],
disease limited to the supraclavicular nodes after appropriate multimodality breast cancer treatment
[2]
. As a result, American Joint Committee on Cancer (AJCC) staging system now includes isolated
[2]
supraclavicular metastases in the stage III/LABC disease category . Five-year survival for stage III
breast cancer is approximately 50%, compared with 87% for stage I. In India 60% of breast cancer
present as LABC.

Diagnosis

Tissue Diagnosis

Establishing a tissue diagnosis is the initial priority on presentation of LABC. In many patients, core
biopsy of the tumor, either freehand or under ultrasound guidance, is diagnostic. Core needle is
preferred over fine needle aspiration, as cytology is insufficient to confirm lymphovascular invasion.
Additionally, multiple cores should be extracted both to confirm invasive cancer and to evaluate
hormone receptor status and HER2/neu expression. A negative or nondiagnostic needle biopsy with a
clinically suspicious lesion is an indication to proceed to diagnostic open biopsy; cases characterized
by skin involvement may be amenable to punch biopsy. If matted, fixed, axillary, or supraclavicular
adenopathy is present, fine needle aspiration of the nodes should be performed for staging.

Bilateral mammography

Prompt bilateral mammography in this setting is essential (except in known contraindications of BCT
e.g. inflammatory breast cancer, ulcerative lesions), regardless of patient age and date of her most
recent study. Diffuse, suspicious microcalcifications or multiple lesions in different quadrants indicate
multicentric disease, and are a contraindication to breast conservation therapy (BCT)[14]. If BCT is a
consideration, a microclip placed at the primary tumor(biopsy site), under mammographic or
ultrasound guidance, is essential before the initiation of induction therapy, unless the primary tumor is
associated with a cluster of microcalcifications. Up to 50% of patients may have a complete clinical
response, and an unmarked primary site eliminates the possibility of breast preservation in these
cases, as the lumpectomy site will no longer be adequately defined.

Breast and axillary ultrasound

Breast and axillary ultrasound frequently yield valuable information regarding the extent of disease. In
[15], [16]
particular, axillary ultrasound can be used for image-guided FNA ; ultrasound detection of apical
axillary/infraclavicular nodal metastases has been shown to provide important prognostic information
[17]
. Unfortunately, ultrasound has an approximately 20% false-negative rate, as metastases smaller
than 5 mm in size are undetectable.

Metastatic Work up

A baseline bone scan, abdominal, pelvic and chest CT scans are recommended for detection of
metastatic disease. Directed radiographs to sites of new bone pain, or a head CT scan for new
neurologic symptoms are also appropriate in selected cases. The yield of a metastatic work-up in an
asymptomatic, early breast cancer patient is approximately 2% to 3%, but this risk rises to 30% in
LABC [18]. The most common sites of metastasis is bones followed by lung, liver amd brain. The
metastasis to bonesmay be osteoblastic or osteoclastic.

Therapeutic management

Neoadjuvant chemotherapy
Currently, optimal control is achieved with preoperative chemotherapy followed by surgery and
radiation. Preoperative versus postoperative chemotherapy have been directly compared in women
with LABC and also in women with early stage breast cancer. These prospective clinical trials have
demonstrated overall survival equivalence for the two sequences, confirming the oncologic safety of
the neoadjuvant approach [6], [7], [8], [9], [10], [11], [12], [13]. Since patients with LABC benefit from the tumor
downstaging and improved resectability that can be achieved with neoadjuvant chemotherapy, this
sequence has become the preferred approach for patients with bulky, locally advanced disease at
time of diagnosis. Neoadjuvant chemotherapy offers several advantages compared with traditional
postoperative regimens. Invasive breast cancer patients have a significant risk of harboring occult
micrometastatic disease in distant organs.

Neoadjuvant chemotherapy allows for earlier exposure of these micrometastases to

chemotherapeutic agents, and an observed response to chemotherapy in the primary breast disease
site indicates that the regimen has effective antitumor activity.

Patients receiving preoperative chemotherapy should be reassessed after one or two cycles and
again at the completion of therapy to document response and explore surgical options. Repeat
imaging may be useful at the interim evaluation. If minimal or no response is observed after the initial
cycles, a decision should be made to either proceed with surgery or to cross over to a different
systemic therapy. Surgery allows for a full pathologic evaluation, facilitating decisions on adjuvant
therapy. If an alternative regimen is selected, then reassessment after two cycles of the crossover
treatment is necessary. Follow-up imaging is essential after complete delivery of neoadjuvant therapy
for final preoperative surgical planning. Occasional patients that appeared to have a unicentric cancer
density at presentation will experience unmasking of extensive microcalcifications or multicentric
satellite tumors after chemotherapy response, and these findings may convert them to mandatory
mastectomy cases.

Subset analyses of the phase III studies reveal that patients who have a complete pathologic
response (pCR) have a statistically significant survival benefit, substantiating the concept that primary
tumor response is a reliable surrogate for chemotherapy effect on micrometastases. In the NSABP B-
18 trial [4], patients with stage I to III breast cancer randomized to receive preoperative doxorubicin
and Cyclophosphamide and who experienced a pCR had a 5-year overall survival of 86%, statistically
superior to the outcome seen in all other study participants. Predictors of a pCR include relatively
smaller size primary breast tumors, estrogen receptor negativity, and high-grade lesions [5].

Neoadjuvant chemotherapy regimen

Currently, doxorubicin-based chemotherapy is the most widely-studied induction regimen, and it

results in at least 50% tumor shrinkage in more than 75% of cases. The NSABP B-27(1995-2000)
protocol randomized patients with resectable breast cancer to one of three neoadjuvant treatment
arms: (1) doxorubicin and cyclophosphamide alone; (2) doxorubicin, cyclophosphamide, and
docetaxel; or (3) preoperative doxorubicin and cyclophosphamide followed by postoperative
[23]
docetaxel. Preliminary data reveal a pCR rate of 26% associated with the addition of docetaxel to
[24]
the preoperative regimen. Similarly, the University of Texas M.D. Anderson Cancer Center(2000)
has reported a pCR rate of nearly 30% in patients treated with preoperative doxorubicin, Cytoxan, 5-
fluorouracil, and weekly Taxol.

The Aberdeen trial(1996-1999) investigated whether the number of chemotherapy cycles is a stronger
predictor of tumor response compared with chemotherapy type [25], [26], demonstrating that the nature
of the agent is more important than the quantity. They also showed that poor responders may benefit
from crossover to an alternative regimen. Survival analyses at 3 years also suggest improved
outcomes for patients on docetaxel plus doxorubicin [26]. Other neoadjuvant regimens currently being
evaluated include trastuzumab, Navelbine, capecitabine, and gemcitabine. Microarray technology and
gene expression profiling are also being explored to optimize selection of neoadjuvant therapy [29]. In
neoadjuvant chemotherapy all the cycles are given prior to surgery but depending on the response
surgery may be considered early and completion chemotherapy given postoperatively There has
been many combinations and schedule for chemotherapy a few recommended are mentionedas
follows.
FAC 5-FU 500mg/sqm IV day 1 and 8 Doxorubicin 50mg/sqm IV day Cyclophosphamide
500mg/sqm IV day 1 Cycled every 21 days for 6 cycles
AC Doxorubicin 60mg/sqm IV day 1 Cyclophosphamide 600mg/sqm IV day 1 Cycled every 21
days for 4 cycles
AC followed by paclitaxel Doxorubicin 60mg/sqm IV day 1 Cyclophosphamide 600mg/sqm IV
day 1 Cycled every 21 days for 4 cycles followed by paclitaxel 175mg/sqm 3hr IV infusion day 1
Cycled every 21 days for 4 cycles.

Neoadjuvant endocrine therapy

Neoadjuvant endocrine therapy for estrogen receptor-positive LABC also holds great promise. Three-
to-four months of therapy are preferred for an adequate response assessment, and preliminary
[27], [28]
studies suggest that aromatase inhibitors such as letrozole are more effective than tamoxifen .
Presently it is always combined with neoadjuvant chemotherapy

Monitoring response to neoadjuvant chemotherapy

A significant response to the primary chemotherapy regimen is observed in about 80% of cases;
however, accurate prediction of a pCR is challenging. Conventional modalities for assessing
chemotherapy response, including clinical examination, mammogram, and breast ultrasound, are
incorrect in identifying pCR patients in nearly half of cases. The addition of imaging is clearly more
useful than physical examination alone [3], [30]. Breast MRI [31], [32], positron emission tomography [33],
[34], [35]
and nuclear medicine sestamibi uptake scans have been reported in small series as monitoring
strategies with encouraging results but not yet routinely recommended.

Surgical :Breast conservation therapy and mastectomy

Treatment of the primary tumor is surgical. Treatment of the remainder of the breast tissue for control
of occult disease can be accomplished by either surgery or irradiation. The magnitude of the clinical
response(i.e. downstaging of tumour) to neoadjuvant chemotherapy in LABC prompted investigations
of breast conservation for selected patients. Singletary and colleagues [19] conducted a feasibility
study to evaluate the pathologic extent of residual disease in 136 LABC patients treated with induction
chemotherapy. Extensive scrutiny of the postchemotherapy mastectomy specimens revealed that the
residual tumor would have been amenable to lumpectomy in approximately 25% of patients.

From this and other studies [11], several criteria for BCT in postneoadjuvant LABC have been adopted
widely:
 Patient desire for breast preservation
 Absence of multicentric disease (tumors in different quadrants of the breast)
 Absence of diffuse microcalcifications on mammogram
 Absence of skin involvement consistent with inflammatory breast cancer
 Residual tumor mass amenable to a margin-negative lumpectomy resection

Prospective, randomized controlled clinical trial data have confirmed acceptable rates of local control
among LABC patients undergoing breast-conserving surgery after neoadjuvant therapy. Several
prospective, randomized controlled trials of neoadjuvant versus adjuvant/postoperative chemotherapy
have included cohorts of patients with Stage III disease/LABC. Data from these studies have
documented acceptably low rates of local recurrence in LABC patients undergoing breast-conserving
[20], [21]
surgery after neoadjuvant chemotherapy . The NSABP B-18 investigators did note a trend
toward higher local recurrence rates among patients requiring preoperative downstaging in order to
become lumpectomy eligible (15% versus 7% which is statistically significant). This is not necessarily
surprising, however, as postlumpectomy local recurrence is one manifestation of aggressive tumor
biology, and larger tumors are more likely to demonstrate aggressive behavior, even after
mastectomy. The margin for lumpectomy is kept at 1-1.5cm from postchemotherapy tumor edge.
Postmastectomy radiation (PMRT) is recommended for patients with T3 tumors because of this
concept [22]. . Although women with breast cancer are approached with the intention of offering breast-
conserving therapy, there are situations in which that is not possible. Contraindications to breast-
conservation treatment include (1) presence of two or more primary tumors in separate areas of the
breast, (2) diffuse malignant-appearing microcalcifications, or (3) a history of prior therapeutic
irradiation to the breast that precludes full-breast irradiation for the present condition, (4) Active
collagen vascular disease. For women who are not well treated by breast-conserving therapy,
mastectomy is recommended.

Management of Regional Lymph Nodes

Today axillary lymph node metastases are considered a regional manifestation of metastatic breast
cancer. Axillary lymph nodes that are suspicious by palpation for tumor can be evaluated by FNA
cytologic examination when results will affect the order of therapeutic interventions. If axillary lymph
nodes are matted or fixed (N2), the disease has advanced beyond "early" breast cancer. When
mobile axillary lymph nodes contain tumor, an axillary dissection provides excellent local control of
this axillary disease. This is only the surgical aspect of such control, and there is a role for radiation
and systemic therapy as well in controlling disease in the axilla. The primary indication for axillary
surgery today is the provision of pathologic staging. If the axillary lymph nodes are involved, their
removal accomplishes both goals: defining prognosis and diminishing the risk of subsequent axillary
recurrence. Presently, Axillary dissection is preferred modality for treatment of axillary lymph node in
LABC.

Breast reconstruction

LABC traditionally has been perceived as a contraindication to immediate breast reconstruction (IBR),
because of concerns regarding adjuvant treatment delays and the cosmetic effects of PMRT to breast
reconstruction. Newman and colleagues [36] noticed slightly prolonged interval for adjuvant
chemotherapy among reconstructed patients; this did not affect recurrence rates. IBR with implants,
however, was associated with more radiation-related complications; nearly half of the irradiated
patients developed contractures or recurrent infections, necessitating implant removal. Delayed
reconstruction is therefore, usually preferred in LABC patients undergoing mastectomy, because of
the substantial likelihood that PMRT will be necessary, and the potential damaging effects of radiating
the reconstructed breast. Occasionally, LABC patients will require soft tissue coverage of an
extensive chest wall defect at mastectomy. In these cases, a latissimus dorsi flap is the most common
approach, as this flap is a technically straightforward and provides durable, radiation-tolerant
coverage. Breast reconstruction after local failure in the irradiated breast presents a unique challenge
for the oncologic and the reconstructive surgeon. The late effects of radiation are characterized
clinically by a loss of skin elasticity, fibrosis, and decreased blood supply. In a series of 680
consecutive patients who underwent TRAM flap breast reconstruction, 108 had had previous
irradiation, and no difference was found in flap survival in the two groups [40].

Locoregional irradiation

The American Society of Clinical Oncology recommends PMRT for all patients who have four or more
metastatic axillary lymph nodes based upon axillary surgical findings at presentation (without
neoadjuvant chemotherapy), and that PMRT should be considered for all cases of LABC [37].

Patients who have at least four metastatic lymph nodes or 5 cm of residual disease in the breast after
chemotherapy clearly benefit from locoregional irradiation, and all lumpectomy patients require breast
irradiation. A conservative (and aggressive) approach would be to recommend radiation to all patients
that present with LABC, regardless of chemotherapy response. However, patients with little or no
residual breast/axillary disease after chemotherapy may not derive a significant benefit from regional
nodal irradiation. Existing data are limited regarding whether or not comprehensive irradiation is
absolutely necessary to achieve optimal locoregional control of disease in patients presenting with
LABC, but in whom a substantial degree of downstaging occurred with neoadjuvant chemotherapy.

The NSABP B-18 data suggest that surgical pathology indications for locoregional irradiation are the
same for patients that receive neoadjuvant chemotherapy and those that receive postoperative
chemotherapy. In clinical practice, the oncology team should review each patient in a multidisciplinary
fashion, and discussions regarding the complete multimodality management (including final radiation
[38]
planning) should begin at presentation . For whole breast irradiation IMRT is preffered with doses of
45-50 Gy in fraction of 1.8-2 Gy.all doses aregiven at 5doses per week regional irradiation of 50 Gy in
fraction of 1.8-2 Gy.The ASCO guidelines for postmastectomy radiation treatment state that
postmastectomy radiation treatment is indicated when there are four or more pathologically positive
axillary lymph nodes and when the tumor is stage III (except for T3N0M0 lesions); the need for
postmastectomy radiation treatment is uncertain after neoadjuvant systemic chemotherapy, with one
to three pathologically positive axillary lymph nodes, for T3N0M0 tumors, for close or positive margins
of resection, or for positive lymph nodes associated with extracapsular extension.

Postoperative systemic therapy

Patients with hormone receptor-positive breast cancer should receive at least 5 years of either
tamoxifen or an aromatase inhibitor. Aromatase inhibitors should be given only to postmenopausal
women, as these drugs do not block estrogen production from functioning ovaries. Any woman of
unknown menstrual status can have ovarian function assessed by measurement of serum follicle-
stimulating hormone (FSH), luteinizing hormone (LH), and estradiol levels. The role of ovarian
ablation/suppression for premenopausal, hormone receptor-positive breast cancer patients is not yet
[39], [40]
defined. Tumors overexpressing HER2/neu also require treatment with adjuvant trastuzamab .

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 Management of the Axilla in Carcinoma Breast
Gaurav Agarwal, Sendhil Rajan

The legendary American surgeon William Halstead, who propagated the radical mastectomy for
treatment of breast cancer hypothesized that the involvement of the axillary lymph nodes in breast
cancer are due to spread of the tumour in an step-wise manner, where the nodes of the axilla act as
an anatomical barrier, thereby ‘limiting’ the spread of cancer cells. According to this hypothesis,
metastatic spread of breast cancer happens chiefly via the lymphatic system. This ‘contiguous’
theory is applied in the operation room- en-bloc removal of all the nodes and fibro-fatty tissue of the
axilla along with the primary tumour is based on this. Halsted’s theory lasted from the 1890s to the
th
mid part of the 20 century.
However, studies have shown that up to 30% of patients, despite being axillary node-negative; will
ultimately present with distant disease. Also, a considerable number of breast cancer patients are
recognized to have systemic disease at the time of presentation, due to entry of tumour cells into the
bloodstream during initial stages of the neoplastic process.The above data was put forth by Bernard
Fisher in his 1980 paper where he considered breast cancer to be a systemic disease from its very
onset, thus advocating systemic therapy in nearly all patients. Samuel Hellman in 1994 presented his
‘Spectrum’ theory, which stated breast cancer presentation to be a spectrum- as a disease that
always remains local through its course to one that, at its very clinical onset, may be systemic in
nature.

Today, the regional axillary lymph nodes – although thought to be ineffective barriers for spread of
tumour cells, are still considered to be of vital biological and prognostic importance, and are yet to be
superseded by newer molecular prognostic indices. Axillary lymph-node dissection (ALND) has been
an important part of surgical management of breast cancer over more than a century now, and,
besides its therapeutic potential, also provides key prognostic data for to select patients for further
adjuvant systemic therapies. The main factor affecting node positivity is tumour size, although other
features, such as tumour grade, histological type and lympho-vascular invasion also play a part.
Axillary node metastases also have clinical relevance as they may represent either loco-regional
relapse or distant disease by acting as a source for tertiary spread.

In patients with invasive breast cancer, management of the axilla has two critical goals:
1. Prognostic and Staging Goal: Does the metastatic spread extend to the axillary nodes? If yes-
what is the extent of the spread and number of metastatic lymph nodes? Is there any extra-nodal
infiltration?
2. Therapeutic Goal: When axillary lymph node metastases are present, ALND aims for surgical
extirpation of all remaining metastatic disease from the axilla. Also, radiation to the axilla after
surgical intervention is also widely followed. Studies have shown that ALND (without/before post-
operative radiation to axilla) results in enhanced relapse-free survival. However, its role on overall
survival is little less established.

Management of the axilla in patients with breast cancer has improved significantly in the recent
decades, chiefly due to better understanding of the biological models of lymphatic networks within the
breast and patterns of tumour dissemination. The NCI consensus statement of the past recommends
that treatment of potentially curable breast cancer should include level I and II ALND (see below). The
position of routinely performed ALND for the treatment of breast cancer, in the last decade or so, has
been more closely scrutinized due to various reasons. These include an increase in the detection of
small, non-palpable lesions detected mammographically having a low risk of nodal metastases, a
greater knowledge regarding the complications following ALND, and the present treatment paradigm
of providing adjuvant chemotherapy to the majority of patients with breast cancers >1.0 cm,
regardless of axillary lymph node status.

Breast cancer shows heterogeneous patho-biology, therefore making any blanket axillary treatment
unsuitable for disease management. The surgical management of axilla needs to be customized
individually to each patient’s requirement and preference, as well as to the characteristics of the
tumour. It should be in concurrence with local treatment protocols and available facilities. Sentinel
lymph node biopsy (SLNB) is now recognised as the standard of care in most centres the world
over and has revolutionized axillary management through the last decade and a half. Nevertheless,
there is still limited information regarding long-term outcomes, and there are multiple variations in
practice and inconsistencies in methodology. Other procedures like the ‘four node’ biopsy and axillary
sampling are limited to certain centres, and have not gained acceptance in routine clinical practice. In
patients undergoing breast conserving therapy (BCT), axillary irradiation (AI) has been studied as a
substitute for ALND. However, more conclusive studies need to be done for this to be a
recommendation.

This review will seek to outline the scientific basis, technical aspects and outcomes of the current
axillary lymph node management strategies in patients with invasive breast cancers.

Surgical and Applied Anatomy of the Axilla

The lymphatic system of the breast is constituted of a large and complex network of peri-ductal and
peri-lobular lymph vessels, which drain principally to the axillary nodes. There is a connection
between the dermis and the intra-parenchymal lymphatics (via the sub-areolar plexus), which explains
the spread of cutaneous malignancies and drainage of tracer agents to axillary nodes. Sappey's
plexus are specialized lymphatic channels that are present under the nipple and areola. There is uni-
directional flow of lymph from the superficial to deep plexus and from the sub-areolar plexus through
the lymph vessels of the lactiferous ducts to the peri-lobular and deep sub-cutaneous plexus.

SLN biopsy can be accomplished only with knowledge of the intricate lymphatic anatomy of the
breast. Lymphatic anatomy also determines the preferred sites for loco-regional spread of
malignancy. The vast majority of breast tumours metastasise to the axilla regardless of the site of
primary tumor within the breast. The internal mammary nodes constitute an alternative path for
drainage of lymph from the central zone and medial breast quadrants. However, exclusive
involvement of the internal mammary nodes is seen in <10% of node-positive tumours and clinical
signs are rare. Considerable morbidity can result from surgical removal of these nodes, with no
advantage in overall survival. Currently, the clinical and pathological significance of involvement of
internal mammary nodes is uncertain at best.

The axilla is a pyramidal shaped area, medially bounded by the chest wall, laterally by the latissimus
dorsi, posteriorly by the sub-scapularis, superiorly by the axillary vein and inferiorly by the inter-
digitation of the latissimus dorsi and serratus anterior muscles. About 50 lymph nodes are present
within the loose areolar fat of the axilla, although this number is variable. Arbitary division of the lymph
nodes of the axilla is as follows: Level I nodes are those found lateral to the lateral border of the
pectoralis minor muscle; Level II nodes are those in the central axillary group, found under the
pectoralis minor muscle; Level III include the sub-clavicular nodes medial to the medial border of the
pectoralis minor muscle. (Figure-1) Expirtation of these nodes requires either division or retraction of
the pectoralis minor, although dissecting between the two heads of the pectoralis major can also
accomplish this. The pectoralis minor is enclosed in the clavi-pectoral fascia, which extends laterally
to fuse with the areolar tissue of the axilla. One can divide the axillary fascia and expose the contents
of the axilla by dissection along the lateral border of the pectoralis minor.

The axilla contains many clinically important structures, which require preservation during dissection
and removal of the lymph nodes with the fatty areolar tissue of the axilla. Rotter’s nodes are the
inter-pectoral lymph nodes present between the two pectoralis muscles. They are usually seen on the
posterior surface of the pectoralis major, in close relation to the lateral pectoral nerve, which if injured,
results in atrophy of the muscle. The inferior–lateral aspect of the pectoralis major muscle is
innervated by the medial pectoral nerve, which should also be carefully preserved. The second
cutaneous inter-costo-brachial nerve runs in a medial–lateral direction approximately a centimetre
inferior to the axillary vein. Running just posterior to the inter-costo-brachial nerve in the second inter-
costal space is the long thoracic nerve (of Bell), which innervates the serratus anterior muscle. It
should always be identified before proceeding with axillary dissection, at a site just lateral to the
serratus anterior muscle. Any surgical dissection anterior to the inter-costal nerves will safely preserve
the long thoracic nerve as the latter runs in a superior–inferior direction, and is always posterior to the
inter-costal nerves (which run in a medial–lateral direction). Division of the long thoracic nerve results
in “winging of the scapula”. The thoraco-dorsal nerve innervating the latissimus dorsi, is first seen
posterior to the lateral thoracic vein. It then travels infero-laterally, passing over the sub-scapular
muscle, with the sub-scapular vessels, entering the latissimus dorsi muscle in its medial aspect.
Dissection therefore should be done along the lateral or anterior aspects of the latissimus dorsi to
prevent thoracodorsal nerve injury.
Management of Axilla in Invasive Breast Cancer Patients

The single most important prognostic factor in patients with invasive breast cancer is the presence of
axillary lymph node metastases, and therefore evaluation of the axilla is of paramount importance.
Patients who have axillary nodal metastases without systemic metastases exhibit 40% poorer overall
survival at 5 years, when compared to patients who do not have axillary metastases. Also, the
number of positive lymph nodes (>3) and presence of extra-nodal spread into axillary soft tissue are
recognized high-risk factors for loco-regional recurrence and overall survival. An ideal plan of
management of the axilla remains a controversial topic, and it is currently formulated based on the
tumor characteristics, presence of clinically (including radiologically) detected lymphadenopathy,
patients desire, availability of local infrastructure and medical facilities and individual institute
protocols and acceptability of various choices. Table-1 provides a list of several options for
management of the axilla in invasive breast cancer patients.

Table 1: Options for management of axilla in patients with Invasive Breast Cancers
A. Established options backed by sufficiently high quality scientific evidence:
1. Axillary lymph-node dissection level I and II for
(a) patients with palpable axillary lymphadenopathy
(b) patients with metastatic sentinel lymph node

2. Axillary lymph node dissection levels I, II and III in patients with enlarged level III nodes or bulky
level I and II nodes.
3. Sentinel Lymph node biopsy for patients with clinically (including radiologically) impalpable/ non-
enlarged axillary lymph nodes:
(a) Sentinel-lymph-node biopsy with dye and isotope
(b) Sentinel-lymph-node biopsy with isotope only
(c) Sentinel-lymph-node biopsy with dye only
Further management of axilla based on SLN pathology:
(i) ALND if SLN has metastatic deposits (including micro-metastases)
(ii)Avoidance of ALND if SLN has no metastatic deposits or have isolated tumor cells
(sub-micro-metastases) evident on immuno-histochemical studies.

B. Other options- NOT backed by sufficient scientific evidence/ limited evidence:

May be practiced in clinical trial setting, not recommended for routine clinical use
(a) Axillary lymph node sampling
(i) Blue-dye-assisted node sampling
(ii) Blind sampling- such as “four node sampling”
(b) Observation only
(c) Avoidance of ALND in patients with metastatic SLN (except in highly selected very low-risk
patients, as per ACOSOG Z0011 criteria)
(d) ALND in patients with Sub-micro-metastases (isolated tumor cells) in SLN
* While only well established procedures namely ALND and SLNB are mostly practiced, in certain
specific groups e.g. small (<1 cm) low grade tumours with favourable risk profile- axillary surgical
procedures may be avoided.

The foremost intention of axillary surgery in patients of operable breast cancer is to stage the axilla.
Independent predictors of survival include number of lymph nodes and the level of lymph node
involvement.

Staging options
a) Sentinel lymph node biopsy
b) Axillary node sampling
c) Axillary dissection

Sentinel Lymph Node Biopsy (SLNB)

The aims of sentinel lymph node biopsy are axillary staging and avoidance of unnecessary axillary
dissection leading to significant morbidity. The principle behind SLNB is that the sentinel lymph
node(s) is the first (group) of node(s) to drain the tumour bed. If the SLN is free of the tumour then the
nodes at the further station are also tumour free and an axillary dissection can be avoided with
oncological safety. Historically, Sappey in 1980 injected mercury in the lymphatic channels of the
breast and concluded that drainage to the axilla occurs via a sub-areolar plexus although recent
studies have doubted this. The tracer can be injected via the intradermal, sub-areolar or peritumoral
route. Because the skin has richer lymphatics than the parenchyma, it is almost always possible to
differentiate the sentinel from the other higher level nodes when the tracer is injected in the skin. In
the case of non-palpable breast lumps, the dye or tracer needs to be injected under image guidance.
Chapgar et al, in a review of 3961 patients,concluded that the rate of identification by intra-dermal or
sub-areolar injection was 99.3% & 95.6% respectively compared to 91.1 % of peri-tumoral injection.

Indications of SLNB
a) Operable early breast cancer (T1, T2)
b) Clinically node negative

Under Trial/Partial evidence:

a) Locally advanced breast cancer with complete or good partial response after neo-adjuvant
chemotherapy and clinically N0 stage
b) Patients with extensive DCIS undergoing mastectomy.

A patient with clinically-N0 axilla is explained the procedure and consent is obtained to subject her to
a SLNB followed by a possible axillary dissection in case SLNB is reported metastatic. SLNB is
performed using a colour (blue) dye, radio-pharmaceutical or a combination of both, which is the
preferred method, with highest SLN detection rate and lowest false negative rates. The different
agents used for SLNB are:
 Isosulphan blue (Lymphazurin) or Patent blue dye V or Methylene blue
 99m Technetium- labelled albumin / antimony/gold or sulphur colloid

Although the volume of dye used has been different in various studies with similar results, when using
a radio-pharmaceutical, usually 0.5 -6 ml of Tc labelled dye in saline is injected at the periphery of the
tumour or the previous excisional biopsy site directed by manual palpation or USG guidance or
injected around the areola. The gamma probe is then employed to identify the site of maximum
radioactivity in the axilla. A small skin crease incision is made at the point of maximum intensity and
the axillary fat is dissected to reach to the point of the maximum radioactivity, highlighted by maximum
sound emitted by the device. When blue dye is used, 2 - 7.5 ml of sterile isosulphan blue or
methylene blue (more cost effective) is taken and injected just prior to surgical skin preparation. If no
radioactivity is encountered/radiopharmaceutical not used, then the skin is incised between the
pectoralis major and the latissimus dorsi over the lower part of the axilla, axillary fat is dissected to
visualise the blue channels defined by the dye (SLNB is always done before the procedure for the
breast tumour). These channels are traced upto the first node/group of nodes which is/are biopsied
and sent for histo-pathological examination. For each patient, the average yield is found to be more
than one in most studies, highlighting the fact that SLN is not a single node but regularly a group of
nodes. The node(s) is then subjected to frozen section or imprint cytology and if the node is positive
for malignant deposit, a complete axillary dissection is carried out. As only one or two lymph nodes
are submitted for histology, the SLN can be subjected to a more detailed pathological examination
than routine nodal tissue, with multiple-step sections and immuno-histochemical staining - Cytokeratin
(CK) staining is another method employed for intra-operative evaluation of sentinel lymph nodes.

One-step nucleic acid amplification (OSNA) is a recently introduced method for intra-operative
evaluation of sentinel lymph node status in breast cancer – The principle behind OSNA is
measurement of mRNA copy numbers of CK 19 (CytoKeratin19) in the SLN sample, giving a rapid
report. (A vast majority of breast cancers express CK19, therefore it is preferred). In recent times,
researchers have also investigated the possibility of using spectral imaging (which refers to the
formation of a multi-planar image where each pixel in the spatial plane records reflected intensities
from a range of spectral bands) to assess the SLN(s) of breast cancer patients with an idea to
ultimately develop an optical system that can categorize spectra of normal and metastatic tissue in
the visible and near infrared region, providing a report quickly.

Reduction of morbidity, especially arm lymphedema, is a main objective of SLNB. Most studies show
lower rates of morbidity after SLNB compared with ALND. There is an increasing trend toward
omitting ALND altogether in patients with micrometastatic nodal disease identified by SLNB, as shown
by recent studies. The IBCSG 23-01 trial randomized patients with SLN micromets (<2 mm) and
T1/T2 tumours to either completion ALND or no further intervention to the axilla. There was no
significant difference in OS or DFS for patients of either arm at a median follow-up of 49 months. The
recent ACOSOG Z-0011 trial addressed the need for completion ALND for patients with EBC that
were clinically node negative and had less than three positive SLNs; all patients underwent breast
irradiation. At a median follow-up of 6.3 years, there were no significant differences in survival or loco-
regional recurrence between the SLND plus ALND group versus the SLND alone group. The five-year
overall survival, five-year disease-free survival and recurrence rates in the ipsilateral axilla were all
similar between the two arms. The National Comprehensive Cancer Network (NCCN), however, has
not changed its guidelines and continues to recommend completion ALND for all women with positive
sentinel nodes until additional randomized trial results are available. Other recent studies have shown
that SLNB is as accurate in patients presenting with a T3 tumour and clinically negative axilla as in
patients with EBC. Thus, many clinicians do not recognize large breast tumours as a contraindication
to SLN dissection, as long as the axilla is clinically negative.

At SGPGIMS, Lucknow, the SLNB protocol consists of a combination of 1% w/v methylene blue dye
and 99mTc-Antimony colloid, both of which are produced in-house, therefore limiting their costs. A
99m
dose of 40MBq of Tc-Antimony colloid is injected sub-areolarly 12-24 hours prior to surgery. Later,
a few minutes before incising the skin, 1-2 ml sterile methylene blue is injected in the sub-areolar
region. The hand held gamma probe draped in a sterile glove (Neo-probe 2000, Ethicon) is then
employed trans-dermally to search for the “hot” SLN in the axilla, surface marking of which is then
done. A small 1-2 cm skin crease incision, placed posterior to the pectoral fold in the upper axilla or
exactly over the marked SLN is then made. Streaks of blue lymphatics are sought for, and when
found are followed in a supero-medial direction to a blue SLN. The hand held gamma probe is then
used to trace the areas/ SLN with radio-tracer concentration (hot area), once the SLN (blue, and /or
hot) is identified, it is removed intact. Other “hot” areas if found, are explored and further SLN’s are
thereby identified and removed. All the SLNs removed are sent to the pathologist for frozen section
histopathology and/or imprint cytology in cold saline. If the frozen section histology shows metastasis
in one or more of SLN’s- a formal Level I+II axillary dissection is performed, utilizing and extending
the SLNB incision by an extra 3-4 centimeters.

A validation study conducted at SGPGIMS Lucknow, on 120 patients with early breast cancer,
revealed a SLN identification rate of 96% and false negative rate of <4%, thereby now establishing
the oncological safety of this procedure for patients with early breast cancer. Another validation study
in patients with impalpable axillary lymph nodes after undergoing neoadjuvant chemotherapy is
currently nearing completion. Preliminary results for this group show poorer SLN identification rates
and higher false negative rates compared to EBC patients undergoing primary surgery.

Axillary Node Sampling

When the radiotracer and/or blue dye fails in SLN identification, axillary node sampling is done. It may
also be combined with the SLNB to increase the overall sensitivity. The largest nodes (a minimum of
4) are excised. In patients with non-palpable Level I nodes, level II or III nodes are sampled. This
technique therefore permits identification of skip metastases in the axilla although such cases are
relatively rare (5%). Most of the SLN/lymphatic mapping studies have recognized the first draining
node in level I, therefore level I node is most frequently sampled.

Avoidance of ALND and any axillary surgical procedure

Any of the staging procedures of the axilla can be safely omitted in selected clinically node-negative
patients having small (≤1.0 cm) non high- grade (I and II) tumours, in elderly patients associated with
co-morbidities, and also in cases of localised non-palpable DCIS amenable to wide excision. ALND,
however, is no longer an acceptable staging procedure for clinically node-negative patients. Studies
are underway in clinically node-negative patients undergoing preoperative ultrasound-guided biopsy
to identify axillary metastases and, therefore, allowing ALND at the without conventional SLNB.

Axillary Lymph Node Dissection (ALND)

A formal complete ALND is warranted in cases of histologically proven positive axilla by FNAC
(palpation guided or US guided) or cases in which SLN or axillary sampling specimen is positive for
metastases (3). It may also be required additionally in variety of other situations, as listed below.
Indications for ALND
a) Axillary node metastasis proven by fine needle aspiration (FNA), core biopsy, or SLN biopsy
b) Validation trials of SLN biopsy (in which a planned backup ALND is done to establish the
proportion of false-negative results).
c) Failed SLN biopsy (even in expert hands, SLN mapping fails in a few percent of cases).
d) Clinically suspicious nodes palpated at the time of an otherwise successful SLN biopsy
procedure
e) Inflammatory breast cancer (following neo-adjuvant chemotherapy, SLN biopsy appears
accurate for non-inflammatory disease, but remains investigational for inflammatory breast
cancer)
f) Unavailability of SLN biopsy
g) Isolated loco-regional recurrence, either in the ipsi-lateral axilla after SLN biopsy or in the
contra-lateral axilla, with no evidence of a contra-lateral breast primary.

Though still regarded as a beneficial procedure by conferring better regional disease control, the
overall survival advantage with ALND has always been in doubt, since the Halsted era.A large meta-
analysis of about 3000 patients has shown a survival benefit of 5.4% from ALND. However, many
other studies have shown no survival benefit from ALND. The prevalence of node positivity in patients
undergoing ALND mainly depends on the tumour size, although other factors, such as tumour grade
and type, lympho-vascular invasion, are also relevant.

Technique of ALND

Classification of ALND isdone based on the extent

dissected: level I, level I+II, or level I+II+III (‘complete
ALND’). Axillary nodal Levels I & II are routinely dissected
out along with all fibro-fatty and lymphatic tissue. A
minimum of 10 nodes need to be histo-pathologically
examined for optimal axillary staging. When level III nodes
are found to be enlarged, and also in patients exhibiting
bulky level II nodes, a complete level III dissection is
performed. “Skip metastases,” refers to disease limited to
levels II to III, sparing level I, or limited to level III, sparing
levels I-II. As most of these “skip metastases” were found
at level II (isolated level III disease is rare), most Fig 1: Levels of axillary lymph nodes: I, II
recommendations favour a level I+II ALND as the standard and III in relation to the pectoralis minor
procedure. muscle and tendon.

Incisions utilized for ALND may be separate from or in-continuity withthe incision used for the breast
procedure. If a separate incision is employed, it is best made transversely,about two finger-breadths
below the axillary skin crease, gently curved to follow a skin-line. The length should be adequate for
good exposure, but must not extend beyond the anterior pectoral border, where it would be visible –
the incision may be posteriorly extended if required. A
contiguous incision is perfectly rational in patients
undergoing mastectomy without reconstruction or BCS and
for tumours present high up in the axillary tail. In both
cases, SLNB is done through the axillary end of the
incision before the breast procedure. The procedure of
ALND involves dissection and removal of all fibro-fatty and
lymphatic tissue including the lymph nodes from whole of
levels I and II, and if indicated level III. The extent of
dissection is from the axillary vein superiorly, to second
digitations of the serratus anterior muscle inferiorly, and
from the anterior border of latissimus dorsi muscle laterally
to the rib-cage and intercostals muscles medially, with the Fig 2: Completely dissected axilla,
nerve to serratus anterior as a guide to the medial limit. showing intact and skeletonized long
The important structures that are needed to be preserved thoracic nerve and thoraco-dorsal neuro-
include the axillary vein, the long thoracic nerve and the vascular bundle. The axillary vein is not
thoraco-dorsal neuro-vascular bundle (Figure-2). The axilla skeletonized, leaving a layer of fascia
with it, in an attempt to prevent edema of
the arm.
is closed with a suction drain in-situ using interrupted or sub-cuticular sutures, and a compression
dressing applied.

Complications of Axillary Node Dissection

The axillary component of breast cancer surgery is responsible for the majority of post-operative
complications, and minor problems are frequent. Seromas are commonly seen (in up to 30% of
patients), particularly if the axillary drain was removed prematurely. These are managed by aspiration,
performed in the outpatient clinic. Long term complications include numbness over the medial part of
the arm, occurring if the inter-costo-brachial nerve was sacrificed.

The most feared and potentially disabling complications include upper limb lymphedema and
recurrent cellulitis. The incidence of lymphedema contrasts between 7-60% according to the methods
used to assess the arm and the interval between surgery and follow-up. Most recent studies have
reported that, after axillary dissection or axillary irradiation, the incidence of lymphedema is 15-20%;
and that this complication occurs more frequently if the patient received both surgery and irradiation.A
rare sequel of lymphedema is upper extremity angiosarcoma, known as ‘‘Stewart-Treves syndrome’’.
The type of ALND and use of axillary irradiation are the prime factors associated with the
lymphedema formation. Other minor factors include obesity, older patient and infection. Lymphedema
may even manifest years after the operation. Patients should always be advised to avoid arm swelling
and infection by taking precautions not to suffer cuts and scrapes on the operated side, to avoid
injections, blood-pressure monitoring, and IV sampling/access, to avoid constricting clothing and
jewellery, etc. In a study conducted by Warmuth in 1998, of a survey of 330 patients who were
disease-free 2-5 years after surgery for early-stage breast cancer, 35% reported numbness, 30%
reported pain, 15% reported arm swelling, and 8% reported limitation of arm movement.
However,most patients had mild symptoms, not interfering significantly with daily activity.

Summary

Management of the axilla is a fundamental aspect of treating a patient with invasive breast cancer.
Optimal management of the axilla in breast cancer patients has evolved greatly during the last century
and particularly the last two decades, and is continuously undergoing refinement. Today, staging of
the axilla is dominated by SLNB, which is now practiced all across the developed world, usually with
the dual localisation technique; and is rapidly gaining prominence in developing nations such as India.
Other procedures for axillary staging, as well as therapeutic procedures need to be carefully assessed
with respect to individual risk and tailored to patient preference. A custom-made methodology
integrating the variety of options on the basis of risk and cost-benefit ratio, together with the choice of
the patient, will undoubtedly prove to be the most ideal practice. In today’s practice, ALND is indicated
in patients with clinically (including radiologically) enlarged axillary nodes, in those with metastatic
SLN or detection of metastatic nodes on lymph node sampling, and where ever SLN biopsy is not
available or a SLN study has failed to detect the SLN. However, there are currently ongoing studies
that challenge even these indications for ALND. Whenever required, levels I & II axillary nodes are
routinely dissected out along with all fibro-fatty and lymphatic tissue of the axilla. A minimum of 16
lymph nodes need to be examined by the pathologist for optimal axillary staging. In presence of
enlarged nodes in level III, and in patients with bulky levels II nodes, a complete level III dissection is
also performed. Various complications such as seroma, lymphedema and cellulitis can occur post-
operatively and patient education for their prevention and treatment is paramount to their
management.

REFERENCES
1. Ciesl L et al, Alternative sites of injection for sentinel lymph node biopsy in breast cancer, ANZ J Surg 2003;
73: 600–4.
2. Chagpar A, Martin RC 3rd, Chao C, Wong SL, Edwards MJ, Tuttle T, McMasters KM. Arch Surg. 2004
Jun;139(6):614-8; discussion 618-20.
3. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al: A nomogram for predicting the likelihood of additional nodal
metastases in breast cancer patients with a positive sentinel node biopsy. Ann SurgOncol 10:1140-1151, 2003
4. Giuliano AE: Z0011: A randomized trial of axillary node dissection in women with clinical T1 or T2 N0 M0 breast
cancer who have a positive sentinel node. 2003.
5. Warmuth MA, Bowen G, Prosnitz LR et al. Complications of axillary lymph node dissection for carcinoma of the
breast: a report based on a patient survey. Cancer 1998; 83:1362-8.
6. John R Benson, G QuercidellaRovere, and the Axilla Management Consensus Group,Lancet Oncol 2007; 8: 331–
48
7. Giuliano AE, Morrow M, Duggal S, Julian TB. Should ACOSOG Z0011 change practice with respect to axillary
lymph node dissection for a positive sentinel lymph node biopsy in breast cancer? ClinExp Metastasis. 2012
Oct;29(7):687-92. Epub 2012 Aug 29.
8. Galimberti V, Cole BF, Zurrida S, et al. [S3-1] Update of International Breast Cancer Study Group Trial 23-01 To
Compare Axillary Dissection Versus No Axillary Dissection in Patients with Clinically Node Negative Breast
Cancer and Micrometastases in the Sentinel Node. Lancet Oncology 2013 Jun;14(7):e254.
9. Chung MH, Ye W, Giuliano AE, Role for sentinel lymph node dissection in the management of large (>or = 5 cm)
invasive breast cancer. Ann SurgOncol. 2001;8(9):688
10. Cody HS. Axillary Dissection for Breast Cancer. Operatice Tech in General Surg 2006;1524-1540
11. Newman LA, Mamounas EP. Review of breast cnacer trials conducted by the national surgical adjuvant breast
project. Surg Clin N Am. 2007;87:279-305.
12. Pegolo E, Puppin C, Gerometta A, Damante G, Puglisi F, Di Loreto C. One-step nucleic acid amplification (OSNA)
for intraoperative evaluation of sentinel lymph node status in breast cancer: a comparative study between CK19
protein expression and CK19 mRNA level in primary tumors and lymph node metastasis. Virchows Arch. 2013
Jul;463(1):7-15
13. Jack D. O'Sullivan ; Paul R. Hoy ; Harvey N. Rutt, Spectral imaging as a potential tool for optical sentinel lymph
node biopsies, Clinical and Biomedical Spectroscopy and Imaging II, 80872J (June 15, 2011)
14. Bensen JR et al, Management of the axilla in women with breast cancerThe Breast (2007) 16, 130–136
15. Cserni G. What is a positive sentinel lymph node in a breast cancer patient? A practical approach. The Breast
(2007) 16, 152–160.
16. J E A Somner, J M J Dixon, J S J Thomas, Node retrieval in axillary lymph node dissections: recommendations
for minimum numbers to be confident about node negative status; J ClinPathol. 2004 August; 57(8): 845–848
th
17. Diseases of the Breast by Harris PJ, 4 edition 2009; Lippincott Williams & Wilkins
th
18. Sabiston textbook of Surgery, 19 Edition 2012, Saunders.
 Diagnostic Evaluation of a Breast Lump
PN Agarwal, Varun Jain

Introduction

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the
leading cause of cancer death among women. Global cancer statistics show that breast cancer is the
most frequently diagnosed cancer and the leading cause of cancer death among females, accounting
for 23 percent of total cancer cases and 14 percent of cancer deaths. 1 Breast cancer is now also the
leading cause of cancer death among females in economically developing countries. Despite
increasing incidence rates, annual mortality rates from breast cancer have decreased over the last
decade (1.8 percent per year from 1998 to 2007).2

A significant portion of the decline in mortality is attributable to the impact of screening

mammography, which permits diagnosis at an earlier stage of disease. Preinvasive breast cancer
now accounts for 25 to 30 percent of all newly diagnosed, mammographically detected breast
cancers. The majority of breast cancers are diagnosed as a result of an abnormal mammogram, but
not all mammographic findings represent cancer. Women who have an abnormal screening
mammogram often need further diagnostic evaluation with magnification views, spot compression
views and/or targeted ultrasonography to determine the need for tissue sampling or biopsy.
Additionally, not all cancers are detectable on mammography. A clinically suspicious mass should
also be biopsied, regardless of imaging findings, as about 15 percent of such lesions can be
mammographically occult.3 The goal of the initial biopsy is to obtain sufficient diagnostic material
using the least invasive approach and to avoid surgical excision of benign lesions.

Importance of Multidisciplinary Care

A suspicion of breast cancer requires that care be coordinated among clinicians in several specialties.
An integrated approach with breast imagers and breast surgeons can minimize unnecessary biopsies
and expedite diagnosis for the woman who receives a diagnosis of breast cancer. Similarly, once the
diagnosis of cancer is made, multidisciplinary coordination among breast and reconstructive
surgeons, radiation and medical oncologists, radiologists and pathologists facilitates treatment
planning and streamlines patient care.

Approach

Breast cancer evaluation should be an ordered inquiry that begins with symptoms and a general
clinical history. This is followed by a sequence that has become formalized as triple assessment,
which includes the following components:
 Clinical examination
 Imaging (usually mammography, ultrasonography, or both)
 Needle biopsy

This approach naturally lends itself to a gradually increasing degree of invasiveness, so that a
diagnosis can be obtained with the minimum degree of invasiveness and, consequently, the minimum
amount of discomfort to the patient. Because the more invasive investigations also tend to be the
most expensive, this approach is usually the most economical.

The aims of evaluation of a breast lesion are to judge whether surgery is required and, if so, to plan
the most appropriate surgery. The ultimate goal of surgery is to achieve the most appropriate degree
of breast conservation while minimizing the need for reoperation.

Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient
or healthcare provider. Mammographic features suggestive of malignancy include asymmetry,
microcalcifications, and a mass or architectural distortion. If any of these features are identified,
diagnostic mammography along with breast ultrasonography should be performed before a biopsy is
obtained. In certain cases, breast magnetic resonance imaging (MRI) may be warranted.
History

Many early breast carcinomas are asymptomatic, particularly if they were discovered during a breast-
screening program. Larger tumors may present as a painless mass. Pain or discomfort is not usually
a symptom of breast cancer; only 5% of patients with a malignant mass present with breast pain.
Often, the purpose of the history is not diagnosis but risk assessment. A family history of breast
cancer in a first-degree relative is the most widely recognized breast cancer risk factor.

Physical Examination

If the patient has not noticed a lump, then signs and

symptoms indicating the possible presence of breast
cancer may include the following:
 Change in breast size or shape
 Skin dimpling or skin changes (eg, thickening,
swelling, or redness)
 Recent nipple inversion or skin change or other
nipple abnormalities (eg, ulceration, retraction,
or spontaneous bloody discharge)
 Nipple discharge, particularly if bloodstained
 Axillary lump

To detect subtle changes in breast contour and skin

tethering, the examination must include an assessment
of the breasts with the patient upright with arms raised,
arms by the side, leaning forward. The following
findings should raise concern:
 Lump or contour change
 Skin tethering
 Nipple inversion
 Dilated veins
 Ulceration
 Mammary Paget disease
 Edema or peau d’orange

The nature of palpable lumps is often difficult to

determine clinically, but the following features should
raise concern:
 Hardness
 Irregularity
 Focal nodularity
 Asymmetry with the other breast
 Fixation to skin or muscle (assess fixation to
muscle by moving the lump in the line of the
pectoral muscle fibers with the patient bracing
her arms against her hips)

A complete examination includes assessment of the

axillae and supraclavicular fossae, examination of the chest
and sites of skeletal pain, and abdominal and neurologic
examinations. The clinician should be alert to symptoms of
metastatic spread, such as the following:
 Breathing difficulties
 Bone pain
 Symptoms of hypercalcemia
 Abdominal distention
 Jaundice
 Localizing neurologic signs

Brain metastasis on CECT

  Altered cognitive function
 Headache

Imaging

Mammogram
4,5
The majority of breast cancers are associated with abnormal mammographic findings. As an
example, in the Breast Cancer Detection Demonstration Project (BCDDP), fewer than 10 percent of
cancers were detected solely by physical examination and over 90 percent were identified
mammographically.4

If an abnormality is found at mammographic screening,

supplemental mammographic views and possibly ultrasound
should be used for further characterization. A variety of
mammographic techniques, including spot compression and
magnification views and varied angled views, may characterize
a lesion more precisely prior to making a final recommendation
for management.

Some of the most aggressive cancers appear between normal

screening mammograms and are therefore termed interval
Lung metastasis on chest x-
cancers.6 Younger women may present with large tumors prior
to the age at which screening is usually recommended. ray
Accordingly, when women present with a suspicious new mass,
diagnostic mammograms should be part of the initial workup,
despite young age or having had a negative routine screening
mammogram.

Diagnostic mammography is associated with higher sensitivity

but lower specificity as compared to screening mammography.
In one prospective study of women with signs or symptoms of
breast cancer, 15 percent (6279 of 41,427) of diagnostic
mammograms were abnormal.3 The sensitivity and specificity of
diagnostic mammograms declined with breast density, younger
age, and mammographic examination.

BI-RADS diagnostic categories — The radiologist

summarizes the mammographic findings using the American
College of Radiology (ACR) BI-RADS (Breast Imaging
Reporting and Data System) final diagnostic assessment Bone metastasis on bone scan
categories, which indicate the relative likelihood of a normal,
benign, or malignant diagnosis.7

The BI-RADS final assessment categories standardize both the reporting of mammographic findings
and the recommendations for further management (ie, routine screening, short interval follow-up, or
biopsy). Assessments are either incomplete (category 0) or
final assessment categories (categories 1 through 6).

If a mammogram is assigned category 0, additional evaluation

is required for further characterization which may include
additional mammographic views and or ultrasound, and rarely,
magnetic resonance imaging (MRI). A BI-RADS designation of
4c or 5 should alert the pathologist that a malignant diagnosis
is strongly suspected and that further evaluation of the
specimen (and possible rebiopsy) is needed if the biopsy is
initially interpreted as benign.

Mammographic features of breast cancer — There are two

general categories of mammographic findings suggestive of a
breast cancer: soft tissue masses and clustered microcalcifications.
Soft tissue mass/architectural distortion — The most specific mammographic feature of
malignancy is a spiculated soft tissue mass; nearly 90 percent of these lesions represent invasive
cancer
Approximately one-third of noncalcified cancers appear as spiculated masses, 25 percent as
irregularly outlined masses, 25 percent as less specific round, oval or lobulated masses, less than 10
percent as well-defined round, oval, or lobulated masses, and 5 percent as areas of architectural
8
distortion of dense tissue without an obvious mass.
The positive predictive value for malignancy of well-defined solid masses identified by ultrasound with
benign imaging features is between 0 and 7 percent, and biopsy or short-term (three to six months)
follow-up is considered appropriate management.9

Clustered microcalcifications — Clustered

microcalcifications are calcium particles of
various size and shape measuring between 0.1
to 1 mm in diameter and numbering more than
four to five per cubic centimeter.
Microcalcifications are seen in approximately
60 percent of cancers detected
mammographically. Histologically, these
represent intraductal calcifications in areas of
necrotic tumor or calcifications within mucin-
secreting tumors such as the cribriform or
micropapillary subtype of intraductal cancer.
Despite the association of microcalcifications
with ductal carcinoma in situ (DCIS),
mammographic appearance alone cannot
differentiate between purely intraductal and
invasive ductal breast cancers; there is no
mammographic correlate of basement
membrane invasion.10 One-third of invasive carcinomas are associated with microcalcifications, with
or without a soft tissue mass, and 10 percent of intraductal cancers present as a soft tissue mass
without microcalcifications.5

Mammographic findings such as masses and calcifications can be stratified by suspicion for
malignancy. Some experts believe that the single BI-RADS 4 classification does not adequately
communicate the risk of cancer to doctors and the BI-RADS 4a, 4b, and 4c categories are helpful in
alerting the referring physicians, the pathologists, and surgeons to the underlying risk of malignancy. 11
Low risk calcifications are much more likely to be benign.
 4A: low suspicion for malignancy
 4B: intermediate suspicion of malignancy
 4C: moderate concern, but not classic for malignancy

Assessing the extent of disease — Mammographic assessment of the extent of DCIS and early
invasive carcinoma begins during diagnostic mammography and continues through the biopsy,
specimen management, and the postexcision mammogram. Mammography of both breasts is
particularly important in the patient with DCIS or invasive cancer who is considering breast
conservation. Preoperative diagnostic mammography can help to define the extent of disease and
may identify multifocal or multicentric cancer that could preclude breast conservation or signal a
potential difficulty in achieving clear surgical margins. Multifocal disease is usually defined as
involvement of several areas within a breast quadrant, probably representing disease along an entire
duct. In contrast, multicentric disease involves multiple areas within different quadrants, probably
representing involvement of multiple ducts.

Postoperative mammograms to look for residual calcifications after surgical resection should be
considered when the microcalcifications are not clearly or completely documented on the specimen
12
radiograph or when margins are close or positive. If a re-excision is to be recommended on the
basis of residual calcifications, care should be taken to ensure that the calcifications are associated
with malignancy on histopathology and not benign tissue.
A significant limitation of mammographic assessment of disease extent is the obscuring of the borders
or extent of the primary tumor by dense overlying tissue. Dense breasts can limit the sensitivity of
13
mammography both for detection of breast cancers and for delineating disease extent. In this
setting, contrast-enhanced breast magnetic resonance imaging (MRI) may complement
mammographic staging. If the clinical extent of disease is larger than what can be appreciated by
mammography, MRI may be considered.

Mammographic assessment of tumor size for the staging of multifocal disease presents a unique
dilemma. Most staging classifications require that the largest tumor mass be utilized for T staging,
even in cases where multifocal disease is suspected. However, others suggest that the total surface
area, volume, or aggregate measurements are a better indicator of prognosis. 14

For invasive cancers that are contiguous to the chest wall and not completely included on
mammographic projections, ancillary imaging techniques such as MRI may be necessary to assess
posterior tumor extension and pectoralis fascia or muscle involvement if that will determine a change
in surgical approach or the use of neoadjuvant therapy.

Significance of intramammary lymph nodes — Intramammary lymph nodes are detected in 1 to 28

15
percent of patients with breast cancer. Benign nodes can often be distinguished from metastatic or
infiltrated intramammary lymph nodes by their mammographic or sonographic appearance, but
definitive assessment often requires histopathologic study. The presence of intramammary lymph
node metastases appears to confer a worse prognosis, both in women who otherwise have stage I
14
breast cancer based upon tumor size and axillary nodal status and in those with stage II disease.
Isolated intramammary lymph node metastases are considered to represent stage II disease, even if
the axillary nodes are uninvolved.

Ultrasonography
Ultrasound can be used to differentiate between solid and cystic breast
masses that are palpable or detected mammographically. In addition,
ultrasound evaluation of the axilla can be used to detect lymph nodes
that are suspicious for axillary metastases. Ultrasound provides
guidance for interventional procedures of suspicious areas in the
breast or axilla.

Breast ultrasound — Ultrasound (US) examination of the breast is an

important diagnostic adjunct to mammography. In patients suspected
of having a breast cancer, breast USG is most useful in the following
circumstances:
 To further characterize a mammographically detected mass or an area of architectural
distortion. Breast US can help to characterize solid masses as either benign or malignant. In
one report, the sensitivity of US for malignancy was 98.4 percent, and the negative predictive
value 99.5 percent.16
 To identify a cystic mass. Simple cysts need no further intervention because the risk of cancer
is very low. Indeterminate cysts can be aspirated under US guidance. The presence of an
intracystic mass should prompt a fine needle aspiration (FNA) or core biopsy of the mass.
 To further characterize a lesion when a mass detected on clinical breast examination cannot
be seen clearly on mammogram (often in women with dense breasts/ younger than 35 yrs).
 To determine whether a mammographically suspicious lesion can be visualized and therefore
sampled by US-guided biopsy.
 To measure and clip a lesion prior to neoadjuvant chemotherapy. Careful anatomic
localization is critical to ensure that the surgeon can localize the area of tumor after
neoadjuvant therapy.

Axillary ultrasound — For women with clinically suspicious lymph nodes, preoperative axillary US with
fine needle aspiration or core biopsy of suspicious areas provides a means to identify patients who
have positive nodes. This information may be used to guide future additional surgery, radiation, or
systemic therapy.
Breast MRI / MR Mammogram
Nearly all invasive breast carcinomas enhance on
17
gadolinium contrast-enhanced MRI. The sensitivity of
breast MRI for breast carcinomas is between 88 and 100
percent.18 However, a major disadvantage is the limited
specificity of MRI due to enhancement of benign breast
lesions.17

Assessment of ipsilateral disease with breast MRI — MRI is

more sensitive than mammography, ultrasound, or physical
examination and identifies additional ipsilateral disease in
about 16 percent of women with a known breast cancer.19

Because MRI is so sensitive, it was assumed that preoperative MRI would estimate the extent of
disease more accurately than conventional imaging, thereby improving surgical planning (eg,
prompting a change to mastectomy when breast conserving therapy had been previously considered
and enabling surgeons to better obtain clean margins in breast conserving surgery. However,
available data has shown that preoperative breast MRI has not improved outcomes, overestimates
20
the extent of disease, and has overall limited value.

Assessment of contralateral disease with breast MRI — MRI imaging of the contralateral breast
identifies a suspicious, clinically occult finding in 9 to 12 percent of women with a unilateral breast
cancer, but cannot distinguish between benign and malignant lesions. In general, a synchronous
clinically and mammographically inapparent malignancy will be found in 3 to 5 percent of cases,
approximately one-half of which are invasive cancer, and the remainder, intraductal cancer, and
results in about a 12 percent chance of biopsy.21

As an example, in a meta-analysis of 22 studies (3253 women) of women with newly diagnosed

breast cancer, the pooled estimate for detecting a suspicious abnormality that was occult on
conventional imaging was 9.3 percent.22 The incremental cancer detection rate with MRI was only 4
percent because more than half of the suspicious abnormalities detected by MRI alone proved to be
benign.

The clinical significance, especially the survival benefit, of detecting these cancers has not been
addressed. As is the case with MRI of the affected breast, the finding of a contralateral malignancy on
breast MRI may lead to overtreatment. Many of these subclinical cancers are effectively treated with
the systemic therapy used for the treatment of the initial cancer. As an example, in the Early Breast
Cancer Trialists Collaborative Group (EBCTCG) overview analysis, the incidence of contralateral
breast cancer was reduced by 50 percent in patients receiving five years of adjuvant tamoxifen, and
by 20 percent in patients receiving adjuvant chemotherapy.23

Finally, the detection of these contralateral cancers must be weighed against the added time and
additional costs associated with MRI and MRI-guided biopsy. Off MRI-detected lesions recommended
24
for biopsy, only about one in five prove to be malignant.

For all of these reasons, the role of MRI to assess the contralateral breast is controversial and cannot
be routinely recommended for the majority of women with a newly diagnosed breast cancer.
There are some clinical scenarios where breast MRI might be considered prior to therapy to assess
contralateral disease.
High risk women — A contralateral breast MRI is reasonable for women with newly diagnosed breast
cancer who are considered at very high risk for contralateral breast cancer based on the following
criteria:
 The patient is a known carrier of a breast cancer gene mutation in BRCA 1 or BRCA 2
(hereditary breast and ovarian cancer syndrome).
 The patient is a first-degree relative of a known BRCA 1 or BRCA 2 mutation carrier.
 The patient has an estimated lifetime risk of breast cancer of 20 percent or higher, as
estimated using the BRCA-PRO model, used to identify women for breast cancer genetic
testing .
 The patient was previously treated with radiation to the chest wall .
  The patient has a personal history or a first-degree relative with Li-Fraumeni syndrome or one
of the PTEN hamartoma tumor syndromes such as Cowden syndrome.

Positron Emission Tomography

18
Using a wide range of labelled metabolites (eg, fluorinated glucose [ FDG]), positron emission
tomography (PET) can detect changes in metabolic activity, vascularization, oxygen consumption,
and tumor receptor status.

When PET is combined with computed tomography (CT) to assist in anatomic localization (PET-CT),
scans can identify axillary and nonaxillary (eg, internal mammary or supraclavicular) lymph node
metastasis for the purposes of staging locally advanced and inflammatory breast cancer before
initiation of neoadjuvant therapy and restaging high-risk patients for local or distant recurrences.

Role of PET - CT

Primary tumour
The ability of PET to detect breast cancer depends on the tumor's size and histology. The sensitivity
of PET has been reported to be 68% for small (< 2 cm) tumors and 92% for larger (2-5 cm) tumors ,
and its reported overall accuracy for detecting in situ carcinomas is low (sensitivity: 2-25%).25 The
major limitation of PET or PET/CT for breast imaging is its poor detection rate for small breast
carcinomas and non-invasive breast cancers.

However, PET/CT has a role to play in a selected group of patients, such as those with dense breasts
or with implants, for determining tumor multiplicity, for localizing the primary tumor in those patients
with metastases of a breast origin when the mammography is indeterminate.26

PET CT showing Breast primary along with Liver Metastasis

Regional Lymph Node Metastasis

Axillary lymph node metastasis is an important factor when determining the prognosis of patients.
Breast cancer patients with four or more involved axillary lymph nodes have a significantly higher risk
of recurrence . The sensitivity and specificity of axillary PET imaging in breast cancer patient have
been reported as 79-94% and 86-92%, respectively.26 PET/CT can accurately localize and
differentiate the metastatic and reactive lymph nodes when CT shows multiple enlarged lymph nodes
in the axilla.

The metastasis to the internal mammary or mediastinal lymph nodes in breast cancer patients is often
clinically occult. The prevalence of abnormal findings for the internal mammary or mediastinal lymph
nodes by PET was about twice than of conventional CT in those patients with recurrent or metastatic
27
breast cancer.
Distant Metastasis
Distant metastases from breast cancer are frequently found in the lungs, liver and bones. One
advantage of whole-body PET imaging over conventional imaging modalities such as chest films,
bone scanning, and abdominal ultrasound is its ability to detect metastasis at different sites and
organs during a single examination. Moon et al. found that whole-body PET imaging had high
diagnostic accuracy for patients with suspected recurrent or metastatic breast carcinoma. 28 Based on
the number of lesions, its sensitivity for detecting distant metastasis was 85% and its specificity was
79%.
Cook et al. found that PET was superior to bone scintigraphy for detecting osteolytic breast cancer
metastases.29

PET-CT showing primary, axillary and distant metastasis

Treatment Monitoring
To downstage primary tumors prior to surgery and to abolish occult distant metastases, neoadjuvant
chemotherapy is now being increasingly used to manage patients with large and locally advanced
breast cancer. Moreover, several studies have demonstrated that patients with unresponsive tumor
may achieve improved survival by administering alternative chemotherapy and/or prolonged courses
of chemotherapy. Considering the side effects of chemotherapy, there is a need to quickly identify the
non-responding patients early in their treatment.

At present, the anatomical imaging modalities are commonly used to evaluate the response to
treatment by evaluating the changes of the tumor's size. Nevertheless, sequential measurement of
tumor size frequently does not allow the determination of early response. The effect of PET for
evaluating the response to treatment has already been demonstrated for different types of neoplasm,
including breast cancer. In a study by Smith et al, the mean reduction in FDG uptake after the first
cycle of chemotherapy was significantly higher in the lesions that showed a partial, complete
macroscopic, or complete microscopic response than that of the non-responsive lesions, as
determined by histopathological examinations.30 Rose et al. have reported that after a single cycle of
chemotherapy, PET predicted the complete pathological response with a sensitivity of 90% and
specificity of 74%, and by using a decrease of FDG uptake at the threshold of < 55%, as compared
with the baseline scan, all the responders were correctly identified after the first treatment course
31
(100% sensitivity and 85% specificity).

PET/CT may also play a role in radiation therapy planning by providing an accurate estimate of the
extent of tumor.

Recurrence
Detecting early recurrence has an important survival benefit because it prompts clinical consideration
for administering different therapies. However, it is difficult to differentiate true recurrence from
postsurgical sequelae and radiation sequelae with using just the conventional imaging modalities.
Locoregional recurrences predominately affect the breast, skin, the axillary and supraclavicular
nodes, and the chest wall .
Grahek et al. studied 134 patients with suspected recurrence and they found that the sensitivity and
specificity of PET for detecting recurrence were 84% and 78%, respectively, whereas the sensitivities
and specificities of the conventional imaging modalities were 63% and 61%, respectively. 32 PET is
considered to be highly effective for evaluating patients with suspected recurrent breast cancer, and it
surpasses the other conventional imaging modalities in terms of whole-body evaluation. The CT data
from a PET/CT examination allows the appropriate anatomical localization of foci of FDG uptake.
In a single PET study, the local tumor can be characterized, and remote sites can be assessed.
Currently, F-18 FDG PET is mainly used in evaluating breast cancer after treatment, in assessing the
effectiveness of treatment such as chemotherapy, in restaging the disease after therapy, and in
looking for locoregional recurrence.33
It plays an important role in differentiating benign from malignant breast disease.It is sensitive for
detecting breast lesions that are larger than 1 cm, and, while not routinely used for screening,
incidental lesions may be noted.34

Biopsy/ Histology

In the patient with a suspicious mammographic abnormality or

palpable breast mass, the obligatory diagnostic technique is biopsy.
Surgical biopsy should not be utilized as a diagnostic tool unless
percutaneous palpation-guided or image-guided biopsy is not
35
feasible.

Biopsy Techniques for Breast Cancer

TECHNIQUE ADVANTAGES DISADVANTAGES
Fine needle Rapid, painless, inexpensive. Does not distinguish invasive from in-situ
aspiration No incision prior to selection of cancer.
cytology local therapy. Markers (ER, PR, Her-2) not routinely
available.
Requires experienced cytopathologist.
False negatives and insufficient specimens
occur.
Core cutting Rapid, relatively painless, False- negative results.
needle biopsy inexpensive. Incomplete lesion characterization can
No incision. occur.
Can be read by any pathologist.
markers routinely available.
Excisional False-negative results rare. Expensive, more painful.
biopsy Complete histology before Creates an incision to be incorporated into
treatment decisions. definitive surgery.
May serve as definitive Unnecessary surgery with potential for
lumpectomy. cosmetic deformity in patients with benign
abnormalities.

Prognostic and Predictive Factors

A prognostic factor is defined as a measurement taken at the time of diagnosis or surgery that is
associated with outcome (e.g., overall survival, disease-free survival, or local control). Prognostic
factors generally refer to a patient's anticipated outcome at the time of diagnosis in the absence of
systemic therapy; however, they are sometimes useful to estimate outcome following a specific
systemic therapy.

A predictive factor is a measurement that predicts response or lack of response to a specific

treatment.

In practice, some factors are both prognostic and predictive. Establishing the validity of a prognostic
factor (biomarker) requires that the factor have biological relevance, that the methods for determining
the factor be validated and reproducible (i.e., confirmed in a second independent data set) with
optimal cut off values, and that the factor be studied with adequate sample sizes without population
bias. Guidelines for the evaluation and reporting of such biomarkers have been established.

Axillary lymph node involvement

The extent of axillary lymph node involvement by breast cancer is the most established and reliable
prognostic factor for subsequent metastatic disease and survival. This is not surprising since it
reflects evidence of actual metastatic potential.

Tumour Size and Histological Grade

Tumor size and histologic grading also have established prognostic significance. Tumor size is
typically given as the microscopic size of the invasive cancer. Histologic grade is best determined by
an established methodology, such as the Nottingham combined histologic grading system.

ER/PR Receptor Status

Estrogen and progesterone receptor expression are the most important and useful predictive factors
currently available. Patients with invasive breast cancer whose tumors are totally lacking in ER and
PR do not derive benefit from hormonal treatment either in the metastatic or adjuvant setting. Current
assays for ER and PR are performed using IHC techniques, which have the advantages of not being
confounded by endogenous estrogens. Today ER/PR status is critical to current management
guidelines. Although there are convincing data that patients whose tumors have even as few as 1% of
cells staining positively for hormone receptors derive benefit from adjuvant hormonal therapy, it is still
controversial whether laboratories can reproducibly report the percentage of positive ER and PR
36
staining. ER/PR status also has some prognostic value. Patients with ER/PR positive tumors have
improved disease-free survival compared to similarly staged patients with ER/PR negative tumors at 5
years, but this difference is less apparent at 10 years.

Age
Patient age has also consistently been shown to be a prognostic factor. Very young breast cancer
patients (35 years or less) have a poorer prognosis than older patients. The cancers in these patients
tend to be higher grade, less often ER/PR positive, and more likely to have lymphovascular invasion
than cancers in older patients. It is not clear whether these differences in pathologic features fully
explain the worse outcome in very young patients.37

Her-2/neu receptor
Approximately 20% of breast cancer patients have HER-2/neu gene amplification, which results in
glycoprotein overexpression. Approximately 5% of patients have overexpression without gene
amplification, but otherwise gene amplification and expression are highly correlated. HER-2
amplification or overexpression has been associated with higher tumor grade, lack of ER receptors,
higher levels of tumor proliferation, and poorer prognosis. HER-2 status is the major predictive factor
for benefit from trastuzumab (Herceptin). There is some evidence that suggests that HER-2 status is
predictive for benefit from anthracycline-based chemotherapy, although this relationship is not certain,
particularly with the availability of trastuzumab.38

Lymphovascular invasion
Involvement of lymphovascular spaces is associated with a greater likelihood of lymph node
metastases and is an independent adverse prognostic factor in both node-negative and positive
patients.

Other Factors
Numerous other prognostic and predictive factors have been evaluated in patients with early breast
cancer, but have not been widely adopted in routine clinical use. These include markers of
proliferation, such as S-phase fraction, the percentage of cells labeling with thymidine or
bromodeoxyuridine or cellular expression of Ki-67 or MIB-1 (which measure the percentage of cells in
the G1 phase of the cell cycle), and mitotic index.
Ki67 is considered to be a protein associated with cell cycle activity and shows a good correlation with
the growth fraction and has been proposed as a prognostic or predictive marker in breast cancer. The
clinical significance is that it is a promising predictor of bone and liver metastasis for those affected by
breast cancer.
Molecular and Genomic Factors
Gene expression profiling has been used to stratify tumors as having good-risk or poor-risk prognostic
signatures. One of these, MammaPrint (Agendia Br, Amsterdam, The Netherlands), a 70-gene
signature developed in the Netherlands, was given FDA approval in February 2007. Since then,
several additional poor prognosis gene expression profiles have been developed using different
phenotypic characteristics of aggressive cancer biology, such as wound-response and hypoxia-
response.
One molecular test that has been shown to be of use clinically is the Oncotype Dx recurrence score.
The recurrence score is based on a quantitative assessment of 21 genes thought to be relevant to
breast cancer biology, including hormone receptors and HER-2, among others.
These have been shown to be relevant in deciding management in node negative tumours.

Epigenetics
In addition to inherited mutations, sporadic breast cancers exhibit epigenetic mechanisms for
inactivating several important DNA repair genes including BRCA1, ATM, CHK2, and P53. Epigenetics
describes chromatin and DNA modifications that alter gene expression but do not involve changes in
39
the underlying DNA sequence. In cancer, the main epigenetic mechanisms underlying abnormal
gene expression include aberrant CpG-island-promoter methylation of specific TSGs, global changes
in genomic DNA methylation, and alterations in histone modification (deacetylation and methylation).
39
These abnormalities can be reversed by inhibitors of both DNA methyltransferases and HDACs.
This possibility is being explored clinically in an ongoing phase II trial of a new generation HDAC
inhibitor, vorinostat.

Guidelines for Investigation and Management of Invasive Breast Cancer

The evaluation of the newly diagnosed breast cancer patient begins with a determination of
operability. The presence of distant metastases at diagnosis has traditionally been considered a
contraindication to surgery. Some recent studies have suggested a survival benefit for surgery of the
40
primary tumor in the patient presenting with metastatic disease , but systemic therapy remains the
initial therapeutic approach. Extensive evaluations to look for metastatic disease are not warranted in
asymptomatic patients with stage I and II cancer. A review of the detection rate of staging studies in
women with stage I cancer reported a 0.5% incidence of metastases found on bone scan and a 0.1%
incidence on chest x-ray. For stage II disease these figures were 2.4% and 0.2%, respectively.41

The 2012 NCCN guidelines recommend the following laboratory studies for all asymptomatic women
with early-stage breast cancer (stages I and II):
 Complete blood count (CBC) with differential
 Liver function tests (LFTs) and alkaline phosphatise

In addition imaging studies (eg, chest x-ray, chest CT, or CT of the abdomen and pelvis, bone scan
etc) can be considered for women with stage III (locally advanced or inflammatory breast cancer) or
symptomatic disease. Tumor markers (carcinoembryonic antigen [CEA] and CA15.3 or CA27.29) may
also be obtained in these patients.

In patients with stage III disease, occult metastases are more frequent, and staging studies are
recommended by most organizations.41

The detection rate of occult metastases by computed tomography (CT) scans and positron emission
tomography (PET) scans is also low, and the routine use of these tests is neither medically
appropriate nor cost effective.
The major roles for PET/CT in breast cancer are detecting and localizing metastasis, monitoring the
response to treatment and early detection of recurrence. Yet the limitation of PET/CT for breast
imaging is its poor detection rate for small breast carcinomas.

Patients with T4 tumors and those with N2 nodal disease are also not candidates for surgery as the
first therapeutic approach and should be investigated for distant metastasis and treated with systemic
therapy initially. In the patient with clinical stage I, II, and T3N1 disease, the initial management is
usually surgical. In these patients, the evaluation consists of a determination of their suitability for
breast-conserving therapy (using mammogram/MRI) and a discussion of the options of mastectomy
with and without reconstruction. Initial systemic therapy may be used to shrink the primary tumor to
allow BCT in a woman who would otherwise require mastectomy but is not mandatory, as it is for
women with locally advanced and inflammatory carcinoma.42

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11. Sanders MA, Roland L, Sahoo S. Clinical implications of subcategorizing BI-RADS 4 breast lesions associated
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14. Coombs NJ, Boyages J. Multifocal and multicentric breast cancer: does each focus matter? J Clin Oncol 2005;
23:7497.
15. Shen J, Hunt KK, Mirza NQ, et al. Intramammary lymph node metastases are an independent predictor of poor
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cancer studied in IBMC 6883. J Surg Oncol 2005; 92:32.
18. Bluemke DA, Gatsonis CA, Chen MH, et al. Magnetic resonance imaging of the breast prior to biopsy. JAMA 2004;
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19. Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast
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20. Feigelson HS, James TA, Single RM, et al. Factors associated with the frequency of initial total mastectomy:
results of a multi-institutional study. J Am Coll Surg 2013; 216:966.
21. Brennan ME, Houssami N, Lord S, et al. Magnetic resonance imaging screening of the contralateral breast in
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22. Brennan ME, Houssami N, Lord S, et al. Magnetic resonance imaging screening of the contralateral breast in
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 Triage
Gulshanjit Singh

Introduction

Definition: The word triage derives from the French word meaning “to sort”. When applied in a
medical context, triage involves the initial evaluation of a casualty and the determination of the priority
and level of medical care necessary for the victim (1).The goal of triage and acute medical care is to
provide the greatest good to the greatest number.

Dominique Jean Larrey Napoleon’s chief surgeon was one the first to prioritize the need of the
wounded on a mass scale. He believed “it is necessary to always begin with the most dangerously
injured, without regard to rank or distinction (2). Since then, refinements in battlefield medicine and
military triage have continued from World War I to more recent conflicts, including Iraq. The lessons
learnt from the triage and treatment of combat casualties was slow to translate into civilian use.

Why/ where we need triage/ triage situations

Multiple casualty incident (MCI): a disaster in which patient care resources are over extended but
not over whelmed. In such situations, patients with life threatening problems and those sustaining
multiple system injuries are treated first.

Mass casualty event: a disaster in which patient care resources are over whelmed and cannot be
immediately supplemented. In such situations, the patients having the greatest chance of survival and
requiring the least expenditure of time, equipment, supplies and personnel, are treated first. Thus the
focus of medical care can no longer be on each individual and must shift to population as a whole (3).

Of all trauma patients, only 7-15% have injuries that require the facilities of a dedicated trauma center
(4).By sorting out minor injuries, triage lessens immediate burden on medical facilities.

Common Types of Triage (5)

1. ED triage: used daily to prioritize patient assessment and treatment in the emergency
department during routine functioning. Priority is given to those most in need. Resources are
not rationed.
2. Inpatient triage: applied day-to-day in a variety of medical settings, such as ICU, medical
imaging, surgery and outpatient areas, to allocate scarce resources. Priority is given to those
most in need based upon medical criteria. Resources are rarely rationed.
3. Incident triage: used in multiple casualty incidents such as bus accidents, fires, or airline
accidents to prioritize the evacuation and treatment of patients. These events place significant
stress on local resources but do not overwhelm them. Resources are rarely rationed, and
most patients receive maximal treatment
4. Military triage: used on battlefield, modern military protocols most reflect the original concept
of triage and include many of the same principles. Resources are rationed when their supply
is threatened.
5. Disaster triage: used in mass casualty incidents that overwhelm local and regional
healthcare system. Disaster triage protocols both prioritize salvageable patients for treatment
and ration resources to ensure the greatest good for the greatest number.

The principles of triage are not taught in many medical schools or in residency training. This is why
education and training assumes major importance in the care of mass casualties from any form of
disaster, in view of how different the decision-making must be if the salvage of life is to be maximized
(6).
Principles of Triage (3)

1. Do the most good for the most patients using available resources: This is the central guiding
principle that underlies all other triage principles, rules, and strategies.
2. Decision making and triage tools.
3. Triage occurs at multiple levels.
4. Know and understand the resources available.
5. Planning and rehearsal
6. Determine triage category types and documentation for triage.
7. Triage is continuous (Re-triage)

Decision Making and Triage Tools

Trauma triage decisions are usually made within a limited time frame and are based on information
that can be difficult to obtain. Physiologic and anatomic criteria, mechanism of injury, and co morbid
factors are used in the triage decision making process. Unfortunately, all these criteria have
limitations that affect their validity in certain situations. The judgment of experienced triage officer is
also a key factor in triage (18).

Commonly used trauma triage criteria (7,8,9,10,11) are:

Physiologic and Anatomic criteria

 Glasgow coma scale of 13 or less
 Systolic blood pressure of 90 or less
 Respiratory rate of 10 per minute or less, or greater than 29 per minute
 Sustained pulse rate of 120 per minute or more
 Head trauma with altered state of consciousness, hemiplegia, or uneven pupils
 Penetrating injuries of the head, neck, torso, and extremities proximal to the elbow or knee
 Chest trauma with respiratory distress or signs of shock

Pelvic fractures or amputations above the wrist or ankle

Limb Paralysis
 Two or more proximal long bone fractures
 Combination of trauma with burns
 Mechanism of injury and high energy impact
 Fall of 20 feet or more
 Patient struck by a vehicle moving 20 MPH or more
 Patient ejected from a vehicle
 Vehicle rollover with the patient unrestrained
 High speed crash (initial speed of more than 40 MPH) with 20 inches of major front end deformity,
12 inches or more deformity into the passenger compartment
 Patient was a survivor of a MVA where death occurred in the same vehicle

Other Criteria
 Age of less than 5 years old, or over 55 years old
 History of cardiac/ respiratory disease, insulin dependent diabetes, cirrhosis, or morbid obesity
 Pregnancy
 Immunosuppressed patients
 Patients with bleeding disorders, or patients on anticoagulants
 Burns of greater than 30 % of body surface area in adults, or 15 % body surface area in children
 Burns of head, hands, feet, or genital area
 Inhalation injuries
 Electrical burns
 Burns associated with multiple trauma or severe medical problems

Triage Occurs at Multiple Levels (3, 19)

1. Primary Triage :
Triage at the seen or site of the event as decisions are made regarding which patient to treat first
and the sequence in which patients will be evacuated. It is often performed by paramedics and
based on very simple criteria that can be rapidly assessed.
2. Secondary Triage :
Triage just outside the hospital to determine whether patients will be transported within the facility
(emergency department, operating room, ICU, ward or clinic). It is typically performed by
emergency physicians or surgeons. Here treatment decisions may be more accurate than in the
field, but they will remain limited until further information about the event or predicted outcomes
can be ascertained. The goal is to provide critical care initial ABC (airway, breathing, circulation)
interventions rather than full resuscitation.
3. Tertiary Triage :
Triage in preoperative area as decisions are made regarding the sequence in which patients are
taken for operation. The third stage of triage is of primary relevance to the critical care physicians
because the situation and the patient’s characteristics call for definitive critical care management.

Triage areas (12)

For efficient triage there is a need to bring together all those injured to a secure location like school
buildings, play ground, etc. A good water supply and ease of access are important. Areas should then
be reserved for holding patients, emergency treatment and decontamination (in the event of discharge
of hazardous materials). An area should also be kept as a morgue, preferably a little away from
holding and treatment areas.
Practical triage (12)
Emergency life saving measures should proceed alongside triage and help the decision making
process. The assessment and restoration of airway, breathing and circulation are critical and a visual
check of the injuries is reliable. Vital signs and a general physical examination should be combined
with a brief history taken by a paramedic or volunteer worker if it is available.

Know and Understand the Resources Available/ Resource Management

Resource rationing: The term rationing refers to the resource allocation strategies employed when
supply will not meet demand (5).
In medicine, triage has evolved as a tool to address significant resource shortfalls (5, 13, 14). Triage
officer must have knowledge and understanding of the available resources at each level or stage of
patient care and must be immediately aware of changes in resources, whether additional or fewer.
Surgeon could be the ideal triage officer for hospital triage positions as he or she understands all
components of hospital function including the operating rooms. In field, the medical incident
commander should be the highest ranking medical professional on scene who is trained in disaster
management.

Planning and Rehearsal

Creating mock drills and real life situations can be used in broad planning and fine tuning of facility
responses. This can be used to improve standards and re build resources which are deficient. It can
also establish deficiencies in the communication and passage of information among different
departments involved.

Triage Category Types and Documentation of Triage (12)

Priority Colour Medical need Clinical status Examples

First (I) Red Immediate Critical but likely to Severe facial trauma, tension
survive if treatment pneumothorax, profuse external
given early bleeding, hemothorax, flail chest,
major intra abdominal bleed,
extradural hematomas
Second Yellow Urgent Critical, likely to Compound fractures, degloving
(II) survive if treatment injuries, ruptured abdominal
given within hours viscus, pelvic fractures, spinal
injuries
Third Green Non urgent Stable, likely to survive Simple fractures, sprains , minor
(III) even if treatment is lacerations
delayed for hours to
days
Last (0) Black Unsalvageable No breathing, Severe brain damage, very
pulseless, so severely extensive burns, major
injured that no medical disruption/loss of chest or
care is likely to help abdominal wall structures
Many systems add another color, such as blue for “expectant patients”-
those who are so severely injured that, given the current number of
casualties requiring cases, the decision is made to simply give palliative
treatment while first caring for red (and perhaps yellow patients) (3).

Accurate documentation is an inseparable part of triage and should include

basic patient data, vital signs with timings, brief details of injury (preferably
on diagram) and treatment given. In addition, a system of color coded tags
attached to the patient’s wrist or around the neck is employed by
emergency medical services. The color denotes the degree of urgency with
which patient requires treatment (12).

Specific Triage Methods (18)

Disaster Triage: “START”- Simple triage and rapid treatment

The objective of this system is to triage large number of patients rapidly. It
is relatively simple and can be used with simple training (15). The focus of
START is to evaluate four physiological variables:

 The patient’s ability to ambulate

 Respiratory function
 Systemic perfusion
 Level of consciousness

If the patient can walk they are classified as a delayed transport, but if not, ventilation is assessed. If
the respiratory rate is >30, perfusion is assessed. A capillary refill of >2seconds will mandate an
immediate transport. If the capillary refill is <2seconds the patients level of consciousness is
assessed. If the patient cannot follow commands, they are immediately transported, otherwise they
are delayed transport.

In some systems the START system is coupled with severity scores:

 Immediate category trauma scores varies from 3 to 10

 Urgent category the trauma score varies from 10 to 11
 Delayed category (non urgent) group the trauma score is 12

Field Triage System (4): This decision scheme describes indications for transport of the trauma
victims to a trauma center based on specific physiologic and anatomy of injured variables. In addition,
mechanism of injury and co-morbid factors are evaluated and, if specific criteria are met, may also
indicate transport to a trauma center.
Triage is Continuous (Retriage)
Triage is not at one point of time. It should be continuous and repetitive at each level. Triage is a
dynamic process that makes it more likely to correct inevitable instances of undertriage and
overtriage.

Undertriage occurs when the severity of a patient’s illness or injury is not appropriately recognized,
which results in delayed treatment that places the patient at risk of dying. Particularly in day-to-day
situations, undertriage is minimized through the use of protocols that tend to overtriage patients to
higher levels of care than they require (13,16,19).Such protocols are not foolproof, however, because
overtriage has been shown to decrease overall survival rates among critically ill or injured victims
(16). Overtriage may increase mortality by depleting resources, fatiguing staff, and impairing efficient
flow of critically ill or injured patients through the system to definitive care.

The physiology of a patient is just a snapshot in the well being of an injured patient (17) and is not
constant or predictable. There may be deterioration of the patient’s condition leading to up gradation
of triage category perhaps from yellow to red. In others, an open fracture may be discovered after
initial triage has been completed, mandating an upgrade in triage category from green to yellow. An
important group requiring retriage is the expectant category. For example patient initially labeled as
having no survivable injuries, this may change after all red patients have been cared for or evacuated
(a young patient with 90 % burns may survive if burn center becomes available).

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16. Rocca Fort JD, Kushman JG. Disaster preparedness, triage, surge capacity for hospital definitive care areas:
optimisizing outcomes when demand exceeds resources. AnesthesiolClin. 25(1):161-177, xi., 2007
17. Champion HR: Triage. In Cales RH, Heileg RW, eds, Trauma Care Systems. Rockville, MD: Aspen publishers,
986, p. 79
th
18. Feliciano, Mattox, Moore; Trauma, 6 ed. 2008.
19. Michael DC, J. Christopher Farmer, Brian PY; Fundamental Disaster Management: Disaster triage and allocation
of scarce resources.
 Disaster Management - An Overview
Ajit Sinha, R. K. Soni
Disaster
It is a sudden, unpredictable, unfamiliar, calamitous event, bringing great damage, uncertainty, and
destruction of life and property. WHO defines disaster as an “Any occurrence that cause, ecological
disruption, loss of human life, deterioration of health & health services, on a scale, sufficient to
warrant an extraordinary response from outside the affected community or area”
From medical perspective, disaster may be defined as events in which needs of patients overwhelm
the resources needed to care for them.

Type of Disaster
No. Category of Hazard Type of Disasters
1 Geological Earthquake
Tsunami
Landslide
2 Hydro-Metrological Flood
Flash Flood
Storm
Cyclone
Drought
3 Biological Outbreak
Epidemic
Pandemic
Plant & Animal disease
4 Technological Transportation
Industrial
5 Environmental Bush, Forest Fire
6 Political, Social, Extremism Conflict
Terrorism
7 Weapons of Mass Destruction Chemical, Biological, Radiological, Nuclear and
(WMDs) Explosives

A disaster is followed by:

a) Large number of dead, injured and missing.

b) Large number of unaccompanied children.
c) Loss of normal source of food and potable water.
d) Loss of shelter and household necessities
e) Loss of means of livelihood.
f) Overcrowding and spread of communicable disease.
g) Destruction of environment and communication.
h) Logistics problems.
i) Insecurity and tension.

Disaster Management

Disaster Management can be defined as: the systematic process of using administrative decisions,
organization, operational skills and capacities to implement policies and strategies and enhance
coping capacities of the society and communities to lessen the impacts of hazards and related
environmental and technological disasters.

Disasters often differ in quantity of damage caused or in quality of the type of medical consequences.
For example earthquake cause a lot of physical injury and fractures, floods cause drowning deaths
and infections, chemical leaks cause toxic manifestations, etc. The impact of different disasters
demand different type of response or management approach.
Disaster Management follows a multi-disciplinary approach which includes bringing together
specialization of different domains into disaster management. Disaster Management Official must
have prior coordination and agreements in place with government hospital, police authorities, fire
brigade personnel, youth organizations, NGOs. This will ensure immediate response to the disaster
with minimum chaos. Disaster managers must ensure that law and order is maintained and people
receive adequate information about their missing family members and relatives, regarding their living
status and location.

Disaster Managers must get a resource mapping done of the community so as to have available
resources on time when required. Also, mock drill can be conducted with community so that they don’t
panic in times of disaster and quickly move to safe shelters which are pre-located during the time of
resource mapping. Various resources to be indentified are: Water source, safe shelter for community
in times of flood, earthquakes, cyclone etc., disaster helpline number, medical assistance number, fire
brigade number etc.

Phases of Disaster Management

”The Fundamental Principle of Disaster
Management is to do the maximum good to the
maximum number of persons.”

I. Disaster Phase
During this phase the event of the disaster takes
place. This phase is characterized by profound
damage to the human society. This damage / loss
may be that of human life, loss of property, loss of
environment, loss of health or anything else. In this
phase, the population and society is in a state of
profound shock.
II. Post Disaster Phase

a) Rescue phase – This is the period

that immediately follows the
occurrence of the disaster. All individuals respond to the disaster, but in their own ways.
Almost everyone is willing to help. The first important step during first 48 hours after a
disaster is to save maximum number of lives as possible. Food, shelter, clothing can be
taken care of in later stage. The immediate need is to have search and rescue teams in
place along-with emergency medical assistance which can save lives.

b) Relief Phase – Disaster Management must stress on immediate need assessment

after a disaster. This assessment will be important for government organizations, NGOs
as well as international bodies. The accuracy of need assessment will determine the
efficiency of management.

Depending on the initial needs assessment, immediate relief like food, clothing and shelter is
provided to the survivors. The relief must be adequate and appropriate to the culture of the
affected community. The relief is generally provided by external agencies (NGOS, INGOs)
and Government resources. Immediate need includes immediate medical assistance, safe
drinking water, nutritious food, temporary shelters, clothing, and information on missing
relatives, psycho-social assistance to trauma victims, special care to children, elderly and
physically challenged and special attention to pregnant and lactating women.

c) Recovery Phase / Rehabilitation phase – When the immediate needs of the population
are met, when all medical help has arrived and people have settled from the hustle –
bustle of the event, they begin to enter the next phase, the recovery phase, which is the
 most significant, in terms of long term outcome. It is during this time that the victims
actually realize the impact of disaster. It is now that they perceive the depth of the loss
that they have suffered.
They are often housed in a camp or in some place which is often not there in home, along
with other victims. After the victims have recovered from the both physical and mental
trauma, they realize the need to return back to normal routine i.e. to pre-disaster life. During
this phase, they need resources and facilities so as to enable them to return back to their own
homes, pursue their occupation, so that they can sustain their life on their own, as the help
from the government and other non-governmental organizations is bound to taper in due
course. Thus, they are provided with a whole new environment, adequate enough for them to
pursue a normal or at least near normal life. This is called rehabilitation.
During rehabilitation phase, adequate care is taken to follow all safety measure to prevent
and minimize future impact of hazard. Also, the sustainable development approach is kept in
mind while keeping restructuring the community. During this phase, earthquake resistant
houses are built; Tsunami and cyclone resistant houses and flood resistant raised platform
houses are built. During rehabilitation, the community is settled in a safe location and as far
as possible mixed community settlement is preferred to eliminate social issues of caste and
class.

III. Pre-Disaster Phase

a) Prevention phase - This is the phase which indicates the start of pre-disaster phase. It
engrosses measures to be taken in order to prevent a specific disaster from happening
again. There are different measures required for different disasters. Working on this
phase is the responsibility primarily of the government. The actions taken in this phase
are required to be of high quality and of long term benefit. Only the government has the
strength to implement these activities with high funds and necessary resources in place.
The measures include increasing the capacity of a dam to prevent floods, activities
promoting communal harmony at all levels to prevent riots, high construction and safety
standard in industries, government offices and all other structures to be fire and
earthquake resistant. Prevention should be at all levels- community levels, local level and
government level.
b) Mitigation phase – In this phase, measure are taken in advance of a disaster aimed at
reducing its impact on society and environment, if ever a disaster takes place. This phase
includes technology and scientific techniques too. For example,
i) Predicting the path, time to be taken of a cyclone after knowing that it is approaching
the country is one mitigation strategy so as to avoid losses of lives and property.
ii) Having a natural mangroves plantation along the coast is one mitigation measure.
iii) Construction of earthquake resistant building is another mitigation measure. Working
on mitigation phase is also the responsibility of the government because such
initiative at the local and community level is very difficult as huge funds and resources
are required.
c) Preparedness phase – This phase involves the development of awareness among the
population on the general aspects of disaster and on how to behave in the face of a future
disaster. This includes education on a warning signs of disasters, methods of safe and
successful evacuation and first aid measures. Preparedness must be on part of individual
organizations as well as community as a whole. Preparedness phase also deals with the
predations which are needed on individual, community, authoritative level when a disaster
occurrence cannot be avoided and a disaster is sure to happen. Community based
disaster management plans must be formed with the help of NGOs.

Community Planning

 Should involve acute care specialists, local hospitals, as well as officials of the local police,
fire, security, public health and government agencies.
 Should be frequently tested and reevaluated.
  Must provide for a mean of communication considering all contingencies, such as loss of
telephone land line and cellular circuits.
 Must provide for storage of equipment, supplies, and any special resources that may be
necessary.
 Must prepare for the transportation of casualties to other facilities by prior agreement.

Hospital Planning – It is vital that each hospital develop a disaster plan. Once a state of disaster has
been declared, the hospital disaster plan should be put into effect. Specific procedures should be
automatic and include:

 Establishment of an incident command post (ICP).

 Notification of on-duty and off-duty personnel.
 Preparation of decontamination, triage and treatments areas.
 Checking of supplies and other materials, essential to sustain hospital operations.
 Establishment of a public information center and provision of regular briefings to inform family,
friends, the media, and the government.

Departmental Planning
Since patient care can best be delivered to individuals patients by care providers working in small
teams, every hospital department with responsibility for the care of injured patients must identify its
medical response teams in advance. They should also be readily accessible in the event of disaster.
The ultimate objective of any specific disaster management process is to reduce the impact of
disaster in order to save maximum number of lives and to avoid property damage. We calculate risk in
terms of the hazard, vulnerability and the coping capacity.

HAZARD X VULNERABILITY
DISASTER RISK = -----------------------------------------------------
COPING CAPACITY

There are three ways to reduce the risk of a disaster. This are-

 Avoid the hazard or minimize the probability of a hazard happening.

 Reduce the vulnerability of the community residing.
 Increase the coping capacity of the community residing.

Hazards – Hazards is a potential threat which can create disaster. A hazard poses a significant risk of
a disaster. A hazard can be existence of fire, chemical industries, earthquake, flood, etc. For example,
earthquake in a desert will just be a hazard and not a disaster. However, earthquake in an urban or
rural settlement where population resides can be a huge disaster.

Vulnerability - Vulnerability is defined as the characteristic of a person or group and their situation
that influences their capacity to anticipate, cope with, resist and recover from the impact of a natural
disaster. Vulnerability can be classified under different heads. These are –

a) Physical vulnerability: This type of vulnerability means the direct physical exposure of an
individual to the hazard. The vulnerability also depends upon the age, sex, location, physical state
of the individual. Physical vulnerability plays important part at the time of actual disaster. A person
who is aged is more vulnerable physically than a person who is young.
b) Social vulnerability: This type of vulnerability considers the social patterns existing in the society.
This include the class-caste system in the society, status of woman in the society, status of
physically and mentally challenged population in the community and such related social practices.
Such type of a vulnerability matters mostly at the time of relief and rehabilitation phase of disaster
management. In these phases, a family from a lower cast is more vulnerable that an upper class
family, a mentally challenged person is more vulnerable that a sound person.
c) Economical vulnerability: Economical vulnerability deals with the economic aspect of an
individual or a family. It included the income, economic stability, insurance availability of
 individuals and families. A person who is economically strong is less vulnerable than a person
who is economically not healthy.
d) Geographical vulnerability: This type of vulnerability deals with respect to the location of the
community. This vulnerability is disaster is specific. For floods, people living on height (more
above sea level) are less vulnerable than people living on low height. In the same way, in a
landslide prone hills, people living on the slops are more vulnerable that the people living on the
ridge of the hill.

Coping Capacity – Coping capacity encompasses those strategies and measures that act directly
upon damage during the event by alleviating or containing the impact or by bringing about efficient
relief. Coping capacity can be summed up as the ability of a group or household to resist a hazard’s
harmful effects and to recover easily.

Indian Perspective
The recent floods and landslides in Uttarakhand have been a rude reminder for India of its historical
disasters, which were overwhelmingly intimidating for the country. Some of the deadliest disasters
which happened in India are –

 Bangal famine (1943) - killed at least 40 lakh people.

 Latur earthquake (1993) – killed more than 20 thousand people, damaged more than 2 lakh
houses.
 Gujrat (Bhuj) earthquake (2001) - killed 30 thousand people.
 Indian Ocean Tsunami (2004) – affected 1, 50,000 people, killed more than 10,000 people in
India alone.

To enhance the preparedness to tackle such catastrophes in a more organized way On 23 December
2005 Government of India enacted Disaster Management Act and formed National Disaster
Management Authority (NDMA) -Headed by Prime Minister.

NDMA is an Apex body mandated to lay donor policies, plans, and guidelines for disaster
management to ensure timely and effective response to disasters with the aim to build a safer and
disaster resilient India by developing a holistic, proactive, multidiscipline and technology driven
strategy for disaster management through collective efforts of all governmental and non-governmental
organizations.

At the state level State Disaster Management Authority (SDMA) has been formed by various states,
headed by Chief Minister.

National Institute of Disaster Management (NIDM) - is a statutory body of government of India formed
under the Disaster Management Act-2005 for research, documentation and assisting the government
in ( under ministry of home affairs) policy planning on all aspect of disaster management.
This body is preparing a detailed report on mega disaster of flash floods and landslides in
Uttarakhand on 16th and 17th June 2013.to understand the causes, impact and lesson learnt.
It also publishes a biannual Journal “Disaster and Development”.

National Disaster Response Force (NDRF) – It is a specialized force for specialized response to
natural and manmade disasters. This force is under direction and control of NDMA, and is supervised
by Director General NDRF.

Conclusion
Disaster management involves people from various sectors and from various levels. Coordination
among all of them is the key to achieve maximum benefit. Proper planning, preparedness, immediate,
and coordinated response helps in reducing impact of disaster and save precious human lives.
 Gunshot injuries
Vivek Agrawal, Mohit Kumar Joshi

Learning Objectives

1. Burden of gunshot injuries in our country

2. Overview of firearms
3. Basics of a firearm: the anatomy of
a. Gun
b. Ammunition
4. Gunshot injury patterns
5. How to record a gunshot wound: the medico-legal implications
6. Management of a patient with gunshot injury
Introduction

Gunshot injuries constitute a small number as compared to all other modes of injuries (how many
patients with gunshot injury do you encounter during a routine call day in surgical emergency as
compared to all the trauma patient you manage that day?). Despite their relative infrequency, gunshot
injury retain the pride of place among all the mechanical injuries because of a large number of arms
from which they may be fired, varied injury patterns they produce, their often fatal consequences and
associated medico-legal consequences.

Management of a patient with gunshot injury follows the same principles as that of any other patient of
trauma so it may not be much difficult to manage such patients surgically. The thing which the treating
doctor might find difficult and which is so intimately associated with the overall management of a
patient with gunshot injury is the basic knowledge of firearms, preparation of an injury report with
regards to different injury patterns of gunshot injury and different nomenclature associated with this
special kind of assault. In addition, there always is a fear of associated medico-legal implications. We
feel that this ‘fear’ is valid as what all we are taught regarding gunshot injuries during our training as
doctors constitutes a small part of forensic medicine as a subject (unfortunately there is no formal
teaching or training in this specialized area of jurisprudence after medical graduation).

In the present article we intend to explain the basics of firearms, their injury patterns and preparation
of injury report of a patient with gunshot injury in a simple way. We hope that this effort will alleviate
the ‘fear of unknown’ associated with the gunshot injuries to some extent. We will also discuss in
short the principles in managing a patient with gunshot injury.

Guns and gunshot injuries in our country

Although the latest statistics suggest that the incidence of firearm related crime has declined over the
past decade in our country,1 still the burden of firearm related injury remains high. A large number of
persons die and many more survive with disabilities following gunshot injuries. In addition the social
stigma associated with the gunshot injury and the financial burden of fighting an often lengthy medico-
legal case (which may run through years) make the matter worse for the sufferers and their family.

Possession of firearm in our country is controlled by law. No one can just acquire a firearm without
explaining to the law officials the compelling reason for its acquisition and without obtaining a valid
arms license which follows rigorous scrutiny (or this is believed at least). However, there are a large
number of illegal factories which manufacture wide variety of guns that range from highly
sophisticated weapons to improvised guns made from crude pipes and local firing mechanisms
(known as country made weapons). In an estimate the total number of guns held by civilians (means
those excluding the defense and the police personnel) in India is 40,000,000, however the number of
 2
issued arm licenses are 6,30,000. This amounts to a staggering figure of 33,700,000 unlawfully held
guns in our country (mind you this is just an estimate, the true number may be much more than this).

The presence of such varied types of firearms and the myriad of injury they produce makes the job of
treating surgeon and the forensic expert truly challenging. On one hand the appearance of wounds
produced by such country made weapons usually shows deviation from the established gunshot
wound patterns produced by the licensed weapons (which conform to manufacturing specifications)
and thus may confuse the surgeon while recording the injury; on the other hand forensic and ballistic
expert may find it difficult to estimate the bore of the weapon and the distance from which the shot is
fired as these weapons do not follow the size and kinetics of a standard firearm. Moreover, assailants
can easily dispose such weapons without much financial loss and, therefore, these guns cannot be
traced to an owner. According to the latest report of National Crime Record Bureau (NCRB), in year
2012, 3781 persons were murdered by guns, of which only 323 were killed by licensed weapons and
3
rest 3458 (nearly 90%) were killed through the use of unlicensed guns.

Anatomy of a firearm: general considerations

A basic understanding of guns and ammunition is essential and is complimentary in managing
patients with gunshot injuries. As previously discussed, a large variety of guns are available. A
detailed description and subtle modification of all firearms is beyond the scope of the present article,
however the general description of components of a basic firearm is as follows.

1. Barrel: Every firearm consists of a hollow metal pipe called barrel which is closed at one end and
is open at the other. The open end is called the ‘muzzle end’ and the closed end the ‘breech end’.
The guns in which the cartridge is loaded from the muzzle end are called ‘muzzle loaders’
whereas the ones in which the cartridge is loaded from the breech end are known as ‘breech
loaders’. All authorized gun manufacturers make breech loading guns that strictly adhere to the
specified norms. The barrel of a breech loader has three parts. From breech end to the muzzle
these include-
a. Chamber: is part of barrel which is meant to hold the cartridge. It is larger in diameter
than the rest of the barrel. On its posterior aspect there is a small metal part called the
‘breech block’ which can be opened to load a cartridge in the barrel and is closed
following loading.
b. Taper: also called ‘lead (or leed)’ in rifled firearm and ‘chamber cone’ in smooth bore
weapons is the intervening part of barrel between the chamber and the bore.
c. Bore: is the rest of the barrel up to the muzzle. Bore might have spiral grooving from
inside in case of rifled firearms or it might be smooth in case of smooth bored weapons.
2. Breech action: is the part of a firearm that loads, fires, and ejects a cartridge. Various
firearms have different mechanisms that may constitute lever action, pump action, bolt action,
semi-automatic and automatic action.
3. Breech face: is the flat part of the breech block that seals the breech end of the barrel. It is
pierced in the centre to accommodate the firing pin.
4. Hammer and firing pin: Hammer is a metal rod or plate that is attached to a pointed metal
structure called firing pin. Hammer is attached to the trigger with a spring action. When the trigger
is pressed hammer is released, moves forward with great speed and the firing pin strikes the
cartridge through the hole in the breech face.
5. Stock: is the supporting part or simply the handle of the firearm. The end of the stock is
called the ‘butt’. Usually the stock of the gun accommodates the action and the trigger mechanism
of the weapon. In the hand held firearms, stock is provided with grips which facilitate the grasping
of a firearm. In long barreled weapons the butt is elongated and contoured to fit on the shoulder.
6. Safety catch: is a safety device present in all firearms (except revolver and improvised
country made guns). When activated this locks the firing mechanism. It needs to be released
before the shot can be fired.

The functioning of a firearm: How it fires a shot?

A cartridge (or shot) is loaded to the chamber of a gun and the chamber is closed for firing (the
maneuver to close the chamber may differ with the breech action of the firearm being used). Once
closed, the barrel comes into position along the breech face. The weapon is then cocked (ready to be
fired), this pulls back the hammer and attached firing pin against a strong spring and is held there
resting on a small notch. When the trigger is pressed, the hammer disengages from the notch and
due to the spring action moves forcibly forward to strike the firing pin. This in turn strikes the back of
the cartridge through the hole in the breech face igniting the powder that the cartridge contains. This
creates an explosion and the gases so produced generate enough energy that propels the projectile
(bullet or pellets) in the cartridge with great speed forward through the muzzle of the weapon.

Due to this explosion flame, smoke, unburnt and partially burnt powder are produced that also leave
the barrel through the muzzle end and travel up to varying distances when the weapon is fired. If they
happen to come in contact with the victim’s body, they may leave their imprint on the skin, and this
forms the basis of estimation of the range of fire during criminal investigations.

Classification of firearms: Rifled or smooth bored

weapons
The firearms are broadly classified into rifled or smooth
bored ones depending on whether the inside of barrel
contains spiral grooving (called rifling) or not. In rifled
weapons the inside of the barrel contains a number of spiral
grooves which run parallel to each other but are twisted
spirally from breech to muzzle end (Figure 1 a & b). The
grooves are called ‘rifling’ and the projecting ridges between
the grooves are called ‘lands’. The distance between the two
diagonal lands is called ‘calibre’ that denotes the size of the
rifled weapon (Figure 1 a). The guns which do not have
these riflings in their barrel are called smooth bored
weapons or ‘shot guns’. The size of the smooth bore
weapon is designated by gauze.

Why some weapons are rifled?

When a bullet passes through the bore of a rifled firearm,
the bullet acquires a spinning motion. This bullet comes out through the muzzle end with great speed
spinning on its own axis. This spinning motion gives the bullet

a. Greater power of penetration.

b. Straight trajectory towards the target.
c. Steady movement while the bullet travels in air.

The rifled firearms therefore can strike to a greater range with better accuracy and because of the
greater speed and penetrating power of their projectile, are more lethal than their counter part - shot
guns. In smooth bored weapons (the shot guns), the projectile does not get this spin and therefore the
range and accuracy of the projectile is comparatively less. This does not mean that the shot guns are
any less lethal. From a limited range they are either as much or may be more lethal than the
sophisticated rifled firearm.

Common types of firearms used in India

Although the assailants cherish a variety of sophisticated and improvised guns in India, four types of
firearms are most commonly used. These include revolver, semi-automatic pistol, rifle and shot guns.
Out of these revolvers, semi-automatic pistols and rifles are rifled weapons whereas shot guns are
smooth bored weapons.

1. Revolver: is a hand held gun with a rifled barrel. It contains a revolving chamber that usually
accommodates six cartridges (however the number may vary from 4 to 12). With each fire the
chamber revolves and brings the next cartridge in line with the barrel ready to be fired.
2. Semi-automatic pistol: This again is a hand held gun which is rifled. However unlike a
revolver it does not contain a revolving chamber. A number of cartridges (5-30) can be loaded in
the magazine housed in the hollow hand grip of the gun. Once a shot is fired, the spent cartridge
is ejected from the weapon and the chamber is replaced by a fresh cartridge from the magazine
automatically, making the gun ready for the next shot. Are you wondering then why this arm is the
not called an automatic gun? This is because only one shot is fired once the trigger is pulled. For
the next shot the trigger needs to be pulled again. In a truly automatic weapon, the gun keeps on
firing cartridges as long as the trigger is kept pulled. Machine gun is a typical example of a truly
automatic weapon; however a truly automatic pistol virtually does not exist.
3. Rifle: This is a firearm with a long rifled barrel and a relatively large stock. Unlike its rifled
hand held counterparts (revolver and semi-automatic pistol), a rifle is designed to fire with two
hands while the stock is supported on the shoulder. As the length of the barrel is directly
proportional to the velocity and the stability of the ejected projectile, the rifles can fire to a greater
distance with more accuracy than the weapons with smaller barrels.
4. Shotgun: A shotgun is a weapon that is designed to be held by both hands with stock resting
on shoulder (same as a rifle). The biggest difference from the other weapons is that the inside of
the barrel of this gun is smooth and does not contain rifling (that is why it is also called a smooth
bored weapon). They come in different designs varying from manually loaded single or double
barrel guns to self loading guns.
Although the barrel of a shotgun is smooth but to
produce the concentration of the shot, the distal 3-4
inches of barrel of a shotgun may have a contraction
known as ‘choke’ (Figure 2). Depending on this degree
of contraction, the choke is variably referred as full,
half or quarter choke. The benefits of choking are :-
a. Decreases the extent of spread of the shots (more choke, thereby concentrates the shots
towards the target).
b. Increases the explosive force of the projectile and thereby increases the velocity and
penetrating power of the shots.
As previously mentioned the range and accuracy of a shotgun is less, however the cone like
spreading of the shots coupled with their large numbers makes this weapon lethal in short range.

Ammunition used in firearms

Ammunition used in firearms comprises following parts-

1. Missile: is a bullet in case of a rifled firearm and shots

(pellets) in case of a shotgun. A bullet is made up of lead
which usually is hardened by alloys of Antimony and Barium
and is mounted on a cartridge case. To further harden them
the bullets may be covered by a ‘jacket of metal alloy’.
Depending on the extent of jacketing, the bullets may be
unjacketed, semi-jacketed or fully jacketed.
The shots are in the form of small lead balls or pellets
contained in a shotgun cartridge. Like bullets, alloys may be
used to harden them which increase their penetrating power.

2. Cartridge: The cartridge is a hollow cylinder which holds together the missile, powder, primer
and ignition cap. It is made up of brass for use in rifled
weapons and paper and brass for use in shotguns (Figure 3 &
4). When a gun is fired, the cartridge case falls at the scene
and the bullets (or shots) move to a varying speed (depending
on the type of weapon) towards the target, thus cartridge case
may serve as an evidence in forensic investigations and may
help identify the weapon from which it was fired.

3. Primer: The primer is a small amount of stable but highly

shock sensitive explosive material commonly made up of lead
azide or potassium perchlorate. This small amount of charge is
 housed in small copper or brass cup on the bottom of the cartridge case. When the trigger is
pulled, hammer and the firing pin move forcibly forward and strike the primer with a crushing blow.
The charge gets ignited by this blow and the flames so produced explode the main powder
charge.
4. Powder: is the chemical material that when undergoes combustion (due to flames produced
by the ignited primer) produces enough pressure from the produced gases to propel the missile
from the cartridge with violent force towards the target. Two types of powders are used in firearm
ammunition viz., black powder and smokeless powder.
Black powder: is rarely used now as it produces lots of black gas resulting in soiling of the
firearm and the hands of the person firing the gun. It contains potassium nitrate, sulphur and
charcoal.
Smokeless powder: is not completely smokeless although the amount of gas produced is
small and is not black, so it does not soil the firearm and the assailant’s hand. It is frequently
used in modern firearm ammunition. It may be ‘single based’ when it contains nitrocellulose
as the main ingredient and ‘double based’ when contains nitrocellulose and nitroglycerine as
the principle ingredients.
5. Wadding: is a piece of either plastic, fiber or felt which is housed between the powder and
the shots (thus it is present only in shotguns, see figure 4). Wad prevents escaping of gases and
acts as piston to push the shots out of the cartridge case. Although not a projectile by themselves,
the wads may travel up to some distance from the firearm, thus may act as helpful material for
forensic evidence in establishing the position of the assailant and at times the type and make of
weapon as some manufacturer imprint the wad with their symbol and encrypt the size of shot
contained in that cartridge.

What is ballistics?
The study of motion of a projectile with regards to a firearm is called ballistics. It has three parts

1. Internal ballistics: The study of motion of projectile inside the barrel of the gun. Ballistic
experts deal with internal ballistics.
2. External ballistics: The study of motion of the projectile after it leaves the barrel and before it
hits the target. This too comes in purview of the ballistic experts.
3. Terminal ballistics: also called wound ballistics is the study of projectile’s impact on the
tissues. This comes in domain of the doctor treating a patient with a firearm injury or in case of
death, a forensic expert. As a doctor is the first person to evaluate the wounds of a person injured
by a firearm, it is his responsibility to record the wound precisely so as to help the law enforcing
personnel in investigating the crime. Any callousness in recording the wound may seriously
jeopardize the vital forensic evidence.

Let us now focus on to the various patterns of injury a firearm can produce.

Gunshot injury patterns

A projectile (bullet or shots) fired from a gun may produce a variety of wounds. A firearm projectile
crushes the tissues that come in its path thus creating a hole along the path it traverses, producing a
‘permanent cavity’. This is unlike a stab wound where the tissues retract to their normal position once
the weapon is withdrawn from the body. In addition, the kinetic energy of the bullet may also generate
shockwaves while traversing through the body and injure the tissues that does not even come in its
contact (this mechanism of injury is called ‘temporary cavitation’).

A gunshot wound may also show other characteristics on the victim such as impression of the muzzle
in case the barrel of the gun was held tightly against the body, the unmistakable appearance of the
products of combustion like that of flame, the smoke produced and that of unburnt powder around the
gunshot wound which are not present in wounds produced by any other weapon. However, a number
of factors such as the type of firearm and ammunition used, the distance from which the shot is fired
and the presence of clothing on the site of wound, affect the appearance of gunshot wounds so one
should be aware of these morphologic deviations of the gunshot wound.

When a gun is fired the projectile is released along with flame, smoke and the partially burnt
gunpowder. They cause following impressions/ damage to body:

1. Flame: the flame emanating from the gun may cause burning of the skin (superficial burn) and
singeing of the hairs in the region. The distance to which the flame can emanate from a firearm is
limited approximately to 30 cms, so burning/ singeing is not usually seen when the gun is fired
from more than 30 cms on an average. The presence of thick clothing at the site of gunshot may
guard the skin from burning/ singeing.
2. Smoke: produced may be deposited on the skin and appear as blackened area over the skin
(known as blackening) that may easily be wiped off by a damp cloth. The blackening may be less
or even absent in case where smokeless powder is used in the ammunition. Again the presence
of clothes at the site may prevent blackening. Like flame, the smoke can also travel to a maximum
of 30 cms, so beyond this distance blackening is not usually seen.
3. Gun powder residue: The partially burnt or unburnt gun powder thrown out from the
cartridge may get embedded in the skin and produce a characteristic stippled appearance on the
skin known as ‘tattooing’. As in the tattoos which are made for style statements, the ink is
deposited subdermally so that it cannot be removed by washing or wiping, similarly the deposition
of gunpowder residue in a firearm wound is subdermal so it also cannot be removed by wiping or
cleaning the wound. The average distance up to which the gun powder residue can travel is
approximately 45 cms so tattooing is not usually seen beyond this distance. Like singeing and
blackening the presence of thick clothing at the site may prevent tattooing.
4. Wad: In case of a shotgun, the wads contained in the cartridge may be driven to some
distance inside the wound when the gun is fired at a distance of less than 2 meters. Beyond this
distance the wads lose enough of their kinetic energy to penetrate the skin.
5. Entry wound of the projectile: The projectile when strikes the body, indents the skin,
stretches it inwards and then perforates it at the centre of maximum stretch. After the projectile
enters the body the skin recoils back and comes to its original position due to its elasticity. During
entry of the projectile into skin, the skin around this point of entry gets violently rubbed against the
projectile producing a rim of abrasion around the entry wound known as abrasion collar.
At times, the debris, oil or grease from barrel of the gun may be deposited around the wound of
entry which appease as a black rim just outside the abrasion collar and is known as dirt/ grease
collar.
The wound of entry may be circular when the entry of the projectile is at right angles to the skin,
however the shape may be elliptical once the projectile enters at an angle to the skin. The
margins of the wound may be sharply defined and are inverted. However, at places where the
elasticity of the tissues at the site of entry is less or there is underlying bone, the wound may have
irregular margins and thus may appear lacerated. The size of the wound of entry may not
corroborate with the size of projectile. Because of the elasticity of the skin, the size of the wound
of entry may be smaller than the size of the projectile or at places where it lacerates the skin and
underlying tissues, the size may be larger than the size of projectile.
The above description holds true for wounds produced by bullets and shotgun wounds when fired
from a close range (usually less than 2 meters where the all the shots contained in the cartridge
enter the skin as a single mass). Beyond approximately 2 meters the pellets/shots of the shotgun
cartridge starts dispersing and there are satellite entry wounds of individual shots in addition to a
main entry wound from where most of the undispersed shots enter the body. The main wound
progressively becomes smaller with the increase in distance from the gun and the point of entry,
such that beyond 6 meters the main wound is not usually seen and only multiple entry wounds
produced by individual shots is seen distributed over a large area on the body.
6. The wound of exit: This is seen only where the projectile has sufficient kinetic energy and
comes out through the body without getting lodged inside. Unlike the wound of entry, the size of
this wound is usually larger, the margins everted and irregular and is conspicuous by the absence
of the effect of flame (burning/ singeing), smoke (blackening) and gunpowder (tattoing).
7. Grazed or gutter wound: When
a bullet strikes the skin tangentially,
 it may not enter the body instead it forms a track damaging the skin and subcutaneous tissues
such that the entry and exit wounds are joined together (Figure 5). However the wound may still
show other features of gunshot wound like singeing, blackening and tattooing.

How to record a gunshot wound?

Now when you know the various characteristics a gunshot wound may have, these should be looked
for diligently and recorded at the first sight. This does not mean that recording the injury should take
precedence over the resuscitation of the gunshot victim, but one may have the mental impression of
the wound (you may also take a photograph) and as soon as the initial assessment and management
of the patient is completed, record the injuries. This is of paramount importance as the wound may
change in appearance during management. For instance, the soot may get wiped off while cleaning
and the wound may change in size and shape once it is enlarged for securing hemostasis or for
debridement. This may destroy the vital forensic evidence which may be of much help in identifying
the type of firearm used and estimating the distance and direction of the fire.

As soon as you encounter a patient of gunshot injury, police needs to be informed and the case is
registered as medico-legal. A short, relevant history should be taken (from the patient, if possible or
from the accompanying persons) that should include the time and place of assault, the approximate
distance of fire, number of assailants, number of shots fired and type of firearm used. You may not be
able to obtain all these parameters but record whatever you can gather. Start writing with the date and
time of your assessment and always begin by using the words ‘Alleged history of’. If you are not using
these words, it may be inferred from the records that you are confirming what the patient or the
accompanying person is saying and you know that you can never be sure of the facts. Following
history you should record the brief general evaluation of the patient based on ATLS protocols (see
later).

The state of clothes should be seen and recorded. Clothing should be carefully removed by cutting
through the areas not affected by the gunshot and submitted to the police. In addition, any soot
present around the site of wound should be wiped by a dry swab, loose foreign material like pellets,
wad or bullet are collected in suitable containers, duly labeled and are submitted to the Police
personnel. This should be recorded in your notes. You must also record the name and the
identification number (DD number) of the Police personnel to whom you submitted these articles.

Then follows the written description of the gunshot wound. As described above, a firearm wound can
be of three types - Entry wound, exit wound and gutter/ grazed wound. These wounds have
previously been described under the heading ‘firearm injury patterns’. The shape, size, margins of the
wound should be recorded in detail. You may draw a diagram to make the things clear. The presence
of dirt collar, abrasion collar, blackening and tattooing must be mentioned, if present. These are the
characteristic features of a gunshot entry wound and in no other mechanical injuries these features
are present. Failure to record these features may land the medical expert in trouble and may also
jeopardize the forensic investigations.

I recall a case where in court the prosecutor denied a wound to be caused by a firearm as the wound
was described as a ‘lacerated’ one with no description of blackening, singeing or tattooing although in
the history which was recorded by the same doctor the wound was mentioned to be caused by a
firearm.

At times it may be difficult to differentiate between the wound of entry and that of exit, for example
depending on the velocity of the projectile and the distance of fire the size of entry wound may be
smaller, equal or larger than the exit wound. You need not worry; record the characteristics of wound
carefully without labeling them the wound as that of entry or exit. The matter should be left for further
investigations by forensic ballistic experts. There is a word of caution here- if blackening, singeing or
tattooing is absent on an area which is usually clothed you must inspect the clothing of the individual
over that area and record the findings of the state of clothing.

Although you may be able to derive the approximate distance of fire from the wound characteristics
but it may vary considerably depend on the type of gun and ammunition used (this becomes more
complex when country made weapons are used for assault that do not follow the estimated range
applied to standard firearms). It is better to refrain yourself on commenting on the estimated range of
fire during the initial assessment of wound in your records. In fact this is not required and is best left to
the ballistic expert to determine.

There is no single characteristic of wound that is indicative of the manner of sustaining the injury
whether suicide, homicide or accidental. Determining the nature of assault requires multiple pieces of
evidence which includes interviewing the victim and other witnesses, the nature of wounds,
examination of gunshot residue and other ballistic investigations. You should not comment on this in
your initial records and leave the same for further investigations. Saying this, I must emphasize that
your records depicting the alleged history and carefully mentioned wound characteristics will help the
forensic investigations immensely that will help determine the exact nature of assault.

Mode of death following gunshot injury

The projectile from a firearm crushes and directly damages the tissues while traversing through the
body, creating a permanent cavity. In addition, the high kinetic energy of the projectile generates
shock waves that may injure the tissues around the permanent cavity to a variable distance. The
organs which come in the way of projectile and shock waves are damaged (lacerated by crushing
effect and contused or ruptured by shock waves) with varying consequence.
Denser a tissue is, greater is the damage by the projectile. Elastic tissues suffer less damage. Thus,
lung tissue of low density and high elasticity is damaged much less as compared to muscles which
have higher density and some elasticity when subjected to the same momentum of the projectile.
Solid visceral organs like liver, spleen and brain have little tensile strength and elasticity and are
easily crushed. Fluid-filled organs like urinary bladder, heart, great vessels and bowel can rupture
because of shock waves generated by the projectile. A bullet when strikes a bone may cause
fragmentation of bone or at times of bullet itself. These fragments of the bone or that of bullet move
further with high speed due to momentum of the projectile and themselves may act as secondary
missiles, each having potential for additional damage.
Immediate death occurs if vital organs like brain and heart are damaged. The torn large vessels like
aorta and vena cava cause sudden exsanguination and death. Other medium or small caliber vessels
like those of mesentery and those supplying the organs like liver, spleen, kidney, liver and extremities
may bleed significantly and can give rise to hemorrhagic shock and death. Injury to gut will cause
peritonitis with its dreaded consequences. The death following gunshot injury is preventable to a large
extent and the key lie in early recognition of injuries and their aggressive management.

Principles of management of a gunshot victim

The principles of managing a patient with gunshot injuries are same as that of any other patient of
trauma. The first and foremost thing needs to be evaluated is to recognize what is killing the patient.
The specific diagnosis as to which organ is injured may be difficult to make and is not at all required
during initial evaluation and resuscitation of a gunshot victim.

The philosophy of ATLS

It has now been well recognized that the Advanced Trauma Life Support (ATLS) protocol is one safe
and effective way of managing a trauma victim. Various studies conducted all across the globe have
proved the efficacy in saving the life of a trauma victim when ATLS protocols are applied. 4 The ‘Initial
assessment’ of a trauma patient as per ATLS protocol focuses on to identify what is killing the patient
and simultaneous correction of same. This has been described by ‘ABCDE’ that stands for Airway
(with cervical spine control), Breathing (with ventilation), Circulation (with hemorrhage control),
Disability (neurologic disability) and Exposure (with environment control). This suggests the priority of
evaluation and correction of the patient’s airway over evaluation and correction of the ‘breathing
problem’ which takes precedence over the assessment and the control of hemorrhage and so forth.
This makes sense as a blocked airway will kill the patient faster than a hemo or pneumothorax which
will kill the patient faster than bleeding and a closed head injury.

Primary management
The evaluation and resuscitation of the patient goes hand in hand. No time is spared in completing
the medico-legal formalities. As soon as you come across a patient with gunshot injury look for
ABCDE and manage them simultaneously. This may require tracheal intubation or surgical
cricothyroidotomy for securing the airway, putting in a needle to drain a tension pneumothorax or an
intercostal chest tube to drain hemo or pneumothorax. A hemodynamically stable patient may be
safely observed initially. If there is any bleeding from the surface, direct pressure should be applied
which is effective most of the times in controlling the hemorrhage. With any evidence of bleeding
inside the abdomen (a patient with a gunshot injury to abdomen who presents with persistent shock
despite adequate fluid resuscitation), urgent laparotomy will be required for controlling the
hemorrhage. Similarly a patient with continued bleeding from the chest tube that makes the patient
hemodynamically unstable or the one who requires continuous infusion of fluids, blood and blood
products to maintain the hemodynamics will require thoracotomy for control of bleeding. The presence
of peritonitis is again an indication of laparotomy.

To conclude

 Patient with an extremity wound with hemorrhage requires hemorrhage control which may
require application of external pressure or exploration of missile tract. Following hemorrhage
control, the wound may require debridement and any associated vascular or neural injury is
treated accordingly.
 For continued bleeding inside a cavity (Thorax or abdomen) urgent exploration (Thoracotomy
or laparotomy) is warranted.
 The presence of peritonitis mandates laparotomy.
 The specific organs injured are managed in the same way as they are managed following
damage by other mechanisms.

Although abdominal gunshot wounds may be observed and a selective non surgical approach may be
successful in a subset of such patients (like in abdominal stab wounds) but the chances of failure of
non-operative management of gunshot wounds is higher as the extent of damage to surrounding
tissues may be much more than anticipated due to the damage produced by the shock waves.

Management of gunshot wound

The gunshot wounds of the extremity require a thorough evaluation. Such wounds may injure bone,
muscles, vessels or nerves. Frequent evaluation is the rule and helps in minimizing the incidence of
missed neural and vascular damage. Although we are discussing the injury to each of these
structures separately, they may be injured together in a patient.
Fracture will be apparent and is managed by early fixation (internal or external) with debridement of
devitalized and dead soft tissue and thorough lavage of the wound. I emphasize here again that these
fixation methods should be considered in a patient with isolated limb injury only. In presence of other
life threatening injuries, the fractured limb should simply be splinted and is taken care of once the
patient is stabilized and there is no imminent danger to life. The help of an orthopedic colleague is
indispensable.
The limb should be carefully examined for any neural or vascular deficit. In a hemodynamically stable
patient, clinical evidence of nerve injury calls for an early exploration of the wound once other
associated injuries have been addressed. The damaged nerve should be exposed and is repaired
primarily. However in presence of a segmental loss of nerve or wound contamination, the ends of the
nerve should be marked by long silk sutures and the nerve should be repaired at a later date.

Absent or diminished pulsation in an extremity with obvious signs of ischemia distal to the wound
suggests an arterial injury. However, this may also occur with a venous injury once a hematoma or
edema develops in an osteo-fascial compartment and compresses the accompanying artery. These
signs of vascular impairment mandate the exploration of the wound in its entire extent and repair of
vascular injuries. In patients with combined arterial and venous injuries, associated fracture or where
the injury is more than 6 hours old, a fasciotomy should be done as these factors are associated with
a high risk of development of compartment syndrome.5-7 In some patients however, these hard signs
of vascular injury may be absent. Such patients may be subjected to further investigations like duplex
5,8
ultrasonography, CT or MR angiography.

In patients with no vascular or neural injury, the wound should be thoroughly examined for presence
of foreign material like patients own clothing, loose wad or projectile (bullet or pellets). These should
be removed and are preserved for forensic investigations. Any dead and devitalized tissue should be
excised and the wound should be thoroughly irrigated by copious amount of warm saline solution.
There is no need to irrigate the wound with antibiotic solution. Also there is no need to remove the
projectile unless it comes in the wound during its management or it is lodged in a structure which
needs exploration and repair for eg. a projectile lodged in a major vessel. The wound should not be
closed primarily. They can be allowed to heal by secondary intention or may be closed by delayed
primary suturing. With simple punctures and no apparent tissue disruption no debridement or wound
exploration is needed. Such wounds require simple cleaning and dressing. A gunshot wound is not
sterile and a brief course of oral or intravenous antibiotics lasting for 3 to 7 days is required.

With injury from high velocity projectiles (like the one fired from a rifled weapon), there is a possibility
of injury to surrounding structures adjacent to the tract of the projectile due to shock waves. Provided
neural and vascular injuries are excluded, such injuries can safely be managed by local debridement,
wound toilet and administration of systemic antibiotics. There is no need for extensive wound
exploration in such patients. Although few studies recommend routine evaluation of such wounds by
MRI scan,9,10 this should be reserved for a small number of patients having complex wounds with long
tracts in which the clinical evaluation of the wound may not be accurate.

Some interesting myths about gunshot injuries

1. In movies, you must have seen the gunshot victim being thrown backwards when struck with
the bullet. In fact, a person can never get displaced because of the momentum of the bullet.
The maximum momentum that can be transferred from projectile to an individual weighing 80
kg is only 0.01 to 0.18 m/s, which is negligible as compared to the 1 to 2 m/s velocity of a
pedestrian. The incapacitation of a gunshot victim primarily depends on the area of the body
injured. Immediate incapacitation may occur with gunshot wounds to the brain and upper
cervical cord. Rapid incapacitation may occur with massive bleeding from major blood vessels
or the heart.
2. Contrary to the popular belief and the known possession of heat in the fired projectile, the
bullet wounds are not sterile. The bullet may be contaminated by the oil/ grease used in gun
barrels for lubrication. In addition, the bullet may carry the bacteria on the skin and clothing of
the victim into the track of the wound. Also, the pressure difference between atmosphere and
the wound cavity drives air to sweep debris inward into the track of the wound leading to
wound contamination. Because of all this gunshot wounds are prone to infection like any
other wound.
3. It is commonly seen in Hindi cinemas (and this is also a popular belief in the general public)
that the bullet lodged in the body of a gunshot victim requires retrieval. This is far from truth.
Although retrieval of a lodged bullet will be of great asset for forensic investigations, it does
not require retrieval just for investigative purposes. Wherever the attempts to retrieve a
lodged bullet may pose additional risk to the life or limb of the patient, the bullet can be safely
 left in the body. A retained bullet rarely causes a problem. It is retrieved only if it is easily
recoverable during exploration of the wound in extremity or a body cavity or else if the lodged
bullet poses a threat to life or limb of a patient, for example the one lodged in a heart, major
vessel, orbit or a joint cavity.

Suggested readings
th
1. Lyon’s Medical Jurisprudence & Toxicology. TD Dogra, Abhijeet Rudra. 11 Ed 2005. Publisher- Delhi Law House.
th
2. Advanced Trauma Life Support for Doctors (ATLS) Student Course manual. 9 Ed 2012. American College of
Surgeons Committee on Trauma.
REFERENCES

1. Kohli, A, Karp A, Marwah S.’Mapping Murder: The Geography of Indian Firearm Fatalities IAVA Issue Brief No. 2;
p. 1. New Delhi: India Armed Violence Assessment / IAVA and the Small Arms Survey (Geneva);2011.
2. Gunpolicy.org [Internet]. India-gun facts, figures and the law. Accessed Sep 2013. Available from:
http://www.gunpolicy.org/firearms/regions/india.
3. Crime in India 2012. Accessed Sep 2013. Available from: http://www.ncrb.gov.in.
th
4. Course overview. In: ATLS student course manual 9 edition 2012. American college of surgeons committee on
trauma. p. xxiii-xxx.
5. Waes O, Lieshout E, Hogendoorn W, Halm JE, Waes J et al. Treatment of penetrating trauma of the extremities:
ten years’ experience at a dutch level 1 trauma center. Scand J Trauma Resusc Emerg Med. 2013 Jan 14;21:2.
doi: 10.1186/1757-7241-21-2.
6. Branco BC, Inaba K, Barmparas G, Schnüriger B, Lustenberger T, Talving P et al. Incidence and predictors for the
need for fasciotomy after extremity trauma: a 10-year review in a mature level I trauma centre.
Injury. 2011;42:1157-63.
7. Berg RJ, Okoye O, Inaba K, Konstantinidis A, Branco B, Meisel Ec et al. Extremity firearm trauma: the impact of
injury pattern on clinical outcomes. Am Surg. 2012;78:1383-7.
8. Burg A, Nachum G, Salai M, Haviv B, Heller S, Velkes S et al. Treating Civilian Gunshot Wounds to the Extremities
in a Level 1 Trauma Center: Our Experience and Recommendations. IMAJ.2009;11:546-51.
9. Parker SJ, Jarvis LJ, Dale RF. Magnetic resonance imaging in the evaluation of a high-velocity gunshot wound to
the thigh. Br J Surg. 1997;84:11-19.
10. Hess U, Harms J, Schneider A, Schleef M, Ganter C, Hannig C. Assessment of gunshot bullet injuries with the use
of magnetic resonance imaging. J Trauma. 2000;49:704-9.
 Blast Injuries
S.V. Kumar

Introduction
Blast injuries due to explosions remain the leading cause of death and injury to combatants and
civilian population. Blasts can produce horrific injuries to patients with the burn component and
amputation being the most obvious of first contact.

The management of blast injury casualties is complex due to presentation in mass-casualty events,
the presence of multiple penetrating wounds and the possibility of coexisting primary, secondary,
tertiary and/or quaternary injuries.
Blast exposure has the potential to derange
multiple body systems and each having
implication for early treatment. Explosions cause
injury by means of
• Pressure differentials (Figure 1)
• Fragmentation
• Violent displacement
• Collapse of infrastructure, heat and
• Exacerbation of chronic illness

Primary Blast Injuries

• Pressure differentials upon tissues of
heterogeneous densities i.e. AIR FILLED
organs are mainly responsible for these
primary injuries.
• Rupture of tympanic membrane (TM) is
known to be the first organ to get effected by
the blast and as little as 5psi (Pounds per square inch) of pressure is enough to cause damage.
• An intact TM doesn’t indicate the lack of pulmonary injury1.
• In Blast Lung: Alveoli become flooded with fluid and cellular debris.
• Mild traumatic brain injury (mTBI) results from free radical release and neuronal cell death.

Secondary Blast Injuries (SB)

• More common than primary injuries.
• They result from objects that have been ENERGIZED by the explosion to become projectiles.
• These secondary blast injuries are the real killers of explosions.
• Injuries to head, neck or chest carry high mortality.
• Close proximity injuries can result in
 Decapitation
 Dismemberment
 Extreme tissue devastations
If the local pressure exceeds 100psi, projectiles can cause 20 – 25times far greater degree of soft
tissue derangement and cavitation than the size of fragment itself.

Tertiary Blast Injuries

Structural collapse, violent
displacement and entrapment cause
tertiary injuries. This mechanism has
the potential to kill a large number of
victims at the scene.

Quaternary Injuries

Figure 2. New York City, September 11 2001

The thermal effects of blast exposure and other environmental factors are responsible for these
injuries. These comprise

 Burns
 Inhalation injuries and
 Exacerbation of pre-existing medical conditions like COPD, CAD etc.

Treatment General Guidelines

The management of these complex multiple wounds will test even the seasoned team. Triage and
scene safety are particular importance. Penetrating blast injuries to the head, neck, face and chest
cause most fatalities after an explosion.

 The first priority is securing the airway, once the patient is transferred to a safe location.
 To minimize significant blood loss tourniquets should be applied to the extremity injuries.
 Treatment of hemorrhagic shock is a central theme in those who do not succumb
immediately.
 In patients requiring massive transfusions a 1:1 ratio of packed red blood cell units to plasma
units be achieved.
 Early pain control with morphine also helps to decrease the incidence of post traumatic stress
disorders.
 Since the TM is most sensitive to the blast pressure wave, the absence of rupture would
greatly decrease the risk of blast injury to lung, bowel or brain. If TM rupture is present, further
efforts to rule out injury to the above organs should be undertaken. TM rupture in most cases
can be treated conservatively.

Wound Management – Primary Treatment

 It can be difficult to initially appreciate the entire zone of some large blast injuries. Repeated
debridement every 24-48hrs may be indicated2, 3.
 Primary closure of blast wounds greatly increases the likelihood of infection. Wound left open
until they are clean and granulation tissue has appeared.
 Wound should be ready for delayed primary closure, skin grafting or other coverage 4-6 days
after primary surgery4,5.
 If repair of damaged tendons and nerves is deemed possible, they may be tagged with
sutures6,7. Alternatively, they can be left untagged in situ for secondary surgery8.

The use of Silver Impregnated Dressings in Blast Injuries9

Blast injuries may cause human tissues, fecal matter and other foreign bodies to become
impregnated within the tertiary injuries. Use of anti microbial silver in conjunction with topical negative
pressure greatly reduces the chances of developing sepsis or SIRS.

Specific Injuries and their Management

Pulmonary Injury: Blast lung is rare but insidious presentation as decrease in oxygen saturation or
frothy sputum and inability to oxygenate may be the initial clinical picture.
Subcutaneous emphysema also suggests severe pulmonary injury. High flow oxygen with
endotracheal intubation and judicious fluid administration are main lines of treatment.

Secondary penetrating injuries to the chest are frequently fatal because of the energy and multiplicity
of wounding. Tube thoracostomy and rarely formal thorocotomy may be required for these injuries.
Abdominal Injuries: Also known as Blast Abdomen and they include abdominal hemorrhage and
abdominal organ perforation. The most common organ in the abdomen to be injured are small bowel
(48%), spleen (21.5%) , kidney (20%) and liver (15.3%). CT scan is used for stable patients and
focused assessment sonography for trauma (FAST) is helpful for unstable patients.

The clinical manifestations include abdominal or testicular pain, tenesmus, rectal bleeding, nausea
and vomiting and may require primary anastomosis or repair in majority of patients10.

Extremity Injuries: There is a high incidence of extremity injuries in patients who survive the initial
event11, 12. The majority of the extremity injuries are caused by penetrating secondary effects and are
typically associated with severe soft tissue and bony destruction. With the primary goals of
management being preservation of limb length and viable tissues for later coverage.

Traumatic Brain Injury: mTBI / Concussion after IED exposure is increasingly recognized as a
sequel of primary blast injury. Altered consciousness, headache, dizziness, nausea and vomiting and
difficulty in concentration are the common presenting symptoms.
In the vast majority the symptoms of mTBI are self limited and symptomatic treatment is all that is
necessary.

Cardiovascular Dysfunction13: When a patient present with profound shock without signs of
hemorrhage are other common causes for hypotension, cardiovascular dysfunction should be
suspected. Associated lung injury is common and inotropic support may be provided.

Crush Syndrome: Skeletal muscle is compressed releasing

 Myoglobulin
 Urates
 Phosphates and
 Potassium
Cellular death results in renal dysfunction and cardiac arrest. The main stay of treatment is
aggressive hydration, alkalinization of the urine and forced diuresis.

Special Considerations: These exist in pregnancy, children, elderly and disabled. Psychological
issues are also required to be considered.

 Pregnancy: Injuries to the placenta are possible and continuous fetal monitoring along with
an expert OBG/Gyn consultation are best line of management.
 Children: History of event or complaints may be difficult to obtain in children. Pulmonary
contusion is one of the most common injuries from blast thoracic trauma. Referral to
specialized pediatric trauma centre may be required.
 Elderly: There is a high risk of mortality and inhospital stay be more prolonged and
complicated. Orthopedic injuries may be more prevalent and blunt chest trauma should be of
special consideration.
 Disabled: Special consideration should be given to patients with underlying medical
conditions and it may be stressed that untreated or inadequately treated fractures may lead to
severe and long lasting disabilities.
 Underwater Blast: If a blast occurs underwater,
there is a compounding effect of the energy as
blast wave attempts to pass through water, which
is greater in density than air. However, it also
dissipates more quickly and the shrapnel travels a
short distance as friction reduces its velocity. A
greater blast energy imparted on the abdomen
than the lungs.

Fig 3. INS Sindhurakshak, 15 Aug 2013,

Mumbai
  Psychological Issues: The common sequel from an explosive event includes anger,
frustration, helplessness and desire to seek revenge and may require psychological
counseling.

Conclusion
Patients with blast injuries are difficult to manage because their most obvious injuries may not be the
most likely to contribute to their mortality. Blast injuries may cause LOTS of casualties with LOTS of
injuries. Secondary blast trauma is the biggest killer. From full thickness burns to partial and full
amputations, blast injury survivors may present with graphic injuries. These patients are best
managed in advanced trauma centers.

REFERENCES

1. Peter Peters; Primary Blast Injury: An intact tympanic membrane does not indicate the lack of a pulmonary blast
injury. Military Medicine 2011: 176: 110-114.
2. Coupland RM ; Technical aspects of war wound excision. Br J Surg 1989;76:663-7.
3. Stanee Z. Skurbic S et al; High energy war wounds. Flap reconstruction. Ann Plast Surg . 1993:31:97-102
4. Ryan JM, Cooper GJ, Harwood IR, Milner SM; Field surgery on a future conventional battle field. Strategy and
wound management. Ann R Col Surg Engl. 1991:73:13-20
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129 – 34.
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8. Bajec J, Gang RK, Larl AR; Post Gulf war explosive injuries in liberated Kuwait. Injury 1993: 24: 517-20.
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urban battlefield. J Trauma 2000: 29: 515-29.
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Trauma 2007:62:902-12
13. Nelson TJ, Clark T, Stedje – Larsen ET et al; Close proximity blast injury patterns in Iraq. J Trauma 2008:65:212-7.
 Prevention of Surgical Site Infections
VK Malik, Ashish Dey

th
The principles of antisepsis by Joseph Lister and Pasteur’s germ cell theory in the 19 century have
led to a better understanding in the etiopathogenesis of post operative wound infection. Despite
improvements in operating room practices, instrument sterilization methods and better surgical
technique, surgical site infections (SSIs) remain a major cause of post operative morbidity and delay
in discharge from the hospital.

SSI are the third most commonly reported nosocomial infections and accounts for 14-16 per cent of
all nosocomial infections among hospital inpatients. Organisms associated with SSIs vary with the
anatomic location of the operation and the procedure performed. The most common organisms
isolated from SSIs are Staphylococcus aureus (coagulase negative staphylococci), enterococcus
species and Escherichia coli For most SSIs, the source of the pathogen(s) are endogenous and
comes from the patient’s skin, mucous membranes or bowel. Exogenous SSI pathogens are
occasionally responsible and includes aerobic staphylococci and streptococci. These organisms
mostly come from members of the surgical team (e.g., hands, nose or other body parts),
contaminated surfaces in the operating room, even the air; and contaminated instruments, surgical
gloves or other items used in surgery.

At the end of surgery bacteria and other microorganisms contaminate all surgical wounds, but only a
small number of patients actually develop a clinical infection. Whether an infection actually occurs
depends on the number of bacteria entering the wound, type and virulence of the bacteria and the
host defense mechanisms. In a study done to find the incidence of SSIs in clean and clean
contaminated surgeries it was found that the risk also increases in cases where a darin was put as
compared to cases without drainage.

Other factors affecting rates of SSIs include Obesity, malnutrition, associated comorbidities and
immunocompromised states.

A system of classification for operative wounds that is based on the degree of microbial contamination
was developed by the US National Research Council group in 1964. Four wound classes with an
increasing risk of SSIs were described: clean, clean-contaminated, contaminated and dirty. The
simplicity of this system of classification has resulted in it being widely used to predict the rate of
infection after surgery. The surgical wound classification system can be divided into the following four
categories:

Class I—clean. Uninfected operative wound with no inflammation and in which the respiratory,
gastrointestinal, genital and urinary tracts were not entered. Clean wounds are closed at surgery and,
if necessary, drained with closed drainage.

Class II—clean-contaminated. Wound in which the respiratory, GI, genital or urinary tract(s) were
entered under controlled conditions but without unusual contamination or spillage of contents.

Class III—contaminated. Open, fresh accidental wound or an operation with a major break(s) in
aseptic technique (e.g., open cardiac massage) or gross spillage from the GI tract. Also included are
incisions in which acute, nonpurulent inflammation is found.

Class IV—dirty or infected. Old wounds with dead tissue and those that involve existing clinical
infection or a perforated bowel, suggesting that the pathogens causing the postoperative infection
were present in the wound before the surgery.
DEFINITION OF SSIs

Surgical site infections- Either an incisional or organ/space infection occurring within 30 days after
an operation or within 1 year if an implant is present, and at least one of the following:
 Purulent drainage, with or without laboratory confirmation, from the superficial incision.
 Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial
incision.
 At least one of the following signs or symptoms of infection: pain or tenderness, localised
swelling, redness, or heat and superficial incision is deliberately opened by surgeon, unless
incision is culture-negative.
 Diagnosis of superficial incisional SSI by the surgeon or attending physician

Incisional SSIs are further divided into superficial incisional (that only involves skin and
subcutaneous tissue) and deep incisional (those involving deeper soft tissue, including fascia and
muscle layers).

Organ/ Space SSI are those infections occurs within 30 days after the operation if no implant is left in
place or within one year if implant is in place and the infection appears to be related to the operation
and infection involves any part of the anatomy (e.g. organs or spaces), other than the incision.

Reducing the Risk of Surgical Site Infections

Changes in definition of surgical site infection have focused attention on the factors associated with
SSIs and are now being studied with a view to limiting the risk of infection. Host-related factors that
lead to an increased risk of SSI include: -
 Extremes of age.
 Morbid obesity.
 Other co-morbid illness.
 Increased glucose levels (>200 mg/dL) in the immediate post-operative period (48- hours) were
associated with increased SSI risk.
 Smoking delays primary wound healing and may increase the risk of SSI.
 Patients who are receiving steroids or other immuno-suppressive drugs pre-operatively may be
predisposed to developing SSI.
 Malnutrition
 Prolonged pre-operative hospital stay.
 Perioperative transfusion.

Research has shown that surgical techniques, skin preparation and the timing and method of wound
closure are significant factors that can influence the incidence of subsequent infection. Antibiotic
prophylaxis has also had a positive impact after certain types of surgery. Many other factors have
been identified as having an effect on the potential for infection and healthcare professionals should
consider these before, during and after surgery. In 1999, CDC issued a number of guidelines for
reducing the risk of SSIs. They can be grouped as follows

Operating Room Measures: Although all guidelines regarding Intraoperative Operating Room
ventilation may not be financially possible they should be adhered to as much as possible.

a. Ventilation

1. Positive-pressure ventilation in the operating room with respect to the corridors and adjacent
areas should be maintained.
2. A minimum of 15 air changes per hour, of which at least 3 should be fresh air should be
ensured.
3. Air should be introduced at the ceiling, and exhaust near the floor.
4. Operating room doors should be kept closed except as needed for passage of equipment,
personnel and the patient.
 5. The number of personnel entering the operating room should be limited to necessary
personnel.

b. Cleaning and disinfection of environmental surfaces

When visible soiling or contamination with blood or other body fluids of surfaces or equipment
occurs during an operation, a disinfectant should be used to clean the affected areas before
the next operation.

c. Sterilization of surgical instruments

1. All surgical instruments should be sterilized according to published guidelines.

2. Flash sterilization should be performed only for patient care items that will be used
immediately (e.g., to reprocess an inadvertently dropped instrument). It should not be used for
reasons of convenience, as an alternative to purchasing additional instrument sets, or to save
time.

Preoperative Measures
a. Method of hair removal- In a Cochrane review that included Eleven RCTs that compared hair
removal (using either depilatory cream or razors) with no hair removal showed no statistically
significant difference between the groups in terms of surgical site infections. It also showed that there
were statistically significantly more SSIs when people were shaved rather than clipped. There were
also no difference in SSIs when patients are shaved or clipped one day before surgery or on the day
of surgery. The recommendations therefore are: -
1. Hair should not be removed preoperatively unless the hair at or around the incision site
interferes with the operation.
2. If hair is removed, it should be removed immediately before the operation, preferably with
electric clippers.
3. Serum blood glucose levels should be adequately controlled in all diabetic patients
4. Stopping use of tobacco products should be encouraged preoperatively. Patients should be
instructed to abstain from smoking for at least 30 days before elective operation.
5. The incision site should be thoroughly washed and cleaned to remove gross contamination
before performing antiseptic skin preparation.
6. Whenever possible, all infections remote to the surgical site should be identified and treated
before elective operation.
7. An appropriate antiseptic agent for skin preparation should be used (Table 1). Wide prepping
of the proposed incision site with antiseptic solution preoperatively helps keep
microorganisms from migrating into the wound (breakthrough) if the site towels or drapes
become wet during surgery

Characteristics of Antiseptic Solutions and suggested application

Antiseptic Mechanism of Antimicrobial Coverage Onset Duration Application
Action
Aqueous- Free iodine − Excellent for gram +ve Intermediate 2 hours 2-step scrub and
iodophor protein, DNA bacteria, good for gram paint
damage −ve, fungi, virus,
mycobacteria
Aqueous- Disrupts Excellent for gram +ve, Intermediate 6 hours 2-step scrub and
CHG membranes good for gram –ve and dry, repeat
virus, fair for fungus, poor
for mycobacteria
Alcohol- Denatures Improved gram –ve Rapid 48 hours 1-step paint Dry
iodophor protein, free ,mycobacteria activity time, minimum of 3
iodine − min on hairless
protein, DNA surface
damage
Alcohol-CHG Denatures Improved gram −ve, Mtb, Rapid 48 hours Dry site: 30-sec
protein, fungal activity Moist site: 2-min
disrupts Dry time, minimum
membranes of 3 min on
hairless surface
CHG- chlorhexidine gluconate.

b. Hand/forearm antisepsis for surgical team members

1. Nails should be kept short.
2. A preoperative surgical scrub should be performed for at least 2 to 5 minutes using an
appropriate antiseptic. The hands and forearms should be scrubbed up to the elbows.
3. Wearing of hand or arm jewellery should be discouraged

c. Surgical attire - A surgical mask that fully covers the mouth and nose should be worn throughout
the operation. A cap or hood that fully covers the hair on the head and face should be worn when
entering the operating room. Surgical gowns and drapes that are wet are ineffective barriers and
should be avoided. Scrub suits that are visibly soiled, contaminated and/or penetrated by blood or
other potentially infectious fluids should be changed.

d. Asepsis and surgical technique

1. Principles of asepsis when placing intravascular devices (e.g., central venous catheters),
spinal or epidural anesthesia catheters, or when dispensing and administering intravenous
drugs should be adhered to.
2. Good surgical technique is indispensable as it minimizes tissue trauma, controls bleeding,
eliminates dead space, removes dead tissue and foreign bodies, uses minimal suture and
maintains adequate blood supply and oxygenation. Specifically, it is important to handle soft
tissue gently to avoid crushing that can result in tissue necrosis. Electrocautery should be
sparingly to control bleeding because it leaves behind dead tissue that is more likely to
become infected.
3. Absorbable suture should be used whenever possible because permanent suture, especially
silk suture, reduces the number of bacteria necessary to cause infection
4. Closed suction drains that exit through a separate stab wound helps prevent accumulation of
tissue fluid in the dependent portion of the wound. Preventing this is especially important in
obese patients and may reduce SSIs. Passive drains, such a Penrose drain, exiting through
the bottom of the incision should not be used.

e. Antimicrobial prophylaxis: Experimental studies published during the early 1960s helped to
achieve a more scientifically accurate approach to antimicrobial prophylaxis. Most important was the
report by Burke which demonstrated the crucial relationship between timing of antibiotic
administration and its prophylactic efficacy. His experimental studies showed that to greatly reduce
experimental skin infection produced by penicillin-sensitive S. aureus, the penicillin had to be in the
skin shortly before or at the time of bacterial exposure. This important change in strategy helped
correct the common error of first administering the prophylactic antibiotic in the recovery room.

As early as 1964, Bernard and Cole reported on the successful use of prophylactic antibiotics in a
randomized, prospective, placebo-controlled clinical study of abdominal operations on the
gastrointestinal tract.

A prophylactic antimicrobial agent should be used only when indicated, and selected based on its
efficacy against the most common pathogens causing SSI for a specific operation and published
recommendations.
1. The initial dose of prophylactic antimicrobial agent should be administered by the intravenous
route, timed such that a bactericidal concentration of the drug is established in serum and
tissues when the incision is made. Therapeutic levels of the agent in serum and tissues
should be maintained throughout the operation and until a few hours after the incision is
closed
2. The use of antibiotics preoperatively can reduce the rate of infection, particularly wound
infections, after certain operations. For most procedures, an inexpensive, first- or second-
generation cephalosporin, which has a moderately long half-life and is active against
staphylococci and streptococci, has been effective when given intravenously (IV) 30 minutes
before surgery.
 3. Also, third- and fourth-generation cephalosporins should not be used for routine surgical
prophylaxis because they are expensive, their spectrum of activity includes organisms rarely
encountered in elective surgery and their widespread use may promote the emergence of
resistance.

Antibiotic Prophylaxis before Elective Colon Resection

The human colon and distal small intestine contain an enormous reservoir of facultative and
anaerobic bacteria, separated from the rest of the body by the mucous membrane. A reliable method
of sterilizing the colonic contents has been a goal of surgeons throughout this century. In the past 25
years, clinical trials have demonstrated that to substantially reduce septic complications after elective
colon surgery, antibiotics must have activity against both colonic aerobes (e.g., Escherichia coli) and
anaerobes (e.g., Bacteroides fragilis). Today, approaches to mechanical cleansing differ widely.
Modern approaches include standard outpatient mechanical cleansing with dietary restriction,
cathartics, and enemas for a 2-day period, or whole-gut lavage with an electrolyte solution of 10%
mannitol, Fleet's phospho-soda, or polyethylene glycol, done the day before the operation.

Most surgeons use both antibiotics and mechanical cleansing for preoperative preparation before
elective colon resection. The most popular regimen in the United States has been the neomycin-
erythromycin base preparation, which was introduced in 1972. The use of outpatient bowel
preparation is increasing; however, patient selection is critical, and education is needed to reduce the
rate of complications.

Antibiotic Prophylaxis for Appendectomy

The pathologic state of the appendix is the most important determinant of postoperative infection.
Wound infection after appendectomy for perforative or gangrenous appendicitis is four to five times
higher than for early disease. Because the pathologic state of the appendix often cannot be
determined before or during operation, a parenteral antibiotic agent is recommended as prophylaxis in
all patients. Regimens with activity against both facultative gram-negative bacilli and anaerobes are
more effective than those active only against aerobes.

Antibiotic prophylaxis in Urogenital surgeries.

Antibiotic prophylaxis is recommended in transrectal prostate biopsy, in ESWL, in PCNL, endoscopic
ureteric stone removal and highly recommended in TURP. This is to prevent batereriuria, urinary tract
inection and subsequent urosepisis. Gram(-) bacilli and Enterococcus are the predominant
organisms . Cefazolin is the recommended drug and Ciprofloxacin the alternative antibiotic.

Antibiotic prophylaxis in Upper G I surgery

Antibiotic prpphylaxis is recommended in gastric surgeries including gastric bypass and small
intestinal surgery. Predominant organisms include Enteric Gram(-) bacillind Gram(+) cocci. Preferred
antibiotic for prophylaxis is Cefazolin and Clindamycin + Aminoglycoside being the alternative
regimen.

Antibiotic prophylaxis in Biliary tract surgery

Antibiotic prophylaxis is recommended is recommended in biliary surgery, pancreatic surgery, liver
surgery and in high risk patients for gal lader sugery. However for patients undergoing routine
laparoscopic gall bladder surgery in general risk patients, antibiotic prophylaxis is not recommended.
Predominant organisms again include Enteric Gram(-) bacillind Gram(+) cocci. Preferred antibiotic
for prophylaxis is Cefazolin and Clindamycin + Aminoglycoside being the alternative regimen.
Preventive Antibiotic Use in Traumatic Chest Injuries
Recently published studies have shown the value of parenteral antibiotic prophylaxis in the prevention
of pneumonia or empyema after the placement of a chest tube to correct the hemopneumothorax
associated with chest trauma. In both studies patients receiving antibiotics had substantially lower
infection rates than those receiving placebos.

In spite of the use of prophylactic antibiotics, SSIs are still a real risk of surgery and represent a
substantial burden of disease for both patients and healthcare services in terms of morbidity, mortality
and economic cost. Factors like Prolonged preoperative hospitalization exposes patients unduly to
hospital flora including multidrug-resistant organisms. Prompt postoperative discharge reduces the
risk of infection, provided patients are able to take care of themselves at home. A combined effort
between the health care providers including hospital staff and nursing personnel can go a long way in
preventing surgical site infections and reducing the burden of health care costs to a great extent.

Suggested reading

1. Micah L Hemani, Herbert Lepor, Skin Preparation for the Prevention of Surgical Site Infection: Which Agent Is
Best?, Rev Urol. 2009; 11(4): 190–195.
2. A J Mangram et al, Guideline for Prevention of Surgical Site Infection, 1999 (Infection Control and Hospital
Epidemiology 20 (April 1999) 250-280.
3. Lilani SP, Jangale N, Chowdhary A, Daver GB, Surgical site infection in clean and clean-contaminated cases.
Indian J Med Microbiol. 2005 ;23(4):249-52.
4. Ronald Lee Nichols, Preventing Surgical Site Infections: A Surgeon's Perspective, emerging infectious diseases, Vol. 7, No. 2
Mar–Apr 2001.

Other surgeries where antibiotic prophylaxis is recommended is shown in Table 1

 Parenteral Nutrition
Amit Sachdeva

Introduction

Malnutrition, including the depletion of essential micronutrients and erosion of lean body mass, is very
common in patients who are critically ill, with 20 to 40% of such patients showing evidence of
malnutrition. The incidence of malnutrition worsens over time in patients who require prolonged
hospitalization. Malnutrition before and during hospitalization is associated with increased morbidity
and mortality in hospitalized patients. However, the relationship between malnutrition and adverse
clinical outcomes is complex, because malnutrition may contribute to complications that worsen
nutritional status, and patients who are more difficult to feed are more critically ill and at higher risk for
death and complications.

This significance is particularly noted in the ICU. Critical illness is typically associated with a catabolic
stress state in which patients commonly demonstrate a systemic inflammatory response. This
response is coupled with complications of increased infectious morbidity, multi-organ dysfunction,
prolonged hospitalization, and disproportionate mortality. Over the past 3 decades, the understanding
of the molecular and biological effects of nutrients in maintaining homeostasis in the critically ill
population has made exponential advances. This support had 3 main objectives: to preserve lean
body mass, to maintain immune function, and to avert metabolic complications. Recently these goals
have become more focused on nutrition therapy, specifically attempting to attenuate the metabolic
response to stress, to prevent oxidative cellular injury, and to favorably modulate the immune
response. Nutritional modulation of the stress response to critical illness includes early enteral
nutrition, appropriate macro- and micronutrient delivery, and meticulous glycemic control.

There are now several updated practice guidelines by various clinical nutrition societies worldwide
which can be referred to for reasonable optimal patient care approach.
Parenteral nutrition (PN) represents an alternative or additional approach .The main goal of PN is to
deliver a nutrient mixture closely related to requirements safely and to avoid complications. Parenteral
nutrition (PN), either alone or in combination with enteral nutrition, can improve nutrient delivery to
critically ill patients

International Guidelines on Standardized Parenteral Nutrition

ASPEN Guidelines (American Society of Parenteral & Enteral Nutrition)

The evidence suggests advantages in efficiency, economy, and clinical appropriateness with the use
of standardized PN formulations compared with individualized PN formulations in select patient
populations.

The term standardized is often misinterpreted. A standardized PN formulation is a PN formulation

intended to meet the daily maintenance requirements of a specific patient population (eg, age-,
stress-, or disease state–specific) and differentiated by route of administration (central vs peripheral
vein). A standardized, commercial PN product is a standardized PN formulation available from a
manufacturer and requiring fewer compounding steps before administration. Current examples of
these products are multichamber bags of these products, often called premixed solutions.

Standardizing the macronutrient and micronutrient content of PN has been of interest since the
therapy was developed. PN is a complex formulation with unique physical and chemical
characteristics that create challenges in assuring that sterile, stable, and compatible formulations are
prescribed, prepared, and administered. Standardizing the content of PN may improve the clinician’s
prescribing of a complete, balanced formulation, thereby avoiding nutrient omission and subsequent
deficiency symptoms or nutrient excess and toxicity symptoms.

A standardized PN formulation eases the burden on the pharmacist in assuring a stable, compatible
admixture because these criteria would be considered in the development of the formulation.

Scientific Justification for exemption

As per the international guidelines Aminoacids alone are not sufficient enough to control or improve
nutritional status. Apart from aminoacids other macro nutrients like Fats and Carbohydrates have a
substantial role in improving the Nutritional status of the patients. Micronutrients like vitamins and
mineral play a very vital role.

Non protein calories are considered to be an integral part of Nutrition therapy. As per the guidelines
more than 70 – 80% calories should come from Non Protein part.
The “intensive care unit” (ICU) or “critically ill” patient is not a homogeneous population. Energy
(calorie) needs in adult patients in the ICU often vary considerably because of day-today changes in
clinical conditions. The most common is the Harris–Benedict equation, which incorporates the
patient’s age, sex, weight, and height. Current clinical practice guidelines suggest that an adequate
energy goal for most ICU patients is approximately equivalent to the measured or estimated resting
energy expenditure multiplied by 1.0 to 1.2. An alternative method is to use 20 to 25 kcal per kilogram
of body weight as the total caloric target range for most adults in the ICU.

The principal macronutrient components of central venous parenteral nutrition include amino acids,
lipids, and dextrose. PN consists of a complex mixture of macronutrients (carbohydrates, proteins,
lipids), micronutrients (vitamins, minerals, trace elements), fluid and electrolytes. Carbohydrates are
supplied as dextrose, proteins as amino acids, and lipids as intravenous fat emulsions (IVFEs). When
all 3 nutrients are combined in a single solution, it is called a total nutrient admixture or a 3 in 1
admixture.. The common recommendation for the amino acid dose ranges from 1.2 to 1.5 g per
kilogram per day for most patients with normal renal and hepatic function, although some guidelines
recommend higher doses (2.0 to 2.5 g per kilogram per day) under specific conditions. The
recommended maximal dose of lipid emulsion infusion is approximately 1.0 to 1.3 g per kilogram per
day. In central venous parenteral nutrition, a reasonable initial guideline is to provide 60 to 70% of
non–amino acid calories as dextrose and 30 to 40% of non–amino acid calories as fat emulsion.
In general, PPN solutions should not exceed 850 mOsm/L.

1. Carbohydrates:
Glucose constitutes a convenient and safe source of calories for use in PN.

 The minimal amount of carbohydrate required is about 2 g/kg of glucose per day
 Each gram of Dextrose provides 3.4 Kcal.

2. Proteins:
The principal goal of protein/amino acid administration in critical illness is to provide precursors for
protein synthesis in tissues with high turnover and to protect skeletal muscle mass and function.
When PN is indicated, a balanced amino acid mixture should be infused at approximately 1.3–1.5
g/kg ideal body weight/day in conjunction with an adequate energy supply.

 Each gram of amino acid provides 4 Kcal.

3. Lipids:
Early PN formulations consisted primarily of high concentrations of glucose and amino acids in order
to provide adequate calories and were often associated with a number of complications. Prolonged
use of these formulations was associated with essential fatty acid (EFA) deficiency because they did
not provide linoleic acid or alpha-linolenic acid, which are not synthesized by the body and must be
obtained from the diet.
The incorporation of lipids into PN formulations has addressed many of these issues. Lipids provide a
more energy-dense source of calories (approximately 9 kcal/g) than either amino acids (4 kcal/g) or
dextrose monohydrate (3.4 kcal/g). Therefore, the fluid volume of PN required to achieve adequate
caloric intake can be substantially reduced. The reduced fluid volume and increase in osmolarity of
formulations incorporating LEs permit the safe administration of PN via the peripheral and central
routes. Currently available parenteral LEs also contain sufficient LA and ALA to prevent EFA
deficiency. Perhaps most importantly, the use of LEs in PN is associated with a reduction in the
metabolic complications.
Fatty acids play key roles in determining the structural integrity and fluidity of cell membranes and can
give rise to several important bioactive mediators.

 Intravenous lipid emulsions (LCT, MCT or mixed emulsions) can be administered safely at a rate
of 0.7 g/kg up to 1.5 g/kg over 12 to 24 h
 Several studies have shown specific clinical advantages over soybean LCT alone but require
confirmation by prospective controlled studies.
 Olive oil-based parenteral nutrition is well tolerated in critically ill patients.

Requirements in Critically ill Patients

The table clearly highlights that all critically ill patients need a balance mix of macro and micro
nutrients.

Conclusion

 Malnutrition continues to be a serious problem in hospitalized patients and is associated with poor
patient outcomes.
 Aminoacids alone not sufficient enough to control or improve nutritional status.
 Parenteral nutrition support has expanded its role in our clinical practice today.
 When PN is indicated, a balanced mixture should be infused in conjunction with an adequate
energy supply. The minimal amount of carbohydrate required is about 2 g/kg of glucose per day.
Lipids should be an integral part of PN for energy and to ensure essential fatty acid provision in
long-term ICU patients.
 PN admixtures should be administered as a complete all-in-one bag.
 All PN prescriptions should include a daily dose of multivitamins and of trace elements.
 Olicilinomel Contains a balance mix of macro and micronutrients essentially required by critically
ill patients.
 Correction of Malnutrition results in decreased mortality, ICU stay, Ventilatory days stay ,
comorbid infections.
 Oliclinomel has several studies to prove its safety and efficacy in crtitically ill patients.
 The value of immunonutrient formulas in the management of critically ill and postoperative
patients is now acknowledged by many medical practitioners. However, it is important that the
clinician be aware that “one size does not fit all”.
 PN has evolved during the last four decades from a supportive therapy to a clear therapeutic role.
Like any other form of therapy, it will benefit patients when apropriately indicated and prescribed.
It may cause undesirable outcomes when poorly ordered.
Since we have seen lot of benefits about how improvement of Nutritional status could impact the
mortality , ICU stay etc we some whrere need to work upon the measure how to make it make
Parenteral Nutrition more affordable to the population. We need to seek out for the help from
Government to encourage the policies on Nutritional improvement.

Oliclinomel provides the balance mix of macro and micro nutrients

Peripheral vein Central vein

Nutritional Assistance Nutritional Total Parenteral
Assistance Nutrition
N4-550 N7-1000 N7-1000
E = WITH ELECTROLYTES E E E E
Volume (L) 1L 2L 1L 2L
Total calories (kcal) 610 1215 1200 2400
NP (Non-protein) calories (kcal) 520 1040 1040 2080
Nitrogen (g) 3.6 7.3 6.6 13.2
NP calorie-nitrogen ratio (kcal/g 144 144 158 158
N)
Glucose (g) 80 160 160 320
Lipids (g) 20 40 40 80
Carbohydrate-lipid ratio 62/38 62/38 62/38 62/38
Electrolytes (mmol)
Sodium 21 42 32 64
Otassium 16 32 24 48
Magnesium 2.2 4.4 2.2 4.4
Calcium 2 4 2 4
Phosphate 8.5 17 10 20
Chloride 33 66 48 96
Acetate 30 61 57 114
Osmolarity (mosm/l) 750 750 1450 1450

NUTRITIONAL ASSISTANCE TOTAL PARENTERAL

NUTRITION
PERIPHERAL VEIN CENTRAL CENTRAL VEIN
VEIN
N4-550 N7-1000 N7-1000
E = with electrolytes E E E E
Volume (L) 1L 2L 1L 2L
Total calories (kcal) 610 1215 1200 2400
NP (Non-protein) calories (kcal) 520 1040 1040 2080
Nitrogen (g) 3.6 7.3 6.6 13.2
NP calorie-nitrogen ratio (kcal/g N) 144 144 158 158
Glucose (g) 80 160 160 320
Lipids (g) 20 40 40 80
Carbohydrate-lipid ratio 62/38 62/38 62/38 62/38
Electrolytes (mmol) Yes Yes Yes Yes
Osmolarity (mosm/L) 750 750 1450 1450
REFERENCES
 Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, Griffiths R, Kreyman G, Leverve X, Pichard
C, ESPEN. ESPEN Guidelines on Parenteral Nutrition: Intensive care. Clin Nutr. 2009 Aug;28(4):387-400.
 McClave SA, Martindale. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult
Critically Ill Patient:: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral;
JPEN J Parenter Enteral Nutr 2009; 33; 277.
 ESPEN Blue Book-2011; Basics in Clinical Nutrition. Forth Edition. Editor in Chief - Lubos Sobotka. Publishing
House - galen. www.espenbluebook.org; www.galen.cz
 Calder Philip C,. Jensen Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and
future directions; Intensive Care Med (2010) 36:735–749.
 Juan Carlos Bucobo. Parenteral nutrition 101: a user’s guide. Gastrointestinal Endoscopy 2009; Volume 69, No. 7:
1351-1353.
 Ziegler TR. Parenteral Nutrition in the Critically Ill Patient: N Engl J Med 2009;361:1088-97.
 Mizock Barry A. . Immunonutrition and critical illness: An update :Nutrition 26 (2010) 701–707.
 Ulcerative Colitis: Surgical Aspects
Sundeep Saluja, Saleem Naik

Ulcerative colitis (UC) is an inflammatory ulcerating disease of the mucosa of large intestine of
unknown cause. It varies in severity. It is an inflammatory bowel disease that can be cured by
surgery. Although primarily treated by medical management, one third of patients require surgical
1
resection, which most of them undergo within 10 years of initial diagnosis . Till late 1960s, surgical
options were limited to total proctocolectomy with Brooke ileostomy or subtotal colectomy with
ileorectal anastomosis. Later, two other surgical options were developed, continent reservoir
ileostomy (kock pouch) and ileal pouch anal anastomosis2. The latter one revolutionized the surgical
management of UC and has become the procedure of choice.

INDICATIONS FOR SURGERY

Elective surgery
Approximately 70% of patients undergo surgery for chronic disease. Since there is no clear
demarcation for referring these cases, close consultation between surgeon, gastroenterologist and
patient is necessary to prevent excessive delay in surgical intervention which may affect the surgical
outcome with increased complication rates. The indications for elective surgery are:

a) Failure of medical treatment can be due to following reasons

i) Steroid resistant ulcerative colitis: Response to steroids has been variously defined, but
can be regarded as clinical improvement after treatment with high-dose oral steroids (40-60
mg prednisone or equivalent) within 30 days, and in severe ulcerative colitis, clinical
improvement after treatment with high-dose intravenous steroids within 7-10 days3,4.
Conversely, patients who fail to respond to steroids within these timeframes have been
defined as steroid-resistant. It constitutes 20-30% of patient undergoing surgery.
ii) Steroid dependent ulcerative colitis: Patients with ulcerative colitis who require several
courses of systemic steroids in order to achieve remission, but are followed by relapse of
symptoms during steroid tapering or soon after their discontinuation. This pattern of drug
response is known as steroid-dependency. Approximately 20-30 % patients are steroid
dependent3.
iii) Steroid complicating ulcerative colitis: Complications of long term steroids like diabetes
mellitus, osteoporosis, cataract etc constitutes a subgroup, which require surgical
intervention.
Procedure: These patients may undergo either two-stage or three stage pouch procedure
depending upon their general condition.

b) Cancer or cancer prophylaxis: 10% patients of UC undergo surgery for cancer or dysplasia5.
The independent risk factors identified include long duration of disease, presence of pancolitis,
associated primary sclerosing cholangitis and early onset of disease. The cumulative probability is
6
estimated to be 3%, 5% and 9% at 15, 20 and 25 years respectively or an increase of 0.5-1%
7
yearly after 8-10 years of duration . Hence, surveillance is recommended after 8years in patients
with pancolitis and 15 years in those with left sided colitis.
8
Procedure: depends on type of lesion –
i) Low grade dysplasia, high grade dysplasia, dysplasia associated lesion or mass (DALM) and
obstructive lesion are treated with restorative proctocolectomy with IPAA.
ii) Malignancy
 Localized colon cancer: Restorative proctocolectomy, mucosal proctectomy with IPPA
 Colon cancer of uncertain stage: Staged colectomy with ileostomy and Hartmann
followed by IPAA (favourable pathology) or permanent ileostomy (unfavourable
pathology).
 Metastatic or advanced colon cancer: Colectomy with permanent ileostomy and
Hartmann or ileorectal anastomosis.
 High rectal cancer (early stage): Restorative proctocolectomy, mucosal proctectomy with
IPAA
  High rectal cancer (advanced stage): Subtotal proctocolectomy with ileostomy with low
Hartmann closure of the rectum followed by adjuvant treatment. If no recurrence till 2
years, then IPAA can be planned.
 Distal rectal cancer: Total proctocolectomy with permanent ileostomy

c) Debilitating extra-intestinal manifestations are very rare independent indication for surgery.
Progressively destructive pyoderma gangrenosum or Coomb’s positive hemolytic anemia
unresponsive to steroids may rarely necessitate colectomy. Primary sclerosing cholangitis,
ankylosing spondylitis and sacroileitis do not respond to colectomy, while arthritis and skin lesions
respond well.
Procedure: Restorative proctocolectomy, mucosal proctectomy with IPAA

d) Malnutrition and growth retardation are significant problem in pediatric patients which may
necessitate colectomy1.

Emergency surgery9

Approximately 20% patients require urgent or emergent surgery for acute complications.
a) Toxic colitis: failure to respond to intensive treatment (nil per oral, intravenous fluids, parenteral
steroids and antibiotics) for 3-5 days10.
Procedure: subtotal colectomy with Hartmann/ mucous fistula and end ileostomy is procedure of
choice in these patients.

b) Toxic megacolon: It is a variant of toxic colitis with dilatation of colon (transverse colon diameter
6 cm). Evidence of free perforation or generalized peritonitis is indication for immediate surgery.
Septicemia, failure to respond to medical management (24-72hrs) and major colonic hemorrhage
are indications for urgent surgery. Incidence of this complication has decreased.
Procedure: Decompressive blow hole transverse colostomy and diverting loop ileostomy followed
11
by colectomy was considered to be safest procedure in 1960s . With better medical management
(increased awareness and earlier diagnosis of toxic megacolon), recognition of need for early
surgery, better antibiotics and postoperative supportive measures, most of these patients are
managed with subtotal colectomy with ileostomy and mucous fistula12.

c) Perforation peritonitis: is the most lethal complication and usually occurs in setting of toxic
megacolon. Signs and symptoms may be minimal in these patients as they are on high steroid
doses. Mortality may be as high as 50%.
Procedure: Best managed by subtotal colectomy with ileostomy and mucous fistula

d) Massive hemorrhage: accounts for 10% of all emergency colectomies for UC.
Procedure: Most patients are managed by subtotal colectomy with ileostomy and Hartmann’s
procedure. Additional proctectomy is rarely required for stump bleeding.

SURGICAL OPTIONS
While selecting the procedure, following parameters are taken under consideration
 Age
 General Condition
 Status of Continence
 Patient’s desire for continence
 Presence of dysplasia/ carcinoma
 Emergency/elective operation
 Diagnostic uncertainty
13
Total Proctocolectomy and Brooke Ileostomy
Total proctocolectomy and Brooke ileostomy is the earliest operation performed for UC. It removes all
the diseased mucosa and eliminates the risk of future cancer. As for cure of disease, it still remains
the gold standard. Added advantages include, absence of functional problems associated witth a ileal-
anal pouch. Major drawback of this operation is permanent ileostomy that has poor social acceptance
and causes psychological trauma. It is mostly performed as an elective procedure
Indications
a) Patients with poor sphincter tone
 b) Old patients (> 60 years) who are not good candidates for IPPA
c) Lifestyle related contraindication: keeps away from toilet facility
d) UC with distal rectal cancer

Complications
 Ileostomy related complications
 Pelvic dissection related: sepsis, hemorrhage, sexual and urinary dysfunction.
 Perineal wound related complications
Overall morbidity is 40%, 30% and 20% for emergency, urgent and elective cases.

Total Proctocolectomy with Continent Ileostomy (Kock pouch) 12,13

To reduce the esthetic appearance of the conventional ileostomy, a continent ileostomy was
developed from terminal ileum by Kock in 1969. This pouch provides internal storage for intestinal
contents and is attached to the abdominal wall with a flush ostomy opening. The patient empties the
pouch 4-6 times a day using a catheter, thereby eliminating the need for external appliance. The
operation was modified by addition of an intestinal nipple valve, using intusscepted ileum. The
procedure has not enjoyed widespread acceptance because of its intricate construction and relatively
high risk of valvular dysfunction, requiring one or more revision procedures. Satisfactory long term
function has been reported in two third of patients14.

Indications
a) Patient already with permanent ileostomy and wishes to be continent
b) Patients who are poor candidates for IPAA and wish to be continent
c) Those with failed IPAA:

Contraindications
a) Obese patients
b) Psychological unstable patients

Complications
a) Valvular dysfunction: revision rate 20%
b) Nonspecific reservoir ileitis 10%
c) Pouch skin and pouch enteric fistula

Subtotal colectomy with ileostomy 15,16

It is the most common procedure in the emergency condition. The principle is to remove most of the
diseased colon and retain rectum for establishing continence later. This avoids the pelvic dissection in
emergency situation and its attendant complications. Patients can recover from the ill effects of
disease and steroid before definitive surgery is planned.
Indications
a) Emergency surgery in UC
b) Indeterminate colitis
c) Patients on long term steroids
d) Patients with significant malnutrition
Contraindication
a) haemodynamically unstable patients, especially toxic megacolon with sepsis

Hartmann Vs mucous fistula

Most patients do well with Hartmann procedure. If the bowel is friable then the mucous fistula should
be taken out to avoid pelvis sepsis.

Subtotal colectomy with ileorectal anastomosis10

Ileorectal anastomosis at the time of subtotal colectomy converts the procedure into a definitive one.
The principle is to remove most of the diseased colon with maintaining anal continence. Bowel
frequency varies from 2-4/day with loose consistency. Another advantage is the pelvic dissection is
avoided in these patients. The major disadvantage of this procedure is that, it retains rectum which is
at risk for a) recurrence of disease b) malignancy (13- 20% after 20-30 years). These patients require
long term surveillance. The major complication is leak, which in elective setting is <2%.
Indications
a) UC and advanced PSC with portal hypertension
b) UC with advanced colonic malignancy
c) Chronic UC with rectal sparing (rare)
Contraindications
a) During emergency setting as leak rate are high
b) Presence of perianal disease or rectal stricture

Restorative Proctocolectomy
Restorative proctocolectomy has become the procedure of choice for patients with ulcerative colitis.
The principle is to remove the whole of diseased colon and rectum with preservation of the anal
sphincter and hence maintain continence. A pouch is constructed from 2- 4 ileal loops which
increases stool holding capacity and thereby reduces the bowel movements.

Contraindications
a) Patients with poor sphincter tone
b) UC with distal rectal cancer

Relative contraindication
a) Patients > 60 years
b) Lifestyle related contraindication: keeps away from toilet facility

Technical considerations and controversies of IPAA 13,15

Pre operative preparation
 Procedure is preceded by careful counseling. If possible, patient should talk to the previously
operated patients, to have realistic expectations.
 Site of the ileostomy should be marked
 Deep vein thrombosis prophylaxis
 Bowel preparation is not given as it may precipitate acute attack.
 Steroids should be continued preoperatively

Procedure (key points)

Colectomy starts with mobilization of right colon, followed by rest of the colon. Both flexures are
carefully brought down. Ileocolic trunk is preserved while middle colic is tied flush with superior
mesenteric vessels. The omentum is excised along with transverse colon by some as it reduces
adhesions in the postoperative period, while others retain it as it limits infection17. Terminal ileum is
transected flush with the caecum. Rectal mobilization is carried out along with mesorectum till the
pelvic floor.

Hand sewn vs stapled: In hand sewn anastomosis, rectum is divided 3 cm above the dentate line.
Mucosectomy is carried above dentate line transanally. Ileal pouch is brought through the rectal cuff
and hand sewn anastomosis is completed circumferentially at dentate line. While in stapled
anastomosis rectum is divided 2 cm above the dentate line using linear stapler. The pouch anal
anastomosis is carried out using end to end circular stapler without any mucosectomy.

Proponents of stapled anastomosis 18

 It is technically easier and faster.
 It maintains the transitional zone of anal mucosa which may improve neorectal sensation and
continence.
 A finite risk of malignancy or disease recurrence still remains as all rectal mucosa is not
eliminated after mucosectomy.

Proponents of hand sewn anastomosis

 As it removes the complete rectal mucosa therefore has minimal risk of flare up or
malignancy.
 Mucosectomy does not affect the continence.

A recent meta-analysis of 4183 patients shows that stapled IPAA offered improved nocturnal
continence which was reflected in higher physiologic measurement. A risk of increased incidence of
dysplasia in stapled group was not statistically significant 19. Therefore stapled IPAA is probably better
choice except in patients with dysplasia or rectal cancer and patients with extraintestinal
manifestations.

Pouch design: To reduce the bowel frequency, rectum like reservoir was devised from ileum. Parks
2
and Nicholls (1978) described an ileal reservoir in S configuration using 3 loops . Utsunomiya devised
20
a simpler configuration (J pouch) using 2 loops . After a decade of experimentation with various
configuration of pouch (S, J, H and W), the J configuration has been accepted as standard operative
technique. Evidence suggests that pouch compliance correlates with the length of the intestine used
rather than actual design. 30-40 cm of the ileum is required to achieve the optimal results.

Advantages of J pouch: easier to construct, better efficiency of evacuation and excellent fit into the
concavity of sacrum.
W and S pouch have longer length and can be used if J pouch is not reaching down. W pouch has the
poorest results in emptying.

Mobility of pouch13: Pouch should reach 4-6cm below pubic symphysis without stretching. Sometime
the apex of the pouch may not comfortably reach down. It can occur in tall/obese patients or in
patients who have undergone previous surgeries.

Operative techniques employed to improve the mobility of the pouch are

a) Mobilization of the small bowel mesentery to the third part of duodenum
b) Transverse incisions of the peritoneal layers of the small bowel mesentery. Avoid any
excessive skeletonization of the blood vessels that may result in tearing of blood vessels.
c) Division of either distal ileocolic or branches of superior mesenteric arteries provided an
adequate supply is available through marginal vessels.
d) Preservation of middle colic and its right branch during vascular ligation of colon. The
mesentery of colon with its marginal artery proximal to this point is preserved. With this
maneuver both ileocolic and distal superior mesenteric artery are ligated.
e) Alternative pouch configuration S and W shaped pouch.

Diverting ileostomy: Proponents suggests using a temporary diverting loop ileostomy allows fecal
diversion during early weeks following surgery to allow ileal pouch and ileoanal anastomosis heal,
thereby significantly reduces the post operative complications like pelvic sepsis and anastomotic
dehiscence. The function of the anal sphincter is restored in the resting phase. Opponents argue that
incidence of small bowel obstruction increases with ileostomy. It adds an extra procedure and thereby
increases the hospital stay. It avoids disuse atrophy of pouch and anal sphincter. Proximal ileostomy
may obstruct the marginal artery and lead to pouch ischemia. Evidence suggests that loop ileostomy
may be omitted in selected cases where patient is on low dose steroids, good general condition and
nutritional status and had no technical problems during surgery21. Diverting ileostomy does not
prevent leak but significantly reduce complication flowing leak most importantly pelvic sepsis, which is
the most important independent prognostic factor, for pouch function.
22
Laparoscopic IPAA : It is a difficult procedure involving all four quadrants of abdomen and quite
often a friable colon. Recent reports suggest laparoscopic IPAA is safe and feasible. Surgical time is
much longer than conventional surgery. It is possible in patients who had prior colectomy. It has been
shown to have less pain, adhesions, with improved cosmesis and fertility rates and better quality of
life.

Special considerations
Age: most patients undergoing pouch surgery are in thirties and forties. Earlier, age> 55 years was
considered as an absolute contraindication for pouch surgery. Now with increasing experience older
patients with good sphincter function are being offered pouch surgery. However, increased incidence
of nocturnal evacuation and incontinence occur in these patients.
Women: women with active ulcerative have reduced fertility as a result of disease activity and
23
extensive pelvic dissection and IPAA further decreases fecundicity . Therefore consideration should
be given to delayed proctectomy and IPAA reconstruction in child bearing age if it is safe to do so.
Pregnancy itself is safe and most of the patients are able to carry to term. One third of patients
experience transient disturbances in pouch function, mainly during third trimester and three months
following delivery. The type of delivery does not affect the pouch function postpartum. Presence of
ileal pouch does not mandate cesarean section13.

Complications
Early
a) Small bowel obstruction is the most common complication. The frequency varies from 11-
26%24-26. Three fourths of patients are managed conservatively. The most common site of
27
obstruction is at the ileostomy . Other causes include adhesions, internal hernia, stenosis and
volvulus around the ileostomy.
24-26
b) Sepsis occurs in 3-15% patients . Causes include a leak of the pouch or pouch anal
anastomosis and contamination of the peritoneal cavity at surgery. In the recent years incidence
of pelvic sepsis has come down.
c) Urinary retention
d) Hemorrhage, deep venous thrombosis and pulmonary embolism are other rare complications.

Late
a) Pouchitis is the most frequent late complication occurring in 10- 28% of patients24-26. It is
characterized by fever, abdominal pain and increased stool frequency and urgency with peak
incidence at 18 months after surgery. The key components are sign and symptoms, endoscopic
findings and histology. Most patients have intermittent symptoms and respond well to
metronidazole and ciprofloxacin. Some patients may experience chronic pouchitis that may
ultimately lead to pouch excision.
b) Pouch fistulas occur in 2-8-9.7 % of cases24-26. It usually occurs between pouch and perianal
skin or pouch and vagina. Factors that may predispose to these fistula include ischemia of pouch,
leak, inadvertent inclusion of vagina in the anastomotic suture line and crohn’s disease. If the
fistula occurs early after IPAA it is likely to be secondary to anastomotic leak. Antibiotics, drainage
of associated pelvic abscess and prolonged ileal diversion are required to manage these patients.
They may close spontaneously or persistent fistula may be treated with advancement flaps or
28
pouch reconstruction .
c) Pouch failure: it occurs in about 5-20% of patients29. Causes of pouch failure include pelvic
sepsis, anastomotic stricture, fistula, pouchitis, poor functional result or crohn’s disease. Pelvic
sepsis and anastomotic failure are the main and often interrelated cause of pouch failure30. Pouch
salvage surgery with reanastomosis may be successful in about 60% cases31.
d) Sexual and urinary dysfunction

Long term functional results and quality of life

Functional results after IPAA improve during the first year. Initial frequency of 8-10 stools per day
improves to 4-6 stools per day at 1 year. Factors associated with slightly worse pouch function include
age greater than 50, presence of extra-intestinal manifestations, anastomotic strictures and pouchitis.
Overall patients are not bothered by minor degree of incontinence and 93% patients reported an
excellent quality of life24. Several studies have shown better quality of life in patients with IPAA than in
medically treated patients or patients with TPC and permanent ileostomy32.

Summary
Although since long, surgery is known to be potentially curative for ulcerative colitis, a fewer patients
opted for it. Surgical management of ulcerative colitis has changed since the development of pouch
procedure. However, it requires a lot of motivation from the patient to go through a long period of
convalescence. In specialized center, 80% patients are continent with frequency of 4-6 stools per day
and good quality of life.

REFERENCES
1. Becker JM. Surgical therapy for ulcerative colitis. Gastroenterology clinics of North America 1999;28:371-90.
2. Parks AG, Nicholas R. Proctocolectomy without ileostomy for UC. BMJ 1978;2:85-88.
3. Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in
Crohn's disease. Gut 1994; 35: 360–2.
4. Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974; 303:
1067–70.
5. Lavery IC. Cancer in mucosal ulcerative colitis. In: Jagelman DG editor. Mucosal Ulcerative colitis. Mount Kisco
NY, Futura, 1986: 177-88.
6. Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in extensive
ulcerative colitis: findings among 401 patients over 22 years. Gut. 1990;31:800-6.
7. Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease.
Aliment Pharmacol Ther. 2003;18 Suppl 2:1-5.
8. Stucchi AF, Aarons CB, Becker JM. Surgical approaches to cancer in patients who have inflammatory bowel
disease. Gastroenterol Clin North Am. 2006;35:641-73.
9. Oakley JR. Management of toxic ulcerative colitis. Fazio VW, Church JM, Delany C. 2 ed.Current therapy in colon
and rectal surgery Mosby, 2005. St Louis 219-24
10. Blumberg D, Beck DE. Surgery for ulcerative colitis. Gastroenterol Clin North Am. 2002;1:219-35.
11. Turnbull RB, Hawk WA, Weakley FL. Surgical treatment of toxic megacolon: Ileostomy and Colostomy to prepare
patients for colectomy. Am J Surg 1971;122:325-31.
12. MRB Kieghley Acute fulminant colitis and emergency colectomy. MRB Keighley, NS Williams (eds) Surgery of the
anus rectum and colon Vol.2 WB saunders company Ltd, 1993. London 1379-97.
13. Mcmurrick PJ, Dozois RR. Chronic ulcerative colitis: Surgical options. Fazio VW, Church JM, Delany C. 2
ed.Current therapy in colon and rectal surgery Mosby, 2005. St Louis 211-18
14. Lepistö AH, Järvinen HJ. Durability of Kock continent ileostomy. Dis Colon Rectum. 2003;46:925-8.
15. Kelly KA, Dozios RR. Chronic ulcerative colitis. Kelly KA, Sarr MG, Hinder RA. 1 ed. Mayo Clinic Gastrointestinal
Surgery WB saunders, 2004 Pennsylvania 533-52
16. Hawley PR. Emergency surgery for ulcerative colitis. World J Surg. 1988;12:169-73.
17. Ambroze WL Jr, Wolff BG, Kelly KA, Beart RW Jr, Dozois RR, Ilstrup DM. Let sleeping dogs lie: role of the
omentum in the ileal pouch-anal anastomosis procedure. Dis Colon Rectum. 1991;34:563-5.
18. Gemlo BT, Belmonte C, Wiltz O, Madoff RD. Functional assessment of ileal pouch-anal anastomotic techniques.
Am J Surg. 1995;169:137-42
19. Lovegrove RE, Constantinides VA, Heriot AG, Athanasiou T, Darzi A, Remzi FH, Nicholls RJ, Fazio VW, Tekkis PP.
A comparison of hand-sewn versus stapled ileal pouch anal anastomosis (IPAA) following proctocolectomy: a
meta-analysis of 4183 patients. Ann Surg. 2006;244:18-26.
20. Utsunomiya J, Iwama T, Imajo M et al. Total colectomy, mucosal proctectomy, and ileoanal anastomosis. Dis
Colon Rectum.1980 Oct;23(7):459-66.
21. Larson DW, Pemberton JH. Current concepts and controversies in surgery for IBD. Gastroenterology.
2004;126:1611-9.
22. Simon T, Orangio G, Ambroze W, Schertzer M, Armstrong D. Laparoscopic-assisted bowel resection in
pediatric/adolescent inflammatory bowel disease: laparoscopic bowel resection in children. Dis Colon Rectum.
2003;46:1325-31.
23. McGuire BB, Brannigan AE, O'Connell PR. Ileal pouch-anal anastomosis. Br J Surg. 2007;94:812-23.
24. Fazio VW, Ziv Y, Church JM et al. Ileal pouch-anal anastomosis complications and function in 1005 patients. Ann
Surg 1995;222:120-8.
25. Marcello PW, Roberts PL, Schoetz DJ et al. Long term results of the ileoanal pouch procedure. Arch Surg
1993;36:1105-11.
26. Wexner SD, Wong WD, Rothenberger DA et al. The ileoanal reservoir Am J Surg 1990;159:178-85.
27. Marcello PW, Roberts PL, Schoetz DJ et al. Obstruction after ileal pouch-anal anastomosis: A preventable
complication? Dis Colon Rectum 1993;36:1105-11.
28. Whitlow CB, Opelka FG, Gathright JB et al. Treatment of colorectal and ileoanal anastomotic sinuses. Dis Colon
Rectum 1997;40:760-3
29. Fazio VW, Tekkis PP, Remzi F et al. quantification of risk for pouch failure and life expectancy of ileoanal pouch.
Ann Surg 2003;238:605-17
30. Olangunju A, Korsgen S, Keighley MRB. Pouch salvage: long term outcome. Dis Colon Rectum 1997;40:548-52
31. Galandiuk S, Scott NA, Dozios RR et al. Ileal Pouch anal anastomosis; Reoperation for pouch related
complications. Ann Surg 1990;212:446-54
32. Pemberton JH, Philiphs SF, Reddy RR et al. Quality of life after Brooke ileostomy and ileal pouch anal
anastomosis. Ann Surg 1989;209:62-628
 Retroperitoneal tumors
Jainendra K. Arora

Introduction
The retroperitoneum can host a wide spectrum of pathologies, including a variety of rare benign
tumors and malignant neoplasms that can be either primary or metastatic lesions. Malignant tumors of
the retroperitoneum occur four times more frequently than benign lesions. Sarcomas comprise a third
of retroperitoneal tumors(1). The retroperitoneum represents the second most common site of origin
of malignant mesenchymal tumors after the lower extremities. Retroperitoneal tumors present several
therapeutic challenges because of their relative late presentation and anatomical location. This review
highlights the presentation, evaluation and initial management of patients presenting with
retroperitoneal tumors and the surgical management of retroperitoneal sarcoma (RPS).

Classification
a) Primary tumors: formed from retroperitoneal tissue independent of the organs and the major
vessels contained therein.
i) Tumors of mesodermal origin (75%)
a. Fatty tissue origin Lipoma/Liposarcoma
b. Smooth muscle origin Leiomyoma/Leiomyosarcoma
c. Connective tissue origin Fibroma/ Fibrosarcoma
d. Lymphatic origin Lynphangioma/Lynphangiosarcoma
e. Mesenchymal origin Myxoma/Myxosarcoma
f. Vascular origin Hemangioma/Hemangiosarcoma/Hemangioperycitoma
g. Unknown origin Xanthogranuloma
ii) Tumors of neurogenic origin (25%)
a. Neural origin Neurofibroma/Neurilemmoma/malignant Schwannoma
b. Sympathetic origin Ganglioneuroma/Ganglioneuroblastoma/Neuroblastoma
c. Adreno‐ chromaffin origin Cortical Carcinoma/Paraganglioma/Pheocromocytoma
iii) Tumors of notochordal or embryonic rests origin
a. Embryonic origin: Benign or malignant Teratomas
b. Notochordal origin: Chordomas

b) Secondary tumors
By frequency
 Most frequent Cervix, colon, prostate or bladder
 Less frequent Pancreas, ovary, uterus, stomach, breast, lung, testicle

Malignancies in the retroperitoneal may result from the following:

i) Extra capsular growth of a primary neoplasm of a retroperitoneal organ such as the kidney,
adrenal, colon, or pancreas.
ii) Development of a primary germ cell neoplasm from embryonic rest cells.
iii) Development of a primary malignancy of the retroperitoneal lymphatic system, for example,
lymphoma.
iv) Metastases from a remote primary malignancy into retroperitoneal lymph node, for example,
testicular cancer.
v) Development of a malignancy of the soft tissue of the retroperitoneal, for example, sarcomas
and desmoids tumors

Patients suffering from von Recklinghausen's disease and Li-Fraumeni syndrome have an increased
likelihood of developing retroperitoneal sarcoma. Additionally, patients who exhibit mutations of the
p53 and RB-1 genes-also appear to have similar predilection, suggesting that these genes may play
an important regulatory rote in the malignant transformation to sarcoma.

Clinical Presentation

The symptoms of retroperitoneal sarcoma are due to compression and less frequently due to invasion
of the nearby structures. These include.
a) Asymptomatic abdominal mass.
b) Abdominal pain which is usually chronic and vague, but may sometimes be acute and severe.
The pain may be
 i) Colicky due to obstruction of bowel, ureter or biliary system.
ii) Neuralgic due to involvement of nerves or bones.
c) Gastrointestinal compressive symptoms such as abdominal discomfort, nausea, emesis, early
satiety, change in bowel habit, constipation, and obstipation.
d) Gastrointestinal bleeding due to invasion or venous congestion.
e) Abdominal distention and increasing weight.
f) Neurological symptoms including neuralgic pain, parasthesia, hyposthesia and progressive lower
extremity weakness.
g) Genitourinary symptoms such as flank pain, frequency, urgency and hematuria.
h) Generalized symptoms such as anorexia, weight loss, fatigue and fever in patients with more
aggressive tumors.

Quite often the initial presenting symptom is an abdominal mass and the patient admits to the
presence of additional symptoms only on further questioning. With increasing use of diagnostic
imaging, a larger number of retroperitoneal sarcomas are being detected while they are small and
non-palpable.

Retroperitoneal tumors grow slowly with little tendency to invade surrounding structures or
metastasize. Moreover, retroperitoneum is a loose, expandable space without rigid bony boundaries.
Hence, retroperitoneal tumors grow to very large size before becoming symptomatic.(2) The
diagnosis of retroperitoneal tumor is often one of exclusion.
a) Lymphoma: Fever, night sweats, and weight loss (B symptoms) are classically associated with
lymphoma and their presence warrants a complete lymphoma evaluation, including an
examination of all lymph node basins and laboratory work up including a serum LDH level.
b) Germ cell tumor: All men should receive a testicular examination, a testicular ultrasound and
measurement of serum HCG (human chorionic gonadotropin) and alpha-fetoprotein levels.
c) Metastasis to retroperitoneum: To evaluate for primary carcinomas, patients should undergo a
detailed history of gastrointestinal obstructive symptoms, a breast examination/a digital rectal
examination with a stool occult blood examination, and a chest radiograph. Negative findings from
this evaluation will minimize the diagnosis of primary colon, breast, prostate, or lung carcinoma,
and the diagnosis of sarcoma can be assumed.
d) Children: In children neuroblastoma, hepatoblastoma and Wilm's tumor form important differential
diagnosis.

Investigations

Radiographic imaging is a key component of the evaluation of a patient with a retroperitoneal mass.
The various imaging options include:

a) Ultrasonography: This is frequently the first imaging modality used in all patients with abdominal
masses. However, it is of limited value for complete evaluation of retroperitoneal tumors.
b) CT scan: Double contrast CT is the preferred investigation because it not only provides accurate
data regarding tumor location and size, but also supplies crucial information regarding the
relationship of the tumor to the surrounding tissues and structures such as aorta and vena cava,
and to organs/structures that may need to be sacrificed. Liver is also evaluated for metastasis.
Many patients presenting with abdominal complaints are increasingly evaluated with an imaging
modality shortly after a physical examination. Modern spiral computed tomography (CT) scanners
provide an excellent understanding of the relationship between nearby structures and are critical
to preoperative planning. Given a patient presenting with a palpable abdominal mass, the
modality of choice should be a high-resolution, thin-cut CT scan with intravenous and oral
contrast.(3) The images allow for further distinction between intra-abdominal and retroperitoneal
structures. Additionally, the difference between a primary visceral retroperitoneal lesion,
retroperitoneal adenopathy (possibly from another source), and a retroperitoneal sarcoma along
with involvement of adjacent viscera may be ascertained. This allows for an upfront discussion of
the need for biopsy if indicated, the operative plan, and the preparedness of the operative team,
as well as a discussion with the patient regarding the risks and benefits.

Primary Retroperitoneal Neoplasms: CT Imaging Findings with Anatomic and Pathologic

Diagnostic Clues (3)
Tumor Location
Characterization of the Retroperitoneal Space: The first step is to decide whether the tumor is
located within the retroperitoneal space. It is useful to observe the displacement of normal
anatomic structures (a). Anterior displacement of retroperitoneal organs (eg, kidneys, adrenal
glands, ureters, ascending and descending colon, pancreas, portions of the duodenum) strongly
suggests that the tumor arises in the retroperitoneum . Major vessels and some of their branches
are also found in the retroperitoneal cavity, so that displacement of these vessels can be helpful
as well

Identification of the Organ of Origin: Before a tumor can be described as primarily retroperitoneal,
the possibility that the tumor originates from a retroperitoneal organ must be excluded. Some
radiologic signs that are helpful in determining tumor origin include the “beak sign,” the “phantom
(invisible) organ sign,” the “embedded organ sign,” and the “prominent feeding artery sign” (b).
When there is no definite sign that suggests an organ of origin, the diagnosis of primary
retroperitoneal tumor becomes likely.

Beak Sign—When a mass deforms the edge of an adjacent organ into a “beak” shape, it is likely
that the mass arises from that organ (beak sign). On the other hand, an adjacent organ with dull
edges suggests that the tumor compresses the organ but does not arise from it

Phantom (Invisible) Organ Sign—When a large mass arises from a small organ, the organ
sometimes becomes undetectable. This is known as the phantom organ sign. However, false-
positive findings do exist, as in cases of huge retroperitoneal sarcomas that involve other small
organs such as the adrenal gland.

Embedded Organ Sign.—When a tumor compresses an adjacent plastic organ (eg,

gastrointestinal tract, inferior vena cava) that is not the organ of origin, the organ is deformed into
a crescent shape . In contrast, when part of an organ appears to be embedded in the tumor
(negative embedded organ sign). the tumor is in close contact with the organ and the contact
surface is typically sclerotic with desmoplastic reaction. Occasionally, the contact surface
becomes ulcerative. When the embedded organ sign is present, it is likely that the tumor
originates from the involved organ

Prominent Feeding Artery Sign.- Hypervascular masses are often supplied by feeding arteries
that are prominent enough to be visualized at CT or MR imaging, a finding that provides an
important key to understanding the origin of the mass.

Imaging Features That May Complicate Differential Diagnosis: Familiarity with the specific
features of various retroperitoneal tumors often allows accurate diagnosis and helps suggest
proper management.

Specific Patterns of Spread: Some retroperitoneal tumors have specific patterns of growth and
extension that aid in narrowing the differential diagnosis.

Lesions That Extend Between Normal Structures—Some tumors grow and extend into spaces
between preexisting structures and surround vessels without compressing their lumina.
Lymphangiomas and ganglioneuromas are examples of such tumors.

Lymphangiomas represent about 1% of all retroperitoneal neoplasms. Most cases are detected in
the first 2 years of life on the basis of symptoms like abdominal distention or pain; however, they
can manifest in older patients as a huge, asymptomatic mass. At imaging, they appear as fluid-
filled, unilocular or multilocular cystic masses with minimal contrast enhancement.

Lesions that extend along normal structures (paraganglioma - along sympathetic chain).

Characteristic tumor components

i) Fat (lipoma, liposarcoma)
ii) Myxoid stroma (neurogenic tumors)
iii) Necrosis (leiomyosarcoma)
iv) Cystic portion (lymphangiomas, mucinous cystic tumors) ,-
v) Small round cells (homogenous with minimal contrast enhancement - lymphoma)
 vi) Vascularity
 Extremely hypervascular (paragangliomas)
 Moderately hypervascular (leiomyosarcomas)
 Hypovascular (lymphoma)

c) MRI: Magnetic resonance imaging is extremely accurate at imaging retroperitoneal masses, yet
the slightest amount of motion artifact is detrimental to the MRI evaluation of surrounding organ
involvement. If CT does not provide sufficient information regarding tumor-organ involvement, T1
-weighted MRI images may provide improved tumor delineation and aid in preoperative planning.
In addition, MRI can aid in the identification of vascular involvement, most specifically with tumors
involving the aorta and the vena cava.

d) Angiography, PET scan: While angiography is rarely required in the presence of good CECT, PET
scan may be required to look for metastasis.

Tissue Diagnosis:
Careful consideration of the cross-sectional imaging and history is key in determining whether a
biopsy of the lesion is indicated. For patients in whom preoperative systemic therapy or radiation is
deemed to be potentially beneficial, a biopsy is mandatory. Aside from patients receiving preoperative
therapy, preoperative CT-guided biopsy is often utilized if the imaging and history are suggestive of a
lesion other than sarcoma or if the lesion has characteristics of an intermediate- to high-grade
retroperitoneal sarcoma such as large nodules, enhancement, and/or necrosis. If the lesion is arising
from the stomach and may be a gastrointestinal stromal tumor, perform a biopsy of the tumor using
endoscopic ultrasound to avoid the theoretical risk of seeding the peritoneal cavity. Do not consider a
preoperative biopsy for lesions that appear to be well-differentiated retroperitoneal liposarcomas as
the sensitivity of CT for low-grade lesions is nearly 100%, and there is virtually no role for
preoperative therapy for these tumors.(4)

If a patient with a retroperitoneal mass undergoes a complete evaluation and has no findings
suggesting lymphoma, germ cell tumor, or metastatic carcinoma, and the radiographic appearance of
the mass is consistent with a localized, resectable sarcoma, then there is no role for preoperative
tissue sampling. Appropriate treatment should be initiated without a confirmatory tissue diagnosis.
However, if one of the above diagnoses is suspected and treatment or prognosis may change, biopsy
is justified. Additionally, when a patient with a suspected retroperitoneal sarcoma is found to have
unrespectable or metastatic disease, tissue diagnosis is necessary to guide further therapy.

When tissue is needed, it should be obtained by CT-guided core needle biopsy. This is superior to
fine needle aspiration, which lacks architectural diagnostic ability. Operative (laparoscopic or open)
core biopsies, which risk tumor seeding and require general anesthesia, are unnecessary. Incisional
biopsies are notably contraindicated, because they compromise future possibility of curative
resection.

Although arising from different cell types, the histologic variants collectively known as sarcoma are
grouped together due to their similar biologic activity. These subtypes share a tendency to be locally
aggressive; expand in a smooth, non-invasive fashion; and rarely achieve metastatic potential, usually
only after growing to a large size. Despite these similar characteristics, there is value in identifying,
understanding, and analyzing these different histologic subtypes for future improvement in
management. All of the histologic subtypes of soft tissue sarcoma occur in the retroperitoneum, with
liposarcoma and leiomyosarcoma being the commonest. Further complicating the classification of
retroperitoneal sarcomas is the fact that poorly differentiated tumors may resemble multiple histologic
subtypes, leading to inconsistent and varying diagnoses by different pathologists.

Histologic Subtypes

The most common histology is liposarcoma, followed by leiomyosarcoma. Other rare subtypes
include fibrosarcoma and malignant peripheral nerve sheath tumors that are found in the
retroperitoneum. Historically, most soft tissue sarcomas were classified as malignant fibrous
histiocytomas, but recent work has demonstrated a significant proportion of these tumors are actually
dedifferentiated liposarcomas. More exact diagnoses such as this are possible largely due to recent
advances in immunohistochemistry (IHC) assays. Newer IHC capabilities allow the subtypes to be
more clearly defined based on cell surface markers rather than histology alone.

Liposarcomas are mesenchymal neoplasms with atypical adipocytes and lipoblasts in a background
of mature adipose tissue. They can appear anywhere in the body. They represent a spectrum of
tumors with variable behavior that ranges from a low risk of metastatic potential with well-
differentiated tumors to a more aggressive biology with dedifferentiated lesions. Liposarcomas
comprise the most common subtype of retroperitoneal sarcomas. Primary retroperitoneal
liposarcomas carry a worse overall prognosis when compared with liposarcomas that arise from the
trunk and extremities.

Liposarcomas can be subdivided into four main histologic subtypes: well-differentiated,

dedifferentiated, myxoid, and round cell.(5) The dedifferentiated category represents the subtype with
a more malignant behavior and worse overall survival. This aggressive histologic subtype may
present as an initial presentation or may be found in patients with disease recurrence. Liposarcoma
recurrence is often more difficult to resect with negative margins due to involvement of adjacent
structures and the development of dedifferentiation.

CT imaging classifies them as either well-differentiated or dedifferentiated based on characteristics

such as their percent of fat, focal nodular/water density, ground glass opacities, and hypervascularity.
Dedifferentiated lesions were more likely to be infiltrative, hypervascular lesions with areas of necrosis
and focal nodular/water density. Focal nodular/water density is very sensitive (97.8%) but has a low
specificity (51.5%) on final pathology. A radiologic diagnosis of a well-differentiated lesion is accurate
in 100% of patients and as such may be used as a criterion to avoid preoperative biopsy.

Leiomyosarcomas These tumors comprise the second most common histology of retroperitoneal
sarcomas. They can arise anywhere in the body but are typically more aggressive when found in the
retroperitoneum, major vascular structures, or intra-abdominal viscera rather than the skin or
subcutaneous tissues. On histology, these tumors appear as cells in wavy sheets with cigar-shaped
nuclei, and all cells stain positive for actin on IHC assays.

Currently, the American Joint Committee on Cancer (AJCC) staging system is the most widely used
for retroperitoneal sarcoma. This system uses the well-known TNM classification with an additional
4th category that accounts for tumor grade.(6)

The American Joint Committee on cancer staging system for soft tissue sarcoma
Grade (G)
Gx Grade cannot be assessed
G1 well differentiated Low grade
G2 Moderately differentiated Low grade
G3 Poorly differentiated High grade
G4 Undifferentiated High grade

Primary tumor (T)

Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor < 5 cm
T1a Superficial tumor
T1b Deep tumor
T2 Tumor >5cm
T2a Superficial tumor
T2b Deep tumor
Regional nodes (N)
Nx regional lymph nodes cannot be assessed
N0 No regional lymph node involvement
N1 regional lymph node involvement

Distant metastases (M)

Mx Distant metastases cannot be assessed
 M0 No distant metastases
M1 Distant metastases

Staging
Stage I T1a, 1b, 2a, 2b N0 M0 Low grade
Stage II T1a, 1b, 2a, N0 M0 High grade
Stage III T2b N0 Mo High grade
Stage IV Any T N1 M0 Any grade
Any T Any N M1 Any grade

Staging UICC
TNM Classification (UICC, 2009)
Primary Tumor
Tx Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
T1 Tumor ≤5 cm.
T2 Tumor ≥5 cm.
T3 Macroscopic invasion: bones, vessels or nerves.
Regional lymph node
Nx Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Regional lymph node metastasis.
Distant metastasis
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
. M1 Distant metastasis.
Histological Grade
Gx Tumor grade cannot be assessed
G1 Low grade of malignancy
G2 Moderate grade of malignancy
G3 High grade of malignancy

Surgical excision is the treatment of choice for primary retroperitoneal tumors. Radiotherapy is
increasingly being tried to improve the local control. Chemotherapy has limited role and is offered as a
part of investigational protocol for metastatic disease.

Complete Gross Resection (CGR) is the only factor which improves the long term survival of the
patient. Due to their location, resection of retroperitoneal sarcoma is often technically difficult,
involving en bloc resections of surrounding organs and vasculature, with high operative morbidity.
Commonly taken en bloc are kidney, colon, small bowel, and even portions of the inferior vena cava.
There is no survival advantage with incomplete resection, with the exception of well differentiated
liposarcoma.(7) Tumor respectability dramatically decreases with each reoperation. Thus, the
standard of care for retroperitoneal sarcoma is not just CGR, but CGR at the time of initial
presentation and first exploratory laparotomy.

The basic surgical principles include:

a) Adequate preoperative investigation to identify the local extent of the tumor and the need for, and
extent of, removal of adjacent structures.
b) Availability of experienced surgeon with necessary intra-operative and post-operative facilities.
c) Readiness for a prolonged and exacting surgical procedure.
d) Adhering to the correct technique and principles of resection, including:
i) Proper positioning of the patient so that the gravity assists the surgeon. Various positions,
depending on the location of the tumor are.
 Upper quadrant or flank tumors - Later position with affected side up
 Midline abdominal or pelvic tumors – Supine\
 lliac fossa tumors with involvement of underlying bone - Lateral or semilateral with
affected side up and leg prepared to permit hip flexion to relax vessels and nerves
 Tumors needing resection of lower sacrum - Supine with ipsilateral buttock raised on
sandbag
 Tumors needing resection of upper sacrum – Lateral
 ii) Suitable incision for resection of retroperitoneal sarcoma depends on the location and size of
the tumor and include
 Abdomino-thoracic incision - Upper quadrant tumors
 Midline incision - Midline abdominal tumors
 Midline with T extension - Flank tumors
 Midline with bilateral T at lower end up to pubic tubercles with cutting of Rectus
Abdominis tendons - Pelvic tumors with need for excision of pubic symphysis
 Abdomino-inguinal incision - Tumors of iliac fossa

iii) For tumors close to midline it is better to first mobilize the tumor from its bed before
approaching the major midline vessels, as these may have to be excised. This is in
contradiction to 'pedicle first' approach usually advised for other malignancies.
iv) Application of surgical techniques from other disciplines such as liver transplantation is useful
in case midline vessels are involved. These include anatomic and non-anatomic liver
resection, venous grafting, veno-venous bypass, and total circulatory arrest with profound
hypothermia.(8)
v) Principles of Damage Control Surgery, including temporary packing, shifting to ICU for
resuscitation and re-operation some hours later, may be needed in case of uncontrollable
intra-operative bleeding.

The high rate of local failure has prompted investigation of combined modality treatment (surgery with
radiotherapy) in an attempt to lower the rate of local recurrence. Radiotherapy improves local control
in extremity sarcomas and has become standard practice. However, RPS presents several
radiotherapeutic challenges. These tumors are often adjacent to radiosensitive structures with low
radiation tolerance. Retroperitoneal sarcomas compose a heterogeneous group of pathologies with
variable radiosensitivity.

Several retrospective and observational studies have been published to evaluate the feasibility and
outcome of pre-, intra- and postoperative radiotherapy in the management of RPS. The advantages of
preoperative radiotherapy include: the tumor is clearly demarcated for radiotherapy planning, the
tumor is displacing some of the radiosensitive adjacent organs and an equivalent therapeutic dose of
radiotherapy may be lower in the preoperative setting. Postoperative radiotherapy makes it possible
to select those patients at highest risk for recurrence based on the grade and margin status. However,
in the postoperative setting, the adjacent organs will move into and become adherent to the tumor
bed, increasing the risk of radiation-associated toxicities. In an attempt to reduce the radiation
toxicities, studies have evaluated the treatment planning with conformal therapies such as intensity-
modulated radiation therapy or the use of intraoperative radiotherapy.

Planning the surgery in consultation with radiation oncologist to maximize the benefit of RT, if
required. Radiation oncologists typically rely on a variety of data to determine target volumes for
treatment planning, including physical examination, preoperative imaging, operative reports,
radiopaque clips, scars, and drain sites. The various aspects that must be ensured include.
a) Imaging obtained before surgery should encompass the entire area of radiographic
abnormality with margin to allow for adequate tumor targeting with radiotherapy.
b) It is preferable to obtain these images in treatment planning position.
c) Avoidance of high-dose regions in areas destined to be incision or drain sites, potentially
reducing wound complications.
d) Avoid placement of surgical incisions, drain sites, and biopsy sites overlying or adjacent to
sensitive structures (uninvolved compartments, visceral organs, genitalia) as this may result
in the need to include them in the radiation field, hence increasing the risk for toxicity.
e) Radiopaque surgical clips should be placed at the time of resection to assist in delineating the
tumor bed and the area at high risk.

Indication of RT: In most centers, radiotherapy is often reserved for patients who have high-grade
lesions or in patients in whom a margin-positive resection is anticipated. The goal of therapy is to
allow a margin-negative resection, which would result in better local control and improved survival.(9)

Timing of RT: This may be given pre or post- operatively. The pros and cons of these two methods
include:
 a) Pre-operative RT: This is the preferred method of RT because
i) Small bowel toxicity is minimized as the small bowel is mobile and moves in and out of
radiation field
ii) Treatment volumes are often smaller because they are based on treating the tumor
volume with a margin for microscopic extension
iii) Improved oxygenation of the tumor bed in the preoperative setting, a factor known to
enhance sensitivity of tumors to ionizing radiation
iv) If pre-operative RT is considered, a biopsy is required to verify histology before
commencing RT(10)

b) Post-operative RT: While post-operative RT allows the selection of patient at highest risk of
recurrence, based on margin status, it has several drawbacks.(11) These include:
i) There is increased risk of bowel toxicity as these become adherent to tumor bed.
ii) Treatment volumes are often larger as the radiation is given to entire tumor bed with
additional margins

Delivery methods: These include external beam radiation therapy (EBRT), intra-operative electron
beam radiation therapy (IOERT), brachytherapy (BT), and intensity-modulated radiation therapy
(IMRT).
a) External beam RT: This is the usual mode of RT in the pre-operative setting. However, the
maximum tolerated dose is 45Gy, which is much less than 'sarcomacidal' dose. To improve the
benefits of RT, while keeping toxicity within tolerable limits, various dose boosting delivery
methods are used. These include
b) Intra-operative RT, Brachytherapy and Intensity Modulated RT.

Side effects of RT: Toxicities of RT for retroperitoneal sarcomas include mild to moderate toxicities of
enteritis, nausea, and vomiting and late toxicities of bleeding gastric ulcers, small bowel obstruction,
strictures, and impaired wound healing.

Thus, the current trend is toward bowel-tolerant doses of EBRT given preoperatively with boost doses
via IOERT, BT, or IMRT. The classic dilemma of all radiation protocols for retroperitoneal sarcoma
has been finding the right balance between effective sarcoma treating dosing and acceptable
radiation toxicity.

Chemotherapy
Neoadjuvant/adjuvant chemotherapy for the majority of histological subtypes has not shown
consistent evidence of a disease-free survival benefit although there may be certain situations where
it is advantageous. For subtypes such as the Ewing family of tumors, for which chemotherapy is an
essential part of primary management, chemotherapy has definitely improved survival. There is a role
for agents such as doxorubicin and ifosfamide in the palliation of symptomatic advanced sarcoma.
There is increasing specialisation of chemotherapy according to histological subtype, such as the use
of taxanes for angiosarcoma, gemcitabine and docetaxel for leiomyosarcoma, and trabectedin for
leiomyosarcoma and myxoid/round cell liposarcoma.

Retrospective studies on the efficacy of postoperative chemotherapy for retroperitoneal sarcoma have
not shown significant benefits. Limited experience with preoperative chemotherapy for sarcoma has
also been disappointing. As such, adjuvant therapy in retroperitoneal sarcoma is offered in the context
of a clinical trial. It may also play a role in the palliation of symptomatic inoperable disease.

Treatment recommendations for low-grade soft tissue sarcoma(12)

Stage I:
a) Surgery is the primary treatment for stage I sarcoma; it is considered definitive when margins are
> 1 cm or if the fascia is still intact
b) Re-resection or adjuvant external beam radiation therapy (XRT) is recommended to prevent local
recurrence or if margins are < 1 cm or when location makes it difficult to resects at time of
recurrence
c) Radiation therapy is associated with decreased local recurrence but not overall survival
d) Definitive radiation therapy is recommended for patients who are not surgical candidates;
radiation doses range from 70-80 Gy
e) Re-resection is associated with improved 5-y disease-free survival (DFS)
Treatment recommendations for high-grade soft tissue sarcoma
Stages II-III:
a) Tumors in this stage can be > 8-10 cm and have a high risk of recurrence and potential
metastases
b) For patients with resectable disease, surgery followed by radiation therapy with or without
adjuvant chemotherapy or surgery alone is recommended; preoperative radiation therapy,
chemotherapy, or chemoradiation prior to surgery are alternatives
c) Patients with unresectable disease should be treated with preoperative radiation therapy,
chemotherapy, or chemoradiation with doxorubicin-based regimens

Role of radiation therapy in the locoregional management of soft tissue sarcoma

Preoperative XRT:
a) Benefits of using preoperative therapy are that large retroperitoneal or inguinal tumors may
become resectable; a smaller treatment field is needed; and potentially less tumor seeding may
occur during resection
b) The common dose for XRT is 50 Gy
c) Negative aspects of using this therapy include increased wound-healing complications
d) If margins are close (< 1 cm) or positive, consider boost with brachytherapy, intraoperative
radiation therapy (IORT), or XRT/intensity modulated radiation therapy (IMRT) at doses ranging
from 10-26 GY

Postoperative brachytherapy:
a) Common doses for brachytherapy are 45 Gy or XRT with doses of 50 Gy
b) Consider re-resection if margins are positive
c) Consider XRT even when negative margins are achieved with re-resection and the patient is older
and/or has stage III disease
d) When re-resection is not an option, consider postoperative radiation therapy
e) Benefits include the fact that wound-healing complications are minimized

Treatment recommendations for metastatic disease

Stage IV:
a) In metastatic disease, it is important to differentiate between limited and disseminated metastases
b) Limited metastasis is limited to one organ and should be considered for resection for improved
disease-free survival (DFS) and overall survival (OS)
c) Disseminated metastases can be managed with observation, palliative therapy (palliative
radiation therapy, chemotherapy, or palliative surgery)
d) The trigger for initiating palliative chemotherapy should be based on histology, tumor growth rate,
chemosensitivity, and associated symptoms
e) Adjuvant chemotherapy is not generally considered as first-line therapy
f) Several single-agent and combination chemotherapies are used in metastatic disease; compared
with single-agent chemotherapies, combination therapies have higher response rates, although
they are associated with greater toxicities and no survival advantage
g) The decision for combination therapies should be individualized and take age, performance
status, and organ function into account
h) Combination therapies may require growth factor support.
i) If the patient is asymptomatic and has a slow tumor growth rate, then observation with close
monitoring is a reasonable option
j) Patients with limited metastatic disease or recurrent disease after primary therapy should be
considered for surgery, radiofrequency ablation (RFA), embolization, or radiation therapy with
curative intent
k) There are no clear guidelines for metastatic and recurrent disease, as it is dependent upon the
disease-free interval, performance status, and histology
l) In stage IV sarcoma, patients with limited disease should also be considered for resection or other
definitive intervention, as this is associated with improved disease-free survival
m) Consider re-resection for positive or close margins.
n) Prevention of local recurrence may require additional radiation and/or chemotherapy
Recurrent disease
Local recurrence is common for RPS and remains the major cause of death. Tumor biology reflected
in tumor grade is a significant prognostic factor for patients with recurrent RPS; local recurrence rates
are higher in patients with high-grade tumors and occur at an earlier interval compared with patients
with low-grade tumors. Most reports on this subject are retrospective with different management
strategies and variable results. CT is indicated when patients exhibit new symptoms or a mass is
palpable on clinical examination. Further surgery is advised if the patient develops significant
symptoms or if further delay will make eventual surgery more difficult.

The likelihood of obtaining negative margins is significantly lower at the time of local recurrence and
each successive operation is more difficult than the last. Nevertheless, resection should be
considered in symptomatic patients with first and subsequent local recurrence as it provides good
palliation and a possible improved survival for selected patients. Palliative surgery (incomplete
resection leaving unresectable tumor) for recurrent sarcomas of low or intermediate grade can be
offered for symptom control and may improve quality of life.

The management of unresectable sarcoma should be tailored to the individual patient depending on
the patient's overall functional status, extent of disease, and symptoms. Options, such as neoadjuvant
therapy with the attempt to render disease resectable, are possible.(13) Alternative options include a
palliative approach. Palliative options can include supportive care, surgical therapy, radiotherapy, and
chemotherapy Some evidence exists that incomplete resection might provide a survival benefit for
patients who have retroperitoneal sarcomas, specifically in patients who have well-differentiated
liposarcomas.

Prognosis

Factors involved in a good prognosis:

a) Early diagnosis.
b) Complete resection (resectability).
c) Factors involved in a poor prognosis:
d) Histology: vascular invasion, high microvascular density of the tumor, high S phase fraction,
overexpression of proliferation markers, p53 mutation, MDM2 amplification, absence
of retinoblastoma gene expression, cyclin D1 overexpression.
e) Size.
f) Degree of differentiation.
g) Positive margins.
h) Necrosis.
i) Age >50 years.
j) Males.
k) Distant metastases are rare (5%, to lung, liver, bone, and CNS), but adjacent organs are
frequently involved (60‐70%).

5‐year survival rate is low. Median survival of 60 months after complete resection. Local recurrence of
primary tumors after resection in 40‐82% of cases (between 15‐44months). This is the leading cause
of cancer‐specific mortality.(14)
Followup: the first 2‐3 years with CT scan or MRI

Patients who have high-grade tumors should undergo frequent clinical and imaging surveillance to
evaluate for recurrent disease. Surveillance imaging should include CT of the chest, abdomen, and
pelvis at intervals of every 3 to 6 months for the first 2 years for low- and high grade lesions, followed
by biannual evaluations in patients who have high-grade tumors and annual evaluations in patients
who have low-grade tumors.

REFERENCES
1. Lewis JJ, Leung D, Woodruff JM, Brennan MF Retroperitoneal soft-tissue sarcoma: analysis of 500 patients
treated and followed at a single institution.. Ann Surg. 2012 Sep; 228(3):355-65.
2. Liles JS, Tzeng CW, Short JJ, Kulesza P, Heslin MJ. Retroperitoneal and intra-abdominal sarcoma. Current
Problems in Surgery (2009);46(S):445-503.
3. Nishino M, Hayakawa K.Minami M, Yamamoto A, Ueda H, Takasu K. Primary retroperitoneal neoplasms: CT and
MR imaging findings with anatomic and pathologic diagnostic clues. Radio Graphics (2012);23:45-57.
4. Strauss DC, Qureshi YA, Hayes AJ, Thway K, Fisher C, Thomas JM. The role of core needle biopsy in the
diagnosis of suspected soft tissue tumors. J Surg Oncol. 2010 Oct 1;102(5):523-9. doi: 10.1002/jso.21600.
5. Murray F . Soft tissue sarcomas. In: Devita, Hellman, Rosenberg. Cancer Principles and Practice of Oncology:
Section 1, chapter 45. 8th ed. Lippincort Williams and Wilkins.
6. Van Dalen T, Hennipman A, Van Coevorden F, Hoekstra HJ, Van Geel BN, Slootweg P, et al. Evaluation of a
clinically applicable post-surgical classification system for primary retroperitoneal soft-tissue sarcoma. Annals of
Surgical Oncology (2004);11(5):483-90.
7. Karakousis CP, Kontzogiou K, Driscoll DL.Resectability of retroperitoneal sarcomas: a matter of surgical
technique? European Journal of Surgical Oncology (1995);21:617-622.
8. Facciuto ME, Singh MK, Rocca JP, Rochon C, Davalos MIR, Eshghi M, et al. Benefits of liver transplantation
surgical techniques in the management of extensive retroperitoneal tumors. World J Surg (2008);32:2403-2407.
9. Kaushal A, Citrin D. The role of radiation therapy in the management of sarcomas. Surg Clin N Am (2008);88:629-
646.
10. Hueman MT, Herman JM, Ahuja N. Management of retroperitoneal sarcomas. Surg Clin N Am (2008);88:583-597.
11. Strander H, Turesson I, Cavallin-Ståhl A systematic overview of radiation therapy effects in soft tissue sarcomas.
E. Acta Oncol. 2011; 42(5-6):516-31
12. Strauss DC, Hayes AJ, Thomas JM. Retroperitoneal tumors: review of management.
13. Retroperitoneal sarcomas: combined modality treatment approaches. Ann R Coll Surg Engl. 2011 May;93(4):275-
80. doi: 10.1308/003588411X571944.
14. Mäkelä J, Kiviniemi H, Laitinen S. Prognostic factors predicting survival in the treatment of retroperitoneal
sarcoma. Eur J Surg Oncol. 2012 Sep;26 (6):552-5.
 Malignant Melanoma
Ravi Kannan, Ritesh Tapkire, Rajeev Kumar

Introduction

Malignant melanoma is a relatively uncommon malignancy in India with an incidence of less than 0.5
per 1,00,000 population (1). While it accounts for only 3% of all skin cancers, it is the most lethal of all
skin cancers accounting for over three-fourths of skin cancer deaths. The high incidence in individuals
of Caucasian origin, its unique natural history, ability to regress spontaneously and more recently
potential for use of treatment against molecular targets incites a great deal of interest in melanoma.

Malignant transformation of melanocytes, which are cells derived from the neural crest, results in
melanoma. While they commonly occur on the skin, malignant melanoma also arise in other locations
where neural crest cells migrate, such as in the mucus membranes, gastrointestinal tract, eye or
brain. In India, the incidence of melanoma peaks in the 6th and 7th decades (2) while in the western
hemisphere and Australia it peaks in the fourth decade. It is equally prevalent in both sexes. A
patient's risk of developing a second primary melanoma after diagnosis of the first one is 3-5%. The
incidence of cutaneous melanoma has been rising steadily at the rate of 5-7% per year in the white
population. (3).

Queensland, Australia and Israel report the highest incidence of melanoma in the world of
approximately 57 and 40 cases per 100,000 people per year respectively. The incidence of malignant
melanoma is increasing rapidly worldwide as is the melanoma specific mortality (4).

Melanoma is twenty times more common in whites than in blacks and Asians. White people with dark
skin also have a much lower risk of developing melanoma than do those with light skin. The typical
patient with melanoma has fair skin with freckles and a tendency to sunburn rather than tan.

Aetiology

Cutaneous melanoma may

develop de novo or in or near a
previously existing precursor
lesion often induced by solar
irradiation. Melanoma also may
occur in unexposed areas of the
skin, including the palms, soles,
and perineum. Lesions
considered to be precursor
lesions include the common
acquired nevus, dysplastic nevus,
congenital nevus, and cellular
blue nevus (5).

Genetics: Many genes are

implicated in the development of
melanoma, including CDKN2A
(p16), CDK4, RB1, CDKN2A
(p19), PTEN/MMAC1, BRAF and
RAS. CDKN2A (p16) appears to
be especially important in both
sporadic and hereditary
melanomas (Figure 1). This tumor
suppressor gene is located on
band 9p21, and its mutation plays
a role in various cancers
(6,7,8,9,10).

Ultraviolet radiation (11):

Exposure to ultraviolet radiation
(UVR) is a critical factor in the development of most melanomas. Ultraviolet A (UVA), wavelength 320-
400 nm, and ultraviolet B (UVB), 290-320 nm, are potentially carcinogenic and may work in tandem in
melanomagenesis. UVR appears to induce melanoma through suppression of the immune system of
the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte
DNA. Interestingly, melanoma does not have a direct relationship with the amount of sun exposure
because it is more common in white-collar workers than in those who work outdoors.

Sunburn: Recurrent, acute, intense, and intermittent blistering sunburns, especially on areas of the
body that only occasionally receive sun exposure, are the greatest risk factor for the development of
sun exposure–induced melanoma. This is different from that for squamous and basal cell skin
cancers, which are associated with prolonged, long-term sun exposure. Lentigo maligna melanoma is
an exception to this rule, because it frequently appears on the head and neck of older individuals who
have a history of long-term sun exposure and resulting actinic damage to the skin.

Additional risk factors: Other factors like chemicals and viruses have been implicated in the
development of melanoma (12).
The possibility of a malignant melanoma is greatly elevated in:
 Preexisting mole changing colour, size and shape, itching and bleeding
 Dysplastic nevi in familial melanoma
 More than 50 nevi, 2 mm or greater in diameter

The incidence of cutaneous melanoma is moderately increased when:

 One family member diagnosed with melanoma
 Previous history of melanoma is present in the individual
 Sporadic dysplastic nevi are detected
 Congenital nevus/i are present

Slightly elevated risk factors for cutaneous melanoma include:

 Immunosuppression
 Sun sensitivity
 History of acute, severe, blistering sunburns and Freckling

Molecular biology
Although melanoma has been seen to sometimes arise in pre-existing nevi, recent data have
demonstrated that typical nevi represent senescent lesions that may be irreversibly growth arrested. It
is therefore plausible that melanomas may alternatively emerge from normal melanocytes via
alternative pathway(s), which may involve similar oncogenes implicated in nevi (1). A step wise
progression from normal melanocyte through dysplastic melanocytic lesions (figure 2), melanoma in
situ, invasive and metastatic melanoma has emerged, each step correlating with increasing genetic
changes. This is beginning to open up exciting opportunities to treat melanoma and other
malignancies as well (13, 14, 15, 16. 17).

As many as 70% of melanomas harbor somatic mutations or deletions affecting the CDKN2A locus on
chromosome 9p21. Germline homozygous deletions of CDKN2A has been identified in familial
melanoma kindred. It acts by inhibiting both the retinoblastoma (RB) and P53 suppressor pathways
through the production of two separate transcripts (18).

The different morphological varieties of malignant melanoma have different genetic changes (DNA
copy number changes, including subtype-specific gene amplifications and deletions) as evidenced by
comparative genomic hybridisation techniques (table1). Most melanomas harbour mutations in critical
protein kinase pathways. Superficial spreading, nodular and lentigo maligna melanoma arise on
ultraviolet ray (from the sun) exposed skin. The role of UV radiation is uncertain in the causation of
acral lentiginous melanomas (arising on the palms and soles) and not implicated in mucosal
melanomas. Lentigo maligna melanoma that occurs in areas of chronic sun exposure and that have
histologic evidence of chronic sun damage also exhibit markedly different chromosomal and gene
copy number changes compared with cutaneous melanomas without chronic sun damage.

Uveal melanomas are characterised by genetic changes distinct from all other melanomas.
Figure 2: from reference 17.

Table1: Genetic changes in different morphological types of melanoma

Gene change --> BRAF NRAS c-KIT C-KIT GnἀQ
Melanoma type mutation mutation mutation amplification mutation
Sun- exposed 43% 26% <2% 0-7% <1%
cutaneous without
actinic damage
Acral lentiginous 18% 4% 18% 24% <1%
Lentigo maligna 9% 0% 2-17% 6% NA
Mucosal 6% 14% 24% 26% <1%
Uveal 1% <1% 1% <1% 45%

Pathology
The most crucial part in the management of melanotic lesions is to determine if the lesion is benign or
malignant. Routine histopathology can diagnose malignant melanoma reliably. Characteristic
histologic findings include cytologic atypia, with enlarged cells containing large, pleomorphic,
hyperchromic nuclei with prominent nucleoli, numerous mitotic figures and pagetoid growth pattern
with upward growth of the melanocytes

Immunohistochemistry using one of the markers- S-100, HMB 45, melan A or MART-1 is a mandatory
part of the histopathology. Melanoma resembling Spitz nevi, blue nevi, deep penetrating nevi,
combined nevi and nevoid melanoma (melanoma that display many features of standard, commonly
acquired, or dysplastic benign nevi) often cause diagnostic problems.
There is no single feature to distinguish a nevus from a melanoma. Sometimes it is not possible for a
pathologist to distinguish between the two when they are labelled as melanotic lesions of uncertain
malignant potential (Mel TUMP). Opinions from other experienced pathologists are warranted.
Analysis of the primary tumor by molecular techniques such as comparative genomic hybridization
(CGH) or fluorescence in situ hybridization (FISH) has the potential to provide useful additional
information that may assist in classifying it as a melanoma if multiple chromosomal aberrations or
melanoma-specific mutations are detected.

The transition from normal melanocyte to metastatic melanoma involves several histologic
intermediate stages including melanocytic atypia, atypical melanocytic hyperplasia, radial growth
phase melanoma, vertical growth phase melanoma, and metastatic melanoma. These are marked by
sequential accumulation of genetic mutations. Atypical melanocytes arising in a pre-existing nevus or
de novo are very common but rarely progress to melanoma. Confluent atypical melanocytic
hyperplasia at the dermal/epidermal junction or nests of atypical melanocytes in the epidermis or at
the dermal/epidermal junction warrants a diagnosis of melanoma. Early superficial spreading, lentigo
maligna melanoma and acral lentiginous melanoma usually proceed to grow radially (radial growth
phase (RGP)) for years before infiltrating vertically (vertical growth phase (VGP)).

During the radial growth phase, the melanoma may remain in situ (MIS) or superficially invade into
the papillary dermis. Melanoma in RGP present clinically as asymptomatic enlarging macules or very
minimally raised papular lesions, which are typically (but not always) pigmented. The changing nature
of these RGP lesions often is adequate for diagnosis. If not treated, these lesions progress to the
vertical growth phase, manifesting clinically as a nodular growth of the lesion within the RGP
component and encompassing only part of the RGP. RGP melanoma have low metastatic potential
and there exists a window of several months to years before the vertical growth commences.

Amelanotic melanoma are non-pigmented and early stages are missed. Nodular melanoma do not go
through the RGP or have an extremely short RGP. Occasionally metastatic disease is discovered and
the primary remains undetected -either because it has undergone spontaneous regression or is too
small in inaccessible locations in the mucosa or leptomeninges.

Clinically, lesions are classified as thin if they are 1 mm or less in depth; moderate if they are 1-4 mm
in depth; and thick if they are greater than 4 mm in depth. Histologically melanoma is classified into 5
types:
a) Superficial spreading melanomas
b) Nodular melanomas
c) Lentigo maligna melanomas
d) Acral lentiginous melanomas
e) Mucosal lentiginous melanomas

Superficial spreading melanomas (SSM): Approximately 70% of cutaneous malignant melanomas are
the superficial spreading melanoma type and often arise from a pigmented dysplastic nevus. The
development of a melanoma in a long-standing stable nevus is heralded by typical changes including
ulceration, enlargement, or color changes. An SSM may be found on any body surface, especially the
head, neck, and trunk of males and the lower extremities of females.

Nodular melanomas (NM): Nodular melanomas represent approximately 10-15% of melanomas and
also are found commonly on all body surfaces, especially the trunk of males. These lesions are the
most symmetrical and uniform of the melanomas and are dark brown or black. The radial growth
phase may not be evident in NMs; however, if this phase is evident, it is short-lived, because the
tumor advances rapidly to the vertical growth phase, thus making the NM a high-risk lesion.
Approximately 5% of all NMs are amelanotic melanomas.

Lentigo maligna melanomas (LMM): Lentigo maligna melanomas also account for 10-15% of
melanomas. They occur on sun-exposed areas that have suffered actinic damage. LMMs may have
areas of hypopigmentation and often are quite large. LMMs arise from a lentigo maligna (melanoma in
situ) precursor lesion. A centrally located erythematous papule in a macular lentigo maligna
represents the invasive melanoma.
Acral lentiginous melanomas (ALM): Accounting for about 5% of melanomas in the white races, acral
lentiginous melanomas are the only melanomas that have an equal frequency among blacks and
whites. They occur on the palms, soles, and subungual areas. It is thought to be linked to repetitive
trauma caused by bare foot walking. Subungual melanomas often are mistaken for subungual
hematomas (splinter hemorrhages). These are the commonest type of melanoma and occur almost
exclusively in the feet in India. ALM are aggressive lesions that rapidly progress from the radial to
vertical growth phase.

Others forms of cutaneous melanoma

Lentiginous Melanoma: Early radial growth phase melanomas sometimes are hard to classify into the
typical patterns of lentigo maligna, superficial spreading melanoma, or acral lentiginous melanoma. A
recent report defined a distinct entity of lentiginous melanoma. Its features include diameter 1 cm or
greater, elongated and irregular rete ridges, confluent melanocytic nests and single cells over a broad
area of the dermal/epidermal junction, focal pagetoid spread, cytologic atypia, and possible focal
dermal fibrosis.

Desmoplastic Melanoma: Desmoplastic melanoma is an uncommon form of melanoma, histologically

manifested by dermal melanocytes in a background of dense stromal response. These lesions are
usually nonpigmented having lost the melanin production pathway. They usually stain negative for
MART-1/MelanA, gp100, and tyrosinase, but they do stain for S-100. The lack of pigmentation and the
dense stromal response often interfere with clinical and histologic diagnosis. It occurs most commonly
in the head and neck, but it may occur in other body sites. Desmoplastic melanoma may appear de
novo as a nonpigmented skin papule or as a dermal/vertical growth phase component arising from a
pre-existing lentigo maligna or other pigmented junctional lesion. Desmoplastic melanomas may have
neurotropic features and have been associated with a high rate of local recurrence. Recent reports
suggest that if adequate margins are taken, the risk of local recurrence is low. The overall mortality
risk for desmoplastic melanomas is comparable to that of other invasive melanomas of similar depth
of invasion. However, the risk of lymph node metastasis is lower than for other invasive melanomas.
One report from Memorial Sloan-Kettering Cancer Center found that sentinel node biopsies were
negative for all of the 22 pure desmoplastic melanomas. The same report found local recurrences in
7% of pure desmoplastic melanomas, compared to only 2% of other cutaneous melanomas.

Malignant melanoma in sites other than the skin

The majority of melanomas are in the skin, but other sites include the eyes, mucosa, gastrointestinal
tract, genitourinary tract, and leptomeninges. Metastatic melanoma with an unknown primary site may
be found in lymph nodes only.

Mucosal lentiginous melanomas: Mucosal lentiginous melanoma (MLM) develops from the mucosal
epithelium that lines the respiratory, gastrointestinal, and genitourinary tracts. These lesions account
for approximately 3% of the melanomas diagnosed annually and may occur on any mucosal surface,
including the conjunctiva, oral cavity, esophagus, vagina, female urethra, penis, and anus.
Noncutaneous melanomas commonly are diagnosed in patients of advanced age. MLM appear to
have a more aggressive course than cutaneous melanomas, although this may be because they
commonly are diagnosed at a later stage of disease than the more readily apparent cutaneous
melanomas.

Diagnosis
The classic appearance of primary cutaneous melanoma is summarized by the mnemonic ABCD for
asymmetry, border irregularity, color variation, and diameter greater than 6 mm (19). Because
melanoma arise from melanocytes, which contain the melanin-synthetic pathway, melanoma
classically are distinguished by their pigmentation which may have shades of brown, black, blue, red,
and white. Some have no visible pigment and appear skin-colored. When melanomas have all of the
classic ABCD features, they are typically easy to diagnose. However, those melanomas that lack
some of these features can be difficult to diagnose. In addition, in patients with large numbers of
atypical nevi, which may also have ABCD features, this mnemonic is often inadequate to aid in early
diagnosis. The other important findings that may aid in early diagnosis are a change in a lesion over
time or new development of a lesion. These warrant evaluation, and in high-risk patients there should
be a low threshold for biopsy. Dermatologists recommend considering the ugly duckling sign: a lesion
that stands out as different from the patient are other nevi should be evaluated and possibly biopsied.
This can be particularly helpful in a patient with a large number of clinically atypical nevi. Both of these
approaches may help to identify amelanotic (nonpigmented) melanomas, which often do not meet the
ABCD criteria. Some melanomas are not diagnosed until they become symptomatic. Symptoms of
bleeding, itching, pain, and ulceration usually connote deep vertical growth and are hallmarks of a late
diagnosis.

Standard recommendation state that an excision biopsy with narrow (2 mm) margins be performed
when a biopsy is taken from a primary skin lesion to confirm or exclude a diagnosis of melanoma,
unless clinical reasons dictate otherwise. Orientation of the incision used for an excisional biopsy
should be considered in the context of a future need for wider re-excision. When in doubt about the
optimal orientation, a circumferential incision leaving the wound open for secondary or delayed
primary closure would be appropriate. Subungual melanoma usually originates at the proximal end of
the nail bed and presents a challenge for biopsy. The melanoma usually extends along the length of
the nail. Access to that location often requires removal of all or a large part of the nail.

Shave or punch biopsies, are not usually recommended because they are associated with an
increased risk of mis-diagnosis as a result of sampling errors in a heterogeneous lesion or there being
insufficient tissue for adequate assessment of the pathologic criteria necessary to permit correct
diagnosis. Moreover, the depth of invasion may be inaccurately assessed in partial biopsies.

However, clinical features must considered when determining the most appropriate biopsy technique.
An excision biopsy would be inappropriate for large lesions occurring on cosmetically or functionally
sensitive anatomic sites such as the face, palms, or soles when the clinical diagnosis is uncertain. In
such instances a full thickness wedge biopsy (including subcutaneous fat) through the most
representative and deepest part of the lesion along with a 2 mm rim of normal skin would be
appropriate. This will allow the architecture of the lesion, depth of infiltration and desmoplasia to be
assessed. Punch biopsies may be used to map the extent of large melanocytic lesions (eg, on the
face, digits, palms, or soles) to facilitate surgical planning for wide local excision. If the clinical
suspicion is high, a repeat biopsy is warranted after a negative partial biopsy.

If the pathologist considers that the specimen does not contain enough histologic evidence for a
straightforward diagnosis of nevus or melanoma, a descriptive diagnosis of atypical melanocytic
proliferation may be made, usually followed by a comment stating if a benign or malignant diagnosis is
favored (21).

Staging work up
Staging investigations include complete blood counts, complete chemistry panel (including alkaline
phosphatase, hepatic transaminases, total protein, and albumin) and serum lactate dehydrogenase.

Imaging an essential part of staging will include chest radiography, magnetic resonance imaging of
the brain (in stage IV melanoma), ultrasonography (possibly the best imaging study for diagnosing
lymph node involvement) and computed tomography of the chest, abdomen, or pelvis (depending on
the location and for stage IV melanoma).

Positron emission tomography (PET): PET-CT may be the best imaging study for identifying the
primary (when it is occult) and other sites of metastasis
American Joint Committee on Cancer (AJCC), TNM Staging System for Melanoma (7th ed., 2010)
Primary Tumor (T)
TX Primary tumor cannot be assessed (eg, curettaged or severely regressed melanoma)
T0 No evidence of primary tumor
Tis Melanoma in situ
T1 Melanomas 1.0 mm or less in thickness
T2 Melanomas 1.01 -- 2.0 mm
T3 Melanomas 2.01 -- 4.0 mm
T4 Melanomas more that 4.0 mm
2
Note: a and b sub categories of T are assigned based on ulceration and number of mitoses per mm
as shown below:
T classification Thickness in mm Ulceration status/ mitosis
T1 </= 1.0 a: w/o ulceration and mitosis <1/mm 2
 b: with ulceration or mitoses 3 1/mm 2
T2 1.01-2.0 a: w/o ulceration
b: with ulceration
T3 2.01-4.0 a: w/o ulceration
b: with ulceration
T4 >4.0 a: w/o ulceration
b: with ulceration

Regional Lymph Nodes (N)

NX Patients in whom the regional lymph nodes cannot be assessed (eg, previously removed
for another reason)
N0 No regional metastases detected
N1-3 Regional metastases based upon the number of metastatic nodes and presence or
absence of intralymphatic metastases (in transit or satellite metastases)

N1-3 and a-c sub categories are assigned as shown below:

N stage No. of metastatic nodes Nodal metastatic mass
N1 1 node a: micrometastasis*
b: macrometastasis**
N2 2-3 nodes a: micrometastasis*
b: macrometastasis**
c: in transit met(s)/ satellite(s) without
metastatic nodes
N3 4 or more metastatic nodes, or matted
nodes, or in transit
met(s)/satellite(s) with metastatic node(s)
*Micrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy
(if performed).
**Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic
lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

M Classification
M0 No detectable evidence of distant metastases
M1a Metastases to skin, subcutaneous, or distant lymph nodes
M1b Metastases to lung
M1c Metastases to all other visceral sites or distant metastases to any site combined with an
elevated serum LDH

Note: Serum LDH is incorporated into the M category as shown below:

M classification Site Serum LDH
M1a Distant skin, subcutaneous, or nodal mets Normal
M1b Lung metastases Normal
M1c Any distant metastases Elevated

Anatomic Stage/Prognostic Groups

Clinical Staging*
Stage 0 Tis N0 M0
Stage IA T1a N0 M0
Stage IB T1b N0 M0
T2a N0 M0
Stage IIA T2b N0 M0
T3a N0 M0
Stage IIB T3b N0 M0
 T4a N0 Mo
Stage IIC T4b N0 M0
Stage III Any T N>/= 1 M0
Stage IV Any T any N M1
*Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for
metastases. By convention, it should be used after complete excision of the primary melanoma with
clinical assessment for regional and distant metastases.

Pathologic Staging**
Stage 0 Tis N0 M0
Stage IA T1a N0 M0
Stage IB T1b N0 M0
T2a N0 M0
Stage IIA T2b N0 M0
T3a N0 M0
Stage IIB T3b N0 M0
T4a N0 Mo
Stage IIC T4b N0 M0
Stage IIIA T(1–4)a
N1a M0 T(1–4)a N2a M0
Stage IIIB T(1–4)b N1a M0
T(1–4)b N2a M0
T(1–4)a N1b M0
T(1–4)a N2b M0
T(1–4)b N2c M0
Stage IIIC T(1–4)b N1b Mo
T(1–4)b N2b M0
T(1-4)b N2c M0
Any T N3 M0
Stage IV Any T Any N M1
**Pathologic staging includes microstaging of the primary melanoma and pathologic information about
the regional lymph nodes after partial or complete lymphadenectomy. Pathologic Stage 0 or Stage IA
patients are the exception; they do not require pathologic evaluation of their lymph nodes.

Prognostic factors
The presence or absence of metastatic disease is the single most important prognostic feature
determining survival.

Localised melanoma (stage I,II): The prognosis for patients with localized melanoma is generally
favorable. Tumour thickness (Breslow) (22,23,24,25), ulceration and mitotic rate are the three
independent prognostic factors in non-metastatic melanoma (26).

Primary tumor thickness is determined after excision and was introduced as a prognostic factor by
Alexander Breslow in 1970, and has subsequently been validated in multiple studies. At present, the
AJCC staging system uses tumor thickness cut points of <1.0 mm (thin), 2.0 mm (intermediate
thickness 1mm-4.0mm), and 4.0 mm (thick >4mm) to define T-category. In 27,000 patients from the
AJCC melanoma staging database with stage I or II disease, as primary tumor thickness increased
there was a significant decrease in survival

Ulceration is defined on histology as lack of an intact dermis overlying the primary tumor. Ulceration
represents a more aggressive tumor phenotype with a higher likelihood of metastasis and worse
prognosis. Analysis of the original AJCC melanoma staging database (published in the 2002 and
validated in the 2008 data base analysis) demonstrated that survival outcomes for patients with
ulcerated tumors were similar to those of patients with non-ulcerated tumors of the next highest T
category (27).

Increasing mitotic rates correlate with decreased survival. Multivariate analysis of 10,233 patients
from the updated AJCC melanoma staging database with localized melanoma (stages I and II)
revealed mitotic rate as the second most important predictor of survival, after tumor thickness,
particularly for patients with T1 melanoma. The 10-year survival rate was 95% for non-ulcerated T1
melanomas with a mitotic rate of less than 1/sq.mm, which reduced to 88% if the mitotic rate was
1/sq.mm or more (P<.0001). Ulcerated T1 melanomas were associated with a mitotic rate of 1/sq. mm
or higher in 78% of patients. The survival in T1 ulcerated melanoma is the same regardless of the
mitotic rate. Clarke's level (23), which is less reproducible amongst pathologists, is no longer a
significant variable.

The mitotic rate of the primary melanoma is determined following excision of the lesion. The
recommended technique is to first find the area within the dermis containing the melanoma with the
most mitotic figures, the so-called hot spot. After counting mitoses in the hot spot, the count is
extended to adjacent fields until an area of 1 sq. mm is assessed. The count is then expressed as
mitoses/sq. mm. If no hot spot is present, then a representative mitosis is chosen, and beginning with
that field, the count is then extended until an area corresponding to 1 sq. mm is assessed. Individual
microscopes should be calibrated for accurate recording. If the area of dermal infiltration is less than 1
mm, the simple presence or absence of a mitosis can be designated as at least 1/ sq.mm (mitogenic)
or 0/sq.mm (non-mitogenic). About 10% patients with thin melanoma with either ulceration or Clark's
level V infiltration or mitosis>1/ sq. mm will harbour occult nodal metastases and will benefit from
sentinel node biopsy.

Stage III Melanoma: Patients with regional metastasis (regional lymph node, satellite, and/or in-transit
metastasis) represent a heterogeneous group. Regional lymph nodes are the most common first site
of metastasis in melanoma patients. The number of metastatic regional lymph nodes, regional node
tumor burden (empirically classified as microscopic vs macroscopic), and ulceration of the primary
tumor are independent predictors of survival in this cohort (28).

Regional Lymph Nodes: As for other solid tumours, the number of metastatic nodes has replaced
nodal size as a criterion for staging and prognostication of melanoma. Regional node tumor burden is
the second most important prognostic factor in patients with stage III disease. Microscopic disease
refers to metastatic deposits detected on histologic analysis following elective or sentinel lymph node
dissection. Macroscopic disease refers to nodal metastases that are clinically or radiographically
apparent and pathologically confirmed. These definitions are thus based on method of detection.
Analysis of patients in the AJCC melanoma staging database demonstrated significant differences in
survival when accounting for nodal tumor burden (29,30)

The same data base showed that older age was an independent adverse prognostic factor, regardless
of nodal tumor burden. In patients with nodal micro-metastases, thickness, mitotic rate, ulceration,
and anatomic location of the primary tumour were found to significantly impact on survival. In contrast,
these primary tumor features were not independent predictors in patients with nodal macro-
metastases. These results reveal important differences regarding prognosis based on nodal tumor
burden.

Similar to its impact on survival for stage I and II melanoma, primary tumor ulceration is associated
with decreased survival in stage III, upstaging such a patient to that of a patient with a nonulcerated
primary who has a higher nodal tumor burden category. 5-year survival is 53.9% and 46.6%,
respectively, in patients with 2 to 3 microscopically involved regional nodes and an ulcerated primary
melanoma, versus 2 to 3 macroscopically involved lymph nodes in patients whose primary tumor is
not ulcerated.

In-Transit and Satellite Disease: In-transit disease or satellite lesions are indicative of intra-lymphatic
metastases.. Patients with in-transit or satellite disease in the absence of nodal metastases are
designated N2c, while patients with concomitant nodal metastases and in-transit and/or satellite
lesions are classified as having N3 disease. Based on current analyses of the AJCC melanoma
staging database, patients with N2c disease have 5- and 10-year survival rates of 69% and 52%,
respectively(31).

Stage IV Melanoma: Historically, the 5-year survival of stage IV melanoma patients has been under
10%. The site/s of distant metastases, the number of metastases and levels of serum lactate
dehydrogenase (LDH), a non-specific marker of tumour burden were analysed to detect differences in
survival amongst patients in this cohort. Analysis of the updated database of over 8000 patients
showed these to be significant independent prognostic factors in stage IV melanoma. Patients with
metastasis to distant skin, subcutaneous tissues, and/or lymph node basins (M1a) have the highest 1-
year survival rate (62%) among patients with stage IV disease followed by patients with pulmonary
metastasis (M1b) who have an intermediate prognosis (1-year survival rate, 53%). Patients with non-
pulmonary visceral metastases and/or an elevated serum LDH (M1c) have the worst 1-year survival
among stage IV patients (33%). The AJCC melanoma database analysis revealed that 1- and 2-year
survival rates for stage IV patients with a normal LDH were 65% and 40%, respectively, compared
with 32% and 18%, respectively, in those patients with an elevated LDH level. Identifying and
quantifying distant disease is a diagnostic challenge which makes it difficult to incorporate the
number/ volume of metastatic disease as a formal criterion in staging (32,33).

Treatment

Surgical resection is the mainstay of treatment of malignant melanoma. Surgery aims to address the
primary, regional nodes and occasionally metastases as well. The role of chemotherapy,
immunotherapy, biochemotherapy and radiation therapy is evolving. Before treatment is begun, a
detailed discussion with the patient and the family about the options of treatment, expected outcomes,
issues with cosmesis including the length and location (surgery for a 1 cm melanoma could result in a
scar that is 5 cm long) of the scar, surgery for lymph nodes and plan for adjuvant treatment is
necessary.

Management of the primary(34):

a) Surgery: A wide local excision, the margin being dictated by the thickness of the melanoma, is the
primary surgery for most cutaneous melanoma. The specimen would normally include the
subcutaneous fat but not the deep fascia. Special attention to the third dimension is necessary where
disease infiltrates the subcutaneous fat and sometimes underlying structures as well. The radial
margins are measured from the perimeter of the melanoma or the excision biopsy scar. Local
recurrences after appropriately wide excision are a result of lymphatic tumor emboli and behave
similar to in-transit and satellite disease.

A circular incision is often converted into an ellipse to facilitate primary closure without dog ears. On
the extremities, the ellipse is oriented parallel to the long axis of the limb. This orientation facilitates
primary closure, maximizes excision of lymphatics that are at risk for tumor cell emboli, and may
decrease subsequent lymphedema risk. On the trunk, the incision should be oriented in a way that
optimizes primary closure while ideally incorporating at-risk lymphatic tissue. At times, a modified
ellipse may be necessary using a “hurricane” or “lazy S” incision.

The specimen should always be carefully oriented for the pathologist before being completely
removed from the intact tissues. It is common for 2-cm margins, to require the mobilization of full-
thickness advancement flaps. Closed-suction drainage may be used. Multilayered closure consists of
sutures approximating the subcutaneous fat, intradermal sutures and subcuticular or interrupted
nonabsorbable sutures or skin staples. Dermal adhesives or adhesive bands may also be used. When
primary closure is not possible, consideration must be given either a skin graft or local/ distant flap
technique. Skin grafts allow for the careful monitoring of the primary excision site in patients with
locally advanced melanomas. They are more disfiguring, insensate, and provide less protection to the
underlying tissues. Split-thickness skin grafts are generally harvested from the posterior thigh (of the
contralateral lower limb for an acral melanoma). Full-thickness skin grafts may be harvested from the
inguinal groin crease, the lower neck region over the area of the clavicle, and behind the ear.

Subungual Melanoma are treated by amputation at the level of the metatarsophalangeal joint.
Melanoma arising from the skin of the auricle necessitate resection of the underlying cartilage.

Melanoma arising from the weight bearing skin of the sole of the foot needs special consideration – a
medial plantar artery or a reverse sural flap or a distant free flap will be needed for covering the
defect. A skin graft will not suffice. In clinical practice in India, acral melanoma are often advanced
with the vertical growth invading underlying tissues in the foot that sometimes necessitate an
amputation (35)

Moh's microsurgery is an option for lentigo maligna (melanoma in situ)

Mucosal melanoma have a higher incidence of local recurrence and poorer survival. Melanoma-free
margins are difficult to achieve because of the close proximity of critical anatomic structures. Mucosal
melanoma behave aggressively with satellite formation, multifocality, angiolymphatic invasion, and
submucosal spread. A wide excision of all affected tissues (head and neck in the paranasal sinuses
and oral cavity, anorectal melanoma and vulvovaginal melanoma) is preferred over mutilating
procedures since they do not impact on survival (36).

b) Adjuvant treatment: After completion of surgery, patients with Ib (0.76-1mm thick with ulceration or
mitosis> 1/sq.mm, N0) or stage II melanoma (more than 1 mm, N0) could either receive interferon
alpha or be observed. The best course would however be to participate in a clinical trial.

Patients in whom negative margins cannot be ensured (mostly head and neck mucosal melanoma),
patients with recurrent resected melanoma or with desmoplastic melanoma with close margins should
receive post operative radiation therapy (37).

Management of regional lymph nodes

a) Surgery: Involvement of the regional nodes is the most important prognostic factor influencing
overall survival of patients with stage I and II melanoma. Historically, in an N0 situation, following
surgical excision of the primary, the regional nodes were either observed and dissected if nodes
appeared on follow up (called therapeutic lymph node dissection) or dissected immediately (elective
lymph node dissection).

Following a therapeutic dissection, rates of distant metastatic disease and relapse in the treated nodal
basin were 50% and 15% to 50%, respectively (38). The use of ELND was controversial because
only 15% to 20% of patients had pathologically positive nodes. Lymph node dissection has significant
morbidity in the form of lymphoedema especially in the lower limbs. In certain anatomic locations in
the trunk, the cancer had the potential to drain into more than one nodal basin. Importantly,
randomised trials failed to demonstrate a survival benefit of ELND when all patients were considered
(38,40,41,42).

The concept of lymphatic mapping (39) and sentinel node biopsy is based on two principles (i) the
existence of an orderly and predictable pattern of lymphatic drainage to a regional lymph node basin
that would predict the potential routes of metastatic spread of cancer cells via the lymphatics to
regional lymph nodes and (ii) the functioning of a first lymph node as an effective filter for tumour cells
(40). The first lymph node(s) receiving direct afferent lymphatic drainage (sentinel lymph node) is/are
the most likely to contain metastatic disease if any regional lymph nodes are involved. Successful
identification and careful histologic examination of all sentinel nodes in a patient should accurately
identify patients with lymph node metastases. Patients who have metastatic sentinel nodes undergo
an 'early therapeutic lymph node dissection'.

Clinical studies have validated this concept. The false negative rates are less than 5%. Sentinel
node “negative” patients have been followed up and have been reported to have “in-basin” failure of
4% or less. Of note is that these figures were based on conventional histopathology. False
negativity may be due to failure in identifying the sentinel node, failure of histopathology in identifying
metastases or presence of microscopic in-transit deposits that have not reached the sentinel node.

Historically, the standard approach for evaluating lymph nodes was to bivalve each clinically negative
node and evaluate a section from each half using hematoxylin and eosin staining. As a result, only a
very small percentage of each lymph node was actually sampled, resulting in underestimation of the
incidence of regional nodal disease in stage I and II melanoma patients. While the definition of
histologic examination continues to evolve, it is more feasible to examine multiple sections and use
immunohistochemical analysis to one or two or three 'sentinel' lymph nodes, rather than to the 20 to
30 lymph nodes submitted following a formal elective node dissection. Testing for melanoma proteins
like tyrosinase upstages nodal stage. It has however not been shown to impact on survival.

The incidence of metastases in thin melanoma is about 5%. This increases in melanoma with
ulceration or mitosis>1/ sq. mm or melanoma with vertical growth phase or those thicker than 0.75
mm are considered.

Sentinel node biopsy is indicated in all patients with primary 1 mm or thicker. It is indicated in thick
melanoma also even though they are at a greater risk for distant metastases since the status of the
sentinel node is the single most important prognostic factor. More over in this group of patients it will
still contribute to regional control of disease. SLNB is also indicated in melanoma less than 1 mm
thick if a) they are ulcerated, b) they have mitosis rates of 1 or more per sq. mm, c) they have a
vertical growth phase, d) they are of Clarke's level IV or more, e) the third dimension is positive after
an excision biopsy, f) there is a true local recurrence after excision of a previous primary, g) the
thickness cannot be estimated after an excision, h) the primary cauterised with cryo or electrocautery
or i) the atypical melanocytic lesion's nature is indeterminate on histopathology.

SLNB may be performed by lymphoscintigraphy with a hand held gamma camera and intraoperative
lymphatic mapping, by using vital dyes like patent blue or by a combination of both methods.
Intradermal injection of 99mTc-labelled colloid around the primary melanoma or excisional biopsy site
allows the localization of lymph node basin/s and potential sentinel nodes. The detection rate of the
sentinel lymph node by SLNB is improved with the use of vital dye in addition to the radiolabeled
tracer, but dye is often not used in the head and neck area because of the risk of leaving a permanent
tattoo in an exposed area. A combination of both methods is superior to either method alone. The
hand held gamma camera will also detect sentinel nodes outside the draining lymph node basin in in-
transit locations.

Several centres have investigated ultrasonography in combination with fine-needle aspiration cytology
for the monitoring of regional lymph nodes and detection of metastases earlier than clinical
examination only. This technique has been reported to be associated with a high sensitivity and
specificity. It is not standard of care at present.

In clinically node negative patients, tumour thickness, ulceration and mitotic rate were independent
prognostic factors for survival and for sentinel node positivity. Sentinel node status was also a
prognostic factor for overall survival.

Multicentre trials have shown that patients who have positive sentinel nodes and therefore undergo an
early therapeutic lymphadenectomy have a better survival than those who undergo lymphadenectomy
after nodes are clinically detected (72.3% and 52.4% at 5 years respectively). The number of
metastatic nodes detected on sentinel node biopsy and lymphadenectomy is 1.4 as opposed to 3.3
nodes for therapeutic lymph node dissection (43).

The most common site of failure after wide excision for malignant melanoma are the regional lymph
nodes. Following a therapeutic lymphadenectomy, the incidence of regional node basin failure varies
from 9 to 50% depending on the site, size, number and presence or absence of extracapsular disease
in the nodes. This is in contrast to a 10% regional failure after an elective nodal dissection.

All patients who have metastases in the sentinel node/s must undergo a complete lymphadenectomy.
There are trials currently underway that are examining the issue of omitting lymphadectomy for select
patients.

When nodes are regional palpable at presentation or on follow up, a therapeutic complete lymph node
dissection is indicated.

b) Adjuvant radiation: may be considered if 3 or more nodes have metastases, if nodes are larger
than 3 cm or there is macroscopic extracapsular disease. In the neck radiation would be indicated
even if nodes 2 cm or more and if 2 or more nodes have metastases. Radiation therapy has shown
improvement in regional disease control but not overall survival.

After completion of surgery, (and radiation if indicated) all patients with node positive disease could
either be observed or given interferon alfa. The level of evidence favouring interferon alfa in stages
Ib, II and III is at best category 2b.

Metastatic Disease
a) Management of in-transit metastases: Complete surgical excision if feasible is the mainstay for in-
transit metastases.
Regional chemotherapy for in-transit melanoma is an effective therapy for melanoma isolated to the
extremity, with response rates far exceeding those seen with current systemic therapy. Both
hyperthermic isolated limb perfusion HILP) and isolated limb infusion (ILI) have similar complete
remission rates, ILI being easier to perform. It is well tolerated. HILP provides more durable
responses (31% for ILI and 63% for HILP with a 38% 5 year survival). Melphalan is the most
commonly used agent. Regional chemotherapy could potentially use agents capable of overcoming
classic chemotherapy resistance pathways, normalizing abnormal tumor vasculature, modulating the
immunologic response, and correcting altered cell-signaling pathways that lead to unchecked
proliferation and decreased apoptosis.

Intralesional BCG or interferon, or topical imiquimod (for dermal lesions) are immunomodulators that
have been tried. Local ablation with cryotherapy or laser, radiation therapy and systemic
chemotherapy have also been tried.

If patient achieves a complete response, high dose interferon for 1 year (or pegylated interferon alfa
2b for 5 years) may be administered. While it improves the disease free interval, its impact on overall
survival is unclear.

b) Distant metastatic disease (Stage IV): Treatment for stage IV metastatic melanoma depends on
whether disease is limited (resectable) or disseminated (unresectable). Surgical resection after a
short period of systemic therapy (or observation) should be considered for patients with solitary or
limited resectable distant metastases. The period of systemic chemotherapy before surgery along
with a PET CT is to maximise the chances of chosing a patient who does not have occult metastases
elsewhere. These patients then would receive systemic treatment preferably as part of a clinical trial.

Patients with disseminated disease are managed by systemic therapy, clinical trial, or best supportive
care. schedule is influenced by risk of recurrence, previous primary

Systemic therapy
The therapeutic landscape for metastatic melanoma is rapidly changing (figure 3). Ipilimumab is a
monoclonal antibody directed to the immune checkpoint receptor termed “cytotoxic T lymphocyte
antigen-4 (CTLA-4)”. It activates cytotoxic T cells and is associated with grade III and IV
autoimmune reactions including diarrhoea. Clinical response (around 20%) may take months to
manifest but are durable. Approximately 45% of patients with metastatic melanoma harbor an
activating mutation of the intracellular signaling kinase, BRAF. Vemurafenib is a specific inhibitor of
signaling by mutated BRAF. Its adverse effects include cutaneous squamous cell carcinoma or
keratoacanthoma, photosensitivity reactions and arthralgias. About half of the patients will
demonstrate response, but the duration of response is usually 5-6 months. Imatinib, a tyrosine kinase
inhibitor may be used in patients who demonstrate the c-KIT mutation.

Commonly used chemotherapeutic agents include dacarbazine, temozolomide, and paclitaxel with or
without carboplatin. Little consensus exists regarding standard chemotherapy for patients with
metastatic melanoma.

Bio-chemotherapy, a combination of chemotherapy and biological agents like interleukin 2 or

interferon alfa, is investigational. It is not associated with either improved quality of response or
overall survival and is substantially more toxic.
Figure 3

Points to take home

1. A diagnosis of malignant melanoma must be entertained for all pigmented lesions of the skin and
mucous membranes.
2. Malignant melanoma is rare in the dark skinned races due to the protective effect of melanin from
UV rays from the sun. Most of the cutaneous melanoma seen in India are acral lentigenous
melanoma in the feet. Uveal melanoma and mucosal melanoma are also seen albeit uncommon.
3. Full thickness excisional biopsy with narrow margins is the minimum diagnostic procedure for a
pigmented lesion. In certain situations a full thickness wedge biopsy through the thickest part of
the lesion is acceptable. The orientation of the incision for excision biopsy should be planned with
the incision for definitive wide excision in mind.
4. Biopsy report must include
a) Breslow thickness (mm)
b) Histologic ulceration (present or absent)
c) Dermal mitotic rate per mm 2,3
d) Clark level (encouraged for lesions</=1 mm,optional if lesions > 1 mm)
e) Peripheral and deep margin status of biopsy (positive or negative).
f) Microsatellitosis (present or absent).
g) Location
h) Regression
i) Tumor infiltrating lymphocytes (TIL)
j) Vertical growth phase (VGP)
k) Angiolymphatic invasion
l) Neurotropism
m) Histologic subtype
n) Pure desmoplasia, if present or specify pure vs. mixed desmoplastic with spindle cell and/or
epithelioid cells
Comparative genomic hybridization (CGH) or fluorescent in situ hybridization (FISH) may be
usefulfor histologically equivocal lesions.
5. Margins during definitive excision will depend on the thickness of the melanoma
6. A sentinel node biopsy would be indicated for all node negative (clinically and by imaging) except
stage 1a melanoma. It could be considered for T1a melanoma that is more than 0.75 mm thick. All
 patients with clinically or sentinel node biopsy detected metastatic nodes should undergo a
complete regional lymph node dissection.
7. Adjuvant Radiation therapy for the primary site is indicated for desmoplastic melanoma with
narrow margins, for recurrent melanoma and melanoma exhibiting nerve infiltration on
histopathology.
8. Adjuvant radiation for regional nodes is indicated when there is macroscopic extracapsular
disease, when more than 3 nodes show metastases, when nodes are larger than 3 cm. In the
cervical region adjuvant radiation therapy would be considered if nodes are more than 2 cm or
they are larger than 2 cm. It would also be considered after resection of recurrent regional lymph
nodes.
9. Palliative radiation is indicated for in-transit lesions that cannot be treated by other methods,
unresectable primary or recurrence, symptomatic bone or soft tissue disease and cerebral
metastases.
10. All patients being considered for systemic therapy are best treated as part of a clinical trial.
11. Adjuvant interferon therapy can be considered for patients with stage III melanoma after
completion of local forms of treatment.
12. Vemurafinib can be considered for patients with mutation of the BRAF gene. Ipilimumab acts by
activating cytotoxic T lymphocytes. Both these agents can be considered in metastatic
melanoma. They are however associated with significant toxicity. Imatinib may be considered if c-
KIT mutation is present. Systemic therapy is evolving.

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 The Surgeon and Molecular Knowledge
Ravi Kant, Bina Ravi

The molecules in the DNA are signaling pathway, and can inform us today as to what will happen to
the cell in future. The molecular signature can forecast whether it will (a) become malignant, (b)
respond to certain medicines or not, (c) metastasize to Lymph nodes, and (d) respond to radiation or
chemotherapy or newer drugs. We can tailor our treatment in most cases using the detailed molecular
knowledge. Some tumors look alike in histological slides; yet by molecular stain, we can identify each
tumor in correct manner, allowing us to choose the proper treatment. Examples are confusion
between (a) Undifferentiated Adenocarcinoma and Lymphoma, (b) Gastrointestinal tumor and
Leiomyoma, and (c) colorectal cancer metastasizing more and also resistant to some newer
treatments, and (d) Soft tissue sarcoma subtypes, as each subtype has a different prescription- some
need more of surgery whereas some need more of multi-modality treatment. Spread of tumor is also
linked to molecular and genetic knowledge as size of tumour or histology alone cannot predict the
course of disease; especially in Breast Cancer and Lymphoma. Aggressive type of tumor will need a
more aggressive treatment whereas indolent type of tumor will need a more conservative approach.
The current molecular knowledge has altered the management pathways of cancers of breast, lung,
thyroid, head and neck, GIST (gastrointestinal stromal tumors), stomach, pancreas, colon, melanoma,
and soft tissue. It is essential for the surgeon to be familiar with new advances in molecular and
genetic knowledge.

Breast Cancer
Molecular classification of Breast cancer is essential to predict (1) prognosis & (2) treatment
response. Among the subtypes of breast cancer, (a) Luminal A has best overall survival (OS) and
best disease free survival (DFS), apart from Estrogen positive receptor status (ER+); (b) Luminal B is
ER + and Her2 +; and is helped by administration of Her2 blocker drug Trastuzumab (Herceptin); (c)
Intermediate type is Her2 positive but ER negative & PR (Progesterone receptor) negative; and (d)
Basal Type is Triple negative (ER negative, PR negative and Her2 negative) and carries the worst
prognosis. PARP inhibitors in basal type of breast cancer are promising as conventional treatment is
invariably unsuccessful. The size of tumor is insufficient indicator of prognosis; instead molecular
classification stratifies the breast cancer in low or high risk category; avoiding over- treatment in low
risk category. Gene based-assay predicts better than Adjuvant –Online, software based analytical
tool.

Prognostic and predictive Markers in Breast Cancer include IHC4. It provides a risk of recurrence
based on ER, PR, Her2 and Ki67 proteins. Mammaprint is a microarray based analysis of 70 genes
in breast cancer tissue; can identify 40% of patients with low risk in comparison to the 15% that are
identified with conventional methods; thus preventing numerus unnecessary under or over treatments.
Mammaprint had the highest accuracy in predicting distant metastasis and overall survival compared
to historical factors such as age, tumor size, tumor grade and estrogen status, as well as the Adjuvant
On-line software model and Nottingham and St. Gallen staging criteria. It identifies early metastasis
risk with highest accuracy (RASTER study). Oncotype Dx is 21 gene analysis of breast cancer tissue
(RT-PCR assay). It can predict a ER positive, axillary node negative patient on Tamoxifen, who can
benefit from chemotherapy. It strongly predicts risk of recurrence. Mammostrat Markers-Mammostrat
detects the presence of five proteins (SLC7A5, p53, NDRG1, TRMT2A (HTF9C), and CEACAM5.
Mammostrat Risk Index denotes a relatively high, moderate, or low risk of recurrence. Other Newer
Prognostic Indicators include- Wound response gene– activation of fibroblasts and quick wound
healing predict risk of metastases and death; and Two gene recurrence score–Homeobox 13 & IL
17B gene. High ratio between these two genes shows poor outcome. Thus, in such a scenario,
Tamoxifen alone will not help in T1, ER positive, Node negative tumors, and addition of further
treatment like chemotherapy will also be required.

We can predict response to therapy in early breast cancer based on tumor and host characteristics.
Tumor characteristics are assessed by gene assay like Oncotype Dx (TAILORx), or by Mammaprint
(MINDACT trial). Host characteristics are enzymes which are needed for metabolization of drugs.
Such enzymes include CYP450 encoded enzymes- CYP 2, CYP 3, CYP2D6, & CYP2C19. A
diagnostic tool like AmpliChip CYP450 by Roche can identify presence or absence of these
enzymes.1,2,3
Thyroid Cancer
BRAF is the new adverse prognostic marker in Papillary cancer of Thyroid mandating Total
thyroidectomy. So, even a smaller tumor with low risk profile in Papilary Thyroid Carcinoma with
BRAF will maximal treatment. PTEN and PPARy can also predict survival of Papillary Thyroid cancer.
RAS & CTNNB can also predict survival of Follicular thyroid cancer. This information is a tool for
future research on possible role of new drugs for these solid tumors, as by blocking these pathways,
we can alter the course of disease. 4,5

Gene- based diagnosis as well as surgery in Medullary Carcinoma Thyroid (MCT) is the new norm. In
presence of expression of RET gene, even a two year old child with normal serum calcitonin and
without any visible thyroid nodule will need maximal surgery in Medullary Carcinoma of Thyroid (MEN
Type 2b). The advanced MCT will need PET or Somatostatin receptor scintigraphy for detection of
location. We can ablate advanced tumor by MIBG.

Head & neck cancer

Human Papilloma Virus (HPV 16) results in early DNA changes in Tonsillar and Oral cancer. Epstein
Bar virus associated DNA changes are seen in early stage of Oral and Burkitt’s Lymphoma. The
knowledge has resulted in new technology for early diagnosis and possible use of vaccines for
prevention. The DNA based saliva test, for oral cancer is the new way of diagnosing early cancer.
Premalignant phase can be diagnosed by chromosomal and molecular study. Role of HPV vaccine in
selected population to prevent oral cancers is an option.

Stomach cancer
H. Pylori Cag A gene expression is up regulated in presence of intra-luminal salt. Helicobacter Pylori
eradication can prevent secondary cancer. The genetic marker may provide a clue of early gastric
cancer, much earlier then provided by conventional diagnosis methods. There is also role of Antibody
G17DT for prevention as well as in early reversal of gastric cancer. CDH1 gene is associated with
familial gastric cancer. Wnt signaling pathway and E –cadherin have a major role in development of
6
gastric cancer.

Pancreas cancer
Dismal five-year survival and poor prognosis of pancreas cancer despite heroic surgery mandates
new areas of molecular research in solid tumors. New markers for diagnosis are still at experimental
stage. The possible new markers include Mesothelin, MIC-1 (Macrophage inhibitory cytokine-1),
Mitochondrial mutations, Aberrant miRNA, APC & p16 gene, DNA methylation, PanIN (Preneoplastic
pancreatic intraepithelial neoplasia). Possible future treatment of Pancreatic cancer include Biologic
therapy e.g. Anti-angiogenic drugs, (Thalidomide as anti-angiogenic agent, Anti- VEGF like
Bevacizumab); the MMP, COX 2 & Lipooxygenase inhibitors, Tyrosine Kinase Inhibition by
Panitumumab, EGFR blockers, and use of drugs which alter Intra-celluar signalling pathway
(MAPK/MEK).

GIST (Gastrointestinal tumor) tissue diagnosis by CD117 stain has significantly diminished the true
incidence of Leiomyomas. PET scan is the investigation of choice in diagnosis in GIST. The tyrosine
kinase pathway and receptors like PGDFR (Platelet derived grown factor receptor) in Cajal cells
mandates the role of Imatinib and Sumanitib in adverse prognosis or in incompletely resected GIST.
The new concept of immunomodulator has changed the earlier dismal scenario. Lymph node
dissection in GIST is not required unlike carcinoma of stomach.

Colorectal cancer
DNA examination of stool is better tool then Occult blood testing for diagnosis of early Colo-rectal
cancer, though cost and availability is the major issue. With K-ras, p53, APC & MIS – Bat 26; the
sensitivity is 91%; & Specificity is 93%. If we Exclude K-ras, then Specificity is 100% in detection of
adenoma of >1cm size (sensitivity 73% & specificity 100%). An easy explanation of aetiology of colo-
rectal cancer classifies genes as Gatekeepers, Caretakers and Landscapers. On a molecular level,
Chromosomal instability (B-catenin pathway, deleted in cancer gene DCC, silent gatekeeper theory),
Microsatellite instability (MIS), and Transforming growth factor-β pathway are involved in colorectal
cancer. The primary defect is Chromosomal instability in Familial Adenomatous Polyposis (FAP) with
methylation defect; and Mismatch Repair Gene (MMR) in cases of Hereditary Non-polyposis Colon
Carcinoma (HNPCC) or Lynch’s syndrome. Each of six type of Mismatch Repair (MMR) gene like
hMSH2, hMSH6, hMLH1, hMLH3, hPMS1, and hPMS2 has a different clinical spectrum; and entirely
a different prognosis. Molecular knowledge is essential for proper treatment and correct prognosis of
the colorectal cancer. New entities like DCC and Familial Cancer X are equally relevant to understand
varied behavior of the colo-rectal cancer.

Prognosis in Colo-rectal cancer also depends on K-ras mutation as it denotes increased nodal
metastases, higher recurrence rate and poor survival. The K-ras mutation (excluding wild type of K-
ras) also precludes use of Cetuximab in advanced colorectal cancer. Predicting response to 5FU is in
colo-rectal cancer is an option if levels of Thymidine synthase (TS) & Thymidine phosphorylase (TP)
are analysed. Bevacizumab – an angiogenesis blocker monoclonal antibody is also approved for
addition to FOLFOX (5FU+ Oxaliplatin) as first line in metastatic cancer. Molecular imaging of
advanced colorectal cancer by PET scan of hepatic metastases, and local recurrence is beneficial.
The molecular imaging, molecular diagnosis and molecular therapy has changed the previously
7
inoperable Colo-rectal cancer into a possible second look surgery; and improved overall survival.

Soft Tissue sarcomas

the new classification and diagnostic tool is chromosomal, & gene based. The chromosomal
knowledge in soft tissue sarcoma is essential for optimum plan of treatment and prognosis. Mistakes
8,9
in diagnosis are quite common without use of the chromosomal study.

In Summary, knowledge of molecular abnormalities can help us in prevention, vaccines, diagnosis,

treatment, and prediction of prognosis. The knowledge of molecular pathways and knife of the
Surgeon are entwined.

REFERENCES
1. Sotiriou, Christos, Pusztai, Lajos. Gene-Expression Signatures in Breast Cancer. N Engl J Med 2009; 360:790-800.
2. Trapé AP, Gonzalez-Angulo AM. Breast cancer and metastasis: on the way toward individualized therapy. Cancer
Genomics Proteomics. 2012 Sep-Oct;9(5):297-310
3. Paik S. Is gene array testing to be considered routine now? Breast. 2011 Oct;20 Suppl 3:S87-91. doi:
10.1016/S0960-9776(11)70301-0.
4. Volkert B. Wreesmann, Bhuvanesh Singh. Clinical Impact of Molecular Analysis on Thyroid Cancer Management.
Surgical Oncology Clinics of North America. Volume 17, Issue 1, Pages 1-35, January 2008.
5. Edna T. Kimura, Marina N. Nikiforova, Zhaowen Zhu, Jeffrey A. Knauf, Yuri E. Nikiforov, and James A. Fagin. High
Prevalence of BRAF Mutations in Thyroid Cancer: Genetic Evidence for Constitutive Activation of the RET/PTC-
RAS-BRAF Signaling Pathway in Papillary Thyroid Carcinoma. Cancer Research 63, 1454–1457, April 1, 2003.
6. Vanessa R Blair, Familial gastric Cancer: genetics, Diagnosis and Management. Surgical Oncology Clinics of
North America Vol 21, Issue 1, Pages 35-56, January 2012.
7. Akiyoshi T, Kobunai T, Watanabe T. Predicting the response to preoperative radiation or chemoradiation by a
microarray analysis of the gene expression profiles in rectal cancer. Surg Today. 2012 Aug;42(8):713-9. doi:
10.1007/s00595-012-0223-8. Epub 2012 Jun 16.
8. Mertens F, Panagopoulos I, Mandahl N. Genomic characteristics of soft tissue sarcomas. Virchows Arch. 2010
Feb;456(2):129-39. doi: 10.1007/s00428-009-0736-8. Epub 2009 Feb 3.
9. Szuhai K, Cleton-Jansen AM, Hogendoorn PC, Bovée JV. Molecular pathology and its diagnostic use in bone
tumors. Cancer Genet. 2012 May;205(5):193-204.
 Periampullary carcinoma
Sundeep Singh Saluja, Sandip Chandrasekhar, John M Manipadnam

Introduction
Periampullary carcinoma is a term to describe a heterogenous group of neoplasms arising from
the head of pancreas, distal common bile duct, duodenum and the ampulla. The ampulla of
Vater is formed by the duodenal aspect of the sphincter of Oddi muscle, which surrounds the
confluence of the distal CBD and main pancreatic duct as well as the papilla of Vater, a mucosal
papillary mound at the distal insertion of these ducts on the medial wall of the duodenum. The great
majority of tumors arising in these areas are adenocarcinomas.

The first successful local resection of a periampullary carcinoma was performed way back in 1898 by
Halstead but the patient died 7 months later of a recurrence. The standard operation for periampullary
carcinoma is Whipple procedure. Pancreaticoduodenectomy was described by Whipple in 1935.
Initially performed in two stages with gastrojejunostomy and biliary diversion in the first setting
followed by resection in the second sitting, he modified the operation in 1941 to a one stage operation
incorporating pancreaticojejunostomy.[1] Advances in anaesthesia, surgical technique and critical
care have contributed to the decline in postoperative morbidity and mortality thereafter.

Incidence
The incidence of periampullary carcinomas is low compared to colorectal, breast & lung cancers. The
most common periampullary adenocarcinoma is pancreatic, followed in order by ampullary, distal
cholangiocarcinoma & duodenal. Pathological examination of resected specimen reveals that
approximately 40-60% are of pancreatic adenocarcinoma, 10-20% for ampullary, 10% for distal
cholangiocarcinoma & 5-10% for duodenal adenocarcinoma.[2] The incidence of pancreatic
carcinoma is 8 to 9 cases per 1 lakh population with majority are beyond sixth decade of life with male
preponderance. India and Middle East have lowest incidence of pancreatic carcinoma. Ampullary
carcinoma has overall incidence of 6 cases per million. Although its incidence is lower than pancreatic
cancer, it accounts for higher percentage of operative cases because the lesions are more amenable
to complete resection. Distal bile duct carcinoma & periampullary duodenal adenocarcinoma occur
less frequently than pancreatic and ampullary carcinoma.

Ampullary carcinomas
They are defined as those that arise within the ampullary complex, distal to the bifurcation of the distal
common bile duct and the pancreatic duct. The tumors of the ampulla show either intestinal or
pancreaticobiliary morphology. The intestinal type is associated with presence of preinvasive lesions
(adenomas, low grade dysplasia) with resemblance to the colorectal adenocarcinoma with good
prognosis. Pancreaticobiliary type however shows desmoplastic stromal reaction, adenomatous
areas are infrequent and the prognosis is worse. The incidence of Ki-ras mutation in ampullary
cancer is lower than in pancreatic carcinoma (35% vs. 90%). The overall pattern of mutation in
ampullary carcinoma more closely resembles that of colorectal than pancreatic cancer. Ampullary
carcinomas account for up to 6 % of all periampullary malignancies and they present at an earlier
stage. The strategic location leads to an early presentation with jaundice, biliary colic,
bleeding or even pancreatitis. Five-years survival is favourable in patients with ampullary
carcinoma, ranging from 34% to 45%, but recent studies have reported as high as 50%.

Subdividing adenocarcinomas of the ampulla of Vater according to histologic subtype and

immunohistochemical staining pattern into distinct subsets with differing biologic behavior has
prognostic importance. In a retrospective study of 208 patients treated for ampullary
adenocarcinoma in Sydney, Australia, those with a histomolecular pancreaticobiliary phenotype
(CDX-negative, MUC1 positive) had a significantly worse outcome than did those with an intestinal
phenotype (CDX-positive, MUC1-negative), with median survival of 16 versus 116 months.[3] When
histomolecular phenotype was combined with the lymph node status, three subsets of ampullary
adenocarcinomas emerged with significantly different survival outcomes:
 Patients with a node-negative, non-pancreaticobiliary histomolecular phenotype tumor had an
excellent prognosis (five-year survival 88 percent).
 Patients with a node-positive pancreaticobiliary phenotype had a poor prognosis (five-year
survival 20 percent).
 The remaining patients (node-positive non-pancreaticobiliary phenotype, node-negative
pancreaticobiliary phenotype) had an intermediate prognosis (five-year survival 47 percent).
Duodenal adenocarcinoma
Of all the periampullary tumors the duodenal type is the least common. Nearly all are mucin-
producing adenocarcinoma and may be ulcerative or polypoid. Although the disease may present in
younger patients most patients are typically within the 6th to 8th decade of life and it displays no
particular gender predominance. The most common presenting signs and symptoms are abdominal
pain (50%), iron-deficiency anemia (40%), weight loss (40%), nausea and vomiting (30%) and
obstructive jaundice (20%). Duodenal adenocarcinoma have the longest survival ranging from 22-
53% when compared with other periampullary tumors.

Distal Cholangiocarcinoma
Cholangiocarcinoma is a rare malignancy and 27% occur in the distal bile duct. The commonest
presentation is with jaundice and weight loss. Among pathological characteristics, the diameter is
usually 2 cm and sclerotic adenocarcinoma moderately differentiated occurs in the majority of the
patients. Five year survival after operation is 24%. Extrapancreatic nerve plexus invasion is found to
be 29% compared to only 3 % in ampullary cancers.

Pancreatic carcinoma
Incidence of carcinoma pancreas seems to be increasing and symptomatology is vague leading to
advanced disease at presentation. The prognosis of pancreatic adenocarcinoma is the most dismal of
all cancers, approximately 95% of all patients diagnosed with pancreatic cancer will die within one
year. After potentially curative resection the 5 year survival is 5% to 20% making the worst survival of
periampullary cancers. Examination of tumor spread reveal a high incidence of nodal involvement
(75% of patients) and extrapancreatic plexus invasion found in 60% of patients.

Risk factors
Risk factors for pancreatic adenocarcinoma has been studied in detail than other periampullary
varieties. Established risk factors for pancreatic cancer are tobacco usage & inherited susceptibility.
Chronic pancreatitis, DM & obesity are associated with pancreatic cancer and are considered as
weak risk factors. Physical inactivity, consumption of high carbohydrate diet and exposure to certain
pesticides are possible risk factors but data are inconsistent. Gallstones, coffee consumption,
exposure to ionizing radiation & alcohol once considered as risk factors are not true risk factors any
more.

Most studies have proved that smoking results in two fold increased risk for pancreatic cancer. [4,5]
There is a definite dose response relationship with higher pancreatic cancer with heavier smoking
exposure. A study of 50 year follow up in British physicians showed that pancreatic cancer rates in
non smokers, ex smokers & current smokers were 21, 31 & 39 per 100,000 person years
respectively.[6] Some of dietary factors with protective effect are consumption of diet with high fiber,
Vitamin C, green leafy vegetables but these are not well established.
Several risk factors for distal cholangiocarcinoma are inflammatory bowel disease, sclerosing
cholangitis, choledochal cyst, choledocholithiasis.

Genetic alterations and periampullary carcinoma

Familial clustering of pancreatic cancer accounts for 10% of all pancreatic cancer.[7] Only 20% of
familial pancreatic cancer occur as a part of named syndromes.[8] Genetic syndromes associated
with pancreatic adenocarcinoma are Hereditary pancreatitis, Hereditary non polyposis colorectal
cancer (HNPCC), Peutz Jeghers syndrome, Familial Atypical Multiple Mole Melanoma syndrome
(FAMMM), Familial Adenomatous Polyposis (FAP), BRCA 2 mutation familial breast cancer & Ataxia
telangiectasia.

The progression from histologically normal pancreatic ductal epithelium to low grade PanIN to high
grade panIN is associated with specific genetic alterations. Early changes include Her-2/neu and K-
ras mutations, intermediate changes include p16 mutations and alterations associated with
insitu and invasive cancer include p53, BRCA2 and DPC4 mutations. Almost all pancreatic
cancer is associated with mutation in codon 12 of K-ras oncogene. P53 tumor suppressor gene
mutation is observed in 75% of pancreatic cancers. Over expression of EGF receptor is associated
with poor prognosis. Increased expression of HER2 is associated with better tumor differentiation.
Other growth factor systems implicated in development of pancreatic cancer are HGF and TGF beta.
Ampullary and duodenal adenocarcinomas occurs with increased frequency in patients with HNPCC,
Peutz Jeghers syndrome, FAP and Gardner’s syndrome.

Diagnostic Evaluation
Diagnosis of periampullary carcinoma is usually made based on clinical findings, laboratory data and
radiological imaging. In case of duodenal and ampullary lesions, tissue diagnosis may sometimes be
of benefit since local resection can be performed if it proves to be benign. If clinical, laboratory and
radiological imaging is suspicious of malignancy, then surgery to be performed since majority of
patients resected will indeed have a cancerous lesion. A negative biopsy of periampullary lesion has a
significant rate of being falsely negative for malignancy. Biopsy confirmation is mandatory if the lesion
is unresectable or if neoadjuvant therapy is being planned.

Tumour Markers
There are no definitive tumor markers for periampullary carcinoma. CA 19-9, a glycoprotein
synthesized from epithelial cells of pancreas and biliary tract is elevated in 75% of pancreatic cancer.
However it has its own limitations. CA 19-9 is not specific for pancreatic cancer since it is also
elevated in benign conditions like cholangitis, IBD, cirrhosis and in smokers. Secondly its sensitivity is
reduced since 10-34% of patients who test negative for Lewis blood group antigen A and B cannot
synthesise CA 19-9.[9] However CA 19-9 best serves as marker for treatment response and
recurrence in patients with pancreatic cancer. CEA levels may be elevated in bile duct and duodenal
adenocarcinoma. Biliary CEA levels is found to be useful in suspicious cases of bile duct
adenocarcinoma. Several groups have tried in detecting K-ras mutations in duodenal and biliary
aspirates and in stools in cases of pancreatic cancer as nearly 100% of pancreatic adenocarcinomas
have K-ras mutations .[10,11]

Ultrasonography
Transabdominal ultrasonography (US) should be the first imaging study ordered for patients with
suspected periampullary carcinoma since US is simple, cheap, easily available and non invasive
modality. It can identify the location of biliary obstruction with 95% sensitivity and 98% specificity. It
can detect more ominous signs of advanced disease like liver metastases and ascites. Combined with
Doppler it can be useful in assessing the SMA, SMV involvement with reasonable accuracy. Newer
technologies like US elastography and CO2 microbubble as contrast are used for better evaluation.
However it is operator dependent and overlying bowel gas frequently obscures the distal bile duct,
ampulla, and pancreas.

Abdominal CT should be ordered as the next diagnostic procedure. A "pancreatic mass protocol" CT
should be ordered. Specifically, patients should receive water as the oral "contrast agent" (to distend
the duodenum and improve visualization of the duodenal lumen and adjacent pancreas), and IV
contrast is injected as a bolus to permit both arterial- and venous-phase imaging. Images are
acquired at 1.0 to 2.5 mm intervals to improve the sensitivity of pancreatic imaging. Typically
pancreatic cancer is seen as a low density (hypodense) lesion, best seen during venous phase of
contrast enhancement. Pancreatic protocol CT show the relationship between tumor and surrounding
vessels including SMA, SMV, PV and branches of celiac axis. It can reliably predict vascular
involvement in 80-90% of cases.[12,13] CT is also useful to evaluate for the presence of distant
metastatic disease which most frequently involves the regional lymph nodes, liver, peritoneum, lungs,
and bone. However CT is not a good modality for detecting surface liver metastases <1cm and
peritoneal deposits. Additionally arterial phase with 3D reconstruction assist in surgical planning by
identifying vascular variations most notably replaced right hepatic artery, which is seen in one in six
patients. A meta analysis of 68 articles showed an overall diagnostic sensitivity of 91% and specificity
of 81% [14] and sensitivity and specificity of 81% and 82% respectively regarding determination of
respectability.

CT Scoring system for vascular involvement in pancreatic cancer has been proposed by
Raptopoulous in 2007, which takes in to account the length of tumor contact, circumferential extent of
tumor involving SMV, PV, SMA, contour deformation of veins. If <90 degree contaco of vessel with
tumor, the chance of actual vascular involvement is 3%, 29-57% if 90-180 degree contact and >80% if
>180 degree vascular contact. Although helical CT can detect masses obstructing the distal CBD, its
sensitivity usually does not permit the visualization of small ampullary neoplasms within the duodenal
lumen.[15] In one report, the overall accuracy was only 20 percent in detecting ampullary masses.[16]
Furthermore, CT by itself is inadequate for staging ampullary cancers because it lacks the spatial
resolution to determine the degree of local tumor invasion into the duodenal wall, adjacent pancreas,
or the presence of major vascular involvement.[17]

Side Viewing Endoscopy Most ampullary cancers are obvious endoscopically. If an exophytic
ampullary tumor is identified that has the appearance of an adenoma, malignancy should be strongly
suspected if the mass is ulcerated or over 3 cm in size. However, because the false negative rate of
endoscopic biopsy is as high as 50 percent, a negative result is insufficient to exclude the presence of
malignancy in an ampullary lesion [18-24] the overall accuracy of diagnosis with ERCP in one report
was 88 percent (p>0.05).[25]

Attempts to enhance the accuracy of endoscopic biopsy include the acquisition of tissue at least 48
hours following sphincterotomy[26,27] the performance of multiple biopsies [28] and the use of
polymerase chain reaction (PCR) or immunohistochemical staining to detect p53 (a tumor suppressor
gene that is frequently lost in periampullary neoplasms) or K-ras gene mutations in case of pancreatic
cancer[29,30] DNA ploidy analysis. Sensitivity of brush cytology is highest for distal bile duct tumors,
intermediate for pancreatic cancers and lowest when obstruction is due to metastatic disease. The
sensitivity of brushing increases from 40% for one brushing to 62% for 3 brushings in documented
cases of distal cholangio carcinoma. The overall sensitivity increases to 80% when biopsy used in
combination with cytology brushing.

ERCP- In a jaundiced patient with suspected malignant bile duct obstruction, ERCP used to be the
preferred initial endoscopic study since it permits simultaneous endoscopic visualization of the
ampulla, cholangiography of the pancreatic and bile ducts, biopsy from the papilla and ampullary
segment of the CBD or pancreatic duct, and placement of a stent for biliary decompression, if
necessary and technically feasible. However, ERCP cannot determine the extent of local tumor
invasion of an ampullary carcinoma into the adjacent duodenum or pancreatic parenchyma,
information that is essential for preoperative staging and surgical planning. With the improvement of
cross sectional imaging, the use of ERCP strictly for diagnostic purpose is currently unsupported.
MRI/MRCP- In imaging for pancreatic cancer, there is no advantage for MRI compared to CT scan in
staging and assessment of respectability except in patients with renal impairment or sensitivity to
intravenous contrast used for CT. When distal bile duct obstruction is suspected but CT did not show
discrete mass, then there is a role for cholangiography. In recent years, MRI/MRCP has been used in
place of ERCP in patients who will not tolerate invasive procedures or in whom a large tumor
occludes the orifice of the pancreaticobiliary ducts, thus preventing cannulation and duct opacification
at the time of ERCP. Ampullary carcinomas appear as masses (filling defects) protruding into the
duodenal lumen, with characteristic delayed enhancement and hyperintensity on diffusion-weighted
imaging.[31] However the disadvantage of MRCP is that it has no potential for therapeutic
maneuvers.

Endoscopic ultrasonography (EUS) — Endoscopic ultrasonography (EUS) is as sensitive as ERCP

and superior to CT and transabdominal US for detecting small ampullary tumors. Furthermore, EUS
may identify an invasive carcinoma that was not evident on other imaging tests or endoscopic
biopsies. However, the great majority of cancers are obvious endoscopically, and EUS is not helpful
for those benign lesions that contain only a small focus of adenocarcinoma other than to ascertain
lack of invasive carcinoma. On the other hand, EUS may be a useful diagnostic modality for the
occasional biopsy-negative ampullary lesion that has equivocal endoscopic features of malignancy.
Although EUS cannot exclude the presence of a malignant focus within an adenoma, fine-needle
aspiration (FNA) of the ampulla, papilla, and surrounding deeper structures including local lymph
nodes can be obtained during the procedure.

In one report, the overall accuracy of EUS-guided fine-needle aspiration biopsy (FNAB) for primary
masses of the ampullary region was 89 percent with a sensitivity 82 percent and specificity of 100
percent. Because biliary and pancreatic sphincterotomy and stent placement cannot be achieved
during EUS, patients who require therapeutic intervention must also undergo an ERCP, which can be
performed concomitantly.

The utility of EUS is far greater for preoperative staging of ampullary carcinomas than it is for
diagnosis. EUS is capable of obtaining images of the distal biliary and pancreatic ducts, permitting
assessment of local intraductal tumor extension. Furthermore, EUS accurately demonstrates the
depth of tumor penetration into the duodenum by demonstrating obliteration of the interface between
the tumor and the muscularis propria of the duodenum (a feature that upstages the tumor to T2).
Tumor extension into the pancreas is assessed by the depth of invasion (<2 cm signifying T3, and >2
cm or contiguous spread to adjacent organs signifying T4 disease).

EUS is the most accurate modality available to assess the T-stage of ampullary tumors, which is
critical for planning surgical intervention. Multiple series consistently document primary tumor (T)
staging accuracies of 70 to 90 percent. EUS staging methods tend to overestimate, rather than
underestimate, the depth of tumor invasion and resulting T stage. Accuracy may be decreased in the
presence of an endobiliary stent.

EUS is less accurate for nodal (N) staging. Ampullary cancers drain into two lymph node basins: the
retroduodenopancreatic chain and the superior mesenteric chain. One study reported a sensitivity and
specificity of 67 and 96 percent, respectively, for EUS detection of nodal metastases when abnormal
nodes were defined as those over one centimeter in diameter and located in the above two positions.
Another series found sensitivity and specificity rates of 69 and 38 percent when all visualized lymph
nodes present around the duodenopancreatic block were presumed to be metastatic, regardless of
size or position. However, others have reported sensitivity rates as low as 21 percent for detection of
nodal metastases by EUS.

EUS-guided FNA of suspicious lymph nodes may further increase the accuracy of nodal staging. EUS
can also be used therapeutically as EUS guided celiac plexus block for palliating pain in pancreatic
cancer.

Intraductal ultrasonography — The technical evolution of EUS has led to the development of small
caliber intraductal ultrasound (IDUS) miniprobes (approximately 2 mm), which can be passed through
standard endoscopes directly into the bile or pancreatic duct. The small caliber, flexibility, and
excellent image quality produced by these catheters makes them useful for evaluating a variety of
biliary and pancreatic disorders. IDUS accurately visualizes the anatomy of the papilla and is the
only procedure that reliably differentiates the sphincter of Oddi muscle from the remainder of
the papilla. As a result, IDUS can be useful for diagnosing and assessing the size and extent of
papillary tumors. In a study of 40 patients with ampullary carcinoma, EUS was more accurate than
EUS for T-staging and evaluating ductal invasion.

Magnification endoscopy with narrow band imaging — Narrow band imaging uses optical filters to
enhance visualization of microvessels and mucosal surface architecture in gastrointestinal diseases.
The technique demonstrates abnormal vessels associated with high-grade dysplasia on the surface of
high-grade adenomas and adenocarcinomas. Abnormal vessels have not been identified on the
surface of benign ampullary adenomas with hyperplastic or inflammatory histology. Preliminary
studies have suggested a potential role for evaluation of ampullary lesions.

Staging

The staging of periampullary and pancreatic cancer is staged by the seventh edition of the American
Joint Committee on Cancer(AJCC).[32] Staging of pancreatic and ampullary carcinoma is described
below.
AJCC staging of pancreatic cancer:
1A – Tumor limited to the pancreas <2cm in greatest dimension
1B – Tumor limited to the pancreas >2cm in greatest dimension
IIA – Tumor extend beyond the pancreas but without involvement of the celiac axis or SMA
IIB – Regional lymph node metastasis
III – Tumor involves the celiac axis or SMA
IV – Distant metastasis

Localised resectable disease – Stage I and II

Localised advanced unresectable – Stage III
Distant metastatic disease – Stage IV

Signs of unresectability – Distant metastases, ascites, involvement of celiac or SMA. Venous vascular
involvement is considered potentially resectable in AJCC staging
AJCC staging of ampullary carcinoma
Stage I – tumor limited to ampulla
Stage II – tumor involving duodenal wall and invades <2cm in to pancreas
Stage III – regional lymph node involvement
Stage IV – tumor extends >2cm in to pancreas with or without distant metastasis
Distal cholangiocarcinoma is staged based on AJCC extra hepatic bile duct guidelines and duodenal
periampullary carcinoma, based on AJCC small intestine guidelines

Preoperative Evaluation
Health status- A thorough evaluation of the patients ability to undergo operation is carried out which is
not based on age alone. Optimisation of cardiac, pulmonary and renal functions is important.

Nutritional assessment- Although many of these patients have lost weight, most are still adequately
nourished to safely undergo the operation. However, if the serum albumin is <3 g/dL, or if surgery
must be delayed for more than two weeks, supplemental nutrition is to be provided, preferably enteral
or partial TPN.

Role of preoperative biliary stenting- The establishment of a definite diagnosis and accurate staging of
pancreatic cancer is imperative prior to consideration of preoperative biliary drainage because direct
and indirect complications of preoperative biliary drainage may impact the outcome in a patient
undergoing pancreatic curative intent surgery.
Endoscopic re-intervention after primary stent placement should be considered in patients who fail to
achieve adequate normalization of serum bilirubin in 6 weeks if previous bilirubin level was >10 mg/dL
and in 3 weeks if their previous bilirubin level was <10 mg/dL. (33). Hyperbilirubinemia due to
obstructive jaundice damages hepatic function, clearance of circulating endotoxins, coagulation
system,immune function, and gastrointestinal barrier (34-36). To avoid the poor outcome, routine
preoperative biliary drainage (PBD) has been used to reduce the postoperative morbidity and
mortality of these patients in the past.
However, PBD has also many drawbacks, such as biliary stent-induced bacterial contamination and
risk of cholangitis due to clogging. Several prospective randomized and retrospective studies
compared the effect of routine PBD with surgery without PBD on malignant obstructive jaundice and
showed that routine PBD cannot improve the postoperative outcome but can increase the overall
complication rate.[37,38] Indication for PBD include presence of cholangitis, bilirubin >15-20mg%, pre
existing medical condition delaying surgery, nutritional impairment delaying surgery, intractable
pruritus. One can follow an algorithm as follows [39]
Management

Neoadjuvant therapy
When preoperative imaging reveals borderline resectable pancreatic carcinoma with venous
involvement or unresectable with arterial involvement, neoadjuvant chemotherapy or
chemoradiotherapy is to be considered. MD Anderson group published two phase II trials of
gemcitabine based chemoRT or gemcitabine plus cisplatin based chemoRT, reported 74% and 58%
respectability rates respectively with median survival of 34 and 31 months respectively.[40]

Surgical management
Surgical resection by pancreatico duodenectomy remains the only potentially curative therapy for
periampullary carcinoma. However only minority of patients (20-30%) diagnosed with pancreatic
cancer are candidates for curative resection as compared to other periampullary carcinomas (80%).
Advances in surgical technique have reduced the operative mortality rate to below 5% in high-volume
centers.[41] Nevertheless, operative morbidity remains high, occasionally approaching 30% to 40%
(42,43). Two operation techniques are performed predominantly in the treatment of periampullary and
pancreatic head cancer: the classic Whipple (CW) operation developed by Kausch and Whipple and
the pylorus-preserving Whipple (PPW) procedure inaugurated by Watson and popularized by
Traverso and Longmire. Multiple RCT have shown no superiority of PPW over CW.

A standard pancreaticoduodenectomy involves a distal gastrectomy with removal of the pancreatic

head, duodenum, first 15 cm of the jejunum, common bile duct, and gallbladder. A pylorus-preserving
pancreaticoduodenectomy preserves the gastric antrum, pylorus, and the proximal 2 to 3 cm of the
duodenum, which is anastomosed to the jejunum to restore gastrointestinal continuity. In experienced
hands, the median operative time for the Whipple procedure is 5.5 hours, with a median blood loss of
350 mL and mortality of less than 4 percent.

The surgical resection is divided into the following clearly defined steps:
a) The initial step is to isolate the infra-pancreatic SMV and separate the colon (and its mesentery)
from the duodenum and pancreatic head
b) The Kocher maneuver is begun at the transverse portion (third portion) of the duodenum by
identifying the inferior vena cava. All fibrofatty and lymphatic tissue medial to the right ureter and
anterior to the inferior vena cava is elevated, along with the pancreatic head and duodenum. The
Kocher maneuver is continued to the left lateral edge of the aorta, with care taken to identify the
left renal vein.
c) The portal dissection is initiated by exposing the common hepatic artery (CHA) proximal and
distal to the right gastric artery and the gastroduodenal artery (GDA). The CHA is exposed by
removing the large lymph node that lies directly anterior to this vessel. The right gastric artery and
then the GDA are ligated and divided.
d) The stomach is transected with a linear gastrointestinal stapler at the level of the third or fourth
transverse vein on the lesser curvature and at the confluence of the gastroepiploic veins on the
greater curvature so as to perform a standard antrectomy
e) The jejunum is then transected with a linear gastrointestinal stapler approximately 10 cm distal to
the ligament of Treitz, and its mesentery is sequentially ligated and divided
f) After traction sutures are placed on the superior and inferior borders of the pancreas, the
pancreas is transected with electrocautery at the level of the PV. If there is evidence of tumor
adherence to the PV or SMV, the pancreas can be divided at a more distal location in preparation
for segmental venous resection. The specimen is separated from the SMV by ligation and division
of the small venous tributaries to the uncinate process and pancreatic head . Complete removal of
the uncinate process from the SMV is required for full mobilization of the SMPV confluence and
subsequent identification of the SMA. Failure to fully mobilize the SMPV confluence risks injury to
the SMA and usually results in a positive margin of resection caused by the incomplete removal of
the uncinate process and the mesenteric soft tissue adjacent to the SMA. In addition, without
complete mobilization of the SMV, it is difficult to expose the SMA maneuver necessary for direct
ligation of the inferior pancreaticoduodenal artery. Mass ligation of this vessel (or vessels) with
mesenteric soft tissue is the major cause of postoperative hemorrhage as this vessel retracts from
its poorly placed tie or ligature.

Vascular resection: Resection of portal vein and SMV should be performed when adherence or
infiltration of tumor is present, since perioperative morbidity, mortality and long term survival are
similar to those in whom R0 resection can be performed without portal vein resection. Moreover the
long term survival in patients with PV resection is far superior to those in whom only palliative bypass
was performed. Resection of arteries during pancreatic resection did not show improvement in long
term outcome, hence cannot be recommended as a standard technique as of today. [44,45]

Role of extended lymphadenectomy: Extended lymphadenectomy in periampullary carcinoma did

not show any survival benefit with increased overall morbidity due to increase in incidence of diarrhea
and delayed gastric emptying.[46]

Complications
Most common complications of PD in decreasing order of frequency are delayed gastric emptying,
wound infection and pancreatic fistula.

Delayed gastric emptying — Vomiting after oral intake is resumed could be due to delayed gastric
emptying. The mean incidence of delayed gastric emptying is 17 percent although the range varies
widely among trials. Although delayed gastric emptying can be due to several causes, it is important
to not overlook a fistula, which is a treatable condition. To manage postoperative vomiting, a
nasogastric tube is reinserted and an abdominal CT scan is obtained. This would reveal a fluid
collection near the stomach, which may represent an undrained pancreatic fistula or other process.
Percutaneous drainage and culture of the fluid should be done.
Gastric function usually returns when the fluid collection is treated appropriately, or after a period of
nasogastric suction if no other abnormalities are found. Gastric promotility agent (prokinetics) are also
administered if gastric emptying is delayed.

Pancreatic fistula — Pancreatic fistulas are defined by the International Study Group on Pancreatic
Fistula Definition as a drain output of any measurable volume of fluid on or after postoperative day
three with an amylase content greater than 3 times the serum amylase. A pancreatic fistula
complicates 2 to 22 percent of pancreaticoduodenectomy operations, when the
pancreaticojejunostomy does not heal. Pancreatic fistulas can lead to sepsis and hemorrhage. These
complications are associated with mortality of 20 to 40 percent, prolonged hospitalization and
increased hospital expenses.
Pancreatic leaks are more common when the pancreatic parenchyma is soft and holds sutures poorly
(eg, cysts, ampullary cancers that do not obstruct the pancreatic duct), and when the pancreatic duct
is small. In patients with pancreatic cancer where the pancreatic duct is commonly obstructed by the
tumor, the pancreas is firm and a pancreatic fistula is uncommon. There is no clear evidence favoring
any specific pancreaticoenteric anastomosis or pancreatic ductal obliteration to prevent fistula
formation.

Bile leaks from the choledochal-jejunal anastomosis occur in 1 to 2 percent of cases, and are
heralded by the appearance of bile in the drain fluid. If this occurs, the drain should be left in place
until the leak stops. If it is still present when the patient is ready for discharge, the patient can go
home with the drain in place. It can be removed in the office when there is no longer any bile present.
If there is no evidence of a biliary leak, the biliary drain is removed the day after the patient begins
oral intake.

Adjuvant therapy

The best studied variety of all periampullary carcinoma for adjuvant therapy is pancreatic carcinoma.
GITSG trial showed patients who receive adjuvant chemoradiotherapy showed improved survival.
ESPAC 1 trial demonstrated systemic 5 FU based chemo alone is superior to chemoradiotherapy.
ESPAC 3 trial showed better toxicity profile with gemcitabine than 5 FU based chemotherapy. Other
smaller prospective trials suggested a potential benefit of chemoradiotherapy over chemotherapy
alone, hence still debatable. Role of chemoradiothaerapy in other periampullary carcinomas were less
well understood

Palliation

The aim of the palliative therapy is to improve the quality of life and include palliation of jaundice,
gastric outlet obstruction and pain. All three components are usually seen in pancreatic cancer while
in periampullary jaundice is the most common component requiring palliation.

Operative palliation: When the patient undergoes surgery and the tumor found to be unresectable,
decision is to be made whether to operatively palliate the patient. Operative palliation is performed in
patients without widespread metastatic disease and with life expectancy more than several months.
The jaundice can be palliated either by cholecystojejunostomy or hepaticojejunostomy, the most
effective being Roux-en-Y hepaticojejunostomy. Gastrojejunostomy (GJ) is performed for duodenal
obstruction. The role of prophylactic GJ is often debated. A prospective RCT was performed in 87
patients with unresectable periampullary carcinoma without duodenal obstruction in which patients
were randomized to undergo either GJ or no bypass.[26] In none of patients who underwent
prophylactic GJ did duodenal obstruction subsequently develop, whereas symptoms requiring
intervention later developed in 19% of patients who did not undergo bypass. Operative chemical
splanchnicectomy can be performed for palliation of pain by injecting 20ml of 50% ethanol or saline
on either side of aorta at the level of celiac plexus.

Non operative palliation

Palliation of obstructive jaundice – can be achieved by ERCP or PTBD. Most centers use ERCP
first and use PTBD only if former fails or not technically feasible. RCT comparing 10F plastic stents
with 30F metallic stents have shown metallic stents are associated with lower rate of cholangitis and
stent replacement and fewer inpatient stays.

Duodenal obstruction – earlier achieved by placement of endoscopic gastrostomy tube, now

replaced by gastroduodenal expandable metallic stents, which can be achieved in 80-90% of patients
with periampullary carcinoma

Pain– Standard management for pain relief was based on opiods or NSAIDS. In view of systemic side
effects CT or EUS guided celiac plexus block have been used more recently in an attempt to target
the neurogenic pain caused by periampullary carcinoma. Several RCT comparing opiods and nerve
block have demonstrated more efficient pain relief and significant reduction in narcotic use in patients
undergoing nerve block.

Palliative chemotherapy
Gemcitabine based regimen is used as palliative chemotherapy in patients with locally advanced
unresectable or metastatic pancreatic carcinoma. Other agent recently found to be effect is Erlotinib.

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 Benign Biliary Stricture
PK Mishra, Harsh Shah

Introduction

Benign biliary stricture is a feared complication of many surgical and endoscopic procedures. If
improperly treated, it may lead to cholangitis, portal hypertension (PHTN) & cirrhosis. Treatment of
this disease is challenging as well as rewarding, as most of the patients are in younger age group.

Causes of Benign Biliary Stricture1

A list of causes of benign biliary stricture is as underneath. By far, the most important cause of biliary
stricture is an injury to bile duct during cholecystectomy. Bile duct injury may lead to loss of reputation
& may also lead to litigation.

I. Congenital strictures
(a) Biliary atresia
II. Bile duct injuries
(a) Postoperative strictures
(i) Cholecystectomy or common bile duct exploration
(ii) Biliary-enteric anastomosis
(iii) Hepatic resection
(iv) Portocaval shunt
(v) Pancreatic surgery
(vi) Gastrectomy
(vii) Liver transplantation

(b) Strictures after blunt or penetrating trauma

(c) Strictures after endoscopic or percutaneous biliary intubation
III. Inflammatory strictures
a) Cholelithiasis or choledocholithiasis
b) Chronic pancreatitis
c) Chronic duodenal ulceration
d) Abscess or inflammation of liver or subhepatic space
e) Parasitic infection
f) Recurrent pyogenic cholangitis
IV. Primary sclerosing cholangitis
V. Radiation-induced stricture
VI. Papillary stenosis

Incidence: Bile duct injuries are reported in 0.2 to 0.3 % of open cholecystectomy and 0.4 to 1.3% of
laparoscopic cholecystectomy in larger studies2,3. Actual incidence may be higher.

Mechanism of injuries

Laparoscopic cholecystectomy is one of the commonest surgical procedures in the world. Higher
injuries in laparoscopic cholecystectomies may be due to the learning curve and inherent problems of
laparoscopic approach as even experienced laparoscopic surgeons may inflict some of these. Mostly,
4
it is due to wrong interpretation of the biliaryanatomy e.g. mis-identification of the common bile duct or
aberrant right sectoral duct as the cystic duct. An important aspect in the prevention is to remember
that there is no normal biliary anatomy. If the clip does not fit across the entire width of the cystic duct,
the surgeon must consider the possibility that the structure about to be divided is not the cystic duct
but the common duct. Upward traction on the gallbladder, with insufficient lateral traction on the
infundibulum, fails to open Calot’s triangle adequately. This causes the cystic duct and common
hepatic duct to become aligned within the same plane.Classical laparoscopic injury consists of
removal of a portion of CBD with or without clipping of the proximal hepatic duct 5. Excessive
dissection of CBD may disrupt its blood supply and lead to late stricture. Operating in patients with
inflammation or choledocho-duodenal fistula orMirizzi‘s syndrome is also potentially hazardous. Plane
of dissection away from gallbladder wall into the liver bed may injure Right hepatic duct. Injudicious
use of electrocautery for dissection or bleeding control is hazardous.

Classification

Bismuth’s classification6 is the most accepted classification of biliary injuries.

1. Low common hepatic duct stricture: hepatic duct stump >2 cm
2. Proximal common hepatic duct stricture: hepatic duct stump <2 cm
3. Hilar stricture with no residual common hepatic duct: hepatic duct confluence intact
4. Destruction of hepatic duct confluence: right and left hepatic ducts separated
5. Involvement of aberrant right sectoral hepatic duct alone or with concomitant stricture of the
common hepatic duct

Strasberg classified bile duct injuries from A to E7. Type A is minor leak still in continuity with CBD,
such as from cystic duct stump or injury to duct of Luschka. Type B is ligation of right aberrant
sectoral duct. Type C is transection of rightaberrant sectoral duct without occlusion reflecting the leak
of bile. Type D is a lateral injury to bileduct. Type E is bile duct stricture classified as per Bismuth from
E1 to E5. Although widely used,both these classification do not factor in the vascular injury, presence
of sepsis or cholangitis,pattern of presentation, time since injury or presence of portal hypertension.
Several otherclassifications have been proposed like Hannover, Siewert, Neuhaus and Stewart –
Way. Each has its drawbacks and is not used extensively like Strasberg – Bismuth system.
Figure 2 Bismuth's classification

Type 1 Type 2 Type 3 Type 4 Type 5

Presentation Figure 1: Strasberg classification

Some of these injuries may be obvious intra-operatively.

Experienced help should be sought in dealing with these.
Some of these repairs may present later with biliary
strictures. Any patient, who does not recover normally
after cholecystectomy or develops mild jaundice, should
be suspected for bile duct injury. Initial signs may be
subtle, such as malaise, mild fever, uneasiness or
tachycardia. Patients with bile duct leaks present early
with signs of sepsis or general illness (2nd category). If the
rd
drain is in place, bile leak is obvious (3 category).
Patients with complete cut off also present early with
progressive jaundice. Fifth category of patients is of those,
who have partial injuries which gradually present over
next few months. These also include patients with leak
which have stopped with constriction of the bile duct.
About 70% of injuries have presented by 6 months. Some
of these may have recurrent cholangitis, fever, pruritus or
unexplained malaise and weakness. During examination,
tender hepatomegaly may be seen in those having long
standing obstruction, cholangitis or abscess. Presence of
splenomegaly should alert the surgeon for portal
hypertension. This may arise due to concomitant vascular
injury, secondary biliary cirrhosis, recurrent cholangitis or coexistent liver disease. Icterus and signs of
pruritus are usually present.

Pathological consequences

Portal hypertension: Patients with biliary stricture can develop portal hypertension secondary to
portal fibrosis, portal vein injury and/or underlying liver parenchymal disease. As these patients with
portal hypertension have a hospital mortality of 25- 40%, documentation with liver biopsy is must for
both management and medico legal purpose. Recently, it has been found that patients of Biliary
stricture, even without portal injury, usually have latent portal hypertension (mild to moderate). They
may not have clinical features of portal hypertension. Portal pressures normalizes after Biliary
decompression9.

Fibrosis: The high concentration of bile salts in the biliary canaliculi incite a inflammatory process
resulting in fibrogenesis which is the deposition of collagen and other extracellular matrix proteins8.
Biliary obstruction cause secondary biliary cirrhosis, it rarely results in typical features of cirrhosis. In
advanced cases there is marked fibrosis with well-preserved lobular structure. Though it takes several
years to manifest these pathological features, it can occur within two years of development of
stricture. After biliary decompression, these pathological changes are potentially reversible and the
liver function gradually normalizes. If patient develops clinical features of liver failure- like spider
angiomata or encephalopathy, preexisting liver parenchymal disease should be ruled out.

Atrophy: In view of prolonged asymmetric involvement of biliary ducts and associated vascular injury,
there usually develops a lobar atrophy with compensatory hypertrophy of the remaining liver resulting
in rotational deformity and anatomical changes in the hilar area which influence the operative
approach for these patients. Usually in long standing benign biliary strictures, there is atrophy of right
lobe with gross hypertrophy of left lobe.

Investigations

Biochemical parameters:Liver function tests usually show evidence of cholestasis with fluctuating
serum bilirubin level. When elevated, serum bilirubin is usually below 10 mg/dL, unless secondary
biliary cirrhosis has developed, or there is complete cut off. Serum alkaline phosphatase is usually
elevated. Serum aminotransferase levels can be normal or minimally elevated except during episodes
of cholangitis. If advanced liver disease exists, hepatic synthetic function can be impaired, with
lowered serum albumin and a prolongation of prothrombin time.

Radiologic Examination: Detailed pre operative evaluation of the type and extent of bile duct
injurywith stricture with control of sepsis, cholangitis & bilioma optimizes the chances for favorable
outcome. Abdominal ultrasound and computed tomography (CT) play an important initial role in the
evaluation of patients with benign postoperative biliary strictures.

Ultrasonography abdomen as an initial, non-invasive study can assess for dilated

intrahepaticradicals, bilioma, approximate level of biliary obstructionand stricture. Along with Duplex
10
imaging it can be used to assess the vascular injury, which occurs in about 12-32% of the patients .
This evaluation is very important in terms of successful outcome of the surgical biliary reconstruction,
as biliary injury along with vascular injury has less favorable outcome. It also has medico-legal
implications. Though it guides us initially, it is limited in assessing the extent and type of Biliary
stricture. It is also operator dependent.

Contrast enhanced CT abdomen is probably best initial study to evaluate a case of Bile ductinjury.
Properly done CT helps in assessing any intra abdominal collection, definite level of bileduct stricture,
dilated intrahepatic radicals with cholangitic abscess and also vascular injurywith liver atrophy-
hypertrophy complex. But CT is also limited in evaluation of the type andextent of biliary stricture.

The gold standard for evaluation of patients with established bile duct strictures is cholangiography.

Percutaneous transhepatic cholangiography (PTC) is usually more valuable than endoscopic

retrograde cholangiography (ERC). PTC is more useful in that it defines the anatomy of the
proximal biliary tree that is to be used in the surgical reconstruction. Furthermore, PTC can be
followed by placement of percutaneous transhepatic catheters, which can be useful in decompressing
the biliary system either to treat or prevent cholangitis or to control an ongoing bile leak. These
catheters can also be of assistance in surgical reconstruction and provide access to the biliary tree for
non-operative dilation. Although some groups have advocated routine use of these stents, we have
not felt the need for these for identification of ducts at GB Pant Hospital. Also this introduces resistant
sepsis, which is a potential problem. ERC is often less useful than PTC because the discontinuity of
the extra hepatic bile duct usually prevents adequate filling of the proximal biliary tree. But for patients
with lateral injury with bile leak, ERCP is both diagnostic and therapeutic in identifying the leak and
biliary stenting at the sametime, which may avoid surgical intervention.

The development of magnetic resonance cholangiopancreatography has provided a non-invasive

technique that provides excellent delineation of the biliary anatomy11. The qualityof these images
have led this technique to be advocated as the initial step in the evaluation of patients with suspected
bile duct injuries. It may eliminate the need for a diagnostic ERC/PTC in most patients.

In patients suspected of having early postoperative bile duct injury, a radio-nucleotide biliary scan
(HIDA) can confirm bile leakage. It can be useful in assessing patients with underlying liver disease to
document liver dysfunction or obstruction to clearance and their relative contribution.
In patients with postoperative external biliary fistula, injection of water-soluble contrast media through
the drainage tract (Fistulogram) can often define the site of leakage and the anatomy of the biliary
tree. This is a simple and easily available tool, which may give valuable information. However, this
may lead to cholangitis and should be sparingly used under antibiotic cover.

Distinction between benign and malignant stricture

Though it is very difficult to clearly distinguish the nature of stricture pre operatively, certain features
can guide us in their differentiation.

Benign Malignant
Age Usually young Elderly
Duration of symptoms Variable Short duration
Cholangitis Usual Unusual, if no intervention
Depth of Jaundice Variable usually <15mg% >15mg% not unusual
Weight loss/Anorexia Rare Common
Imaging of stricture Long stricture with regular Short stricture, irregular margins, thick
margins & sectoral walled, more dilated proximal ducts with
involvement bile duct hyper enhancement in portal
venous phase
Other features History suggestive of difficult May have other signs as gastric outlet
cholecystectomy, bile leak with obstruction, ascites etc.
normal histology of GB

Management

Theoretically, these patients can be managed by endoscopic, radiological percutaneous and surgical
therapy. However, endoscopic and radiological methods, although very useful as adjuncts, are
suitable for definitive management in very few cases. By and large these patients are young and
surgery is the treatment of choice.

Preoperative management
Aim of the preoperative management is to precisely define the injury, determine any complications
like atrophy-hypertrophy, portal hypertension, or secondary biliary cirrhosis. Associated renal
complications, cholangitis, coagulopathy and sepsis should be taken care of. Patients with severe
cholangitis and sepsis are unlikely to respond to antibiotics alone and should be submitted to
percutaneous drainage before surgery. Essentially the surgery should be done in optimum condition
without any hurry about 8-12 weeks after the injury12. Some surgeons have advocated early repair.
Advantage is decreased morbidity for the patient. However, we follow a delayed approach, which
stabilizes the stricture & optimizes local conditions. Early surgery is done in our cases in case it
presents within 48hrs and in cases of complete cut off without bile leak or sepsis. Associated medical
risk factors should be also optimized. In the immediate preoperative period coagulopathy should be
corrected with vitamin K, sepsis controlled and fluid and electrolytes corrected. Adequate blood and
fresh frozen plasma should be arranged. Type IV injuries may require hepatotomy and are generally
more difficult. Similarly, patient with portal hypertension and secondary biliary cirrhosis may have
difficult operative course. At the time of consent these information should be discussed with relatives.

Operative Procedure
The first surgical reconstruction (“end-to-side” Choledochoduodenostomy) of iatrogenic bile duct injury
was performed by Mayoin 1905. The first Roux-en-Y hepaticojejunostomy (HJ) was described by
Monprofit in 1908. Dahl noted Rouxen-Y HJ for surgical treatment of bile duct injury in 1909. In1969,
Smith created a mucosal graft anastomosis in the repair of the damaged proximal bile duct. In 1954,
Hepp and Couinaud described the hilar plate and long extrahepatic course of the left hepatic duct.

Restoration of bile flow is achieved by a bilio-enteric anastomosis. Rarely, when the stricture is in
pancreatic or immediate supra-duodenal CBD, a choledocho-duodenostomy can also be constructed.
Most often the reconstruction is by a Roux loop with hepaticojejunostomy. Requirements of a good
bilio-enteric anastomosis are:
1. Adequate stoma size (>2cm)
2. Good vascular supply
3. Tension free anastomosis
4. Should drain all segments of the liver
5. Mucosa to mucosa anastomosis.

Access to proximal ducts is relatively easy in Bismuth type I and II strictures. In Type III and
IVstrictures the hilar plate lowering technique described by Blumgart is used. In this Hepp-Couinaud
technique the left duct is approached by incising the Glisson‘s capsule at the base of Quadratelobe.
This lowers the left bile duct and by further dissection, gradually the area of confluence and the extra
hepatic right duct. This allows space for mucosa-to-mucosa side-to-side anastomosis between the
jejunal Roux loop and the healthy bile duct above the stricture. If extra length of left duct is required
the dissection can be taken into the ligamentum Teres. Type IV strictures mayrarely require
hepatotomy or part excision of quadrate lobe to approach the right duct.

Isolated Sectoral duct Injury. These are difficult to manage especially if accompanied by bile
leak,as the ducts are small and difficult to approach. Asymptomatic remote injuries should be left
alone. Symptomatic injuries with recurrent cholangitis should be treated with repair or resectionof the
segment depending on the atrophy.13 Recent asymptomatic injuries should be treated with repair to
prevent atrophy and complications.

Use of stent for bilioenteric anastomosis is controversial. Some use it routinely in all cases14.
Advantage being post-operative decompression, access for imaging and intervention. We use it only
in cases of difficult or unsatisfactory anastomosis or in small ducts. How long should thesestents be
kept is also variable and can be from couple of weeks to a year. When it isanticipated that patient may
again have stricture or in cases of second or more interventionsafter Hepaticojejunostomy, an access
15
loop is made . The distal limb of the roux loop, beyondthe HJ, is left long and brought out
subcutaneously or subperitoneally. This allows for easyaccess for radiologic interventions.

Results: Previous series reported 5-8% mortality. This has been reduced substantially with wider
experience in specialized centres and many large series have reported no mortality. Still, patients
may succumb while awaiting definitive management with sepsis and complications. Overall 80-90%
good results are reported1, 16.

Poor prognostic factors:

 Proximal stricture (Bismuth types 3 and 4)
 Multiple prior attempts at repair
 Portal hypertension
 Hepatic parenchymal disease (cirrhosis or hepatic fibrosis)
 End-to-end biliary anastomosis
 Surgeon inexperience
 Intrahepatic or multiple strictures
 Concurrent cholangitis or hepatic abscess
 Intrahepatic stones
  External or internal biliary fistula
 Intra-abdominal abscess or bile collection
 Hepatic lobar atrophy
 Advanced age or poor general health

Non-operative Approaches: These include endoscopic and the radiologic percutaneous balloon
dilatation and stenting. These can only be used for partial injuries (Strassberg type A & D) and the
results are not better than the surgical management17.. However in post-operative strictures, in
patients in whom surgery is contraindicated and as part of multimodality approach these are
extremely useful.

Biliary stricture with Portal Hypertension: This is a difficult group of patient with high rate of
complication and mortality16, 18. If serious bleed is encountered than a splenorenal shunt should be
done before definitive repair.

Liver Transplantation: Very rarely, transplant may be required for long standing biliary stricture with
secondary biliary cirrhosis with portal hypertension although even there it should not be the first line
approach19.

Biliary Stricture after Other Operations

These may arise after Gastric and hepatic resection, portocaval shunts and CBD explorations.
Bilioenteric anastomosis may also become strictured after reconstruction. They can be managed as
per the principles outlined. Strictures after liver transplantation are another category of patients, which
should be dealt with at specialized centres only.

Post-Inflammatory Bile Duct Stricture

Recurrent cholecystitis in some cases may lead to ongoing inflammation and stricture of the bileducts.
Gallstones may erode into the CBD in Mirizzi’s syndrome. Recurrent pyogenic cholangitis may lead to
intra-hepatic stones and strictures. Chronic pancreatitis causes a smooth, long stricture at thelower
end. If the liver function tests are normal it need not be treated even if severe stenosis is seenon
imaging except if the patient is being operated for chronic pancreatitis
itself.Choledochoduodenostomy is simpler but recurrent inflammation and fibrosis may necessitate
Hepaticojejunostomy.

Post Traumatic Biliary Stricture

Both blunt and penetrating injuries may lead to biliary stricture. Hemorrhage and associated injuries
take precedence in management. Bile flow is diverted and a later definitive repair is done. Biliary
fistulas after hepatic injury, which do not close after prolonged conservative treatment, can be
anastomosed to roux loop. Bilio-enteric anastomosis is done for ductal injuries. Endoscopic or
percutaneous approaches can also be used.

Our Experience at GBPH

Out of 205 bile duct injuries that we have encountered, 133 were open and 72 were laparoscopic. The
presentations included acute bile duct injury (n=9), bile collection (n=64), external biliary fistula (n=74)
and stricture (n=58). After initial management 4 patients died (sepsis n=2, pseudo aneurysmal bleed
n=2). Of 164 patients who underwent definitive repair, 3 died (portal hypertension n=2, sepsis n=1). At
30 months median follow-up 154 (93.9%) patients had good outcome (grade A, B) and seven had bad
outcome (grade C, D) as per McDonald grading.

REFERENCES
th
1. Coevera CU, Alemi F, Jarnagin WR. Benign Biliary stricture.Blumgart’s surgery of Liver,biliary tract & pancreas.5
ed. 2012, Saunders, Philadelphia.
2. Roslyn JJ, et al Open Cholecystectomy :A contemporary analysis of 42,474 cases.AnnSurg 218; 129- 37.
3. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic
cholecystectomy. J Am CollSurg Am 1995:180: 101-125.
4. Way LW, Stewart L, Gantert W, et al. Causes and prevention of laparoscopic bile duct injuries: analysis of 252
cases from a human factors and cognitive psychology perspective. Ann Surg 2003;237(4):460–9.
5. Branum G, Schmitt C, Baillie J, et al. Management of major biliary complications after laparoscopic
cholecystectomy. Ann Surg 1993;217(5):532–40
6. Bismuth H. Postoperative stricture of the bile duct. In Blumgart LH ed : The biliary tract:Clinical Surgery
International. Churchill Livingstone. Edinburgh. 209-18.
7. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic
cholecystectomy. J Am CollSurg 1995;180(1):101–25.
8. Friedman SL et al.Molecular mechanisms of hepatic fibrosis and principles of therapy. J Gastroenterol. 1997
Jun;32(3):424-30.
9. Ibrarullah M, Sikora SS, Agarwal DK, Kapoor VK, Kaushik SP, 'Latent' portal hypertension in benign biliary
obstruction.HPB Surg. 1996;9(3):149-52. .
10. Mathisen O, Soreide O, Bergan A. Laparoscopic cholecystectomy: bile duct and vascular injuries: management
and outcome.Scand J Gastroenterol 2002;37(4):476–81
11. Ragozzino A, De Ritis R, Mosca A, et al. Value of MR cholangiography in patients with iatrogenic bileduct injury
after cholecystectomy. AJR Am J Roentgenol 2004;183(6): 1567–72.
12. Lillemoe KD.Current management of bile duct injury.Br J Surg 2008;95(4):403–5.
13. Lillemoe KD, Petrofski JA, Choti MA, Venbrux AC, Cameron JL. Isolated right segmental hepatic ductinjury: a
diagnostic and therapeutic challenge J Gastrointest Surg. 2000 Mar-Apr;4(2):168-77.
14. Lillemoe KD, Melton GB, Cameron JL, et al. Postoperative bile duct strictures: management andoutcome in the
1990s. Ann Surg 2000;232(3):430–41.
15. Al-Ghnaniem R, Benjamin IS. Long-term outcome of hepaticojejunostomy with routine access loopformation
following iatrogenic bile duct injury. Br J Surg 2002;89(9):1118–24.
16. Mishra PK, Saluja SS, Nayeem M, Sharma BC, Patil N. Bile duct injury – from Injury to repair: an analysis of
Management and Outcome. Indian Journal of surgery.
17. Lillemoe KD, Martin SA, Cameron JL, et al. Major bile duct injuries during laparoscopiccholecystectomy. Follow-
up after combined surgical and radiologic management. Ann Surg1997;225(5):459–68
18. Chapman WC, Halevy A, Blumgart LH, et al. Postcholecystectomy bile duct strictures. Managementand outcome
in 130 patients. Arch Surg 1995;130(6):597–602
19. Nordin A, Halme L, Makisalo H, et al. Management and outcome of major bile duct injuries afterlaparoscopic
cholecystectomy: from therapeutic endoscopy to liver transplantation. Liver Transpl2002;8(11):1036–43.
20. Mishra PK, Saluja SS, Nag HH, Goel N, Jain A, Kujur D. Isolated extrahepatic bile duct injury after blunt trauma
abdomen. American surgeon 2012;78:104-16
 Liver Abscess
Pardeep Garg

Liver is the commonest solid viscera affected by abscess. While pyogenic abscess is commonly seen
in western countries, amoebic abscess is common in India.

PYOGENIC LIVER ABSCESS

The literature of liver abscess can be traced since the time of Hippocrates and through centuries it
was considered invariably fatal. Oshner et al. in 1938 presented a seminar which revolutionized and
gave a new horizon to the management of pyogenic liver abscess.

Mc Fadzean et al. presented a paper reporting percutaneous drainage of abscess with its promising
results. With the advent of USG an CT, delayed diagnosis and localization which for long remained
the bottle neck for management was also streamlined. Presently percutaneous needle aspiration/
percutaneous catheter drainage under radiological guidance is the first line of management for
pyogenic liver abscess.

Causes
1. Hepatobiliary (40%)
a) Benign:
i) Hepatolithiasis
ii) Cholecystitis
iii) Biliary manipulation
b) Malignant:
i) Cholangiocarcinoma
ii) Ca Gall bladder
iii) Ca ampulla of vater.
2. Portal (20%) - Incidence reducing due to better management of causes.
a) Benign:
i) Diverticulitis
ii) Appendicitis
iii) Anorectal suppuration
iv) Intestinal perforation
b) Malignant:
i) Colonic cancer
ii) Gastric cancer
3. Hepatic Artery Route (12%)
a) IV Drug abuser
b) Systemic bacteremia
c) Hepatic artery chemoembolisation
d) ENT/ Dental infection
4. Traumatic (4%)
a) Penetrating trauma in liver
b) Cryosurgical ablation of liver
5. Cryptogenic(20%) - Associated with immunocompromised states, DM, malignancy. Recent
studies are relating cryptogenic abscess to anaerobic colonies.

Pathology and Microbiology

These abscesses are usually small and multiple. Abscess is more common in right lobe of liver.
PLA<2cm is described as microabscesses.

Following is the Spectrum of micro organisms causing PLA:

a) Gram Negative Aerobes:
i) E. coli
ii) Klebsiella pneumoniae
iii) Proteus
b) Gram Positive Aerobes:
 i) Streptococcus milleri
ii) Staphylococcus aureus
iii) Enterococcus sp
c) Gram Negative Anaerobes:
i) Bacteroides
ii) Fusobacterium
d) Gram Positive Anaerobes:
i) Clostridium sp
ii) Peptostreptococcus

Among them E. coli is most commonly isolated in developed countries and Klebsiella in developing
countries. However Cryptogenic PLAs are more likely to have negative cultures from blood where as
PLAs secondary to biliary tract disorders are more likely to have positive culture from pus and blood.
Streptococcus and staphylococcus are most commonly isolated when abscess is associated with
septicemia. Stapylococcus aureus isolation from blood of children should always raise suspicion of
Chronic granulomatous disease.

Clinical Features
 Majority of liver abscess are clinically silent.
 Peaks at 5th to 7th decade
 M:F=2:1
 Symptoms are vague and highly non specific including fever which can be continuous or spiking,
chills, malaise, anorexia, weight loss, pain, diarrhea, pruritis, cough.
 Signs include Hepatomegaly, tenderness in right upper quadrant.
 Jaundice and pleural effusion are rare.

Investigations
 Hematological Investigations
i) Patient is anaemic. PCV<36%
ii) Leucocytosis WBC >15000/mm
 Biochemical Investigations
i) Hypoalbuminemia. Albumin <3gm/dl
ii) Liver function tests deranged. Alkaline phosphatase, gamma glutamyl transpeptidase,
SGOT and bilirubin raised.
 Blood culture:positive in only one third of patients.
 Pus culture
 Radiological Investigations:
i) X ray Abdomen: not of much help. It may show air fluid level in abscess cavity, elevation
of right cupola of diaphragm.
ii) USG Abdomen: not only helpful in diagnosis but also indicates stage of resolution of
abscess with medical therapy
Features:
a. Sharp margin
b. Hypoechogenecity
c. Posterior acoustic window
d. Thickened irregular wall
iii) Computed tomography: accuracy is as high as 95% and remains the investigation of
choice. It can detect an abscess as small as 0.5cm in diameter
Features:
a. Sharp margin
b. Low attenuation
c. Ring enhancement
iv) MRI: MRI does not seem to have much advantage over CT and USG in diagnosis of PLA
however it is used when liver resection is planned to properly delineate the hepatic
venous anatomy and when suspecting biliary tract disease where MRCP can be used to
identify the nature and site of biliary pathology.

Treatment
An untreated liver abscess is nearly always fatal. Treatment options include:
 a) Antibiotics
b) Aspiration
c) Percutaneous drainage
d) Surgical drainage

Antibiotics
PYOGENIC ABSCESS

PERCUTANEOUS ASPIRATION OF PUS

SENT FOR CULTURE AND SENSITIVITY START EMPIRICAL TREATMENT

BASED ON REPORT

MODIFY AND STREAMLINE ANTIBIOTICS

Aminoglycosides or 3rd generation cephalosporin with metronidazole is drug of choice. IV antibiotics

are continued for 2 weeks and continued with oral antibiotics for 4 weeks. PLAs too small to be
aspirated are treated by antibiotics alone.

Aspiration: best tool for diagnosis (culture) and treatment. It is always done under radiological
guidance. Two options available:
a) Percutaneous needle aspiration (PNA) - Some patients experience complete resolution with
single PNA but most require repeated aspiration. An abscess < 5cm is most likely to respond
to PNA. Causes of failure:
i) thick pus
ii) non collapsible wall
In these condition PCD is performed

b) Percutaneous catheter drainage (PCD) - Indications include:

i) failure of PNA
ii) abscess > 5cm
iii) pus too thick
iv) wall of abscess thick and non collapsible
v) PLA multiloculated

Surgical Drainage: Exploratory laparotomy now a days has limited role. It can be used for treatment
of both abscess and its source. Indicated only following complication of abscess like burst, bleeding,
peritonitis and abscess inaccessible to PCD. Approach:
a) Extra peritoneal - This is used when abscess is located superiorly in liver dome
i) Subcostal
ii) Transpleural
iii) Retroperitoneal

b) Transperitoneal: It is treatment of choice for surgical drainage.

 Bimanual exam of liver and intraoperative USG if possible
 Abscess opened with cautery after localisation
 Loculations broken down with finger dissection
 Biopsy of abscess wall and liver taken
 Abscess site irrigated and soft, closed-suction drain kept.
 Following evacuation a drain is placed in the dependent area for irrigation and drainage.
Hepatic resection: Wedge resection or formal lobectomy. Indicated when:
a) isolated lobe is involved with single or multiple non healing abscess
b) Patient with infected hepatic malignancy
c) Chronic granulomatous disease.

Laparoscopic surgery: has a limited role. Can be used for diagnosis of concurrent abdominal
pathology and for catheter placement.

Prognosis
After the introduction of surgical drainage and systemic antibiotics, the mortality of PLA was reduced
to 50%. Introduction of USG and CT with early diagnosis brought down the mortality to less than 20%.
Improvement in supportive measures with better treatment brought down the mortality to less than
2%. With the present modality of treatment the prognosis mostly depends on the underlying etiology
and comorbid conditions. The risk factors commonly associated with mortality includes septic shock,
clinical jaundice, coagulopathy, leucocytosis, hypoalbuminemia, intraperitoneal rupture and
malignancy.

AMOEBIC LIVER ABSCESS

Amoebic liver abscess is mainly a health problem of tropical and subtropical areas of world.
Approximately 50% population of these areas harbour amoebae. It is third leading parasitic cause of
death worldwide, with incidence of forty million invasive amebiasis and forty thousand deaths each
year.

Historical Aspects
 Description of mucus & blood in stool with ball like abdominal masses (?coexisting hepatic
abscess) is present in ayurvedic literature (Bhrigu samhita) and also in writings of Hippocrates.
 1818 (Ballingall) reported serendipitous liver puncture & drainage of pus giving relief to patient
symptoms.
 1875 (Lesh) described motile amoeba in colonic lesions with acute dysentery.
 1849-1919 various species of amoebae were identified.

Predisposing Factors
 Male gender (male to female ratio 10:1)
 Low socioeconomic group
 Diet rich in iron (country liquor) and carbohydrates
 Immunocompromised patients
 Pregnancy
 Recent travel to an endemic area
ALA is uncommon in menstruating females, infants and breastfed children.

Etiopathogenesis
Causative organism i.e. Entamoeba Histolytica, a protozoan exists in two forms- Cysts and
Trophozoites. Cysts ingested via fecooral contamination develop into trophozoiets which adhere
colonic mucosa by surface glycoprotein (galactose N-acetylgalactosamine).

Factors responsible for colonic invasion are:

 LECTIN –causes host cell activation to produce caspases which cause cell damages.
 AMEBOPORES-are inserted in to host cells and cause disruption of barrier function.
 CYSTINE PROTEASES cause degradation of extracellular matrix.

From colon, amoeba reaches liver via portal blood. Here, it causes liquifactive necrosis of liver lobule
leading to abscess formation. Amoeba lies peripherally in abscess. Glisson’s capsule is resistant to it
and limits its extent. Glisson’s capsule also lines blood vessels and biliary channels which appear on
USG as fibrous septae inside pus. Attempt to break these septae can cause bleeding or bile leak in
cavity. Abscess is
 Typically Anchovy sauce
 Without odour
 Sterile on culture
  Usually solitary and large
 Ill defined abscess wall with minimal fibrous tissue

Clinical Features
 Peak incidence occurs in 20- 60 year males.
 Right hypochondrium pain and fever are cardinal symptoms.
 Other nonspecific symptoms include anorexia, weight loss, nausea and vomiting.
Examination reveals
 Tender soft hepatomegaly
 Low grade jaundice(serum bilirubin<3)
 Signs due to right basal lung atelactesis
 Features of toxemia may suggest secondary bacterial infection in ALA.
Differentials include acute cholecystis, hepatitis, pyogenic liver abscess. Rarely atypical presentatiom
of hydatid cysts and hepatocellular carcinoma can also mimic it.

Investigations
 Increased leucocyte count without eiosinophilia
 Deranged liver function tests
 Increased prothrombin time (most common abnormality in LFTs)
 Chest X Ray-although nonspecific may show elevated right hemidiaphragm with anterior
bulge on lateral view, enlarged liver shadow, basal atelactesis right lung, right pleural effusion
may be present.
 Ultrasonography- 90% diagnostic accuracy. Usually single abscess cavity located peripherally
in contact with capsule. It has hypoechoic nonhomogenous contents with internal echoes.
80% of ALA present in right lobe, 10% in left lobe, remaining have multiple abscess cavities.
 CT scan and MRI- do not give extra information for management seldomly required in
suspected HCC or hydatid cysts.
 Amoebic Serology – positive in 90-95% cases. Commonly used to differentiate. between ALA
& PLA
 Gallium Scan- It can also differentiate between ALA( appear as cold spots) & PLA(appear as
hot spots) but its role is limited due to its availability and cost factor.

Management
Four modalities of treatmentof ALA
a) Conservative drug therapy
b) USG guided aspiration
c) Percutaneous catheter drainage
d) Surgical approach

Conservative drug therapy: Used for uncomplicated abscess, without features of rupture or
impending rupture (due to large size) and abscess with no compression effect.
 Metronidazole (800 mg tds orally or 500 mg iv 6 hrly) clinical improvement starts by 3rd day
with 85% cure rates in 5 days and 95% cure rates in 10 days .Other imidazoles e.g tinidazole
secnidazole are also used.
 Chloroquine (600mg base bd for two days then 300 mg bd for two to three weeks) It have no
luminal activity and used mainly for recurrent abscess, ruptured abscess (abd and pulmonary
extention of ALA).
 Emetine hydrochloride not used routinely due to its adverse effects and paucity of availability.
Luminal agents (diloxanide furoate, paramomycin, iodoquinol, teclozon) are to be used for
asymptomatic carriers and in close inmates of patient.

Therapeutic aspiration –It is indicated for following cases:

 When drug therapy is contraindicated (e.g pregnancy)
 No clinical response to drug therapy in 3 to 5 days of drug treatment.
 Ruptured or impending burst abscess cavity (exetremly large size)
 left lobe abscess
 seronegative abscess (unable to differentiate from pyogenic abscess)
 suspicion of secondary bacterial infection
Mean resolution time of ALA despite adequate treatment (with amoebicidal drugs or aspiration) is 6-9
months. So serial USG scanning is not warranted for patients showing clinical response to therapy
and monitoring should be based on clinical response.

Percutaneous catheter drainage: It should be done in all above indications, if abscess is very thick
and not aspirable by wide bore needle.

Surgical intervention - Required rarely now a days when there is clinical deterioration despite
needle aspiration and adequate drug therapy and in cases of complicated abscess with features of
generalized peritonitis. Mortality in such cases even after surgery is 12 to 50% and adequate drug
therapy with metronidazole and broad spectrum antibiotics should be instituted even post operatively.

Complications

Peritonitis: Peritonitis associated with amoebiasis due to spontaneous rupture is 2.7 to 17%. The
rupture becomes localized due to adherence of omentum, colon or diaphragm And free peritoneal
rupture is rare and seen only in immunocompromised and moribund patients. When localized, a
hepatogastric, hepatoduodenal and hepatocolonic fistula may occur and the patient may present with
hemetemesis or blood in stools respectively.
At times diagnosis can only be ascertained on laparotomy. During laparotomy irrigation of cavity is
done with normal saline and emetine hydrochloride 65mg in 100 ml of normal saline is instilled in
cavity for 3 to 5 min.
Thoracic Involvement: Abscess present in posteriosuperior part of liver near the diaphragm may
rupture into pleural cavity, lungs or bronchial tree. Patient may present with cough, dyspnoea and
right hypochondrial pain. Treatment consist of thoracocentesis. Chest tube should be placed high as
the diaphragm is lifted up high in such cases. Bronchial rupture manifested by cough with
expectoration of chocolate colour sputum. It proves beneficial to the patient as it provides drainage
pathway without surgical intervention.
Pericardial Involvement: Due to rupture of left lobe abscess detection of pericardial thickening or
effusion is indication for aspiration of left sided amoebic abscess.

Prognosis
Uncomplicated amoebic liver abscess has a mortality rate of <1% if diagnosed early. However, for the
complicated disease, the mortality can be as high as 17 to 20%. Untreated, the mortality is 100%.
Poor prognostic factors include
 Serum bilirubin <3.5
 Encephalopathy
 Hypoalbumenemia (serum albumin <2 mg/dl)
 Multiple abscess cavities
 Total cavity size > 500 ml

REFERENCES
1. Hippocrates. 1886: The Genuine Works of Hippocrates, vols 1 & 2. Transl [from the Greek with a preliminary
discourse and annotations]. New York: William Wood & Co., 1886: 57,58,266,267.
2. Attar B, Levendoglu H, Cuasay NS. CT-guided percutaneous aspiration and catheter drainage of pyogenic liver
abscesses. Am J Gastroenterol 1986;81:550-555.
3. Balasegaram M, 1981: Management of hepatic abscess. Curr Prob Surg 18: 282-340.
4. Chan SC, et al, 1999: hepatic abscess due to geastric perforation by ingested fish bone demonstrated by
computed tomography. J Formos Med Assoc 98:145-147
5. Oschner A et al, 1938; Pyogenic abscess of liver: an analysis of 47 cases with a review of the literature. Am J
Surg 40:292-319.
6. Rintoul R, et al, 1996: Changing management of pyogenic liver abscess. Br J Surg 83:1215-1218.
7. McFadzean AJ, et al, 1953: solitary pyogenic abscess treated by closed aspiration and antibiotics: a report of 14
consecutive cases with recovery. Br J Surg 41;141-152.
8. Lublin M, et al, 2002: Hepatic abscesses in patients with chronic granulomatous disease. Ann Surg 235:383-391.
9. Chu. Yu S et al, 1997: Pyogenic liver abscess: treatment with needle aspiration. Clin Radiol 52:912-916
10. Giorgio A et al, 1995,: Pyogenic liver abscess: 13 years of experience in percutaneous needle aspiration with US
guidance. Radiology 195:122-124.
11. Martinez Baez M, 1986: Historical introduction. In Martinez-Palomo A (ed):Amebiasis: Human Parasitic Diseases,
No. 2. Amsterdam, Elsevier, pp 1-9.
12. Haque, R, et al, Amoebiasis. N Engl J Med 2003; 345:1565.
13. Perez,J, et al, Amebic liver abscess at Sto. Tomas University Hospital; Proc. of 4th Asian-Pacific Cong. Of Gastro;
Manila 1972; 130-140
14. Sharma, MP; Amebic liver abscess. Trop. Gastroenterol 1993; 14: 3.
15. Perez, J, Management of amebic hepatic abscess; Drugs. 1978; 49-52
16. Wells CD, Arguedas M, 2004: Amebic liver abscess. South Med J 97:673-682.
 Choledochal cyst
Shivendra Singh, Nikhil Gupta

Choledochal cyst (CC) is a rare congenital anomaly of biliary system with reported rates from western
literature being 1 in 100000- 150000. Incidence is higher in Asian population (1:1000) with Japan
constituting two thirds of the cases. Reason for this higher incidence in Asian population is unclear.
Also there is an unexplained female preponderance (M:F= 1:4).

Classification

Alonso- Lej first classified biliary cystic dilatation in 1959. They divided these ducts in three types:
congenital cystic dilatation (the most common), congenital diverticulum of the common bile duct, and
congenital choledochocele. Todani and colleagues expanded it in 1977 to include both intrahepatic
and multiple cysts. This is the most commonly used classification worldwide. According to this
classification, choledochal cysts have been classified as -:
a) Type IA is marked cystic dilation of the entire extrahepatic biliary tree, with sparing of the
intrahepatic ducts. The cystic duct and the gallbladder arise from the dilated common bile
duct (CBD).
Type IB is defined by focal, segmental dilation of the extrahepatic bile duct. Although by
definition the cyst can arise from anywhere within the extrahepatic biliary tree, it is most
commonly distal CBD, with the cystic duct branching off a normal CBD. The biliary tree
proximal to the gallbladder is usually normal.
Type-IC cysts are smooth fusiform dilations of the entire extrahepatic bile duct, usually
extending from the pancreaticobiliary junction to the intrahepatic biliary tree.
In 2011, Michaelides et al proposed a new variant of type I CCs and called it the Type ID. In
this, apart from the dilatation of the common hepatic and the common bile duct, dilatation of
the central portion of the cystic duct was also observed, giving a bicornal configuration to the
cyst.
b) Type-II cysts are discrete diverticuli of the extrahepatic duct with a narrow stalk connection to
the CBD.
c) Type-III cysts are also called Choledochoceles owing to their similarity in morphology, and
postulated etiology, to ureteroceles. They consist of dilation of the distal CBD that is confined
to the wall of the duodenum, and often bulge into the duodenal lumen. Although the outer
lining of the cyst is always lined by duodenal mucosa, the inner lining can either be duodenal
or biliary epithelium.
d) Type-IV cysts are multiple and are further subdivided based on intrahepatic duct
development.
Type-IVA cysts are multiple intrahepatic and extrahepatic dilations. The intrahepatic duct
dilation can be cystic, fusiform or irregular. These cysts have further been classified as cystic–
cystic, cystic–fusiform or fusiform–fusiform to better delineate the nature of their intrahepatic
and extrahepatic morphologies.
Type-IVB cysts refer to multiple dilations of the extrahepatic biliary tree only, described
radiographically as either a “string of beads” or “bunch of grapes” appearance.
e) Type-V CCs referred to as Caroli’s disease (also known as communicating cavernous
ectasia) consists of multiple saccular or cystic dilations of the intrahepatic bile ducts.
Combination of ductal ecatsia with intrahepatic fibrosis is known as caroli’s syndrome. This
ectasia is usually confined to smaller ducts.
f) Type VI has been described as cystic dilatation of cystic duct alone.
g) Form Fruste- described by Lilly et al as cysts present with typical symptoms of abdominal
pain and obstructive jaundice, without bile duct dilation, but exhibiting an abnormal
pancreaticobiliary duct junction (APBDJ). The risk of malignancy in these patients is similar or
even higher compared to other CCs. Thus they need to be managed accordingly.

Distribution of the different types of CCs are as follows: 50%–80% are type I, 2% type II, 1.4%–4.5%
type III, 15%–35% type IV and 20% type V.
 Fig. 1. Choledochal cyst classification. (A) Type-IA cystic dilation of the extrahepatic duct. (B)
Type-IB focal segmental dilation of the extrahepatic duct. (C) Type-IC fusiform dilation of the entire
extrahepatic bile duct. (D) Type-II simple diverticula of the common bile duct. (E) Type-III cyst/
choledochocele distal intramural dilation of the common bile duct within the duodenal wall. (F)
Type-IVA combined intrahepatic and extrahepatic duct dilation. (G) Type-IVB multiple extrahepatic
bile duct dilations. (H) Type-V/Caroli disease multiple intrahepatic bile duct dilation

Etiopathogenesis
Etiology of CCs is still not clear. Theory of abnormal pancreaticobiliary ductal junction (APBDJ)
proposed by Babbitt has been most commonly accepted. According to this theory, there is an
abnormally long common channel of bile duct and the pancreatic duct such that they meet outside the
duodenal wall. Authors have arbitrarily defined abnormal common channel from 10mm to 45mm.
Okada has defined APBDJ as any length of common channel which meets outside duodenal wall.
Komi et al have further divided APBDJ into three types: (1) A right-angled union without an accessory
pancreatic duct; (2) An acute-angled union without an accessory pancreatic duct; and (3) A right- or
acute-angled union with an accessory pancreatic duct.
As a result of this long common channel, there is mixing of pancreatic juice and bile causing activation
of pancreatic enzymes because the sphincter of oddi cannot regulate the ducts. These activated
enzymes cause damage to biliary epithelium causing inflammation and weakening of the wall and
leading to its dilatation. Moreover, pressure in the pancreatic duct is higher compared to bile duct
which further causes biliary dilatation. Studies of biliary amylase from CCs have confirmed higher
values of amylase in bile. Amylase is just a marker of pancreatic reflux. It means higher levels of
trypsinogen and phospholipase A2 which cause biliary inflammation. Administration of secretin which
increases pancreatic secretion has shown to dilate CBD in CCs thus further confirming pancreatic
reflux theory. However, this theory is not universally accepted. APBDJ is found in only 50- 80% of
CCs and neonatal acini do not make sufficient pancreatic enzymes to cause neonatal CCs.
Another theory by Basu and Davenport states that CCs are purely congenital in origin and it is the
overproduction of epithelial cells which cause biliary dilatation during the cannulation period of
development. According to this theory, round cysts are congenital in origin due to agangilonosis of
cyst and distal dilatation (similar to Hirschprung’s disease). Fusiform cysts are acquired due to
APBDJ.

Other authors speculate that all adult cysts are acquired owing to distal obstruction, with longer and
narrower stenosis leading to round lesions and shorter and wider stenosis leading to fusiform lesions.
Cause for this distal obstruction can be either APBDJ or sphincter of oddi dysfunction. Type IVA cysts
are associated with distal, hilar and intrahepatic stenosis.

According to Singham et al, biliary dilation can be a result of embryologic overproliferation of epithelial
cells within solid bile ducts during the fetal life.

Type II cysts may actually be a true diverticula rather than biliary dilatation with little inflammation and
carcinogenic potential. Thus they might be considered as biliary duplication cysts rather than cystic
dilatation. Regarding the etiology of caroli’s disease, it is suggested that arrest of remodelling of biliary
th
ductal plate during 12 week of embryology may lead to formation of Caroli’s disease.

Associated anomalies
Numerous associated congenital anomalies have been associated with CCs- Colonic atresia,
duodenal atresia, imperforate anus, pancreatic arteriovenous malformation, multiseptate gallbladder,
OMENS plus syndrome, ventricular septal defect, aortic hypoplasia, pancreatic divisum, pancreatic
aplasia, focal nodular hyperplasia, congenital absence of the portal vein, heterotopic pancreatic tissue
and familial adenomatous polyposis.

Clinical presentation
Most common age of presentation for CCs is before 10yrs. Classic triad of presentation is abdominal
pain, jaundice and palpable mass although it is present in less than 20% of patients (mostly
neonates). 85% of children have at least two features of the triad at presentation, compared with only
25% of adults. Adults usually present with pain in abdomen, fever, vomiting and jaundice. Symptoms
in adults are usually due to complications of cholangitis and pancreatitis.

Complications of choledochal cysts

a) Malignancy- It is a well accepted fact that CCs are premalignant. The risk of malignancy has been
reported to be about 10- 15% and it increases with age. Most commonly it occurs in the fourth
decade 20 years earlier than the general population. Most common site of cancer is extrahepatic
bile duct (50- 60%), gall bladder (35- 45%), intrahepatic ducts (2.5%), liver and pancreas in 0.7%.
A review by Todani and colleagues found that 68% of cancers were associated with type-I, 5%
type-II, 1.6% type-III, 21% type-IV and 6% type-V CCs. Other studies suggest highest incidence
in type V cysts. Abnormal pancreaticobiliary duct junction has a 16%–55% risk of malignancy with
or without bile duct dilation, and cancer has been reported in 12%–39% of form fruste patients.
Most common site of malignancy in form fruste is gall bladder leading to the hypothesis that
malignancy occurs in the site of bile stasis (cyst in CCs and gall bladder in form fruste). Cancer
occurs due to chronic inflammation occurring in the mileu of bile stasis. Chronic infection by gram
negative bacteria like E. coli metabolizes bile acids into carcinogens.
b) Cholangitis- Chronic inflammation due to bile stasis leads to stone and sludge formation. This
may lead to the symptoms of pain abdomen, fever and obstructive jaundice.
c) Pancreatitis- Stone and protein plug formation in distal bile duct and pancreatic duct may lead to
pancreatitis. Over 70% of patients with pancreatitis have pancreatobiliary maljunction.
d) Secondary biliary cirrhosis- stricture and recurrent cholangitis in patients with type IVA and V
cysts may lead in the long term to secondary biliary cirrhosis. Such patients may present with
signs and symptoms of portal hypertension such as upper GI bleed, hypersplenism or ascites.
Rarely, portal hypertension may occur by shear mechanical compression of portal vein by a large
cyst.
e) Spontaneous rupture- 1-2% of patients may present with spontaneous rupture of CCs presenting
with signs and symptoms of peritonitis. Site of rupture is usually junction of cystic duct and CBD
as this is the site of poor blood flow.
f) Cystolithiasis- Prevalence of cystolithiasis is about 2- 72%. Most of these stones are pigmented,
earthy and soft in consistency and occur in type IVA cysts as these cysts have been associated
with hilar stenosis.

Diagnosis
a) Ultrasound is the initial investigation of choice for a patient presenting with pain in abdomen and
jaundice. Sensitivity of ultrasonography in making the diagnosis is 71%–97%.
b) HIDA scan has been used to diagnose CCs. It may present as a large cyst with biliary continuity.
Sensitivity of HIDA scan for type I cyst is 100%. It falls sharply to 65% for type IVA cysts owing to
poor visualization of intrahepatic cysts. It can also be used to differentiate biliary atresia from CC
in a neonate. CCs will show contrast entering the bowel. HIDA scan is also used to diagnose cyst
rupture.
c) CT scan is used to delineate intrahepatic bile ducts, distal bile duct and pancreatic head. Extent of
intrahepatic involvement can be easily delineated in type V cysts- localized or diffuse. CT scan
also helps to diagnose malignant transformation of cyst along with its local and distal extent to
plan surgical treatment.
d) Cholangiography either in the form of ERCP, PTC or MRCP is useful for complete delineation of
biliary anatomy. Moreover, APBDJ, strictures, stones and malignancy can also be identified by
cholangiography. MRCP is considered gold standard imaging to diagnose CCs. It is non invasive,
operator independent, no radiation hazard and no complications like pancreatitis or cholangitis.
However, ability to diagnose APBDJ is poor (46- 60%).
e) Choledochoceles can be best diagnosed by endoscopic ultrasound. In patients with Caroli
disease, ultrasounds and CT and MRI scans show multiple saccular dilations, which can be focal
or diffuse and contain bile, sludge and stones. Bloustein and colleagues described the “central dot
sign,” which is a dilated duct surrounding a portal bundle, as pathognomic for Caroli disease.
Initially found on ultrasounds, this sign can also be seen on MRI and CT scans.

Management
Management of CCs depends on type of cysts. Apart from Caroli’s disease (type-V choledochal
cysts), choledochal cysts are best treated with complete excision, followed by hepaticojejunostomy
when technically feasible. General principle of surgery is to remove maximum possible biliary
epithelium with re-establishment of bilio enteric continuity. Benefits of this surgery are that it
separates the pancreatic juice from bile thus avoiding the activation of pancreatic enzymes. Also the
premalignant mucosa is also removed thus minimizing the incidence of malignancy. Thus complete
excision of the cysts should be performed from hilum to just above the pancreatic duct whenever
possible. In patients with recurrent cholangitis, cyst might be stuck with portal vein. In such cases,
part of cyst wall adhered to cyst can be left behind with stripping of mucosa as described by Lilly.

Both hepatico-duodenostomy (HD) and hepatico-jejunostomy (HJ) have been performed after
excision of cyst. But HJ is supposed to be better as HD is associated with higher incidence of bile
reflux, gastritis or esophagitis. Also pancreatic reflux from HD may lead to malignant transformation at
anastomotic site. Thus HJ is better compared to HD.

Internal drainage of cysts (type I- type IVA) was the most commonly practised surgery. Cysts were
incised and anastomosed to either duodenum or jejunum. Although there was significant relief from
symptoms, reflux of contents often lead to recurrent cholangitis. Most dreadful complication was the
occurrence of malignancy in the cyst. Risk of malignancy was as high as 30%. It was also associated
with higher morbidity and reoperation rate. So, presently internal drainage is not recommended.

Type I cysts require complete cyst excision with anastomosis.

Type II cysts need to surgically excised. Depending on the size of the neck, opening can either be
primarily closed (transversally) or over a T tube.

Type III cysts were initially treated with transduodenal cyst excision with re anastomosis of both biliary
and pancreatic ducts in the duodenum. This form of treatment is being replaced by endoscopic
sphincterotomy of the papilla. Concern regarding this form of treatment is the risk of malignancy.
However, the risk is so low that radical cyst excision may not be justified.

Regarding the management of type IVA cysts, extrahepatic portion is treated like type I cysts. Most of
the authors just excise the extrahepatic portion and keep the intrahepatic portion on continuous
surveillance. It is said that the intraphepatic ducts come back to normal size within a span of one year
in most of the patients. But malignancy has been found to occur in the intrahepatic component of the
cyst. If extensive intrahepatic component is present, surveillance is the best option. In case of limited
liver involvement, partial hepatectomy should be added to completely remove the at risk mucosa.

Type V cysts or Caroli’s disease is a separate entity altogether. It is mainly treated conservatively with
antibiotics, drainage and ursodiol. For patients with localized disease (most commonly left side),
segmental resection or hepatectomy is the treatment of choice. For patients with bilateral disease,
monolobar hepatectomy with bilioenteric anastomosis was initially considered the treatment of choice.
However, liver transplantation is now considered the best treatment (especially in the presence of
portal hypertension) as it avoids the complication of cholangiocarcinoma.

There are two schools of thoughts for patients with APBDJ without biliary dilatation (form fruste).
Some perform only prophylactic cholecystectomy and some routinely excise extrahepatic bile duct
and perform a bilioenteric anastomosis.

Timing of surgery
Surgery for CCs should be done as soon as possible, once the diagnosis is made. But, the dilemma
comes in the neonatal CDC. Various studies have been published comparing surgical outcomes of
prenatally diagnosed cysts versus postnatally diagnosed cysts. Prenatally diagnosed cases were
operated earlier and were associated with better outcome. Patients operated later had higher
complication rate and higher incidence of liver fibrosis. Thus CCs should be operated as early as
possible. Germani et al have recommended surgery after 3 months of life for best surgical outcomes.

Complications of surgery
Early complications of surgery include anastomotic leak, pancreatic leak, pancreatitis, bowel
obstruction, bilioma. Late complications include anastomotic stricture, peptic ulcer disease,
cholangitis, biliary and intrahepatic stones, liver failure and biliary cancer. Damage to pancreatic duct
may lead to pancreatic duct stricture with pancreatitis.

Post excisional malignancy has also been reported. Recurrence of malignancy following excision of
CC is mainly at or near the choledochoenteric anastomosis, intrahepatic cyst and distal choledochus.
Most of the patients who develop malignancy after excision do give history of recurrent cholangitis
and stone formation. Thus underlying stricture and recurrent inflammation may be the cause of
recurrent malignancy in these patients. Thus to avoid malignancy, complete resection with wide
drainage of the duct should be performed.
 Rationale of investigations in a case of obstructive jaundice
Aswini K Pujahari

Introduction
Flow of bile from the liver to the small bowel is physiological and it takes place through biliary ductal
system. Though obstruction may occur at various levels but only when it is at or below the
confluence of the left and the right duct, it qualifies as surgical obstructive jaundice (SOJ). No age
from new born to elderly is immune to SOJ. The rationale of evaluation depends on the information
required by the treating team of the particular case. The commonly required information are-
a) Is it obstructive jaundice?
b) Where is the obstruction?
c) What is the cause of obstruction? ( benign or malignant)
Level 1 tests = Is it obstructive jaundice?
(a) Biochemical (LFT) and (b) trans-abdominal ultra sound (TAUS)

Biochemical tests (Liver function Tests (LFTs)) are first-line tests in any biliary evaluation. LFT
includes serum bilirubin, the transaminases, alkaline phosphatase, total protein, albumin, prothrombin
time and others. If liver function is found normal it is advisable to perform the least invasive imaging
1
modality. Abnormal LFTs raises the diagnostic value of imaging . In obstructive jaundice, evidence
looked for by surgeons include conjugated hyperbilirubinemia, raised ALP and dilated biliary tree
proximal to the obstruction. Just below the dilatation is the area of obstruction. Rise of alanine
aminotransferase greater than aspartate transferase in a sample is one of the best predictors of
choledocholithiasis in cholangiogram in presence of cholangitis2. Conjugated hyperbilirubinemia
indicates cholestasis of various cause and not
merely surgical obstructive jaundice (SOJ). A
variety of anatomic, infectious, autoimmune,
and metabolic diseases can lead to conjugated
hyperbilirubinemia3. The hall mark of
obstruction is elevated serum alkaline
phosphatase(SOJ)1.

Serum alkaline phosphatase (SAP) and

5'nucleotidase are significantly increased in all
cases of chronic active hepatitis and
obstructive hepatic disease. However, the
elevation observed in the latter is significantly
higher than the former4. Dubin-Johnson
syndrome is a rare benign chronic disorder of
bilirubin metabolism, characterized by Fig-1(Blue liver in Dubin-Johnson syndrome)
conjugated hyperbilirubinemia, darkly
5
pigmented liver (Fig-1) and presence of abnormal pigment in hepatocytes .

(b). Trans Abdominal Ultra-Sound- (TAUS) - This is

good for initial routine CBD evaluation for SOJ as it is
easily available at low cost. The result is more reliable
when the biliary tree is dilated. It mostly evaluates the
supra-duodenal area and is operator dependant. The hall
mark of biliary obstruction is dilated intra hepatic biliary
radicals (IHBR) (Fig-2). Other typical signs like the
triangular cord sign may be a useful sonographic finding
for diagnosing biliary atresia rather than gallbladder
6
length and contraction . It is a proven good modality in
7
children for hepatobiliary and pancreatic ascariasis .
However, a drawback is the low detection of CBD stones Fig-2( dilated IHBR on US)
8 .
of only 20% . Occasionally there may not be IHBR
dilatation despite SOJ and hence needs further evaluations to find the cause9. Even though the
dilated biliary tree is the hall mark of SOJ, dilatation alone may be seen without jaundice. They
include juxtapapillary duodenal diverticulum (22.5%), benign stricture (20.4%), distal CBD mass
(4.1%), choledochal cyst (4.1%), anomalous union of the pancreaticobiliary duct(AUPBD) (4.1%) and
choledochal cyst with AUPBD (4.1%). Other causes include post cholecystectomy status10 and Opium
addiction10,11,12.

Level II- What is the level of obstruction?

Magnetic Resonance Cholangio-pancreaticogram (MRCP) is by far the most reliable test to locate the
level of obstruction (Fig-3). MRCP has the advantages of being non invasive, without radiation risk,
leads to good delineation of biliary tree without contrast and has no failure. Drawbacks are longer
duration and its need to be done in a fasting state. It is a non-dynamic study and hence cannot show
real time flow. The sensitivity, specificity and accuracy for detection of ductal stone are 90%, 88% and
89% respectively. After the exclusion of stones < 6 mm, the sensitivity, specificity and accuracy were
8, 13
100%, 99% and 99%, respectively. MRCP accuracy is hence related to stones size. .

MRCP can be used effectively for evaluation of the biliary

system in children. It is a reliable screening technique for
pre-operative exclusion of CBD stones, obviating the
necessity for per-operative cholangiogram14. MR
Cholangiogram (MRC) can not only accurately identify
CBD stones preoperatively in patients with gallstone
pancreatitis but also provides valuable information with
respect to other biliary pathology, including cholelithiasis,
15
acute cholecystitis and pseudocyst . MRC is an effective
noninvasive screening tool for CBD stones, appropriately
selecting candidates for preoperative ERCP and sparing
others the need for an endoscopic therapeutic procedure
with its associated complications15,16,17,18 . Dilation of both
PD and CBD on computed tomography / MRCP imaging
is suggestive of pancreatic malignancy and merits further
Fig-3 (MRI showing biliary stricture
diagnostic evaluation (Fig-4).
and dilated proximal ducts)
Endoscopic ultrasound-FNA is highly accurate for
diagnosing malignancy in this setting19. 3D virtual
cholangioscopy provides detailed preoperative
reconstruction of biliary anatomy and reliable identification
of choledocholithiasis with acceptable sensitivity and
specificity in a clinical setting. Newer software
developments may further enhance its accuracy, so that
MR virtual cholangioscopy (MRVC) might challenge or
replace more invasive diagnostic measures in the near
future20. MRVC and pancreatic duct scopy can provide
additional information on the gallbladder, bile duct, and
pancreatic duct lumen identical to the actual luminal
diameter could be obtained with a threshold of less than
20%. MRVE images of the gall bladder do not significantly
improve diagnosis (P=0.311), but those of the bile and Fig -4 MRI showing CBD and MPD
pancreatic ducts did (P<0.05). In addition, MRVE may aid dilated till lower end
navigation during cholangioscopy. Thus, MRVE is a
21
clinically useful technique for examining lesions of the biliary tract and pancreas . Gadolinium
ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-Gd-EOB-DTPA-enhanced MRC
yields information that complements T2w-MRC findings and improves the identification and
localization of the bile extravasations (84 % accuracy, 100 % specificity, P < 0.05). Gd-EOB-DTPA-
enhanced MRC is recommended in addition to T2w-MRC to increase the preoperative accuracy of
identifying and locating extravasations of bile22. Common causes of obstruction are given in table
number-1

Table no.1: Common causes of biliary obstruction

Intrahepatic Porta hepatis Suprapancreatic Pancreatic Ampulla
SOL Liver Klatskin Post traumatic Pancreatitis Periamp Ca
RPC Ca GB Stone CA pancreas Ca duodenum
PSC Metastatic Round worm Stone Ampullary stenosis
 Stone
(SOL- Space Occupying Lesion, RPC- Recurrent Pyogenic Cholangitis, PSC- Primary Sclerosing Cholangitis,
Ca- Carcinoma, GB-gall Bladder)

Level III evaluation - cause of obstruction and tissue diagnosis

Endoscopic procedure (a)EUS (b) TDUS (d) Side viewing endoscopy and tissue diagnosis

(a) Endoscopic US (EUS) -US probe is taken to the tip of endoscope with special care to free air at
the transducer before the EUS is ready. It is a very good modality for detecting tumors and their
23
invasion along with lymph nodal metastasis. US guided biopsy can also be taken . Operator
dependency is a drawback as in TAUS. Detection of CBD stone is very high, hence it is
24
recommended to do EUS before ERC . Reported sensitivity, specificity, positive predictive value,
negative predictive value, and accuracy is 86%, 100%, 100%, 57%, and 88%, respectively for
detecting CBD stone25. EUS is indicated in unexplained biliary colic and in acute pancreatitis for
suspected microlithiasis 26. EUS yield is low in cases of biliary dilatation in the setting of normal serum
liver enzymes; its preferential use would potentially avoid unnecessary costly MRCP and invasive
27
ERCP .

EUS-FNA had a positive impact on patient management in 84% of patients: with FNA for imaged bile
duct mass lesions and for obtaining a tissue diagnosis in patients with suspected cholangiocarcinoma,
this technology may represent a new approach to diagnosis especially when other methods fail. The
ability to obtain a definite diagnosis has a significant impact on patient management 28.EUS should be
the test of choice for further evaluation of CBD dilatation; its preferential use would potentially avoid
unnecessary MRCP and ERCP29. Combined EUS/EUS-FNA and therapeutic ERCP is technically
feasible, with a complication rate no higher than the component procedures, while efficiently providing
tissue diagnosis and biliary drainage30,.A non significant trend toward lower biliary stent placement
success rates with combined ERCP procedures merits further study. Benefits of a combined
31
procedure may include expedited patient evaluation and the avoidance of repeated sedation . EUS-
guided transluminal cholangiodrainage (EUCD) is an elegant, not yet fully established, but rather still
experimental procedure of interventional endoscopy / EUS, which needs great expertise of the
endoscopist in an interdisciplinary centre of visceral medicine. In experienced hands, a safe
procedure can be provided, for which a systematic follow-up and a multicentre evaluation of
periinterventional management are still needed in order to achieve a final assessment of EUCD for
guideline approval32. Recently investigators reported that using molecular analysis of EUS-FNA
samples can achieve a higher diagnostic efficacy. Further research is encouraged to optimize the
33
EUS-FNA procedure to reach its maximum diagnostic yield for solid pancreatic masses .

Intra Ductal Ultra Sound – (IDUS) In this, an Ultra Sound transducer is passed through the Biopsy
channel of the endoscope in to the bile duct and US recording is done. This makes it very special with
a 95% detection rate of CBD stone and tumor reported8. IDUS is a sensitive and specific method for
the diagnosis of Mirizzi syndrome with a. sensitivity of 97 % and specificity of 100%34. It is best done
post ERCP for confirmation of stone clearance and to look for periductal tumor invasion to find
8
operability . IDUS+ transpapillary endoscopic biopsies ETP substantiate the diagnosis and further
management of ampullary tumors. ETP alone is not useful in detecting malignancy (false-negative
rate of 31.3%). IDUS accurately predicts T and N stages in patients and is able to accurately predict
cases which potentially are treatable endoscopically35. IDUS shows good results for accurate
diagnostics of bile duct strictures of uncertain etiology thus allowing for adequate further clinical
management36. Advanced T staging of these lesions with endoscopic ultrasound and intraductal
ultrasound, while useful tools for selection of candidates for snare polypectomy, should be limited to
lesions either greater than 3 cm, bearing the macroscopic appearance of malignancy or unamenable
to endoscopic therapy. Intraductal ultrasound has demonstrated T-staging accuracy superior to
37
endoscopic ultrasound .

Endoscopic Retrograde Cholangio Pancreaticogram (ERCP)-. This is an invasive procedure with

injection of contrast through the papilla. Being a dynamic study it gives a good quality picture. Apart
from diagnostic capability like tissue brush cytology/ biopsy, its advantages are performance of
therapeutic procedure like papillotomy, stone basket extraction and stenting . The disadvantages are
cholangitis, pancreatitis, bleeding, duodenal injury and occasional failures. ERCP is the standard
procedure for ductal stone extraction and treatment for bile leak without disconnection of the CBD.
.
ERCP can be therapeutic in 60.3% of patients requiring stone extraction or implantation of endobiliary
stent while only 37.7% require surgical treatment 38. In experienced hands, endoscopic papillectomy
of noninvasive, benign ampullary lesions is a safe, technically feasible, and effective alternative to
surgical resection. But it continues to mitigate concerns regarding incomplete removal of ampullary
37.
neoplasias and post procedure complications Thus ERCP is no more a diagnostic test but is also a
therapeutic procedure.

CT Scan and cholangiogram- CT scan is indicated in hepatobiliary malignancy to look for any nodal
disease beyond the preview of EUS/ IDUS and for metastatic work up. Newer machines have
multidetector computed tomographic (MDCT) cholangiography with multiplanar reformation (MPR)
technique, resulting in a fast and non-invasive evaluation with relatively high sensitivity and specificity
for the diagnosis of the causes of biliary obstruction39. 3D and multiphase fusion images may be an
accurate and routinely applicable tool for the diagnosis and therapeutic management of patients with
40
biliary system abnormalities . 3D images provide accurate information about the relationship
between hilar cholangiocarcinoma and adjacent vessels. This technique is a powerful new tool for
improving the proportion of potentially curative resection 41. In patients with bile duct obstruction,
double contrast percutaneous transhepatic cholangiographic CT DC-PTC-CT is a feasible technique
offering both important diagnostic value and drainage application42. HBC and cystadenocarcinoma
may give rise to obstructive jaundice in which evaluation with cross-sectional imaging techniques is
43
useful. ERCP is a useful tool to differentiate extraductal from intraductal obstruction

Biliary tumor marker: Vascular endothelial growth factor (VEGF)-C , over expression in extrahepatic
cholangiocarcinoma (ECC) has been shown to be correlated with lymph node metastasis. The
quantification of VEGF-C mRNA of ECC with real-time PCR using endoscopic samples was useful for
preoperative detection of VEGF-C overexpression44. Calcium-binding protein S100P is a novel
marker of cholangiocarcinoma. Detecting the S100P expression levels in brushing cytology samples
has a diagnostic value, which will be helpful for better diagnosis of cholangiocarcinoma [ 45].

Pancreatic tumor markers: By far the best tumor marker for adenocarcinoma pancreas is CA 19-9.
But for any surgical therapeutic modality, imaging study is always added to locate the mass. Although
several potential serum and tissue markers for pancreatic cancer are currently undergoing evaluation,
none are sufficiently validated for routine clinical use. CA 19-9 thus remains the serum pancreatic
cancer marker against which new markers for this malignancy should be judged 46.There are two
tumor markers identified for pancreatic adenocarcinoma. They are laminin gamma C2(LAMC2],which
is a new serum biomarker positive in 65% of cases 47 and CA242, which could play different roles in
the diagnosis of pancreatic cancer. Though the sensitivity of CA242 is lower than that of CA19-9, its
specificity is greater 48.

Elevated Serum bilirubin and CA 19-9, dilated MPD and CBD are useful in predicting malignancy in
patients with CCP and head mass49. Because of the poor prognosis related to untreated
pancreatic cancer, the general recommendation is to perform resection of the tumor when technically
50
possible and when carcinoma cannot be ruled out completely .( Table no 2)
Table number 2: difference between Benign and
malignant stricture
Benign Malignant
Gradual tapering Abrupt end
Symmetrical narrowing Asymmetrical
Regular margin Irregular margin
Short 13.6+/-1.9mm Long 30+/- 8.5mm
No double duct sign Yes double duct sign
No vascular infiltration Yes-vascular invasion
Concentric thickening Irregular thickening
distal CBD proximal to obstruction
SAP (163.9 - 145.1) 407 - 481
CA19-9 25 - 41 615 - 818
Duct wall thickness > 5 mm
<5mm
Lymph node <1cm >1 cm
Conclusion
Conjugated hyperbilirubenemia, raised serum alkaline phosphatase in a setting of itching and pale
stool raises the doubt of obstructive jaundice, which gets confirmed by partial or total dilated biliary
tree. MRCP, EUS, IDUS gives the level of block and cause of obstruction to be overcome by ERCP in
majority. High resolution CT with 3D imaging helps in taking a decision for surgery based on the
involvement of important vasculatures along with correlation of tumor markers.

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 Abdominal Tuberculosis
Shaji Thomas

Introduction
 Tuberculosis is the most prevalent infectious disease in the world. It infects 1.6 billion people
worldwide (one third of world population). 14.4 million people have clinical disease at any one
time.
 Upto 25% of household contacts of an index case may acquire infection. Development of disease
occurs in less than 10% of infected persons.
 The species M tuberculosis causes the vast majority of human tuberculosis. Infection by
Mycobacterium Tuberculosis is common in India.
 M bovis causes disease in cattle and spreads to humans through animal contact and
consumption of unpasteurized milk. It has also been demonstrated that M bovis can be
transmitted from human to human.
 Primary infection is usually acquired by inhalation. Usually 50-200 organisms are required for
development of active infection. Clinical disease develops in less than 5% of people exposed to M
tuberculosis.
 Majority of cases of tuberculosis are due to reactivation of infection acquired years earlier.
Reactivation may be due to immunosuppression, malnutrition, Vitamin D deficiency, diabetes,
end-stage renal disease, silicosis, lung malignancy, gastrectomy and transplantation.
 If properly treated, TB caused by drug-susceptible strains is curable in virtually all cases. If
untreated, the disease may be fatal in 50-65% within 5 years.
 Abdomen is a frequent site of tuberculosis in India (rates 50 times higher than in Europe) and in
those immunosuppressed with HIV. It should be suspected in any individual with features of ill
health and altered bowel habits.

Pathology of Abdominal tuberculosis

 Various pathogenetic mechanisms maybe involved
a) Patient of pulmonary tuberculosis swallows infected sputum – direct seeding.
b) Could also be due to hematogenous spread of mycobacteria.
c) Ingestion of milk from cows affected by bovine TB.
d) Spread of disease from infected adjacent viscera.
 Ileocaecal area is a commonly affected site of tuberculosis in the abdomen due to the abundance
of lymphoid tissue (Peyer’s patches). Increased physiological stasis, increased rate of fluid and
electrolyte absorption, and minimal digestive activity permitting greater contact time between the
organism and the mucosal surface in the ileocecal region render this region more vulnerable to
development of intestinal TB.
 Organism colonizes lymphatics of terminal ileum. Causes transverse ulcers with undermined
edges. Serosa is studded with tubercles. Histology shows caseating granulomas with giant cells.
Terminal ileum and caecum are the sites most commonly involved.
 Can be of ulcerative, hypertrophic, ulcerohypertrophic, diffuse colitis, and sclerotic forms.
 Ulcerative type – severe form of disease. Virulence of the organism outstrips the resistance of the
host. Usually seen in malnourished patients.
 Hyperplastic type – host resistance is stronger than virulence of the organism. Commonly seen in
well nourished young patients. Can also be caused by drinking infected milk. Marked
inflammatory reaction causing hyperplasia and thickening of lymphoid follicles and narrowing of
lumen and obstruction. Marked mesenteric lymphadenopathy. Areas of stricture and fibrosis.
Shortening of bowel with caecum being pulled up into subhepatic position.
 Localized areas of ascitis occur in the form of cocoons.
 Lungs and other organs may also show involvement.

Classification of Abdominal tuberculosis

Gastrointestinal tuberculosis
Ulcerative
Hypertrophic
Ulcerohypertrophic
Sclerotic
Diffuse colitis
 Peritoneal tuberculosis
Acute peritoneal tuberculosis
Chronic peritoneal tuberculosis
Ascitic form
Encysted (loculated) form
Fibrous form
Tuberculosis of the mesentery and its
contents
Mesenteric adenitis
Mesenteric cyst(s)
Mesenteric abscess(es)
Bowel adhesions
Rolled-up omentum
Tuberculosis of the solid viscera
Liver, biliary tract and gall bladder
Pancreas
Spleen
Retroperitoneal lymph node tuberculosis

Clinical features
 Weight loss, anorexia, chronic cough, malaise, fatigue, evening rise of temperature with sweating,
vague abdominal pain with distension, alternating constipation and diarrhea. Severe malabsorption.
Palpable abdominal mass. Ascitis.
 May present in emergency with acute distal small bowel obstruction from strictures of the small bowel.
Abdominal pain and distension, constipation and bilious and faeculent vomiting are typical.
 May present with features of peritonitis from perforation of tubercular ulcer in the small bowel. Or from
direct spread of tubercle bacilli from ruptured lymph nodes and intraabdominal organs or
hematogenous seeding.
 Acute peritoneal tuberculosis may present as an acute abdomen and may often be subjected to
emergency surgery. Operative findings will be straw colored fluid along with tubercles scattered over
the peritoneum.
 Less commonly, the presentation may mimic acute appendicitis.
 Diarrhea often alternating with constipation maybe seen in up to 20% of patients.
 Gastrointestinal bleeding is a rare presentation.
 Associated menstrual abnormalities may be present in upto one-third of female patients.
 In patients with HIV / AIDS, the incidence of extra-pulmonary TB maybe as high as 50%. Fever,
weight loss, and extra-abdominal lymphadenopathy are more common in patients with HIV, as also
intra-abdominal lymphadenopathy and visceral lesions.
 Examination – chronically ill patient. ‘Doughy’ feel to abdomen. Distended abdomen with increased
peristaltic activity. Mass in right iliac fossa in hyperplastic type. Some patients may also have fistula-
in-ano with undermined edges and watery discharge.

Investigations
 The definitive diagnosis of tuberculosis requires identification of the pathogen in a patient’s secretions
or tissues. Therapy is often initiated before a definitive diagnosis has been made, but this should be
always pursued to determine the drug susceptibility of the organism which guides individual treatment
regimens.
 Low haemoglobin. Raised ESR and CRP. Positive Mantoux test.
 Two or three early morning sputum specimens for AFB by ZN staining, culture and sensitivity. Sputum
induction by ultrasonic nebulization of hypertonic saline. Fiberoptic bronchoscopy with bronchial
brushings, endobronchial biopsy, bronchoalveolar lavage.
 Chest X-ray may show associated pulmonary TB in about 25% cases.
 Plain X-ray of the abdomen may show calcified lymph nodes, dilated loops with fluid levels.
 Ultrasound – localized ascitis, dilated bowel loops, enlarged lymph nodes. In intestinal TB, bowel wall
thickening is usually uniform and concentric as opposed to the eccentric thickening at the mesenteric
border seen in Crohn’s disease.
 Barium meal and follow through – increased transit time with hypersegmentation and flocculation of
barium may be an early sign, rapid transit and lack of barium retention in an inflamed segment,
 strictures of small bowel, high subhepatic caecum, with narrow ileum entering ileum directly from
below upwards in a straight line rather than at an angle.
 Abdominal Computed Tomography. High density ascitis, enlarged lymph nodes, thickened bowel
loops and ascitis. Short segments of homogenous circumferential thickening with normal intervening
bowel associated with ileocaecal involvement strongly suggests TB. Mesenteric infiltration, omental
masses, peritoneal thickening.
 A successful diagnosis is usually made by colonoscopy. Ileocaecal valve maybe oedematous or
deformed. Nodules, ulcers, pseudopolypoid folds and strictures maybe seen. Multiple biopsies are
taken.
 Abdominal paracentesis and ascitic fluid examination, laparoscopy with biopsy, needle biopsy of
peritoneum, diagnostic laparotomy are useful in confirming the diagnosis.
 Laparoscopy reveals tubercles on the bowel serosa, multiple strictures, high caecum, enlarged lymph
nodes, areas of caseation and ascitis. Lymph node and peritoneal biopsies taken.
 Peritoneal fluid is exudative, with lymphocytes typically predominating. A serum-ascitis albumin
gradient (SAAG) is usually <1.1 g/dl. Acid-fast smear is seldom positive, and culture is positive in only
25% cases. An elevated adenosine deaminase level in ascitic fluid may be helpful. Analysis of
peritoneal fluid by PCR may also be diagnostic, although sensitivity is low. Cultures of ascitic fluid
maybe helpful. In absence of other foci of tuberculosis, peritoneal tissue must often be obtained to
make the diagnosis.
 Obstruction- gross dehydration. Plain X-rays – typical small bowel obstruction.
 Appropriate body fluids / tissues must be obtained for microbiological and histological examination,
with the aid of ultrasound, CT or MRI scanning. Tissue biopsies should be divided and a fresh
specimen sent to microbiology, and one in formalin to histology. Tissue is better for culture than
necrotic material and old pus.
 Culture of the organism with subsequent testing for drug sensitivity from clinical specimens is the
cornerstone of diagnosis and ultimate treatment: this is particularly important with the emergence of
drug resistant TB, as ‘blind’ therapy in the absence of sensitivity testing may increase the risk of multi-
drug resistance.
 Genetic techniques. The polymerase chain reaction (PCR) – rapid detection of low levels of infection.
Possibility of immediate probing for known drug-resistant genes. PCR positivity in sputum may persist
during treatment and after clinical cure. Major role of PCR is to determine drug sensitivities in culture
and smear-positive specimens.
 Serodiagnosis. Serodiagnostic techniques do not perform well enough for routine use. Alterations in
antibody levels over time are also not a useful guide to clinical response to treatment.

Treatment
 If no diagnostic results are forthcoming in patients in whom tuberculosis is a possibility, the clinician
may reasonably resort to a trial of therapy. A diagnostic trial of therapy should last at least 4 weeks.
Improvement of symptoms and a decrease in the acute phase response (ESR, CRP, etc) are
sufficient indication to move from the diagnostic trial to full therapy.
 Ideally should be under combined care of physician and surgeon.
 Vigorous supportive and full course of anti-tubercular chemotherapy.
 The aim of multidrug regimens is to kill M tuberculosis, interrupt transmission by rendering the patient
noninfectious, and prevent morbidity and death by curing patients with TB, whilst preventing the
spontaneous emergence of drug-resistant mutants. Patients should never be prescribed fewer than
three drugs initially, and seldom fewer than four if there is any chance of resistance or a history of
previous therapy irrespective of the sensitivity of the organism involved.
 Sputum smears that are positive after 3 months of treatment when the patient is known to be
adherent are indicative of treatment failure and possible drug resistance. The isolate should be tested
for susceptibility to first and second line agents. A cardinal rule is always to add more than one drug
at a time to a failing regimen.
 M bovis is characteristically resistant to pyrazinamide.
 Once diagnosis is established, surgery is deferred if possible until the results of chemotherapy have
been assessed.
 On completion of medical treatment, patient’s small bowel is reimaged to look for significant strictures.
 If patient has recurrent subacute intestinal obstruction, limited bowel resection / strictureplasty is
done.
 Emergency patient – difficult and challenging situation. Poor socioeconomic background, poor
nutritional status, late presentation of acute distal small bowel obstruction, dehydrated, anaemic,
 active pulmonary tuberculosis. Vigorous resuscitation required. At laparotomy, minimum life-saving
procedure is carried out. Chemotherapy and nutritional care. Monitored by inflammatory markers,
weight gain, and negative sputum culture.
 Perforation peritonitis treated by resuscitation and resection of affected segment, and anastamosis or
exteriorization is done followed by restoration of bowel continuity after full course of anti-tubercular
chemotherapy and improvement in nutritional status.

Comparison of assays used in the diagnosis of active tuberculosis

Clinical laboratory Diagnostic Advantages Limitations

question assay
Are mycobacteria Culture on Gold standard for isolating M Viable growth takes 3-8
present in a clinical solid media tuberculosis. Provides organisms wk
specimen? for speciation, strain identification,
susceptibility testing.
Culture in Sensitivity / specificity similar to Does not detect mixed
liquid broth solid media. Provides organisms cultures.
for speciation, strain identification,
susceptibility testing. Growth
detected in 7-21 days.
Acid-fast Same-day results. Simple Less sensitive than
stain technology. Inexpensive. culture. Requires 10000
organisms/ml. Cannot
distinguish M
tuberculosis from other
mycobacteria.
Nucleic acid Same day results. Sensitivity Advanced laboratory
amplification intermediate between AFB stain techniques. Cannot
(polymerase and culture. distinguish viable from
chain dead organisms. Culture
reaction – needed for speciation,
PCR) strain identification, and
susceptibility testing.
Is mycobacteria Nucleic acid (see above) (see above)
isolated a member of amplification
M tuberculosis Nucleic acid Results available in 2 hrs. Requires at least 105
complex? (M probes Sensitivity / specificity approach organisms.
tuberculosis, M 100%.
bovis, M bovis-BCG, BACTEC Provides preliminary identification
M africanum, M assay of M tuberculosis.
microti, M canetti) High- Same day results. Sensitivity /
performance specificity approach 100%. Can
liquid distinguish M bovis-BCG from
chromatogra other members of M tuberculosis
phy (HPLC) complex.
To which species of Colony Classic approach for speciation of Time consuming and
M tuberculosis morphology M tuberculosis. labor intensive.
complex does the and
isolate belong? biochemical
assays.
PCR May rapidly distinguish among M Not yet commercially
genomic tuberculosis complex species. available.
analysis
Do different M Genotyping Sophisticated assay
tuberculosis isolates available only in
represent the same specialized centers.
strain?
Is an M tuberculosis Agar Quantifies proportion of Requires as long as 8 wk
isolate drug proportion organisms resistant to a drug.
 resistant? method
Liquid Results within 5-14 days. Does not quantify
BACTEC proportion of resistance.
method
Molecular Allow same-day determination of Needs to be validated.
tests for drug resistance. Most promising
chromosomal for rifampicin resistance
mutations mutations.
associated
with drug
resistance

Drug resistant TB
 Multidrug-resistant TB (MDR-TB) – bacilli resistant at least to isoniazid and rifampicin.
 Extremely drug-resistant TB (XDR-TB) in which MDR-TB is compounded by additional resistance to
the most powerful second-line anti-TB drugs (fluoroquinolones and at least one of the injectable drugs
amikacin, kanamycin and capreomycin).
 Drug resistant TB can be either primary or acquired. Primary drug resistance is that which develops in
a strain infecting a patient who has not previously been treated. Acquired resistance develops during
treatment with an inappropriate regimen.
 Drug-resistant TB can be prevented by adherence to the principles of sound therapy: the inclusion of
at least two bactericidal drugs to which the organism is susceptible, the use of fixed-drug combination
products, and the verification that patients complete the prescribed course.
 Acquired rifamycin resistance is seen almost exclusively in patients with advanced AIDS who receive
intermittent antituberculosis therapy. HIV-infected patients with fewer than 100 CD4 Tcells/mm 3
should not receive once- or twice-weekly regimens. These patients should receive daily therapy
during the intensive phase, and daily or thrice-weekly doses during the continuation phase.

Impact of HIV
 HIV seropositive patients are more susceptible to infection by M Tuberculosis.
 Reactivation of tuberculosis occurs at least 10 times more frequently.
 HIV predisposes to atypical, nodal and extrapulmonary disease. Upto two-thirds of HIV-infected
patients with TB may have both pulmonary and extrapulmonary TB, or extrapulmonary TB alone.
 Diagnosis of TB maybe unusually difficult. Overall, sputum smears maybe positive less frequently
among TB patients with HIV infection. There are also a variety of HIV-related pulmonary conditions
mimicking TB. Atypical radiographic findings, lack of classic granuloma formation in the late stages,
and a negative tuberculin skin test maybe seen.
 In general, standard treatment regimens are equally efficacious in HIV-negative and HIV-positive
patients. Current recommendation of antituberculosis therapy is to treat for the same duration
regardless of HIV status.
 Three important considerations are relevant to TB treatment in HIV-infected patients-
a) Increased frequency of paradoxical reactions.
b) Drug interactions between ART and rifamycins.
c) Development of rifampin monoresistance with widely-spaced intermittent treatment.
 Exacerbations in systemic or respiratory symptoms, signs, and laboratory or radiographic
manifestations of TB – termed the immune reconstitution inflammatory syndrome (IRIS) – have been
associated with the administration of ART.
 Adverse drug effects maybe more pronounced in HIV-infected patients.
 Rifampin, a potent inducer of enzymes of the cytochrome P450 system, lowers the serum levels of
many essential drugs used in ART. In such cases, rifabutin, which has a much less enzyme-inducing
activity, has been recommended in place of rifampin.
 Patients with HIV-associated TB whose immunosuppression in advanced (CD4+ cell counts of
<100/yl) are prone to treatment failure and relapse with rifampin-resistant organisms when treated
with ‘highly intermitttent’ (ie, once- or twice-weekly) rifamycin containing regimens. Consequently, it is
recommended that these patients receive daily therapy for at least the initial phase.

Vaccines
 Live attenuated BCG vaccine – leads to a local immune response and ultimately scar formation.
 Poor correlation between tuberculin reactivity after vaccination and protection against disease.
 BCG vaccine efficacy is about 60-80%. Most effective in preventing serious disease in children.

False-negative tuberculin reaction

 General illness. Protein malnutrition. Sarcoidosis. Intercurrent viral infections. Vaccination with live-
virus vaccines (measles, smallpox). Reticulendothelial disease. Corticosteroid therapy.
 During the first 3 to 9 weeks of initial infection the tuberculin may be negative.

REFERENCES
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2009. p. 275-293.
2. Freidland JS. Tuberculosis and other mycobacterial infections. In: Cohen J, Powderly WG, Opal SM, editors. Infectious
Diseases. New York: Mosby Elsevier; 2010. p. 309-27.
3. Fitzgerald DW. Mycobacterium Tuberculosis. In: Mandell GL, Bennet JE, Dolin R, editors. Infectious Diseases.
Philadelphia: Churchill Livingstone; 2010. p. 3129-64.
4. Raviglione MC, O’Brien RJ. Tuberculosis. In: Longo DL et al, editors. Harrison’s Principles of Internal Medicine. New
York: McGraw Hill; 2012. p. 1340-58.
5. Datta PK, Lal P, Bakshi SD. Surgery in the Tropics. In: Williams NS, Bulstrode CJK, O’Connel PR, editors. Bailey &
Love’s Short Practice of Surgery. London: Hodder Arnold; 2008. p. 49-70.
 Asymptomatic Gall Stones
R S Mohil, Shailendra Singh

From inability to leave well alone

From too much zeal for what is new and contempt for what is old;
From putting knowledge before wisdom, science before art, cleverness before common sense;
From treating patients as cases; and
From making the cure of a disease more grievous than its endurance,
Good Lord, deliver.
Sir Robert Hutchinson (1871- 1960)

Gallstone disease is one of the most common gastrointestinal disorders we encounter in our daily
practise. With the advent of laparoscopic surgery there is a feeling amongst the surgeon and to a
certain extent patients that cholecystectomy can now be done with minimal morbidity and mortality.
That may only be partly true as outcomes are related to many variables and the incidence of common
bile duct injuries have increased with the advent of laparoscopic cholecystectomy. Furthermore,
performing a surgery, which may not be required, adds to the financial burden of the health care
system.

Management of asymptomatic gallstones (AGS) poses a dilemma. Managing a very young patient
with AGS gallstones living in a high gall bladder cancer belt of North India, especially Delhi may be
tricky, as we don’t have much data to fall back upon. There is general consensus that asymptomatic
gallstones should not undergo cholecystectomy but the recommendation is debatable in certain
groups1.

Historical background

Reports on gallstone disease are mentioned as early as 2000 BC, when the Babylonians first
described bile duct system 1, 2. Galen (A.D 130-200) stated that humans have a single bile duct, or
perhaps paired bile ducts. Gallstones were also found in a Mummy from 21st dynasty, 1085-945 BC.
The Italian physician, Gentile de Foligna was the first one to describe gallstone in man during 14 th
century. In 16th century, Vesalius and Fallopius described gallstones in the gallbladders of dissected
human bodies (Schwartz, 1981). Morgagni (1769) reported deformations of the gallbladder; may have
been first to see torsion of the gallbladder. Filipi, Mall, and Reosma (1985) performed first animal
laparoscopic cholecystectomy. Mühe Successfully treated patients by laparoscopic cholecystectomy
but Mouret (1987) is generally credited with first human laparoscopic cholecystectomy3.

Incidence of Gallstones

Gallstone disease is one of the commonest digestive disease and its prevalence is related to many
factors, including age, gender, and ethnic background. The overall prevalence of GS disease in most
4,
developed nations, including US, UK, Italy and the Scandinavian nations, is between 10% and 20%
5
. Women are three times more likely to develop gallstones than men, and first-degree relatives of
6
patients with gallstones have a twofold greater prevalence . The prevalence of gallstones increases
with age, at the age of 65, about 30% of women have GS, and by the age of 80 years, 60% of both
males and females have GS. The large majority of these (70–85%) are asymptomatic7.

Natural history of the Cholelithiasis

With increased availability and more frequent use of ultrasound, CT scan and MRI etc the incidence
of asymptomatic gallstone disease has increased significantly. However, the natural history of
gallstone disease indicates two thirds of gallstones remain asymptomatic throughout their life. For
unknown reasons, some patients progress to a symptomatic stage, with biliary colic caused by a
stone obstructing the cystic duct. Symptomatic gallstone disease may progress to complications
related to the gallstones.26*
Complications
???  Acute Cholecystitis
 Empyema
 Gangrenous GB
Symptomatic  Cholangitis
ASG
Gall Stones  Pancreatitis
 Cholecystoenteric fistula
 Obstructive jaundice
 Gallstone ileus
 GBC??
Approximately 3% of asymptomatic individuals become symptomatic per year (i.e., develop biliary
colic). Once symptomatic, patients tend to have recurring bouts of biliary colic. Complicated gallstone
disease develops in 3 to 5% of symptomatic patients per year6. However it is very rare for an
asymptomatic gall stones to develop complications without experiencing biliary pain even once.
In a study in Denmark, asymptomatic gallstones were detected by ultrasound screening in a
population, which were then followed up for 11 years. Complication rates (acute pancreatitis,
8, 9
obstructive jaundice, cholecystitis) were 0.2 - 0.8% per annum . A longitudinal follow – up study of
asymptomatic gallstones at the University of Michigan, showed that over a 20 year period only 18%
developed biliary pain and that the mean yearly probability of the development of biliary pain is 2%
during the first 5 years; 1% during the second 5 years; 0.5% during the third 5 years; 0% during
the fourth 5 years. A very important observation noted in that study, was that no person ever
presented a biliary complication as an initial manifestation of biliary disease. None of these individuals
died because of gall stone disease10, 11. Although gallstones are associated with gallbladder cancer
(GBC), the risk of developing cancer in patients with AGS is < 0.01%—less than the mortality
associated with Cholecystectomy.

In a recent study by Malte Schmidt, Trygve Hauske, 134 patients with gallstones in 1983 were traced
for follow up for a period of 24 years. The rate of cholecystectomy was low in a conservative setting
12
and no adverse events could be ascertained from such a policy . Schmidt et al 2011 again studied
the feasibility and safety of observation after extended long-term follow-up in a RCT. A total of 137
patients (40.5% of those assessed) were randomized to observation or cholecystectomy group and
followed up for 14 years. In this particular study they concluded that cholecystectomy was the
preferred treatment after extended long-term follow-up, but conservative management for
symptomatic gallstone disease is an alternative to surgery in the elderly 13. However the sample size
was too low to make any recommendations and probably this is the only study with this conclusion.
According to the National Institute of Health consensus conference report, 10% of patients develop
symptoms during the first 5 years and 20% by 20 years14. Thus over a 20-year period, about two
thirds of asymptomatic patients with gallstones remain symptom free.

Definition of AGS
“Gallstones that cause no gallstone related symptoms or complications and are diagnosed during
routine ultrasound/CECT/MRI, or during the course of surgery for other abdominal conditions are
called asymptomatic gallstones”15. Attributing “dyspeptic symptoms” like bloating, intolerance to fatty
food, belching, abdominal fullness or discomfort to GS can be erroneous.

Are there patients more prone to develop symptoms/ complications?

It is very difficult to define such groups but certain factors have been attributed to confer higher risk
progression from asymptomatic to symptomatic and or complications include7, 16-18.
 Age< 55 years
 Smoking
 Female sex
 Obesity
 Presence of 3 or >3 GS
 Floating GS
 Life expectancy > 20 years
 Calculi > 2cm
 Patent cystic duct
 Non functioning GB
 Perioperatively detected GS

What about GB cancer risk?

GBC risk is increased in patients with19,20
 Polyps > 1cm & associated GS
 Calcified (Porcelain) GB (13 – 22%)
 Large stones > 3cm (10 times)
 Xanthogranulomatous cholecystitis
 GB packed with stones
 Ethnic groups in high incidence areas.
Besides this there are special groups of patients which merit special attention.

1. Sickle cell anaemia

Veno-occlusive crises that occur in these patients may mimic biliary complications of gallstones (e.g.
acute cholecystits etc.) and pose serious problems in the early diagnosis resulting in high incidence of
complications. The onset of gallstones at a young age in sickle-cell disease raises the lifetime risk of
biliary complications. Also, surgery of gallstones in emergency setting is usually associated with
increased morbidity and mortality. Prophylactic cholecystectomy has a distinct role in this subset of
patients15, 21.

2. Immune-compromised/ Organ transplant individuals

Includes individuals suffering from chronic debilitating diseases and who are on long-term steroids
etc. The progression of disease is rapid and acute symptoms and signs may be masked in these
individuals that lead to a delay in the diagnosis and frequent presentation with serious complications,
which ultimately results in increased morbidity and mortality. The indications of cholecystectomy for
patients with HIV are same as general population but in patients with AIDS, it is recommended that
the elective operations should be postponed (If possible, as there is no contraindication for surgeries
indicated for life threatening conditions) with the aim of starting the patient on antiretroviral
medication, as operating on a patient with a high CD4 count and low viral load is beneficial.
Prophylactic cholecystectomy has been advocated in patients with asymptomatic gallstones prior to
organ transplant, most commonly heart transplant candidates, due to high rates of symptomatic
gallstones and operative morbidity and mortality post-transplant. Pretransplant laparoscopic
cholecystectomy can be performed safely in stable patients, including those awaiting a heart
transplant. Also the immune-suppressive drugs like cyclosporine and tacrolimus that are used in post-
transplant period have been shown to be prolithogenic.

Recent studies in patients with renal transplant suggest no increase in morbidity, mortality or graft
loss with expectant management of AsGS and cholecystectomy only when they become
symptomatic15,25,26. Kao et al. reported a comparative mortality of 5:1,000 deaths for prophylactic
postcardiac transplant cholecystectomy compared to a figure of 80:1,000 deaths and 44:1,000 deaths
for pretransplant cholecystectomy and expectant management, respectively27. By and large, most
recent studies report favourable results of expectant management in patients undergoing cardiac and
bone marrow transplantation and suggest that cholecystectomy after onset of symptoms is safe28.

3. Diabetes Mellitus
Previously diabetic patients with gallstones were thought to have a higher incidence of gallstone
disease and more prone to develop complications29. This led some authors to advocate prophylactic
cholecystectomy in asymptomatic diabetic patients30,31. More recent studies have now confirmed that
prophylactic cholecystectomy for asymptomatic gallstones in diabetic patients does not increase life
expectancy or improve quality of life. Recommendation at present is that Diabetic patients should
undergo cholecystectomy for the same indications as for the general population albeit early surgery is
32-35
highly recommended for diabetic patients with symptomatic gallstones .

4. Common bile duct stones

The individuals with asymptomatic gallstones with associated stones in the common duct are at a
higher risk of developing potentially severe complications. Prophylactic cholecystectomy is highly
recommended in this group15,36.

5. Incidental cholecystectomy for perioperative discovery

Role of prophylactic cholecystectomy has been discussed in a subgroup of patients who are planned
for abdominal surgery unrelated to gallbladder and asymptomatic gallstones are discovered
incidentally in the perioperative period. It has been observed that the incidence of biliary symptoms
and associated complications increase after laparotomy for conditions unrelated to biliary tract.
Concomitant cholecystectomy seems to benefit this subset of patients. The goal of concomitant
cholecystectomy is to keep the morbidity to a minimum acceptable level for which a proper patient
selection is necessary. Concomitant cholecystectomy should not add to the risk and contraindicated
if any kind of prosthesis is used during the surgery. If the gallstones are discovered in the
preoperative period, the purpose and safety of concomitant cholecystectomy should be discussed
with the patient with informed consent on possible complications related to cholecystectomy as well.
Simple cholecystectomy is now a widely accepted procedure for incidental gallstones during
laparotomy for some unrelated abdominal procedure33.

6. Individuals with ASG with no immediate access to health care facilities

Prophylactic cholecystectomy has also been recommended in those groups or individuals who have
37
no immediate access to health care facilities (e.g. missionaries, military personnel, peace corps
workers, relief workers).

7. Cirrhosis of liver
Cirrhosis of liver has been described as a risk factor for the development of gallstones, commonly
bilirubinate stones due to chronic hemolysis caused by ongoing hepatic necrosis and hypersplenism.
However in most of these patients the gallstones remain asymptomatic 38-40. Despite high prevalence
of gallstones in this subgroup, majority of the individuals do not go on to develop symptoms of
gallstone disease. The risk is higher in women with cirrhosis especially with a positive family history
and advanced age as compared to males with alcoholic cirrhosis39. There is a risk of high morbidity
with cholecystectomy in these patients, especially in the advanced stages of cirrhosis. Prophylactic
cholecystectomy is not justified in cirrhotic patients with AsGS, but close follow-up with early elective
41.
operation when symptoms supervene should be recommended

8. Prophylactic removal of GB without stones

Patients with the short-bowel syndrome have a significant risk for cholelithiasis and early development
of biliary complications if the intestinal remnant length is less than 120 cm, total parenteral nutrition is
42
required, and the terminal ileum is resected. Prophylactic cholecystectomy is recommended .
Despite increase in incidence and symptoms of gallstones in patients who underwent
esophageal/gastric resections, laparoscopic Roux-en-Y gastric bypass it cannot generally be
recommended to remove a normal acalculous gallbladder during upper GI surgery as late
cholecystectomies can be performed safely and because the additional calculated morbidity for these
operations is lower than the morbidity for simultaneous cholecystectomy43,44.

9. Gallbladder cancer
A true cause to effect relationship has not been proved as yet between GBC and presence of
gallstones. As stated earlier with increasing number and size the risk of GBC also rises. Progressive
changes in GB wall from chronic cholecystitis, hyperplasia, metaplasia, dysplasia, carcinoma in situ to
invasive cancer have been reported from Chile – the time course of which lends credence to a
gradual progression from chronic inflammation to dysplasia to invasive carcinoma45. The incidence of
GBC is also reported to be higher in patients with xanthogranulomatous cholecystitis and Mirizzi’s
46-48
syndrome – both associated with long-standing GS disease . In many geographical areas where
GS are common do not have a high prevalence of GBC and that not all GBCs are associated with
stones15.

Traditionally the risk of developing GBC in individuals with asymptomatic gallstones is estimated to be
approximately <0.01. There are, unfortunately, no large studies on the natural history of AsGS from
high-GBC-incidence areas. Individuals, especially females from Chile, have been reported to develop
49,50
symptoms of GS disease at a younger age and >50% of them become symptomatic . The Pima
50
Indians of the United States, especially females, have an unusually high incidence of gallstones . In
fact, since Chile has one of the highest incidence rates of GBC in the world, cholecystectomy is
usually advised for GS between the ages of 30– 40 years in women and 40–50 years in men,
irrespective of the presence or absence of symptoms 50. In contrast, the Masai of East Africa have a
very low incidence of cholelithiasis51. No data on natural history of AsGS is, however, available from
India.

In one study by Randi G et al in 2006 showed that Delhi in Northern India has the highest incidences
of gallbladder cancer in the whole world. According to this study, in Delhi, between 1993-1996, the
incidence rates per million population was found to be 21.5 for females and 7.1 for males52,53.

Prophylactic Cholecystectomy

It would be very rare for AGS to present with complications without first experiencing even one
episode of biliary colic. The real challenge in decision making would be to strike a balance between
projected prognosis of expectant management versus the risk of possible complications and the cost
involved for any given patient. It would be appropriate if the health benefits exceed its health risk by a
wide margin54.

Every procedure is associated with potential complications and laparoscopic surgery is no exception.
The possible complications including the most dreaded bile duct injuries (BDI) are still significant with
both laparoscopic and open cholecystectomy. Most series quote incidence rates of 0.3% for open
cholecystectomy, whereas the incidence of BDI during laparoscopic cholecystectomy is 0.4% or
55,56
higher depending on the experience of the surgeon, difficulty during surgery etc .

Table 1: Some common complications of laparoscopic cholecystectomy.

Complication Incidence (%)
Haemorrhage 0.11-1.97
Bile duct injury 0.26 -2.7
Bile leak 0.3-0.9
Retained /spilled stones 2.3
Peritonitis 0.2
Wound infection 1
Incisional hernia 0.1-0.3
Pneumoperitoneum related 0.2
complications
Trocar related complications 0.2

Who should then undergo LC/ Cholecystectomy for ASG?

Identification of those individuals with increased risk of developing symptomatic gallstone disease;
complications or gallbladder carcinoma would definitely justify the role of prophylactic
cholecystectomy in individuals with ASG15.

Table 2: Possible Indications for Prophylactic Cholecystectomy in ASG

Definite (sufficient data to make reasonably firm recommendations)

Porcelain gallbladder
Child with Sickle cell Anaemia
Incidental perioperative discovery
ASG with common bile duct stones
Polyps > 1 cm, single, and/or sessile with GS
Individuals with ASG with no immediate access to health care facilities

Possible (insufficient data to make definite recommendations)

Gallstones >3 cm, Floating small multiple stones, GB packed with stones
Xanthogranulomatous cholecystitis,
On Total parenteral Nutrition
Immunocompromised individuals
Patients requiring Organ transplant

However, it is important to understand that the decision to operate has to be taken in each individual
case based on various factors including age, ASA grade, any comorbidities etc. For example an 80
years plus patient with 3cm ASG , is diabetic and suffered a myocardial infarction in recent past may
not require an aggressive management compared to a young 30 years old female with similar sized
ASG with no associated comorbidities.

Is advising prophylactic cholecystectomy to ASG individuals in high GBC incidence areas cost
effective?
As discussed earlier such a practice is indeed being recommended in Chile and recommended by
some Indian authors too. What it would mean in our context as North India has almost a similar risk?
Going by the known prevalence quoted earlier, ASG among general population in Uttar Pradesh
57
(nearly 20 crores inhabitants by census 2011 ) would be approximately 4 crores ( 20%). The
 expected incidence of GB cancer in Delhi as mentioned earlier is anyway between 2-40/lakh general
population58. This means that in U.P (if we consider the same incidence rate) nearly 80,000 patients
(40 /100,000 x 20 crores) will develop a gallbladder cancer.

The average cost of a cholecystectomy for a patient is a minimum of nearly Rs. 10,293 (CGHS rates,
Ministry of Health & Family welfare website http://mohfw.nic.in). That means if prophylactic
cholecystectomy is routinely advised in patients with ASG as a means to prevent GB cancer, total
cost of preventing GB cancers in U.P alone would come around (4 crores x 10,000) Rs. 40,000
crores. Added to this would be the possibilities of various complications including the bile duct injuries
(BDI). The expected number of BDI alone (0.4%- 2.7% ) associated with LC could be approximately
1.6 lakhs (4 crores x 0.004). In fact the expenditure on health in India in the year 2012-13 was
approximately Rs.16,043 crores, much less than what will be required to treat ASG in UP alone.
(http://ccahealth.gov.in/Health/ViewAccountDetails). Further developing GBC without even suffering
one episode of biliary pain is extremely rare. Therefore in a developing country like India with limited
resources, operating on all ASG is neither desirable nor is it feasible.

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 Surgery in Acute Pancreatitis
Rajneesh Kumar Singh, Rakesh Kumar Singh

Introduction
Acute pancreatitis remains an unpredictable, potentially lethal disease with significant morbidity and
mortality rates. New insights in the pathophysiology of acute pancreatitis have changed management
concepts. In the first phase, characterized by a systemic inflammatory response syndrome, organ
failure, not related to infection but rather to severe inflammation, dominates the focus of treatment. In
the second phase, secondary infectious complications largely determine the clinical outcome. As
infection is associated with increased mortality in acute pancreatitis, numerous prophylactic strategies
have been explored in the past two decades. Antibiotic prophylaxis has been the subject of many
RCT's without showing convincing evidence of their efficacy. Probiotics, although theoretically
capable of lowering the rate of infection, also had no effect on infectious complications, and
consequently, no effective strategy to lower the rate of infectious complications is currently available.
All the interventional techniques have in common their aim to lower the invasive character,
hypothesizing that lowering the surgical trauma will improve survival and lower complication rates.
Recent advances include postponing intervention as a strategy to facilitate necrosectomy and
improve prognosis and the "step-up approach" in case of infected necrosis. The step-up approach
includes percutaneous catheter drainage as the first step, to be followed by necrosectomy, either
through a minimally invasive approach or by open necrosectomy, as the next step.

Historical perspective of surgery in acute pancreatitis

Surgical management of acute pancreatitis changed as understanding of pathophysiology changed.

Moynihan in 1925 advised for exploration of the lesser sac, aspiration of peripancreatic fluid, incision
of the pancreatic capsule to allow drainage, and cholecystostomy. Altemeier and Alexander in
described an operative approach to patients with pancreatic abscess. Some authors recommended
increasingly aggressive surgical approaches, including pancreatectomy. In the 1970s, Warshaw and
colleagues adopted a policy of sump drainage of the pancreas with cholecystostomy, gastrostomy,
and feeding jejunostomy for patients with severe acute pancreatitis or pancreatitis with subsequent
deterioration. In the 1980s, in addition to the use of peritoneal lavage or sump drainage of the
pancreatic bed, the use of surgical debridement of the necrotic pancreas was recommended by many
authors.

Table 1: Indications for surgical or interventional therapy in acute pancreatitis

 Suspected intraabdominal catastrophe (perforation, ischemia)
 Gallstone pancreatitis
o ERCP for obstructive jaundice
o Cholecystectomy to prevent recurrent attack
 Infected pancreatic necrosis
 Severe sterile pancreatic necrosis
 “Organized” pancreatic necrosis
 Delayed complications (pseudocyst, fistula)

Indication of surgery in acute pancreatitis

Infected Pancreatic Necrosis

For patients with pancreatic necrosis who develop superinfection of the necrotic parenchyma,
mortality is virtually 100% without débridement [1]. With surgical débridement of the pancreas,
mortality remains up to 15- 30%.[2]. Infected pancreatic necrosis has therefore been considered an
unequivocal indication for aggressive intervention. Diagnosis of infected pancreatic necrosis usually
requires CT or guided percutaneous FNA of the pancreatic necrosum, as the clinical distinction
between infected and sterile pancreatic necrosis can be impossible. Guided FNA of the pancreas is
standard in most centers for patients with pancreatic necrosis who develop end-organ dysfunction or
who fail to improve clinically. It may require several repeat aspirations if clinically indicated, as one or
several negative aspirations do not rule out the future development of infection. The presence of
microorganisms on Gram stain of the pancreatic aspirate has generally been considered an indication
for urgent intervention. Patients with infected pancreatic necrosis have typically been thought to
require urgent debridement and/or drainage by surgical or radiographic means.
Timing of surgical intervention in infected pancreatic necrosis is questionable[3]. Trends are towards
the initial conservative therapy, including antibiotic therapy and maximal supportive care [4]. Surgical
therapy, when required, was often delayed to a later stage of disease, when the systemic
inflammatory response had been stabilized and necrotic pancreas had become demarcated. There is
suggestion that all patients with pancreatic necrosis should be initially managed with maximal medical
support, regardless of the status of infection. Initial therapy would necessarily include broad-spectrum
antibiotics, with earlier operative therapy reserved for those with clear clinical deterioration [5].

The concept of delayed intervention in the setting of known or suspected infected pancreatic necrosis
is not universally accepted. As early surgical débridement for infected pancreatic necrosis has been
considered standard of care, no data exist for the use of longterm antibiotic therapy in this setting.
However, the experience is informative in this regard. Three meta-analyses of prophylactic antibiotic
therapy [6-8] suggested a trend to decreased mortality or a statistically significant decreased mortality
with antibiotics. Routine use of prophylactic broadspectrum antibiotics for pancreatic necrosis leads to
a significant change in bacterial flora, from predominantly Gram-negative organisms to an increase in
resistant bacteria, Gram-positive organisms, and fungi [9–12]. The use of antibiotics to delay surgical
therapy in the setting of infected pancreatic necrosis has not been widely tested and prompt surgical
treatment for infected necrosis remains the gold standard of therapy. Delayed surgical therapy of
infected pancreatic necrosis has been facilitated in some cases by the use of percutaneously placed
drainage catheters[13]. This concept has the theoretical benefit of avoiding major surgical intervention
precisely when pancreatic inflammation is most severe. Aggressive surgical therapy might therefore
be temporized until demarcation of the pancreatic necrosum has occurred, thus facilitating the
procedure.

Severe sterile necrosis

The role of aggressive surgical debridement in cases of severe sterile pancreatic necrosis is less
clear. Most patients with sterile pancreatic necrosis will respond to supportive care without the need
for surgery. However, some patients progress to a more aggressive disease process with organ
failure while receiving maximal medical support, despite a lack of demonstrable infection. Because of
this several authors have suggested that patients with progression of disease or even with failure to
improve might benefit from surgical débridement, regardless of the status of infection [14,15]. Thus, a
growing consensus is sterile pancreatic necrosis should be treated nonoperatively, however some
patients with severe sterile necrosis and clinical deterioration may require surgical intervention but this
is debatable. [16]. There is no specific validated criteria for identifying those patients with sterile
pancreatic necrosis who might benefit from débridement. Pancreatic necrosis greater than 50% of the
pancreatic parenchyma [14] or rapid clinical deterioration with multiple organ failure despite maximal
intensive (17) has been suggested as a selection criterion for surgery. [18,19], The absolute
indications for operative therapy in patients with sterile necrosis have been difficult to define. As there
are no markers to identify which, if any, patients with sterile necrosis might benefit from intervention,
significant surgical restraint is warranted when
approaching these patients.

According to JPN guideline [20], patients with sterile pancreatic necrosis should be managed
conservatively and undergo surgical intervention only in selected cases, such as those with
persistent organ complications or severe clinical deterioration despite maximum intensive
care.

For patients with acute pancreatitis who do eventually require intervention, a general consensus has
emerged supporting delayed surgical therapy if possible. Preoperative stabilization of severe organ
dysfunction may contribute to lower observed perioperative mortality, as might the improved
demarcation of necrotic tissue and ease of differentiating necrotic from viable pancreas.
Approximately 4 weeks after the onset of pancreatitis has been viewed as an optimal time to pursue
necrosectomy, and is associated with decreased local and systemic complications [16].

Organized pancreatic necrosis

Patients with sterile pancreatic necrosis who do not progress to infection, most improve to the point
where no further intervention is required. However, a subset of patients experience a prolonged
clinical course marked by persistent pain, general malaise, and inability to eat. Such patients
experience a difficult and lengthy recovery. The need to eventually intervene surgically in this group of
patients has gained increasing recognition. This pathologic process and the associated clinical
phenomenon of malaise have been described by Baron et al. as “organized pancreatic necrosis” [22].
The precise indications, timing, and mode of intervention have not been defined for these patients.
Some suggested that there is no added benefit to delaying surgery longer than 4 weeks from the
onset of symptoms [23]. Nonrandomized studies have shown improved outcomes with late versus
early débridement [21] and operative débridement is significantly facilitated by the demarcation of
healthy from necrotic tissue.

Surgical emergency
Rarely, patients with acute pancreatitis need surgical exploration for reasons other than pancreatic
necrosis. The conservatively managed patient with known pancreatic necrosis may develop evidence
of an unrelated surgical emergency, such as perforation or ischemic bowel. Some patients may
require emergency laparotomy for suspicion of such an abdominal catastrophe at initial presentation.
Clear indications for exploration, such as peritonitis, ischemic bowel and GI bleed must be
recognized. When laparotomy is undertaken for suspected intraabdominal emergency and only signs
of pancreatitis are identified, a dilemma exists regarding surgical management. Drainage alone is
likely to merely increase the risk of subsequent infection. While pancreatic débridement might prevent
future superinfection of the necrotic pancreas and potentially avoid future operation, such a procedure
early in the course of pancreatitis can be fraught with difficulty and has high risk of hemorrhage. In
this situation, only clearly necrotic and demarcated tissue should be débrided, followed by the
placement of drains in the pancreatic bed. If demarcation is not obvious, it may be best to simply
close the abdomen and continue conservative management.

Duodenal perforation or proximal bowel perforation usually heals spontaneously. Colonic pathology
(necrosis, perforation) complicating acute pancreatitis is known to be associated with high mortality
about 40 % or higher [24,25]. This colonic involvement is estimated to occur in 1% of all patients with
acute pancreatitis [26,27] and in 6-40% in those with the severe necrotizing form [24,28-31]. Colonic
perforation usually require surgery. The treatment of choice is resection of the involved segment of
the colon with construction of a (temporary) colostomy [29,31-33].Diversion of the small bowel,
leaving the colon in situ for later reconstruction has been suggested [28,32,34]. But if successfully
treated conservatively, pericolitis may cause secondary complications such as stenosis or fistula
during follow-up [35[.

Gallstone pancreatitis: Cholecystectomy

Gallstones are associated with acute pancreatitis in approximately 40–60% of cases. A significant
proportion of cases of idiopathic pancreatitis have occult biliary sludge as an etiology [36]. In patients
with gallstone pancreatitis who recover with medical management, recurrence of acute pancreatitis
can be seen in 30–60% of patients [37,38]. For this reason, cholecystectomy has been recommended
to prevent recurrent attacks. Cholecystectomy is recommended when the patient has recovered from
the acute episode of pancreatitis, preferably during the same hospital admission [39]. Alternatively, in
severe gallstone pancreatitis, cholecystectomy is recommended when the acute inflammatory
process has subsided enough to facilitate safe dissection [40,41]. For the patients who have
undergone ERCP with endoscopic sphincterotomy for biliary obstruction early in the course of acute
pancreatitis, indications for subsequent cholecystectomy are based on risks of subsequent
pancreatitis or biliary complications. While the short-term risk of recurrent pancreatitis is relatively low,
particularly if a large portion of the pancreas has necrosed, recurrent biliary complications occur in a
significant percentage. Cholecystectomy is therefore recommended to avoid recurrence of gallstone-
associated acute pancreatitis. Although endoscopic sphincterotomy alone may be an alternative in
poor operative candidates [42].

According to UK guideline on biliary pancreatitis and cholecystectomy, after an attack of mild acute
pancreatitis, patients with gall stones should undergo definitive treatment in order to prevent
recurrence of pancreatitis. Definitive treatment of gall stones will usually be by cholecystectomy,
either laparoscopic or open, unless there are significant risk factors for operative treatment. For unfit
patients, endoscopic sphincterotomy alone is adequate treatment. All patients who have gall stones
and acute pancreatitis require imaging of the bile duct. Definitive treatment should not be delayed
more than two weeks after discharge from hospital, and that it is preferable to achieve this goal during
the same admission. Cholecystectomy should be delayed in patients with severe acute pancreatitis
until signs of lung injury and systemic disturbance have resolved.
Surgery for complication of acute pancreatitis (pseudocyst, fistula)
Generally agreed indications for drainage treatment of pancreatic pseudocysts include (1)
accompaniment by symptoms, such as abdominal pain; (2) complication by infection or bleeding; (3)
increase in size during the observation period; (4) a diameter of 6 cm or more; and (5) no tendency to
decrease in size during at least 6 weeks of observation [20]. Indication 4 and 5 is debatable. In
present era, pancreatic pseudocyst can be managed by percutaneous, endoscopic or surgical
methods.

Pancreatic abscess
About 78%–86% of patients with pancreatic abscess can be managed by percutaneous drainage
alone [44,45]. When no improvement in clinical findings is observed after percutaneous drainage,
surgical drainage should be performed immediately instead of monitoring the clinical course.[46].

Surgical procedure for Infected Pancreatic Necrosis

Strategies for necrosectomy:-

Open approach:
a) Open necrosectomy with closed packing
b) Open necrosectomy with open packing
c) Open necrosectomy with continous postoperative lavage
d) Programmed open necrosectomy

Minimal invasive techniques:

a) Endoscopic techniques:
i) NOTES
ii) Necrosectomy through PEG
iii) Sinus tract endoscopy
b) Laparoscopic techniques:
i) VARD
ii) Single-port laparoscopic necrosectomy
iii) Retrogastric approach
iv) Transgastric approach
v) Transmesocolic approach
vi) Hand-assisted laparoscopic necrosectomy
c) Radiological techniques:
i) Transperitoneal drainage
ii) Retroperitoneal drainage
iii) Transmural drainage—stomach, duodenum
d) Step-up approach:
i) Radiological drainage
ii) Minimal invasive surgery
iii) Open surgery
Rationale for necrosectomy and débridement
The general rationale for necrosectomy of devitalized pancreatic tissue is based on two major
aspects.
a) Local focus control by removal of necrotic intrapancreatic and extrapancreatic tissue as well as
pancreatogenic ascites in order to interrupt the ongoing inflammatory process and the systemic
release of various inflammatory mediators that account for remote organ failure.
b) The preservation of remaining vital intact pancreatic tissue in order to decrease long-term
endocrine and exocrine functional impairment and quality of life.

Open Necrosectomy

The open necrosectomy, originally described by Beger et al., [47] consisted of a laparotomy through a
bilateral subcostal incision. After blunt removal of all necrotic tissue, two large-bore drains for
postoperative lavage were inserted, and the abdomen was closed.
Débridement and continuous closed Lavage
After division of the gastrocolic ligament the lesser sac is exposed and necrosectomy is either done
digitally or by careful use of instruments. After surgical débridement an extensive intraoperative
lavage is performed using 6–12 L of isotonic saline in order to clear the surface of the pancreatic bed
and the extrapancreatic spaces affected by fatty tissue necrosis. For postoperative continuous local
lavage large-bore single lumen (24–28F) and double-lumen (16–18F) catheters are placed into the
lesser sac and brought out through either side of the lateral abdominal wall at the level of the
retroperitoneal spaces. At the end of the procedure the gastrocolic and duodenocolic ligaments are
sutured to create a closed compartment for a regionally restricted lavage. Initial postoperative
continuous lavage uses 24 L/day of a commercial hyperosmolar potassium-free dialysis fluid (CAPD).
If the peritoneal cavity is also affected, local lavage is combined with short-term peritoneal lavage.
Lavage therapy is stopped when the effluent is clear without signs of active pancreatic enzymes
(amylase and lipase levels) or positive bacteriology.

Table 2: Results of necrosectomy and closed lavage

Reference Patients Preoperative Death Fistula Bleeding
severity
Larvin et al 14 5 (3-8) Ranson 3 (21%) 0 1 (7%)
[50] 17 (7-38) Apache II
Pederzoli et al 263 Not recorded 47 (18%) 22 (8%) 21 (8%)
[49]
Buchler et al 28 4 (0-7) Ranson 6 (21%) 8 (29%) 2 (7%)
[55] 13 (6-22) Apache II
De Waele et 17 7(±1.4) Ranson 9 (53%) 3 (18%) 0
al[52] 26(±9.3) Apache II
Wig et al[53] 58 8 (3-17) Apache II 17 (29%) 9 (16%) 8 (14%)
Besselink et 53 Not recorded 13 (25%) Not recorded 17 (32%)
al[55]
Farkas et 220 16 (11-32) Apache II 17 (8%) 24 (11%) 6 (3%)
al[54]
Rau et al [48] 285 5 (0-10) Ranson 72 (25%) 77(27%) 44 (15%)
11(0-28) Apache II
Total 938 184 (20%) 143 (16%) 99 (11%)

Debridement and open packing/staged laparotomy

The abdomen is entered through a midline or bilateral subcostal incision and the pancreas is
approached by dividing the gastrocolic ligament. After opening the peritoneum overlying the
pancreas, peripancreatic and pancreatic necrosectomy is performed by careful blunt finger dissection,
extensive lavage, and aspiration of debris. Vascular trauma should be avoided, especially of the
splenic and middle colic vessels and the inferior mesenteric vein. The left and right colonic flexures as
well as the pancreatic head should be mobilized to access the retroperitoneal extensions. CT images
are used as a “road-map.” Necrosis is removed as completely as possible, but hypervascular friable
tissue should not be disturbed in order to minimize bleeding. The débrided areas irrigated extensively.
After débridement, soft large-caliber drains are placed in the most dependent positions away from
large vessels, colon, and small intestine and externalized in the flanks. The cavities are packed with
gauze. When technically feasible, a cholecystectomy is performed since the presence or development
of biliary sludge and lithiasis is high. The abdomen is temporarily closed using a zipper, a prosthesis,
or adhesive plastic sheeting sewn to the fascial edges. Operative evaluation and débridement of
ongoing necrosis is repeated every 48–72 hours until devitalized tissue is removed and granulation
tissue starts to develop. The decision to repeat the procedure is based on the appearances at the end
of each operative session (significant necrotic material remaining) and/or on the images from
postprocedural contrastenhanced CT (persistent collections). When the cavities are collapsing and
lined by granulating tissue with no necrotic debris, further débridement is no longer needed. A large
drainage tube is left in the peripancreatic space with or without a lavage system, and the abdomen is
definitively closed, if possible. The amylase level of the drainage fluid is checked. The drainage tube
is replaced by a smaller one, and gradually shortened as soon as drainage stops. Open packing and
staged laparotomy has a high morbidity and mortality. Overall, mortality is 25%. Almost all the
surviving patients develop complications, which include: pancreatic fistula in 30%, gastrointestinal
fistula in 23%, bleeding in 17%, abscess in 9% and residual hernia in 34%.
Debridement and closed packing

Surgical technique
Abdomen opened through upper midline incision. Next, the necrosis cavity is entered via the
transverse mesocolon, preferably to the left of the middle colic artery. Depending on the locations of
the necrotic areas, incisions can also be made to the left of the ligament of Treitz (tail) or to the right
of the middle colic artery (body and part of the head). If collections are present in the pararenal or
paracolic spaces, they should be accessed by mobilization of the hepatic or splenic flexures. Next, a
thorough blunt debridement of the devitalized tissue, mostly by means of finger dissection, is
accomplished. Effort should be made to drain all fluid collections and to remove the majority of the
necrotic debris. Any string-like or firm attachments should by clamped and tied, avoiding as much as
possible removal of viable tissues. Following blunt debridement the necrosis cavity should be irrigated
profusely. A cholecystectomy can be performed at this time if indicated. Placement of a gastrostomy
tube can also be performed to allow gastric decompression if necessary and early resumption of
enteral feeding. Upon completion, pack the cavity with combinations of 2.5-cm (1-inch) Penrose
drains stuffed with gauze and closed suction drains (Jackson-Pratt type) which are exteriorized
individually and sutured to the skin after abdominal closure. These drains are removed in stages
allowing the cavity time to collapse, starting 7–10 days following surgery. The last drains to be
removed are the closed suction drains, which are withdrawn only after their output is minimal. In a
study by Rodriguez et al [56], in 167 patients who underwent this procedure most common
postoperative complication was pancreatic fistula ( in 42% of patients). Enteric fistulas developed in
15% of patients. Endocrine and exocrine insufficiency occurred in 16% and 20% of patients,
respectively. The reoperation rate was 12.6%, and 30% of patients required placement of at least one
postoperative interventional radiology drain. Overall mortality rate was 11.4%.

Minimal-access surgical treatment of necrotizing pancreatitis and pancreatic abscess

Two main types of minimal-access technique have been described for the management of infected
pancreatic necrosis: Laparoscopic (transperitoneal) pancreatic necrosectomy and minimal-access
retroperitoneal approach.

Laparoscopy
Laparoscopic transgastric and transmesocolic necrosectomies have been described [57,58]. These
techniques risk contaminating the peritoneal cavity, are lengthy, and require advanced laparoscopic
skill. The advantage of laparoscopy over other minimally invasive techniques is the opportunity of
dealing with other intra-abdominal pathology (e.g., colon or gallbladder as well as debriding material)
under direct vision. Disadvantages are procedure is not readily repeatable and subsequent
radiological intervention may be required. In the largest series dealing with infective necrosis by
laparoscopy, the mortality was 18% with an median postoperative stay of 21 days[59].

Minimal access retroperitoneal approach

Technique [60]
First under USG or CT guidance retroperitoneal access to the necrosis is established. The patient is
positioned supine on the operating table with a sandbag directly under the point of entry of the
radiologically placed percutaneous catheter. The entry site is prepared with a waterproof urologic
“catch all” drape as large volumes of irrigation are required. Under fluoroscopic control, the
percutaneous catheter is exchanged for a guidewire and using a renal dilatation set a 30F tract can
be created. The dilators should pass without resistance into the cavity once the muscular and fascial
layers of the retroperitoneum have been traversed. With the tract dilated, an Amplatz sheath is placed
over the 30F dilator allowing the dilator to be removed and the rigid operating nephroscope to be
introduced. Warm normal saline is used as the irrigant and under direct vision the necrotic tissue can
be removed. The rocedure is repeated on a weekly basis until all visible necrosis is removed. At the
end of the procedure a 10F nasogastric tube is sutured to a 28F chest drain; this is then introduced
into the cavity and secured with a suture to the skin. The cavity can then be continuously irrigated with
normal saline at a rate of 50–250 mL/hour depending on the degree of contamination until the next
procedure. Gastrostomy feeding tube with or without a jejunal extension can be performed at the
same procedure to provide a reliable and comfortable method of enteral feeding. The irrigation and
repeat procedures continue until all visible necrosis is removed and the patient is well and the
inflammatory markers have returned to normal. Irrigation can then be reduced and stopped if the
patient remains well. The drains are gradually shortened and replaced with smaller-caliber (14F)
catheters.

Main contraindication to minimal-access pancreatic necrosectomy is lack of a safe access route, ~ in

25% of patients [61]. In addition, if there is any concern over coexistent intraperitoneal pathology such
as colonic necrosis or gangerous cholecystitis, then a laparotomy should be performed. Isolated right-
sided necrosis also poses a difficult problem for retroperitoneal approach.

Outcome
There are no randomized data comparing open necrosectomy with minimally invasive necrosectomy.
A summary of published series (Table 3) showed an overall mortality of 16%, consistent with what is
achieved in most major open series. Only 51% required postoperative intensive care and 23% of
patients subsequently required open intervention.

Table 3: Summary of published reports of minimal access pancreatic necrosectomy via

Retroperitoneal approach
Reference N Infected >50% Median Intensive Mortality Open
necrosis necrosis hospital care (N) procedure
(N) (N) stay required (N)
(days) (N)
Connor et al 47 38 42 92 23 9 12
[61]
Elgammal et 46 46 22 8
al[66]
Gambiez et 20 13 62 2 5
al[67]
Mui et al [65] 13 13 2 84 8 1 2
Castellanois et 11 11 98 2 0
al[62]
Hovarth et al 6 6 0 2
[64]
Cheung et 4 2 1 3 1 2
al[63]
Total (%) 147 129 45 (70%) 56/110 23 (16%) 23
(88%) (51%)

Step up approach

The first step was percutaneous or endoscopic transgastric drainage. The preferred route was
through the left retroperitoneum, thereby facilitating minimally invasive retroperitoneal necrosectomy
at a later stage, if necessary. If there was no clinical improvement (according to prespecified
criteria24) after 72 hours and if the position of the drain (or drains) was inadequate or other fluid
collections could be drained, a second drainage procedure was performed. If this was not possible, or
if there was no clinical improvement after an additional 72 hours, the second step, video assisted
retroperitoneal debridement (VARD) with postoperative lavage was performed

VARD Procedure (Video-Assisted Retroperitoneal Debridement)

Technique
VARD procedure is advocated by Dutch group as a part of a ‘‘step-up approach’’ consisting of
percutaneous retroperitoneal catheter drainage (PCD) followed, if necessary, by VARD [68]. Catheter
drainage (radiologic) is done often via a left-sided retroperitoneal route. The patient is positioned in
supine position and 30 degree tilted towards the right side using an inflatable surgical positioning
mattress or by a roll under the left flank. The left arm is positioned over the patients head. The 4–5 cm
incision site is performed over one or two fingers below the left costal margin over the mid axillary
line, near the percutaneous routing drain. Subsequently the drain is located with the palpating finger
and followed into the collection with infected necrosis. Once the collection is opened, pus will drain
spontaneously. The very first necrosis is removed blindly using finger fracture, suction and an
extended ring forceps (e.g., similar to that used for vascular graft tunneling in vascular surgery). Next,
a zero degree laparoscope is introduced through the incision and the ring forceps is used parallel to
the videoscope, in order to remove the necrosis under full videoscopic vision. Only loose necrosis is
removed to minimize the risk of bleeding from viable pancreatic tissue and nearby blood vessels. It is
not the goal of VARD to remove all necrosis. However, leaving large undrained pockets of necrosis
should be avoided because this may cause ongoing sepsis. After completion of the procedure, two
large bore surgical drains are placed into the collection, one deep in the collection and one more
superficial. The fascia must be closed over the drains. The skin can be closed or left open for healing
by secondary intention. Postoperatively, the drains are continuously lavaged with increasing amounts
of saline, building up to 10 l per 24 h in the first 3 days. Stepwise retraction of the drains was done
once the cavity has collapsed as shown on sonogram or CECT.

Table 4: Outcome of VARD procedure

Total hospital

Complication

hollow organ
procedure

Success with

procedure
References

stay

Enteric fistula
Bleeding (%)

hernia (%)
(mean)

(%)

(%)

(%)

(%)
Additional

Mortality (%)

fistula (%)
No of pts.

Incicional
No of VARD

VARD alone

Pancreatic
Perforation of
Gambiez 20 5 10 2- 62 2 6 (28) 3 0 2 (10) 2 2
et al[69] (50) laparoto (10) (15 (10) (10
my ) )
Horvrath 6 1 4 2-open Nr 0 Nr 0 0 0 1 1
et al[70] (60) necrosec (17) (17
tomy, )
2-
percutan
eous
drainage
VonSant 24 1 15 9- 67 6 15 (63) 7(1 3 (13) 8 (33) 1 (4) 3
vroot et (63) laparoto (25) 6) (13
al[71] my )
Horvrath 25 1 15 10-open 65 1 (4) Nr 2(8 0 5 (20) 0 2
et al[72] (60) necrosec ) (8)
tomy
Castellan 32 4 Nr Nr 78 5 3 (9) 0 0 1 (3) 0 2
os et (16) (6)
al[73]
Baker et 6 2 5 1- 130 2 5 (83) 0 1 (17) 4 (67) 0 1
al[74] (83) laparoto (33) (17
my, 1- )
percutan
eous
drainage

Long term complication of necrosectomy

Diabetes
Insulin-dependent diabetes is observed in 15–30% of patients during the long-term follow up after
pancreatic necrosectomy[77-80] and another one-third of patients have impaired glucose tolerance
[81-84]. Factors responsible for diabetes development may be multiple like acute disease disease
itself, surgical treatment or increased insulin resistance [80]. Most patient become symptomatic after
3 yr of surgery.

Exocrine Insufficiency
Excorine insufficiency is observed in the long term in about 25% of the patients[77–79]. Half of these
patients have also developed diabetes [77]. Most of the patients already have symptoms of excorine
insufficiency during the initial hospitalization and this insufficiency rather improved than deteriorated
during the follow up [77].Most commonly present with diarrhea. Measurement of fecal elastase-1
concentration and fecal fat excretion are simple test for the detection of exocrine insufficiency.
Pseudocyst
Most of the local complications (Abscesses, acute fluid collections, and fistulae)of acute necrotizing
pancreatitis develop early in the course of the disease.In long term, pseudocyst may form because of
encapsulation of acute fluid collections or as a result of closure of a pancreatic fistula. Overall around
10% of patients have been detected as having a pseudocyst in a 2- to 4-year follow up[76,82,86].

Recurring Disease
Overall, a good number of patients with acute pancreatitis of any severity develop recurrent disease.
These recurrencies is mainly alcoholic acute pancreatitis, since the recurrence of biliary pancreatitis
may be prevented by adequate gallstone surgery performed immediately after recovery. Half of the
patients who have recovered from the first acute alcohol-induced pancreatitis of any severity develop
a recurrent disease in a 10- to 20-year follow up. Usually recurrence occur within the first 3–4 years
after convalescence from the first episode [75]. The major determinant of the recurrency is whether
the patient continues alcohol consumption or not.Also, the less severe the first attack of pancreatitis,
the more likely is the development of multirecurring acute pancreatitis or chronic disease [75].
Rcurrent acute pancreatitis is observed in only about 5% of patients after necrosectomy [76].

Quality of Life
Overall quality of life may be compromised by diabetes and its treatment, excocrine insufficiency
appearing as diarrhea, and abdominal pain (5–10% of patients late after necrosectomy) [76,77,85].
After a period of convalescence, most of the patients are able to return to their preillness activities,
including work [77].

Conclusion

Acute pancreatitis is a lethal disease. Understanding of pathophysiology is evolving as is the

management. Most cases of acute pancreatitis is mild which respond with conservative management.
About 5-10 % of acute pancretitis patient require surgical management. The goal of surgical or
interventional therapy for acute pancreatitis is primarily the removal of necrotic debris and the
products of local inflammation in order to minimize infection and systemic sepsis. Open surgical
debridement has been the gold standard of surgical intervention for pancreatic necrosis, by removing
necrotic pancreatic and peripancreatic tissue and establishing a means of postoperative drainage or
irrigation, while preserving viable pancreatic parenchyma. Different methods of debridement and
drainage are variations of three approaches: debridement with closure over drains, debridement with
open packing of the pancreatic bed, or debridement with closure over irrigation drains. Mortality and
complication rates for published series using these techniques vary widely as studies are complicated
by the lack of standardization of disease severity or operative indications. No method is universally
accepted, and these techniques have not been subjected to a prospective randomized trial. A number
of minimally invasive and percutaneous techniques have been described as adjuncts or alternatives
to surgical débridement. These methods may provide patients with less traumatic means of removing
necrotic tissue, infected debris, and inflammatory mediators of the necrotic pancreas. In recent years,
minimally invasive and percutaneous techniques have been shown in some series to reduce the
morbidity of open pancreatic debridement. While indications for therapy remain the same, drainage
and debridement of the pancreatic bed can often be achieved via less invasive means. Risks of
inadequate debridement and drainage are always present to these methods, and studies have not
compared minimally invasive methods with the open surgical débridement. However, as experience
grows with minimally invasive and percutaneous techniques, the role for open surgical debridement
may continue to decrease. Recent concept of step up approach for management of acute severe
pancreatitis promised lower mortality.

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 Gastric Outlet Obstruction
Manoj Andley
Introduction
Gastric outlet obstruction (GOO, also known as pyloric obstruction) is not a single entity; it is the
clinical and pathophysiological consequence of any disease process that produces a mechanical
impediment to gastric emptying. Clinical entities that can result in GOO generally are categorized into
2 well-defined groups of causes—benign and malignant. This classification facilitates discussion of
management and treatment. In the past, when peptic ulcer disease (PUD) was more prevalent,
benign causes were the most common; however, one review shows that only 37% of patients with
[1]
GOO have benign disease and the remaining patients have obstruction secondary to malignancy.
Gastric outlet obstruction can be a diagnostic and treatment dilemma. As part of the initial workup,
exclude the possibility of functional non-mechanical causes of obstruction, such as diabetic
gastroparesis.

Once a mechanical obstruction is confirmed, differentiate between benign and malignant processes
because definitive treatment is based on recognition of the specific underlying cause.

Carry out diagnosis and treatment expeditiously, because delay may result in further compromise of
the patient's nutritional status. Delay will also further compromise edematous tissue and complicate
surgical intervention.

Epidemiology

Frequency
The incidence of gastric outlet obstruction (GOO) has been reported to be less than 5% in patients
with PUD, which is the leading benign cause of the problem. Five percent to 8% of ulcer-related
complications result in an estimated 2000 operations per year in the United States. [2]
The incidence of GOO in patients with peripancreatic malignancy, the most common malignant
etiology, has been reported as 15-20%.

Etiology

The major benign causes of gastric outlet obstruction (GOO) are PUD, gastric polyps, ingestion of
caustics, pyloric stenosis, congenital duodenal webs, gallstone obstruction (Bouveret syndrome),
pancreatic pseudocysts, and bezoars.

PUD manifests in approximately 5% of all patients with GOO. Ulcers within the pyloric channel and
first portion of the duodenum usually are responsible for outlet obstruction. Obstruction can occur in
an acute setting secondary to acute inflammation and edema or, more commonly, in a chronic setting
secondary to scarring and fibrosis. Helicobacter pylori has been implicated as a frequent associated
finding in patients with GOO, but its exact incidence has not been defined precisely.

Within the pediatric population, pyloric stenosis constitutes the most important cause of GOO. Pyloric
stenosis occurs in 1 per 750 births. It is more common in boys than in girls and also is more common
in first-born children. Pyloric stenosis is the result of gradual hypertrophy of the circular smooth
muscle of the pylorus.

Pancreatic cancer is the most common malignancy causing GOO. Outlet obstruction may occur in 10-
20% of patients with pancreatic carcinoma. Other tumors that may obstruct the gastric outlet
include ampullary cancer, duodenal cancer, cholangiocarcinomas, and gastric cancer. Metastases to
the gastric outlet also may be caused by other primary tumors.

Pathophysiology

Intrinsic or extrinsic obstruction of the pyloric channel or duodenum is the usual pathophysiology of
gastric outlet obstruction; as previously noted, the mechanism of obstruction depends upon the
underlying etiology.

Patients present with intermittent symptoms that progress until obstruction is complete. Vomiting is
the cardinal symptom. Initially, patients may demonstrate better tolerance to liquids than solid food.
In a later stage, patients may develop significant weight loss due to poor caloric intake. Malnutrition is
a late sign, but it may be very profound in patients with concomitant malignancy.
In the acute or chronic phase of obstruction, continuous vomiting may lead to dehydration and
electrolyte abnormalities.

When obstruction persists, patients may develop significant and progressive gastric dilatation. The
stomach eventually loses its contractility. Undigested food accumulates and may represent a constant
risk for aspiration pneumonia.

Presentation

Nausea and vomiting are the cardinal symptoms of gastric outlet obstruction. Vomiting usually is
described as nonbilious, and it characteristically contains undigested food particles. In the early
stages of obstruction, vomiting may be intermittent and usually occurs within 1 hour of a meal.

Patients with gastric outlet obstruction resulting from a duodenal ulcer or incomplete obstruction
typically present with symptoms of gastric retention, including early satiety, bloating or epigastric
fullness, indigestion, anorexia, nausea, vomiting, epigastric pain, and weight loss. They are frequently
malnourished and dehydrated and have a metabolic insufficiency. Weight loss is frequent when the
condition approaches chronicity and is most significant in patients with malignant disease.
Abdominal pain is not frequent and usually relates to the underlying cause, eg, PUD, pancreatic
cancer.

Physical examination often demonstrates the presence of chronic dehydration and malnutrition. A
dilated stomach may be appreciated as a tympanitic mass in the epigastric area and/or left upper
quadrant.

Dehydration and electrolyte abnormalities can be demonstrated by routine laboratory examinations.

Increases in BUN and creatinine are late features of dehydration. Prolonged vomiting causes loss of
hydrochloric (HCl) acid and produces an increase of bicarbonate in the plasma to compensate for the
lost chloride and sodium. The result is a hypokalemic hypochloremic metabolic alkalosis. Alkalosis
shifts the intracellular potassium to the extracellular compartment, and the serum positive potassium
is increased factitiously. With continued vomiting, the renal excretion of potassium increases in order
to preserve sodium. The adrenocortical response to hypovolemia intensifies the exchange of
potassium for sodium at the distal tubule, with subsequent aggravation of the hypokalemia.

Once the diagnosis is suspected, request a surgical consultation.

Patients with gastric outlet obstruction (GOO) due to benign ulcer disease may be treated medically if
results of imaging studies or endoscopy determine that acute inflammation and edema are the
principle causes of the outlet obstruction (as opposed to scarring and fibrosis, which may be fixed). If
medical therapy conducted for a reasonable period fails to alleviate the obstruction, then surgical
intervention becomes appropriate. Typically, if resolution or improvement is not seen within 48-72
hours, surgical intervention is necessary. The choice of surgical procedure depends upon the patient's
particular circumstances; however, vagotomy and antrectomy should be considered the criterion
standard against which the efficacy of other procedures is measured.

In cases of malignant obstruction, weigh the extent of surgical intervention for the relief of GOO
against the malignancy's type and extent, as well as the patient's anticipated long-term prognosis. As
a guiding principle, undertake major tumor resections in the absence of metastatic disease in a
patient who can withstand such a procedure from a nutritional standpoint. In patients with largely
metastatic disease, determine the degree of surgical intervention for palliation in light of the patient's
realistic prognosis and personal wishes.

Most patients benefit from an initial period of gastric decompression, hydration, and correction of
electrolyte imbalances. In patients who are severely malnourished, postponing surgical intervention
until the nutritional status has been optimized may be wise. In selective cases, some patients may
benefit from total parenteral nutrition (TPN) or distal tube feeding (eg, placed via a percutaneous
jejunostomy).
Overall, every patient with gastric outlet obstruction deserves evaluation by a surgeon. Even if the
patient has unresectable disease, palliative surgical measures may improve the quality of life.

Laboratory Studies
 Obtain a CBC. Check the hemoglobin and hematocrit to rule out the possibility of anemia.
 Obtain an electrolyte panel. As noted previously, identifying and correcting electrolyte
abnormalities that tend to occur is essential.
 Liver function tests may be helpful, particularly when a malignant etiology is suspected.
 A test for H pylori is helpful when the diagnosis of PUD is suspected.

Imaging Studies
 Plain abdominal radiographs, contrast upper GI studies
(Gastrografin or barium), and CT scans with oral contrast are
helpful. (See images below.)Plain radiograph of the abdomen.
Enlarged stomach with calcified content. Contrast study
demonstrating an enlarged stomach. The point of obstruction is
visualized at the pyloric-duodenal junction (string sign).
 Plain radiographs, including the obstruction series (ie, supine
abdomen, upright abdomen, chest posteroanterior), can
demonstrate the presence of gastric dilatation and may be helpful
in distinguishing the differential diagnosis.

Diagnostic Procedures
 Upper GI endoscopy can help visualize the gastric outlet and may
provide a tissue diagnosis when the obstruction is intraluminal.
 The sodium chloride load test is a traditional clinical non-imaging study that may be helpful.
 The traditional sodium chloride load test is performed by infusing
750 cc of sodium chloride solution into the stomach via a
nasogastric tube (NGT).
 A diagnosis of gastric outlet obstruction (GOO) is made if more
than 400 cc remain in the stomach after 30 minutes.
 Nuclear gastric emptying studies measure the passage of orally
admin istered radionuclide over time. Unfortunately, both the
nuclear test and the saline load test may produce abnormal
results in functional states.
 Barium upper GI studies are very helpful because they can
delineate the gastric silhouette and demonstrate the site of
obstruction. An enlarged stomach with a narrowing of the pyloric
channel or first portion of the duodenum helps differentiate GOO
from gastroparesis.
 The specific cause may be identified as an ulcer mass or intrinsic tumor.
 In the presence of PUD, perform endoscopic biopsy to rule out the presence of malignancy.
 In the case of peripancreatic malignancy, CT scan–guided biopsy may be helpful in establishing a
preoperative diagnosis.
 Needle-guided biopsy also may be helpful in establishing the presence of metastatic disease.
This knowledge may impact the magnitude of the procedure planned to alleviate the GOO.

Histologic Findings
Histologic findings relate to the individual underlying cause.

Medical Therapy

Initial management of gastric outlet obstruction (GOO) should be the same regardless of the primary
cause. After a diagnosis is made, admit patients for hydration and correction of electrolyte
abnormalities. Remembering that the metabolic alkalosis of GOO responds to the administration of
chloride is important; therefore, sodium chloride solution should be the initial IV fluid of choice.
Potassium deficits are corrected after repletion of volume status and after replacement of chloride.
Place a NGT to decompress the stomach. Occasionally, a large tube is required because the
undigested food blocks tubes with small diameters.
When acute PUD has been identified as a primary cause of gastric outlet obstruction (GOO), focus
treatment on the reduction of acid production. Histamine-2 (H2) blockers and proton pump inhibitors
are the mainstay of treatment.

Treat H pylori infection, when identified, according to current recommendations. Although most
patients improve temporarily with treatment, scarring and fibrosis may worsen over time. Pneumatic
balloon dilatation of a chronic, benign stricture can be performed via endoscopy. Patients who are
candidates for balloon dilatation are likely to present with recurrent GOO. Published series using this
technique report success rates of over 76% after multiple dilatations,[3] , although the rate of failure
and recurrent obstruction is higher in patients treated with balloon dilatation who have not also been
treated for H pylori infection.[4] Patients who are negative for H pylori do not respond favorably to
[5]
balloon dilatation and should be considered for surgical treatment early in the process.

Further treatment is tailored to the underlying cause; this is where the distinction between benign and
malignant disease becomes important.

Surgical Therapy

Management of benign disease

More than 75% of patients presenting with GOO eventually require surgical intervention.[6] Surgical
intervention usually provides definitive treatment of GOO, but it may result in its own comorbid
consequences. Operative management should offer relief of obstruction and correction of the acid
problem.

The most common surgical procedures performed for GOO related to PUD are vagotomy and
antrectomy, vagotomy and pyloroplasty, truncal vagotomy and gastrojejunostomy, pyloroplasty, and
laparoscopic variants[7] of the aforementioned procedures.

Vagotomy and antrectomy with Billroth II reconstruction (gastrojejunostomy) seem to offer the best
results. Vagotomy and pyloroplasty and pyloroplasty alone, although used with some success, can be
technically difficult to perform due to scarring at the gastric outlet. A combination of balloon dilatation
and highly selective vagotomy has been described, but it is associated with gastroparesis and a high
recurrence rate.

Placement of a jejunostomy tube at the time of surgery should be considered. This provides
temporary feeding access in already malnourished patients. Also, in chronically dilated partial
obstructions, the stomach may be slow to recover a normal rate of emptying.

The role of the laparoscopic approach in the treatment of GOO is under investigation and may
represent a valid form of therapy with low morbidity. The experience of several international centers
has been published. One group in China performed laparoscopic truncal vagotomy and
gastrojejunostomy for GOO related to PUD, with nearly complete resolution of symptomatology. The
investigators reported no conversions to open procedure or mortalities. Twenty-seven percent of
patients did experience transiently delayed gastric emptying, which resolved with conservative
[8]
measures.

Kim et al also reported good results from the use of laparoscopic truncal vagotomy with
gastrojejunostomy, including shorter operating times and hospital stays in comparison with the open
procedure.[9]

Hall et al performed a double-blind, multicenter, randomized, controlled trial comparing patient

recovery following laparoscopic pyloromyotomy to that after open pyloromyotomy in infants with
pyloric stenosis.[10] The investigators found that among the 87 infants who underwent the
laparoscopic procedure, the median (interquartile range) postoperative time needed to achieve full
enteral feeding was 18.5 hours, compared with 23.9 hours in the 93 infants who underwent open
pyloromyotomy. The median postoperative length of stay in the laparoscopic and open
pyloromyotomy groups were 33.6 hours and 43.8 hours, respectively.
The study also found that the incidence of postoperative vomiting was similar in the open and
laparoscopic groups, as was the frequency of intraoperative and postoperative complications. The
authors suggested that open and laparoscopic pyloromyotomy are safe means of treating infantile
pyloric stenosis. Because of its apparent advantages, however, they recommended that in centers
with suitable laparoscopic experience, the laparoscopic form of the procedure be used.

Management of malignant disease

The management of GOO secondary to malignancy is controversial. Of patients with periampullary
[11, 12]
cancer, 30-50% present with nausea and vomiting at the time of diagnosis. Most of these tumors
are unresectable (approximately 40% of gastric cancers and 80-90% of periampullary cancers).[13,
14]
When tumors are found to be unresectable, 13-20% of patients eventually develop GOO before
they succumb to their disease. The 1-year survival rate is poor.

Gastrojejunostomy remains the surgical treatment of choice for GOO secondary to malignancy.
Although surgeons traditionally have preferred an antecolic anastomosis to prevent further obstruction
by advancing tumor growth, a publication evaluating the retrocolic anastomosis in this setting
[15]
challenges conventional wisdom. Results demonstrate that a retrocolic anastomosis may be
associated with decreased incidences of delayed gastric emptying (6% vs 17%) and late GOO (2% vs
9%). Other groups have illustrated that partial stomach-partitioning gastrojejunostomy decreases the
[16]
rates of delayed gastric emptying as compared with traditional gastrojejunostomy. Feeding
jejunostomy should again be considered to combat malnutrition and slow recovery of gastric
emptying.

Internationally, studies are underway using laparoscopic gastrojejunostomy instead of the open
procedure. In the United States, critics cite a nearly 20% conversion rate and a delay in the return of
gut function as reasons to not perform the procedure laparoscopically. Comparisons of laparoscopic
GI anastomosis versus the open procedure have revealed less morbidity and mortality, shorter
hospital stays, fewer blood transfusions, and faster GI transit recovery time. [17, 18]

Researchers at Johns Hopkins Hospital have attempted endoscopic transgastric approaches to

create a gastrojejunostomy in a porcine model.[19] As natural orifice transluminal surgery gains more
widespread interest, these novel approaches may become more popular.

Chopita and colleagues reported on the use of magnetic endoscopic gastroenteric anastomosis in 15
patients with malignant gastroenteric obstruction. The procedure had an 86.7% success rate, with the
authors noting the additional benefits of shorter duration of hospital stay and good quality of life in
[20]
patients. Although still experimental, this procedure may one day be a surgical option.

No and colleagues reported that gastrojejunostomy was preferable to metal stent placement in
providing palliation of GOO caused by unresectable or metastatic cancer in patients with a good
performance status.[21]

Self-expandable metallic stents also have been used for the treatment of GOO in a malignant setting.
Metallic stents have previously been used successfully to treat stenosis of such areas as the blood
vessels, bile duct, esophagus, and trachea. With the development of newer stents and delivery
systems, metallic stents may have a role in the nonsurgical treatment of gastroduodenal obstruction.
Stents may allow the physician to avoid complicated surgical procedures. Currently, only the
Wallstent has FDA approval for palliation in malignant gastroduodenal obstruction. Significant
complications include the following: malposition, misdeployment, tumor ingrowth or overgrowth,
migration, bleeding, and perforation.[22]

A review of 19 studies published in 2004 quoted clinical success rates of 80-90%.[23] Subsequent
multicenter trials using the enteral Wallstent in 176 patients with malignant GOO resulted in 89% of
patients tolerating oral intake for a median of 219 days postprocedure. Of the 84% in whom the stent
was successful after the initial procedure, 22% required restenting to tolerate an oral diet. In addition,
as other studies have demonstrated, chemotherapy was independently associated with an increased
[24]
tolerance in oral intake.

One proposed solution uses covered metallic stents that have a lower incidence of tumor ingrowth. A
60% rate of tumor ingrowth in uncovered stents versus a 10% rate of tumor ingrowth in covered
stents has been reported. Furthermore, with the double stent technique, that is, simultaneous
placement of both covered stents and uncovered stents, lower early restenosis rates have been
achieved. A stent patency of 21.5 days for uncovered stents versus 150 days for double stents has
been achieved.[25] Of the 62 patients studied by Maetani et al, half received uncovered stents and half
covered stents. The authors found no statistical differency in pate4ncy, but the triple-covered stent
[26]
resulted in less frequent dysfunction four weeks after stenting.

Several retrospective studies have been performed to compare the results of stenting versus surgical
intervention. Survival rates are equivalent; however, costs, length of stay, and number of subsequent
procedures are all decreased following stenting.[27, 28] In addition, a delay of gastric emptying and
morbidity decrease with the use of metallic stents.[29] These promising results suggest that stents may
eventually replace surgery as palliative intervention for unresectable periampullary malignancies.
A 2011 study from the Netherlands discusses the use of a D-Weave Niti-S nitinol stent specifically for
the duodenum. A key outcome in this palliative procedure was a significant improvement in global
health status and median 82-day survival. The authors report a marvelous technical and robust
clinical success rate with patency up to 190 days, and a 25% complication rate. [30]

Preoperative Details

 Perform standard preoperative evaluation in these patients. Correct fluid and electrolyte
abnormalities prior to surgery.
 Perform gastric decompression by NGT and suction and alert the anesthesiologist to the potential
risk for aspiration upon induction.
 Perform a preoperative nutritional evaluation and initiate appropriate nutritional therapy (ie, TPN
or enteral feedings via a percutaneous jejunostomy placed distal to the obstruction) as soon as
possible. Maximizing preoperative nutrition can greatly reduce or eliminate postoperative
complications related to delayed healing.

Intraoperative Details
Intraoperative details depend upon the etiology of the underlying disease and the reason that the
specific surgical procedure is undertaken.

Postoperative Details
 Admit patients to a monitor unit after the procedure. Pay special attention to fluid and electrolyte
status.
 Most surgeons agree that perioperative antibiotics are advisable but may be limited to use during
the immediate perioperative period in the absence of intervening infection.
 If a gastric reconstruction is performed, an NGT is recommended. The length of time that the NGT
should remain in place is controversial; however, it is important to remember that a previously
dilated stomach, the performance of a vagotomy, and the presence of metastatic cancer may all
contribute to decreased gastric motility. An anatomically patent gastrojejunostomy may fail to
empty for days. This syndrome of delayed gastric emptying is a well-known entity and requires
surgical patience. Again, preoperative planning for feeding access becomes important during this
immediate postoperative period.
 Aggressive pulmonary toilet, prophylaxis for gastritis and deep venous thrombosis (DVT), and
early ambulation are advisable.

Follow-up

Closely monitor patients after surgery and upon discharge.[31] After relief of gastric outlet obstruction,
patients may continue to experience gastric dysmotility and may require medication to stimulate
gastric emptying and motility.

In patients with malignancy, the potential for progressive and recurrent disease always remains.
These patients should be monitored by a surgeon or an oncologist.
Closely monitor patients whose treatment consisted of balloon dilatation because most of these
patients require subsequent dilatations to achieve satisfactory results.
 Complications

Although the risk is small, patients undergoing endoscopic treatment with either balloon dilatation or
stenting are at risk for perforation. Several literature reports exist regarding migration of the stents and
reocclusion requiring further intervention.

Operative complications in patients undergoing surgery for gastric outlet obstruction (GOO) often are
related to the nutritional status of the patients. Commencing nutritional support upon recognition of the
presence of GOO is important. If surgery is anticipated, delaying the surgery or any intervention until
TPN has been instituted for at least 1 week is often prudent.

Acute intervention may be technically difficult because of significant gastric dilatation and gastric wall
edema. This circumstance may increase the rate of anastomotic leak. On occasion, delaying surgical
intervention for several days while the stomach is decompressed by nasogastric suction may be
prudent.

Alert patients undergoing gastric resection for benign or malignant disease to the possibility of well-
known postgastrectomy syndromes, such as dumping, alkaline gastritis, and afferent loop syndrome.
Severe symptoms may be present in 1-2% of patients.

Outcome and Prognosis

Gastric outlet obstruction (GOO) is a clinical condition that may result from a number of underlying
causes, both benign and malignant. Despite medical advances in the acid suppression mechanism,
the incidence of GOO remains a prevalent clinical problem in benign PUD. Also, an increase in the
number of cases of GOO seems to be noted secondary to malignancy; this is possibly due to
improvements in cancer therapy, which allow patients to live long enough to develop this
complication.

Orient initial management to identification of the primary underlying cause and to the correction of
volume and electrolyte abnormalities. Barium swallow studies and upper endoscopy are the main
tests used to help make the diagnosis. Tailor treatment to the specific cause.

Future and Controversies

The role of prophylactic gastrojejunostomy in cases of malignant gastric outlet obstruction (GOO) is a
question that has not been answered. Some surgeons argue that prophylactic gastrojejunostomy may
increase postoperative morbidity, primarily due to delayed gastric emptying.

Lillemoe and Cameron addressed this issue in a publication.[32] Of patients with unresectable
periampullary cancer, 87 were randomized to receive or not receive a prophylactic gastrojejunostomy.
Although results demonstrated that no significant differences exist in morbidity, length of hospital stay,
and survival rates, the group in which prophylactic gastrojejunostomies were performed had a 0%
(0/44) incidence of GOO versus 19% (8/43) in the other group. The authors concluded that
prophylactic gastrojejunostomy significantly decreased the incidence of late GOO and should be
performed routinely when a patient is undergoing surgical palliation for periampullary cancer.
Comparable data are supported by other series.

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 Bladder Outlet Obstruction [BOO]
Kim Mammen, Navin Suthahar

Bladder outlet obstruction is a blockage at the base of the bladder that prevents, reduces or
hampers the flow of urine into the urethra. It often presents with difficulty of micturition. The cardinal
symptoms are the direct consequence of obstruction and are hesitancy, poor stream and post
micturition dribbling. In addition a phenomenon known as pis-en-deux may be observed where the
stream may stop in the middle and restart after a short period. The irritative symptoms that
accompany the cardinal symptoms are increased frequency, nocturia, urgency and incontinence.

Numerous gender-specific etiologies are responsible for bladder outlet obstruction (BOO). BOO
produces compression or resistance upon the bladder outflow channel at any location from the
bladder neck to urethral meatus. This induced resistance initiates a bladder response that is variable
and unpredictable. The characteristic symptomatic response with some combination of obstructive
and irritative complaints is nonspecific for causation and intensity. Therefore, disabling irritative
symptoms can exist with minimal objective findings, whereas complete decompensation of the lower
urinary tract may be identified in an otherwise asymptomatic individual.

LUTS – lower urinary tract symptoms (as defined by the International Continence Society) are the
subjective indicator of a disease or change in condition as perceived by the patient, caregiver or
partner and may lead him/her to seek help from health care professionals. LUTS can be classified as
storage, voiding, and post micturition symptoms. LUTS, however, cannot be used to make a
definitive diagnosis.

Although urodynamic evaluation and pressure flow evaluation is the gold standard diagnostic tool for
the assessment of LUTS, other modalities including post void residual analysis, urinary flow rates,
cystoscopy and selected radiologic ones can also be used. Patient self-appraisal of symptoms using
various inventories such as the American Urologic Association Symptom Index or the
International Prostate Symptom Score is useful for the initial assessment and subsequent follow
up. Analysis of secondary symptoms of obstruction in women is often performed using a subjective
symptom appraisal and is determined urodynamically, assessing the pressure-flow relation during
voiding. The complete assessment of LUTS arising from BOO often includes several of these
modalities to fully define the obstructive impact on the individual’s urinary function and quality of life.

• Bladder storage (irritative) symptoms are experienced during the

storage phase of the bladder and include: increased daytime frequency,
nocturia, urgency, and urinary incontinence
• Voiding (obstructive) urinary symptoms are experienced during the
voiding phase and include: slow urinary stream, splitting or spraying of
the urinary stream, intermittent urinary stream, hesitancy, straining to
void, and terminal dribbling
• Post micturition symptoms include feeling of incomplete emptying and
post micturition dribbling.

Bladder Outlet Obstruction in Men

Male bladder outlet obstruction is far better documented and studied not only because of its frequency
but also because of more obvious clinical correlations.

Etiology
Bladder outlet obstruction in men is caused by several factors, the most common etiology being
benign prostatic enlargement (BPE). Recent terminological changes have led to the use of benign
prostatic obstruction/enlargement (BPO/BPE) in the place of eponyms such as benign prostatic
hyperplasia (BPH) in several texts. Other prevailing causes of BOO in men include urethral stricture
disease. Previously considered to be primarily due to inflammatory disorders such as urethritis,
urethral stricture disease is now considered to be most commonly due to trauma. Although not that
frequent, the factors other than BPO that can cause BOO are posterior urethral valves, dysfunctional
voiding, neurogenic based Detrusor Sphincter Dyssynergia (DSD) and very rarely primary bladder
neck obstruction. The bladder outlet obstruction in men is almost always associated with storage,
voiding and post-micturition symptoms collectively called as LUTS.

Overactive Bladder in Patients With BPH

BOO is a common urological clinical problem, resulting mainly from prostatic hyperplasia, urethral
stricture disease or other congenital anomalies such as posterior urethral valve in children. BOO
induces significant alterations in the morphology and physiology of the urinary bladder and also
results in an impaired ability of the urinary bladder to store and empty urine. Much of our current
knowledge based on animal experiments suggests that in PBOO there is an increase in urethral
resistance, followed by an increase in bladder wall tension and micturition pressure. This leads to an
increase in bladder wall thickness over time and induces changes in the DSM (Detrusor smooth
muscle) morphology, progressive bladder wall denervation, alteration in detrusor receptor density and
a decrease of blood flow to the bladder wall.

Detrusor over activity after partial bladder outlet obstruction (PBOO)

PBOO associated with bladder dysfunction involves obstructive symptoms such as weak stream and
irritative symptoms such as frequency, urgency and nocturia. The occurrence of irritative symptoms
implies that the obstruction also impairs storage function of the bladder. Non voiding contractions can
result from hypersensitivity of the contractile system and / or a reduced sensitivity of the relaxant
system. There is an impairment of beta-adrenergic relaxation of bladder smooth muscle and an
enhancement of the alpha adrenergic contraction in PBOO.

The obstructed bladder is partially denervated in several animal species including humans resembling
neurogenic and aged bladder. Immunologic investigations showed that the nerve distributions were
significantly changed in the obstructed rat bladder and alteration of responses to muscarinic receptor
agonists in BOO has been observed. Besides the possible alterations in the muscarinic receptors, the
balance between contraction mediated by the alpha-1 adrenergic receptors and the relaxation
mediated by the beta receptors may also be changed in BOO. The duration and the severity of
obstruction have an important influence on the adrenergic receptor mediated responses in the
bladder.

Detrusor muscle contractility change after PBOO

The primary bladder dysfunction associated with BOO is a decreased ability to sustain bladder
contractions during the voiding phase of the micturition cycle. In response to BOO, the DSM
undergoes hyperplasia/ hypertrophy to expel the urine effectively against the increased urethral
resistance. In the compensatory phase, the DSM hypertrophies while prolonged obstruction leads to
decompensation and bladder dysfunction. In addition to smooth muscle hypertrophy, the increased
bladder mass can also be associated with alterations in extracellular matrix. Several reports have
described the alterations in DSM contractile and regulatory proteins after partial bladder obstruction.
Besides altering contractile proteins in DSM, BOO also induces a change of regulatory proteins such
as Rho-kinase and protein kinase C.
Cyclic ischemia and reperfusion (I/R) changes are major etiologic factors in the progression of bladder
dysfunction in partial bladder outlet obstruction. These changes are directly associated with a
decrease in energy produced by oxidative phosphorylation in mitochondrial electron transport chain.
Furthermore, defects in this chain lead to the generation of a significant quantity of reactive oxygen
species in addition to cell apoptosis. Thus, antioxidant agents and mitochondrial respiratory chain co-
enzymes can decrease PBOO induced I/R damage in the bladder.

Current drugs under evaluation for overactive bladder in patients with BPH
 Beta 3- AR agonists
 Purinoceptor Antagonists
 Drugs Interfering with Vanilloid Receptors ( Capsaicin and Resinferatoxin)
 Botulin toxin
 Inhibitors / antagonists of Endothelin generation or receptors
 Inhibitors / antagonists of Cyclooxygenases / Prostanoid receptors

Assessment of BOO – minimally invasive paradigm

Two techniques are used for the assessment of bladder outlet obstruction. Both these methods use
pressure transmission through a standing column of fluid, associated with an isovolumetric detrusor
pressure with occlusion of the urethral meatus during free urinary flow. For the occlusion of the
urethral meatus, the first technique uses a condom catheter and occlusion technique with pressure
transduction occurring distal to the urethral meatus. The other method uses a cuff that is inflated to
compress the urethra. The pressure associated with interruption of urinary flow is then equated to the
isovolumetric detrusor pressure.

The bladder outlet obstruction number (BOON) can be used to predict infravesical obstruction in
patients with BPE. Before calculating the BOON, an initial evaluation with IPSS has to be made. The
mean voided volume urine is determined from frequency-volume chart and the prostate volume by
transabdominal ultrasound. A complete urodynamic study including uroflowmetry has to be also
performed.

BOON can then calculated using the formula: prostate volume (cc)-3 x Qmax (ml/s)-0.2 x mean
voided volume (ml). Following the comparison of different cut-off values of BOON according to the
obstruction, the BOON >-20 has been found to be the most accurate obstruction indicator (sensitivity
76.5% and specificity 68.2%), with post-test probability of 77%. The BOON may be used in daily
urological practice as a valid, non-invasive indicator of infravesical obstruction in patients with BPE,
with a possibility of correct classification of obstruction in approximately 75% of the cases.

What does the term benign prostatic enlargement (BPE) mean?

The term BPE has very different meanings to the pathologist, radiologist, practicing urologist and the
patient. The pathologist makes the diagnosis based on cellular proliferation of the stromal and
epithelial elements of the prostate. The radiologist confirms the diagnosis of BPE on basis of enlarged
prostate using the ultrasound and diagnostic imaging techniques. The urologist looks for the signs
and symptoms caused by BOO together with ultrasound imaging while the patients primary concern is
the impact of BPE on the quality of life. Thus the term BPE has diverse connotations and is best
characterized as microscopic BPE, macroscopic BPE or clinical BPE.

 Microscopic BPE represents histologic evidence of cellular proliferation of the prostate.

Aging and the testes as the source of androgens are required for the development of
microscopic BPE.
 Macroscopic BPE refers to enlargement of the prostate resulting from microscopic BPE.
This results in an increase of the size of prostate as well as the volume. The crude
prostate size can be evaluated by Digital rectal examination (DRE) and a more accurate
estimate will be obtained using transrectal ultrasonography or magnetic resonance
imaging. The PSA value, in the absence of adenocarcinoma, may be used as an indicator
of prostate volume.
 The clinical manifestations of BPE include LUTS, poor bladder emptying, urinary
retention, an overactive bladder, UTI, hematuria, bladder stones, urosepsis and renal
insufficiency resulting from macroscopic BPH.
There is a relationship between prostate volume and both LUTS and BOO especially in men with
large prostates. Men with prostate volumes > 50 cm3 have a 5 times greater risk of having
clinically moderate to severe LUTS and a 3 times greater risk of having significant bladder
outlet obstruction, defined by a peak flow rate < 10 mL/sec. Although enlarged prostate means
the probability of developing LUTS is higher, it is important to note that enlarged prostate is not the
only reason for LUTS.

Aging men with a variety of lower urinary tract pathologic processes may exhibit similar, if not
identical, symptoms. These include prostate cancer, prostatitis, bladder cancer, bladder stones,
overactive bladder, interstitial cystitis, radiation cystitis, UTI, primary bladder neck hypertrophy,
urethritis, diabetes, Parkinson’s disease, lumbosacral disc disease, and multiple sclerosis. Often,
clinical BPH is a diagnosis of exclusion once these other clinical entities have been ruled out.

Prevalence

With the development of self-administered quantitative indices for measuring the severity of LUTS,
transrectal ultrasonography (TRUS) for accurately assessing prostate volume and sophisticated
instruments for performing simultaneous pressure-flow urodynamic studies, it is theoretically possible
to accurately define prevalence rates for these parameters in the general male community.

However, in reality, the evaluation of the prostate volume in the general population is a very difficult
task as measuring the prostate volume with transrectal ultrasonography and bladder outlet obstruction
with pressure-flow urodynamic devices is very expensive and invasive to perform in the general,
healthy population. Another limitation related to determining prevalence rates for these parameters is
that there is no consensus regarding what specifically constitutes an enlarged prostate or an
obstructed bladder. It is therefore unlikely that the exact prevalence rates for bladder outlet
obstruction and prostate enlargement will ever be determined in the general community.

Etiopathogenesis of BPH

Benign prostatic hyperplasia (BPH) is a well-known condition characterised by prostate growth

accompanied by lower urinary tract symptoms. Several mechanisms are involved in the development
and progression of BPH. These represent age-related tissue modifications, hormonal alterations and
interactions, familial and genetic contributions, metabolic syndrome as well as inflammation.

1. Tissue remodelling in the ageing prostate

Ageing is the most significant risk factor for the development of BPH and the occurrence of LUTS.
There is a direct relationship between age and markers of BPH progression. Prostatic volume
changes by about 0.6 ml per year of age, which corresponds to a median growth rate of 2.5%. A
significant tissue-remodelling process takes place within the prostate of ageing males, especially in
the transition zone. Specifically, the most significant modifications take place in the basal cells, which
change their intracellular metabolism and become enlarged and hypertrophic. There is also alteration
in the secretions of luminal cells which leads to the occurrence of prostatic calculi and clogged ducts.
All of this tissue remodelling leads to alterations of highly specialised cell types responsible for tissue
homeostasis and function.

2. Abnormal apoptosis
Because cell growth is a consequence of either increased cell proliferation or decreased cell death,
abnormal regulation of apoptosis is as a key cofactor in BPH development and progression. The
enhanced expression of antiapoptotic proteins play a vital role in the deregulation of the normal
apoptotic cell death mechanisms in the human prostate in both the glandular and epithelial cell
compartments, thus resulting in a growth imbalance in favour of cell proliferation that might ultimately
support hyperplasia. Subsequently, the induction of apoptosis and/or necrosis has become more and
more appealing in the design and testing of novel therapies for prostatic diseases.

3. Hormonal alterations
 Role of DHT - Luminal secretory cells of the prostate require androgens, particularly the
intracellular metabolite of testosterone, dihydrotestosterone (DHT), for terminal differentiation and
secretory functions. DHT is the principal prostatic androgen and is predominantly generated by
 the reduction of testosterone by the prostatic enzyme 5 alpha reductase. This enzyme is present
in fibroblasts of the stroma and in basal epithelial cells. The levels of DHT are increased in BPH.
Although the causative role of DHT in BPH has not been firmly established, recent studies have
revealed that DHT undoubtedly has at least a permissive role.

Four different androgen-responsive genes have been quantified —ELL associated factor 2
(EAF2), elongation factor - RNA polymerase II 2 (ELL2), FK506 binding protein 5 (FKBP5), and
phosphoserine aminotransferase 1 (PSAT1)—in both BPH and normal tissue. All of the genes
displayed increased expression in BPH as compared with the adjacent normal glandular tissue.
The androgen signalling is also significantly elevated in hyperplastic tissue relative to the adjacent
normal prostate. Novel approaches for the prevention and / or treatment of BPH could be
developed by understanding the mechanisms causing elevated androgen signalling.

 Role of Estrogens - The effects of estrogens on the prostate are associated with multiple
mechanisms including apoptosis, aromatase expression and paracrine regulation via
prostaglandin E2. Circulating levels of free estradiol remain constant in the ageing man due to an
age-related increase in body weight and adipose cells. The prevalence of fat tissue is responsible
for the expression of high levels of aromatase which produces estrogenic conversion. The
increased estrogenic stimulation of the prostate in the ageing man may lead to the
reactivation of prostatic growth. In addition to epithelial effects, estrogens also stimulate
stromal cell proliferation. Several studies have shown that the addition of androgens down
regulated the estrogen receptor and various stroma-derived growth factors. Selective estrogen
receptor modulators or other agents that can influence intraprostatic estrogen levels might be
used as potential therapeutic agents for the treatment of BPH in the future.

 Interaction between steroid hormones and local growth factors is another important factor in
the development of hyperplastic tissue within the prostate. These growth factors include a diverse
stimulatory group such as insulin-like growth factor (IGF), transforming growth factor-beta (TGF-b)
and other epithelial type growth factors.

4. Familial and genetic contributions also play a vital role in the development of the hyperplastic
prostate. Prostatic hyperplasia associated with familial inheritance patterns usually is characterized by
larger glandular size compared to men with sporadic BPH.

5. Metabolic syndrome
Metabolic syndrome itself or the single components (obesity, dyslipidemia, hypertension and insulin
resistance) influences the initiation and clinical progression of both BPH and prostate cancer.
 The association of BPH and Diabetes may be due to the fact that both these conditions can cause
similar urologic symptoms. Both BPH and diabetes are associated with LUTS and studies show
that men with NIDDM had a higher median annual prostate growth rate as compared with those
without diabetes. Type 2 Diabetes induced vascular role also has a role in promoting BPH
although the exact mechanism is not known.
 Hypertension has also been suggested to be involved in the pathophysiology of BPH. Arterial
hypertension occurs in about 25% of patients with BPH and studies have shown that hypertensive
men are more likely to develop BPH and to undergo medical and surgical therapy than healthy
men. Catecholamine levels are high in essential hypertension and it has been hypothesised that
noradrenergic nerves may contribute to the functional component of bladder outlet obstruction
due to BPH.

6. Inflammation
Chronic inflammation is believed to support the process of fibromuscular growth in BPH. The
prostate is normally populated by small numbers of T cells, B lymphocytes, macrophages, and mast
cells and several studies showed that the prostatic tissue in BPH patients contains a disseminated
infiltration of T and B lymphocytes and numerous colonies of macrophages. This inflammation
evidenced in BPH may contribute to tissue injury, and cytokines produced by inflammatory cells may
serve to drive local growth factor production and angiogenesis in the tissues as a ‘‘wound healing’’
response. There is also an up regulation of a set of proinflammatory cytokines including IL-8 in
the BPH tissue. IL-8 has also been proposed as the link between chronic prostate
inflammation and autocrine/ paracrine stromal cell proliferation. During the inflammation-based
tissue remodelling, the proliferating cells have increased oxygen demands and local hypoxia
develops. Prostatic stromal cells respond to hypoxia by up regulating the secretion of several growth
factors that can also trigger prostatic growth.

CONCLUSIONS
 Although the pathogenesis of BPE is not yet fully understood, several mechanisms seem to be
involved in the development and progression of the disease.
 Tissue remodelling in the ageing prostate and abnormal apoptosis play a crucial role
 Androgens per se do not cause BPE, they however play a permissive role in the development
of BPE
 Several studies support the association between noninsulin-dependent diabetes mellitus,
hypertension, obesity, and low high-density lipoprotein cholesterol and the development of BPE
 Familial and genetic factors also play a role in the development of BPE
 Chronic inflammation and local hypoxia can trigger prostate growth
 Recent evidence suggests that BPE consists of an inflammatory-based disorder. There is a
statistically significant association between inflammation and BPE severity and progression
suggesting that BPE is an immune inflammatory disease.

Natural History

The natural history of a disease refers to the progression of the untreated disease over time. Clinical
endpoints of progression for BPH include the development of more severe symptoms; bladder
dysfunction manifested by incomplete emptying or detrusor instability, more severe bladder outlet
obstruction, acute urinary retention (AUR), recurrent UTI, urosepsis, chronic renal insufficiency,
bladder stones, incontinence and hematuria.

The natural history of BPH is incompletely understood because of the absence of a uniform definition
of the disease and the lack of rigorous studies. We have already mentioned that such a study is
practically not feasible owing to the high cost of pressure-flow urodynamic studies and the lack of
willingness from healthy men to subject them to an unnecessary TRUS.

Objectives of Diagnostic Evaluation

The Agency for Healthcare Research and Quality and the International Consultation on BPH have
published recommendations for the initial evaluation of BPH using evidence based approach.

The primary objective of the diagnostic evaluation of men with LUTS is to exclude other urologic and
non-urologic conditions that may masquerade as BPH. A secondary objective is to determine the
severity of BPH.

Men older than 50 years are at risk for clinical BPH and may have coexisting conditions mimicking
BPH. Therefore, all men older than 50 years should undergo an evaluation that includes
determination of the American Urological Association (AUA) symptom score and a detailed medical
history, a DRE, a urinalysis and a serum PSA measurement. Urinary cytologies, TRUS of the
prostate, uroflowmetry, post void residual urine volume (PVR) measurement, pressure-flow
urodynamics and filling cystometry are optional studies that should be performed with a specific
purpose as related to confirming the diagnosis, evaluating the severity of BPH or selecting treatment.

Medical History

A detailed medical history should be obtained to identify other causes of voiding dysfunction or
comorbidities that may complicate treatment. Specific additional areas to discuss when taking the
history of a man with BPH symptoms include a history of hematuria, UTI, diabetes, nervous system
disease (e.g., Parkinson disease or stroke), urethral stricture disease, urinary retention, and
aggravation of symptoms by cold or sinus medication. Current use of prescription and over-the-
counter medications should be discussed to determine whether the patient is taking drugs that impair
bladder contractility (anticholinergic agents) or that increase outflow resistance (α-sympathomimetic
agents). A history of prior lower urinary tract surgery raises the possibility of urethral or bladder neck
stricture. Use of a voiding diary (recording times and volume) may help identify patients with polyuria
or other nonprostatic disorders.
Physical Examination

A DRE and a focused neurologic examination should usually be performed. In addition, examination
of the external genitalia is indicated to exclude meatal stenosis or a palpable urethral mass and an
abdominal examination is necessary to exclude an over distended, palpable bladder.

DRE provides a sufficiently accurate measurement of the prostate gland. The size of the prostate is
essential to select the most appropriate pharmacologic or technical approach. A more accurate
measurement of prostate volume is given by ultrasonography (transabdominal or transrectal). It is
now established that a larger gland, and consequently a higher PSA, is associated with a greater risk
of BPH progression.

The DRE and focused neurologic examination can be used to detect prostate or rectal malignancy, to
evaluate anal sphincter tone and to rule out any neurologic problems that may cause the presenting
symptoms. The presence of induration is as important a finding as the presence of a nodule and
should be correlated with a serum PSA value so that the need for prostatic biopsy can be assessed
and acted upon.

Symptom Assessment

Patient self-appraisal of symptoms using various inventories such as the American Urologic
Association Symptom Index or the International Prostate Symptom Score is useful for the initial
assessment.

The International Prostate Symptom Score (IPSS) is recommended as the symptom scoring
instrument to be used for the baseline assessment of symptom severity in men presenting with LUTS.
When the IPSS system is used, symptoms can be classified as mild (0 to 7), moderate (8 to 19), or
severe (20 to 35). The IPSS should also be the primary determinant of treatment response or disease
progression in the follow-up period. Although other symptom score questionnaires are used, the IPSS
is now the U.S. and international standard.

However, the IPSS cannot be used to establish the diagnosis of BPH. Men (and women) with a
variety of lower urinary tract disorders (e.g., infection, tumor, neurogenic bladder disease) will have a
high IPSS. Nonetheless, the IPSS is the ideal instrument to grade baseline symptom severity, assess
the response to therapy and detect symptom progression in those men managed by watchful waiting.

Symptom scores alone do not capture the complete picture of a prostate problem as perceived by the
individual patient. Symptom impact on a patient’s lifestyle must be considered as well. An intervention
may make more sense for a moderately symptomatic patient who finds his symptoms very
bothersome than for a severely symptomatic patient who finds his symptoms tolerable.

Urinalysis

A urinalysis must be done either by using a dipstick test or by examining the spun sediment to
evaluate glucosuria and to rule out UTI and hematuria. The presence of UTI or hematuria requires
additional testing to exclude genitourinary malignancies and other conditions unrelated to BPH. Urine
cytology should be considered in men with severe irritable symptoms, especially if they have a history
of smoking. If a dipstick approach is used, the test should include leukocyte esterase and nitrite tests
for the detection of pyuria and bacteriuria. Urinalysis also assists in distinguishing diabetes, UTIs and
bladder cancer from BPH. These conditions may produce urinary tract symptoms (such as frequency
and urgency) that mimic BPH.

Serum Creatinine Measurement

The AUA guidelines on BPH and the Sixth International Consensus report no longer recommend
routine creatinine measurement in the standard patient. It was previously recommended to exclude
renal insufficiency caused by the presence of obstructive uropathy. It is, however, well established
that BPH patients with renal insufficiency have increased risk for postoperative complications. The
risk is 25% for patients with renal insufficiency, compared with 17% for patients without the condition.
Moreover, the mortality increases up to six fold for BPH patients treated surgically if they have renal
insufficiency. Elevated serum creatinine levels in a patient with BPH are an indication for imaging
studies (usually ultrasonography) to evaluate the upper urinary tract.

Serum Prostate-Specific Antigen

Prostate cancer can lead to LUTS by producing bladder outflow obstruction similar to BPH. Moreover,
localized prostate cancer commonly coexists with BPH. In most men with a 10-year or longer life span
the knowledge of concomitant prostate cancer may well alter management of the BPH component. A
PSA test and DRE increase the detection rate of prostate cancer over DRE alone. Therefore
measurement of the serum PSA value should be performed in patients in whom the
identification of cancer would clearly alter BPH management.

There is significant overlap between the serum PSA values of men with BPH and those of men with
clinically localized prostate cancer. Twenty-eight per cent of men with histologically proven BPH have
a serum PSA level greater than 4.0 ng/mL. Serum PSA trends over time (PSA velocity), measurement
of free versus complexed PSA, and PSA density may help to improve the specificity of PSA testing in
men with BPH.

There is also a strong correlation between prostate volume and serum PSA levels. Thus in the
absence of prostate cancer the PSA value provides both a guide to prostate volume and also
an indication of the likelihood of response to therapy with 5α-reductase inhibitors. However, in
men with BPH already treated with a 5α-reductase inhibitor serum PSA is reduced 40% to 50% after 6
months of treatment. Failure to establish a baseline (pre-treatment) PSA level may therefore
complicate interpretation of future PSA values. Men who are taking these agents should have their
PSA value doubled to correctly assess their risk of harboring a prostatic adenocarcinoma.

Newer markers such as the PCA-3 test (Prostate Cancer gene) and PSMA (Prostate specific
membrane antigen) can also help to differentiate BPH from prostate cancer.

Imaging in BPH

Transrectal Ultrasonography (TRUS) provides a more accurate assessment of prostate volume than
DRE. A precise prostate volume measurement is not necessary in most cases for the evaluation of
LUTS or selection of therapy. In special cases in which the prostate is very large on DRE, a TRUS
should be performed in order to determine the optimal approach to prostatectomy. More than 90% of
prostatectomies can be performed via the transurethral route. Very large prostates are more safely
approached using an open surgical technique.

Urethroscopy/ Imaging of the upper tract should be performed only if LUTS are accompanied by a
UTI, hematuria or a positive urinary cytologic finding.

Urodynamics in BPH

1. Uroflowmetry is the electronic recording of the urinary flow rate throughout the course of
micturition. The results of uroflowmetry are nonspecific for causes of the symptoms. For example, an
abnormally low flow rate may be caused by BOO (hyperplastic prostate, urethral stricture, meatal
stenosis) or by detrusor hypo contractility. Flow rate measurements are inaccurate if the voided
volume is less than 150 mL. There is no consensus as to the maximum flow rate (Qmax) “cut point”
discriminating obstruction from non-obstruction. Qmax values suggestive of BOO range from 12 mL/s
to 15 mL/s. The maximum flow rate has limited ability in predicting surgical outcomes or response to
medical therapy. The ACHPR guideline panel's conclusions regarding uroflowmetry (McConnell et al,
1994) still apply.

The AHCPR Guideline Panel reached the following conclusions regarding uroflowmetry
 Flow rate measurements are inaccurate if the voided volume is less than 125 to 150 mL.
 Flow rate recording is the single best non-invasive urodynamic test to detect lower urinary
tract obstruction. Current evidence, however, is insufficient to recommend a given “cut-off”
 value to document the appropriateness of therapy.
 The peak flow rate (PFR; Qmax) more specifically identifies patients with BPH than does
the average flow rate (Qave).
 Although PFR decreases with advancing age and decreasing voided volume, no age or
volume correction is currently recommended for clinical practice.
 Although considerable uncertainty exists, patients with a PFR greater than 15 mL/sec
appear to have somewhat poorer treatment outcomes after prostatectomy than patients
with a PFR of less than 15 mL/ sec.
 A PFR of less than 15 mL/sec does not differentiate between obstruction and bladder
decompensation.

2. Post voidal residual volume (PVR) is the volume of fluid remaining in the bladder immediately
after the completion of micturition. Studies indicate that residual urine volume normally ranges from
0.09 mL to 2.24 mL, with the mean being approximately 0.53 mL. Seventy-eight per cent of healthy
men have PVRs of less than 5 mL, and 100% have volumes of less than 12 mL. PVR measurement
can be performed by noninvasive (ultrasonography) or invasive (catheterization) methods. The most
common method is ultrasonography. Small, portable, 3-dimensional ultrasound devices are widely
used to measure PVR in the office setting. The reported accuracy of these devices is comparable to
that of more expensive ultrasound units and catheterization. Over the years, the clinical performance
of this 3-dimensional technology has evolved to out-perform large, stationary ultrasound. In the AUA
Outcome Study, Barry and colleagues found a significant correlation between high PVR and low flow
rates but no correlation with IPSS .Therefore, large PVRs may exist in men who have minimal
symptoms. No concrete evidence is available, as of now, to assume that increasing PVRs denote
significant bladder dysfunction and increased risk of developing UTI.

3. Pressure flow studies

Pressure-flow studies differentiate between patients with a low Qmax secondary to obstruction and
those in whom a low Qmax is caused by a decompensated or neurogenic bladder. Pressure-flow
studies correlate poorly and irregularly with severity of LUTS and are therefore limited in determining
the cause of LUTS. Pressure-flow studies should be performed when the distinction between urethral
obstruction and impaired contractility will affect therapeutic decision making. Patients with a history of
neurologic diseases known to affect bladder or sphincteric functions, as well as patients with normal
flow rates (Qmax <15 mL/s) but bothersome symptoms, may also benefit from urodynamic evaluation,
especially if surgical therapy is contemplated.

Pressure-flow studies provide much more specific insight into detrusor function and the
etiology of voiding dysfunction than do flow rate measurements. However, a number of
outcome-based investigations demonstrate only a modest additional value of pressure-flow studies
over symptom and flow rate evaluation.

5. Filling Cystometry (Cystometrography) – Filling cystometry is an invasive urodynamic study and

provides information on bladder capacity, the presence and threshold of uninhibited detrusor
contractions (UDCs) and bladder compliance. Filling cystometry adds limited information to the
evaluation of most men with LUTS and is not recommended in routine cases. The test may have
value in the evaluation of patients with known or suspected neurologic lesions and LUTS but
pressure-flow studies provide more specific information.

MEDICAL MANAGEMENT

Alpha adrenergic blockers are the most commonly used medical treatment for BPH. They relieve
not only obstructive but also irritative symptoms in patients with BPH. Alpha-blockers were first used
in clinical practice for the treatment of LUTS secondary to BPH in 1978, after the demonstration of
adrenoceptors in human prostate smooth muscle. Alpha adrenoreceptors maintain the smooth muscle
tone of the prostate.

The non-selective alpha-blocker, phenoxybenzamine was the first one to be introduced. Due to its
unselective nature and side effect profile it was not tolerated by many patients. Subsequently, alpha1-
adrenoceptor blockers, which were selective and better-tolerated, were developed. A large number of
alpha1-selective, alpha-blockers are currently available (tamsulosin, alfuzosin, doxazosin, indoramin,
prazosin, terazosin) and all have a similar efficacy and side-effect profile. Alpha adrenoceptor
antagonists act on prostate and urethral smooth muscle to reduce the dynamic component of
urethral resistance and thus alleviate voiding symptoms. Patients taking alpha-1 blockers regularly
also have significant improvements in the irritative symptoms such as hesitancy, impaired stream,
nocturia, urgency and frequency.

Alpha-blockers can be taken orally by all men with uncomplicated LUTS and the dosage depends on
the half-life of the relevant drug. Tamsulosin, alfuzosin, terazosin and doxazosin have the advantage
of being long-acting, once-daily preparations. Symptoms can improve within 48 hours. An I-PSS
assessment requires at least one month of therapy.

Patients may choose to stop taking medication for a number of reasons. The two very important
reasons are, namely, the occurrence of adverse effects and lack of efficacy. The most commonly
reported side-effects with alpha-blocker therapy are headaches, dizziness, postural hypotension,
asthenia, drowsiness, nasal congestion and retrograde ejaculation. Tamsulosin resulted in less
orthostatic hypotension than alfuzosin under test conditions. Terazosin therapy does not affect blood
pressure control in patients receiving concurrent anti-hypertensive medication. Approximately 30 per
cent of men will not respond to the treatment and in these cases, the therapy should be terminated
after one month of unsuccessful therapy.

5-alpha reductase inhibitors (5-ARIs) are the other group of drugs that are frequently used in the
medical management of BPH. The commonly used 5-ARIs are Finasteride and Dutasteride. They act
by the mechanism of androgen suppression. The efficacy of 5-alpha reductase inhibitors is
unquestionable and has been demonstrated over large clinical trials. They can reduce the size of the
prostate gland by 20-30% and improves symptom scores by approximately 15% and can also cause a
moderate improvement in the urinary rate of 1.3-1.6 mL/s.

Finasteride reduces dihydrotestosterone (DHT) by about 70% in the serum and by 90% in the
prostate by supressing the type 2, 5-alpha reductase enzyme and significantly reduces acute urinary
retention and the need for surgical treatment in men with BPH. It relieves LUTS by reducing the
prostate volume and it should be offered to men with moderate-size or large prostates (> 40
cm3). A meta-analysis of six randomized clinical trials showed that baseline prostate volume was a
key predictor of various treatment outcomes and that finasteride was more effective in prostates
larger than 40 mL. It is, however, not contraindicated in smaller sized prostates. Another important
benefit of finasteride in common clinical urological practice is that it can be used to treat haematuria
associated with BPH.

The long-term effects of finasteride have also been examined by several studies. According to the
Scandinavian finasteride study group the maximum efficacy of finasteride action is obtained after 6
months and this improvement could be maintained for at least 6 years. The North American
Finasteride Study Group reported that patients treated with finasteride maintained a reduction of
prostate volume and an improvement in symptom score and maximal urinary flow rate over a period
of 5 years.

The side-effects of finasteride are mainly related to sexual function and occurred mainly during the
first year of therapy. In the PLESS study the side effects reported were decreased libido (6, 4%),
impotence (8, 1%), decreased ejaculate (3, 7%) and in less than 1% of the patients other disorders
such as rash, breast enlargement and breast tenderness. It has also been shown that the four year
inhibition with finasteride does not adversely affect bone mineral density.

Finasteride also lowers serum PSA levels. Studies show that a 12 month therapy with finasteride,
5 mg/day, reduces serum PSA levels by 50%. Finasteride treatment also does not mask the
detection of prostatic adenocarcinomas. However, during long term therapy with finasteride, the PSA
levels have to be doubled to appropriately interpret PSA values

It is known that finasteride suppresses dihydrotestosterone (DHT) by about 70% in the serum and by
90% in the prostate. The remaining DHT is the result of type 1, 5-alpha reductase activity.
Dutasteride is a new drug that has the ability to suppress both type 1 and type 2 isoenzymes
and can decrease the serum DHT levels up to 90%.
According to several randomized controlled studies dutasteride can reduce prostatic volume by
almost 26%, improve symptoms and urinary flow rate and also decrease the incidence of acute
urinary retention and BPH related surgery. The adverse event profile of dutasteride is quite similar to
finasteride and includes erectile dysfunction, ejaculatory disorders and gynecomastia.

Combination therapy
Recently the results of a multicentre randomized, placebo-controlled double-blinded trial (MTOPS
trial), have shown that the combination of finasteride to doxazocin is beneficial. The combination
therapy is superior to either drug alone in reducing AUA symptom scores, in increasing median
maximal flow rates and in reducing the likelihood of acute urinary retention and surgery.

A multicentre, placebo-controlled study (SMART study), [Symptom Management After Reducing

Therapy], on the short term combination of dutasteride and tamsulosin involving 327 patients showed
that there is no significant symptom deterioration after discontinuing the alpha blocker following 9 to
12 months of combination therapy. Thus the combination of a 5-alpha reductase inhibitor with an
alpha-blocker is beneficial according to the currently available data.

Acute urinary retention

 Several short-term randomised studies have shown that in men with acute urinary retention, a
trial without catheter (TWOC) after a blockade for 3–5 days increased the likelihood of
spontaneous voiding. Although a substantial number of patients will eventually require
surgery within 6–12 months, about 20% will avoid surgery in the long term. Therefore, a
TWOC should be offered to all patients presenting with acute urinary retention.
Benign prostatic enlargement–related haematuria
 Randomised controlled trials (RCT) have demonstrated that 5-ARIs have a positive effect on
BPE related haematuria as they down regulate the angiogenesis in the prostate gland and
thereby decrease the vasculature. The positive effect of 5-ARIs on the natural history of the
disease (reduction of the risk of acute urinary retention or risk of surgery) renders this
therapeutic approach particularly attractive for men with BPE-related haematuria and prostate
volumes >30–40 ml.

Phosphodiesterase inhibitors (PDE5 inhibitors)

Phosphodiesterase (PDE5) inhibitors are used in the treatment of erectile dysfunction and in primary
pulmonary hypertension. Recently it has been found that PDE5 isoenzymes are highly expressed in
human LUT tissues and PDE5 inhibition results in smooth muscle relaxation and increased pelvic
blood perfusion in these tissues and modulates afferent nerve activity. This activity may reduce the
nonvascular or vascular smooth muscle tone of the prostate and inhibit human stromal cell
proliferation through the cGMP pathway.
Thus, PDE5 inhibitors are thought to have a great potential in the treatment of LUTS secondary to
BPH.

Sildenafil shows an improvement in lower urinary tract symptoms and quality of life for BPH patients
in uncontrolled studies. However, tadalafin has already undergone a prospective, double-blinded,
placebo-controlled, multicenter trial regarding its efficacy in controlling LUTS. 1-2 weeks of treatment
with tadalafin causes marked improvement in both storage and voiding urinary symptoms. This could
be caused by smooth muscle cell relaxation in the bladder neck, prostate and urethra with the
maintenance of effect supported by the smooth muscle cell relaxation of these organs' vascular
supply and increased blood perfusion and oxygenation. The other PDE5 inhibitors that are currently
under evaluation are vardenafil and udenafil.

Botulin Toxin
Botulin neurotoxin A can induce relaxation of the prostate, atrophy and a reduction in size through
inhibition of the autonomic system on the prostate. The neurotoxin also inhibits sensory nerves along
the spinal cord to the prostate, thus possibly reducing lower urinary tract symptoms.

Phytotherapy for BPH

Phytotherapy or the use of plant extracts for treatment of lower urinary tract symptoms (LUTS)
consistent with benign prostatic hyperplasia (BPH) was first described in Egypt in the 15th century
BC. Phytotherapy is currently common in Europe and is increasing in the Western Hemisphere. About
30 phytotherapeutic compounds are used for the treatment of BPH. Phytotherapeutic agents
represent nearly half the medications dispensed for treatment of BPH in Italy, compared with 5% for
alphablockers and 5% for 5-alpha reductase inhibitors.

In Germany and Austria, phytotherapy is the first-line treatment for mild to moderate lower urinary
tract symptoms and represents more than 90% of drugs prescribed for treatment of BPH. In the
United States, phytotherapies for BPH are available as non-prescription dietary supplements.
Phytotherapeutic compounds are, however, unlicensed and do not require evidence of efficacy, safety
or purity. The most commonly used phytotherapeutic compounds which are effective are

1. Serenoa repens (saw palmetto)

The most widely used phytotherapeutic agent for BPH is the extract of the dried ripe fruit from the
American dwarf palm plant, saw palmetto, Serenoa repens. It has been approved in France and
Germany for treatment of BPH. The mechanism may include alteration of cholesterol metabolism,
anti-estrogenic, anti-androgenic (including 5-alpha reductase inhibitor activity), anti-inflammatory
effects and a decrease in available sex hormone binding globulin.

Extracts from the saw palmetto plant provide modest improvement in urinary symptoms and flow
measures. Compared with finasteride Serenoa repens produces similar improvements in symptoms
and flow measures, has fewer adverse treatment effects (erectile dysfunction) and cost less. The
long-term safety and efficacy of Serenoa repens and its ability to prevent complications from BPH are
not known. Standardized preparations are often not available. The most extensively investigated
preparation of Serenoa repens is manufactured in France and sold as Permixon. The most commonly
reported dosage is 160 mg twice per day.

2. Hypoxis rooperi (South African star grass, beta-sitosterol)

Phytosterol extracts derived from the South African star grass, Hypoxis rooperi, are also used
sometimes for the treatment of BPH. The presumed active constituent is beta-sitosterol and the
mechanism of action may be related to cholesterol metabolism or anti-inflammatory effects (via
interference with prostaglandin metabolism).

In the short term, beta-sitosterol improves urological symptoms and flow measures. Their long term
effectiveness, safety and ability to prevent BPH complications are not known precisely as the existing
evidence is limited to trials of short duration, few patients in the study and the lack of standardized b-
sitosterol preparations.

3. Secale cereale (rye-grass pollen)

Rye pollen extract (Cernilton) is prepared from the rye-grass, Secale cereale. It is used by several
men worldwide and is a registered pharmaceutical throughout Western Europe, Japan, Korea and
Argentina. In the United States, Cernilton is used as a nutritional supplement. One dose contains 60
mg of Cernitin T60, a water-soluble pollen extract fraction, and 3 mg of Cernitin GBX, an acetone-
soluble pollen extract fraction. The acetone-soluble fraction contains beta-sterols. In vitro studies
suggest that Cernilton may have anti-androgenic effects, relax urethral smooth muscle tone and
increase bladder muscle contraction, or may act on the alpha-adrenergic receptors and relax the
internal and external sphincter muscles. Cernilton is well tolerated and modestly improves
urologic symptoms. Since the trials had a small sample size and were of short duration, the long-
term safety and effectiveness is not known.

4. Pygeum africanum (African plum)

Traditionally the bark of the African plum tree (Pygeum africanum) was collected and powdered, then
drunk as a tea to improve genito-urinary symptoms. Purified bark extracts have been used throughout
Europe for the past 30 years. The postulated active components include phytosterols, especially beta-
sitosterols, pentacyclic triterpenoids and esters of long-chain fatty alcohols. Pygeum africanum extract
may suppress LUTS by reducing bladder hyper reactivity, decreasing inflammation and protecting
against abnormal prostate growth. Thus the African plum may be a useful treatment option for BPH.
However, inadequacies in the reporting of outcomes limit the ability to estimate its safety and efficacy.
5. Urtica dioica (stinging nettle)
Extracts from roots of the stinging nettle are often used in Germany for the treatment of BPH.
Proposed mechanisms of action include inhibition of prostatic growth factor including blocking the
conversion of testosterone to dihydrostersterone. Evidence from randomized trials suggests that
combination preparations of Urticae compared with finasteride there were no differences in IPSS
scores, peak urine flow or residual urine volume. More adverse events were associated with
finasteride, including more cases of erectile dysfunction, diminished ejaculation volume, and
headaches. Compared with placebo, the combination of Sabal±Urtica (Prostagutt) improved IPSS
scores by 17% (23.5 IPSS points). Stinging nettle extracts, alone, however do not appear to be
beneficial.

Recommendations and conclusions

Phytotherapy is widely used for the treatment of BPH symptoms. They cost less and are better
tolerated, at least in the short term, than either alpha-blockers or finasteride. But plant extracts have
not yet been demonstrated to reduce complications from BPH or the need for surgical intervention in
comparison with interventions such as finasteride.
Despite their popularity and the existence of over 40 randomized controlled trials involving nearly
5000 men, the available data do not yet provide clear evidence of efficacy for most phytotherapeutic
products. Therefore, if the primary goal is to reduce symptoms, alpha-blockers such as doxazosin,
tamsulosin, alfuzosin or terazosin are a better choice than phytotherapy.

Alpha blockers 5-alpha reductase Phosphodiesterase-5 Phytotherapy

inhibitors (5-ARIs) (PDE-5) Inhibitors
First Generation Type II – 5 ARI  Sildenafil  Serona repens
(alpha1, alpha 2)  Finasteride  Tadalafil (saw palmetto)
 Phenoxybenzamin Type I and II – 5 ARI  Vardenafil  Hypoxis rooperi
e  Dutasteride  Udenafil (South African star grass)
Second Generation  Secale cereale
(selective alpha1) Combination (rye-grass pollen)
 Terazosin  Tamsulosin +  Pygeum africanum
 Doxazosin Dutasteride (African plum)
 Urtica dioica
Third Generation (stinging nettle /
(alpha 1a and alpha 1d) Prostagutt)
 Alfuzosin
 Tamsulosin
 Silodosin

SURGICAL MANAGEMENT

The most frequent indication for surgical management is bothersome LUTS refractory to medical
management. The following complications of BPH/BPE are considered strong indications for surgery:
 refractory urinary retention
 recurrent urinary retention
 recurrent haematuria refractory to medical treatment with 5-alpha reductase inhibitors
 renal insufficiency
 bladder stones.

Increased post-void residual volume may also be used as an indication for surgery. However, there is
a great intra-individual variability and an upper limit requiring intervention has not been requiring
intervention has not been defined. Variables that most likely predict the outcome surgery are severity
of LUTS, the degree of bother and the presence of BPO. The various surgical options available are
TURP, open prostatectomy and the minimally invasive surgeries such as TUIP, TUMT TUVP and
TUERP.
 Anatomy of the Prostate

Embryology of the prostate - In the 4th week of gestation, the urogenital septum divides the cloaca
into two parts: The rectum posteriorly and the primitive urogenital sinus anteriorly. In the 5th week, the
distal portions of the Wolffian canal and the Mullerian canal attach to the posterior aspect of the
primitive urogenital sinus to form an elevation called Mullerian tubercle. The tubercle divides the
primitive urogenital sinus into vesico-urethral canal superiorly and definitive urogenital sinus inferiorly.

The Wolffian canal forms the vas deferens, the ampulla of the vas and the seminal vesicle. The
Mullerian canal regresses to form the utricle. Formation of the prostate begins at the 10th week of
gestation by proliferation of the epithelium of the posterior urethra around the orifices of the Wolffian
canal, to surround the urethral circumference. The prostatic glands formed anterior to the urethra
regress and are replaced by fibromuscular stroma. The secretory function of the glands starts about
the 13th week of gestation.

Gross anatomy of the prostate and its relations

The term “prostate” was originally derived from the Greek word “prohistani”, meaning “to stand in
front”, and has been used to describe the organ located in front of the urinary bladder. The prostate is
conical in shape with its long axis directed inferiorly and anteriorly. The shape and size of the prostate
may vary with age. The prostate of an adult man measures 20 – 25 gms in weight.

 The BASE of the prostate is directed superiorly and in contact with the bladder base.
 The APEX is directed inferiorly and in contact with the external sphincter above the deep fascia of
the urogenital membrane.
 The anterior border is separated from the symphysis pubis and pubic bones by the retropubic
space called the cave of Retzius which contains loose areolar tissue, preprostatic venous plexus,
lymphatics, nerves and puboprostatic ligaments. The trapezoid area is an extraprostatic area of
anatomic weakness. It may be involved by carcinoma extending through the inferior neurovascular
pedicle. This area bounded by the prostate proximally, the rectourethralis muscle distally, the
membranous urethra anteriorly and the rectum posteriorly
 Posteriorly, the prostate is related to the rectum and is separated from it by the Denoviller’s
fascia which extends superiorly, behind the seminal vesicles up to the peritoneal reflection. The fascia
 represents the serosal remnants of the pouch of Douglas, pointing down to the urogenital diaphragm.
 At each posterolateral aspect of the prostate, the hypogastric pelvic fascia contains the
neurovascular bundle of the prostate, seminal vesicles and bladder neck.

Lobar concept of intraprostatic anatomy

In 1912, Lowsley demonstrated the first detailed description of the anatomy of the prostate. This
traditional concept which is no longer used, divided the prostate into lobes: an anterior, posterior,
middle and two lateral lobes. This method has been used to identify the prostate and prostatic
disease for about 60 years. The anterior lobe was situated from the anterior margin of the gland to the
level of the prostatic urethra. The middle lobe was a small area between the proximal prostatic urethra
and the ejaculatory ducts. This lobe extends from the base of the prostate to the level of
verumontanum. The posterior lobe was situated posterior to the ejaculatory ducts and extends to the
posterior margin of the gland. The two lateral lobes extend from the lateral margin of the gland
bilaterally toward the middle part of the gland. None of these lobes has clearly defined medial margin.

Zonal concept of intraprostatic anatomy

The understanding of the gross and microscopic anatomy of the prostate has changed during the past
few decades. Since 1965, a zonal concept of anatomy has evolved initially developed by McNeal and
then modified over about three decades. The prostate is best considered to be a fusion of
different glandular regions contained within a discontinuous capsule. The prostate is composed
of four glandular regions and a nonglandular region which is the anterior fibromuscular stroma.

Zonal anatomy of the prostate. A: Young male with minimal transition zone hypertrophy. Note
preprostatic sphincter and periejaculatory duct zone (central zone of McLean) are clearly defined.B:
Older male with transition zone hypertrophy, which effaces the preprostatic sphincter and compresses
the periejaculatory duct zone. SV, seminal vesicle; CZ, central zone; PZ, peripheral zone; TZ,
transition zone; AFS, anterior fibromuscular stroma.

 The fibromuscular stroma (FMS) is the anteromedial portion of the gland is devoid of glandular
tissue. This region is generally considered to be of less clinical significance.
 The peripheral zone (PZ) comprises the largest portion of the glandular prostate in young man (70%).
The PZ is situated posteriorly, posterolaterally and a thin layer of this tissue also extends up laterally and
anterolaterally. Distal to the verumontanum, the PZ often surrounds the urethra and occupies the apical
region if the prostate.
 The transition zone (TZ) is situated on both sides of the proximal prostatic urethra and comprises
only 5 to 10% of the glandular tissue in the non-hyperplastic prostate. The surgical capsule is an interface
between the PZ and TZ. In the aging prostate where the TZ can show marked glandular hyperplasia and
may constitute the majority of prostatic glandular elements.
 The periurethral glandular zone (PUG) consists of mucosal glands in the prostatic urethra itself and
represents only a tiny fraction of the glandular prostate. This zone may become hyperplastic with age to
form the “median lobe” which may obstruct the bladder neck.
 The central zone (CZ) is cone-shaped with its base forms the base of prostate, bordering the urinary
bladder and seminal vesicles and its apex is at the verumontanum The CZ forms about 25% of the
glandular prostatic tissue. The CZ surrounds the ejaculatory ducts throughout their entire courses in the
prostate. The site where the ejaculatory ducts enter the CZ is devoid of prostatic capsule. The
extraprostatic space invaginates around the ejaculatory ducts down to the verumontanum forming the
“invaginated extra prostatic space”. If the ejaculatory ducts are invaded by carcinoma, the tumor will have
a ready “highway” to the seminal vesicles and extraprostatic space.

Correlation of the lobar and zonal concepts of anatomy of the prostate

A comparison of Lowsley lobar and McNeal zonal concepts of anatomy is possible and important to
compare the clinical findings. Clinicians may still refer to lobar anatomy while radiologists use zonal
anatomy. So, the anterior lobe correlates with the anterior fibromuscular stroma. The medial lobe and
the CZ are similar. The sum of the posterior and two lateral lobes correlated to a large extent with the
PZ.

Arterial supply, venous drainage and lymphatic drainage

The arterial supply is derived from the inferior vesical artery, a branch of the internal iliac artery. It
gives off two branches. The urethral branch supplying the urethra, periurethral glandular tissue and
transitional zone and the capsular artery which runs with the cavernous nerves in a neurovascular
bundle supplying the capsule. The prostatic veins coalesce as the dorsal venous plexus that also
receives the deep dorsal vein of the penis and drains into the internal iliac veins. The main lymphatic
drainage is to the obturator and internal iliac nodal groups. Further drainage is through the presacral
or external iliac groups.

Nerve supply
Prostatic plexus. Sympathetic and parasympathetic innervation.

Transurethral Resection of Prostate (TURP)

TURP is the second most common surgical procedure in men over the age of 65. It is also the first
truly minimally invasive, endoscopic surgery via natural orifice with direct access to the offending
pathology. For more than 60 years, TURP has been the undisputed reference standard for elderly
men with lower urinary tract symptoms (LUTS) caused by benign prostatic enlargement (BPE) and
benign prostatic obstruction (BPO). It is also the surgical procedure of choice in men with prostate
adenocarcinoma or bladder neck contracture.

Monopolar TURP
Conventional electro resection is performed by monopolar, HF current with a maximum cutting power
of 200W. A microprocessor-controlled electrical unit with an active electrode that transduces
permanent signals to the processor allows real-time power adjustment. Coagulation depth during
cutting depends on the intensity of the light bow (voltage), so the degree of coagulation is adjusted to
the individual tissue properties. Peak powers in the millisecond range may reach 230 W, but the total
power for TURP is lower than that of earlier generators. Coagulating intermittent cutting was
developed to realise blood-sparing TURP by modifying a standard HF generator.

Intraoperative complications
 Bleeding
 TURS
 Injury of orifices and external sphincter

Perioperative / Early operative complications

 Bladder tamponade
  UTI
 Urinary retention

Long term complications

 Urinary incontinence
 Urethral strictures
 Bladder neck stenosis
 Retrograde ejaculation

Bipolar TURP
In recent years, other techniques, including the use of bipolar TURP (B-TURP) have challenged
conventional monopolar TURP (M-TURP). Bipolar design incorporates the active and return poles on
the same electrode rather than the return pad used in monopolar TURP. Significantly lower voltages
(220–320Vrms) can be used to push electrical current around the bipolar circuit. This is a fraction of
the high voltages (1,000–3,000Vrms) used in monopolar designs. HF energy up to 160W passes
through the conductive irrigation solution which results in a vapour layer of plasma that contains
energy-charged particles that induce tissue disintegration through molecular dissociation, leading to a
lower resection temperature than conventional monopolar systems and thus theoretically reducing
thermal damage to surrounding tissue. The most important innovation was the introduction of bipolar
TURP using normal saline or lactate ringer as the irrigation fluid which eliminates the risk of
electrolytic disturbance from systemic uptake, such as TUR syndrome. Nevertheless, one must be
fully aware that isotonic irrigants will not be able to prevent severe cardiac/pulmonary failure in cases
of large volume uptake.

B-TURP offers a lower risk of bleeding because of the cut and seal effect of the plasma created by
bipolar energy. The resection time can be decreased because of reduced bleeding and improved
visibility. However, during prolonged resection the patients need to be carefully monitored for fluid
load and blood loss as it can be substantial. The electrophysical behaviour of the bipolar current is
also important in the histological analysis of prostatic chips as cautery artefacts translate into difficult
histopathological evaluation of prostatic chips. The histological status of the tumour base will have
great impact on the management plan. Reports indicate that cautery artefacts between bipolar and
monopolar resections are quite similar.

Conclusion
TURP remains the gold-standard therapy for advanced cases with LUTS resulting from BPE and
BPO. It is still unsurpassed for long-term outcome: Currently, only HoLEP reaches the TUR niveau.
A state-of-the-art technique including video resection and continuous-flow instruments ensures
excellent long-term results with low morbidity. The advent of bipolar resection has abandoned the
“rare” TUR syndrome and enables safe endoscopic treatment of larger glands.

Minimally Invasive Methods for the Treatment of BPH

During the past 20 years, this role of TURP in the management of BPH been increasingly challenged
by the development of medical and, particularly, of minimally invasive treatment options, such as intra
prostatic stents, transurethral needle ablation (TUNA), transurethral microwave thermotherapy
(TUMT), Transurethral Incision of Prostate (TUIP), Highly focused ultrasound (HIFU) and laser
procedures. The new minimally invasive techniques have been developed so that they will have less
complications than TURP, less requirement for anesthesia, a shorter hospital stay and if possible will
be less expensive.

Intraprostatic Stents
The idea of using stents for splinting the lobes of the prostate was derived from their original use in
the cardiovascular system, where they are used to prevent arterial re-stenosis after angioplasty.
Fabian first described the use of stents in urology in the year 1980 when he suggested their
usefulness in the treatment of bladder outlet obstruction secondary to prostate enlargement. After
sometime the use of stents was advocated in the treatment of urethral strictures and
subsequent to this the use of prostatic stents became widespread. The major role of prostatic
stents is in the management of patients who are unfit for surgery in which the alternative would have
been a long time or indeed a lifetime of indwelling urethral catheterization. A wide variety of stents are
now available in different lengths, diameters, materials, and designs. These stents can be divided into
2 categories - temporary stents and permanent stents.

Temporary Stents
Temporary stents are tubular devices that are made of either a nonabsorbable or a biodegradable
material. They remain in the prostatic urethra for a limited period of time; they neither become
covered by the urethral epithelium nor become incorporated into the urethral wall. The nonabsorbable
stents need to be removed every 6 to 36 months, depending on which type of material is used. They
can usually be removed, and, if necessary, replaced, without difficulty with the patient under topical
anesthesia with sedation.

Temporary stents are designed for short-term use, to relieve bladder outlet obstruction (BOO),
and to act as an alternative to an indwelling urethral or suprapubic catheter in high-risk
patients considered unfit for surgery. In such patients these temporary stents permit normal
micturition with an acceptable side effect profile. Success rates have been reported in the range of
50% to 90%. They are easy to reposition or replace, but catheterization or cystoscopy cannot be
performed while the stent is in place. Complications are encrustation, migration, breakage, stress
incontinence and bacteriuria. Temporary stents can be spiral stents, polyurethane stents, the spanner
(modification of the Foley's catheter) and bio-degradable stents.

1. Spiral Stents

1.1. First-Generation Stents – The Urospiral (Porges) and the Prosta Kath (Pharma-Plast) are
examples of first-generation spiral stents. The former is made of 21-Fr stainless steel and varies
between 40 and 80 mm in length. The latter is also made of 21-Fr stainless steel but is gold plated
in an attempt to prevent encrustation. It varies in length between 35 and 95 mm. Neither stent
should remain in the prostatic urethra for longer than 12 months. A spiral stent should be inserted
with a 21-Fr panendoscope using either a 30-degree or a 0-degree lens under direct vision and
with the aid of a grasping forceps. It may also be inserted over a catheter guide under ultrasound
visualization. Ultrasonography or endoscopy was used to facilitate stent placement. Retention
was relieved in most of the patients and bladder emptying was complete after the insertion of
these stents. Complications in both groups include clot retention, encrustation, urinary tract
infection, stent migration, stricture formation and failure to void.

1.2. Second-Generation Stents - Other spiral stents have been developed as second-generation
models in an attempt to overcome the problems of the first-generation stents while maintaining
the efficacy and ease of insertion. These are the Memokath and the Prosta Coil.
 The Memokath is made of nitinol, a nickel-titanium alloy, which has the property of shape
memory. It is malleable and heat expandable at a temperature of 45° C to 50° C. Like
other temporary stents, it is easy to insert and maintains its expanded position in the
prostatic urethra. Of 22-Fr caliber, it has a length of 35 to 95 mm. It permits the passage
of a flexible cystoscope and may be left in place for up to 36 months. Hyperplastic growth
of the urethral epithelium through the gaps in the expanded spiral is minimal using the
latest model of Memokath.
 The Prosta Coil is a self-expanding and self-retaining stent made of a nickel-titanium
alloy. It is inserted by being mounted on a 17-Fr delivery catheter under fluoroscopy.
Once released from the mounting it takes the form of a wave-shaped tube whose
diameter varies from 24 to 30 Fr. Its length is from 40 to 80 mm, and it can be left in
position for up to 36 months.

Both these stents can be used in patients who are unfit for surgery. The success rate is
around 80%. Normal voiding with optimal peak urinary flow rates occurs in most of the patients.
Complications occur in a significant minority and include urinary retention, hyperplastic growth of
the epithelium, urgency incontinence, stent failure and stent migration. New models have reduced
such complications as encrustation and urothelial hyperplasia, but stress incontinence and
urgency incontinence still occur, as does displacement of the stent. However, they are easy to
insert and do not require general anesthesia. Although the follow-up is relatively short term, in
most of the reported series, good success rates are reported.
2. Polyurethane stents - There are three types: the intraurethral catheter, the Barnes stent and the
Trestle stent.

2.1. The intraurethral catheter, the first to be introduced is made of a type of polyurethane
known as Puroflex and has a fixed 16-Fr caliber. Its length varies from 40 to 60 mm and it can be
left in place for up to 6 months. It has a double device at its proximal end shaped like the head of
a de Pezzer or Malecot catheter. It has a nylon string at its distal end and a flared split end
proximally, which sits in the bladder. It is inserted under topical anesthesia using a 22-Fr
cystoscope. The nylon string is cut after placement, and any positional adjustment required can
be performed by the use of a grasping forceps. Voiding was normal in most of patients although
the risk of urinary retention was observed in a significant minority. The intraurethral catheter
should not be inserted in the presence of bladder stones or anything else likely to block or have a
ball-valve effect on the device.

The Barnes stent and the trestle stent are used to overcome the
early retentive effects of heat treatment to the prostate
although such a therapeutic strategy effectively doubles the cost
of the treatment and so makes it less attractive. However, it is an
attractive way of overcoming an early complication of heat
treatment.

2.2. Barnes Stent. It has a 16-Fr caliber and is of a single length. It also has a de Pezzer end
proximally, but a single one. It is thus a modification of the original intraurethral catheter. It can
be used in patients undergoing heat treatment to the prostate or in patients who had undergone
endoscopic laser ablation of the prostate (ELAP) with a good success rate. Early stent migration
can occur in a few but the chances for late migration are almost nil. The stent can be inserted with
ease could be removed with ease is relatively inexpensive.
2.3. Trestle Stent. The trestle stent or prostatic bridge catheter has been described and
consists of two tubes and an interconnecting thread. The tube that lies in the prostate has a 22-Fr
diameter and has a 30-degree angulation. The length is 75 mm, and it has a smooth tip. It is to be
used in prostates with a volume of less than 80 mL. The connecting thread is 25 mm, which
passes through the distal sphincteric mechanism. The second tube lies in the bulbar urethra and
is 35 mm long. It is inserted with the patient under topical anesthesia using a delivery system
comprising a positioning stylet, an inflatable balloon with injection cannula, and an outer pusher
tube.

3. The Spanner has a design very similar to the proximal 4 to 6 cm of a Foley catheter. It includes a
balloon to prevent displacement, a port for urine drainage that lies proximal to the balloon, and a
reinforced stent of varying length that spans most of the prostatic urethra. They are only a very few
adverse effects.

4. Biodegradable stents - These stents do not need to be removed, and eventually they disappear
by biodegrading.

Permanent Stents

Permanent stents were initially introduced as treatment for recurrent urethral strictures and were
subsequently used in patients with lower urinary tract symptoms (LUTS). In urologic terms,
permanent stents are being used preferentially for the treatment of detrusor-sphincter
dyssynergia, postbrachytherapy BOO, anastomotic strictures and urinary incontinence after
radical prostatectomy, and complex urethral strictures . Long term follow up of the patients
originally treated with permanent stents are, however, needed to know more about their effectiveness.

 The UroLume endourethral prosthesis is a woven tubular mesh that maintains its position in
the urethra by outward external pressure, thus maintaining the patency of the prostatic urethra.
The original 42-Fr device was made of metal superalloy and varied in length from 1.5 to 4.0 cm. It
is inserted with a special 21-Fr deployment tool using a 0-degree panendoscope. Gradually,
epithelialization occurs, ideally in a smooth manner, covering the individual wires of the mesh.
The stent can be removed by securing about 5 mm of the distal aspect in the jaws of a grasping
forceps and then pulling the distal end inside a resectoscope sheath to minimize any possibility of
 urethral trauma while removing it.
 The ASI stent - It is introduced on a balloon, which is then inflated, thus expanding the stent.
Although improvement in symptom scores were obtained, several complications also occurred
that made it less attractive for general use. It has since been withdrawn from production.
 The Ultraflex stent is made of nickel-titanium alloy that also has a capacity to expand to a
caliber of 42 French when exposed to body heat. It is available in lengths varying from 2 to 6 cm.
It has been used in patients with prostatic obstruction and with detrusor-sphincter dyssynergia.
The incidence of epithelial hyperplasia and migration is very low.

Conclusion
Originally, permanent prostatic stents were introduced as a definitive treatment for prostatic
obstruction, particularly for patients unfit for prostatic surgery who presented with urinary retention.
Patients were able to void satisfactorily in most cases, but complications were relatively high. Urolume
and the other stents have not yet received attention in the literature as a specific treatment for BPH.
Temporary stents are receiving widespread attention, but the original idea that they should be used as
a temporary expedient to overcome outflow problems in the medically unfit population is being
modified. The newer stents, whether biodegradable or not, are being viewed as possible methods of
overcoming the temporary retention that can occur secondary to treatments such as laser therapy or
high-energy TUMT.
Transurethral Needle Ablation of the Prostate (TUNA)
Heat treatment of whatever kind to the prostate is intended to reduce outflow resistance and the
volume of the obstruction by increasing the temperature to above 60° C within the prostate. This will
induce necrosis of prostatic tissue. The underlying
principle being TUNA technology is to induce
necrosis within the prostatic parenchyma, sparing
the urethra to minimize post-operative side effects.
Transurethral needle ablation of the prostate (TUNA)
uses low-level radiofrequency (RF) energy that is
delivered by needles into the prostate and that
produces localized necrotic lesions in the hyperplastic
tissue. It has previously been used to ablate cardiac
nerve bundles in the Wolff-Parkinson-White syndrome
and to destroy malignant tissue. The advantage of
TUNA is that it can be delivered under topical
anesthesia to patients with symptomatic BPH, causing
very precise and reproducible lesions within the
prostate. The patient most likely to benefit from TUNA would be one who had lateral lobe enlargement
and a prostate of 60 g or less.

Transverse section of human prostate at veru montanum plane (v), demonstrating gross appearance
of TUNA lesion. Thermal ablation lesion is seen within left lobe 2 weeks in vivo following TUNA
procedure as compared with right untreated lobe (control). Well-demarcated thermal ablation lesion
(1.3-cm diameter) appears congested and severely hemorrhagic.

(A) Transverse section of prostatic lobe (in vitro) showing pale, gross appearance of TUNA lesion, with needles in
situ, (B) Same lesion shown without needles.

Transurethral Microwave Therapy (TUMT)

Transurethral microwave therapy has been much evaluated in the past decade and has been widely
used. The current transurethral method has developed from the early transrectal devices that supplied
heat ranging from 42° C to 44° C. The results with this early form of treatment were rather
disappointing, and transurethral catheters were developed that would allow higher temperatures to be
used while cooling the urethral mucosa. The procedure involves insertion of a specifically designed
coude-type catheter into the bladder allowing a microwave antenna to be properly positioned within
the prostatic fossa. It uses radiant heating to destroy the prostate tissue. One major distinction
between different TUMT devices is the presence or absence of cooling systems. The two most
commonly used devices are the Prostatron and the Targis. They are “high energy” TUMT devices
containing a microwave antenna, a closed water-cooling circuit and a retention balloon. The cooling
fluid in the catheter maintains the urethral temperature at about 44° C or lowers while producing
temperatures within the prostate of up to 70° C. The Prostatron has three different types of software
programs, ranging from relatively low to higher energy: the Prostasoft 2.0, 2.5 and more recently.

Method of Action
The effect of TUMT on prostatic tissue has been studied widely, and a number of different theories
have been presented. These cover heat changes and differential blood flow in the prostate,
coagaulative necrosis of the tissue, damage to the sympathetic nerve endings and induction of
apoptosis.

TUMT versus TURP

 TUMT offered less morbidity than TURP but was not as effective as TURP in improving
symptoms or reducing BOO.
 TUMT does not have a measurable effect on the prostate because the elasticity of the
urethra is increased after treatment.
 The symptomatic improvement that occurs after TUMT seems to be energy related.
 TUMT is associated with a lengthy period of catheterization after treatment, thus causing
the higher rates of urinary tract infection and urinary retention.
 The sexual side effects such as erectile dysfunction and retrograde ejaculation were
significantly less common than after TURP.
 TUMT can be performed as a day case with the patient under mild sedation is an important
positive side of the procedure.
 The success associated with this treatment cannot be guaranteed in every patient, as can
be seen from the relatively high number of nonresponders in many series.

Contraindications
 Penile or urinary sphincter implants
 Metallic implants in the region of hips or pelvis
 Urethral stricture disease
 Peripheral arterial disease with intermittent claudication
 Patients post radiation therapy to the pelvic area

Transurethral Incision of Prostate (TUIP)

TUIP is a minimally invasive surgical procedure to treat BPH. An instrument that generates an electric
current or laser beam is introduced through the urethra to make incisions in the prostate where the
prostate meets the bladder. Cutting muscle in this area relaxes the opening to the bladder, decreasing
resistance to the flow of urine out of the bladder. No tissue is removed and is done under general or
spinal anesthetic. TUIP usually requires an overnight stay in the hospital and a catheter is left in the
bladder 1 to 3 days after surgery. The rates of developing complications after TUIP are as follows :
retrograde ejaculation 6-55%, erection problems (4-25% and incontinence (1%). Almost 10% of the
patients require a re-operation after 15 years.

Transurethral Electrovaporization of the Prostate (TUVP)

TUVP is one of the recent promising minimally invasive procedure to treat BPH. This was first
described by Bush et al in 1993, who used a grooved ball electrode and pure cutting current to sculpt
out the prostatic bed, and claimed advantages of little or no bleeding, minimal fluid absorption and
electrolyte imbalance. The most extensively studied instrument for electro vaporization is the
VaporTrodes, a grooved electrode from Circons, ACMI. Recently, three studies using a spiked
electrode from Storz were published according to which the efficacy, safety and durability of TUVP
was equal to TURP.

Heat damage during prostate vaporization

A high cutting current is which generates a significant amount of heat during the electrovaporization of
the prostate. The potential heat damage to the vital periurethral structures during prostate
vaporization with VaporTrodes or conventional TURP was clinically evaluated by Patel et al, in a
prospective study. The results showed that there was no significant rectal or sphincteric heating with
either procedure. The extra energy used during TUVP provided the benefit of improved coagulative
haemostasis concurrently with tissue vaporization without compromising treatment safety.

Histopathological changes after prostate vaporization include a zone of coagulative necrosis 1-2 mm
deep at the base of crater adjacent to the normal prostate tissue.
 TUVP vs TURP
 Reduced blood loss in TUVP as compared to TURP groups
 No incidence of TUR syndrome after TUVP
 Shorter catheterization time (mean -30h) and consequently shorter hospital stay (mean 1.4
days) in TUVP patients
 Irritative symptoms slightly more common postoperatively in the vaporized patients
 The detrusor pressure at peak flow reduced significantly after vaporization and was
comparable to that of the TURP groups
 Comparable and durable improvement in symptom score of 73% and mean Q max of 20ml/s
postoperatively up to one year

Long-term complications of TUVP compared to TURP

 Incontinence occurs in about 2% of the patients which is slightly higher than that of TURP
(1%)
 Urethral stricture and bladder neck stenosis after TUVP is comparable to that of TURP (1-3%)
 Reoperation rate of about 13% in 3 years for both the procedures
 Erectile dysfunction is higher post TUVP (12%) as opposed to TURP (5%)
 Retrograde ejaculation is comparable in both groups (80-85%)

One of the drawbacks of TUVP is that prostate vaporization does not provide tissue for histological
examination. Therefore, the incidental finding of prostate cancer, which is historically present in
approximately 10% of men having TURP for apparently benign disease, may be missed. This issue of
incidental finding of prostate cancer may be overcome by obtaining a prostate chip for histological
examination using the standard loop before starting the vaporization.

Is TUVP suitable for prostates larger than 60 g?

In all the PRT reviewed, the size of the prostate was less than 60 g. Although vaporization is suitable
for larger prostates, it takes longer to vaporize these prostates than to resect them. Some authors
suggested the use of the ‘sandwich technique therapy’ for prostates larger than 60 g where they
initially performed vaporization using smooth roller electrode followed by resection with standard loop
for rapid tissue removal, and finally the use of the roller electrode for haemostasis. Others used a
modified loop resection followed by electrovaporization to achieve optimal results for prostates larger
than 40 g. Unfortunately, there are no prospective randomized trials to compare prostate vaporization
to resection in prostates larger than 60 g.

Overview of Lasers for BPH

Laser technology has been applied to treat LUTS secondary to BPH for more than 15 years. It has
been popularized in the recent days due to technological advancements, growing clinical experience
and the development of newer techniques. Various lasers have been introduced as alternatives to
TURP, mainly the neodymium: yttrium aluminium garnet (Nd:YAG), the holmium (Ho):YAG, and the
frequency-doubled Nd:YAG (potassium titanyl-phosphate [KTP]) laser.

1) Nd:YAG laser - The Nd:YAG laser is a solid-state laser. Its wavelength (1064 nm) is invisible and
has a very low absorption coefficient in most tissues so that it penetrates tissue deeply between 4 and
18 mm. Therefore, the energy density in tissue is low resulting in coagulative necrosis. Resection and
enucleation of prostatic tissue is impossible although excellent hemostasis is achieved.

 VLAP (Visual laser ablation of the prostate) has been performed since the early 1990s as a
transurethral procedure under general or spinal anesthesia. Although no tissue is obtained for
histologic analysis, the reduction of prostate volume is greater than TURP and so are the
improvement in symptom score and peak flow rate. The need for blood transfusions and the
incidence of stricture formation is almost nil post VLAP. However due to the unpredictable outcome,
high reoperation rate, and long-term retention requiring extended catheterisation up to 4 weeks VLAP
is not currently used
 Interstitial laser coagulation (ILC) - In this procedure, the laser fiber is pushed into the prostatic
adenoma under endoscopic control and the laser energy is emitted radially into the tissue, which
causes heat-induced coagulative necrosis. The intraprostatic lesions undergo reabsorption and
secondary atrophy lasting one to three months, which finally results in some volume reduction of the
prostate. No tissue is obtained for histologic analysis. The main advantage of ILC is that it can be
used for treating outpatients as it has been successfully performed under local anesthesia although
in most cases, it is performed under general or spinal anesthesia. Improvement in the symptom and
flow rates is almost comparable to that of TURP. However, the early postoperative morbidity is high,
a long postoperative catheterisation (2 – 4 weeks) is required and urinary tract infection develops in
as many as 35% of patients. The retreatment rate is also significantly high and therefore ICL is
recommended only for selected BPH patients suffering from coagulation disorders.

2. Frequency-doubled Nd:YAG laser (KTP laser / green light laser / photo selective
vaporization of the prostate {PVP})

When the Nd:YAG laser beam is passed through a potassium-titanyl-phosphate (KTP) crystal, it
doubles its frequency and halves its wavelength. The invisible 1064 nm wavelength of the Nd:YAG
laser is shifted to a 532 nm wavelength, which is within the green light spectrum. The frequency-
doubled Nd:YAG laser is therefore also called KTP laser or ‘‘green light’’ laser. The wavelength is
not absorbed by water but strongly absorbed by haemoglobin. Because of the instant and nearly
complete absorption in blood, the absorption length in vascularised tissue such as the prostate is only
1–3 mm, and the high-energy density causes rapid photo thermal vaporisation of intracellular water
(photo selective vaporisation of the prostate [PVP]). The short depth of coagulation prevents the
large-volume sloughing that is seen with the Nd:YAG laser alone. Like all other vaporising modalities,
a channel is created through the adenoma to a variable degree to produce a TUR-like cavity.

The complications are minimal and the rates of recatherisation, dysuria, urinary tract infection,
incontinence, urethral strictures, and bladder-neck contractures are low and in the same range as in
TURP and HoLEP. The greatest advantage is that almost no intraoperative or postoperative blood
transfusion is required and hence, PVP is feasible in high-risk anticoagulated patients, even if large
prostates are to be treated.

3. Ho:YAG laser
The holmium laser is a pulsed solid-state laser with a wavelength of 2140 nm. It is strongly
absorbed by water. The absorption length in prostatic tissue is only 0.4 mm, and the resulting energy
density is high enough to heat prostatic tissue to temperatures in excess of 100 C, which creates
vaporisation without deep coagulation. This allows clean char-free and precise cutting, incision and
dissection of the prostatic lobes under endoscopic control when the laser fibre is brought into direct
contact with and moved through the prostate. Dissipating heat causes simultaneous coagulation of
small and medium-sized vessels, to a depth of 2–3 mm. These unique properties of the holmium
laser can not only make it a useful tool for prostate surgery but also the ideal intracorporeal
lithotripter for virtually all stones and an ideal wavelength for endoscopic multiple soft-tissue
applications such as ablation of tumours and incision of strictures of the upper and lower urinary tract.

 HoLAP was first reported in 1994. A side-fire fibre is moved in a ‘‘painting’’ near-contact mode
across the surface of the prostatic lobes to immediately vaporise/ablate prostatic tissue and
obtain a prostatic cavity reminiscent of that obtained with traditional TURP. Invisible deep tissue
damage as in VLAP or ILC is impossible and only what we see is what is destroyed. This method
is easy to learn and very adequate in smaller glands. Ablation by vaporisation with the newer 100
W machines allows more effective power settings with better operative times. With this technique
there is a significant improvement in the peak flow rates, maximum flow rates and mean AUA
scores The reoperation rate is also low. When compared with TURP, HoLAP is associated with
less bleeding, a shorter hospital stay and routine next day catheter removal and patient
discharge.

 HoLRP and subsequently HoLEP were developed to increase the efficacy of HoLAP. In
HoLRP, the laser fibre cuts the prostatic lobes into pieces small enough to be evacuated through
the resectoscope sheath, while dissecting the adenomatous tissue down to the prostatic capsule
to create a TUR like cavity. The development of a transurethral mechanical tissue morcellator has
enabled a true enucleating technique. In shelling out the adenoma, the laser fibre moves in
exactly the same plane as the surgeon’s index finger does when performing open prostatectomy.
 The prostatic lobes are enucleated in their entirety and pushed into the bladder where they are
fragmented and aspirated with the morcellator. The excellent hemostatic properties of the
holmium wavelength and the use of iso-osmotic saline solution as irrigating fluid enable
operations to be performed on prostates of all sizes. The transfusion rate is minimal, and TUR
syndrome cannot develop. Studies on several hundred patients have demonstrated that HoLEP is
a true endourologic alternative to open prostatectomy in large prostates, and glands of >300 g
have been successfully enucleated. In addition, patients who are normally considered unfit for
TURP, that is, those with significant comorbidities, such as coagulopathy, anticoagulant
dependency, and significant anemia, can be treated safely with the holmium laser.

HoLEP is the first and only endourologic procedure that has been shown to provide better
relief of bladder outflow obstruction in urodynamic studies than TURP. A comparison of 120
patients randomised to open prostatectomy or HoLEP was made. There were no differences in
symptom scores, peak urinary flow rates, and residual urine volumes. The amounts of tissue that
were removed indicate that HoLEP is the endoscopic equivalent to open prostatectomy.

HoLEP also produces lasting improvement of micturition. The comparison of HoLEP with open
prostatectomy showed that HoLEP was equivalent in improving symptoms, residual urine volumes,
and flow rates at 6 months, 18 months and 3 years. Mean catheterisation time and hospital stay were
1–2 and 1–3 days, respectively. The pooled results of large case series revealed low complication
rates of recatheterisation (2.9%), urinary tract infection (2.3%), urethral stricture/bladder-neck
contracture (3.2%), and reoperation (2.8%). The perioperative mortality rate was 0.05% (1 of 1847
patients).

HoLRP/ HoLEP compared very favourably with TURP and open prostatectomy in randomised trials.
The operation time was significantly longer in the HoLEP group, but the perioperative morbidity was
significantly lower. The blood loss was significantly less, and no blood transfusions were required.
The catheter time and hospital stay were significantly shorter. In large prostates of >100 g weight,
the rate of urethral strictures/bladder-neck contractures was identical in HoLEP and open
prostatectomy. In randomised trials the reoperation rate of HoLEP at 3 and 4 yr after operation were
just as low as in TURP and open prostatectomy. In a large series on >200 patients with an average
enucleated tissue weight of 70 g, 90% of patients were discharged home on postoperative day 1 or
earlier without a catheter.

Future Directions for treating BPH

 Gene therapy using PSA-HSV-TK gene expression cassette
 Phosphodiesterase Inhibitors
 Botulin Toxin
 Vitamin D3 Receptor Analogs
 LHRH (GnRH) Antagonist and Progestogens
 Hydroxytamoxifen
 NX-1207 and PRX302
 Combination of Finasteride and a COX-2 inhibitor

FACTORS OTHER THAN BPO THAT CAUSE BOO in men

 Posterior urethral valves
 Dysfunctional voiding is being increasingly recognized as a component of chronic pain in
LUTS syndromes, such as chronic prostatitis.
 Neurogenic-based DSD (Detrusor Sphincter Dysynergia) is commonly seen in various
spinal cord and suprasacral neurologic processes.
▪ True dyssynergia is limited to spinal lesions that are suprasacral but infra-pontine
in location.
▪ Pseudodyssynergia has been attributed to bradykinesia of the sphincter in
Parkinson’s disease and may also be present in other movement disorders, such as
multiple systems atrophy.
 Primary bladder neck obstruction in men is a much more common entity than in women,
with incidence more substantially weighted towards younger men. The contribution of smooth
muscle tone as a basic etiology for primary bladder neck obstruction in men has been well
documented.
 Genitourinary tuberculosis
Madhu Sudan Agrawal, Manoj Sharma

Introduction

Globally, tuberculosis (TB) is a leading cause of death from infectious disease, second only to AIDS.
Its impact on the society is huge; also because it affects mainly young adults in their most productive
years, with two-thirds of cases estimated to occur among people aged 15-59.

In 2011 there were 8.7 million new cases of TB and 1.4 million deaths (this includes 430,000 deaths
among people who were HIV-positive). Incidence of tuberculosis in developing countries is 440 per
10000 population, in developed world the incidence is 13/10000 population. The vast majority of
deaths from TB, over 95 percent, are in the developing world.

The genitourinary system is a common site of extra-pulmonary tuberculosis (TB), accounting for 15-
20% cases of total extra pulmonary TB.i GUTB in developing countries comprises approximately 15-
20% of extra-pulmonary cases of TB while in developed world this figure is 8-10%. Approximately
4%–8% of patients with pulmonary tuberculosis will develop clinically significant genitourinary infection.

Genitourinary tuberculosis (GUTB) may involve the kidneys, ureter, bladder, or genital organs. Clinical
symptoms usually develop 10-15 years after the primary infection. Only about a quarter of patients
with GUTB have a known history of pulmonary TB; about half of these patients have normal chest
radiography findings. ii

Etiology

The most common pathogen associated with TB is Mycobacterium tuberculosis.

Uncommonly implicated pathogens include the following:
 Mycobacterium kansasii
 Mycobacterium fortuitum
 Mycobacterium bovis
 Mycobacterium avium-intracellulare
 Mycobacterium xenopi

Pathophysiology

Generally primary infection is in form of pulmonary tuberculosis. Genito-urinary tract is believed to be

involved secondarily, usually after an interval of several years.

Kidney
Tuberculosis may involve the kidney as a part of generalized disseminated infection or as localized
genitourinary disease. Kidney is usually infected by hematogenous spread of bacilli from the primary
focus of infection.

Multiple granulomas form at the site of metastatic foci. In the kidneys, they are typically bilateral,
cortical, and adjacent to the glomeruli and may remain inactive for decades. iii Although both kidneys
are seeded, clinically significant disease usually develops in only one kidney. The medullary
hypertonic environment impairs the phagocytic function.

A single ulcer develops in cortex adjacent to blood vessels. This ulcer breaks into pelvi-calyceal
system, spreading the bacilli to the renal pelvis, ureters, bladder, and other genitourinary organs.
Depending on the status of the patient's defense mechanisms, fibrosis and strictures may develop
with chronic abscess formation. Extensive lesions can result in nonfunctioning kidney. Hypertension in
persons with renal TB is twice as common as it is in the general population.

Ureter
Tuberculous ureteritis is always an extension of the disease from the kidney. Ureteral TB develops in
about half of all patients with renal TB. Ureteral TB often causes ureteral strictures and
hydronephrosis. The commonest site is the lower third of ureter or the uretero-vesical junction.
Occasionally, severe cases can cause stricture of virtually the entire ureter. Such type of strictured
ureter takes the form of corkscrew or pipe stem ureter. In such patients, the kidney shows extensive
disease, is often non-functioning, and may be calcified.

Bladder
Bladder lesions are without exception secondary to renal TB. The earliest forms of infection start
around one or another ureteral orifice. It initially manifests as superficial inflammation with bullous
edema and granulation. Fibrosis of the ureteral orifice can lead to stricture formation with
hydronephrosis or scarification (i.e., golf-hole appearance) with vesicoureteric reflux.
Severe cases involve the entire bladder wall, where deep layers of muscle are eventually replaced by
fibrous tissue, thus producing a thick fibrous bladder with progressive reduction of bladder capacity
(Thimble bladder)iv.

Prostate
Prostatic TB is also the result of hematogenous spread, but involvement is rare. In many cases
pathologist diagnose it incidentally after TURP. On DRE it feels like a firm granulomatous nodule, and
needs to be differentiated from malignacy. Very rarely in acute fulminating cases it spreads rapidly
and presents as peri-anal sinus.

Epididymis and testis

The higher frequency of isolated epididymal TB lesions in children favors the possibility of
hematological spread of infection, while adults seem to develop tuberculous epididymo-orchitis
caused by direct spread from the urinary tract through retrograde route. The formation of a draining
sinus is uncommon in developed countries, but epididymal induration and beading of the vas are
common.

Involvement of the testis is usually due to direct extension. Infertility may result from bilateral vasal
obstruction. Nodular beading of the vas is a characteristic physical finding. Orchitis and the resulting
testicular swelling can be difficult to differentiate from other mass lesions of the testes.

Clinical Presenatation

Symptoms
The presentation is often vague, and physicians must have a high degree of awareness to make the
diagnosis. Symptoms are generally chronic, intermittent, and nonspecific. Genitourinary tuberculosis
(GUTB) often manifests as repeated urinary tract infections that do not respond to the usual
antibiotics.

Persons with GUTB rarely display the typical symptoms of TB. The most common symptoms are
urinary frequency, urgency, dysuria, suprapubic pain, blood or pus in the urine, and fever. Urinary
urgency is unresponsive to all treatment when the bladder is extensively involved.
Gross hematuria occurs in approximately 10% of cases and is usually total and painless. Microscopic
hematuria is present in around 50% of cases. Asymptomatic patients are not uncommon.
Unexplained infertility in both men and women may be attributable to GUTB.

Examination
Physical examination is typically unremarkable. Renal tuberculosis usually does not present with any
positive physical signs. Tender testicular or epididymal swelling, nodularity and beading of the
spermatic cord and vas may be the most tell-tale physical signs of genitor-urinary tuberculosis one
can find. In late cases, epididymo-cutaneous sinus formations may develop.

Investigations

Lab Studies
 Tuberculin skin test results are positive in about 90% of patients, but this finding denotes
only prior exposure to mycobacteria rather than active disease.
 Complete blood cell count, sedimentation rate, serum chemistry, and C-reactive protein
studies are helpful to assess the severity of disease, renal function, and response to
treatment.
  AFB smear: Serial early-morning urine collection for acid-fast smear (at least 3) is a specific
v
(89-96%) but less sensitive (approximately 52%) tool.
 AFB urine cultures are still considered the criterion standard for evidence of active disease,
with sensitivity of 65% and specificity of 100%. Every effort should be made to process the
samples immediately after collection. Sending cultures before starting anti-tubercular
treatment and adjusting therapy according to sensitivity in case of resistance is always
recommended. The following methods are available:
 Solid media: The Lowenstein-Jensen medium yields results in more than 4 weeks.
 Radiometric media: The BACTEC 460 medium yields results in 2-3 days.
 PCR: The polymerase chain reaction (PCR) test has been extensively studied and has been
proven highly sensitive, specific, and rapid. In various studies, data show sensitivity ranging
from 87-100% (usually >90%) and specificity from 92-99.8% (usually >95%). Compare this
with cultures (37%), bladder biopsies (47%), and intravenous pyelography (IVP) examinations
(88%). Along with an accurate clinical assessment, PCR is the best tool available for avoiding
vi vii
a treatment delay because results are available in only about 6 hours. , The following PCR
tests are available with near-equivalent quality:
i) Genus-specific 16S rRNA PCR test
ii) Species-specific IS6110 PCR test
iii) Roche Amplicor MTB PCR test
iv) Amplified Mycobacterium tuberculosis Direct Detection Test (AMDT)
 TB PNA FISH: Fluorescence in situ hybridization (FISH) using peptide nucleic acid (PNA)
probes allows differentiation between tuberculous and non-tuberculous mycobacteria in
smears of mycobacterial cultures. PNA molecules are pseudopeptides with DNA-binding
capacity in which the sugar phosphate backbone of DNA has been replaced by a polyamide
backbone.
 Nucleic acid amplification (NAA): Nucleic acid amplification allows both detection and
identification of M tuberculosis through enzymatic amplification of bacterial deoxyribonucleic
acid (DNA). The most widely used technique is PCR, but transcription mediated amplification
(TMA) and strand displacement amplification (SDA) are also commercially used. The
sensitivity of this test is higher than that of smear microscopy but it is slightly lower than that
of culture techniques. The main advantage of these tests is that they offer quick results,
paired with a high level diagnostic accuracy.
 Transcription mediated amplification (TMA). AMPLIFIED MTD (Mycobacterium Tuberculosis
Direct) Test: TMA can identify the presence of genetic information unique to M tuberculosis
directly from pre-processed clinical specimens. AMPLIFIED MTD Test (Gen-Probe, Hologic)
detects Mycobacterium tuberculosis ribosomal ribonucleic acid (rRNA) directly and rapidly,
with sensitivity similar to that of culture techniques. The sensitivity of this test is of 96% and its
specificity is 100% for M tuberculosis on specimens that are smear-positive for acid-fast
bacilli. One other disadvantage of the technique is that positive results are recorded for both
viable and dead bacilli.

Imaging Studies
Radiography
 Chest and spine radiographs may show old or active
lesions. In 50% of patients, chest radiographic findings
are negative.
 Kidney, ureter, and bladder (KUB) radiographs reveal
calcifications in the kidney and ureter in approximately
50% of patients. Calcifications are intraluminal, as
opposed to schistosomiasis, which produces intramural
calcifications. Calcifications in the bladder are
uncommon.

Intravenous Urography
 These tests are the standard diagnostic imaging studies Fig 1: IVU: Early GUTB
for renal TB and have 88-95% sensitivity. They also help
define the extent and severity of disease. Approximately
10%–15% of patients who present with active renal
viii
tuberculosis will have normal urographic findings.

Fig2 IVU: Advanced GUTB

  The earliest radiographically detectable changes are cavitary lesions that progress to the
papilla and invade the collecting system, causing calyceal disruption. Findings of infundibular
stenosis and multiple ureteral strictures are highly suggestive of renal TB. Later findings may
include calcifications, scarring, stricture formation. Triangular ring like calcifications within the
collecting system are characteristic of papillary necrosis. ix A nonfunctioning or extensively
diseased kidney indicates irreversible tuberculous disease. A small contracted bladder
suggests extensive bladder TB. (Fig 1-2)

Sonograms
 Ultrasongraphy may reveal cystic or cavitary lesions, cortical scarring, hydronephrosis, and
x
abscess in kidneys; ultrasonography is very sensitive in testicular TB. (Fig 3)
 In recent years, high-resolution transrectal
ultrasonography (TRUS) has become a very useful
noninvasive technique. TRUS can reveal abnormalities in
the seminal vesicles and ejaculatory duct and can help
assess the status of the prostate.

CT scan
This imaging test is increasingly being used as the primary
modality of investigation in disorders of the genitor-urinary tract. It Fig 3: USG: Early Changes of
is a very sensitive investigation, and can detect disease in early GUTB
stage (Fig 4). It is a useful adjunct to IVP and is helpful in late or
advanced disease for assessing the extent of disease xi
This study is very sensitive for detecting calcification and
thickened walls of the ureter and bladder. xii

Retrograde pyelography is rarely indicated now except

in patients with renal failure in whom the kidneys cannot
excrete contrast and to evaluate stricture in the upper
urinary tract. It also helps for sampling urine from
individual kidneys for microbiology.

Diagnostic Procedures
 Diagnostic Laparoscopy: The discovery of
peritoneal tubercles during tubal ligation is not Fig 4: CT: Early Changes of GUTB
uncommon in developing countries.
 Biopsies of genital ulcers; tubercles in the bladder, especially if scattered away from the
ureteric orifice (an uncommon feature of bladder TB); and any lesion with even a slight
possibility of malignancy. The yield of biopsy for TB is about 45%.
 Fine-needle aspiration (FNA) as a minimally invasive technique plays a prime role in the
diagnosis of tubercular epididymitis and epididymo-orchitis. Acid-fast bacilli (AFB) may be
detected on FNA smears in up to 60% of these patients.
 Histology Findings: Findings include granuloma with central Langerhans cells surrounded
by lymphocytes, fibrocytes, and epithelioid cells, which later progress to central caseous
formation and varying degrees of fibrosis and calcification

Treatment

Medical Care
Genitourinary tuberculosis (GUTB) responds better to a short course of treatment than pulmonary TB
because GUTB carries a lower mycobacterial load. Also, isonicotinic acid hydrazide (INH) and
rifampin penetrate well into the cavitary lesions associated with GUTB. A high concentration of INH,
rifampin, and pyrazinamide are maintained in urine.

The primary aims of treatment are to preserve renal parenchyma and function, to make the patient
noninfectious, and to manage co- morbid conditions. Standard treatment is rifampin, INH,
pyrazinamide, and ethambutol for 2 months, then rifampin and INH for 4 more months unless
resistance to either agent exists. In cases of resistance to first line drugs, culture and sensitivity
reports need to be obtained and the regimen changed if necessary. Aminoglycosides and quinolones
are the most commonly used second line / adjunct drugs.
Drug doses:
 INH (Isoniazid) 300 mg PO
 Rifampicin 600 mg PO
 Pyrazinamide 1.5 – 2.5 g PO
 Ethambutol 15 – 25 mg/kg PO
 Streptomycin 15 mg/kg

 In patients who are HIV-positive, continue treatment for a total of 9 months to one year.
 Special considerations apply to patients with impaired renal function. Rifampicin, isoniazid,
pyrazinamide, ethionamide, and prothionamide may be given in normal doses because they
are either eliminated in the bile or broken down to metabolites. Ethambutol and
aminoglycosides should be avoided in these patients.

Steroids
Indications:
 Severe bladder symptoms
 Tubular structure involvement (e.g., ureter, fallopian tubes, spermatic cord)
High-dose prednisone (i.e., at least 20 mg tid) for 4-6 weeks is recommended because rifampicin
reduces effectiveness and bioavailability of prednisone by 66%.

Surgical Care

Although chemotherapy is the mainstay of treatment, surgical intervention, either as ablation or

reconstruction, is often required during the course of GUTB. Generally, at least 4-6 weeks of
chemotherapy with appropriate agents is first tried if immediate surgery is not necessary. In a recent
European series, the overall frequency of surgical management in GUTB in the past 20 years was
0.5% of total urological surgical procedures.

A) Ablative surgery
a) Nephrectomy / Nephro-uretrectomy
Indications
 Non-functioning kidney with or without calcification
 Extensive disease involving whole kidney, with hypertension, UPJ obstruction
 Coexisting renal carcinoma
b) Partial nephrectomy
Indications
 Localized polar lesion containing calcification that has failed to respond after 6 weeks of
intensive chemotherapy.
 An area of calcification that is slowly increasing in size and is threatening to destroy
kidney.
c) Epididymectomy
Indication: Caseating abscess not responding to chemotherapy

B) Reconstructive surgery
a) Ureteric stricture: Reconstructive surgery is required most commonly for stricture of ureter
either presenting at the time of initial diagnosis or developing during the course of anti-
tubercular treatment due to fibrosis.
Strictures of the lower end of the ureter occur in approximately 9% of patients. If obstruction
at the lower end of the ureter is present at the start of chemotherapy, careful observation is
required. These strictures may result from edema, and they respond to chemotherapy. The
patient should receive chemotherapy and should be monitored by ultrasonography and / or
intravenous urograms at regular intervals. Corticosterioids can be added to chemotherapy if
there is deterioration or no improvement after 3 weeks.

a) Endoscopic management: If there is deterioration or

no improvement after a 6-week period, mild strictures in
early stages of the disease can be managed by endoscopic
means. Balloon dilatation and placement of double J

Fig 6: Psoas hitch procedure

stent can help resolve the obstruction and give permanent relief in a significant proportion of
patients.

b) Surgical management: Surgical repair of the stricture is carried out if an initial attempt at
dilatation has failed. Since lower third of ureter including the uretero-vesical junction is the
most common site of stricture in these cases, ureteric reimplantation into the urinary
bladder is the most appropriate treatment. This can be done by either trans-vesical Politano-
Leadbetter submucosal tunneling technique, or the Lich extra-vesical approach (Fig 5 a-c).
Psoas hitch (Fig 6) or Boari flap (Fig 7) procedures may be required if the length of ureter is
found to fall short for direct uretero-neocystostomy.

Fig 5 a, b, c : Politano-Leadbetter uretero-neo-cystostomy

For the less common strictures of the middle third of the ureter, excision of the stricture and
spatulated end-to end uretero-ureterostomy is the first choice (Fig 8 a, b, c). Alternatively,
especially in case of difficulty due to short length of ureter, the Davis intubation ureterotomy
technique should be chosen. The stent should be left in place for at least 6 weeks.

Fig 7 a, b, c : Boari flap procedure

Fig 9: Ileal replacement of

Fig 8 a, b, c : End-to-end Uretero-Ureterostomy ureter

Finally, in patients where the entire length of ureter is strictured, and unsalvageable, the final
choice may be ileal replacement of ureter, which is done transperitoneally, using a
vascularised iso-peristaltic segment of ileum. (Fig 9) The proximal end of this defunctionalised
ileal segment is anastomosed to the proximal unobstructed part of ureter or the renal pelvis,
and the distal end is attached directly to the urinary bladder.
 b) Augmentation cystoplasty: In advanced stages, the bladder capacity is severely reduced
due to fibrosis, resulting in contracted (thimble) bladder. The patient typically presents with
severe frequency of micturition, both day and night, together with pain urgency and
hematuria. In early stages, symptoms can be relieved with medical treatment, but once
fibrosis is advanced, no relief can be obtained by any medical therapy. The treatment of
choice in these cases is augmentation cystoplasty. A vascualrised segment of terminal ileum
or sigmoid colon is defunctionalized, detubularised, and attached to the bivalved urinary
bladder to increase its capacity. (Fig 10)

GUTB & Immuno-deficiency (HIV-Positive Individuals)

Approximately 10% of all cases of tuberculosis worldwide are
HIV related, but in sub-Saharan Africa, the percentage is much
higher, as high as 60% in some regions. The incidence is
expected to rise in Africa and also in Asia. Tuberculosis was the
cause of death in approximately 30% of the 3 million patients who
were dying of AIDS in 1999xiii. In those who are only mildly
immune-suppressed, the disease resembles that in HIV-negative
individuals. In the more profoundly immune-suppressed,
particularly those with CD4+ T-cell counts of 50/cu.mm or lower,
a high viral load, and a negative tuberculin test, the disease often
is disseminated and the kidney is involved incidentally with
various pathologic manifestations, including granulomatous
interstitial nephritis. The incidence of renal involvement may be
higher than currently believed. In an autopsy study in India, 24 of Fig 10: Augmentation cystoplasty
35 kidneys from patients who died of AIDS showed evidence of
infection, including 17 cases of tuberculosis. In a similar study in Mexico City, renal disease was
demonstrable in 87 of 138 (63%) autopsies on AIDS patients: infection was the cause of the renal
disease in 36 cases, with 19 being due to M. tuberculosis. xiv

GUTB in CA Bladder
An acute mycobacterial cystitis commonly is induced by local instillation of BCG for the treatment of
urothelial carcinoma in situ and superficial bladder cancer. Usually this causes only a self-limiting, low-
grade, superficial cystitis, but sometimes the inflammatory reaction is more severe. Cases of
disseminated infection have been recorded, and ureteric involvement with ureteric obstruction was
observed in 0.3% cases in a large series xv. Renal involvement was found in 0.1% of the 2602 patients
in this series, presumably from ascending infection rather than hematogenous spread. Histologically,
the lesions caused by BCG are indistinguishable from those seen in classical tuberculosis, and
caseation may be present. Organisms may be demonstrated by standard techniques such as Ziehl-
Neelsen staining.

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14. Soriano-Rosas J, Avila-Casado MC, Carrera-Gonzalez E, Chavez-Mercado L, Cruz-Ortiz H, Rojo J: AIDS-
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 Renal Transplantation
Sandeep Guleria

Introduction

Human organ transplantation ranks as one of the most outstanding achievements in medical history.
The procedure involves the expertise of various branches of medicine and is often the only hope for
survival for patients. Advances in immunosuppressant technology are translating into not only longer
graft survival, but also transplant of organs like bones, uterus and even intestines. The donor pool has
similarly expanded, encompassing living donors and increasingly non-heart beating donors.

Historical Aspects

The refinement in vascular anastomosis pioneered by Alexis Carrel, father of transplantation, led to
attempts at solid organ transplantation in the early nineteenth century. Voronoy is credited with the
first renal allograft (1933-1949). However, all they failed, as the concept of immunology was largely
unknown. Gibson and Medawar carried out experiments on skin transplantation in response to search
for treatment of badly burned pilots in Second World War. They concluded that an auto graft survives
indefinitely, while an allograft is not only destroyed, but induces memory and accelerated destruction
in further transplants.

Murray et al did the first successful renal transplant between identical twins in 1954. Starzl first
attempted liver transplantation in man in 1963. The first successful clinical heart transplant was
performed in 1967 by Dr. Christian Barnard at University of Cape Town. Hardy performed the first
human lung transplant 1963 in a patient with carcinoma left lung. Kelly at the University of Minnesota
initiated pancreatic transplantation in 1966.

However, the success rate was very limited until effective immunosuppresion was developed. Among
the first drugs to be used was Azathioprine, developed by Ellion and Hitchings, used for renal
transplants by Murray. Steroids were added to the immunosuppressive regimen later. Cyclosporine,
discovered by Borel in 1976 was the most significant advance in immunosuppression. Calne is
credited for introducing its widespread usage, initially in renal and later all transplants. The
introduction of tacrolimus in the early 1990’s by Thomas Starzl further added to the
immunosuppression protocol and resulted in a definite improvement in graft survival.

Types of Grafts
 Allograft: Transplantation from one individual to another
 Isograft: Transplantation between identical twins
 Xenograft: A transplant performed between different species
 Orthotopic: A transplant placed in its normal anatomical site
 Heterotopic: A transplant placed in a site different to that where the organ is normally located

Immunological Response

HLA system
Antigens on the transplant tissues are recognized by the non-identical recipient as foreign. This
process of self and non-self recognition initiates rejection. The specificity of the antigens involved in
graft rejection is under genetic control. A single chromosomal complex of closely linked genes makes
up the code for the major histocompatibility antigens. The major Histocompatibility complex (MHC) in
humans is termed the HLA system (Human Leukocyte Antigen), as it was initially detected in
leukocytes. This gene is found in the short arm of chromosome 6. It has at least seven loci, A, B, C,
D, DR, DQ and DP; each highly polymorphic.

HLA-A, B and C are grouped together as Class I antigens. They are present in virtually all nucleated
cells in the body, including Lymphocytes and platelets. They are composed of a heavy (Alfa) chain
and light (Beta-2 microglobulin, a non-MHC coded peptide) chain. They act as targets of cytotoxic
(CD8) T cells.
Class II antigens include HLA-D (DR, DP and DQ) antigens. They are expressed only on B
Lymphocytes, monocytes, activated T lymphocytes and some endothelial cells. They are composed
of and alpha and one beta chain. They stimulate the proliferative response of Mixed Lymphocyte
culture (MLC) and are vital for antigen presentation in vivo. They are preferentially recognized by
Helper (CD4) T lymphocytes.

Allograft rejection is a complex event that results from the cytodestructive effects of activated helper T
cell, cytotoxic T cells, B-lymphocytes, antibodies and activated macrophages. The initiating event
seems to be activation of CD4 cells by class II antigens in the graft. This releases various cytokines,
most importantly Interleukin 2 (IL-2). Class I antigens stimulate CD8 T cells to develop IL-2 receptors.
In addition, activated macrophages secrete Interleukin 1 (IL-1), which in turn stimulates secretion of
IL-2. IL-2 interacts with various IL-2 receptors expressed on T Lymphocytes to stimulate their clonal
proliferation. In essence, the activation of helper T cells by alloantigens and IL-1 stimulates the
release of a variety of lymphokines from CD4 cells and this in turn activates macrophages, CD8 cells
and antibody secreting B-lymphocytes. Also, the continued viability of activated T cell clones is IL-2
dependant. Thus, IL-2 is at the centre of all rejection phenomenon and most of the
immunosuppressant drugs aim to attack this phenomenon.

Histocompatibility Testing and Cross-Match

a) ABO blood group compatibility is considered essential in most of the solid organ transplants, liver
being an exception.
b) HLA Histocompatibility testing is done primarily to search for HLA identical siblings. It is not of
much value in choosing between parents, offspring, or HLA non-identical siblings as donors. Even
in perfect matching of MHC antigens in an HLA identical sibling match, immunosuppression will
be required due to incompatibility at minor Histocompatiblity loci. HLA matching is usually not
done in cadaver renal transplants. Nevertheless, a six antigen match (at the DR, B and A, in the
order of importance, also known as full house match) cadaver kidney donors has a better long-
term survival than lesser-matched grades. Currently almost all HLA typing is done by a
lymphocyte cytotoxicity procedure. The clinical application of histocompatibility holds great
relevance for the transplantation of most solid organs. The presence of HLA antigens on a cell
surface can be detected both functionally and serologically. Both tests are frequently performed
before transplantation because the functional method is most specific for class-II antigens while
the serologic method detects those in Class I. The serologic method uses antigen-specific
antisera that bind to cells expressing that specific antigen. The functional method measures the
reactivity of the lymphocytes of a potential recipient to the donor. The responding lymphocytes will
proliferate in response to transplantation antigens they recognize as foreign. Only HLA (MHC)
antigens can be detected with the functional method. The antigens most effective at generating
this response are those of the Class II MHC. However, since Class I antigens also play an
important role in transplantation, antisera specific for each of the Class I loci (A, B or C) are also
used for serologic typing of a potential donor and recipient.
c) A complement mediated cytotoxic crossmatch with pretransplant recipient sera against non-
activated T lymphocytes expressing class I antigens, and not class II, from the potential donor is
essential. Presence of IgG antibodies against class I MHC antigens represents a positive test and
an absolute contraindication for renal transplant. This test screens for preformed antibodies in the
recipient against donor antigens thus, avoiding Hyperacute reaction.

The Rejection Phenomenon

Rejection is invariable in transplants between non identical twins without immunosuppression. A

Perfect HLA match in non identical twins is very rare owing to the extreme polymorphism in the HLA
system.
The various types of Rejection are:
a) Hyperacute Rejection (HAR): It is due to presensitisation of the recipient to an antigen expressed
by the donor. The recipient has circulating antibodies prior to transplant owing to prior exposure
through pregnancy, previous transplants or blood transfusion to donor alloantigens. A
complement-mediated lysis is initiated resulting in immediate graft thrombosis. The graft swells up
and becomes blue and hard on the operating table itself. The only measure against it is
prevention. The tests used preoperatively are the ABO compatibility and lymphocytotoxicity cross
match. They effectively prevent HAR in 99.5% of transplants.
b) Accelerated Rejection (Vascular Rejection): This is a delayed variant of HAR. The mechanism
seems to be presence of alloantibodies at levels undetectable buy the crossmatch assay, in spite
of presensitisation. Sometimes, massive antibody production by T cell dependant B cell activation
may cause de novo accelerated rejection. Thus, the graft initially functions well, but deteriorates
by day three. Pulse therapy and plasmapheresis may reverse the condition in certain cases.

c) Acute Rejection (AR): This is a T cell dependent process and the only variant that can be
effectively treated. It commonly occurs within the first six months of transplant. Acute rejection is
invariable in transplants between non identical twins without immunosuppression. The incidence
of acute rejection declines with decreasing MHC disparity, though even a full house match
mandates immunosuppression. Activation of CD4 T cells leads to IL-2 secretion ultimately
resulting in massive infiltration of the graft of mainly CD8 cells and its destruction. A cell-mediated
counterpart of HAR is also known; presensitisation at T cell level causing accelerated form of
acute rejection mediated by memory T cells. Prompt recognition and treatment leads to graft
function retrieval in 90 to 95% of patients. Biopsy should be performed in unexplained graft
dysfunction (Impaired LFT, raised liver enzymes, increased urinary amylase). Biopsy would reveal
lymphocytic infiltration (eosinophilic also in liver). In renal transplant, the onset of oliguria, weight
gain, hypertension and impaired renal function signals AR. The classic signs of fever, graft
enlargement and tenderness are seen infrequently in patients treated with cyclosporine.
The differential diagnoses could be cyclosporine toxicity (Levels are high), Acute tubular necrosis,
extrinsic compression on the graft or ureteric obstruction.
Diagnostic modalities include renal diuretic scan with pertechnetate Tc 99, Ultrasound
(prominence of renal pyramids and loss of renal sinus fat, hematoma) .

d) Chronic Rejection (Chronic Allograft Nephropathy): This is a poorly understood process leading to
insidious, slow and irreversible graft loss. It usually occurs over a period of months to years. It is
not treatable by any method yet. Histologically it is characterized by replacement of graft
parenchyma with fibrous tissue with a relatively sparse lymphocyte infiltrate. Non-immunological
factors may also play a part. AR may sometimes cause rapid deterioration in a known case of CR
and if treated, may lead to partial return of graft function. The only treatment is re-transplantation.

Immunosuppressant Drugs

Immunosuppression is a vital part of transplantation. However, it is a double-edged sword, carrying

with it the risks of infection and malignancy, apart from the side effects of the drugs itself. The
immunosuppression in the initial postoperative period is intense as the chances of rejection are
maximum during this period, known as induction immunosuppression. They are also used as Rescue
agents, used to reverse an established rejection episode. The dosage of immunosuppressants
gradually tapers off, known as maintenance immunosuppression.

The various drugs available for immunosuppression are:

a) Steroids: The most commonly used steroid is Prednisolone. It alone is ineffective and usually is
added to Azathioprine and Cyclosporine in the most commonly used regimen for
immunosuppression. The glucocorticoid effect causes a generalized immunosuppression by
blunting T-cell proliferation. High dose Methylprednisolone (500-750mg/day IV bolus X 3-5 days)
is used as a rescue agent for reversing acute rejection. Steroids are responsible for cushingoid
features like acne, obesity, diabetes and peptic ulceration. They may cause growth retardation in
pediatric transplants. The trend now is towards minimal steroid usage and even steroid free
immunosuppression.

b) Azathioprine: The first immunosuppressive used, it is an antimetabolite. It is a prodrug, which is

metabolized to 6-Mercaptopurine and then its derivatives. These then deprive the cell of
adenosine, a vital ingredient in DNA synthesis. It is relatively nonspecific acting on all rapidly
dividing cells. Its chief use is for maintenance immunosuppression and has no value as induction
or rescue agent. It is rarely used in liver transplants. The dosage is usually 1-2 mg/kgBW. The
dose limiting side effects are bone marrow depression and hepatotoxicity. Hence, the dose is
withheld or reduced if TLC is less than 3000 cells/cc or liver dysfunction is present.
c) Mycophenolate Mofetil (MMF): It is also an antimetabolite. It is a reversible inhibitor of IMP
dehydrogenase, interfering in Nucleic acid synthesis. It is relatively specific against lymphocytes
as they lack the salvage pathway (HGPRT catalyzed GMP production). Both T and B cell
proliferation in response to antigen stimulation is blocked. The drug has potential for both
induction and maintenance therapy. The side effects, including bone marrow depression are
minimal. It is gradually replacing Azathioprine, especially in patients with high risk of rejection. It is
regularly used in liver transplants in place of azathioprine due its low hepatotoxicity.

d) Cyclosporin: Discovered by Borel in 1976, it came into clinical practice in 1983. It is at present
the mainstay of maintenance therapy in almost all type of transplants. It is a calcinueurin inhibitor,
binding cyclophilin and inhibiting the transcription of IL-2 gene and thus T cell activation. It is
remarkably specific against immunocompetent lymphocytes. However, it cannot be used as
rescue agent presence of IL-2 in the graft bypasses the drug effect. At present, a micro emulsion
formulation that has better bioavailability and pharmacodynamics is used. Since most of the
metabolism is through the cytochrome P 450 enzyme system, Hepatic dysfunction mandates
reduced dosage. The absorbed drug is almost totally metabolized and excreted in bile. Also,
drugs influencing the cytochrome enzyme system alter the metabolism of cyclosporine (increased
by rifampin, Phenobarbital, Phenytoin, decreased by ketoconazole, erythromycin and calcium
channel blockers). The usual dosage is 7.5 to 25mg/kg. The main toxicity is Nephrotoxicity due to
vasoconstrictor effect on proximal renal arterioles. Hyperkalemia, Hemolytic Uremic syndrome,
Hypertrichosis, Gingival Hyperplasia, Neurotoxicity are the other side effects seen. This mandates
strict monitoring of cyclosporine levels to avoid toxicity. Usually the level of cyclosporine 2 hours
after intake is measured (C2levels).

e) Tacrolimus (FK506): It is a macrolide calcinuerin inhibitor. It blocks IL-2 translation by binding to

FK Binding Protein, the effect and toxicity being additive to cyclosporine. Tacrolimus is 100 times
more potent than cyclosporine. However, unlike the latter, it can be used as a rescue agent. The
side effect profile is similar to cyclosporine, with more pronounced neurological and diabetogenic
effect Tacrolimus is today the drug of choice for liver renal and pancreas transplantation.

f) Sirolimus (Rapamycin/Rapamune): It is the latest immunosuppressant agent for solid organ

transplants, prescribed for induction therapy, refractory rejection, steroid withdrawal, and
combination therapy. It is an immunophilin binding drug, blocking signal transduction by the IL-2
receptor, hence the response of T-cells to IL-2. It is structurally similar to but antagonizes the
action of Tacrolimus and is synergistic with cyclosporine. It is at present in use for renal and heart
transplants. The main toxicity of sirolimus is hypertriglyceridemia and pulmonary toxicity.

g) Monoclonal antibody (muromonab-CD3/OKT3): They are produced using the Hybridoma

technology, developed by Kohler and Milstein in 1970. The immunoglobulin is targeted against
the CD3 molecule, part of T Cell Receptor found Thymocytes and mature T cells. It is used for
treatment of acute rejection episodes, usually steroid refractory cases. The side effects include a
systemic cytokine release syndrome, which can cause hypotension, pulmonary edema, fatal
cardiac myodepression and aseptic meningitis. Pretreatment with high dose methylprednisolone,
antihistamines and antipyretics reduces the side effects. The usual adult dose is 5mg/kg/day for
10-14 days. Use of OKT3 is also associated with increased risk of cytomegalovirus, Epstein Barr
and in children, varicella viral infection.

h) Anti Lymphocyte Globulin/Anti Thymocyte Globulin (ALG/ATG): This is a polyclonal serum

developed by collecting antibodies produced by various animals against human lymphocytes.
Most commonly, Horse or rabbit are used. ATGAM is the purified IgG fraction most commonly
used. The antibody coats the T cells and promotes its clearance. The drug is most commonly
used as part of multidrug induction immunosuppression. Severe thrombocytopenia is occasionally
seen. The patient is usually pretreated with antipyretics, antihistamines and antipyretics. Viral
infections, both primary and reactivation are seen more frequently in patients treated with this
drug.

i) Anti IL-2 Receptor Antibody (Basiliximab/ Daclizumab): The chimaeric monoclonal antibody
basiliximab specifically binds the alpha subunit of the interleukin-2 (IL-2) receptor on activated T
lymphocytes. Renal transplant patients usually receive basiliximab 20 mg 2 hours before and then
4 days after transplantation surgery. These antibodies have been shown to reduce the incidence
 of acute rejection without increasing the incidence of opportunistic infections or malignancy. Side
effects are not very significant. Longer follow up however, is required to fully evaluate the efficacy
of these agents.

Complications of Immunosuppression
Immunosuppression is not obtained without paying a significant price in terms of side effects. Infection
and malignancy are the most frequent complications encountered with the use of non-specific
immunosuppressive agent.
a) Infection. Transplant recipients who receive immuno-suppression encounter a greatly increased
incidence of infection, which remains the most common cause of mortality. Most deaths used to
be due to invasive infections. These have been controlled by antibiotics. Nowadays most
infections are caused by opportunistic pathogens, including fungi, protozoa and viruses, the latter
being specially common among kidney transplant patients. Candida albicans and Aspergillus
species are the most common fungi encountered in transplant patients. The latter produces upper
lobe pulmonary cavities. The protozoan Pneumocystis carinii is also a frequent cause of
pulmonary infection, producing n alveolar infiltrate with severe dyspnoea and cyanosis. However,
it is seen less often since the use of prophylactic trimethoprim and sulfamethoxazole in transplant
recipients.Among the viruses, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) commonly
infect transplant patients. CMV is the most important virus infection seen in immunosuppressed
transplant patients. The virus itself produces severe immunosuppression rendering the patient
susceptible to bacterial and fungal opportunists.

b) Malignancy: Cancer is seen more often in transplant recipients than in the general population.
Most cancers that arise in transplanted patients are either epithelia l(carcinomas of the cervix an
lip and basal cell carcinomas, constitute about one half of these) or lymphoid( B-cell lymphomas).

c) Other complications: are mostly due to the use of steroids: Cushing's syndrome, cataracts,
gastrointestinal bleeding, hypertension, pancreatitis, and avascular necrosis of the femoral heads.

Organ retrieval & Organ Preservation

Graft damage must be minimized from the time the organ is removed from the donor to the time it is
implanted into the recipient. Graft damage may start while the organ is still within the donor while
awaiting consent for donation. This damage may also occur during removal, storage and transport of
the graft or during the transplantation operation.

Organ Preservation
The kidneys are usually perfused with a special solution. This could be Phosphate based Sucrose,
Hyperosmolar Citrate, or the University of Wisconsin Solution. The essential components of
preservation include:
1. Hypothermia: Cooling of the organ to 4-10 degrees C. markedly reduces the metabolic rate and
prolongs the storage time of 1 to 2 hours to about 12 hours.
2. Prevention of Cell Edema: This is done by using a hyperosmolar flushing solution with an
impermeable solute to achieve a ‘No flow’ phenomenon. This solute could be Mannitol, Sucrose,
Glucose or Raffinose.
3. Energy Source and lysosomal stabilizers: This is usually achieved by steroids and the use of
Magnesium
4. Free Oxygen Radical Scavenger: like Gluthaione and Allopurinol inhibt organ damage.
5. Continuous cold perfusion: combines all these benefits : hypothermia, continuous buffering,
continuous provision of oxygen and nutrients, and continuous washout of accumulating toxic
metabolites.This is usually done in marginal donors and asystolic donors.

Indications for Renal Transplant:

A. Glomerulonephritis D. Systemic Diseases
Idiopathic and post Cresentic Diabetes
Membranous Cystinosis
Mesangiocapillary Amyloid
Focal Glomerulosclerosis E. Obstructive Uropathy
Anti – GBM F. Irreversible Acute Renal Failure
IgA Nephropathy
 B. Toxic G. Multi - System Disease
C. Trauma SLE
Vasculitis

Contraindications to renal transplant:

STRONG CONTRA-INDICATIONS RELATIVE CONTRAINDICATIONS
Unresolved Malignancy Obesity or malnutrition
Ongoing Metabolic disease Urinary tract infection
Active Sepsis Severe peripheral vascular disease
Active tuberculosis Poorly controlled diabetes
Severe Vasculitis Prior Malignancy
End Stage Vascular disease History of non compliance
Active AIDS Inadequate social support
Active Drug Abuse Life expectancy less than five years
Active Lupus Emotional Instability
Recent MI Decreased mental capacity
Insufficient Financial Resource

Bilateral nephrectomy: is now rarely performed. The only indications for this in the current day and
age is intractable upper urinary tract infection, Severe hypertension refractory to medical treatment,
Complex renal cyst with suspicion of malignancy or large polycystic kidneys precluding placement of
graft are other rare indications for a bilateral nephrectomy.

The Donor

Living kidney donation appears to be safe with low morbidity and mortality2. It offers several potential
benefits, including better results for the recipient enhanced self esteem for the donor and reduced
financial burden to the society. The success of live kidney donor transplantation has been so
overwhelming that from 2000 to 2004 in the United States, the number of live donor kidneys
surpassed that of cadaver donors . However in most parts of the world cadaver organ donation is still
limited and live kidney donors are the most common source of organs for organ transplantation.

Conservative estimates put the annual incidence of ESRD in India at 80-100 per million populations
(PMP). This would mean approximately 80,000 to 1, 00,000 new patients every year not including the
patients living in rural areas who never seek specialist advice because of ignorance and poverty. The
final acceptance rate of patients for renal replacement therapy turns out to be less than 5 PMP per
year.

The high costs associated with long term dialysis makes renal transplantation the only viable
alternative for long term survival of ESRD patients in the developing nation. Organized cadaver donor
programs do not exist and transplants are almost exclusively done using living donors.

Despite reduced morbidity and mortality of the donation process it is important to discern patients who
are not candidates for organ donation because of the risk on immediate and future health . However
singular abnormalities such as well controlled hypertension and obesity are no longer considered
absolute contraindications to organ donation. Living donors present unique ethical, legal and social
implications that must be addressed to protect the health and rights of the donor.

Living Donors: There are many reasons that can be cited for the continued use of live donors.
Among them has been the more favourable results that can be achieved with a well matched kidney.
With the introduction of monoclonal and polyclonal antibody immunosuppression as well as the use of
calcineurin inhibitors and other new immunosuppressive drugs live kidney donors still have a 10-12%
better survival rate at one year and a significant higher probability of function thereafter.

Another justification for using living donors is that the timing of the operation can be planned and the
operation can be performed when the recipient is in optimal medical condition.
Despite these compelling reasons for using living donors the procedure could not be justified if
unacceptable morbidity or mortality were to be incurred by the donor. The concept of removal of an
organ for transplantation is unique among major surgical operations that it exposes the healthy donor
to the risks of surgery solely for the benefit of another individual.

With the advent of minimally invasive techniques including the mini donor nephrectomy to living
kidney donation, the potential adverse impact of the operation has become less significant. The major
advantages to the donor are decreased morbidity of the surgery and quicker return to normal daily
activities including earlier return to work.

Informed Consent
An extremely important part of living kidney donation involves informed consent. Emphasis on the
adequacy of the consent process is important as unlike standard procedures, living kidney donation is
not specifically designed to help the donor or advance the donor’s health. The person who gives
consent to donate an organ must be competent (possessing decision making capacity) , willing to
donate, free from coercion medically and psychosocially suitable ,fully informed of the risks and
benefits of donation and fully informed about alternative treatments available to the recipient. The
donor must understand that that in the absence of donation the patient can in most circumstances,
continue dialysis and is unlikely to die. Two other principles of living renal donation have been
endorsed that of “equipoise” – the benefits to both the donor and recipient must outweigh the risks
associated with the donation and that the transplantation of the live donor organ – and that it must be
made clear to the potential donor that his participation is completely voluntary and may be withdrawn
at any time.

Risks to the Donor

Living donor nephrectomy is a major surgical operation. Responsibility for the donor lies ultimately
with the surgeon performing the donor operation but optimal care demands cooperation with the
anaesthetists, the operating room nurses as well as post operative care by the surgical team can be
divided into the early risks associated with the donor operation (i.e. peri-operative mortality and
morbidity) and the late or long-term risks of life with a single kidney. In the absence of national donor
registries or large prospective studies with effective follow-up, the long-term risks of donor
nephrectomy remain incompletely defined. There is, however, a wealth of retrospective evidence,
which suggests that kidney donation is associated with a low level of medical risk in a healthy donor.

Peri-operative Mortality
Estimates of living donor mortality are available from three large American surveys (covering nearly
10,000 operations) and numerous single centre reports . The reported death rates are variable but 1
in 3000 is accepted as an accurate assessment of peri-operative mortality. The most common causes
of death being pulmonary embolus, hepatitis and cardiac events (myocardial infarction and
arrhythmias)

Peri-Operative Morbidity
The precise peri-operative morbidity of living donor nephrectomy is difficult to ascertain because
some reports give overall complication rates whilst others present data relating to specific
complications. Moreover, variations in the precise definition of specific complications may result in
apparent differences in their incidence. This factor also affects the classification of complications into
major and minor sub-groups. Notwithstanding these problems, the reported peri-operative
complication rates for living donor nephrectomy have been summarised for a large number of single
centre studies . The mean overall complication rate was 32% and the major peri-operative
complication rate was 4.4%.
The estimated 'major complication' rate in a survey by Bay and Hebert was 1.8% whereas the
American Society of Transplant Physicians (ASTP) survey reported that 22 out of 9692 (0.23%)
kidney donors experienced 'potentially life-threatening or permanently debilitating' complications.
Kasiske et al extracted data from a large number of published reports and calculated the reported
rate (mean and SD) for specific complications. In a review of 10828 living donor nephrectomies
performed in the USA between 1/1/1999 and 1/7/2001 there was a 0.02% mortality with a further
patient in a persistent vegetative state. The three donors concerned all underwent laparoscopic
nephrectomy.

Long Term Risks

Convincing data on the long-term effect of donor nephrectomy comes from follow-up of living kidney
donors from a single unit in Stockholm that performed 459 living donor nephrectomies over a 20-year
period from 1964 onwards. All 430 donors still living in Sweden were traced and actual survival was
compared to national mortality rates. The cause of death in the kidney donors was similar to that seen
in the general population: most deaths were due to cardiovascular disease and cancer. Actuarial
survival at 20 years was 85% compared to an expected survival rate of 66%.

However it is pertinent to note that renal failure has been reported in donors. The living renal donors
in the OPTN database were cross referenced against the renal waitlist. Fifty six previous living donors
were identified as having been subsequently listed for cadaver donor renal transplantation. None of
them had evidence of renal disease before kidney donation. Most developed de novo renal disease
and the reported frequency of end stage renal failure in the donor population overall is less than that
seen in the general population.

The Donor Evaluation

The basic evaluation are the standard history and physical examination and haematological and
biochemical profiles. Potential donors remaining after the initial screening process are evaluated
meticulously and repeatedly to confirm excellent general health and bilateral renal functions.

ABO blood grouping and crossmatch testing

ABO blood grouping allows the early identification of individuals who cannot donate because of ABO
blood group incompatibility. After blood group compatibility has been established, initial HLA typing +/-
crossmatch testing should be performed in accordance with recommendations in the Human Organ
Transplant Act 1994. Living donor transplantation across incompatible ABO blood groups can only be
undertaken where there are specific protocols in place to support the management of the potential
recipient. There are encouraging report from numerous centres in india about transplants across the
blood group.

Renal Anatomy
The renal anatomy must be assessed to confirm the presence of two kidneys of normal size and to
identify abnormalities such as a duplex collecting system, hydronephrosis, pelvi-ureteric junction
obstruction and calcification in the urinary tract.
IVU may be unnecessary if spiral CT angiography or an angiogram with late films is employed The
presence of a duplex collecting system is not a contraindication to donation and if double ureters are
present in one kidney, the contralateral kidney may be the most suitable choice for transplantation.

The Amsterdam Forum on care of the live donor

In April 2004 at an international meeting of more than one hundred renal transplant surgeons and
physicians at Amsterdam a set of international guidelines were proposed that the World Health
Organization could assist to implement worldwide. These were known as the Amsterdam forum
guidelines

Amsterdam Forum Guidelines

Donor evaluation
Prior to donation, the live kidney donor must receive a complete medical and psychosocial evaluation,
receive appropriate informed consent, and be capable of understanding
the information presented in that process to make a voluntary decision. All donors should have
standard tests performed to assure donor safety.

Hypertension
Patients with a BP _140/90 by ABPM are generally not acceptable as donors. BP should preferably
be measured by ABPM, particularly among older donors (_50 years) and/or those with high office BP
readings. Some patients with easily controlled hypertension, who meet other defined criteria, e.g. _50
years of age, GFR _80 ml/min, and urinary albumin excretion _30 mg/day may represent a low-risk
group for development of kidney disease after donation and may be acceptable as kidney donors.
Donors with hypertension should be regularly followed by a physician.
Obesity
Patients with a BMI 35 kg/m2 should be discouraged from donating, especially when other comorbid
conditions are present. Obese patients should be encouraged to lose weight prior to kidney donation
and should be advised not to donate if they have other associated co-morbid conditions. Obese
patients should be informed of both acute and long-term risks, especially when other comorbid
conditions are present. Healthy lifestyle education should be available to all living donors.

Dyslipidemia
Dyslipidemia should be included along with other risk factors in donor risk assessment, but
dyslipidemia alone does not exclude kidney donation.

Acceptable donor renal function

All potential kidney donors should have GFR estimated. Creatinine based methods may be used to
estimate the GFR; however, creatinine clearance (as calculated from 24-hour urine collections) may
under or overestimate GFR in patients with normal or near normal renal function. Calculated GFR
values (MDRD and Cockcroft-Gault) are not standardized in this population and may overestimate
GFR. A GFR _80 ml/min or 2SD below normal (based on age, gender, and BSA corrected to
1.73/m2) generally precludes donation.

Urine analysis for protein

A 24-hour urine protein of 300 mg is a contraindication to donation. Microalbuminuria determination
may be a more reliable marker of renal disease, but its value as an international standard of
evaluation for kidney donors has not been determined.

Urine analysis for blood

Patients with persistent microscopic hematuria should not be considered for kidney donation unless
urine cytology and a complete urologic work up are performed. If urological malignancy and stone
disease are excluded, a kidney biopsy may be indicated to rule out glomerular pathology, such as IgA
nephropathy.

Diabetes
Individuals with a history of diabetes or fasting blood glucose 126 mg/dl (7.0 nmol/l) on at least two
occasions (or 2-hr glucose with OGTT 200 mg/dl (11.1 mmol/l) should not donate.

Stone Disease
An asymptomatic potential donor with history of a single stone may be suitable for kidney donation if:
No hypercalcuria, hyperuricemia, or metabolic acidosis.
No cystinuria, or hyperoxaluria.
No urinary tract infection.
If multiple stones or nephrocalcinosis are not evident on CT.

An asymptomatic potential donor with a current single stone may be suitable if the donor meets the
criteria shown previously for single stone formers and current stone 1.5 cm in size, or potentially
removable during the transplant.
Stone formers who should not donate are those with:
 Nephrocalcinosis on x ray or bilateral stone disease.
 Stone types with high recurrence rates, and are difficult to prevent.

Malignancy
A prior history of the following malignancies usually excludes live kidney donation: Melanoma,
testicular cancer, renal cell carcinoma, choriocarcinoma, hematological malignancy, bronchial cancer,
breast cancer and monoclonal gammopathy.

A prior history of malignancy may only be acceptable for donation if:

 Prior treatment of the malignancy does not decrease renal reserve or place the donor at
increased risk for ESRD.
 Prior treatment of malignancy does not increase the operative risk of nephrectomy.
A prior history of malignancy usually excludes live kidney donation but may be acceptable if the
specific cancer is curable and potential transmission of cancer can reasonably be excluded.
Urinary tract infections
The donor urine should be sterile prior to donation; asymptomatic bacteria should be treated per
donation. Pyuria and hematuria at the proposed time of donation is a contraindication to donation.
Unexplained hematuria or pyuria necessitates evaluation for adenovirus, tuberculosis, and cancer.
Urinary tuberculosis or cancer is contraindications to donation.

Live unrelated donors

The current available data suggest no restriction of live kidney donation based upon the absence of
an HLA match. An unrelated donor transplant is equally successful to the outcome achieved by a
genetically related family member such as a parent, child, or sibling, who is not HLA identical to the
recipient.

Determination of cardiovascular risk

The clinical predictors of an increased peri operative cardiovascular risk (for non-cardiac surgery) by
the American College of Cardiology/American Hospital Association standards fall into 3 categories:
major, intermediate, minor.

All major predictors: unstable coronary syndromes, decompensated heart failure, significant
arrhythmias and severe valvular disease are contraindications to live kidney donation. Most of the
intermediate predictors: mild angina, previous myocardial infarction, compensated or prior heart
failure, diabetes mellitus are also contraindications to donation; Minor predictors: older age, abnormal
ECG, rhythm other than sinus, low cardiac functional capacity, history of stroke or uncontrolled
hypertension warrant individual consideration.

Assessment of pulmonary issues

A careful history and physical examination are the most important parts of assessing risk. Routine
preoperative pulmonary function testing (PFT) is not warranted for potential live kidney donors unless
there is an associated risk factor such as chronic lung disease. Increased risk of post operative
pulmonary complication is assoc with an FEV1 _70% or FVC _70% of predicted, or a ratio of
FEV1/FVC _65%.

Smoking cessation and alcohol abstinence

Smoking cessation at least 4 weeks prior to donation is advised based on recommendations for
patients undergoing elective surgical procedures.
Cessation of alcohol abuse defined by DSM-3: 60 gm of alcohol/day sustained over _6 months should
be avoided for a minimum of 4 weeks to decrease the known risk of postoperative morbidity.

Cadaver donors

Should not have any disease that could affect the kidney or the potential recipient. These include
Hepatitis, HIV active infection or malignancy.

Criteria for Cadaveric Renal Donor Selection :

Age < 65 years
No Evidence of any renal disease
Pre- Terminal urine output exceeding 0.5cc/kg/hr
Normal Serum Creatinine and BUN
No Evidence of HIV, HbSAg , or Hepatitis C

Kidney Removal

In living related donation the kidney that is usually removed is the left kidney. This is because of the
long length of the renal vein that is available. This can now be done through a flank approach or
transperitoneally. There are number of centers retrieving these kidneys laparoscopically.
Cadaveric harvesting is done through a long midline incision and is usually part of a multi organ
harvest.
The Renal transplant Operation
The surgery for renal transplantation is fairly standardized now. The live donor should be well
hydrated and a flank incision should be used. Meticulous dissection is required and the kidney with
the artery vein and a lot of periureteric fat with the ureter is harvested. This is done so that the blood
supply of the ureter is not compromised. After harvesting the kidney is perfused with a renal
preservation solution and stored in ice before transplanting. The renal transplant operation is carried
out through a right or a left curvilinear extra-peritoneal incision. The external iliac artery and vein are
mobilized and the renal artery and vein anastomosed end to side to the external iliac artery and vein.
The ureter is anastomozed to the bladder by an extravesical nonrefluxing ureterneocystostomy. This
may be done over a double J stent.

Post Operative Care

The patient is usually nursed in an intensive care where attention is given to fluid and electrolyte
balance. Most kidneys from live elated donors have a massive initial diuresis and it is important to
keep the patient well filled. Care is also taken to ensure that electrolyte balance is maintained. Most
patients are eating and drinking by the third or fourth day and can usually be discharged on the tenth
day.

Delayed or Non function of the transplanted Kidney

Causes:
 Acute Tubular Necrosis
 Renal Artery Thrombosis
 Renal Vein Thrombosis
 Hyperacute Rejection
 Ureteric Obstruction

A DTPA scan, A Doppler and an ultrasound can usually help to distinguish between the various
causes. A renal graft biopsy is usually the diagnostic modality of choice.

Results
The one-year graft survival rate in India (A.I.I.M.S.) is currently in the range of 93-94%. Infectious
complications are common due to the poor development of basic amenities. Most of our successful
transplant patients have an excellent quality of life and view their post-transplant period as a rebirth.
Most grafts carried out in the Western world are cadaveric, most of those in the underdeveloped
countries are from living related donors.

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Invest Surg. 2003 Sep-Oct;16(5):243-6
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Sep;159(3):289-94
3. Gibson T, Medawar PB The fate of skin homograft in man Journal of Anatomy:299-309,1943
4. Medawar PB Behaviour and fate o skin autografts and skin homografts in rabbits. Journal of Anatomy 78:176-199
5. Murray JE, Merrill Jp, Harrison JH Renal homotransplantations in identical twins. Surgery Forum 6: 423-426, 1955
6. Starzl TE. The saga of liver replacement, with particular reference to the reciprocal influence of liver and kidney
transplantation (1955-1967) J Am Coll Surg. 2002 Nov;195(5):587-610.
7. Barnard CN. A human cardiac transplant. S Afr Med J 1967; 41 : 1271.
8. Lillehei RC, Idezuki Y, Kelly WD, Najarian JS, Merkel FK, Goetz FC. Transplantation of the intestine and
pancreas.Transplant Proc. 1969 Mar;1(1):230-8.
9. Hitchings GH, Ellion GB Chemical suppression of the immune response Pharmacol Rev 15: 365; 1963
10. Borel Jf, Feurer C et al: Biological effects of Cyclosporine A: a new antilymphatic agent. Agents Actions
6:465,1976
11. Calne RY, White DJB et al: Cyclosporine A in patients receiving renal allograft from cadaver donors. Lancet 2”
1323, 1978
12. Klein J, Sato A: The HLA system.(two parts) N Eng J Med 2000;343:702,782
13. Doxiadis II, Claas FH. The short story of HLA and its methods Dev Ophthalmol. 2003;36:5-11.
14. Rao KV. Mechanism, pathophysiology, diagnosis, and management of renal transplant rejection. Med Clin North
Am. 1990 Jul;74(4):1039-57.
15. Thomson NM Corticosteroid agents in renal disease. Med J Aust. 1987 May 18;146(10):530-1, 534-5, 538
16. Luke PP, Jordan ML. Contemporary immunosuppression in renal transplantation Urol Clin North Am. 2001
Nov;28(4):733-50
17. Shinn C, Malhotra D, Chan L, Cosby RL, Shapiro JI. Time course of response to pulse methylprednisolone
therapy in renal transplant recipients with acute allograft rejection Am J Kidney Dis. 1999 Aug;34(2):304-7.
18. Hricik DE Steroid-free immunosuppression in kidney transplantation: an editorial review Am J Transplant. 2002
Jan;2(1):19-24.
19. Grinyo JM. Mycophenolate-update after it has come of age. Nephrol Dial Transplant. 1999 Jan;14(1):31-4
20. Pirsch JD. Mycophenolate mofetil, tacrolimus, Neoral: from clinical trials to the clinic.Transplant Proc. 1998
Aug;30(5):2223-5.
21. Sievers TM, Rossi SJ, Ghobrial RM, Arriola E, Nishimura P, Kawano M, Holt CD Mycophenolate mofetil
Pharmacotherapy. 1997 Nov-Dec;17(6):1178-97.
22. Vanrenterghem Y. The use of Mycophenolate Mofetil (Cellcept) in renal transplantation Nephron 1997;76(4):392-9
23. Hamawy MM. Molecular actions of calcineurin inhibitors.Drug News Perspect. 2003 Jun;16(5):277-82.
24. Dunn CJ, Wagstaff AJ, Perry CM, Plosker GL, Goa KL Cyclosporin: an updated review of the pharmacokinetic
properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral)1 in organ
transplantation. Drugs. 2001;61(13):1957-2016.
25. Serkova N, Christians U. Transplantation: toxicokinetics and mechanisms of toxicity of cyclosporine and
macrolides. Curr Opin Investig Drugs. 2003 Nov;4(11):1287-96
26. Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y, Nickeleit V, Ryffel B.The side-effects of ciclosporine-A and
tacrolimus. Clin Nephrol. 1998 Jun;49(6):356-63.
27. Lutz G. Effects of cyclosporin A on hair. Skin Pharmacol. 1994;7(1-2):101-4.
28. Hood KA Drug-induced gingival hyperplasia in transplant recipients. Prog Transplant. 2002 Mar;12(1):17-21; quiz
22-3.
29. Levy G, Thervet E, Lake J, Uchida K Patient management by Neoral C(2) monitoring: an international
consensus statement; Consensus on Neoral C(2): Expert Review in Transplantation (CONCERT)
Group.Transplantation. 2002 May 15;73(9 Suppl):S12-8.
30. Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ
transplantation. Drugs. 2003;63(12):1247-97.
31. Hamawy MM Molecular actions of calcineurin inhibitors. Drug News Perspect. 2003 Jun;16(5):277-82
32. Busuttil RW, Lake JR. Role of tacrolimus in the evolution of liver transplantation.Transplantation. 2004 May
15;77(9 Suppl):S44-51.
33. Johnson RW Sirolimus (Rapamune) in renal transplantation. Curr Opin Nephrol Hypertens. 2002 Nov;11(6):603-7
34. Hoffmann RL, Roesch T Update on transplant pharmacology: sirolimus. Dimens Crit Care Nurs. 2004 Mar-
Apr;23(2):69-75
35. Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, Singer J, Shah T, Wilkinson AH.
Sirolimus-associated pulmonary toxicity. Transplantation. 2004 Apr 27;77(8):1215-20
36. Wilde MI, Goa KL. Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ
transplant rejection. Drugs. 1996 May;51(5):865-94.
37. Kennett RH. Hybridomas: a new dimension in biological analyses. In Vitro. 1981 Dec;17(12):1036-50.
38. Bonnefoy-Berard N, Revillard JP. Mechanisms of immunosuppression induced by antithymocyte
globulins and OKT3. J Heart Lung Transplant. 1996 May;15(5):435-42.
39. Loertscher R. The utility of monoclonal antibody therapy in renal transplantation.Transplant Proc. 2002
May;34(3):797-800.
40. Sgro C Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review.
Toxicology. 1995 Dec 20;105(1):23-9.
41. Pascual J, Marcen R, Ortuno J. Anti-interleukin-2 receptor antibodies: basiliximab and daclizumab. Nephrol Dial
Transplant. 2001 Sep;16(9):1756-60.
42. Kasiske BL Bia MJ : The evaluation and selection of living kidney donors. Am J Kidney Disease 26:387, 1995
43. Organ Procurement and Transplantation Network and the Scientific Registry of transplant recipients. 2004 Annual
report : Transplant Data 1994-2003, Rockville, Md, Department of health and Human Services Administration,
Health care systems bureau, Divison of Transplantation, Richmond Va, UNOS Ann Arbor , Mich. Univer sity Renal
Research and Education Association 2004
44. Jha V: End stage renal care in developing countries : The Indian experience. Renal Failure 26: 201,2004
45. Bia MJ, Ramos EL, Danovitch GM, Gaston RS,Hauman WE, Leichtman AB, Lundin PA, Neylan J, Kasiske BL.
Evaluation of living renal donors. The current practice of US transplant centers. Transplantation 1995; 60: 322-
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46. Najarian JS, Chavers BM, McHugh LE, Matas AJ. 20 years or more of follow-up living kidney donors. Lancet
1992; 340:807-810.
47. Uehling DT, Malek GH, Wear JB. Complications of donor nephrectomy. J Urol 1974; 111: 745-746.
48. Delmonico F ; Council of the transplantation Society: A Report of the Amsterdam forum on care of the live donor
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 Rationale for investigations for work-up of a case of renal mass
Sanjay Gupta

Introduction

There are two ways in which a renal mass manifests itself. Either the patient presents with clinical
features of the renal lesion, benign or malignant, or the renal lesion is accidentally detected during
investigations for an unrelated problem. It has been estimated that over half of patients over the age
of 50 years harbor at least one renal mass, and often several are found during one radiologic
1
examination.

In case the patient has presented with symptoms of the renal lesion, investigations are directed to
diagnose the lesion and plan its management. If the renal lesion is accidentally detected and is small
in size, additional issues include the decision to do invasive investigations to confirm the diagnosis
and appropriate management of these lesions. Traditionally, needle biopsy was not done because of
concerns about safety, tumor seeding, and accuracy. Importantly, the idea that biopsy results rarely
changed management plans reduced its utility. But as pathologic assessment has improved, this idea
is being challenged.2 To better understand the rationale for investigations of a renal mass, it is
essential to get an idea about different lesions which may present as a renal mass.

Differential diagnosis of renal lesions

Renal pseudotumors3
Renal pseudotumors may be caused by a variety of conditions including congenital anomalies
(prominent renal columns of Bertin, dromedary humps), inflammatory masses (focal pyelonephritis,
chronic renal abscess, autoimmune disease), vascular structures (renal artery aneurysm or
arteriovenous fistula), or abnormalities relating to trauma or hemorrhage. Some of the renal
pseudotumors may need treatment which is different from malignancy and thus necessitate accurate
diagnosis.

Cystic renal masses3

Cystic renal masses are the most common masses in the kidney, with most being benign simple
cysts. Simple cysts are defined as having a hairline-thin wall, no septa or calcification, and being filled
with simple fluid measuring 0 to 20 HU on CT. There are no soft tissue components within simple
cysts, they do not enhance after the administration of IV contrast, and they are considered benign.
Size is not a good predictor of malignancy in cystic renal masses because small cystic masses may
be malignant and large ones can be benign. With the technological advances in CT during the past 20
years, more cystic-appearing masses measuring less than 1 cm are being detected in the kidneys.
Many of these masses cannot be characterized accurately because of their small size. However, the
probability of a small cystic lesion being benign is extremely high.

Solid renal mass3

Benign solid tumors are usually small (<3 cm) when detected and most commonly are oncocytoma
and angiomyolipoma. Renal malignancies diagnosed in solid renal tumors include renal cell
carcinoma (RCC), lymphoma and metastasis from extra-renal malignancy. In case of multiple solid
tumors of the kidney, the likely diagnosis includes RCC, oncocytoma and metastases. For appropriate
treatment biopsy is necessary.

Meticulous evaluation of all solid renal masses for the presence of fat is imperative to avoid
recommending surgical excision of an angiomyolipoma. When a small amount of fat is suspected in a
renal mass, an unenhanced CT scan with thin sections combined with a pixel analysis is the most
sensitive test to confirm this. MR imaging using T1-weighted sequences with and without frequency-
selective fat suppression or chemical shift imaging can also be used. Approximately 5% of
angiomyolipomas do not contain fat that can be seen at imaging, and the differentiation from other
renal neoplasms is not possible with CT or MR imaging.
Oncocytoma is a benign solid renal mass that cannot be differentiated with certainty from RCC by
imaging. The CT finding of a central scar, previously felt to be specific for oncocytoma, has been
found with RCCs, and the finding is not specific. Percutaneous biopsy is not definitive in all cases,
because some RCCs have oncocytic features, and surgical resection may be needed to make a
definitive diagnosis.

Relation of pathological features and tumor size4

In a large series from Mayo clinic, histopathology of all the patients who underwent radical/ nephron
sparing nephrectomy from 1970 to 2000 was reviewed. The diagnosis of solid renal lesions from this
study is presented in Table 1. This study concluded that a significant number of small renal tumors
are benign and only a small minority represents high grade RCC. As tumor size increases there is a
significant increase in the odds of having a malignant compared to a benign tumor, a clear cell
compared to a papillary RCC and a high grade RCC compared to low grade RCC.

Table 1. Histological subtypes for benign and RCC tumors from patients treated with radical
nephrectomy and nephron sparing surgery.4
Diagnosis Number of cases (%)
Benign
 Oncocytoma 274 (9.3%)
 Angiomyolipoma 67 (2.2%)
 Papillary adenoma 16 (2.3%)
 Not otherwise specified 14 (0.4%)
 Metanephric adenoma 5 (0.1%)
RCC
 Clear cell 1970 (67.1%)
 Papillary 436 (14.8%)
 Chromophobe 125 (4.2%)
 Not otherwise specified 18 (0.6%)
 Collecting duct 6 (0.2%)
 Purely sarcomatoid 4 (0.1%)
Total 2935

Patient assessment5

Initial assessment of the patient can give important information which may influence management and
prognosis. Patients with a renal mass with family history of inheritable renal cancer or high risk of
recurrence may progressively lose renal function with each intervention. These patients may be the
candidates for observation or non-ischemic ablative therapies for masses less than 3cm.

Age and gender also seem to be correlated with malignant potential. Studies have suggested that
younger women and older men are more likely to have benign renal mass. Symptoms at presentation
and a history of smoking increase the likelihood of malignancy.

Measurement of preoperative laboratory values is simple and a reliable way to improve outcome
prediction in patients with renal masses. Many studies have shown that elevated erythrocyte
sedimentation rate, hypercalcemia, and anemia are independent risk factors in increasing the
likelihood of death from clinically confined RCC. There is growing evidence that these inflammatory
markers can be of use in assessment of the tumor biology.

However, while there is no denying that a detailed history and clinical examination is invaluable,
critical diagnostic, prognostic and management related information is obtained only after
investigations.
Investigation modalities

2
Ultrasound
Ultrasound is the most commonly used initially imaging modality for a renal mass and may be used in
subsequent surveillance of the patient. Ultrasound has particular utility in the characterization of cystic
masses, including hyperdense cysts that may pose a diagnostic challenge to CT. Ultrasound is often
sufficient alone to diagnose most category 1 cystic renal masses as benign. Solid renal masses will
only be conspicuous if they are of different echogenicity to the normal renal cortex, or deform the
normal contours of the kidney, or central echo complex. Fat-containing masses such as
angiomyolipoma are highly echogenic, and will readily be seen even when only a few millimeters in
size. Other causes of solid masses have texture more similar to normal renal cortex, which makes
them difficult to discern until over about 2 cm in size.6

Except for the simplest renal cysts, ultrasound is rarely, if ever, the only method used to characterize
a mass. The sensitivity of ultrasound decreases with tumor size, such that at 1 cm, ultrasound is only
able to correctly identify only 20% of masses, as against 76% identified by CT. The sensitivity of
ultrasound improves to 70% for tumors of 2 cm, but is still inferior to that of CT (95%). The detection
rate is not equal until the lesions reach 3.5 cm. Ultrasound is operator dependent, and interpretation is
affected by body habitus and overlying anatomy. Limited assessment of the retroperitoneum and
renal vasculature, which is important in tumor staging, is a disadvantage of ultrasound evaluation.
While US is superior to CT in depicting the internal features of cystic renal masses, the presence of
calcium can obscure other features. In these instances, CT can be useful to characterize these
lesions, as the presence of a small amount of calcium does not hinder characterization.

Contrast-enhanced ultrasound with intravascular microbubble contrast agents can assess

enhancement of vascular elements within tissue. In fact, contrast enhanced ultrasound may be more
sensitive than CT in identifying increased blood flow in hypovascular lesions. The place of contrast
enhanced ultrasound in the management of renal masses is still under evolution.

CT scan6
Evidence of vascularization with contrast enhancement is the key to defining a small renal mass as a
solid tumor. In 1986, Bosniak created a four-part classification of cystic renal masses found on CT
scans. The system uses Hounsfield units to categorize these lesions in order of increasing probability
of malignancy.7

Delayed scans provide evaluation of the urothelium when there is suspicion that the mass may be
urothelial or invasive. Pseudoenhancement of small renal masses can occur as a result of strong
enhancement of surrounding normal renal parenchyma, especially with endophytic masses. Care
must be taken in the measurement of enhancement in heterogeneous masses; the same area of the
mass must be quantified at each time point to reliably determine enhancement.
In addition to the diagnosis, abdominal CT provides information on:
 Function and morphology of the contralateral kidney
 Primary tumor extension (extra-renal spread)
 Venous involvement
 Enlargement of loco-regional lymph nodes
 Condition of the adrenal glands and liver

Image characterization of histologic profiles has proven to be difficult with CT. Conventional clear cell
RCCs are hypervascular in 50– 90% of cases, unlike papillary and chromophobe RCCs which are
hypervascular in less than 10% cases. Necrosis is far more common in clear cell RCCs. The
presence of calcification has not reliably been shown to represent one subtype over another, although
it has been seen to predict malignancy with a 98% positive predictive value.

Limitation of contrast enhancement on CT7

Renal mass enhancement is affected by multiple factors: the amount and rate of the contrast material
injected, scan delay, and the vascularity of the mass. The accuracy of attenuation values are
dependent on multiple factors, including patient size, renal mass size, size and placement of the
region of interest, CT technique, partial volume averaging, and CT scanner type and manufacturer.
7
MRI
MRI has typically been the “problem solving” method for the assessment of renal masses (e.g., for
resolving inconclusive findings on ultrasound or CT) or for patients with contraindications to the use of
iodinated contrast media. Due to absence of ionizing radiation, it may become the investigation of
choice for active surveillance of renal masses.

With the exception of angiomyolipomas and simple renal cysts, unenhanced MRI cannot characterize
renal masses. There is no unanimously accepted way of calculating enhancement using MRI.
Because there is no ready analog to Hounsfield units, the percentage of enhancement over baseline
is used. Image subtraction, using arbitrary signal intensity units to calculate percentage enhancement
and subjective comparison of unenhanced and enhanced images are some of the methods used.
The disadvantage of MRI is the inability to detect calcification, which is an important part of the
Bosniak classification. In some instances, this can be an advantage, compared to CT, where dense
calcification can mask the presence of enhancement.7

Intravenous Urography8
Abdominal radiographs have very poor sensitivity and specificity for evaluating a renal mass.
Intravenous urography (IVU) with nephrotomography has only 67% sensitivity in detecting renal
masses ≤3 cm in diameter, and without tomography, the sensitivity is even less. IVU also lacks
specificity in separating benign from malignant cystic masses. It has value in imaging the upper
urinary collecting tracts, particularly in a patient with lower-tract transitional neoplasm.

Nuclear Medicine8
Radionuclide scintigraphy with a cortical imaging agent (e.g., dimercaptosuccinic acid [DMSA]) has a
limited role in evaluating the indeterminate renal mass, being used primarily to identify the so-called
column of Bertin or junctional zone, which may be causing a pseudotumor effect on IVU or US.
Fluorine-18-2-fluoro-2-deoxy-Dglucose positron emission tomography (FDG-PET) may prove to be
useful in detecting renal tumors and characterizing indeterminate renal cysts. However, it has low
sensitivity for RCC detection and characterization.

Angiography8
Although two-thirds of renal tumors have enough vascularity to allow identification of tumor
neovascularity, angiography has been replaced by CT for diagnostic purpose. Additionally, one third
masses will be of such a hypovascular or "avascular" state that angiography will not help identify the
lesion as benign or malignant. For some applications of nephron-sparing surgery for small renal
neoplasms, aortography or selective angiography may provide a road map to assist in resection.

Diagnostic Needle Core Biopsy8

Historically, concerns about safety and accuracy have limited the application of percutaneous needle
biopsy to provide a histologic diagnosis before treatment. When nephrectomy is done for suspicious
malignant small renal mass on the basis of imaging alone, the final diagnosis is benign in 28- 34%
cases. There has been a renewed interest in renal biopsy with increased accuracy and reduced
complications, with risk of tumor seeding being less than 0.01%. A positive diagnostic rate of 80% is
reported with the first biopsy and similar rate for a repeat biopsy. Ultrasound guidance, CT guidance,
or combined CT and ultrasound are used to achieve optimal targeting. Core biopsies are performed
through a 17-gauge coaxial cannula, which is initially advanced to the tumor surface. Histologic
parameters and tissue molecular markers, afforded by tissue biopsy, may help formulate therapeutic
plan for patients with a renal mass.

Ultrasound guidance seems to have several advantages: It is generally available, most urologists can
perform it by themselves, the device is portable and provides multiplanar and real-time imaging, and
the procedure costs less than CT. Unfortunately, not all renal masses can be visualized on
ultrasound, and adjacent structures and organs cannot be differentiated as well as on CT. In addition,
gas, ribs, and other structures can obscure visibility. Use of ultrasound-guided biopsy also requires a
significant learning curve. Biopsy is indicated in small renal tumor to diagnose malignancy and to
define success or failure after ablative therapy. Frozen section may be insufficient for evaluation of
renal mass, with 75% diagnostic accuracy being reported in one study.9

Radiographic investigations for metastatic RCC

Chest CT is the most accurate investigation for chest staging. However, at the very least, routine
chest radiography must be performed for metastatic evaluation, as a less accurate alternative to chest
CT. There is a consensus that most bone and brain metastases are symptomatic at diagnosis, so that
routine bone or brain imaging is not generally indicated. However, bone scan, brain CT, or MRI may
be used in presence of specific clinical or laboratory signs and symptoms.

Newer modalities9
New technologies in their investigational phases are also being assessed. It has been reported that
iodine-124-labelled antibody chimeric G250 (124I-cG250) positron emission tomography reliably
predicts clear cell renal carcinoma from other lesions. Similarly, experience with arterial spin labeling
(ASL) MRI has shown a significant correlation between an increase in blood flow to the renal mass on
ASL and its potential of being malignant or metastasize in the future.

The recent development of dual-energy CT (DECT) technology has the potential to lower radiation
dose to the patient. DECT involves simultaneous acquisition of CT data at 2 different energies or peak
tube voltages. The single-phase DECT examination has shown a 47% reduction in radiation dose
10
compared with a dual-phase CT examination.

Active surveillance of renal masses11

Patients with serious health risks who are deemed poor surgical candidates or who possess a chronic
disease such as a secondary malignancy that significantly reduces life expectancy are possible
candidates for active surveillance of enhancing small renal masses. While initial size and growth rates
are predictive of tumor behavior, various biomarkers have been studied to determine the initial risk or
progression to metastatic disease. Biomarkers such as carbonic anhydrase IX, vascular endothelial
growth factor, and CD147 have demonstrated some value in predicting tumor characteristics and
prognosis in RCC.

Follow up: which investigations for which patients, and when? 12

Intensive radiological surveillance for all patients is unnecessary. For example, the outcome after
surgery for T1a low-grade tumors is almost always excellent. It is therefore reasonable to stratify the
follow-up, taking into account the risk of a recurrence or metastases developing. Although there is no
randomized evidence, there have been large studies examining prognostic factors with long follow-up
periods, from which some conclusions can be drawn:
 The sensitivity of chest radiography for small metastases is poor and ultrasound has
limitations. Surveillance should therefore not be based on these imaging modalities. With low-
risk tumors, the surveillance intervals should be adapted relative to radiation exposure and
benefit. Magnetic resonance imaging (MRI) can be used to reduce radiation exposure.
 When the risk of relapse is intermediate or high, computed tomography (CT) of the chest and
abdomen is the investigation of choice, although the significant morbidity associated with the
radiation exposure involved in repeated CT scans should be taken into account.
 Surveillance should also include clinical evaluation of renal function and cardiovascular risk
factors.
 Positron-emission tomography (PET) and PET-CT as well as bone scintigraphy are not the
standard of care in RCC surveillance, due to their limited specificity and sensitivity.

REFERENCES
1. Silverman SG, Israel GM, Herts BR, Richie JP. Management of incidental renal mass. Radiology; 249(1): 16- 31.
2. Stakhovsky O, Yap SA, Leveridge M, Lawrentschuk N, Jewett MAS. Small renal mass: what the urologist needs to
know for treatment planning and assessment of treatment results. AJR 2011; 196:1267-1273.
3. Israel GM, Silverman SG. Imaging of incidentalomas. The incidental renal mass. Radiol Clin North Am. 2011;
49(2):369-383.
4. Frank I, Blute ML, Cheville JC, Lhose CM, Weaver AL, Zince H. Solid renal tumors: an analysis of pathological
features related to tumor size. J Urol. 2003 Dec;170:2217-2220.
5. Bagrodia A, Darwish OM, Rapoport Y, Margulis V. Risk prediction in management of small renal masses.Curr
Opin Urol 2012, 22:347–352.
6. Bradley AJ, Lim YY, Singh FM. Imaging features, follow- up, and management of incidentally detected renal
lesions. Clin Radiol 2011; 66(12): 1129- 1139.
7. Higgins JC, Fitzgerald JM. Evaluation of incidental renal and adrenal masses. Am Fam Physician 2001;63:288-94.
8. Bluth EI, Bush WH Jr, Amis ES Jr, Bigongiari LR, Choyke PL, Fritzsche PJ et al. Indeterminate renal masses.
American College of Radiology. ACR Appropriateness Criteria. Radiology. 2000 Jun;215 Suppl:747-52.
9. Remzi M, Marberger M. Renal tumor biopsies for evaluation of small renal tumors: why, in whom and how. Eur
Urol. 2009 ;55(2):359- 367.
10. Kang SK, Chandarana H. Contemporary imaging of the renal mass. Urol Clin N Am. 2012;39:161–170.
11. Mues AC and Landman J. Small renal masses: current concepts regarding the natural history and reflections on
the American Urological Association guidelines. Current Opinion in Urology. 2010; 20:105–110.
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Update March 2013. Available at: http://www.uroweb.org/fileadmin/guidelines/Total_file_2013_large_guidelines_
prints.pdf
 Pheochromocytoma
Deepak Ghuliani

Catecholamine secreting tumours arising from the chromaffin tissue of adrenal medulla and
sympathetic ganglia are called as pheochromocytoma and extra adrenal catecholamine secreting
paraganglionomas (extra adrenal pheochromocytoma) respectively. The term pheochromocytoma
arises from the greek words phaios(dusky), chroma (colour), cytoma(tumour) and reflects the dark
coloured staining reaction caused by oxidation of catecholamines on exposure to dichromate salts.(1)
Since these tumours have similar clinical picture and managed in a similar manner the term
pheochromocytoma is often used for both these tumours. These tumours may arise sporadically or
inherited as a feature of several pheochromocytoma associated inherited syndromes. In contrast to
adrenocortical carcinomas in which 50% of tumours are functional, virtually all pheochromocytomas
are functional and characterised by increased production of catecholamines.

Pheochromocytoma is estimated to occur in 2 -8/ million people per year and forms a curable form of
hypertension in 0.1-0.6% of patients.( 2 ) The classical natural history of pheochromocytoma is
described by a rule of 10 i.e 10% are multiple or bilateral,10% are familial,10% are extra adrenal,10%
are malignant ,10% recur after surgical removal ,10% of benign sporadic adrenal
pheochromocytomas are discovered as adrenal incidentalomas. About 90% of pheochromocytomas
are located in adrenal glands with the right sided adrenal being involved t wice as commonly as the
left and with an average diameter of 4.5 cm.Extra adrenal catecholamine secreting
paraganglionomas (extra adrenal pheochromocytomas) are distributed along the autonomic nervous
system from neck to pelvis.These tumours commonly occur along the paraaortic sympathetic chain
within the organ of Zuckerkandl(at the origin of inferior mesenteric artery), in the wall of urinary
bladder and less than 1% of these tumours are extra abdominal occuring along the sympathetic chain
in the mediastinum or neck.(3) Paraganglionomas of the head and neck region(e.g carotid body
tumours,glomus tumour) usually arise from the parasympathetic tissue and produce little or no
catecholamines while the paraganglionomas seen in the abdomen,pelvis or mediastinum arise from
the sympathetic chromaffin tissue and behave as functional tumours like the adrenal
pheochromocytomas. Uncommon locations for extra adrenal paraganlionomas include the intra atrial
cardiac septum,spermatic cord,vagina, scrotum and sacrococcygeal region.(1) Incidence of
malignancy is more commonly seen with extra adrenal lesions than those arising in the adrenal
glands.

Although the incidence of catecholamine secreting tumours is lo w it is necessary to suspect, confirm,

localise and resect these tumours(a) are potentially curable cause of hypertension.(b) danger of lethal
hypertensive crisis exists(c)Approximately 10% of these tumours are malignant(d) at least 10-20% of
these tumours are familial and their detection ill help in early diagnosis in other family members.

Syndromic forms of pheochromocytoma and paraganlionoma

About 20% of patients with catecholamine secreting tumours have germline mutation in genes
associated with the genetic disease. The mean age at diagnosis for hereditary pheochromocytomas is
about 15 years less than the sporadic tumours(4). Sporadic tumours are diagnosed due to presence
of symptoms or an incidental discovery on abdominal imaging whereas the inherited syndromic forms
are frequently diagnosed early in the course of disease because of biochemical surveillance or
genetic testing.(5)

Multiple Endocrine Neoplasia IIA and IIB (MEN IIA and IIB)
One of the best known pheochromocytoma associated inherited syndrome is the autosomal dominant
disorder ,multiple endocrine neoplasia type A and B. Both MENIIA and MEN IIB are associated with
mutation in RET(Reaaranged during transfection) protooncogene which encodes a tyrosine kinase.
MEN IIA is characterised by Medullary carcinoma of thyroid gland (MTC), Pheochromocytoma and
hyperparathyroidism.MEN IIB also includes MTC and pheochromocytoma along with mucosal
neuromas, intestinal ganglioneuromatosis and marfanoid body habitus. Nearly all patients with MEN II
syndrome develop MTC but pheochromocytoma occuirs only in about 50% of these patients. Virtually
all pheochromocytomas associated with MEN II are bilateral, benign, asynchronous and located in
adrenals.

Von Hippel Lindau syndrome(VHL)

This is an autosomal dominant disorder characterised by pheochromocytoma(usually bilateral),
paraganglionomas(rarely), cerebellar hemangioblastomas, retinal angiomas, clear cell Renal cell Ca,
cystadenoma of the epididymis and multiple pancreatic or renal cysts. Around 20% of patients
withVHL are reported to have pheochromocytoma. These tumours when associated with VHL
predominantly produce nor epinephrine and nor metanephrine while those occurring with MENII
produce epinephrine and metanephrine predominantly. Genetic testing of VHL should be considered
in patients with B/L pheochromocytomas, family h/o pheochromocytoma, pheochromocytoma at a age
< 20 years or associated co-phenotypic disorders.

Neurofibromatosis Type 1(NF 1)

NF1 as the first described pheochromocytoma associated inherited syndrome. It is a autosomal
dominant disorder phenotypically characterised by multiple neurofibromas, café-u-lait spots, axillary
and inguinal freckling of skin and Lisch nodules of the iris. Catecholamine secreting tumours occur in
about 2% of patients ithNF1.(6)The tumour in these patients predominantly solitary adrenal
pheochromocytoma ,occasionally bilateral and rarely abdominal paraganglionoma. Malignant
pheochromocytomas can also be seen in NF1.Unless the patient of pheochromocytoma shows the
additional characterstics of NF1,genetic testing for it is not advised.

Familial Paraganglionoma(The Paraganglionoma syndrome)

It is an autosomal dominant disorder associated with presence of paragangionomas most often
located in head and neck but also in thorax abdomen, pelvis and urinary bladder. Majority of familial
paraganglionmas are due to mutation in succinate dehydrogenase(SDH) subunit genes(SDHB,
SDHC.SDHD) which constitutes portion of mitochondrial complex II. The mean age of diagnosis is 30
-35 years and more than 50% of abdominal paraganglionomas while 5% of head and neck
paraganlionomas show catecholamine hypersecretion.

Paraganglionoma syndrome type II is associated with parasympathetic paraganglionomas classically

seen in head and neck.

Ataxia telengectasia, Tuberous sclerosis and Sturge weber syndrome are other neurocutaneous
syndromes associated with catecholamine secreting tumours.

Clinical presentation

Pheochromocytomas are seen with equal frequency in both males and females. The mean age of
diagnosis is around 40 years although the tumours can arise from early childhood until late in life.
The tumours are rare in children but when seen are usually multifocal and associated with some
hereditary syndrome.

Clinical presentation of pheochromocytoma can be so varied that it is often called as “The Great
Masquerader”.It may present with a wide spectrum of symptoms which predominantly are
manifestations of excess concentrations of catecholamines in circulation.The most dominant
symptom seen in these tumours is hypertension which may be sustained (mimicking essential
rd
hypertension) in about 50% of patients or paroxysmal in 1/3 of patients. (7,8) Rest of the patients
harbouring these tumours are normotensive. Episodic release of catecholamines, lo blood volume
because of persistent vasoconstriction and impaired sympathetic reflexes explain the lability of blood
pressure in patients of pheochromocytoma. Episodic symptoms occur in spells or paroxysms which
classically include palpitations, headache, tremors and diaphoresis. Facial pallor and cold hands and
feet may be seen due to peripheral vasoconstriction associated with a spell. Profuse seating and
increased body heat are the symptoms usually experienced at the end of the spell. Paroxysms of
hypertension with other associated symptoms may be spontaneous or precipitated by heavy physical
exercise, postural change, anxiety,pregnanacy, defecation, urination(particularly bladder
pheochromocytomas, lifting weights and medications like metoclopromide, opiates and tricyclic
antidepressants. Spells may occur multiple times in a day or infrequently occur once in a month.
These spells generally last for less than an hour(15-20 minutes) but may be much shorter or last for
several hours. More than half the patients have impaired glucose tolerance and present with
symptoms of diabetes mellitus like polyuria and polydipsia because of alpha adrenergic inhibition of
insulin release. Symptoms of orthostataic hypotension like light headedness, presyncope and
syncope nay be frequently seen in patients with pheochromocytoma because of chronic
hypovolaemia and altered sympathetic reflexes .Orthostatic symptoms are more commonly seen in
epinephrine and dopamine producing tumours. Other clinical features include hypertensive
retinopathy, nausea, constipation, angina, hypercalcemia, Raynaud’s phenomenon, livedo reticularis,
erythrocytosis, cardiomyopathy, congestive heart failure. myocarditis and mass effects of the tumour.
Tumour resection completely reverses cardiomyopathy whether dilated or hypertrophic. Some of the
patients may remain asymptomatic even with elevated catecholamine levels due to adrenergic
receptor desensitisation by chronic stimulation.

Diagnosis

Biochemical testing for pheochromocytoma must be performed in patients with any one of the
following features.

 Spells of non exertional palpitations, diaphoresis, headache, tremors or pallor

 Resistant hypertension
 Familial syndrome associated with pheochromocytoma
 H/O Pheochromocytoma in the family
 Hypertension at a young age(<20 years)
 Pressor response during surgery, anaesthesia,or angiography
 Idiopathic dilated cardiomyopathy

Pheochromocytomas (both adrenal and extra adrenal) synthesise and store catecholamines like nor
epinephrine, epinephrine and dopamine.Increased plasma and urinary levels of catecholamines and
their methylated metabolites, metanephrines are the cornerstone of diagnosis. Catecholamines and
metanephrines can be measured by high performance liquid chromatography, ELISA or mass
spectrometry. In a patient with clinical suspicion of pheochromocytoma, if the values are three times
the normal.(9) Pheochromocytoma is a highly likely diagnosis irrespective of the assay used. Though
some controversy may exist regarding the optimal single test for establishing the diagnosis of
pheochromocytoma most centres have found measurement of catecholamines, metanephrines(total
or fractionated), VMA in a 24 hour urine sample as the most reliable initial method for diagnosis with a
sensitivity of 95% and specificity of 98%(10). Among these tests fractionated metanephrines and
catecholamines are considered the most sensitive. In a case with high clinical suspicion of
pheochromocytoma fractionated plasma free metanehrines should also be measured. It has a
sensitivity of 96-100% and a specificity of 89%.(11) Due to its poor specificity plasma free
metanephrines is not recommended as the first line test. It can be a good first line test in children here
obtaining a complete 24 hour urine sample may be difficult. Measuring urinary dopamine and plasma
methoxytyramine may be helpful in selecting a rare variant with selective dopamine hypersecretion as
plasma metanephrine fraction is not a direct metabolite of dopamine.

It is preferred that the patients of pheochromocytoma while undergoing a diagnostic ork up should not
receive any medication which can interfere with the interpretation of 24 hour urinary catecholamines
and metabolites. Drugs like tricyclic antidepressants, levodopa and amphetamines should be tapered
and stopped minimum for t wo weeks before the diagnostic hormonal evaluation.

Other tests
Chromogranin A, stored and released from the dense core secretory granules of neuroendocrine cells
is elevated in 80% of patients of pheochromocytoma. But because of its elevated levels in the other
neuroendocrine tumours also, it is not specific for pheochromocytoma. Plasma neuropeptide levels
are elevated in 87% of patients but lacks the accuracy of 24 hour urinary catecholamines and
metanephrines.

Clonidine suppression test

It helps to differentiate between pheochromocytoma and false positive elevations of catecholamines
and metanephrines. Clonidine is centrally acting alpha adrenergic agonist that normally decreases the
catecholamine release from neurons but does not affect the catecholamine secretion from
pheochromocytoma. Plasma catecholamine and metanephrines are measured before and 3 hours
after administering 0.3 mg clonidine orally. In patients with essential hypertension plasma
catecholamine and metanephrine concentrations decrease after clonidine administration but remain
unchanged in patients of pheochromocytoma.(1) Other pharmacological tests such as glucagon
provocation test and phentolamine test are of later sensitivity and are no longer recommended.

Localisation

Localisation studies should be initiated once biochemical investigations have confirmed the diagnosis.
CT or MRI have a similar sensitivity and should be the initial test for localisation. Since 90% of these
tumours are located in adrenals a CT scan ill virtually identify all these tumours and evaluate the
contra lateral gland also. The lipid rich nature of adrenal cortical adenomas and their limited
enhancement on CT after administration of i.v contrast helps in distinguishing them from the
pheochromocytomas which may be B/L and shows marked enhancement with i.v contrast. Since it is
a purely anatomic representation extra adrenal pheochromocytomas may be missed on a CT. In
contrast to CT ,MRI provides both anatomic and physiological imaging capabilities. On T2 eighted
MRI sequences with gadolinium contrast pheochromocytoma and paraganglionomas show a
characteristic high intensity signal and is also considered better for imaging extra adrenal
pheochromocytomas while a benign cortical adenoma is iso intense ith liver on both T1 and T2
weighted MRI sequences.(13)

13 I-Metaiodobenzylguinidine(MIBG) Scintigraphy
Using 123I or 131I tagged MIBG Scintigraphy abnormal adrenergic tissue can be identified. It is
preferentially concentrated in the adrenergic vesicles in catecholamine secreting tumours and their
metastases too. This is usually used for localisation of pheochromocytoma when the results of
abdominal imaging are negative. It may also be indicated if the adrenal pheochromocytoma is > 10
cm in diameter or a paraganglionoma is found as these patients have a higher risk of malignancy and
additional paraganglionomas. To prevent ablation of thyroid during the course of this investigation the
uptake of I123 by thyroid should be blocked with administration of iodide either in the form of Lugol’s
iodine or SSKI starting 24 hours before injection and for a total of 5 days. Drugs like TCA, Ca channel
blockers, labetelol, chlorpromazine, haloperidol may interfere with the MIBG uptake and thus should
be stopped before the imaging is performed.

These tumours can also be localised with positron emission tomography scanning with 18 FDG or
hydroxyephedrine or 18 F fluorodopamine. But these techniques should be reserved for identifying
metastatic sites of disease in patients with negative 123I MIBG scanning.

Treatment

Complete surgical resection is the treatment of choice for pheochromocytomas. Majority of these
tumours are benign, can be removed totally and cures the associated hypertension also. Preoperative
pharmacological preparation prevents a cardiovascular crisis during surgery and is thus crucial for a
successful surgical resection.(14). It is indicated for all patients with catecholamine secreting tumours
because even if the patient’s blood pressure is normal preoperatively severe hypertension can occur
with mild tumour manipulation during the surgery especially in a patient with inadequate preoperative
preparation.(15)
The main aim of preoperative preparation is adequate alpha adrenergic blockade with complete
restoration of the fluid and electrolyte balance.

Alpha adrenergic blockade

Phenoxybenzamine is the alpha adrenergic blocking agent of choice and usually started 7-10 days
preoperatively at a relatively lo dose of 10mg once or twice daily. The dosage is gradually increased
by 10-20 mg in divided doses every 2-3 days until adequate blockade is achieved with the final dose
being typically 20-30 mg three times a day. As the patients are volume constricted a diet liberal in Na
content(> 5000 mg/day) is advised from the second or third day of the alpha adrenergic blockade to
avoid orthostasis.

Beta adrenergic blockade

To control tachycardia and other arrhythmias beta adrenergic blockade is also instituted usually 2-3
days before surgery. Beta adrenergic blockade should be initiated only hen alpha adrenergic
blockade has been established or else the beta blocker ill inhibit epinephrine induced vasodilation
leading to more severe hypertension. Beta blockade is started with Propranalol 10mg TDS/QID and if
tolerated converted to a single long acting dose to achieve a target heart rate between 60-80
beats/minute.

Catecholamine synthesis inhibitor

Metyrosine (Alpha methyl paratyrosine) inhibits catecholamine synthesis by blocking the enzyme
tyrosine hydroxylase. Because its side effects can be disabling it is indicated for preoperative
preparation if other agents have been ineffective, difficult tumour resection with marked tumour
manipulation is expected or if a destructive therapy like radiofrequency ablation is planned.
If the blood pressure is difficult to control with Phenoxybenzamine or if the patient is having intolerable
side effects from the alpha adrenergic blockade other antihypertensives like Calcium channel blockers
may also be used.

Anaesthetic considerations

Resection of catecholamine secreting tumours is a high risk operation requiring a team of

experienced surgeons and anaesthesiologists. Last dose of alpha and beta adrenergic blocking
agents may be administered early on the morning of surgery. Ketamine,Fentanyl and morphine
should be avoided as they can stimulate release of catecholamines from pheochromocytoma.
Because of associated tachycardia parasympathetic blockade ith atropine should be avoided. In
addition use of the anaesthetic gases halothane and desflurane should also be avoided.
Acute hypertensive crisis can occur during or before the surgery and should be managed with Sodium
nitroprusside, Phentolamine or Nicardapine.

Surgery

The principles of resection of pheochromocytoma include a total removal of the tumour intact with
minimal wide fluctuations in blood pressure. The choice of surgical approach is decided by the tumour
size ,signs of local invasion and surgeon’s experience. Traditionally an open anterior approach has
been used as it allows the en block resection of the tumour along with the exploration of the contra
lateral gland and the potential metastatic sites. Currently, in the absence of local tissue invasion,
nodal spread or distant metastases a laparoscopic approach(Transperitoneal or retroperitoneal)
should be preferred especially in patients with solitary adrenal pheochromocytomas less than 8 cm in
size(16). Due to highly improved accuracy of the localisation studies , mandatory exploration of the
contra lateral adrenal becomes unnecessary. Further, the laparoscopic trans peritoneal approach
also allows the evaluation of liver and peritoneal metastases.(17) However whatever the operative
approach, the tumour manipulation should be as little as possible and the tumours venous outflow be
ligated via adrenal vein as early in the procedure as possible.

A cortical sparing adrenlectomy is being also performed especially in patients with bilateral
pheochromocytoma associated with the inherited syndromes like MENII or VHL. Cortical sparing
adrenlectomy avoids the chronic steroid hormone replacement and reduces the risk of addisonian
crisis in most patients. A problem of subtotal adrenelectomy in pheochromocytoma can be persistent
disease especially in a multinodular adrenal tumour hen additional nodules are overlooked during
dissection . Thus intra operative ultrasonography preferably be used in cases planned for a subtotal
adrenalectomy. An anterior midline approach is used for abdominal paraganglionomas with a
thorough inspection of the midline of the abdomen.

Post operatively the patient should be monitored in ICU for at least2 4 hours so that they can be
carefully observed for any arrhythmias or hypotension. Hypotnesion can occur both intra and post
operatively and should be managed with fluids and colloids followed by intravenous pressor agents if
needed. Post operative hypotension is less frequently seen in patients ith adequate preoperative
alpha adrenergic blockade. Adrenocortical insufficiency due to manipulation of both the adrenal
glands during surgery is considered as the probable cause of post operative hypotension. Post
operatively blood glucose levels should be carefully monitored and intravenous fluid to be infused
should be 5% dextrose as hypoglycaemia may occur in the post operative period.

By the time of discharge the blood pressure usually returns to normal but some patients may continue
to be hypertensive for 4-8 weeks after surgery. Persistent longstanding hypertension can also occur
and is explained by accidental ligation of the polar renal artery, resetting of the baroreceptors,
Haemodynamic changes, structural changes of blood vessels, altered sensitivity of vessels to pressor
substances or co incident primary hypertension.

Long term follow up

Fractionated catecholamines and metanephrines should be measured in 24 hour urinary specimen

around 1- 2weeks after surgery. Resection should be considered complete if these levels are normal.
Metastatic disease is present in approximately 5% of patients and may not be apparent for more than
5 years. Thus all patients once operated for pheochromocytoma should undergo yearly evaluation of
fractionated metanephrines and catecholamines or fractionated plasma catecholamines for assessing
metastases, tumour recurrence in the adrenal bedor delayed appearance of multiple primary tumours.
Patients with familial disease, right sided adrenal pheochromocytomas or paraganglionomas have the
maximum recurrence rate(18). CT or MRI are not routinely required in follow up and is required only if
metanephrine or catecholamine levels are increased. The survival rates after resction of benign
pheochromocytomaare nearly same for age matched and sex matched normal controls. Lifelong
glucocorticoid and mineralocorticoid replacementent becomes mandatory if a bilateral adrenalectomy
has been done.

Malignant Pheochromocytoma

The incidence of malignancy in pheochromocytoma is around 10% but has varied from 4%- 22% in
some of the recent series. It is difficult to differentiate between benign and malignant
pheochromocytomas on the basis of cytological, clinical or biochemical features. The term malignant
pheochromocytoma is usually used for tumours with invasion of surrounding soft tissue and presence
of distant metastases which commonly occurs to lungs, bones, liver omentum and the retroperitoneal
lymph nodes.( 19) Malignancy is more common in patients with familial paraganglionomas caused by
mutation in SDHB but rare in the ones with adrenal pheochromocytoma related inherited syndromes.
Recurrent Pheochromocytomas are mostly functioning tumours like the primary tumour and can be
detected wit h 24 hour urine determination of ctecholamines and metanephrines. MIBG scintigraphy
is used for determining the extent and location of metastases.

If possible the metastatic lesion should be resected to decrease the tumour burden. Painful skeletal
metastases can be palliated with external beam radiation or cryoablation. Approximately 60% of
patients show partial and temporary response to local tumour irradiation with therapeutic doses of 131
I MIBG. In case the tumour is aggressive and patient’s quality of life is affected a combination
chemotherapy may be considered. This chemotherapy protocol includes Dacarbazine(600 mg/m on
days 1 and 2), cyclophosphamide(750mg/m on day 1) and vincristine(1,4mg/m on day1) repeated
every 1 days for 3-6 cycles.( 20)

The overall tumour and biochemical response rate is 51% and 79% respectively. Though the 5 year
survival rates for patients with malignant pheochromocytoma is 43%, the prognosis is quite
variable.50% of patients have an indolent course with a life expectancy of more than 20 years hile
other 50% have rapidly progressive disease with a life expectancy of 1-3 years.

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3. Erickson D, Kudva YC, Ebersold MJ et al. Benign paraganglionomas: Clinical presentation and treatment
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5. Palu C, Bausch B, Reisch N, et al. Genetic testing for pheochromocytoma- associated syndromes. Ann
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7. Manger WM. An overview of pheochromocytoma. History, current concepts, vagaries and diagnostic challenges.
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 Neuroendocrine Tumour of Pancreas
SK Mishra, Naval Bansal

Introduction

Pancreatic neuroendocrine tumors (PNETs) constitute 1 to 2% of pancreatic neoplasms and show

unique genetics, biology, and prognosis relative to pancreatic adenocarcinomas. They originate from
diffuse neuroendocrine cells with two probable origins: mature endocrine cells in the pancreas and
multipotent stem cells that can differentiate into endocrine and exocrine cells in the pancreas.
Endocrine pancreas consists of the pancreatic islets, which are distributed throughout the pancreas
and form, in adults, approximately 1 to 2% of the pancreatic mass. PNETs comprise a diverse group
of neoplasms including functional and non-functional tumors as well as tumors that may represent a
manifestation of a hereditary neuroendocrine syndrome. PNETs are classified as either functional or
non-functional, depending on whether a patient experiences symptoms related to excess hormone
(e.g. gastrin, insulin, glucagon, vasoactive intestinal peptide etc.) production by the tumor. Based on
the functional status, WHO classified (2010) of neuroendocrine tumors into three subtypes (Table 1):

Table 1. WHO classification of neuroendocrine tumors 2010: Functional classification

Source: Bosman FT, Carneiro F,Hruban RH,Theise ND. Tumours of the Pancreas. Lyon, France: IARC Press;
2010.

Clinical presentation

Fuctional tumour produce different set of symptoms ( as mentioned above) depending upon the
hormone produced whereas non-functional PNETs typically present with nonspecific symptoms such
as abdominal pain, weight loss, or early satiety, and are locally advanced or metastatic at the time of
diagnosis in greater than 50% of cases.

Insulinoma
It is the commonest neuroendocrine tumor of the pancreas with an annual incidence of four in every 1
million persons & comprises 70% to 80% of all functional neuroendocrine pancreatic tumors. The
median age of patients at presentation is approximately 47 years, and females (59%) show a slight
predominance over males. In sporadic setting 90% are small, single, and benign tumors, with 90%
measuring less than 2 cm and 30% measuring less than 1 cm in diameter. Approximately 10% are
multiple, 10% are malignant, and 16% are associated with MEN-1 Syndrome. They are equally
distributed throughout the pancreas and size > 3cm are likely to be malignant. Malignant Insulinomas
tend to occur more frequently in MEN-1 patients and distant metastasis is considered the only
definitive characteristic of malignancy.

Clinical symptoms are due to hypoglycaemia and adrenergic activity (Table 2). Symptoms are
typically precipitated by fasting or exercise; they can also occur postprandially or can have no
relationship to eating. Another notable manifestation of Insulinoma is weight gain, as patients may eat
frequently to avoid symptoms.

Table 2: Symptom Frequency (%)

Neuroglycopenic Adrenergic

Visual disturbances(59) Sweating (69)

Altered mental status (80) Palpitations (12)

Abnormal behavior (36) Weakness (56)

Amnesia or coma (47) Tremors (24)

 Seizures (17) Hyperphasia (14)

In 1935, Whipple and Frantz described the diagnostic triad for Insulinoma, so-called ‘Whipple’s triad’,
the diagnostic hallmark of Insulinoma

• Symptoms of hypoglycaemia provoked by fasting

• Circulating glucose level less than 50mg/dl at the time symptoms presented
• Relief of symptoms with administration of glucose

Biochemical diagnosis (Service criteria) 14

• Serum Insulin > 10microUnits/mL

• Raised levels of serum C peptide >2.5ng/mL
• Serum glucose < 45mg%
• Negative plasma sulphonylurea
• Negative insulin antibodies
• Insulin : Glucose ratio > 0.4

Gastrinoma (Zollinger–Ellison syndrome (ZES)

Gastrinomas are composed of cells that resemble the G

cells of the gastric antrum and duodenum. Although first
called pancreatic islet cell tumors, many Gastrinomas are
located outside the pancreas, with sites in the duodenal
wall, stomach, jejunum, peri pancreatic tissue, ovaries, and
liver, with 90% of Gastrinomas are seen in‘ Gastrinoma
triangle’ (junction of the pancreatic body and neck, the
junction of the 2nd and 3rd portion of the duodenum and the
junction of the cystic duct and common bile duct , Figure 1).
There is long delay before presentation/diagnosis of these Fig 1. Gastrinoma triangle
Source: O’Grady HL, Conlon KC. Pancreatic
tumours (mean delay around 5years). At least 60% of
neuroendocrine tumors. Eur J Surg Oncol.
Gastrinomas are malignant; however Gastrinomas may 2008;34:324–332
have an indolent course, and Gastrinoma patients with proven lymph node metastases may live for
several decades without apparent tumor progression. Patients with ZES as part of the MEN1
syndrome (MEN1/ZES) present at an earlier age (approximately 1 decade earlier) and may have
relatively mild symptoms.

Almost all patients with ZES initially present with symptoms due to the hyper secretion of gastric acid
which is due to the ectopic release of gastrin from the Gastrinoma. The principal symptoms remain
those due to peptic ulcer disease or severe GERD (abdominal pain, nausea, heartburn, vomiting) with
or without diarrhoea. In contrast to the past, at present patients only present with a complication of
peptic ulcer disease (bleeding, obstruction, penetration, perforation) in a minority of patients
(approximately 33%). The ectopic secretion of gastrin by the Gastrinoma is influenced by the degree
of hypercalcaemia, so that post Parathyroidectomy, there is marked decrease in the acid
hypersecretion.

Seven diagnostic clues suggest the presence of a Gastrinoma:

a) Diarrhoea in a patient with peptic ulcer disease

b) Peptic ulcers persisting after therapy with H2 receptor antagonists or omeprazole
c) Recurrent ulcer after an adequate ulcer operation
d) Pathognomonic jejunal ulcers
e) Large gastric rugal folds, often associated with duodenitis, jejunitis, and rapid transit
f) Multiple atypical peptic ulcers
 g) Marked gastric acid hypersecretion (>15 mEq/hour)

Diagnosis

• Fasting serum gastrin (FSG) : >10 fold normal (usually>1000 pg/ml)

• Gastric pH < 2

Unfortunately, in 60% of ZES patients the FSG is <10-fold elevated and this overlaps with the other
conditions than can cause hyperchlorhydria and hypergastrinemia, in these patients besides
demonstrating hypergastrinenemia in the presence of gastric pH < 2,a secretin test and a complete
gastric analysis is recommended. Patients with ZES without previous gastric acid-reducing surgery
characteristically have an elevated basal acid output (90%) and demonstrate an exaggerated
response to intravenous secretin, with an increase of 120 pg/ml recently shown to have a sensitivity of
94% and specificity of 100% for ZES.

VIPoma

VIPomas characteristically present with large volume, watery diarrhoea that leads to the development
of dehydration and hypokalemia. The excess VIP secretion also can result in hyperglycemia (20–
50%), hypercalcaemia (25–50%), hypochlorhydria (20–50%) and flushing (15–30%).

Diagnosis

• Presence of large volume diarrhoea (usually >3 L/day, and a VIPoma is generally excluded if
the stool volume is <700 ml/day) that is secretory in nature (no osmolar gap in the stool fluid)
• Increase plasma VIP level (usually >500 pg/ml) ( normal <190 pg/ml)

Glucagonoma

At presentation Glucagonomas are characterically large tumors (>5 cm) and in 50–80% of patients
have advanced disease with metastatic liver lesions. Characteristically present with a specific:

• Dermatitis (necrolytic migratory erythema or NME) (55–90%), not specific for this diagnosis as
it also occurs with liver diseases (cirrhosis, hepatitis, liver tumors),pancreatitis, celiac disease
and lung cancer
• Weight loss (60–90%),
• Diabetes mellitus or glucose intolerance (30–90%),
• Mucosal abnormalities (glossitis, cheilitis, stomatitis) (30–40%),
 • Diarrhoea (10–15%)
• Anaemia (30–80%)
• Hypoaminoacidemia (30–100%)

Diagnosis

• Characteristic skin lesion

• Hyperglucagonemia levels >500 pg/ml (normal < 120)

Somatostatinomas (SSomas)

Chracteristically pancreatic SSomas are associated with the SSoma syndrome, whereas small
intestinal SSomas are not. SSoma syndrome include: Diabetes mellitus, gallbladder disease,
diarrhoea, weight loss, steatorrhea

Diagnosis

• In most cases SSomas are not diagnosed prior to surgery/biopsy

• To diagnose the SSoma syndrome plasma SLI levels need to be assessed, it is important to
remember that a number of other conditions are also associated with elevated plasma SLI
levels including; medullary thyroid cancer, lung cancers, pheochromocytomas and
aragangliomas

Nonfunctional PNETs/PPomas

They are not associated with any functional syndrome, therefore their symptoms at presentation are
due to the tumor per se and characteristically include: abdominal pain (35–55%), jaundice (25– 40%),
weight loss (30–45%) and/or an abdominal mass (10–40%). Because the symptoms are nonspecific,
NF-PETs are usually diagnosed late in their disease course with large primaries (mean 4–6 cm), with
most have metastatic disease in the liver (40–90%).

The term NF-PET is actual a misnomer, even though widely used, because even though these tumors
produce no functional PNET syndrome, they are not non-functional in that they secrete may peptides
that do not cause clinical syndromes including pancreatic polypeptide (25–70%) (hence the
alternative name, PPomas), Chromogranin-A (60–100%), Neuron-specific enolase (31%),Ghrelin,
Neurotensin, and subunits of Human chorionic-gonadotrophin (20%).

Diagnosis
Because NF-PETs produce no specific functional syndrome, they can only be diagnosed
preoperatively with a high degree of suspicion. A patient with extensive metastases in the liver with a
pancreatic mass and relatively few symptoms, with minimal signs of advanced metastatic disease,
with a positive somatostatin receptor scintigraphy or with a plasma elevation of one of the nonspecific
NET tumor markers (pancreatic polypeptide, chromogranin-A, neuron-specific enolase) should be
suspected of having an NF-PNET.

Imaging

Computed tomography: Helical multiphasic contrast enhanced CT is recommended for initial

evaluation of PNETs. The sensitivity of this approach is > 80%. The sensitivity is decreased in tumors
smaller than 2cm. symptomatic but non-functioning tumors, VIPomas, and Glucagonomas are usually
>3 cm at the time of diagnosis .The sensitivity of contrast-enhanced CT for these tumors approaches
100%,and it is considered the imaging study of choice
 Magnetic resonance imaging: On MRI, pancreatic On MRI, pancreatic NETs are typically
characterized by low signal intensity on T1-weighted images, and high signal intensity on T2-weighted
images. MRI is a reasonable alternative to CT, as lesions can be visualized without contrast in T1-
and T2-weighted sequences, reducing the variability sometimes seen with CT Imaging.

Endoscopic ultrasonography (EUS): Endoscopic ultrasonography provides high-resolution imaging

of the pancreas, and it can detect lesions as small as 2–3 mm in diameter. EUS has high sensitivity &
specifity (82% & 95%) in detecting PNETs. It is also useful tool for identifying Gastrinomas that arise
in the duodenal wall which are not picked up on CT scan/ MRI. It can be used as tool for EUS-guided
fine-needle aspiration for PNETs.

Somatostatin receptor scintigraphy (Octreoscan): Many pancreatic NETs express high levels of
somatostatin receptors and can therefore be imaged with a radiolabeled form of the somatostatin
analog (111In-DTPA-D-Phel) octreotide. Somatostatin receptor scintigraphy(SRS) has proven
particularly effective for visualizing Gastrinomas (100%), Glucagonomas, and non-functioning
pancreatic tumors. Insulinomas (62%) and poorly differentiated neuroendocrine tumors express low
somatostatin receptor levels and are less likely to be detected on SRS. It has the additional
advantage of whole body scanning, which allows detection of metastases outside the abdominal
region. The accuracy of SRS has improved with the addition of single photon emission computed
tomography (SPECT).

Laser confocal endomicroscopy with fluorescein-labeled somatostatin analogs:

Laser confocal microscopy is a novel technology that has been recently introduced into clinical
diagnostics. A sub-millimeter needle-based confocal laser endomicroscopy(nCLE) probe that provides
real-time imaging at the microscopic level through the EUS-FNA needle, this allows histological
diagnosis of the pancreas or duodenal wall lesions at the cellular and subcellular level in vivo and
provides instantaneous histopathology during ongoing upper (and lower) endoscopy and EUS-FNA.

Arterial stimulation venous sampling: Cases which are radiographically occult but hormonally
functional, Invasive approaches may be necessary to localize tumors to a particular region of the
pancreas for treatment planning. Transhepatic portal venous sampling (THPVS)is a technically
demanding technique in which small peripancreatic veins are accessed and tested for levels of
hormones such as insulin. A more recent innovation, arterial stimulation with hepatic venous sampling
(ASVS), involves selective injection of a stimulating secretagogue (secretin for gastrinomas and
calcium gluconate for insulinomas) into arteries supplying the pancreas with subsequent sampling of
the hepatic venous effluent.

Intraoperative localization techniques: Intraoperative ultrasonography allows a high-resolution

examination of the pancreas. When combined with palpation of the organ, the sensitivity for tumor
detection ranges from 83%to100%. Laproscopic intraoperative transillumination has equivalent
efficacy (sensitivity of83%) for the localization of duodenal wall gastrinomas.

Staging (Seventh edition AJCC staging)

Primary Tumor
Tx: primary tumor cannot be assessed
T0: no evidence of primary tumor
Tis: carcinoma in situ
T1: tumor limited to pancreas, ≤2 cm in greatest dimension
T2: tumor limited to pancreas, >2 cm in greatest dimension
T3: tumor extends beyond pancreas but without celiac or SMA involvement
T4: tumor involves celiac axis or SMA (unresectable primary tumor)
Regional Lymph Nodes
NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastases
N1: regional lymph node metastases
Distant Metastases
M0: no distant metastases
M1: distant metastases

Staging Classification Stage-Specific 5-y Survival (%)

Stage 0 Tis N0 M0 Stage I 61

Stage IA T1 N0 M0 Stage II 52

Stage IB T2 N0 M0 Stage III 41

Stage IIA T3 N0 M0 Stage IV 15

Stage IIB T1-3 N1 M0

Stage III T4 Any N M0

Stage IV Any T Any N M1

Source: Capelli P, Fassan M, Scarpa A. Pathology - grading and staging of GEP-NETs.Best Pract Res Clin
Gastroenterol. 2012 Dec;26 (6):705-17

Pathological classification

In general, neuroendocrine tumors are reported as well differentiated (>90%) or poorly differentiated
(<10%), depending on the degree to which neoplastic cells resemble their nonneoplastic counterparts.
Grade is determined by measure of cellular proliferation using either Ki-67 immunolabeling indices or
mitotic count. Tumor grade and differentiation are closely related. In general, low-grade and
intermediate-grade tumors are well differentiated, whereas high-grade tumors are poorly
differentiated. High-grade, poorly differentiated PNETs are very aggressive malignancies, with a
biology and prognosis that parallel small cell carcinoma. Rarely are patients with poorly differentiated
PNETs surgical candidates. On the other hand, well-differentiated PNETs follow a more indolent
course, and treatment often involves a combination of surgical and nonsurgical therapies

Table 3. Histopathologic classification of PNETs

Low Grade Intermediate Grade High Grade

Ki-67 index <2% 2%–20% >20%

Mitotic count <2/50 HPF 2–20/50 HPF >20/50 HPF

Differentiation Well differentiated Well differentiated Poorly differentiated

Biochemical markers

They are used for diagnostic, prognostic or predictive purposes. Chromogranin A is the most
important general marker and it is recommended to be measured in every patient with a suspected
NET, whereas Neuron Specific Enolase is elevated mainly in poorly differentiated NETs. Pancreatic
Polypeptide is used in the diagnosis of pancreatic non-functioning NETs, whereas Chorionic
Gonadotrophin has an adjunctive role. In the case of functioning tumours,
specific markers should be sought and monitored during follow up.
Table 4:
General markers Tumour specific markers

1.Chromogranins 1.Carcinoid tumours

• Chromogranin A • 24 h Urine 5-hydroxyindole acetic acid

• Chromogranin B • 24 h Urine 5-hydroxy-tryptophan
• Secretogranin II • Plasma serotonin
• Secretogranin III (1B1075) 2.Insulinoma
• Secretogranin IV (HISL-19)
• Secretogranin V (7B2) • Fasting insulin
• Secretogranin VI (NESP55) • Fasting pro-insulin
3. Gastrinoma
2. Neuron Specific Enolase
• Fasting/stimulated gastrin
4.Glucagonoma

3.Pancreatic polypeptide • Fasting glucagon

5.VIP-oma

• Fasting vasoactive intestinal peptide

4. Chorionic gonadotrophin 6.Somatostatinoma
• Fasting somatostatin
Source: Kanakis G, Kaltsas G. Biochemical markers for gastroenteropancreatic neuroendocrine tumours (GEP -NETs). Best
Pract Res Clin Gastroenterol. 2012 Dec;26(6):791-802

Prognostic factors in PNETs

• Presence of liver or lymph node metastases

• Depth of invasion
• Rapid rate of tumor growth
• Elevated serum alkaline phosphatase levels
• Primary tumor site and size
• Various histologic features—vascular or perineural invasion, vessel density, necrosis, and
tumor
• Differentiation
• High growth indices (high Ki-67 index, PCNA expression) or mitotic counts
• Presence of cytokeratin 19
• High CD10 metalloproteinase expression (in series with all grades of NETs)
• Flow cytometric features (i.e., aneuploidy)
• High VEGF expression (in low-grade or well-differentiated NETs only)
• WHO, TNM, and grading classification
• Presence of a pancreatic NET rather than GI NET
• Older age
• Ha-ras oncogene or p53 over expression
• Female gender
• MEN1 syndrome absent
• Presence of nonfunctional tumor (some studies, not all)
• Molecular findings [increased HER2/neu expression] chr 1q, 3p, 3q, or 6q LOH, EGF receptor
overexpression, gains in chr 7q, 17q, 17p, 20q; alterations in the VHL gene
Treatment

Source: Baudin et al. Intervention in gastro-enteropancreatic neuroendocrine tumours. Best Practice & Research Clinical
Gastroenterology 26 (2012) 855–865

Locoregional Disease

Surgical resection is the mainstay of therapy for patients who present with locoregional disease.
Complete tumor extirpation offers the only opportunity for cure and provides symptomatic relief for
patients with functional PNETs. With the exception of most insulinomas, most PNETs are malignant
and resection for these neoplasms should follow sound oncologic principles, including formal
pancreatectomy and regional lymphadenectomy. Depending on tumor location,
pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy is typically performed.

The surgical treatment of pancreatic neuroendocrine neoplasms depends on the type, size and
location of the tumours. The risk of metastatic disease is related to tumour size. Tumours less than 1–
2 cm without growth over a considerable time generally have a low potential of spreading.

Tumours located to the head of the gland usually require a pancreaticoduodenectomy, while tumours
to the left of the mesenteric vessels can be managed by a distal pancreatectomy with splenectomy.
When tumour is benign (e.g. most insulinomas), the spleen may be preserved. Since pancreatic
neuroendocrine neoplasms are usually encapsulated enucleation of small benign tumours (<2 cm) is
an alternative to resection. However, enucleation of tumour close to one of the major pancreatic ducts
(less than 2–3 mm) should be avoided due to the high risk (20–30%) of damage to the ducts with
formation of a pancreatic fistula. Intraoperative ultrasonography is mandatory to locate tumour, its
relation to the ducts as well as the number of tumours.

Patients who present with locally advanced, unresectable disease (ie, encasement of celiac or
superior mesenteric arteries) in the absence of distant metastases require an individualized
therapeutic strategy to provide optimal palliation. There are no data to support debulking or planned
R2 resection of the primary tumor, and such an approach is likely to result in unnecessary morbidity.
Occasionally, these patients may require palliative bypass operations to relieve biliary or gastric outlet
obstruction. Although PNETs are generally regarded as indolent tumors, recurrence after resection
with curative intent is common; therefore, these patients require diligent oncologic surveillance with
the liver is the most common site of recurrence.

Management of Liver Metastases

• Hepatic Resection: If feasible, surgical resection of PNET liver metastases is preferred.

Although complete resection is ideal and offers the only potential for cure.
• Local Ablative Techniques: for surgically inaccessible lesions. Although several forms of
therapy such as cryoablation and percutaneous ethanol injection have been
reported,radiofrequency ablation (RFA) is the preferred technique in most centers.
• Hepatic Arterial Embolization Procedures: Patients with diffuse, unresectable liver metastases
may be candidates for hepatic arterial embolization procedures.
• Liver Transplantation: In the setting of diffuse, unresectable neuroendocrine liver metastases
refractory to other lines of therapy, orthotopic liver transplantation (OLT) may be considered
for select patients. OLT may permit excellent symptom relief in patients with life-threatening
hormonal disturbances and potentially offer cure in patients with metastases confined to the
liver

Medical Therapies for Advanced Disease

The chemosensitivity of pancreatic NET varies with type and differentiation status. Well-differentiated
pancreatic NET proliferate slowly and are generally resistant to most chemotherapeutic agents.
Cytotoxic drugs have an important role to play in the treatment of poorly differentiated and rapidly
growing PNETs. A randomized trial comparing the combination of streptozocin with doxorubicin vs
streptozocin with fluorouracil demonstrated a mortality benefit as well as radiological and biochemical
regressions of 69%. The use of streptozosin-based regimens is, however, limited by their toxicity and
cumbersome administration schedule. Oral temozolomide may be a better tolerated alternative with
comparable efficacy.

Table 5: Various chemotherapeutic agents used for PNETs5

Somatostatin analogs
The activation of SSR may trigger the inhibition of adenylate cyclase and calcium influx, thus in turn
reduce the releasing of bioactive hormones including insulin and glucagon. SSA is often used to
control pancreatic NET-related symptoms before and after surgery.

Newer targeted therapies

Targeted therapeutic agents, especially those inhibiting molecules involving angiogenesis or growth
factor receptor-related signal pathways, have revolutionized the treatment strategy of many cancers.
A number of these agents have been tested and evaluated in pancreatic NET, including sunitinib,
everolimus, bevacizumab, imatinib, gefitinib and bortezomib. Sunitinib and Everolimus are currently
the only targeted agents approved in the United States and Europe to treat patients with pancreatic
NET. Table showing various targeted agents and there response.

Table 6: Various targeted therapies 5

Associated syndromes (Table 7)

SUGGESTED READING
1. Kanakis G, Kaltsas G. Biochemical markers for gastroenteropancreatic neuroendocrine tumours (GEP-
NETs). Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):791-802
2. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical
treatment: advances. Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):737-53.
3. Capelli P, Fassan M, Scarpa A. Pathology - grading and staging of GEP-NETs.Best Pract Res Clin
Gastroenterol. 2012 Dec;26(6):705-17
4. Shin JJ, Gorden P, Libutti SK. Insulinoma: pathophysiology, localization and management. Future Oncol.
2010 Feb;6(2):229-37
5. Zhou C, Zhang J, Zheng Y, Zhu Z. Pancreatic neuroendocrine tumors: a comprehensive review. Int J Cancer.
2012 Sep 1;131(5):1013-22.
6. Dickson PV, Behrman SW. Management of pancreatic neuroendocrine tumors. Surg Clin North Am. 2013
Jun;93(3):675-91.
7. Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zografos GN. Pancreatic insulinoma: current issues and
trends. Hepatobiliary Pancreat Dis Int. 2010 Jun;9(3):234-41.
8. Muniraj T, Vignesh S, Shetty S, Thiruvengadam S, Aslanian HR. Pancreatic neuroendocrine tumors. Dis Mon.
2013 Jan;59(1):5-19.
9. Sundin A. Radiological and nuclear medicine imaging of gastroenteropancreatic neuroendocrine tumours.
Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):803-18.
10. Ito T, Igarashi H, Jensen RT. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent
insights and advances. J Gastroenterol. 2012 Sep;47(9):941-60.
11. Knigge U, Hansen CP. Surgery for GEP-NETs. Best Pract Res Clin Gastroenterol.2012 Dec;26(6):819-31.
12. Chambers AJ, Pasieka JL. Gastrinoma. Cancer Treat Res. 2010;153:213-33
13. Wayne JD, Kaplan EL. Insulinomas .In: Clark OH, Kebebew E, Duh QY, editors. Textbook of Endocrine
Surgery. 2nd ed. Philadelphia: Elsevier Saunders; 2005.p.722
14. Service FJ Endocrinol Metab Clin North Am 2000: 28; 519-532
15. Bosman FT, Carneiro F,Hruban RH,Theise ND. Tumours of the Pancreas. Lyon, France:IARCPress;2010
16. Baudin E, Planchard D, Scoazec JY, Guigay J, Dromain C, Hadoux J, Debaere T,Elias D, Ducreux M.
Intervention in gastro-enteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012
Dec;26(6):855-65.
17. Öberg K. Biotherapies for GEP-NETs. Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):833-41.
 Bone Tumours- Principles of Management: An Overview
Sudhir K. Kapoor

Though the tumours of muscoloskeletal system constitute a small fraction of the spectrum of
neoplasms (1 to 1.5% of total malignancies in the body), they hold an unusual fascination for
clinicians and investigators. This probably is due to the variety of diagnosis, the prevalence of
tumours in younger people and the high virulence of malignant lesions.

Since each component of the osseous system may give rise to several forms of benign and malignant
tumours, the variety of clinical and histological presentations present enormous challenges to the
orthopaedic surgeons and pathologists who deal with these tumours.

An overview of the variety of lesions encountered can be had from the WHO Classification of Bone
Tumours.

WHO Classification of Bone Tumours

PRIMARY TUMOURS
1. Bone Forming Tumors
a) Benign
• Osteoma
• Osteoid osteoma and Osteoblastoma
b) Intermediate
• aggressive Osteoblastoma
c) Malignant- Osteosarcoma
• Central
• Surface
o Parosteal
o Periosteal
o High Grade Surface

2. Cartilage Forming Tumours

a) Benign
• Chondroma
o Enchondroma
o Periosteal
• Osteochondroma
o Solitary
o Multiple hereditary
• Chondroblastoma
• Chondromyxoid fibroma
b) Malignant - Chondrosarcoma
• Differentiated
• Juxtacortical
• Mesenchymal
• Clear Cell

3. Giant Cell Tumour

a) Osteoclastoma

4. Marrow Tumors
a) Ewings sarcoma
b) Neuroectodermal tumour
c) Malignant lymphoma
d) Myeloma
5. Vascular Tumours
a) Benign
• Haemangioma
• Lymphangiona
• Glomas tumour
b) Intermediate
• Hemangioendothelioma
• Hemangiopericytoma
c) Malignant
• Angiosarcoma
• Malignant Hemangiopericytoma

6. Other Connective Tissue Tumours

a) Benign
• Benign Fibrous Histiocytoma
• Lipoma
b) Intermediate
• Desmoplastic fibroma
c) Malignant
• Fibrosarcoma
• Malignant Fibrous Histiocytoma
• Liposarcoma
• Malignant Mesenchymoma
• Leiyomyosarcoma
• Undifferentiated Sarcoma

7. Other Tumours
a) Benign
• Neurilemmoma
• Neorofibroma
b) Malignant
• Chordoma

8. Adamantinoma

SECONDARY MALIGNANT TUMOURS

From primary in:

a) Thyroid
b) Breast
c) Bronchus
d) Kidney
e) Prostate

Surgical Staging System (SSS)

Enneking has evolved a system of Surgical Staging of Bone Tumours. This is based on the
histological grade (G). Anatomic location (T), and the presence of secondary metastases (M). This
system takes into account the fact that mesenchymal sarcomas of bone behave similarly regardless
of histological type. It provides guidelines and protocols of surgical and other therapy as well as for
assessing prognosis.

Stage Grade Site Metastasis

IA LOW (G1) Intracompartmental (T1) None(M0)
IB LOW (G1) Extracompartmental (T2) None(M0)
 II A HIGH (G2) Intracompartmental (T1) None(M0)
II B HIGH (G2) Extracompartmental (T2) None(M0)
III A G1 OR G2 Intracompartmental (T1) Yes(M0)
III B G1 OR G2 Extracompartmental (T2) Yes(M0)

Clinical Features

Age of the patient can definitely help in excluding certain diagnosis. In lesion like osteosarcoma,
Ewing tumor and Osteoclastoma, age is so important that a diagnosis of primary osteosarcoma in a
40yr. Old person is almost impossible. But in Synovial sarcoma, Chordoma, Malignant histocytoma
etc, age is not an important factor in arriving at a diagnosis.

Age: See the chart below showing the relation of the lesion with age.

0 5 10 15 20 30 40 50+
-------adamantinoma-------
Aneurysmal bone cyst
chondroblastoma
---Chondromyxoid fibroma---
---Chondrosarcoma----
Enchondroma
Chordoma
---Demoplastic fibroma---
Eosinophilic granuloma
---Ewing Sarcoma---
Fibrosarcoma
Fibrous dysplasia
G.C.T
Osteosarcoma
Malign F. Histiocytoma
---Myeloma---
Non Ossifying fibroma
Osteoblastoma
----Osteochondroma----
Osteod osteoma
Parosteal sarcoma
Pig. Villonodular syno
--Synovial sarcoma--
Unicameral bone cyst

A bone tumour clinically presents as

 Pain
 Swelling
  Fungation
 Fracture

Diagnostic Approach

The diagnosis of bone tumours requires a multidisciplinary approach. In addition to the surgeons, the
radiologist and pathologist play a significant role in planning the diagnostic and staging strategy
before biopsy. Optimum integration of clinical and radiographic information before biopsy has special
significance for the diagnosis and is a basic requirement for accurate pathological interpretation.

 Radiologic Assessment
Various imaging modalities helpful in diagnosis are:

a) Plain Radiograph: Gives information about:

 Anatomic Site
 Region of bone involved
 Destruction pattern
 Reactive new bone formation

An idea of the malignancy of the neoplasm may be made on X-ray, Irregular Ill-defined
margins, inhomogeneous density, cortical break, soft tissue swelling, periosteal reaction and
skip/metastatic lesions all point to a more malignant lesion.
Three types of bony destruction may be seen on X-rays:

 Geographic: Seen as a well circumscribed hole in bone with a narrow zone of transition
between normal and abnormal bone. This pattern implies a slow growth rate.
Examples are chronic osteomyelitis, brodies abscess, histiocytosis X, Giant cell
tumour and fibro sarcoma.

 Moth Eaten: Multiple scattered holes that vary in size and seem to arise separately.
These scattered holes coalesce to form larger areas of bony destruction. Characteristic of
more aggressive tumours e.g. Ewings sarcoma, lymphoma, osteosarcoma

 Permeative: Characterized by numerous elongated holes or slots in the cortex those run
parallel to the long axis of bone. Indicates an aggressive bone destroying process e.g.
round cell tumour, high grade chondrosarcoma, angiosarcoma

b) Computed Tomography- Gives information about

 Cortical penetration
 Osseous detail
 Matrix calcification
 Involvement of neurovascular bundle
 Pulmonary metastases
 c) Magnetic Resonance Imaging- This is the imaging modality of choice for determining
 Intramedullary extent of neoplasm
 Soft tissue component
 Neurovascular relation

d) Arteriography- Is useful for tumours

 In difficult anatomic locations
 Where vascular reconstruction may be necessary
 Intra-arterial chemotherapy
 Selective embolisation


99
Radio-Isotope Scanning is done with the help of T labeled phosphonates which specifically
concentrate in bone. Useful for finding the:
 Intramedullary extent
 Metastases
 Skip Lesion

 PET scan: This is a glucose metabolism based scan which is able to detect lesions in soft
tissues, skeleton, and other organs of the body. Though costly, it can detect metastasis not
apparent on the radio-isotopes scan.

 Biopsy
 Open Biopsy is the most reliable and accurate method of determining the histo-
pathological diagnosis of the neoplasm. Principles to be followed while doing a biopsy
are:
• Should be done by surgeon himself
• Small incision in the line of ultimate incision
• Direct sharp dissection
• Do not open uninvolved anatomic compartment
• Avoid handling neurovascular bundle
• Meticulous hemostasis
• Watertight closure
Although open biopsy is the gold standard in the diagnosis of bone tumours, it has certain
drawbacks like inpatient costly procedure, risk of infection, hemotoma, dissemination of
tumour etc.

 FNAC (Fine Needle Aspiration Cytology): In contrast to open biopsy, FNAC is a safe
quick, relatively non-traumatic, cost-effective out-patient procedure. It has high rates of
diagnostic accuracy. However,in cases where the fine needle is not able to pierce the
tumour i.e. in bony hard tumours a trephine or trucut needle may be used to increase the
yield in the aspirated.

 Frozen Section (Intra operative Pathologic Consultation)

Indication:

• Adequacy of biopsy material

• To evaluate surgical margins
• Determination of Histological diagnosis
• Triage to guide further workup
Limitations:

• Not possible to bony hard tumours with no soft tissue content

• Danger of incorrect diagnosis
• Non representative sampling
• Interior preparation to paraffic section
It has a high diagnostic accuracy when used as specifically indicated by an experienced
surgeon and pathologist.
Treatment

 Neo-adjuvant Chemotherapy/ induction chemotherapy

Tumors which are chemo sensitive must have pre operative chemo therapy before surgery is
done. This reduces bulk of the tumor as well as the vascularity. This sometimes makes the tumor,
which are otherwise inoperable/operable. The blood loss during the surgery is also reduced. In
most of the centres three cycles of chemotherapy are given at an interval of one to two weeks and
patient is operated between a week to three weeks after surgery

 Surgical Treatment
 Amputation
 Limb Sparing Surgery
Changing scenario in Bone tumour management: As per the world literature, presently it is
possible to salvage a limb in majority of the cases of bone tumor, at the time of presentation.
Limb Salvage (80%) > Amputation(20%)

Contraindications to limb salvage are

 Neuro -vascular involvement
 Displaced pathological fracture
 Massive size
 Infection

A limb salvage prodedure entails three important steps

◦ Resection of Tumour - Guidelines for resection of a neoplasm to be followed
 Isolation of neurovascular bundle
 Wide resection with cuff of normal tissue
 Enbloc removal of biopsy site
 Resection of adjacent joint and capsule

Depending on the margins of excision achieved, resection can be of four types:

 Intralesional – When the dissection passes within the lesion
 Marginal – When the dissection passes within reactive tissue contiguous with the
lesion
 Wide – When the dissection is carried out entirely through normal tissue at a
distance from the lesion
 Radical – When all normal tissues of one or more compartment involved are
removed from origin to insertion

◦ Skeletal reconstruction - An average bone gap of 10-15 cm is required to be filled

during skeletal reconstruction. Methods of achieving this are
 Bone grafts
o Autologous - Free & vascularised
o Allogenic
o Xenografts
 Distraction osteogenesis by Illizarov fixator
 Prosthetic replacement

◦ Soft tissue reconstruction - In a large percentage of bone tumors, a soft tissue

reconstruction may be essential – A classical example would be the gastrocnemius flap
required after successful excision of a malignant tumor of upper end of tibia. An Onco-
orthosurgeon must have basic knowledge of common plastic procedures to carry out an
effective reconstruction after tumor excision.
All of the above are easier said than done and in the words of Sir John Bruce: “Drastic Clearance and
reconstruction requires the imagination of an artist, the courage and ruthlessness of a battlefield
soldier and the technical virtuosity of a high order”
 Hormone therapy in Prostate Cancer
Rishi Nayyar, Raman Tanwar

Introduction

Prostate cancer has seen a rapid rise in the past 2 decades and today it stands as the most common
genitourinary cancer worldwide. In the United States, prostate cancer is the most common non skin
cancer among men, with nearly two million cases currently diagnosed. In 2012 alone there were
xvi
241,740 new cases of prostate cancer (PCa) in the United States of America . It is the second
leading cause of mortality among men there. The impact can be felt even in India and the national
cancer registry (updated till 2004) shows that prostate cancer is among the top five cancers in the
metropolitan cities of Delhi and Mumbai. It is among the top 10 cancers across the major cities of the
country. Cancer is not a notifiable disease in our country and the registry in essentially incomplete.
Prostatic cancer, whose true incidence can be calculated, only when PSA screening covers a large
part of the population, is one of the most severely under reported malignancies of the country. Hence,
it is essential to see prostate cancer in our country in this new light and understand the biology and
management of this malignancy in greater details than before. Prostate cancer is a relatively indolent
disease, considering the facts that it can be easily detected at a much early stage using Prostate
specific antigen screening, managed with radical surgery effectively and locally advanced disease
also has effective therapy available. Incidentally the sporadic form of prostate cancer affects males in
the tail end of life and many a times it may be safely left in situ. There aren’t many malignancies
where you can do that! The unfortunate side is that all forms of therapy are being tried be it surgical,
medical, radiation based, or immunological, and a common consensus on how to effectively apply
them to different stages of the disease is not well defined. The scope of new research in prostate
cancer is vast and research in this era has now reached an advanced stage. Prostate cancer has
been found responsive to alteration in hormonal milieu, androgen being the agent primarily
responsible for prostatic growth. The therapy that reduces or eliminates the action of androgens and
other stimulatory hormones on the prostatic tissue is what best defines Hormonal therapy for prostate
cancer in the present day. This can be done both surgically and medically, or using a combination of
the two. Since the demonstration of response to androgen ablation by Huggins and Hodges in cases
with prostate cancer, androgen deprivation therapy (ADT) has become the cornerstone of
management of advanced prostate cancerxvii.

Hormonal therapy: where does it currently stand?

Hormonal therapy has a role in all clinical scenarios. In a localized form of the disease, primary
hormonal therapy is useful in older patients who have co morbidities precluding surgery, or are
unwilling to undergo a major surgery. The advantage of hormonal therapy in this scenario has not
been statistically proven but along with active surveillance it is administered in all groups of patients
irrespective of their risk.

In the locally advanced form of disease also hormonal therapy has been combined with radiotherapy
and other minimally invasive treatment modalities. In high risk patients it can be given as an adjuvant
xviii xix
therapy, especially benefitting patients with positive nodes and extending survival by 6 months . In
patients with stage T3 disease where the volume of disease is high radical prostatectomy is usually
avoided and the disease is covered with radiotherapy and adjuvant radiation. In low volume T3
disease where surgery may benefit some patients, the role of adjuvant therapy may exist especially
with undifferentiated carcinoma xx and its administration is the usual practice. Early administration of
androgen deprivation therapy may prove beneficial before radical prostatectomy in high risk menxxi.

As a neoadjuvant therapy, hormonal therapy has been shown to be effective before radical
prostatectomy in T1 and T2 disease. Within the first 3 months of treatment, a reduction of up to 30-
50% in the size of the gland, 90% in the PSA level and a significant reduction in tumor volume has
xxii,xxiii
been noted . Apart from a rewarding clinical downstaging, there is a lower but significant
xxiv
pathological downstaging in 10-30% of cases . While it was initially thought that neoadjuvant
therapy with radical prostatectomy was beneficial only in lower stage disease. A long duration recent
study has demonstrated benefit of neoadjuvant androgen therapy before surgery in the overall
survival and progression free survival after radical prostatectomy in non metastatic T3 and T4
diseasexxv. Neoadjuvant therapy in this study made radical prostatectomy a feasible option in
advanced prostate cancer, making it comparable to other treatment options in this scenario. In the
lower clinical stages, neoadjuvant androgen deprivation significantly reduces positive surgical
margins. Use prior to radiation therapy is not presently well supported. Most of the studies
recommend adjuvant use over neoadjuvant use of ADTxxvi. Androgen deprivation therapy (ADT) is
xxvii,xxviii
however an established standard adjunct to radiotherapy for high-risk prostate cancer .

While the indications for administering androgen deprivation therapy have been grossly outlined, the
duration and timing for initiation of androgen therapy are still a matter of debate. Early start for ADT
has been shown to be beneficial. This benefit of immediate therapy is best appreciated in high risk
cases. In low risk patients early androgen deprivation may increase the risk of death due to adverse
effects compared to active surveillance.

The question of when to stop this therapy does not have a single best answer either. Longer duration
of therapy for 24 months has been compared to short therapy for 4 months and there is an
improvement in all outcomesxxix, except for increase in the overall survival. In light of such findings, it
is important that at least patients with high risk disease receive therapy for a prolonged time. Such
patients include those patients with tumor stage T2b or above, Gleason core more than 7 and PSA
more than 10 ng/ml. Patients with low or intermediate disease can be administered therapy for a short
duration of 2-4 months.

Hormonal therapy: How does it help?

Hormones are chemical messengers that perform various vital functions in the body. Androgens in
males are hormones responsible for growth of the prostate and are implicated in prostatic carcinoma.
The two predominant forms include testosterone (T) and dihydrotestosterone (DHT). DHT is available
in the prostate in much higher concentrations and is about five times more potent than testosterone.
Testosterone is the major circulating androgen in the serum. 97-98% of the testosterone remains
bound to protein, and only 2-3% is free. Adrenal androgens are also an important source. These
androgens are weak and by themselves unable to maintain the prostatic epithelium. Blocking the
actions or production of these hormones at various sources, has been shown to be effective in
management of prostate carcinoma. Even though hormone therapy does not provide cure from the
disease it has been shown to increase survival. In patients with less aggressive variants of the
disease the cause of mortality is usually a secondary ailment and not prostatic carcinoma or its
sequel.

What are the agents available for Androgen Deprivation Therapy?

Both surgical and medical alternatives are available for androgen deprivation therapy and a
comprehensive list of these agents has been presented below. Some medical alternatives may
produce a transient upsurge or flare in the levels of testosterone and this has been prevented by the
xxx
addition of antiandrogens to medical and surgical therapy . Such a combination is referred to as
combined Androgen Blockade (CAB). Whether this combination has a definite advantage over
castration is matter of debatexxxi. Only a marginal decrease in the death rate has been demonstrated
xxxii
by adding an antiandrogens .combined androgen blockade has an important role in patient with
symptomatic bony metastasis and impending cord compression where flare may produce severe
symptoms and life threatening complications. These symptoms can also be prevented by a week prior
xxxiii
administration of non steroidal antiandrogens before initiation of LHRH agonist therapy .

Class Drug name Mechanism of action Notable Side effects

Drugs acting on the pituitary

GnRH Agonists Leuprolide Desensitization of LHRH Flare reaction

receptors
Goserelin

Triptorelin

Histrelin

GnRH Antagonists Abarelix Inhibition of LHRH Anaphylaxis

receptors
Degarelix

Drugs acting on the adrenal Gland

Adrenal Ablating Aminoglutethimide Decreases androgen Adrenal insufficiency

agents synthesis from steroid
Ketoconazole precursors
Abiraterone

Drugs acting on the Prostate

Androgen receptor Steroidal: Cyproterone Competitively Inhibit Liver dysfunction,

antagonists Acetate androgen receptor gynaecomastia, breast
ligand binding domain tenderness
First Generation Non
Steroidal: Flutamide,
Bicalutamide,
Nilutamide

Second Generation
Non steroidal: MDV
3100, RD 162xxxiv

5 alpha reductase Finasteride Inhibits conversion of Sexual side effects,

inhibitors testosterone to Erectile dysfunction
Dutasteride dihydrotestosterone

Estrogen Diethylstilbestrol Direct apoptotic effect Cardiovascular

on prostate cells, complications, DVT,
Transient ischemic
Exploits the anti effect, edema,
androgen effects of gynecomastia
estrogen

LHRH Agonists
Chronic exposure of LHRH receptors in the anterior pituitary leads to desensitization of the LHRH
receptors and decrease in the LH and testosterone production. Available formulations are depot
preparations that last from 1 month to a year. LHRH agonists stimulate testosterone production
mediated by LH and produce a flare reaction which may produce a spike in the LH levels, upto 10
times that of the basal levels. This may last for upto a month and causes a severe exacerbation of
symptoms. Antiandrogens administration may be started a week prior and continued for four weeks to
prevent complications from flare reaction.

LHRH Antagonists
LHRH (luteinizing-hormone releasing hormone) Antagonists interfere with the brain signals and
inhibits the activity of LHRH to release LH. Due to lack of LH production, levels of testosterone are
reduced. The main mechanism of action of LHRH antagonists is competitive occupancy of the LHRH
receptor. The advantage over LHRH agonists is that there is immediate and reversible suppression of
luteinizing and follicle stimulating hormonesxxxv. Abarelix and degarelix are the two commonly used
and widely studied drugs available in this category. These drugs have undergone phase III clinical
xxxvi
trials . At present, degarelix is available as a monthly subcutaneous injection. Additional data in
larger numbers of patients with long-term follow-up will help to better define the role of degarelix in the
treatment of Prostate Cancer. Abarelix has a tendency to induce histamine release and has resulted
xxxvii
in a few life threatening systemic reactions , the patient thus needs to be observed for upto an hour
after administering the drug. The clinical profile of degarelix appears to make it a good therapeutic
option for subgroups of patients with prostate cancer, including those with metastatic disease, high
baseline PSA (>20 ng/mL) and severely symptomatic disease as it produces faster suppression of
testosterone with comparable efficacyxxxviii. Advantages need to be proven further with the help of
randomized controlled trials.

Androgen Blockade at source: Orchiectomy

Bilateral orchiectomy causes rapid and sustained suppression of testicular androgens with resulting
circulating testosterone levels <20 ng/ml in most patientsxxxix. This form of therapy is free of
compliance issues and associated with good quality of lifexl, however, patient and physician
acceptance seems to be more with medical castration. Considering the short half life of serum
testosterone, castrate levels are achieved within 1-2 hours of orchiectomy. Only 10% of the
testosterone is left circulating after 24 hours. Testosterone level less than 50 ng/dl is taken as the
criteria for adequate androgen ablation, and this can be achieved with surgical castration alone.
Subcapsular orchiectomy is a less radical procedure of surgical castration which avoids the
psychological impact of absence of testis. Only the intra-testicular tissue is removed leaving the
capsule intactxli. Hematoma may fill the empty capsule and give the appearance of normal testis. The
disadvantage of subcapsular orchiectomy is that, any tissue if left may act as a potential source of
testosterone in the presence of high luteinizing hormone arising from loss of testicular tissue and
negative feedback.

Androgen Blockade at source: Antiandrogens

The first generation antiandrogens include the classic steroidal antiandrogens like Cyproterone
acetate as well as non steroidal agents like Flutamide, Bicalutamide, and Nilutamide. Cyproterone
acetate is a rapidly acting agent, which also mediates its effect through central progestational
inhibition. It thus decreases testosterone levels. This agent was used earlier for management of hot
flushes. Its usual dosage is 100mg twice a day as an oral tablet. Side effects are sexual. In contrast to
steroidal agents the non steroidal agents do not induce a hypogonadal state. They increase LH and
testosterone levels which are subsequently converted to estrogen. Sexual effects are thus present but
to a lesser degree than the steroidal antiandrogens. These agents have a notable side effect of
gynaecomastia and breast tenderness and pain. Liver function also needs to be monitored when on
anti androgen therapy. MDV3100 and RD162 are orally available drugs that bind the AR with a
higher affinity, prevent AR nuclear translocation, and have no agonist activity on androgen
 xlii
receptors . These drugs are in phase III clinical trials and referred to as second generation
antiandrogens.

Drug Name Half Life Dosage Features

Flutamide 6 Hrs 250 mg TDS First pure antiandrogen

Poor compliance due to short half life

Bicalutamide 6 Days 150 mg OD Convenient once daily dosing

Currently the preferred agent for ADT

Nilutamide 56 Hrs 300 mg OD Causes delayed adaptation to darkness

Reversible interstitial pneumonitis and fibrosis

Agents for Ablation of adrenal androgen synthesis

Continuous, specific inhibition of CYP17, a key enzyme in androgen and estrogen biosynthesis, could
induce secondary responses in progressing prostate carcinoma patients, especially those resistant to
initial hormone therapyxliii. The over expression of this enzymexliv due to intra-tumoral synthesis has
been implicated in poor response to first line hormone treatmentxlv. Ketoconazole, a non-specific CYP
inhibitor that weakly inhibits CYP17 at high dosesxlvi. However, the significant toxicities in up to two-
thirds of patients limit its widespread use. It is administered in the dosage of 400mg 8 hourly, and
results in rapid fall in testosterone levels. Unfortunately the rise is also rapid, and missed doses pose
a problem. It has been observed that prolonged therapy is associated with rise in testosterone levels,
suggesting failure of chronic therapy. This agent is thus reserved as a second line hormonal therapy,
in patients failing primary therapeutic response.

Aminoglutethimide is another agent that inhibits steroidogenesis in its initial steps. Due to its action on
the initial steps of pregnenolone formation from cholesterol, this agent inhibits production of
Aldosterone and Cortisol also, and these hormones have to be supplemented when on
Aminoglutethimide therapy. The dosage is upto 1gm/day leading to significant decline in PSA.
Hypothyroidism, nystagmus, anorexia and nausea are some of the side effects commonly seen.

Abiraterone is a dual enzyme inhibitor acting on 17 alpha hydroxylase and 17,20 lyase. It is a more
selective and irreversible inhibitor causing significant suppression of testosterone. This agent is
undergoing phase III trials and its role as a second line therapy of prostate cancer is being tested.
Side effects are due to mineralocorticoid excess and include hypertension, Hypokalemia and edema
of the legs.

Estrogens

As a final option, estrogen therapy can be added to the mix because estrogen also decreases male
hormone levels. Estrogen therapy has been associated with increased cardiovascular side effects
including blood clots and strokes, and is therefore often administered along with an anticoagulant
drug. Diethylstilbestrol administration was a classic form of androgen deprivation therapy that
gradually fell out of favor because of its cardiovascular toxicity, economic disinterest on the part of
manufacturers, and the emergence of novel therapeutic agents with a superior safety profilexlvii. The
cost of contemporary agents and the efficacy of diethylstilbestrol (DES) have perpetuated the
evaluation of this agent. It is by far the most cost effective form of medical castration available.
Monitoring of coagulation parameters and availability of cost effective and easily monitorable therapy
may be useful in reviving its widespread use. In contemporary studies of DES as an agent for ADT in
D2.5 patients, a reasonable response rate (40% to 60%) of modest duration (5 to 8 months) has been
noted. DES has been found to have significant activity in hormone resistant prostate cancer and can
xlviii
be of palliative benefit, with acceptable side effect profile .

What are the side effects of Androgen Deprivation Therapy?

The side effects of androgen deprivation therapy include, Diminished libido, Erectile dysfunction, Hot
flashes, Weight gain of 10 to 15 pounds, Mood swings, Depression, Fatigue, Anemia( Normocytic
Normochromic), Osteoporosis, Memory loss, Elevated Cholesterol and Breast and nipple tenderness.
To reduce these effects the concept of intermittent androgen deprivation (IAD) came into existence.
IAD was also proposed to delay the emergence of hormone resistance. With the current amount of
xlix
data in hand the benefits seem limited with no beneficial advantages in sexual function and quality
l
of life . The reduction in adverse myocardial events and osteoporosis also appear to be comparable
li
with IAD vs. conventional ADT .

Intermittent androgen deprivation is being increasingly used as an alternative to continuous ADT in

advanced and recurrent prostate cancer. There is level I evidence supporting the oncologic
equivalence of intermittent and continuous blockade in patients with biochemical failure. Compared
with CAD, IAD is associated with better quality of life and less side effects; however patient selection
is important to maintain good results. IAD must be administered with caution in men with bone
metastases. In patients who have a complete biochemical response, a trial of IAD can be given. If
there is a rapid rise in PSA, these patients can be restarted on continuous therapylii.

Hot flushes are the most common side effect of ADT affecting the majority of patients. Loss of libido
also is a common side effect, with only about 20% patients being able to maintain sexual activity.
Loss of muscle mass and increase in body fat can lead to change in body habitus and also
predispose to metabolic syndrome, diabetes and cardiovascular morbidity. Painful gynaecomastia can
be cured by prophylactic radiation. Cosmetic concerns are managed by subcutaneous mastectomy or
liposuction. Management of all complications is essentially symptomatic and discontinuation of
therapy is rarely indicated. Interestingly patients who develop resistance to therapy still remain on
ADT.

How is Androgen Deprivation Therapy Monitored?

Serum PSA and serum testosterone are two important indicators for monitoring ADT. Agents must be
able to inhibit testosterone synthesis from the major sources and this is reflected by a reduction in
serum testosterone levels to less than 50ng/dL. If the levels are more than this, the androgen ablation
may be insufficient and prostatic growth may be taking place. The degree of fall in PSA is also an
important predictor of the response to androgen deprivation therapyliii. Monitoring PSA levels can
predict progression and emergence of hormone resistant disease. The absolute PSA levels 6 months
after therapy has also been found to be a useful predictor of response.

ADT is an important form of therapy in managing advanced prostate carcinoma. Its precise role in
various stages of prostate cancer still needs to be decided. The search for newer and selective
agents also continues, while newer drugs find their way out of the clinical trials to routine use. ADT is
not a harmless therapy, neither is it curative, but it still is a big ray of hope for advanced prostate
cancer.

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36. Klotz L, O’Callaghan CG, Ding K, et al. A phase III randomized trial comparing intermittent versus continuous
androgen suppression for patients with PSA progression after radical therapy: NCIC CTG PR.7/SWOG
JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013 [abstract 3]. J Clin Oncol. 2011; 29:7s.
37. Klotz L, Toren P. Androgen deprivation therapy in advanced prostate cancer: is intermittent therapy the new
standard of care? Curr Oncol. 2012 Dec;19(Suppl 3):S13-21.
38. Cooper EH, Armitage TG, Robinson MR, Newling DW, Richards BR, Smith PH, Denis L, Sylvester R. Prostatic
specific antigen and the prediction of prognosis in metastatic prostatic cancer. Cancer. 1990 Sep 1;66(5
Suppl):1025-8.
 Solitary Thyroid Nodule
T K Thusoo

Introduction
Solitary thyroid nodule is a clinical entity where a single nodule is palpable the thyroid gland. In a
significant number of cases diagnosed as solitary thyroid nodule, there is more than one nodule in the
thyroid gland which is not clinically palpable and can be picked up on ultrasound examination.
However, true solitary nodules are not uncommon .Their clinical importance is because of higher
incidence of malignancy as compared to the multi-nodular disease even though 80% of solitary
nodules are benign.
The incidence of palpable thyroid nodules is 4 % - 8% in adults (1). The prevalence of thyroid
nodules increases with age and women have higher incidence (5.3 to 6.4%) as compared to men (0.8
to 1.5%) - (2)

The primary concern of both the patient and the treating physician is whether the nodule in question is
malignant or not. There are certain clinical parameters and investigative modalities such as thyroid
scintigraphy, ultrasound and FNAC to aid in differentiating a malignant from the benign nodules, but
no single modality is fool proof in establishing the correct diagnosis which is of utmost importance to
prescribe a proper treatment.

Clinical Assessment
Following are the clinical parameters which may suggest higher chances of malignancy in a solitary
thyroid nodule:
1. Nodule in a young boy or in a patient beyond the age of 60 yrs.
2. Recently detected nodule of short duration.
3. Local characteristics
a) Hard nodule in absence of any gross calcification.
b) Restricted mobility with deglutition
c) Associated hoarseness of voice or dysphasia
d) Clinically palpable cervical lymph nodes in central or lateral compartment.
4. Previous head & Neck irradiation especially in childhood.
5. Family history of thyroid cancer.
6. Associated other endocrine disorders as a part of MEN syndrome.

Laboratory Investigations

a) Thyroid function test: Out of the three common thyroid functions test viz. FT3. FT4 & TSH,
the last one is the most important as sub normal T3 may suggest a hot or hyper secreting
nodule and a very high TSH may point out to nodule being a part of auto-immune (
Hashimoto’s Thyroiditis). Apart from that, thyroid function tests do not have much role in
assessment of solitary thyroid nodule.
b) Thyroid Antibodies: Estimation of Anti Thyroid Peroxidase and Anti Thyroglobulin Antibodies
needs to be done in case there is high degree of suspicion of auto-immune thyroiditis.The
level is very high in this condition.
c) Serum Calcitonin levels: When there is a suspicion of Medullary Carcinoma, raised serum
calcitonin levels strengthens its diagnosis.

Thyroid Scintiscan
Radio –isotope scan of thyroid is helpful in assessing the functional characteristics of the nodule such
as hot, warm or cold depending upon the isotope concentration within the nodule. The nodule is
called hot if it takes up more or all the isotope as compared to the remaining thyroid tissue, warm if
the concentration is same as in the rest of the thyroid gland and cold if there is no concentration within
the nodule.
A hot nodule virtually exclude the chance of nodule being malignant as the incidence is < 1 % (3,4) ,
in contrast to cold nodule in which the incidence of malignancy varies from 10 to 25% (5) , average
being about 12.5 %. However, thyroid scintigraphy is not of much help in differentiating a malignant
from benign nodule as 80 % of cold nodules are benign. Therefore, radio-isotope study of thyroid is
not routinely recommended for assessment of solitary thyroid nodule as it is neither sensitive nor
specific for malignancy (6,7). It is usually advised in case the TSH is sub normal indicating the
possibility of nodule being hot and hence non malignant thereby obviating the need for biopsy.

Thyroid Ultrasound
High resolution ultrasonography is an important tool to assess the anatomical features of the nodule.
The information provided by ultra sound of the neck is as follows –

a) Echo texture of the nodule- whether solid, cystic or mixed. Pure cyst rarely harbor malignancy
b) Detection of other non palpable nodules there by reducing the chances of malignancy.
c) Any associated enlarged cervical lymph nodes which carry higher chances of malignancy in
the solitary nodules.
d) Other Ultrasonic features s/o malignant probability is marked hypo-echoic texture with
irregular margins, taller than wider shape ,complex cyst with intra-cystic solid projections,
micro calcification and extra thyroidal extension, hyper vascularity..

Though ultrasound is a valuable, non invasive tool with high sensitivity, yet it lacks the specificity to
differentiate malignant nodule from the benign one (8,9)

Fine Needle Aspiration Cytology (FNAC)

Cytological assessment of the solitary nodule by fine needle aspiration is the investigation of choice to
differentiate a malignant from benign nodule with a high degree of specificity to the tune of 95 to 97 %
depending upon the experience of cyto- pathologist. FNAC findings are categorized into :

a) Malignant ( papillary, medullary, anaplastic / lymphoma )

b) Benign –Colloid goiter, thyroiditis
c) Indeterminate / Suspicious of Malignancy: Follicular Neoplasm – adenoma, carcinoma or
adenomatous hyperplasia.
d) Inadequate or inconclusive.

Since follicular adenoma or carcinoma cannot be differentiated on cytology because of failure to

demonstrate capsular or vascular invasion characteristic of follicular carcinoma, a true cut needle
biopsy or hemi thyroidectomy is needed to establish the correct histological diagnosis.

FNAC with 25G or 26G needle is a safe investigation with minimal morbidity as compared to true cut
needle biopsy. FNAC is the most cost effective and accurate diagnostic tool for thyroid nodules (10,
11).Currently, it is the investigation of choice in the evaluation of solitary thyroid nodule.
 SOLITARY THYROID NODULE

TSH Low Thyroid Scan Ablate, Resect

Hot Nodule
Rx Medically

Normal
Cold or Warm Nodule

FNAB

Non Diagnostic Diagnostic

Rebiopsy Benign Suspicious Malignant

Consider LT4 (?) SURGERY

repeat FNA at least Core Needle
Non Diagnostic once Biopsy

USG guided FNAC Growth Progression Inconclusive

Non Diagnostic

Low Risk High Risk HEMI THYROIDECTOMY

Observation
Following is the algorithm to outline the management of Solitary Thyroid Nodule:

Treatment of Solitary Thyroid Nodule

A malignant nodule diagnosed on FNAC is usually treated by Total Thyroidectomy with or without
central node dissection depending upon type of malignancy.

In case of Medullary Carcinoma, a prophylactic ipsilateral functional cervical lymph node dissection is
added to total thyroidectomy.

In a benign nodule, hemi thyroidectomy is advocated for cosmetic reasons, local pressure effects or if
there is associated hyper thyroidism in a nodule of more than 3 cms. A hot nodule of less than 3 cms.
can be treated by radio-iodine ablation.

Pure cyst can be completely aspirated and if cytology is benign, can be observed for any recurrence
in which case hemithyroidectomy is advised.

Thyroid suppression therapy was previously advocated for benign warm nodules, but is now no longer
advocated because it may mask the well differentiated thyroid carcinomas which are hormone
dependent.
For follicular neoplasms, hemi-thyroidectomy is recommended to be followed by completion
thyroidectomy, if the histopathology report of hemi thyroidectomy specimen is invasive follicular
carcinoma. Frozen section in this scenario has not been found to be of much help to avoid a second
surgery i.e completion thyroidectomy.

Italian surgeons ( 12,13,14,15) have treated solid benign toxic thyroid nodules with intra-nodular
ethanol injection with good results, but it has failed to get universal acceptance and more over could
cause a significant morbidity in the form of pain, inflammation or some times recurrent laryngeal nerve
palsy.

REFERENCES
1. Vanderpump MP,Tubridge WM,French JM,Appleton D et al . The incidence of thyroid disorders in the community:
a twenty year follow up of the Whickham Survey. Clinical Endocrinology 1998:43;55-68
2. Tubridge WMG, Evered DC,Hall R et al. The spectrum of thyroid diseases in a community : The Whickhham
Survey . Clinical Endocrinology 1997;7:481-493.
3. Horst W, Rosler H, Schneider C et al. 306 Cases of toxic adenoma : clinical aspects, findings in radio-iodine
diagnostics, radiochromatography and histology; results of I 131 and surgical treatment. J Nucl Med. 1967;8:515
4. Sandeler MP, Fellmeth B, Salhany KE et al. Thyroid carcinoma masquerading as a solitary benign
hyperfunctioning nodule. Clin Nucl.Med .1988; 13:410
5. Burrow GN. Thyroid nodules and neoplasia . In : Felig P, Baxter JD, Broadus AE, Frohman LA, eds.
Endocrinology and metabolism. New York. McGraw Hill Book Co. 1987; pg 473-510
6. Sarda AK, Gupta Anju, Jain PK and Prasad S. Management options in solitary thyroid nodules in an endemic
goitrous area. Postgrad Med 1997; 73:560-564.
nd
7. Noguchi S. Localisation tests in patients with thyroid cancer. In Clark PH; 9ed:Text Book of Endocrine Surgery,2
ed , Philadelphia, Elsevier Saunders.2005, pg 142-150.
8. Rago T, Vitti P, Chiovato L, Mazzeo S, De Liperi A, Miccoli P et al. Role of conventional ultrasonography and color
flow doppler sonography in predicting malignancy in’ cold’ thyroid nodules. European Journal of Endocrinology
1998; 138:41-46.
9. Shimamoto K, Endo T, Ishigaki T, Sakuma S & Makino N.Thyroid nodules : Evaluation with color Doppler
ultrasonography. Journal of Ultrasound in Medicine.1993;12:673-678.
10. Sabel MS, Staren ED, Gianakakis LM, et al. Use of fine needle aspiration biopsy and frozen section in
management of the solitary thyroid nodule.Surgery 1997; 122:1021-1026.
11. Boyd LA, Earnhardt RC, Dunn J, et al. Preoperative evaluation and predictive value of fine needle aspiration and
frozen section in thyroid nodules. J Am Coll Surg. 1998; 187: 494-502.
12. Lippi F, Ferrari C, Manetti L, et al. Treatment of solitary autonomous thyroid nodules by percutaneous ethanol
injection: results of an Italian muticenter study. The Multicenter Study Group. J Clin Endocrinol Metab.1996;
81:3261.
13. Monzani F, Carriacio N, Goletti et al. Five year follow up of percutaneous ethanol injection for treatment of
hyperfunctioning thyroid nodules: a study of 117 patients. Clin Endocrinol. 1997; 46:9.
14. Zingrillo M, Torlantano M, Ghiggi MR, et al. Radio iodine and percutaneous ethanol injection in treatment of large
toxic thyroid nodule: A long term study Thyroid .2000; 10:985.
15. Del Prete S, Russo D. Caraglla M, et at. Percutaneous ethanol injection of autonomous thyroid nodules with a
volume larger than 40 ml : three years of follow up. Clin Radiol.2001; 56:895.
 Multinodular Goiter
Arun K Kakar, Ashish Airen

Introduction

The normal thyroid gland is a fairly homogenous structure, but nodules often form within its
substance. These nodules may be only the growth and fusion of localized colloid-filled follicles, or
more or less discrete adenomas, or cysts. Nodules larger than 1 cm may be detected clinically by
palpation. Careful examination discloses their presence in at least 4% of the general population.
Nodules less than 1 cm in diameter are not clinically detectable unless located on the surface of the
gland which are much more frequent. The terms adenomatous goiter, nontoxic nodular goiter, and
colloid nodular goiter are used interchangeably as descriptive terms when a multinodular goiter is
found.

Etiology

Nodular goiter may be the result of any chronic low-grade, intermittent stimulus to thyroid hyperplasia.
In response to iodide deficiency, the thyroid first goes through a period of hyperplasia as a
consequence of the resulting TSH stimulation, but eventually, possibly because of iodide repletion or
a decreased requirement for thyroid hormone, enters a resting phase characterized by colloid storage
and the histologic picture of a colloid goiter. Repetition of these two phases of the cycles would
eventually result in the formation of nontoxic multinodular goiter. By the time the goiter is well
developed, serum TSH levels and TSH production rates are usually normal or even suppressed.

Factors that may be involved in the evolution of multinodular goiter include:

Primary Factors
• Functional heterogeneity of normal follicular cells, most probably due to genetic and
acquisition of new inheritable qualities by replicating epithelial cells.
• Subsequent functional and structural abnormalities result in growing goiters.
• Gender (women) is an important factor.

Secondary Factors
• Elevated TSH (induced by iodine deficiency, natural goitrogens, inborn errors of thyroid
hormone synthesis)
• Smoking, stress, certain drugs
• Other thyroid-stimulating factors (IGF-1 and others)
• Endogenous factor (gender)

Pathology

Multinodular goiters characteristically present a variegated appearance, with the normal

homogeneous parenchymal structure deformed by the presence of nodules. The nodules may vary
considerably in size (from a few millimeters to several centimeters); in outline (from sharp
encapsulation in adenomas to poorly defined margination for ordinary nodules); and in architecture
(from the solid follicular adenomas to the gelatinous, colloid-rich nodules or degenerative cystic
structures). Frequently the nodules get degenerated and result in cyst formation, with an evidence of
old or recent hemorrhage. and calcification. Often there is extensive fibrosis, and calcium may also be
deposited in these septae. Scattered between the nodules are areas of normal thyroid tissue, and
often-focal areas of lymphocytic infiltration. Radioautography shows a variegated appearance, with
RAI localized sometimes in the adenomas and sometimes in the paranodular tissue. Occasionally,
most of the radioactivity is confined to a few nodules that seem to dominate the metabolic activity of
the gland.
Natural History of the Disease

Multinodular goiter is probably a lifelong condition that has its inception in adolescence or at puberty.
Minimal diffuse enlargement of the thyroid gland is found in many teenage girls and boys, and is
almost a physiologic response to the complex structural and hormonal changes occurring at this time.
It usually regresses, but occasionally it persists and undergoes further growth during pregnancy.

Patients with multinodular goiter seek medical attention for many reasons. Perhaps most commonly
they consult a physician because a lump has been discovered in the neck, or because a growth spurt
has been observed in a goiter known to be present for a long time. Sometimes the increase in the
size of the goiter cause pressure symptoms, such as difficulty in swallowing, cough, respiratory
distress, or the feeling of a lump in the throat. Rarely, an area of particularly asymmetrical
enlargement may impinge upon or stretch the recurrent laryngeal nerve resulting in horseness of
voice. Commonly the goiter is discovered by a physician in the course of an examination for some
other condition. An important scenario is for the patient to seek medical attention especially in elderly
because of cardiac irregularities or congestive heart failure, which proves to be the result of slowly
developing hyperthyroidism. It is rare for any noteworthy spontaneous reduction in the size of the
thyroid gland to occur, but patients often describe fluctuation in the size of the goiters and the
symptoms they percive. These are usually subjective occurrences, and more often than not the
physician is unable to corroborate the changes that the patient describes. On the other hand, it could
be that changes in blood flow through the enlarged gland account for the symptoms.

Occasionally, a sudden increase in the size of the gland is associated with sharp pain and tenderness
in one area. This event suggests hemorrhage into a nodular cyst of the goiter, which can be
confirmed by ultrasound. Within 3-4 days the symptoms subside, and within 2-3 weeks the gland may
revert to its previous dimensions. In such a situation, acute thyrotoxicosis may develop and subside
spontaneously.

Rarely, if ever, do the patients become hypothyroid and if they do, the diagnosis is more probably
Hashimoto´s thyroiditis than nodular goiter. Thyroid function test is illustrated in a patient with
multinodular goiter starting from complete euthyroidism on to overt thyrotoxicosis. Occasionally a
single discrete nodule in the thyroid gland becomes sufficiently active to cause thyrotoxicosis and to
suppress the activity of the rest of the gland. If these patients are given thyroid hormone, continued
function of nodules can be demonstrated by radioiodine scanning techniques. If surgical specimens of
multinodular goiters are examined crefully, 4-17% are found to harbor a carcinoma typically of the
papillary variety.

Symptoms and signs

• Often family history of benign thyroid disease

• Slowly growing anterior neck mass
• Uni- or multinodularity on examination
• Enlargment of thyroid during pregnancy
• Cosmetic complaints
• Asymmetry, tracheal deviation, and/or compression
• Rarelly upper airway obstruction, dyspnea, cough, and dysphagia
• Sudden transient pain or enlargement secondary to hemorrhage
• Gradually developing hyperthyroidism
• Superior vena cava obstruction syndrome (rare)
• Recurrent nerve palsy (rare)
• Horner´s syndrome (rare)

Investigations

• Estimation of serum TSH which may be normal or decreased. If abnormal, free T4, and free
T3 needs to be assayed.
• Serum Tg may be normal or elevated.
 • Thyroid autoantibodies (TPO and Tg) are usually negative
• Scintigraphy is required in case the patient is hyperthyroid. This is carried out to find the
cause of hyperthyroidism- toxic adenoma or diffuse hyperactivity.
• Ultrasound to be carried out in all cases of multinodular goiter to guide fnac analysis for ruling
out a malignant focus.
• Computed tomography and MR imaging are not mandatory and only help in assessing the
anatomical extent of goiter.
• Lung function testing may demonstrate impaired inspiratory capacity
• Guided Fine-needle aspiration cytology is the only way to prove/ ruleout malignant focus.

Characteristics of imaging procedures in relation to nodular thyroid disease

Advantages Disadvantages
Sonography High Availability Operator dependency
High morphologic resolution No information of functionality
No ionizing irradiation Not feasible in substernal goiter
Dynamic picture Poor prediction of malignancy
Blood flow visualization (Doppler)
Biopsy guidance, also of lymph nodes
Moderate precision in volume
estimation
Scintigraphy Information of functionality Requires nuclear medicine
Differentiates between destructive and Ionizing irradiation
hyperthyroid conditions Poor resolution
Measurement of thyroid iodine uptake Poor differentiation between solid and
Predictive of feasibility of ¹³¹I therapy cystic cold nodules
Detects ectopic thyroid tissue Volume estimation accurate
CT Scan High morphologic resolution Ionizing irradiation
Visualization of adjacent structure No information of functionality
Ideal for substernal goiter Poor prediction of malignancy
Planimetric volume estimation
Volume estimation probably accurate
MR imaging No ionizing irradiation Moderate availability
High morphologic resolution Long procedure time
Visualization of adjacent structure Not usable with metallic objects inside
Ideal for substernal goiter patient
Planimetric volume estimation No information of functionality
Volume estimation with high precision Poor prediction of malignancy
PET Information of functionality Low availability and high cost
Metabolic investigations Requires specialized units
Good prediction of malignancy Ionizing irradiation
MR imaging and PET scan have very limited role in pre-operative evaluation of a patient with
multinodular goiter

Treatment of multinodular goiter

In the past iodine supplementation was considered to be an adequate approach for treatment of goiter
because its development was considered to be associated with iodine deficiency in many countries
worldwide.The effect of supplemental iodine has a limited role once a multinodular goiter has
developed.. A major problem of iodine supplementation is the risk for inducing subclinical / clinical
hyperthyroidism (Jod-Basedow). Therefore, aside from a few European Countries iodine is no longer
used alone or associated with L-T4 to treat thyroid enlargement.

This leaves in essence three modalities of therapy, these include

• L-T4 suppressive therapy

• Radioiodine (¹³¹I) alone or preceded by rhTSH
• Surgery

If a clinical and biochemically euthyroid multinodular goiter is small and produces no symptoms,
treatment is controversial. T4 given in an effort to shrink the gland or to prevent further growth is
effective in about one third of the patients. This therapy is more likely to be effective if begun at an
early age while the goiter is still diffuse than in older patients in whom certain nodules may have
already become autonomous. It does not significantly reduces the size of goiter and infact may
precipitate cardiac decompensation in elderly patients.

If the clinically euthyroid goiter is unsightly, shows subclinical hyperthyroidism or is causing, pressure
symptoms, or is having intrathorasic extension,or is suspected to have focus of malignancy,
treatment of choice is Surgery. In children with multinodular goiter surgery is the only modality of
treatment.

The preferred operation for MNG is Total/ Near-total thyroidectomy. Dunnhill operation which includes
lobectomy on one side and subtotal excision of lobe on contralateral side is an alternative to total
thyroidectomy. However patients with unilobar enlargement of thyroid with normal contralateral lobe
can be managed by hemithyroidectomy. Recurrence of goiter after sub-total thyroidectomy is
reported to be approximately 5-10% and usually occurs decades after the first surgery.

Hypothyroidism is nearly 100% and thyroid hormone replacement therapy is mandatory in patients
undergoing total thyroidectomy, patients in whom hemithyroidectomy has been carried out it is
advisable to prescribe suppressive hormone therapy.

Radio-iodine is useful in patiens who are elderly, not willing for surgery, have cardiac problems and
with small goiter. It is to be avoided in children, patients with intrathoracic goiter and in women who
are pregnant or have no children.

SUGGESTED READING

1. Geraldo Medeiros-Neto. Multinodulargoiter. Thyroid disease manager. Feb 2013

2. Porterfield JR Jr, Thompson GB, Farley DR, Grant CS, Richards ML. Evidence-based management of toxic
multinodular goiter (Plummer's Disease). World J Surg. 2008 Jul;32(7):1278-84.
3. Agarwal G, Aggarwal V. Is total thyroidectomy the surgical procedure of choice for benign multinodular goiter?:
An evidence-based review.World J Surg. 2008 Jul;32(7):1313-24
4. Diehl LA, Garcia V, Bonnema SJ, Hegedus L, Albino CC, Graf H. Management of the nontoxic multinodular goiter
in Latin América: comparison with North America and Europe, an eletronic survey. J Clin Endocrinol Metab
90(1):117-23, 2005
5. Papini E, Petrucni R, Guglielmi R, Panunzi C, Rinaldi R, Bacci V, Crescenzi A, Nardi F, Fabbrini R, Pecella CM.
Long Term changes in Nodular Goiter: a 5 yr prospective randomized trial of L-T4 suppressive therapy for benign
thyroid nodules. J Clin Endocr Metab 83:780-783, 1998.
6. Masini-Repiso AM, Cobanillas AM, Bonaventura M, Coleoni AH. Dissociation of thyrotropin-dependent enzyme
activities, reduced iodide transport, and preserved iodide organification in nonfunctioning adenoma and
multinodular goiter. J Clin Endocrinol Metab 79:39, 1994.
 Hyperthyroidism
Sunil Chumber, Pratyusha Priyadarshini

The term thyrotoxicosis comprises of clinical syndrome which results from an excessive circulating
thyroid hormone. It could result either from excessive thyroid hormone production or excessive
release of the thyroid hormones. Hyperthyroidism is a disorder when thyroid gland itself is producing
excessive amount of thyroid hormones .The common causes of thyrotoxicosis relevant to the surgeon
are Graves' disease, toxic multinodular goiter, and solitary toxic nodule .Other rare causes of
thyroxicosis are hashimoto thyroiditis, postpartum thyrotoxicosis , drug induced thyrotoxicosis, struma
ovarii, metastatic thyroid cancer .

Diffuse Toxic Goiter (Graves' Disease)

Graves' disease is the most common cause of hyperthyroidism , accounting for 70% of cases. It is an
autoimmune disease with a strong familial predisposition, female preponderance (10:1), and peak
incidence between the ages of 20 to 40 years. Graves' disease is characterized by thyrotoxicosis,
diffuse goiter, and extrathyroidal conditions including ophthalmopathy, dermopathy (pretibial
myxedema).

Etiology, Pathogenesis, and Pathology

The exact etiology of the initiation of the autoimmune process in Graves' disease is not known.
Genetic factors play an important role, Graves' disease is associated with certain human leukocyte
antigen (HLA) haplotypes—HLA-B8 and HLA-DR3 and HLADQA1*0501 in Caucasian patients .
Polymorphisms of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene also have been found to be
associated with Graves' disease development. TSIs or antibodies that binds TSH-R stimulate the
thyrocytes to grow and synthesize excess thyroid hormone. Graves' disease is associated with other
autoimmune conditions such as type I diabetes mellitus, Addison's disease, pernicious anemia, and
myasthenia gravis.

Macroscopically, the thyroid gland in patients with Graves' disease is diffusely and smoothly enlarged,
with a concomitant increase in vascularity. Microscopically, the gland is hyperplastic, and the
epithelium is columnar with minimal colloid present. The nuclei exhibit mitosis, and papillary
projections of hyperplastic epithelium are common,.lymphocytic infiltrates may be present.

Clinical Features

The clinical manifestations of Graves' disease are divided into those related to hyperthyroidism and
those which are specific to Graves' disease. Hyperthyroid symptoms include heat intolerance,
increased sweating and thirst, and weight loss despite a good appetite. Symptoms of increased
adrenergic stimulation include palpitations, nervousness, fatigue, irritability, hyperkinesis, and
tremors.GI symptoms include increased frequency of bowel movements and diarrhoea.
Cardiovascular symptoms are tachycardia , atrial fibrillation and congestive heart failure. Female
patients often develop amenorrhea, infertility, while male patients may have gynecomastia.

On physical examination, patient appears anxious . The skin is warm and moist . Tachycardia or
atrial fibrillation is present with widening of the pulse pressure . A fine tremor of fingers and tongue
may be elicited. Muscle wasting, and proximal muscle group weakness with hyperactive tendon
reflexes may be present.

On local examination, the thyroid usually is diffusely and symmetrically enlarged. An overlying bruit or
thrill may be present.

Graves’ ophthalmopathy
Approximately 50% of patients may develop ophthalmopathy. Eye signs include lid lag (von Graefe's
sign) and a prominent stare due to catecholamine excess. True infiltrative eye disease results in
periorbital edema, conjunctival swelling and congestion (chemosis), proptosis,extraocular muscle
involvement, keratitis, and even blindness due to optic nerve involvement. The etiology of Graves'
ophthalmopathy is not completely known; however it is presumed that orbital fibroblasts and muscles
share a common antigen, the TSH-R. Ophthalmopathy results from inflammation caused by
cytokines released from sensitized killer T lymphocytes and cytotoxic antibodies,which leads to
glycosaminoglycan deposition and fibrosis of retro-orbital tissue and extra-ocular muscles.

Dermopathy is uncommon. It is due to deposition of glycosaminoglycans leading to thickened skin in

the pretibial region and dorsum of the foot .Rarely, bony involvement may lead to subperiosteal bone
formation and swelling in the metacarpals (thyroid acropachy). Onycholysis, or separation of
fingernails from their beds is more common .

Diagnostic Tests

The diagnosis of hyperthyroidism is made by a suppressed TSH with or without an elevated free T4 or
T3 level. Other tests are not needed in presence of eye signs. However, in the absence of eye
123
findings, an I uptake and scan should be performed. An elevated uptake, with a diffusely enlarged
gland, confirms the diagnosis of Graves' disease and differentiate it from other causes of
hyperthyroidism. If free T4 levels are normal, free T3 levels should be measured (T3 toxicosis). Anti-Tg
and anti-TPO antibodies are elevated in up to 75% of patients, but are not specific. Elevated TSH-R
or thyroid-stimulating antibodies (TSAb) are specific for Graves' disease and are increased in about
90% of patients. MRI scans of the orbits are done in Graves' ophthalmopathy.

Treatment
131
The treatment modalities available are —antithyroid drugs, thyroid ablation with radioactive I, and
thyroidectomy.

Antithyroid Drugs
Antithyroid drugs are used to induce remission and also to prepare for RAI ablation or surgery. The
drugs commonly used are propylthiouracil (PTU, 100 to 300 mg three times daily) and carbimazole
(10 to 30 mg three times daily). They reduce thyroid hormone production by inhibiting the organic
binding of iodine and the coupling of iodotyrosines. PTU also inhibits the peripheral conversion of T4
to T3. PTU has a lower risk of transplacental transfer ,therefore is preferred in pregnancy. Side effects
of treatment include reversible granulocytopenia, skin rashes, fever, and, rarely, agranulocytosis and
aplastic anemia. Patients should be warned to stop these drugs immediately and seek medical advice
should they develop a sore throat or fever. The dose of antithyroid medication is titrated according to
TSH and T4 levels. Most patients become euthyroid in about 6 weeks. Treatment with antithyroid
medications is associated with a high relapse rate , 40 to 80% of patients develop recurrent disease
after a 1- to 2-year course.

Beta-blockers are used to alleviate catecholamine response of thyrotoxicosis . These drugs also
decrease the peripheral conversion of T4 to T3. Propranolol is the most commonly used (20 to 40 mg
four times daily).

Radioactive Iodine Therapy (131I)

The major advantages of radioiodine treatment are reduced treatment costs, and ease of treatment.
Antithyroid drugs are given until the patient is euthyroid and then discontinued to maximize drug
131
uptake. The I dose is calculated after a preliminary scan, and usual dosage consists of 8 to 12 mCi
administered orally. After treatment with RAI, most patients become euthyroid within 2 months. After 1
year, about 2.5% of patients develop hypothyroidism each year. RAI may lead to progression of
Graves' ophthalmopathy (33% after RAI compared to 16% after surgery).

Absolute contraindications to RAI include women who are pregnant or breastfeeding. Relative
contraindications include young patients (i.e., especially children and adolescents), large thyroids, and
those with ophthalmopathy.

Surgical Treatment
The goal of thyroidectomy for Graves' disease is complete and permanent control of the disease .
Surgery is recommended when RAI is contraindicated .It is indicated in patients who are pregnant or
desire to conceive soon after treatment, severe reactions to antithyroid medications, large goiters
causing compressive symptoms. Relative indications are moderate to severe Graves'
ophthalmopathy, poor compliance to antithyroid medications. Patients should be rendered euthyroid
before operation with antithyroid drugs. Lugol's iodide solution or saturated potassium iodide generally
is administered 7 to 10 days preoperatively (three drops twice daily) to reduce vascularity of the
gland and decrease the risk of thyroid storm. The extent of thyroidectomy to be performed is
controversial and is determined by the desired outcome (risk of recurrence vs. euthyroidism) and
surgeon experience.

Historically ,subtotal thyroidectomy was the treatment of choice. The advantages are-reduced
complication(hypoparathyroid, RLN injury), avoidance of postoperative thyroxin. However the
disadvantages are- risk of hypothyroidism in long term, persistent or recurrent hyperthyroidism,
malignancy in remnant thyroid, long term follow up required. Total thyroidectomy has become
standard of care in recent years, the advantages of it being certain in outcome, complications not
increased in experienced hands, long term follow up not required, malignancy treated adequately.
Ophthalmopathy stabilizes or improves in most patients after total thyroidectomy.

Toxic Multinodular Goiter

Toxic multinodular goiter usually occur in older individuals, who have a history of long standing
multinodular goiter. Over several years, enough thyroid nodules become autonomous to cause
hyperthyroidism. Symptoms and signs of hyperthyroidism are similar to Graves' disease, but
extrathyroidal manifestations are absent.

Diagnostic Studies
Blood tests shows a suppressed TSH level and elevated free T4 or T3 levels. RAI uptake also is
increased, showing multiple nodules with increased uptake and suppression of the remaining gland.

Treatment
Hyperthyroidism must be adequately controlled. Surgical resection is the treatment of choice, with
total thyroidectomy being the treatment of choice as it avoids regrowth of goiter and recurrent
thyrotoxicosis.

Toxic Adenoma (Plummer's Disease)

Hyperthyroidism from a single hyperfunctioning nodule usually occurs in younger patients . Physical
examination will reveal a solitary thyroid nodule. RAI scanning shows a "hot" nodule with suppression
the rest of the thyroid gland. These nodules are rarely malignant. Smaller nodules may be managed
with antithyroid medications and RAI. Surgery (lobectomy and isthmusectomy) is preferred to treat
young patients and those with larger nodules.

Thyroid Storm

Thyroid storm is rare but potentially life threatening condition due to acute exacerbation of of
hyperthyroidism. It is characterized by high fever, central nervous system agitation or depression,
cardiovascular dysfunction .It may be precipitated by infection, surgery, or trauma. This condition is
appropriately managed in an intensive care unit setting. Lugol's iodine and PTU are administered to
decrease iodine uptake and thyroid hormone secretion. Supportive therapy in the form of oxygen
supplementation, IV fluids, beta blockers, steroids, external cooling are instituted.

Conclusion
Thyrotoxicosis is a clinical diagnosis which is confirmed using biochemical test. The thyroid scan is
mainly used to differentiate between Graves and toxic MNG when eye signs are not present. Medical
therapy has a high relapse rate. RAI ablation is most suited for small thyroid and in the absence of
ophthalmopathy. Surgery is the treatment of choice in majority of patients. Total thyroidectomy is
becoming the favoured choice because the outcome is certain and long term follow up is not required
and also the complication is not increased in experienced hand.

REFERENCES
1. Nikhil Tandon, Sunil Chumber, Amit Gupta . Thyroid. In: Essentials of Surgery, Sunil Chumber (ed); New Delhi,
Jaypee Brothers 2005; 659-681
2. Schwart’s Principles of Surgery (9th edn). McGraw Hill
3. SabistonTextbook of Surgery – The biological basis of modern surgery (14th edn). WB Saunders Company,
United States of America 2007
4. Johnathan G.H. Hubbard and Paul V.Carroll in Endocrine surgery- Principles and Practice,Springer
5. Harrison's Principles of Internal Medicine 16th Edition; New York, McGraw-Hill Inc, 2005.
 Well Differentiated Thyroid Cancer
NK Shukla

Thyroid cancer is an uncommon cancer, although it is the commonest endocrine malignancy. In

United States constitutes 1% of all cancers. In India according to ICMR registry 2008 the incidence is
1-2/100000 in males and 2-7 / 100000 in females.

WHO has classified thyroid cancer as below:

1. Differentiated thyroid cancer (DTC)

a. Papillary carcinoma thyroid which can be pure or mixed with follicular elements
b. Follicular carcinoma (FTC)
c. Hurthle cell carcinoma
2. Medullary carcinoma
3. Anaplastic Carcinoma
4. Miscellaneous Tumors

The differentiated thyroid cancers arise from the epithelial cells of thyroid follicle.

1. Papillary Carcinoma: Constitutes 80% of DTC. It is predominant in children as compared to

adults. Common age group is 30-40 years. There is female preponderance (2:1). Etiologically
radiation exposure to thyroid is supposed to be an important risk factor. Six percent of PTC
can be hereditary. Pathologically there are papillary projections and psammoma bodies. 30-
70% PTC are multifocal and commonly spread via lymphatics to the cervical lymph nodes.
Lymph node involvement is more common in children (70%) as compared to adults (30-40%).
The incidence of papillary carcinoma is increasing worldwide. In US it was 85% till 1986 and
now it is 98%. In Japan the incidence rose from 78% to 93%. (1)

2. Follicular Carcinoma: Constitute 10% of DTC. The mean age group is 50 years and they are
more common in females (3:1). Capsular and vascular invasion is commonly seen which
leads to spread to lungs, bone and liver. Definitive pre-operative diagnosis is difficult.

3. Hurthle Cell carcinoma: Constitutes 3% of DTC. It is also called Oxyphil carcinoma as the
cell contains pink cytoplasm. The tumor is generally bilateral, multifocal with cervical lymph
node metastasis in about 25% patients. These tumors do not take radio-iodine.

Clinical Presentation

The patients present as central neck swelling moving with deglutition. Thyroid enlargement can
present as a solitary nodule, diffuse swelling and rarely a part of multinodular goiter. There may or
maynot be enlargement of lateral group of cervical lymph nodes. Rarely large tumors can present with
hoarseness of voice, dysphagia and respiratory difficulty.

Diagnostic Work-up (2)

1. Ultrasound Neck: is the first and commonest investigation. It has following advantages
a) It can differentiate between solid and cystic thyroid swelling
b) It can detect non-palpable lesions in 50%
c) In deep seated lesions it can guide for Fine needle aspiration cytology (FNAC)
d) It can detect non-palpable lateral compartment neck nodes
e) Recently it is used for detection of central neck nodes (level VI)
 f) It can differentiate between benign and metastatic lymph node. Features suggestive of
metastatic lymph node are cystic change, calcification, loss of fatty hilus, rounded shape,
hypo-echogenicity and increased vascularity.(3)

2. FNAC: along with ultrasound FNAC forms most important diagnostic work-up of DTC.It is cost
effective and highly sensitive up to 95%. The FNAC report can be positive for PTC, suspicious for
PTC ( 20-30%) and Indeterminate indication follicular neoplasm which in 20% cases is malignant
(FTC). The drawback of FNAC is that it can not diagnose capsular and vascular invasion, and it
cannot diagnose follicular and Hurthle cell carcinoma.

3. Cross-sectional Imaging: Includes Computed Tomography (CT) scan and magnetic resonance
imaging (MRI) scan. CT scan is more commonly used. It is done to evaluate extra-thyroid spread,
involvement of adjacent structures like larynx, trachea and esophagus and lateral and central
compartment lymph nodes including superior mediastinal lymph nodes (level VII). Also helps in
detecting mediastinal extension of thyroid mass and compression of trachea in neck as well as in
mediastinum.

4. Fibre-optic evaluation of Larynx and Trachea should be done in all cases. Subtle vocal cord palsy
is present in 1% of normal population.

Prognostic/Risk factors assessment of DTC

There are nine prognostic classification systems and none of them is accepted universally. The
common systems are:

1. AGES (Mayo Clinic): Age (<45 yrs, >45 years), Grade (Well diff, Poorly diff), Extent
(Intracapsular, Extrathyroid spread) and Size (<5 cm , > 5 cm) as low risk and high risk
respectively
2. AMES (Lahey clinic): based on Age, Metastasis, Extent, Size
3. MACIS: Commonly used after surgical resection of thyroid cancer. It is based on Metastasis, Age,
Completeness of surgical Resection, Invasion and Size.
4. MSKCC: Risk evaluation is done on the basis of age, size, extra-thyroidal extension, presence of
distant metastasis, histological appearance, grade of tumor. The risk groups are divided into low,
intermediate and high risk categories.(4)
5. TNM Staging (2010): This staging should be used as helps in comparing the results.

TX Primary tumor cannot be assessed.

T0 No evidence of primary tumor.

T1 Tumor ≤2 cm in greatest dimension limited to the thyroid.

T1a Tumor ≤1 cm, limited to the thyroid.

T1b Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.

T2 Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.

T3 Tumor >4 cm in greatest dimension limited to the thyroid or any tumor with minimal
extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues).

T4a Moderately advanced disease.

 Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft
tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve.

T4b Very advanced disease.

Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels.

NX Regional lymph nodes cannot be assessed.

N0 No regional lymph node metastasis.

N1 Regional lymph node metastasis.

N1a Metastases to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph

nodes).

N1b Metastases to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV, or V) or
retropharyngeal or superior mediastinal lymph nodes (Level VII).

M0 No distant metastasis.

M1 Distant metastasis.

High Risk factors for DTC

1. Extra-thyroid spread
2. Lymph node metastasis (especially extracapsular spread)
3. Vascular Invasion
4. Distant metastasis
5. Hurthle cell tumor
6. Certain histological subtypes of PTC: e.g. Tall cell, Insular, Columnar cell, Diffuse sclerosing.

The 10 year survival rate in low risk DTC is 98% as compared to 58 % in high risk patients.

Management of DTC

Guidelines for management of DTC are mostly from retrospective analysis as prospective studies are
very few and with less number of patients.

Treatment Objectives

1. Eradication of primary disease in thyroid by thyroidectomy. The extent of thyroidectomy is tailored

according to individual biological need of patients.

2. Appropriate surgical management of involved cervical lymph nodes both lateral and central
compartment.(5–8) The lateral lymph nodes are treated by dissesection of level II to V nodes.
Level I lymph nodes is involved in above 5% of patients. Hence it may not be dissected. In large
 tumor burden as in Indian patients, they should also be dissected. The recent recommendation is
to perform a modified neck dissection type III. Berry picking is not recommended. For level VI
lymph nodes bilateral central compartment lymph node
dissection is recommended. The level VI nodes involves
prelaryngeal, pretracheal, paratracheal. ATA guidelines 2009
recommend bilateral central lymph node dissection (CLND) in all
patients undergoing total thyroidectomy as the incidence of
nodal disease is up to 30%. Similar opinion is given by other
authors (8). Other authors recommend CLND only if node is
abnormal in USG or clinically examination or intra-operative
assessment (7).

3. Prophylactic neck dissection is controversial. It is not required in

low risk patients. Needs to be performed in high risk patients, both central and lateral lymph
nodes should be dissected. In hurthle cell cancer prophylactic lymph node dissection is indicated.

4. Radio-iodine therapy: After total thyroidectomy and neck dissection to ablate any residual / occult
tumor in thyroid bed and in region of lymph node dissection, radio-iodine therapy is advised.

5. TSH suppression: Oral Thyroxin is given after thyroidectomy to prevent hypothyroidism and to
decrease TSH stimulation by tumor. It improves survival.

6. External Radiotherapy: is indicated in extra-thyroidal involvement, bone metastasis, brain

metastasis, SVC obstruction by nodes, etc.

Extent of Thyroidectomy

Controversy is persisting for the extent of thyroidectomy between hemithyroidectomy (lobectomy +

isthmectomy), near total thyroidectomy and total thyroidectomy. According to American Thyroid
Association (ATA) guidelines stage wise management is as follows (9,10)

1. T1 Tumors with low-risk and no evidence of contralateral lobe involvement in USG:

Hemithyroidectomy with lifelong TSH suppression. There is no role of prophylactic neck
dissection.
2. T2 tumors:
a. Low-risk – Hemithyroidectomy.No role of prophylactic neck dissection.
b. High risk- Total thyroidectomy with prophylactic/ therapeutic neck dissection
3. T3, T4a Tumors : Total thyroidectomy with neck dissection of both lateral and central groups.
4. T4b: Radio-iodine therapy and External beam radiotherapy

Role of Radio-iodine Therapy

I 131 therapy is useful for the detection and ablation of residual and metastatic disease. It acts as a
magic bullet due to preferential uptake by residual / metastatic cancer. The protocol for RAI is as
follows

Whole body scan (WBS) after 4 to 6 wks of total thyroidectomy. Oral T4 therapy should be stopped
for 4 wks and TSH should be above 30 mIU/L. The diagnostic dose of RAI is 2 mci, is given to detect
residual disease. If there is any residual disease the ablative dose of 50 to 150 mci is given
depending on volume of residual disease. Post-ablative WBS is done after 3-7 days, if residual
disease present, then ablate again.
Follow-up

During follow-up WBS and thyroglobulin estimation is done every 6 months to detect any recurrence
of disease. If WBS is negative and Tg is high, a FDG-PET/CT scan should be done, which can pickup
non-iodine avid recurrent disease. (11) The recurrent disease in thyroid bed and regional lymphnode
is treated by re-exploration and resection of residual disease. During follow-up if patient develops
pulmonary metastasis, then radio-iodine ablation is recommended with dose of 150mci. For skeletal
metastasis 200mci is required.(6)

REFERENCES

1. Ito Y, Miyauchi A. Prognostic factors and therapeutic strategies for differentiated carcinomas of the thyroid.
Endocr J. 2009;56(2):177–92.
2. Slough CM, Randolph GW. Workup of well-differentiated thyroid carcinoma. Cancer Control J Moffitt Cancer Cent.
2006 Apr;13(2):99–105.
3. Kuna SK, Bracic I, Tesic V, Kuna K, Herceg GH, Dodig D. Ultrasonographic differentiation of benign from
malignant neck lymphadenopathy in thyroid cancer. J Ultrasound Med Off J Am Inst Ultrasound Med. 2006
Dec;25(12):1531–1537; quiz 1538–1540.
4. Shaha AR. Implications of Prognostic Factors and Risk Groups in the Management of Differentiated Thyroid
Cancer. The Laryngoscope. 2004;114(3):393–402.
5. Bardet S, Malville E, Rame J-P, Babin E, Samama G, Raucourt DD, et al. Macroscopic lymph-node involvement
and neck dissection predict lymph-node recurrence in papillary thyroid carcinoma. Eur J Endocrinol. 2008 Apr
1;158(4):551–60.
6. Fritze D, Doherty GM. Surgical Management of Cervical Lymph Nodes in Differentiated Thyroid Cancer.
Otolaryngol Clin North Am. 2010 Apr;43(2):285–300.
7. Md RMC, Md WTS, Md JEG. Extent of Surgery for Papillary Thyroid Cancer: Preoperative Imaging and Role of
Prophylactic and Therapeutic Neck Dissection. Curr Treat Options Oncol. 2012 Mar 1;13(1):1–10.
8. Mulla M, Schulte K-M. Central cervical lymph node metastases in papillary thyroid cancer: a systematic review of
imaging-guided and prophylactic removal of the central compartment. Clin Endocrinol (Oxf). 2012;76(1):131–6.
9. Nixon IJ, Ganly I, Shah JP. Thyroid cancer: surgery for the primary tumor. Oral Oncol. 2013 Jul;49(7):654–8.
10. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association
Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American
Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid.
2009 Nov;19(11):1167–214.
11. Palaniswamy SS, Subramanyam P. Diagnostic utility of PETCT in thyroid malignancies: an update. Ann Nucl Med.
2013 Jun 26;
 Rationale for Investigations for a Patient with Thyroid swelling
Anjali Mishra, Sunil Malla Bujar Barua

Epidemiology

Thyroid nodules are discovered by palpation in 3%-7%, ultrasonography (USG) in 20%-76% and
during autopsy in 50% of the general population. The incidence of thyroid swelling is correlated with
iodine nutrition of the population, age and gender. According to the available estimates, in India about
71 million people suffer from Goiter or other iodine deficiency disorders. The incidence of goiter in
sub- Himalayan region of India continues to be high despite an active National Goiter control
Programme (NGCP). As per generally understood definition goiter is an enlarged thyroid but what
exactly is the cut of enlargement is controversial. So far as thyroid nodule is concerned the “American
Thyroid Association” defines a thyroid nodule as a discrete lesion within the thyroid gland that is
radiologically distinct from the surrounding thyroid parenchyma.

Clinical Evaluation

Clinical examination might not be very accurate in assessing a thyroid swelling. Majorities of nodules
measuring < 1 cm in size are not palpable and some >1cm in diameter are may also be not palpable
on examination. Up to two-third of patients with multiple thyroid nodules >1cm in diameter can be
misclassified as having solitary or no nodules based on clinical examination. Physical examination is
an unreliable detection method for small cervical lymph node metastases from thyroid cancer and
detects only large lymph nodes; even intraoperative palpation will only detect about two-third of lymph
node metastases. There are many causes of thyroid swelling or enlargement. The evaluation of
thyroid swelling is chiefly focused on excluding presence of thyroid malignancy and dysfunction. As
mentioned previously thyroid swelling is a fairly common problem, however majority of nodules are
benign and the incidence of malignancy ranges from 5-15% in different clinical scenario. Non-
palpable nodules have similar risk of being malignant as those palpable. Clinical examination is not
very accurate in predicting malignancy in a thyroid nodule. However, the following features which
heighten the suspicion for malignancy should be noted.

1. Extremes of age < 14 years or > 70 years

2. Male sex
3. History of head and neck irradiation
4. Family history of medullary thyroid carcinoma (MTC), Multiple Endocrine Neoplasis Type-2
(MEN-2), papillary thyroid carcinoma (PTC) or associated syndromes
5. Growing nodule
6. Hoarseness of voice, dyspnea and dysphagia
7. Firm or hard consistency
8. Fixed nodule
9. Associated cervical lymphadenopathy

The most common causes of thyrotoxicosis include Graves’ disease (GD), toxic multinodular goiter
(TMNG), and toxic adenoma (TA). All patients with known or suspected hyperthyroidism should
undergo a comprehensive history and physical examination, including measurement of pulse rate,
blood pressure, respiratory rate, and body weight. In addition, thyroid size; presence or absence of
thyroid tenderness, symmetry, and nodularity; pulmonary, cardiac, and neuromuscular function; and
presence or absence of peripheral edema, eye signs, or pretibial myxedema should be assessed.

Laboratory evaluation

Serum thyrotropin (TSH) is the most useful test in initial evaluation in majority of patients. However,
measurement of free thyroxine (fT4) and thyroninine (fT3) should be done as initial screening if
patients present with sign or symptoms of thyroid dysfunction. Patients with low TSH levels are less
likely to have thyroid malignancy whereas those with elevated TSH or high level values are more
likely to harbor malignancy. If TSH levels are deranged fT4 and T3 are measured to confirm the
diagnosis of clinical hyper or hypothyroidism. Patients with suppressed TSH level need thyroid scan
to establish the cause of thyrotoxicosis. Measurement of thyroid peroxidase antibodies (TPOAb)
supports the diagnosis of immunologically mediated thyroid disorders. Thyroid stimulating
immunoglobulins (TSI), thyrotropin binding- inhibitor immunoglobulins (TBII) measurement is not
routinely recommended. Laboratory test should be interpreted with caution as certain physical
conditions and drugs intake can influence the levels of thyroid hormones and TSH. Not all high
values for T4 and T3, and not all suppressed TSH levels, are associated with hyperthyroidism.
Estrogen administration or pregnancy raises the thyroxine-binding globulin level and results in high
total T4 and T3 levels on but normal fT4 and T3 estimates and a normal result on sensitive TSH
assay. Euthyroid hyperthyroxinemia may also be attributable to other abnormal binding proteins,
including albumin and prealbumin. Similarly, thyroid hormone resistance states can cause increased
serum T4 levels without hyperthyroidism. Administration of corticosteroids, severe illness, and
pituitary dysfunction can be associated with a suppressed TSH level in the absence of
hyperthyroidism. Some patients have elevated serum TSH concentrations (immunologically active
and biologically inactive TSH) despite the presence of central hypothyroidism. Using serum fT4 alone
as a diagnostic test of hypothyroidism detects clinical hypothyroidism but it cannot detect subclinical
hypothyroidism. Also, low fT4 alone is not sufficient to make the diagnosis of central or primary
hypothyroidism. The combination of serum TSH and fT4 is the most accurate test for detecting central
as well as primary hypothyroidism. Addition of serum fT4 to TSH costs more than the single test, but
the accuracy of the test may eventually turns out to be more cost-effective in certain situations e.g. it
avoids frequent repeat testing.

Serum thyroglobulin (Tg) level is raised in many thyroid conditions, therefore, pre-operative estimation
of serum Tg is not recommended as it is not contributory to the diagnosis making and does not
influence management. Routine measurement of serum calcitonin (Ct) though advocated by few is
not generally recommended because of poor yield of MTC. Serum Ct, though, should be measured in
patients who have a family history of MTC, MEN2, pheochromocytoma or when the fine needle
aspiration result suggests MTC. Serum CEA measurement is done is diagnosed cases of MTC.

Ultrasonography (USG)

A thyroid ultrasound is required as part of the evaluation for any nodule suspected on physical
examination. Many nodules suspected on the basis of physical examination are not confirmed upon
ultrasound examination. USG frequently changes the management of patients with known or
presumed thyroid nodules.

Thyroid USG: Objectives of evaluation

1. Confirmation of presence of nodule or enlargement

2. Solitary (STN) versus Multiple (MNG)
3. Characterization of nodule to assess the presence of malignancy
4. Extra-thyroidal recurrence
5. Presence of lymphadenopathy and characterization of lymph nodes
6. Guide Fine needle aspiration

USG should not be used as screening modality in general population. However, it is recommended to
be used as screening of thyroid cancer in certain high- risk group patients eg: familial thyroid cancer,
history of radiation exposure, FDG avid thyroid incidentalomas. USG generally does not contribute to
the diagnosis of thyrotoxicosis. However, in special situation where radio-nucleide scan is
contraindicated e.g .pregnancy or breast feeding an increased vascularity demonstrable on color
Doppler may help in establishing the diagnosis.

USG prediction of malignancy

Cancer risk does not differ among solitary and multiple nodules. Nodule size is not predictive of
malignancy. Following features are indicative of presence of malignancy.

1. Hypoechoic solid nodule

2. Round or more wider than taller nodule
3. Loss of peripheral halo and irregular margins
4. Presence of microcalcifications
5. Chaotic intra-nodular vascularity
6. Complex nodules
7. Extra-thyroidal invasion
8. Presence of cervical lymphadenopathy
9. Features of cervical lymph nodes: enlargement, rounded shape, absent hilum, cystic nature,
micro-calcifications and chaotic hypervascularity.

The specificities of ultrasound features and color Doppler finding for cancer are as follows:
microcalcifications-85-95%, irregular/indistinct nodule margins- 83-85%, chaotic intra-nodular
vascularity 81%. The corresponding sensitivities are: microcalcifications-29-59.2%, irregular/indistinct
nodule margins- 55.1-77.5%, chaotic intranodular vascularity 74.2%

In low-risk patients, most nodules <1 to 1.5cm should be followed without further intervention.
Following sonographic identification of a thyroid nodule >1 to 1.5cm in diameter, euthyroid patients
should be referred for consideration of FNA. Reading et al found four classic patterns of nodules that
did not require biopsy: small (< 1 cm) colloid-filled cystic nodules; a nodule with a honeycomb
appearance consisting of internal cystic spaces with thin echogenic walls; a large
predominantly cystic nodule; and diffuse multiple small hypoechoic nodules with intervening
echogenic bands, which are indicative of Hashimoto’s thyroiditis. USG guided FNAC of a nodule < I
cm in size is generally not recommended unless there are associated high- risk feature eg:
microcalcifications, history of neck irradiation, or a young patient with complex or predominantly cystic
lesions as some PTC’s may be cystic.

USG guided fine needle aspiration cytology (FNAC)

USG-FNA is becoming increasingly popular because of the increased precision and ability to guide
the biopsy needle to the desired location in real time. In one study, 8.7% of aspirates guided via
palpation were inadequate, whereas only 3.5% were inadequate for those obtained with ultrasound-
guidance. If the patient has multiple nodules or a prior thyroid ultrasound was nondiagnostic, only
ultrasound should be employed for guidance. Indications for USG-FNAC are: non diagnostic palpation
guided FNAC, complex nodule if cystic component is more than 25-50%, palpable small nodule
(<1.5cm), posteriorly placed nodules, impalpable incidentalomas, and abnormal cervical nodes. To
avoid the inappropriate use of US-FNA it is essential to determine which thyroid lesions are at risk of
malignancy on the basis of USG characteristics. In the presence of two or more thyroid nodules >1
cm, those with a suspicious sonographic appearance should be aspirated preferentially. If none of the
nodules has a suspicious sonographic appearance and multiple sonographically similar coalescent
nodules with no intervening normal parenchyma are present, the likelihood of malignancy is low and it
is reasonable to aspirate the largest nodules only.

USG Elastography
Elastography has recently been applied in the diagnostic approach to nodular thyroid disease and has
shown a high sensitivity and specificity in selected patients. Larger prospective studies are needed to
establish the diagnostic accuracy of this technique.
Thyroid Scintigraphy

Thyroid nodule patients with low serum TSH concentration need scintigraphy to assess the presence
99
of autonomous nodule(s). FNAC is not necessary for hot nodules. A technetium mTc pertechnetate
123
or I scan can be performed and directly compared to the USG images to determine functionality of
each nodule. FNAC should then be considered only for those isofunctioning or nonfunctioning
nodules, among which those with suspicious sonographic features should be aspirated preferentially.
A radioactive iodine uptake in patients with Graves’s disease is only performed when the clinical
presentation of thyrotoxicosis is not diagnostic. 99mTcO4 is less expensive; more readily available;
and allows more rapid examination, however, technetium is trapped but not organified (risk of false-
positive images); activity in esophagus or vascular structures can be misleading; poor image quality
123
when uptake is low. Use of -I is associated with better visualization of retrosternal thyroid tissue;
better images when thyroid uptake is low; real iodine clearance of the thyroid may be measured
instead of only uptake, however it is costlier and more cumbersome to perform.

Indications of Scintigraphy

1. Thyroid nodules with suppressed TSH

2. To distinguish low-uptake from high-uptake thyrotoxicosis
3. Diagnosis of ectopic thyroid tissue
4. In follicular neoplasms to identify a functioning cellular adenoma which is more likely to be
benign.
5. To determine eligibility for radioiodine therapy

Other imaging techniques

MRI and CT are not recommended for routine use as they are rarely diagnostic of malignancy in
nodular thyroid disease. However in cases of large, fixed and retrosternal goiters, these imaging are
useful in assessing the size, extent of retrosternal extension and relationship of the goiter with
surrounding vital structures in neck and superior mediastinum. FDG-PET is not recommended for
routine pre-operative imaging. X- ray neck AP and lateral view help in assessing tracheal deviation
and narrowing. CECT of thorax abdomen and bone scan are done in select cases of MTC.

Fine needle aspiration biopsy (FNAC)

FNA can decrease the need for surgical thyroidectomy by 30% to 50% while increasing the diagnostic
yield of surgery. It is the most accurate test for determining malignancy pre-operatively. Routine FNA
is not recommended for subcentimeter nodules. In the presence of two or more thyroid nodules >1
cm, those with a suspicious sonographic appearance should be aspirated preferentially. If none of the
nodules has a suspicious sonographic appearance and multiple sonographically similar coalescent
nodules with no intervening normal parenchyma are present the likelihood of malignancy is low and it
is reasonable to aspirate the largest nodules only. In MNG, up to four nodules >1cm may require
aspiration to accurately detect all cases of thyroid cancer. In autoimmune thyroid diseases, such as
Graves' disease and Hashimoto's thyroiditis, a dominant localized abnormality in the thyroid gland is
an indication for FNA.

The results of FNAC are very sensitive for the differential diagnosis of benign and malignant nodules,
although there are limitations: inadequate samples and follicular neoplasia. The reported sensitivity,
specificity, positive predictive value, false- negative rate and false positive rate for FNAC vary from
65-98, 72-100, 50-96, 1-11, and 0-7% respectively in different series. Nondiagnostic biopsies are
those that fail to meet specified criteria for cytologic adequacy that have been previously established
(the presence of at least six follicular cell groups, each containing 10–15 cells derived from at least
two aspirates of a nodule). After an initial nondiagnostic cytology result, repeat FNA with US guidance
will yield a diagnostic cytology specimen in 75% of solid nodules and 50% of cystic nodules.
Therefore, such biopsies need to be repeated using US guidance and, if available, on-site cytologic
evaluation, which may substantially increase cytology specimen adequacy. However, up to 7% of
nodules continue to yield nondiagnostic cytology results despite repeated biopsies and may be
malignant at the time of surgery. Approximately 60% to 70% of FNA samples will prove benign, 5% of
samples will return positive for malignancy and 15% to 25% of aspirations will be adequate though
diagnostically indeterminate (Follicular or Hurthle cell neoplasm). There are different systems of
reporting the FNAC results. Apart from non-diagnostic or inadequate the results can generally be
grouped as benign, malignant, indeterminate and suspicious. Recently National Cancer Institute (NCI)
has adopted the Bethesda system for reporting thyroid cytopathology, which consists of six diagnostic
categories: Non-diagnostic or unsatisfactory, Benign, Follicular lesion, Follicular neoplasm Suspicious
for malignancy, Malignant. The chances of a nodule being proven malignant after surgery vary among
different category of FNAC diagnosis. In case of non-diagnostic: 1-4%, benign: 0-3%, follicular lesion:
5-15%, follicular neoplasm: 15-30%, suspicios for malignancy: 60-75%; and malignant: 97-99%.

Palpation guided fine needle aspiration

Palpation-guidance is reasonable for certain patients in whom ultrasound has validated the presence
of a true thyroid nodule. The nodule must also be easily identified via palpation and should only be
performed on solid nodules (<25% cystic) in patients with normal neck anatomy. Indications for USG
guidance for FNA are discussed under USG section.

Role of Immunocytochemical/ histochemical markers

In one study, 29% of indeterminate aspirates tested positive for mutations in the BRAF, RET-PTC,
RAS, or PAX8/PPAR genes. Galectin 3 -sensitivity and specificity of galectin-3 immunodetection
were greater than 99% and 98%, respectively in one study. A subsequent study reported an 89%
rate of positive immunostaining despite histopathologically confirmed cancer. Thyroid peroxidase,
HBME-1, Telomerase are under evaluation. No single specific tumor marker is available to reliably
distinguish benign from malignant thyroid cellular tumors. Genomic analysis of aspiration material has
been performed and appears to hold promise. A group led by McMillan and Kebebew have developed
96-gene arrays, one such array having a sensitivity of 91% and specificity of 95% in distinguishing
benign from malignant tumors. At present, however, no commercial tests utilizing whole genome
analysis are available.

Thyroglobulin in fine needle aspiration of cervical lymph nodes

FNA-Tg sensitivity was reported to be 84% in one study and increased FNA sensitivity from 76% to
92%

Preoperative Considerations / Investigations

Thyroid dysfunction should be under control with medical treatment so as not to precipitate thyroid or
myxoedematoud crisis. A proper airway assessment is must in cases of large, infiltrative and
retrosternal goiters. X- ray neck AP and lateral view help the Anaesthetist in assessing tracheal
deviation and narrowing. Apart from other blood test required for surgery under general anaesthesia a
serum calcium measurement is helpful particularly if total thyroidectomy is planned.

Vocal Cord examination

Pre- operative laryngeal examination in the form of direct or indirect laryngoscopy is increasingly
being carried out routinely. Vocal cord palsy can be present in normal population (2-3%) patients
without significant vocal symptoms and preoperative voice symptoms are not a reliable indicator of
recurrent laryngeal nerve (RLN) function. Since, many factors are responsible for post-thyroidectomy
voice change a pre-operative laryngeal examination also has medico-legal implications. RLN palsy is
a good predictor of invasive thyroid carcinoma.

 As Per American Thyroid Association Guidelines (2009)

REFERENCES
1. Brander A, Viikinkoski P, Tuuhea J., et al: Clinical versus Ultrasound Examination of the Thyroid Gland in
Common Clinical Practice. J ClinUltrasound1992; 20: 37
2. Danese D, Sciacchitano S, Farsetti A, et al: Diagnostic accuracy of conventional versus sonography-guided fine-
needle aspiration biopsy of thyroid nodules. Thyroid1998; 8:15
3. Bartolazzi A., Gasbarri A., Papotti M., et al: Application of an immunodiagnostic method for improving
preoperative diagnosis of nodular thyroid lesions. Lancet 2001; 357:164.
4. National Institute of Health and Family Welfare (2003). National Iodine Deficiency Disorders Control Program:
National Health Program Series 5, p. 99. New Delhi: Department of Communication, National Institute of Health
and Family Welfare
5. Maruta J., Hashimoto H., Yamashita H., et al: Immunostaining of galectin-3 and CD44v6 using fine-needle
aspiration for distinguishing follicular carcinoma from adenoma. Diagn Cytopathol 2004; 31:392
6. Kebebew E, Peng M, Reiff E et al. Diagnostic and extent of disease multigene assay for malignant thyroid
neoplasms. Cancer 2006; 106(12):2592-7
7. Reading CC, Charboneau JW, Hay ID, Sebo TJ. Sonography of thyroid nodules: a “classic pattern” diagnostic
approach. Ultrasound Q 2005; 21:157– 165
8. Gharib H,Papini E .Thyroid nodules: Clinical importance, Assessment and Treatment. Endocrinol Metab Clin N
Am 2007; 36: 707
9. Bacuzzi A, Dionigi G, Bosco Ad, et al. Anaesthesia for thyroid surgery: Perioperative management. International J
Surg 2008; 6:S82–S85
10. Cooper DS, Doherty GM, Haugen BR, et al: Revised American Thyroid Association management guidelines for
patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009; 19:1167
11. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol 2009;132:658
12. GharibH, Papini E Paschke R et al. American Association of Clinical Endocrinologists, Associazione Medici
Endocrinologi, and European Thyroid Association Medical Guide lines for Clinical Practice for the Diagnosis and
Management of Thyroid Nodules. Endocrine Practice 2010; 16:11
13. Bahn RS, Henry BB, Cooper D et al. Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines
of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocrine Practice
2010; 17(Suppl 1): 1
 Buerger’s Disease (Thromboangiitis Obliterans)
(Pre Senile Gangrene)

M.P. Arora

Introduction

Buerger’s disease is a non-atherosclerotic vascular disease also known as thromboangitis

oblitrans(TAO), is characterised by the absence or minimal prescence of atheromas, segmental
recurring and progressive vascular inflammation, vasoocclusive phenomenon and thrombosis of small
and medium arteries and veins of hands and feet. The first reported case of TAO was described in
Germany by von Winiwarter in the year1879 in an article titled “Strange form of endarteritis and
endophlebitis with gangrene of feet.”[1] A quarter century later in Brookline NY, Leo Buerger
published a detailed description of the disease in which he referred to the clinical presentation of
thromboangitis obliterans as presenile spontaneous gangrene.[2] The paper discussed the pathlogical
findings in 11 limbs amputated from Jewish patients.

Etiology

While the etiology of Buergers disease is unknown, exposure to tobacco is essential for both initiation
& progression of the disease. The notion that it is linked to tobacco exposure is supported by the fact
that the disease is more common in countries with heavy use of tobacco and is more common among
natives of India & Bangladesh where Bidi made from raw tobacco is used. Even chewing of tobacco
can also cause the disease in non smokers.It is strongly assosciated with tobacco use, primarily
smoking, chewing tobacco and nicotine patch.

Possible risk of Rickettsia in this disease has been proposed.

The disease mechanism underlying Burgers disease is not clear, but a few observations have led
investigators to implicate an immunological phenomenon that leads to vasodysfuncton & inflammatory
thrombi.

Pathophysiology

There are characteristic pathologic findings of acute inflammation and thrombosis of arteries and
veins of hands and feet (lower limbs being more common). Underlying mechanisms are still unknown
but smoking and tobacco consumption are major factors associated with it.

It has been suggested that the tobacco may trigger immune response in susceptible persons or it may
unmask a clotting defect either of which could incite inflammatory reaction of vessel wall.Patient with
disease show hypersensitivity to intrdermally injected tobacco extracts, have increased cellular
sensitivity to types 1 and 111collagen, have elevated serum anti endothelial cell anibody titres and
have impaired peripheral vasculature endothelium dependent vasorelaxation. Increased prevalence of
HLA-A9, HLA-A54 and HLA-B5 is observed in these patient, which suggest genetic component of this
disease.
Epidemiology

The prevalence of Buerger disease has decreased over the past half decade, partly because the
prevalence of smoking has decreased, but also the diagnostic criteria has more stringent. In 1947, the
prevalence of the disease in USA was 104 cases per 100000 population. Now the prevalence has
been estimated at 12.6-20 cases per 100000 population.

Mortality and Morbidity

Death from Buerger disease is rare, but in patient with the disease who continue to smoke, 43%
require 1 or more amputations in 7.5 years. Most recently out of 2002 death reported in the USA ,only
9 deaths have been linked to buergers disease depicting male:female ratio 2:1 and white:black
ethnicity ratio of 8:1.

Race

Buerger disease is relatively less common in people of north European descent. Natives of Indian
subcontinent, Korea, Japan and Israeli jews of Ashkenazi descent have the highest incidence of the
disease.[3]

Sex

Though Buerger disease is more common in males, male:ratio is 3:1, incidence is increasing in
female due to increased prevalence of smoking.

Age

Most patients with Buergers disease are aged 20-45 years.

Clinical Presentation

 Most patients (70-80%) present with distal ischemic rest pain and ischemic ulceration in the
toes, feet and fingers.[4],[5]
 Main symptom is pain in affected area at rest and while walking (claudication).
 Paraesthesia (numbness, tingling, burning, hypoaesthesia) and impaired distal
pulse in presence of normal proximal pulses.
 Skin changes occur due to impaired circulation like colour changes, skin may become thin
and shiny with loss of hairs.
 Ulcerations and gangrene of the extremities

Differential Diagnosis

Number of differential diagnosis need to be ruled out before the establishment of firm diagnosis of
Buerger’s disease in which we have to rule out-

 Proximal source of emboli by echocardiography and arteriography

 Hypercoagualble states, Diabetes mellitus and Autoimmune diseases.
Work-up

No specific lab test is available for the diagnosis of Buerger’s disease. The primary goal of lab work-
up is to exclude other differential diagnosis-

 CBC count with differential

 LFT, KFT
 Urine analysis
 Fasting Glucose
 ESR
 CRP
 Rheumatoid factor and other autoimmune antibodies
 Anti nuclear antibody

Imaging studies

Angiography / arteriography

Hallmark findings are non-atherosclerotic, segmental occlusive lesion of small and medium sized
vessel with formation of distinctive small vessels collaterals around areas of occlusion known as cork-
screw collaterals which give “tree root” or “spider leg” appearance such arteriographic findings
suggest Buerger disease but are not pathognomic because similar lesions can be observed in
scleroderma, SLE.

Echocardiography: it is always performed in order to exclude a proximal source of emboli as a cause

of distal vessel occlusion.

Allen test: it is clinical test to test the vessels in the palmar arch by compressing radial and ulnar
artery. A positive Allen test in a young smoker with foot ulceration is highly suggestive of Buerger
disease.

Diagnosis

A concrete diagnosis of thromboangitis obliterans is often difficult as it relies heavily on exclusion of

other conditions. According to OLIN (2000) following criteria has been proposed[6] :-

1. Age younger than 45 yrs

2. Current or recent history of tobacco use
3. Presence of distal extremity ischemia(indicated by claudication, pain at rest, ischemic ulcers,
gangrene) documented by non-invasive vascular testing
4. Exclusion of autoimmune disease, hypercoaguable states and diabetes mellitus
5. Exclusion of proximal source of emboli by echocardiography and arteriography
6. Consistent arteriographic findings in the clinically involved and non-involved limbs.

More recently a point scoring system has been proposed by PAPA by using the following points:

 Distal extremity(feet, toes, hands and fingers) involvement

 Onset before age 44yrs
 Tobbaco use
 Exclusion of atherosclerosis or proximal source of emboli
 Lack of hypercoaguable state
 Lack of definable arteritis(GCA, SS)
 Classic arteriographic findings
 Segmental involvement(“skip areas”)
 Corkscrew collaterals
 Classic histopathologic findings(inflammatory cellular infiltrate within thrombus with sparing
vessel wall)

Positive Points
Age of onset <30 yrs(+2)
30-40 yrs(+1)
Foot intermittent claudication Present(+2)

Upper Extremity Symptomatic(+2)

asymptomatic(+1)
Migrating superficial Present(+2)
Thrombophlebitis By history(+1)
Raynauds phenomenon Present(+2)
By history(+1)
Angiography; Biopsy If typical both(+2)
Either(+1)

Negative Points
Age at onset 40-50(-1)
>50(-2)
Sex, smoking Female(-1)
Non-smoker(-2)
Location Single limb(-1)
no limb(-2)
Absent pulse Brachial(-1)
Femoral(-2)
Atheroscelrosis, Diabetes, HTN, Discovered after diagnosis5-10 yrs(-1)
Hyperlipidemia 2-5 yrs later(-2)

Number of points Probability of diagnosis

0-1 Diagnosis excluded
2-3 Suspected, low probability
4-5 Probable, medium probability
>6 Definite, high probability

Differential Diagnosis

Atherosclerosis, Diabetes Mellitus, Peripheral arterial occlusive disease, Raynaud phenomenon,

scleroderma, SLE, Takayasu arteritis, Thoracic outlet syndrome.

Histological findings

OLIN contends that a biopsy is rarely needed unless the patient presents with unusual
characteristic, such as large artery involvement or age more than 45 yrs. In acute state Buerger
disease is characterised by highly cellular, segmental, occlusive, inflammatory thrombi, with
minimal inflammation in the wall of affected blood vessel. Secondary spreads from the affected
vessels to contiguous veins and nerves is often observed. In the sub acute phase, intraluminal
thrombosis progressively organises, but it may defer vascular recanalisation [7]. The end stage of
the disease is characterised by mature thrombus and vascular fibrosis. In all three stages the
integrity of normal structure of vessel wall including the internal elastic lamina is maintained. This
distinguishes Buergers disease from arterial sclerosis and other types of systemic vasculitis in
which disruption of internal elastic lamina and media can be extensive.
Treatment & Management

1. Smoking cessation: Absolute discontinuation of tobacco use and smoking is the only
strategy proven to prevent the progression of disease. Smoking even 1-2 cigarette/day,
chewing tobacco or even using nicotine replacement may keeps the disease active. [8]

2. Medical Care: Drugs and procedures which causes vasodilatation and effective in reducing
pain.
 Prostaglandins- Limaprost, Iloprost
 Epidural anaesthesia
 Hyperbaric oxygen therapy
 Bosentan- competitive antagonist at endothelin receptors(under study)
 Lifestyle modifications: By using well fitting protective foot wear to prevent foot trauma
and thermal and chemical injury. Early and aggressive treatment of limb injuries to protect
against infection should be adopted. Patient should avoid cold environment and drugs
that lead to vasoconstriction.
 Genetic therapy by using intramuscular gene transfer of Vascular endothelial growth
factor to improve healing of ulcers and relief of rest pain.[9]

3. Surgical Care:
 Lumbar sympathectomy-
 Causes cutaneous vasodilatation with improvement in circulation with relief from rest
pain.
 Spinal cord stimulator implantation (under study)
 Use of vascular growth factor and stem cell cell injections (under study.
 Debridement- done in necrotic ulcers
 Omental Transfer
As omentum is very vascular structure its lengthening is dependent upon its major blood
supply i.e. omental artery.
Indication:
 Failure of lumbar sympathectomy
 Failure of conservative t/t
 Incapacitating rest pain

Principle
 Increasing local collateral circulation.
 Lipid fraction which promotes neovascularisation.

 Amputaion- for “refractory” Buerger’s disease. Limb saving attitude should be adopted.

Prognosis

Prognosis of the patient with Buerger’s disease is dependent upon whether absolute avoidance of
tobacco is achieved. Among the patients who quit smoking, 94% avoid amputation; among
patients who quit smoking before gangrene develops, the amputation rate is near 0%

Prevention
Avoid smoking

NO SMOKING NO BUERGER’S DISEASE

REFERENCES

1. Von Winiwarter F. Ueber eine eigenthumliche From von Endarteritis and Endophlebitis mit Gangran des
Fusses. Arch Klin Chir.1879;23:202-26.
2. Buerger L. Thrombo-angitis obliterans: a study of vascular lesions leading to pre-senile spontaneous
gangrene.Am j Med Sci. 1908;136:567-80
3. Salimi j, Tavakkoli H, salimzadeh A, Ghadimi H, Habibi G, Masoumi AA.Clinical characteristics of Buerger’s
disease in Iran. J Coll Physicians Surg Pak. Aug2008;18(8):502-5.
4. Motukuru V ,Suresh KR, Vivekanand V, Raj S, Girja KR.Theapeutic angiogenesis in buergers disease
(thrmbo-angitis obliterans) patients with critical limb ischaemia by autologous transplantation of bone
marrow mononuclear cells . J Vasc Surg. Dec 2008;48(6 suppl):53S-60S;discussion 60S.
5. Kulkarni S,Kulkarni G, Shyam AK, Kulkarni M, Kulkarni R, Kulkarni V. Management of Thrombo-angitis
obliterans using distraction osteogenesis: A retrospective study. Indian J Orthop. Sep2011;45(5):459-64.
6. Olin JW, Young JR, Graor RA, Ruschhaupt WF, Bartholomew JR.The changing clinical spectrum of
thromboangitis obliterans (Buerger’s Disease) Circulation.Nov1990;82(5 suppl):IV3-8.
7. Giraziani L, Morelli L, Parini F, Franceschini L, Calza S, et al. Clinical outcome after extended endovascular
recanalization in buerger’s disease in 20 consecutive cases. Ann Vasc Surg. Apr2012;26(3):387-95.
8. Lawrence PF , Lund OI, Jimenez JC, Muttalib R, Substitution of smokeless tobacco for cigarettes in
Buerger’s disease does not prevent limb loss. J Vasc Surg. Jul 2008;48(1):210-2
9. Tavakoli H, Salimi J, Rashidi A. Reply.”Treatment of choice for Buerger’s disease(thromboangitis
obliterans):still an unresolved issue”. Clin Rheumatol. Jun 2008;27(6):813.
 Critical Limb Ischaemia
C.B. Singh
Critical limb ischemia is estimated to develop in approximately 500 to 1000 individuals per million
per year1.As vessel narrowing increases, critical limb ischemia can develop when the blood flow
does not meet the metabolic demands of tissue at rest. Critical limb ischemia has two broad
clinical subcategories that are vital to differentiate:

a) Acute limb ischemia

b) Chronic arterial occlusive disease

Acute limb ischemia refers to the acute arterial thrombosis of an extremity, resulting in an abrupt
cessation of flow to the extremity. Acute limb ischemia is a surgical emergency mandating urgent
extremity revascularization to avoid the need for amputation. The potential sources of acute limb
ischemia are arterial embolus, in situ arterial thrombosis in the setting of advanced chronic arterial
occlusive disease, and major arterial trauma.

Chronic arterial occlusive disease with critical limb ischemia is the condition of progressive
atherosclerosis, creating a state of extremity hypoperfusion with insufficient tissue
oxygenation.Chronic critical limb ischemia (CLI) results from chronic poor perfusion of a limb. It is
variably defined but usually includes more than 2 weeks of rest pain and ulcers or tissue loss
secondary to arterial occlusive disease.Outcomes of this presentation are variable.One year after
diagnosis of CLI, 25% of patients die, 30% remain alive with amputations, 20% have ongoing
symptoms, and 25% have their symptoms resolved2.Approximately 10% of patients with
intermittent claudication are estimated to deteriorate to CLI within 5 years, and 20% to 30% of
patients with CLI require a major amputation2.

Chronic arterial occlusive disease warrants prompt treatment but is not an emergent state,
allowing for thorough imaging, patient risk stratification, and planning of revascularization.Patients
with chronic, potentially limb threatening, ischemia having ankle-brachial index of 0.4 or less,
an ankle systolic pressure of 50 mm Hg or less, or a toe systolic pressure of 30 mm Hg or
less are labeled as CLI as defined by the European Consensus Document.The clinical diagnosis
of CLI should be confirmed by haemodynamic parameters such as the ankle- or toe systolic
pressure. Diabetes is the most important risk factor for CLI. The primary goals of treatment in
patients with CLI are to relieve ischaemic pain, heal ulcers, prevent limb loss(amputation),
improve patient function and quality of life and prolong overall survival alongwith assessment and
treatment of cardiovascular risk factors and other co-morbid disease.Best possible or suitable
revascularization should be done whenever technically possible.

In patients with CLI not eligible for arterial revascularization, prostanoids are the only vasoactive
drugs with proven efficacy. The safety and efficacy of the various forms of therapeutic
angiogenesis still have to be proven before one can conclude on its role as an additional limb
saving strategy.
CLI belongs to stage 3 and 4 of Fontaine classification which means

 stage 3, rest pain caused by arterial disease;

 stage 4, ulceration and/or gangrene caused by arterial disease.

The corresponding categories in the Rutherford classification are

 category 4 for ischaemic rest pain,

 category 5 for minor tissue loss and
 category 6 for ulceration or gangrene
Patients with diabetes are more likely than other patients to have distal disease that is less
amenable to bypass grafting. Compared with amputation, revascularization is more cost-effective
and is associated with better perioperative morbidity and mortality. Limb preservation should be
3
the goal in most patients with critical limb ischemia . In clinical settings, bypass surgery (BS) has
been the gold standard for revascularization in CLI patients because the culprit lesions are
commonly occlusive and multilevel or multisegment. If not feasible due to concomitant disease
then endovascular treatment (EVT) should be given. Diabetic patients with coexisting neuropathy
may not experience rest pain despite critically diminished arterial flow, because of chronic
sensory loss. Simultaneous arterial duplex scanning can be performed in the vascular laboratory
to evaluate the location and extent of infra-inguinal stenosis or occlusion. Toe pressures of less
than 30 mm Hg are predictive of nonhealing of pedal ulceration in diabetic and nondiabetic
4
patients alike . More than 95% of chronic lower extremity arterial occlusive disease with limb
threat in western world is secondary to atherosclerotic stenosis or occlusions. Other potential
sources of chronic arterial occlusive disease are history of prior embolization, popliteal artery
aneurysm with chronic thrombosis or emboli, popliteal artery entrapment syndrome, popliteal
adventitial cystic disease, thromboangitis obliterans (Buerger disease), fibromuscular dysplasia,
aortic coarctation, Takayasu arteritis, endofibrosis of the external iliac artery.Patients with
diabetes and PAD have a ninefold higher amputation rate versus patients who are nondiabetic
with PAD5.

Acute Limb Ischemia

Diagnosis of Acute Limb Ischemia

The clinical hallmark of acute limb ischemia is the acute onset of extremity pain in conjunction
with absent pulses in the affected extremity.These patients lack collateral vessels around the
flush occlusion, making the affected limb completely devoid of any arterial flow. The physical
examination findings in this state are the presence of bounding “water hammer” pulses proximal
to the occlusion and absent pulses distal to the occlusion.The distal extremity will be cool to
touch, and after 3 to 4 hours may have neurologic abnormalities (sensory loss followed by motor
loss).

Revascularization within 6 hours is critical to avoid limb loss. In situ arterial thrombosis secondary
to worsening chronic occlusive disease may present in a more indolent fashion. These patients
experience acute primary vessel thrombosis due to either plaque rupture and secondary to
arterial thrombosis, or due to a critically low-velocity flow state resulting in intra-arterial
thrombosis.Emergent arterial imaging is indicated for any patient presenting with acute-onset limb
pain and absent pulses.Imaging options include duplex ultrasound, computed tomography
angiography (CTA), magnetic resonance angiography (MRA), and invasive diagnostic angiogram.

Duplex ultrasound is rapid, can be performed at the bedside, and has near 100% sensitivity for
diagnosing complete arterial occlusion. Ankle-brachial index (ABI) will be near zero for patients
with acute limb ischemia.Evaluating aorto-iliac inflow and tibial arterial outflow vessels may be
suboptimal with duplex alone.CTA has the benefit of rapid availability and high-quality imaging,
which allows for precise planning of revascularization.CTA provides imaging of the entire arterial
tree from the aortic inflow to the digital level.CTA typically requires 150 mL of iodinated contrast
and therefore has to be used with caution in patients with baseline renal insufficiency (glomerular
6
filtration rate <40) same as before invasive angiography .MRA has a limited role in acute limb
ischemia.Invasive angiography has the advantage of allowing for simultaneous percutaneous
revascularization with both mechanical thrombectomy and thrombolytic therapy.
Treatment of Acute Limb Ischemia
Once quality arterial imaging has been obtained, urgent revascularization is undertaken with goal
of having at least one tibial artery patent with angiographic confirmation of outflow to the foot.In
the upper extremity, outflow to the hand via the radial or ulnar artery (ideally both) with filling of
the palmar arch is the treatment goal.

If no contraindication to anticoagulation exists, the patient should be given an intravenous (IV)

heparin bolus of 100 U/kg followed by IV heparin infusion of 15 U/kg with a goal partial
thromboplastin time (PTT) of 60 to 80. If a continuous thrombolytic therapy drip is initiated, then
heparin dose should be reduced to prevent bleeding complications.

There are 2 primary treatment options for acute limb ischemia:

 Percutaneous thrombolytic therapy with adjunctive mechanical thrombectomy

 Surgical thrombectomy with as-needed adjunctive bypass or endarterectomy

The primary predictor of success for percutaneous revascularization of acute limb ischemia is
successful guidewire crossing through the thrombus burden.Thrombolysis is done with both tissue
plasminogen activator (TPA) bolus of 5 mg and mechanical pulse spray/suctioning with the
catheter7.
Fibrinogen level, PTT, international normalized ratio, and hemoglobin should be checked every 6
hours while the TPA drip is ongoing.Follow-up angiography to confirm successful lysis of the
thrombus is done.

For patients experiencing acute embolus to an otherwise normal arterial tree, surgical
embolectomy provides rapid revascularization and is an outstanding treatment option. Muscular
fascia should never be closed after surgical thrombectomy because of the risk for compartment
syndrome. Monitor post procedure for compartment syndrome and rhabdomyolysis. Any post
revascularization compartment pressure greater than 30 mm Hg warrants fasciotomy. Patients
with prolonged (greater than 6 hours) acute limb ischemia are at risk for acute renal tubular
necrosis due to recirculation of the necrotic muscle breakdown product myoglobin.Oliguria and
discolored (pink or red) urine should raise suspicion for rhabdomyolysis. Diagnosis can be
confirmed with urine myoglobin level. Treatment is IV hydration, diuresis with mannitol, and
alkalinization of urine with IV bicarbonate8.

Chronic Critical Limb Ischaemia

Pathophysiology
Under normal circumstances, healing of ulcers occurs unless wound repair mechanisms are
altered.Non-healing wounds occur as the result of arterial insufficiency, neuropathy,
musculoskeletal abnormalities, or a combination thereof 9. Decreased perfusion is most commonly
due to atherosclerotic occlusive disease of major arterial conduits. Blood supply needed to heal
an ulcer is greater than that needed to maintain an intact integument. CLI occurs when arterial
lesions impair blood flow to such an extent that the nutritive requirements of the tissues cannot be
met10. Ordinarily, the skin microcirculation provides it nutrition and exchanges heat during thermal
11
stress .In patients with CLI, compensatory mechanisms of skin perfusion are exhausted; the skin
fails to receive adequate nutrition3. Inadequate perfusion leads to a host of microcirculatory
defects including endothelial dysfunction, altered hemorrheology, inflammation, and loss of
sympathetic autoregulatory response to alteration in posture1.Rheologic disturbances are present
as well, including decreased erythrocyte fluidity, blood viscosity, and erythrocyte volume
12
fraction . The net effect of these derangements is rest pain, trophic changes, and impaired
wound healing.
Clinical Presentation
The development of chronic critical limb ischemia usually requires multiple sites of arterial
obstruction that severely reduce blood flow to the tissues.Critical tissue ischemia is manifested
clinically as rest pain, nonhealing wounds (because of the increased metabolic requirements of
wound healing) or tissue necrosis (gangrene).

Ischemic rest pain is classically described as a burning pain in the ball of the foot and toes that is
worse at night when the patient is in bed. The pain is exacerbated by the recumbent position
because of the loss of gravity-assisted flow to the foot. Ischemic rest pain is located in the foot,
where tissue is farthest from the heart and distal to the arterial occlusions13.Patients with ischemic
rest pain often need to dangle their legs over the side of the bed or sleep in a recliner to regain
gravity-augmented blood flow and relieve the pain. Patients who keep their legs in a dependent
position for comfort often present with considerable edema of the feet and ankles.

Nonhealing wounds are usually found in areas of foot trauma caused by improperly fitting shoes
or an injury. A wound is generally considered to be nonhealing if it fails to respond to a four- to 12-
week trial of conservative therapy such as regular dressing changes, avoidance of trauma,
treatment of infection and debridement of necrotic tissue.Gangrene is usually found on the toes. It
develops when the blood supply is so low that spontaneous necrosis occurs in the most poorly
perfused tissues.

Diagnosis
Typical physical findings include absent or diminished pedal pulses, shiny smooth skin of the feet
and legs, and muscle wasting of the calves. An objective measurement of blood flow is easily
accomplished with the use of a hand-held Doppler probe and a blood pressure cuff to measure
blood pressure over that vessel13. Another widely used parameter is the ankle-brachial index,
which is a ratio of the systolic pressure at the dorsalis pedis or posterior tibial artery divided by the
systolic pressure at the brachial artery. Patients with critical limb ischemia usually have an ankle-
brachial index of 0.4 or less14.Doppler is used to see pulse volume waveform at segmental
locations in the leg arteries. In patients with incompressible lower limb arteries, an ABI > 1.3
represents an independent predictor of major amputation15. Skin microcirculation may be
assessed using capillary microscopy, laser Doppler perfusion, or transcutaneous oxygen pressure
(TcPO2). Nailfold capillary microscopy of the great toe enables visualization of capillary
morphology, density, and erythrocyte velocity at rest and during reactive hyperemia. The use of
dyes such as sodium fluoroscein permits the study of microvascular dynamics, flow distribution,
and microvascular permeability11.Laser Doppler perfusion is used to provide information about
flow in capillaries, deeper vessels, and arteriovenular anastomoses that are involved in
thermoregulation16.TcPO2, a non-invasive measure of skin oxygenation, is reduced in the
presence of impaired blood flow . Cut-off values are
Poor--- capillary density < 20/mm2, absent reactive hyperemia in capillary
microscopy and laser Doppler, TcPO2 < 10 mmHg
Good---Capillary density >20/mm2,reactive hyperemia in capillary
microscopy and laser Doppler, TcPO2 > 30 mmHg)
Intermediate—Values between poor and good

Therapy for patients with critical limb Ischemia

In a large proportion of these patients, the anatomic extent and the distribution of arterial
occlusive disease make the patients unsuitable for operative or percutaneous
revascularization.Consensus Document of the European Working Group on Critical Limb
1
Ischemia, concluded that no pharmacological treatment has been shown to favorably affect the
natural history of critical limb ischemia.Indeed, amputation, despite its associated morbidity,
mortality, and functional implications, is often recommended as a solution to the disabling
symptoms, in particular excruciating ischemic rest pain of critical limb ischemia. A second major
amputation will be required in nearly 10% of such patients.

Symptom management
Risk factor modification, including smoking cessation, blood pressure control, good glycemic
control and reduction of lipid levels, should be instituted.

Opioids remain the cornerstone of the management of severe pain. Doses should be those
required to keep the patient comfortable without substantial side effects.Opioid with strong but
short-lived characteristics like Fentanyl and sufentanil have been used successfully sublingually
and buccally. Adjuvants like Gabapentin, ketamine, and lidocaine have shown some promise in
regard to working alongside opioids to relieve the pain induced by inflammation caused by the
ischemia.CLI might worsen depression, which itself can cause abnormal arterial vasoconstriction
and increased platelet aggregation, exacerbating ischemia and reducing the ability of a patient to
take part in activities that allow for functional improvement. Gabapentin counters this effect of CLI.
Chemical lumbar sympathectomy might be considered to relieve symptoms in those patients not
amenable to revascularization. Spinal cord stimulation, assessed by pain response and a
microcirculatory evaluation, has been suggested to be of potential help17but recent
recommendations suggest against it, based on insufficient evidence18.Most CLI patients have
concomitant cerebrovascular and coronary disease, which accounts for mortality rates of 13.4%
at 6 months, 19–25% at 12 months and > 60% at 5 years.These should be properly treated for
their co-existing diseases19.Another option for selected patients is surgical or chemical lumbar
sympathectomy, which improves skin blood flow in the leg andfoot 20and is associated with 1-year
limb salvage rates of 58–61%. .Prostaglandin Iloprost – an analogue of prostacyclin I2 that acts as
an arterial vasodilator, promotes angiogenesis, decreases inflammation, and inhibits platelets has
been studied for treating CLI and has given mixed results about its efficacy. Therefore
prostaglandins cannot be recommended as therapy for patients with CLI.

Therapeutic angiogenesis

Preclinical studies have indicated that angiogenic growth factors can stimulate the development of
collateral arteries, a concept called “therapeutic angiogenesis. Gene transfer is performed in limbs
of patients with nonhealing ischemic ulcers and/or rest pain . A total dose of 4000 mg of naked
plasmid DNA encoding the 165-amino-acid isoform of human vascular endothelial growth factor
(phVEGF165) is injected directly into the muscles of the ischemic limb. Gene expression is
documented by a transient increase in serum levels of VEGF monitored by ELISA. The ankle-
brachial index improves ; newly visible collateral blood vessels can be directly documented by
contrast angiography ; and magnetic resonance angiographic demonstration of qualitative
evidence of improved distal flow in limbs. Ischemic ulcers heal or markedly improve with
successful limb salvage in patients recommended for below-knee amputation. Tissue specimens
obtained from an amputee 10 weeks after gene therapy show foci of proliferating endothelial cells
by immunohistochemistry. PCR and Southern blot analyses indicate persistence of small amounts
of plasmid DNA. A total amount of 8000 mg pDNA (4000 mg per limb) can be used or given and
Serum VEGF Levels are estimated by ELISA as baseline and weekly up to 12 weeks after the
initial treatment . Complications are transient lower-extremity edema in 60% patients, consistent
with VEGF enhancement of vascular permeability and can be taken as indirect clinical evidence
21
of VEGF overexpression .Therapeutic angiogenesis using stem cells, autologous progenitor
cells,growth factors such as basic fibroblast growth factor (bFGF), and transcription factors such
as hypoxia-inducible factor-1 alpha that induce synthesis of angiogenic cytokines have been
utilized in CLI patients who lack options for endovascular or surgical revascularization.
Operative Intervention

Once the diagnosis of critical limb ischemia is made, patients who are likely to benefit from
revascularization should undergo quality arterial imaging from the abdominal aorta level to the
foot of the affected extremity. Options include invasive diagnostic angiography with the potential
for simultaneous endovascular intervention, CTA, MRA, and arterial duplex scanning. CTA and
MRA provide adequate imaging on which inflow and femoral-popliteal artery revascularization can
be planned. Tibial artery imaging with CTA and MRA is institutionally variable and can be difficult
in CTA because of dense arterial calcification.It is widely accepted to do a preoperative
subtraction angiogram achieved through a catheter inserted as distally as possible within the
affected arterial tree before performing any tibial-level revascularization.

General guiding principles of revascularization are as follows:

1. Endovascular therapy: stenosis at all arterial levels; short-segment occlusions in the iliac
or superficial femoral artery (SFA) distribution
2. Surgical bypass: long-segment arterial occlusions
3. Surgical endarterectomy: occlusion or high-grade stenosis at the common femoral artery
bifurcation level to preserve flow to both the SFA and profunda femoral artery

Endovascular therapy

The following is a simplified summary of endovascular revascularization steps:

1. Obtain arterial access and perform angiography

2. Pass a guidewire beyond areas of stenosis or occlusion
3. Confirm that the guidewire is in the true lumen of the distal arterial tree
4. Perform angioplasty, stent placement, or atherectomy over the guidewire
5. Confirm success of results with completion angiography

Primary indications for stent placement are

 residual stenosis after angioplasty

 presence of dissection after angioplasty

Iliac percutaneous revascularization has primary and secondary patency rates of 67% and 80% at
5 years22.Tibial-level angioplasty is also feasible, but has significantly poorer patency than iliac
and SFA percutaneous interventions. Tibial angioplasty primary patency rates are less than 50%
at 1 year23. Access site complications represent the most frequent morbidity of endovascular
procedures with bleeding, pseudoaneurysm, or arterial dissection and thrombosis inducing a
complication that requires open surgical intervention after 1% to 2% of procedures24.

Open surgical therapy

Surgical bypass is performed for long-segment occlusive disease in acceptable risk patients with
critical limb ischemia. All bypasses should be based on angiographic and hemodynamically
confirmed normal inflow arteries. In the setting of tissue loss, the outflow target should provide in-
line distal flow to the affected foot. The shortest-length bypass that provides in-line flow to the foot
should be performed. Aorto-iliac reconstructions are generally performed with prosthetic Dacron
or polytetrafluoroethylene (PTFE) conduit. Open aorto-iliac reconstruction is preferred for
acceptable surgical risk patients with bilateral occlusive disease. Primary patency for direct aorto-
iliac reconstructions is excellent and approaches 90% in most series25.Patients with high
abdominal operative risk critical limb ischemia with advanced aorto-iliac occlusive disease that is
not amenable to endovascular therapy can be treated with extra-anatomic bypass. Axillary
bifemoral artery bypass can be performed with heavy sedation and local anesthesia and has 3-
year patency rates in the 70% to 80% range.For unilateral iliac occlusion with patent contralateral
iliac artery system, fem-fem bypass is an option.For infrainguinal long-segment arterial
occlusions, surgical bypass with autogenous venous conduit provides the most durable
revascularization. A venous conduit of 3 mm or greater should be sought. Ipsilateral greater
saphenous vein is the first preference. Other options include contralateral greater saphenous vein
and upper extremity cephalic and basilic veins.If no autogenous vein is available, then 6-mm-
diameter PTFE or Dacron conduit is used for infrainguinal bypass. For bypasses to distal tibial
arteries where wound breakdown is particularly common, cryopreserved cadaveric saphenous
vein or composite sequential (proximal prosthetic and distal autogenous) conduit are useful to
reduce the incidence of exposed prosthetic bypass. Thromboendarterectomy with patch
angioplasty remains the gold standard treatment for common femoral artery occlusive disease26.

Hybrid surgical therapy

Combinations of endovascular and open surgical therapies are frequently applicable to patients
with critical limb ischemia with short-segment lesions in one anatomic distribution and more
advanced lesions in another segment. Similarly, outflow vessel angioplasty is an option when a
short focal stenosis exists and the total bypass length can be significantly shortened by treating a
distal lesion with endovascular therapy27.

Postrevascularization surveillance

Regardless of the type of revascularization performed, patients with critical limb ischemia should
be followed with serial arterial duplex and ABI with digital pressures. Angioplasty and stenting
sites are prone to re-stenosis. Lower extremity bypasses are vulnerable to neo-intimal
hyperplasia-induced stenosis anywhere along the length of a vein bypass and near the
anastomosis sites of prosthetic bypasses28.After revascularization, arterial duplex scanning is
done at 1, 3, 6, and 12 months after the procedure and every 6 months thereafter.
Nonreconstructable tibial occlusive disease and critical limb ischemia

Patients with nonreconstructable tibial distribution occlusive disease (no bypass targets) benefit
from intermittent pneumatic compression treatment at the calf level 29.This can be used as a last
measure for attempt at limb salvage before major amputation.

Primary amputation

Selecting patients who should undergo primary limb amputation rather than revascularization
remains daunting. Frequently, intense efforts are made to salvage the ischemic limb using
surgery or endovascular techniques prior to concluding that major amputation is required. 32% of
patients who undergo infrainguinal angioplasty subsequently progressed to major amputation.In
BASIL study, 16% of patients in both the surgery-first and angioplasty first group underwent
repeated procedures only to eventually die or lose their leg (or both) within the first 12 months28.
Amputation is indicated after failed attempts at revascularization, if the patient is unfit or unable to
undergo revascularization, in the presence of extensive tissue loss or infection, and in patients
who do not ambulate. Efforts are made to preserve the knee joint, as the lower energy
expenditure required for ambulation after below-knee amputation (BKA) makes it easier to walk
independently.

REFERENCES

1. European Working Group on Critical Leg Ischemia. Second European consensus document on chronic
critical leg ischemia. Circulation. 1991; 84(suppl IV):IV-1–IV-26.
2. Slovut DP, Sullivan TM. Critical limb ischemia: medical and surgical management.Vasc Med 2008;13(3):281-
91
3. Chronic Critical Limb Ischemia: Diagnosis, Treatment and PrognosisJamie.D,Santilli and Steven
M,Santilli.,Am Fam Physician. 1999 Apr 1;59(7):1899-1908
4. Rastan A, Brechtel K, Krankenberg H, Zahorsky R, Tepe G, Noory E, Schwarzwälder U, Macharzina R,
Schwarz T, Bürgelin K, Sixt S, Tübler T, Neumann FJ, Zeller T. Sirolimus-eluting stents for treatment of
infrapopliteal arteries reduce clinical event rate compared to bare-metal stents: Longterm results from a
randomized trial. J Am Coll Cardiol. 2012;60:587–591
5. Norgren L, Hiatt WR, Dormandy JA, et al, TASC II Working Group.Inter-society consensus for the
management of peripheral arterial disease. J Vasc Surg 2007; 45(Suppl S):22.
6. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium
bicarbonate: a randomized controlled trial. JAMA 2004;291:2328.
7. Sumi M,Ohki T. Rutherford’s vascular surgery. Chapter 85, Philadelphia: Elsevier; 2010
8. Eneas JF, Schoenfield BY, Humphreys MH. The effect of infusion of mannitolsodium bicarbonate on the
clinical course of myoglobinuria. Arch Intern Med 1979;139:801.
9. Sumpio, BE. Foot ulcers. N Engl J Med 2000; 343: 787– 793
10. Norgren, L, Hiatt, WR, Dormandy, JA, Nehler, MR, Harris, KA, Fowkes, FG. Inter-Society Consensus for the
Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45 (Suppl S): S5–S67
11. Rossi, M, Carpi, A. Skin microcirculation in peripheral arterial obliterative disease. Biomed Pharmacother
2004;58: 427–431
12. Holmberg, A, Sandhagen, B, Bergqvist, D. Hemorheologic variables in critical limb ischemia before and after
infrainguinal reconstruction. J Vasc Surg 2000; 31: 691–695
13. Santilli JD, Rodnick JE, Santilli SM. Claudication: diagnosis and treatment. Am Fam Physician.
1996;53:1245–53
14. Cutajar CL, Marston A, Newcombe JF. Value of cuff occlusion pressures in assessment of peripheral
vascular disease. Br Med J. 1973;2(863):392–5
15. Silvestro, A, Diehm, N, Savolainen, H, et al. Falsely high ankle–brachial index predicts major amputation in
critical limb ischemia. Vasc Med 2006; 11: 69–74
16. Ubbink, DT, Spincemaille, GH, Prins, MH, Reneman, RS, Jacobs, MJ. Microcirculatory investigations to
determine the effect of spinal cord stimulation for critical leg ischemia: the Dutch multicenter randomized
controlled trial. J Vasc Surg 1999; 30: 236–244
17. Pedrini L, Magnoni F. Spinal cord stimulation for lower limb ischemic pain treatment. Interact Cardiovasc
Thorac Surg 2007;6(4):495-500
18. Setacci C, de Donato G, Teraa M, Moll FL, Ricco JB, Becker F, et al. Chapter IV: treatment of critical limb
ischaemia. Eur J Vasc Endovasc Surg 2011;42(Suppl 2):S43-59
19. Dorros, G, Jaff, MR, Dorros, AM, Mathiak, LM, He, T.Tibioperoneal (outflow lesion) angioplasty can be used
as primary treatment in 235 patients with critical limb ischemia: five-year follow-up. Circulation 2001; 104:
2057–2062
20. Lantsberg, L, Goldman, M. Lower limb sympathectomy assessed by laser Doppler blood flow and
transcutaneous oxygen measurements. J Med Eng Technol 1990; 14: 182– 183
21. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267:10931–10934
22. Schurmann K, Mahnken A, Meyer J, et al. Long-term results 10 years after iliac arterial stent placement.
Radiology 2002;224:731–8
23. Ferraresi R, Centola M, Ferlini M, et al. Long-term outcomes after angioplasty of isolated, below-the-knee
arteries in diabetic patients with critical limb ischaemia. Eur J Vasc Endovasc Surg 2009;37(3):336–42
24. Met R, Van Lienden KP, Koelemay MJ, et al. Subintimal angioplasty for peripheral arterial occlusive disease:
a systematicreview. Cardiovasc Intervent Radiol 2008;31(4):687–97
25. Dimick JB, Cowan JA, Henke PK, et al. Hospital volume-related difference in aorto-bifemoral bypass
operative mortality in the United States. J Vasc Surg 2003;37:970-6
26. Norgren L, Hiatt WR, Dormandy JA, et al, TASC II Working Group. Inter-Society Consensus for the
Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45:S9A
27. Baril DT, Chaer RA, Rhee RY, et al. Endovascular interventions for TASC II D femoropopliteal lesions. J Vasc
Surg 2010;51(6):1406–12
28. Mills JL. Mechanisms of vein graft failure: the location, distribution, and characteristics of lesions that
predispose to graft failure. Semin Vasc Surg 1993;6: 78–91, 277
29. Kavros SJ, Delis KT, Turner NS, et al. Improving limb salvage in critical ischemia with intermittent pneumatic
compression: a controlled study with 18-month follow-up. J Vasc Surg 2008;47:543–9
 Compartment Syndrome
Sushanto Neogi

Compartment Syndrome is a condition where pressure inside enclosed spaces increases to an

excessive level so as to compromise the vascularity of the tissues inside that compartment.
Mubarak defined it as an elevation of interstitial pressure in a closed osseofascial compartment
that results in microvascular compromise. This usually occurs after accumulation of blood or
inflammatory fluid inside the compartment. Since it is a closed space and does not communicate
with other spaces, the fluid has no way to egress out and progressively accumulates.

Causes
Usually seen after road traffic accidents with crush injuries, long bone fractures, and surgery of
the compartment leading to bleeding inside the space, extrinsic compression like an excessively
tight plaster cast or massive inflammatory edema of a compartment. Sometimes chronic
compartment syndrome occurs in case of people undergoing repetitive actions e,g, runners. Here
1
the compartment pressure increases only during activity.

Types

1. Acute
2. Chronic

Acute compartment syndrome

Clinical signs and symptoms

1. Pain- this is usually an early sign and severe, constant and out of proportion to the level of
physical findings. The pain becomes excruciating on minor movements of the limb.
2. Numbness, parasthesias and tingling are the early features of compartment syndrome. The
patient has a feeling of “pins and needle sensation” of the affected limb
3. Paralysis and pulselessness should not be allowed to set in as these signs indicate that
irreversible changes have occurred in the limb.
4. Examination shows a pale, tense edematous limb. The digits show a prolonged capillary filling
time.
5. Since in a lot of patients the cause is a tight plaster cast or a tight bandage, the whole of the
limb affected by the condition may not be visible for examination at the time of diagnosis.
6. Absence of pulse may not be apparent for a long period as the symptoms of compartment
pressure usually manifest quite early before the pressure can rise to occlude the arterial
pulse. So reliance on absence of pulse to diagnose compartment syndrome can be quite
1
disastrous for the limb.

Pathophysiology

The accumulation of blood or necrotic debris inside the compartment e.g. in fractures result in the
increased compartment pressure as these spaces are restricted by tight fascial coverings. This
leads to decease in the capillary filling pressures.2 This results in acute compartment syndrome
and further leads to increase in the pressure inside the compartment. This compromises the
venous and the lymphatic return of the affected compartment. This is further aggravated by the
interstitial edema. This leads to compromised arteriolar supply the compartment causing tissue
hypoxia. If this condition keeps on persisting, there is muscular and neural ischemia. This leads to
irreversible tissue damage and tissue death. If acute compartment syndrome is extensive and
2
severe and is not treated early, it can lead to rhabdomyolysis and renal failure and even death.
Diagnosis

The first and foremost thing to recognize is that acute compartment syndrome is clinical. This
should be based on the nature of injury or surgery and the circumstances preceding the onset of
symptoms. Examination should be done thoroughly to confirm the diagnosis.

According to Blackman, one of the tools to diagnose compartment syndrome is X-ray to show a
tibia/fibula fracture and combined with numbness of the extremities is good enough to confirm the
presence of compartment syndrome.3

Confirmation is not always required, but can be done using pressure measurements of the
compartment. It is stated that a pressure of 30mmHg or more is indicated for fasciotomy or if
there is a difference of 30mmHg between intracompartmental pressure and diastolic blood
3
pressure.

Various transducers are available for measurement of the pressure of the compartment. Few
examples are mentioned below. They can be used in early cases, where diagnostic difficulties are
arising.

Transducers
1. Arterial line transducer system (see the image below) -
This system, used with a simple or side-port needle,
provides a high degree of accuracy for simple
episodic readings;
2. The commercially available Stryker system (see image
below) provides consistent accurate readings for
episodic and extended monitoring situations;
3. The mercury manometer system is the least accurate
measurement system, is no longer available.
4. Whitesides et al devised a device using a three way
stop cock, tubing, syringe and mercury manometer4 Arterial line transducer
5. Wick’s catheter.
6. An ultrasonic device has been devised that uses a
pulsed phased locked loop to measure
submicrometer displacement of the fascia wall
caused by volume expansion of the muscle
compartment, which is related to changes in
intramuscular pressure. This has not been yet been
proven for human use, but has potential for Stryker Intra- Compartmental
noninvasive detection of compartment pressure.
5 Pressure Monitor System

Boody and Wongworawat compared three commonly used devices and found Whiteside’s device
the least accurate but give reasonable results in absence of availability of rest of the sophisticated
devices. The stryker model is the most expensive but most accurate.5

Treatment

First and foremost split the cast or remove tight bandages. This causes 50 to 85% reduction in
pressure. The limb is not elevated but positions at the level of the heart, as elevation does not
improve the venous outflow so much but compromises arterial inflow. If this does not improve
circulation in the next 30 to 60 minutes, the next step is to take up the patient for fasciotomy.

Acute compartment syndrome requires urgent surgical management and fasciotomy is the
treatment of choice to reduce the compartment pressure. Incisions are defined which release all
the compartments. Even if one compartment is suspected to have raised pressures, all the
1
compartments should be opened up.

Technique of whitesides et al for determination of tissue pressure. A. tissue pressure

is measured by determining amount of pressure within closed system required to
overcome pressure within closed compartment while injecting minute amounts of
saline.4 B. use of wick catheter for monitoring compartment pressures.

Figure. Algorithm for decision making in suspected and proven compartment syndrome.

Fasciotomy incisions1

Leg fasciotomy- Anterior and lateral compartments can be approached by a longitudinal incision
halfway between tibial crest and fibula which divides the anterior intermuscular septum, allowing
access to lateral and anterior compartments. For acute cases it should be liberal and around 15
cm long but for chronic syndrome it can be around 4cm long. Care is taken to preserve the
superficial peroneal nerve near the septum.

Deep and superficial compartments are approached through a 15 cm long incision 2cm posterior
to the palpable medial edge of tibia. The saphenous vein and nerve is retracted and the
superficial posterior compartment is entered. For the deep compartment, the soleus is retracted
and the the fascia covering the posterior digitorum longus is to be incised to release the posterior
compartment. The neurovascular bundle is lying between the soleus and tibialis posterior and is
to be protected.1

The skin is usually left open to allow it to granulate and heal by secondary intention.

Thigh fasciotomy- a lateral incision starting from just distal to intertrochanteric line to the lateral
epicondyle which goes to the iliotibial band and incising this releases the anterior and posterior
compartment. The medial compartment pressure can then be measured and further incision can
be given to release it.1

The patient is again taken up for debridement at 48 to 72 hours. If there is no muscle necrosis,
the wound can be loosely sutured. Otherwise repeated debridements at interval of 48 to 72 hours
and skin closure or grafting should be done at the earliest.

Chronic compartment syndrome

Chronic exertional compartment syndrome (CECS) is recurrence of increased pressure most

often in the anterior or deep posterior compartment, commonly in long distance runners or
6
forearm compartment of weightlifters.

Clinical features
Accurate history cannot be overemphasized. This is usually a competitive runner who complains
of pain and tightness of the limb after 20 to 30 minutes of sustained exercise, this resolves within
15 to 29 minutes of stopping exercise. Parasthesias of the nerves of the compartment is also
7
reported. In 82% patients it is bilateral (Detmer et al ) Fascial hernias have been commonly
reported to have a definite association.

Differential diagnosis ar many and quite varied:

1. Periostitis
2. Superficial Pernoneal nerve entrapment
3. Tendinitis of posterior tibial tendon
4. Stress fracture of tibia
5. Intermittent claudication by anomalous insertion of the medial head of gastrocnemius causing
6,7
Popliteal artery compression.

Pathophysiology

Experimental studies have suggested that significant muscle necrosis can occur in patients with
normal blood flow if the intra compartment pressure is increased to more than 30mm Hg for
greater than 8 hours.

Pedowitz et al have reported good baseline pressure measurements on whose basis diagnosis of
chronic compartment syndrome can be made. One or more of the criteria if present, it is said to
be because of Chronic compartment syndrome.8

1. Pre exercise , resting pressure of 15mm Hg or more

2. Pressure of 30mmHg or more at I minute of exercise
3. Pressure of 20mmHg or more at 30 minutes of exercise

Treatment
This is mainly operative. In patients who are willing to stop their exercise activity can be given
anti inflammatory agents. But most of the patients do not want to stop their exercise; therefore
compartment release is the treatment of choice in most patients.9

Abdominal compartment syndrome

Abdominal compartment syndrome (ACS) is caused usually after abdominal surgeries and after
severe trauma.

Definition- the normal adult intra-abdominal pressure is 5 to 7mmHg. Intra- abdominal

hypertension has been defined by the World Society of the Abdominal Compartment Syndrome
as sustained increased IAP (Intra abdominal pressure) greater than or equal to 12mmHg and
ACS as IAP greater than or equal to 20mmHg with new organ dysfunction or failure. IAP in
excess of 25mmHg (this level is associated with significant organ dysfunction), is the cut off for
need for abdominal decompression.10,11

The causes include

1. Abdominal trauma especially where shock has resulted.
2. Abdominal surgery like liver transplant
3. Massive Burns
4. Sepsis
5. Massive ascites or massive abdominal bleed
6. Vigorous overtraining utilizing eccentric abdominal exercises
7. Pancreatitis
8. Elective or emergent aortic surgery
Pathophysiology
Similar to limb compartment syndromes, the abdominal compartment pressure increases and
venous drainage and subsequently the arterial supply to the intra-abdominal organs are affected.
This leads to further rise in the abdominal pressure and the vicious cycle can cause intra-
abdominal gangrene if not stopped early.

Cardiovascular derangements start occurring at the earliest. These include decrease3d venous
return as early as IAP of 20mmHg. The increased thoracic pressure also leads to cardiac
compression with decreased ventricular end-diastolic volumes.10,11

Renal derangements- oliguria is seen at IAP of 15-20mmHg but leads to anuria at pressures of
30mmHg. The hypothesis of renal derangements with IAH is said to be reduction in absolute and
proportional renal arterial flow, increased renal vascular resistance with changes in intra-renal
regional blood flow, reduced glomerular filtration, and increased tubular sodium and water
11
retention.

Clinical signs and symptoms

The patient profile is that of a severely ill patient and a postoperative patient, who starts
complaining of severe abdominal pain out of proportion to his surgery or the trauma suffered.
Because of the profile of the patient, this may be attributed to the surgery or trauma and ignored
till it is too late.
Examination shows tachycardia, tenderness and rebound tenderness in the abdomen. The
abdomen is tense and distended. There is decreased oliguria or anuria and hypotension. The
patient might show fever and other signs of septicemia.11

Diagnosis
The diagnosis can be self evident sometimes, but sometimes
the condition is diagnosed based on high clinical suspicion. For
confirmation of the diagnosis, sometimes direct pressure
measurement of the intra- abdominal compartment may be
required. This can be done by inserting a pressure monitor
through a bladder catheter.12,13

For measurement, the stop cock is placed at the level of mid

axillary line at the level of iliac crest and the transducer is
zeroed. The bladder is filled at 1ml /Kg to a maximum of 25ml
of normal saline. The stop cock of the syringe is blocked and
Bladder intra-abdominal
the pressure measurement is done after the equilibration has
monitoring system
occurred. Mean can be taken for inspiration and expiration.
This may be repeated to see the effect of treatment and discontinued if the pressure remains less
12,13
than 12mmHg for several hours.

Gastric pressures- IAP can be measured with a transducer in the stomach with a nasogastric
tube. But animal studies have not been able to correlate with human results. 13

Treatment

Treatment of abdominal compartment syndrome is first to start supportive measures like oxygen,
intravenous fluids, analgesics. For specific treatment, patient might require mechanical ventilation,
vasopressors and dialysis for renal shut down. Surgery for abdominal compartment may be
required but the timing is still controversial.
REFERENCES
th
1. Canale ST , Beaty JH.,Cambells Operative Orthopedics.12 ed. ch; St. Louis: Mosby;2012
2. Konstantakos EK, Dalstrom DJ, Nelles ME, Laughlin RT, Prayson MJ . "Diagnosis and management of
extremity compartment syndromes: an orthopaedic perspective". Am Surg.2007; 73:1199–
209. PMID 18186372
3. Bourne RB, Rorabeck Ch. Compartment syndromes of the lower leg. Clin Ortop Relat Res. 1989;240:97
4. Whitesides TE jr, Haney TC, Morimoto K, et al. tissue pressure measurements as a determinant for need for
fasciotomy. Clin orthop relat Res. 113;43:1975.
5. Boody Ar, Wongworawat MD. Accuracy in the measurement of compartment pressures: a comparison of
three commonly used devices. J Bone Joint Surg. 2005;87:2415.
6. Blackman PG. A review of chronic exertional compartment syndrome in the lower leg. Med Sci Sports
Exerc. 2000;32 :4–10.
7. Detmer DE, Sharp K,Sufit RL, et al. Chronic compartment syndrome: diagnosis, management and outcomes.
Am J Sports Med. 1985;13:162.
8. Pedowitz RA, Hargens AR, Mubarak SJ, et al. Modified criteria for the objective diagnosis of chronic
compartment syndrome of the leg. Am J Sports Med. 1990;18:35.
9. Wood ML, Almekinders LC. Minimaly inavasive subcutaneous fasciotomy for chronic compartment
syndrome of the lower extremity. Am J Orthop.2004;33:42
10. Maibrain ML, Ameloot K., Gillebert C, et al. Cardiopulmonary monitoring in intra- abdominal hypertension.
Am Surg 2011;77:23-30.
11. Ameloot K., Gillebert C, Desie, et al. Hypoperfusion, shock states and abdominal compartment syndrome
(ACS). Surg Clin North Am2012;92:207-20.
12. Cullen D J, Coyle J P, Teplich R. et al. Cardiovascular, pulmonary, and renal effects of massively increased
intra-abdominal pressure in critically ill patients. Crit Care Med.;113:431989;17:118–121.
13. Sugrue M, Buist M D, Lee A. et al. Intra-abdominal pressure measurement using a modified nasogastric tube:
description and validation of a new technique. Int Care Med. 1994;20:588–590.

Atherosclerotic Vascular Disease

N.S.Hadke, Ankit Jain

Commonest cause of chronic arterial obstruction of lower extremity in India before 1990 was
Buerger’s disease. Gradually these patients are seen less commonly and during last 10 years
Atherosclerotic arterial appear to be more commonly seen and very few patients with Buerger’s
disease are seen at least in bigger cities. This may be due to

 More patients are manages in peripheral Hospital

 Incidence of Buerger’s disease is decreasing
 Incidence of Atherosclerosis is increasing

Last two causes may be due to improved socioeconomic level and diet of the larger population.
Moreover average age of Indians also is increasing.

Emphasis of evaluation of patient with chronic arterial disease of lower extremity was always to
differentiate Buerger’s disease from Atherosclerosis. This was mainly due to management
strategies for these two diseases are different.

Atherosclerosis is a degenerative disorder. The Basic pathology of atherosclerosis is intimal

damage of arteries followed by deposition and formation of atheroma
leading to arteriolar occlusion. The main cause of intimal damage is
turbulence of the blood flow. Turbulence is caused when the blood is
flowing under pressure from large diameter arteries to small diameter
arteries. When the blood flows from the large diameter to small
diameter artery under pressure it enters as a jet and the jet is pointed
on the wall of artery just distal to opening. Maximum intimal damage
and atheroma formation occurs just distal to origin of artery from aorta.
Whenever atherosclerotic occlusion occurs, it usually involves single
continuous segment and distal arterial tree is usually normal. (Diagram
A) Since the distal tree is normal removal/ bypass of block in these
patients leads to marked improvement in circulation

Force of the blood also depends on proximity to pump (Heart). That is why the main brunt of
turbulence is borne by most proximal vessels of the aorta (coronaries) which are usually involved.

On the contrary Buerger’s disease is an inflammatory disease caused by some constituent in

tobacco. This inflammatory response is systemic which involves all the arteries. The name
Thromboangitis obliterans indicates that this leads to narrowing of arteries. The smallest are
blocked initially and if the insult continues again and again more proximal arteries are involved
progressively. This leads to multiple segment involvement. (Diagram B) In this case when
medium size vessel is involved it implies that distal arterial tree is already diseased and removal
of this block may not improve the circulation

Pathogenesis

‘Response to injury hypothesis’3 considers atherosclerosis to be a chronic inflammatory process

of arterial wall initiated by injury to endothelium which is enhanced by interaction of lipoproteins,
immune cell and normal cellular elements of arterial wall.

1. Endothelial Injury: chronic or repetitive endothelial injury is major initiating factor. Endothelial
injury induced by various mechanisms in experiment models produces atheroma in
presence of high lipid levels. In humans, however, atherosclerosis typically starts at non
denuded endothelium therefore endothelial injury is not mechanical but functional. This is
due to turbulent flow seen in normal circulation at sites such as ostia of vessels arising from
aorta, branching point and posterior wall of aorta. Thus these are common sites of
atherosclerotic plaques3,4. Normal laminar flow in vessels protect against atherosclerosis
by:
 It blocks inflammatory mechanisms that mediate endothelial dysfunction
 It induces anti atherosclerotic genes such superoxide dismutase.

2. Role of inflammation: Inflammatory mechanism plays an important role. Endothelial

dysfunction leads to production of various adhesion molecules which lead to adhesion of
monocytes and T lymphocyte. After monocyte bind to endothelium, they migrate into intima
and transform into macrophage and later foam cells and engulf lipoproteins. These
macrophage produce Il-1, TNF and other chemokines which increase adhesion of
leukocytes. These leukocytes produce oxygen radicals which causes oxidation of LDL and
production of growth factors which promote smooth muscle cell (SMC) proliferation.

3. Role of lipids: dyslipidemia due to various reasons promote atherosclerosis by:

 Hyperlipidemia increases production of oxygen radicals which directly impair
endothelial cell function by inhibiting NO.
 In presence of hyperlipidemia, lipids accumulate in intima.
 Oxidized LDL increases monocytes and leukocytes adhesions in cells and convert them
to foam cells and is also toxic to endothelial cells and SMC.

4. Role of SMC: increased production of growth factors lead to proliferation of smooth muscle
cells and their migration to intima. This converts fatty streak to fibro fatty atheroma.

Earliest lesion in atherosclerosis is fatty streak which is characterized by lipid laden foam cells.
These appear in aorta of children <1yr or all children < 10 yrs. These fatty streaks form at sites of
atheromatous plaques as well as sites which don’t develop plaques. These streaks develop in
people with risk factors and without predisposing factors. Thus these streaks are precursor of
plaques but not all streaks form plaques. The American Heart Association divides atherosclerotic
lesions in 6 types:

Type I (initial) Lesion Isolated macrophage foam cells

Type II (fatty streak) Lesion Mainly intracellular lipid accumulation

Type III (intermediate) Lesion Type II + extracellular lipid pools

Type IV (atheroma) Lesion Type II + extracellular lipid cores

Type V (fibroatheroma) Lesion Lipid core with fibrosis, calcification or both

Type VI (complicated) Lesion

Type VI (complicated) Lesion involves:

 Focal rupture or ulceration of plaques exposes thrombogenic material of plaques which

can embolize in distal small vessels or superimposed thrombus formation with resultant
obstruction of vessels.
 Haemorrhage in plaques can take place due to rupture of fibrin cap or internal capillaries.
This produces a contained hematoma or plaque rupture.
 Aneurysm dilation can occur due to weakening of underlying media by atherosclerosis.

Risk factors3:
Non modifiable

Increasing Age Obesity

Male gender Physical inactivity

Family History Stress(type A personality)

Genetic Abnormalities Postmenopausal estrogens deficiency

Potentially controllable

Hyperlipidemia Alcohol

Hypertension Lipoprotein A

Diabetes Trans saturated fat intake

Smoking

1. Age: it is a prominent factor. Although at tissue level, changes of atherosclerosis starts as

rd th
early as 1st decade, it becomes evident generally by 3 -4 decade and morbidity due to
atherosclerosis increases with increasing age.
2. Sex: Men are more prone to atherosclerosis due to protective effect of estrogens in women.
In post menopausal women, risk of atherosclerosis increases and equalizes by 7th decade of
life.
3. Genetics: family predisposition to atherosclerosis is polygenic and most probably it is due to
clustering of other factors like diabetes, hypertension etc in family. Less commonly there is
hereditary derangement of lipoprotein metabolism with resultant high lipids levels.
4. Hyperlipidemia: It is a major risk factor especially hypercholesterolemia. Increased cholesterol
levels are enough to stimulate lesion development even if other factors are absent. High
levels of LDL cholesterol is a major risk factor because it is the predominant vehicle of
cholesterol supply to tissues whereas HDL cholesterols is good because it removes
cholesterol from peripheral tissues and delivers it to liver. Exercise and small amount of daily
alcohol increases HDL levels. High intake of cholesterol, saturated or trans-saturated fats
raises LDL cholesterol levels.
5. Hypertension: it is a major risk factor at all ages. Increase in BP is associated with turbulent
flow and thus endothelial dysfunction and atherosclerosis.
6. Smoking: it is an important factor which predisposes to atherosclerosis. Nicotine present in
cigarette decreases HDL levels, increase platelet aggregation and promote vasoconstriction
by altering prostaglandin balance5. Recent increase in incidence of atherosclerosis in women
is attributed to rising incidence of smoking in women.
7. Diabetes Mellitus: diabetes is associated with arterial wall degeneration due to alteration in
nitric oxide availability and stimulation of pro-atherogenic activity in vascular smooth cells.
Diabetes also enhances platelet aggregation, increase blood viscosity and increased
fibrinogen levels. Thus diabetes is associated with marked predisposition to atherosclerosis.
Diabetes itself is associated with more incidence of peripheral arterial disease.
8. Lipoprotein Lp(a): it is an altered form of LDL that contains apolipoprotein B-100 portion of
LDL linked to apolipoprotein A. correlation has been seen in increased levels of Lp(a) and
atherosclerosis.
9. Homocystinuria: it is a rare metabolism disorder with elevated homocystine levels. These
patients are predisposed to premature vascular disease. Elevated levels of these amino acids
are toxic to endothelial cells and stimulate smooth muscle cell proliferation. In a patient of
PAD, absence of common factors, sudden onset in young age and rapid progression point to
risk factors like homocysteinemia5.

Multiple risk factors have a multiplicative effect3, 5. 2 risk factors increase risk by four fold and
three risk factors increase by 7 fold. Atherosclerosis is more of by product of aging and people
with no apparent risk factors or genetic predisposition are still predisposed to atherosclerosis.

Chronic limb Ischemia

Patients with asymptomatic Peripheral Arterial Disease diagnosed by Ankle Brachial index <0.9,
may progress to claudication or may not but overall they have higher morbidity and mortality risks
due to systemic effects such as MI or stroke6. Thus these should be managed in same manner as
symptomatic patients. Patients with Chronic Limb Ischemia (CLI) may present with:

a) Claudication is derived from Latin word claudicatio which means to limp or be lame.
Claudication rarely progress to point of amputation.
b) Critical Limb ischemia: it is characterized by rest pain, ischemic ulcers or gangrene. It is
associated with high risk of limb loss in absence of revascularization.

Based on disease location, occlusive arterial disease of lower limb may be classified in 2 groups6:

a) Inflow disease: this is characterized by involvement of supra inguinal vessels mainly infra
renal aorta and iliac arteries. These patients presents with calf and thigh claudication if
external iliac artery is involved. Calf, thigh and buttock claudication if common iliac artery
involved. If involvement of common iliac artery is bilateral and proximal to internal iliac artery
origin, patient develops vasculogenic impotence.(Leriche’s syndrome is characterized by
lower limb claudication, impotence and absent femoral pulse). It is also labelled as Aorto
Iliac disease.

b) Outflow disease: this is involvement of infra inguinal vessels. Superficial femoral artery
involvement is most common. It is associated with calf muscle claudication. Because of
collateral supply from deep femoral artery, more severe form of ischemia rarely occurs.
 Whereas involvement of popliteal and tibial artery causes limb threatening ischemia due to
lack of collaterals. It includes femoropopliteal and tibial disease.

c) Combined: they can present with simple claudication which can start from buttock or calf
depending on severity of individual lesions or limb threatening ischemia.

Intermittent claudication: It is characterized by cramping/aching/fatigue or numbness which is

brought by exercise or activity and relieved by mere stopping of activity. Pain can be in buttock,
thigh or calf. Pain is usually in muscle group distal to site of haemodynamically important
stenosis. Pain results from anaerobic metabolism in muscles due to less supply of O 2 producing
Substance P and also from ischemic neuropathy of small unmyelinated A delta and C sensory
fibres.

Boyd’s classification7 for claudication:

a) Grade I: Patient develops pain but due to increased vascular supply, metabolites are
washed away and pain relieved
b) Grade II: Patient develops pain and continues to walk with effort.
c) Grade III: Patient develops pain and has to rest.
d) Grade IV: Rest pain.

Claudication distance represents the distance patient can walk before having symptoms. This
distance decreases as patients walks uphill or fast or with weights. This pain is brought upon by
similar level of activity and as disease progress, level of activity required to produce symptoms
decrease. Conditions mimicking claudication are spinal stenosis, venous claudication, chronic
compartment syndrome etc.

Patients with claudication slowly progress to shorter walking distance but rarely progress to rest
pain or gangrene especially if risk factors are controlled. But presence of claudication is strong
marker of systemic diseases like coronary artery or cerebro-vascular accidents and is major
cause of morbidity in this group. Risk of amputation is 1%/yr whereas risk of cardiac death is 3-
5%/yr6.

Critical Limb ischemia6,8: it is characterized by rest pain, ischemic ulcers or gangrene. The
diagnosis is confirmed by ankle pressure < 50 mmHg, toe pressure < 30 mmHg or ABI < 0.40.
Presence of ulcer or gangrene increases demands of tissues, thus a higher cut off values are
used for diagnosis( Ankle pressure < 70 and toe pressure < 50mmHg)1.
Critical Limb ischemia is associated with high risk of limb loss in absence of revascularization.
Also presence of Critical Limb ischemia represents advanced coronary and cerebro-vascular
disorder. Without aggressive treatment significant rate of death or major amputation is seen within
1 year6.

Rest Pain: it represents significant decrease in arterial supply causing ischemia of skin and
subcutaneous tissues along with ischemic neuropathy of subcutaneous nerves9. It involves distal
most part of limb. Forefoot and digits are most commonly involved. Pain is often described as
burning or unpleasant paresthesia. Symptoms are classically relieved with limb in hanging
position because gravity aids in circulation and aggravated with limb elevation. Early in course
patients may awaken only and get back to sleep after some time of sitting up. Next patient sleeps
with limb hanging down off bed or chair. In final stages, patient is not able to sleep.

Ischemic Ulcers: arterial obstructive disease is characterized by decreased flow to distal areas
with decreased supply of O2 and nutrients. In an area of trauma, requirement of O2 and nutrients
are increased which could not be met. Thus delayed healing takes place and minor trauma in
areas of fingertips, toes, inter digital areas can produce such ulcers.
These ulcers are shallow, non-healing with pale granulation tissue at base. Pain is due to
ischemic neuropathy of nerves along with exposure of nerves at base of ulcers. Pain due to such
ulcers is severe and is refractory to oral doses of narcotics.

Fontaine Grade and Rutherford Category are defined to stage chronic limb ischemia10:

Fontaine Grade Rutherford Category Clinical Description

0 Asymptomatic
0
1 Mild Claudication
2 Moderate Claudication
I
3 Severe claudication
II 4 Ischemic rest pain
5 Minor Tissue loss
III
6 Major tissue loss

History

Patient can present with any of above symptoms. Detailed history should be taken.

a) If patient present with claudication, site of pain, duration of activity which produces pain,
has the activity required decreased over the period, how much time after stopping activity
does pain decreases, what type of rest decreases pain(lying, sitting, standing) etc.
b) If rest pain, site of pain, preceding claudication, how is pain relieved, interference with
daily life etc should be asked.
c) In any patient suspected of PAD, history of co morbidities such as hypertension, diabetes,
smoking, tobacco, family history should be asked.
d) History of systemic involvement should be asked such as stroke, transient ischemic
events, cardiac event, impotence, post-prandial abdominal pain should be asked.
e) History of treatment already taken and drugs patient is currently on should be taken.

Physical Examination

a) General appearance of patient should be documented. Patient could be obese. Patient

with rest pain may be sitting with limb hanging on bed. Patient with chronic smoker may
be in respiratory distress due to COPD.
b) Pulse and Blood pressure in both arms should be recorded. This can show tachycardia
and hypertension.
c) Conjunctivae and sclera may document hyperlipidemia.
d) Respiratory examination may document COPD changes as impact of smoking.
e) Neurological examination should be done to look for neuropathy due to diabetes.

Limb Examination

a) Due to ischemia, distal limb may show loss of hair, thinning of skin, dry skin and nail
thickening. This occurs because the basal cell layer of skin undergoes high turnover to
replace overlying cells of skin/nails. In presence of ischemia, the metabolic supply
needed for this turnover is not met.
b) In rest pain, pedal edema could be present due to dependent position of limb. Dependent
4,9
rubor and pallor on elevation can be seen .
c) Ulceration or tissue loss could be seen. These are generally located on forefoot or
toes(most distal portion). Site, size, base, margin, pus presence, surrounding temperature
and sensation should be recorded. These ulceration need to be differentiated from
neuropathic ulcers. Ulceration seen on medial side are more commonly due to venous
insufficiency.
 Neuropathic Ischemic
Painless, pulses + Painful, pulse less
Regular margin, punched out Irregular margin
ulcers
Calluses, dilated veins, warm Calluses absent, collapsed vein,
cold
Bony deformity Tissue loss
Red or hyperaemic pale

Foot Claudication Distal obstruction Femoral+ popliteal pulses

present, ankle pulses absent
Leg Claudication Leg muscle Femoral/popliteal Femoral pulse+, distal pulse
wasting Artery involvement absent
Leg + thigh Leg+ thigh External iliac Femoral and distal pulse absent
Claudication muscle wasting involvement
Leg + thigh+ Buttock muscle Common iliac Femoral and distal pulse absent
Buttock also involvement
Claudication
Leg + thigh+ Buttock muscle B/L Common iliac or B/L Femoral and distal pulse
Buttock also aortic involvement absent
Claudication +
impotence

d) Limb could be cold to touch or limb covered with clothes could be warm due to loss of
temperature regulation11.
e) Inspection should be done from buttock to foot to look for muscle wasting. In Thigh
muscle wasting first involves vastus medialis and in leg peroneus group because these
muscle have end arterial supply without any collateral vessels.
f) Also thigh muscles are used for walking whereas leg muscles play minimal role in
walking. Thus loss of thigh muscles can be seen in chronic bed ridden patient whereas
loss of leg muscles is more specific for vascular involvement. Relationship of clinical
findings to site of disease11:
g) Leriche’s syndrome is triad of impotence, absent femoral pulse on both side and
intermittent claudication9.
h) Pulse examination should be done bilaterally and co related with opposite limb.

Investigations

a) Complete blood count: secondary polycythemia in smoker or elevated platelet count in

thrombotic disease.
b) Kidney function test: deranged creatinine level shows kidney involvement which could be
due to diabetes or hypertension or could be effect of hypertension. Also contrast could
not be given in deranged kidney profile.
c) Lipid profile: to document hyperlipidemia.
d) Fasting blood sugar and glycosylated haemoglobin. To document diabetes or in known
patient of diabetes, to document their control.
e) ECG should be done to document any previous cardiac event or as a baseline. Previous
cardiac investigations should be reviewed.
f) ESR: blood fibrinogen level are indicator of hypercoagulability but is not easily available.
ESR level acts as surrogate marker for fibrinogen level and can also help in assessing
6
presence of collagen vascular disease .
g) CRP levels: In various studies, it has been proved that CRP levels correlate inversely with
ABI levels. CRP is also easily available and thus can serve as a marker for worsening
PAD.
h) Hypercoagulable state and Homocystine: In a patient of PAD, absence of common
factors, sudden onset in young age and rapid progression point to risk factors like
homocysteinemia and hypercoagulability. PT, aPTT, Protein C,S assays, factor V assay,
anti thrombin III assay, Lupus anti coagulant assay and homocystine levels.
i) In view of systemic nature of risk factors, all patients with PAD, whether symptomatic for
cerebro-vascular disease or not, should undergo carotid duplex scan.
12
j) Ankle Brachial index (ABI) : it is a non invasive test which can be done easily.
Measuring ankle pressure in relation to brachial serves two purpose:
 Brachial pressure serves as a substitute for central pressure. Measuring ankle
pressure in relation to brachial serves to identify if change in ankle pressure is due to
change in central pressure. Like ankle pressure can be normal in an hypertensive
with PAD.
 ABI give better indication of obstruction by demonstrating the fall in pressure from
central to peripheral artery.

Method: patient is made to lie supine, preferably for 5min. Cuff is placed on led as close to
ankle as possible and inflated above systolic pressure. A hand held Doppler probe is held
over Dorsalis pedis or posterior tibial artery and pressure is measured in both arteries. To rule
out occlusive disease of arm, brachial pressure is measured in both arm and higher of two
pressures are taken.

Rt ABI = Higher right ankle pressure Lt ABI= Higher Left ankle pressure
Higher Arm pressure Higher Arm pressure

> 1.30 Non compressible(arteriosclerotic)

1.00-1.29 Normal
0.91-0.99 Equivocal
0.41-0.90 Mild to Moderate PAD
0.31-0.40 Rest pain
<0.30 Impending gangrene

ABI also correlate with extent of PAD. >0.5 represents single level disease whereas <0.5
represents multilevel disease. Sensitivity of ABI ranges from 80-95% and specificity ranges
from 95-100% for PAD.

Errors in measuring ABI:

 Wrong brachial pressure for measurement of index.

 Failure to have patient supine. With legs hanging, hydrostatic pressure of blood
column adds to blood pressure.
 Improper size cuff.
 Arteriosclerosis like in diabetes. ABI >1.3 suggests stiffened arterial wall.

1) Segmental pressure: This can be used to estimate the level of disease. Blood
pressure is measured with cuffs placed at arm, upper thigh, above knee, below knee
and above ankle. A decrease in pressure of 20 mmHg or more at any level in
comparison to level above it, indicates significant disease.
Errors:
 Well developed collaterals in chronic disease may mask this fall.
 Distal most cuff is at ankle, thus diseases beyond these will not be picked.
 Multi level disease with proximal significant obstruction which limits flow in distal
vessels will not be picked up.
 12
2) Digital Pressure measurement : ABI is prone to errors in presence of calcified
vessels as seen in arteriosclerosis. ABI > 1.3 is indicator of arteriosclerosis. An
appropriate size mini cuff is tied at base of digit and pressure measured with
manometer. Normal toe pressure is 20-40mmHg below ankle pressure. A Toe
brachial index(TBI) .0.7 with absolute digit pressure >50mmHg is indicative of
preserved flow.
It is used in cases in which:

 Pedal arch vessel involvement is suspected.

 Toe/digit pressure can be used when ABI >1.3 which represents tibial vessel
calcification whereas smaller vessels are rarely affected by calcification

12
k) Exercise testing :
Indication: Sometimes patients present with symptoms of claudication but pulses and ABI
are normal. Such patients should be subjected to exercise testing.
Principle: stenosis which is mild to produce pressure change at resting flow, but when
flow rate increases due to vasodilatation by exercises or drugs, turbulence increases and
pressure drop occurs due to loss of energy in turbulent flow.

Method: patient first rest supine and resting pressures are recorded. Then patient walks
at a set speed (2miles/hr) on a treadmill at an inclination of 12о for 5min or until symptoms
force to patients stop. If for symptoms develop, note is made of time to onset and patient
is made to lie supine and pressure measured serially every 2 min for 10 min.

 Patient who is able to walk whole duration without symptom or decrease in ABI, PAD
is ruled out.
 A drop in ABI of 0.20 or drop in ankle pressure of 20 mmHg which doesnot return to
pre exercise level within 3min, suggests PAD.

l) Doppler Ultrasonography: This is based on detection of blood velocity using ultrasound.

Red cells flowing in blood, back scatter ultrasounds that are picked up by transducer.
According to Doppler Effect, red cells moving towards transducer produce shorter
wavelengths and those moving away produce longer wavelengths.
Normal blood flow is tri-phasic with a peak in systole. Reversal of flow in early diastole is
due to peripheral resistance and than a forward diastolic flow. With PAD, earliest feature
is loss of reversal and flow becomes biphasic. With more severe obstruction, widening of
diastolic peak occurs and flow becomes monophasic. These frequency changes are
converted to audio signals. The reduction in the pitch of this signal and a lack of the
phasic components is recognised as abnormal finding.

13
m) Transcutaneous Oximtery (TcPO2) : It is based on the principle that the partial pressure
of the oxygen which diffuses through to the surface of the skin reflects the oxygen tension
of the underlying tissues. It is time consuming and is best used in the selection of
amputation sites since it correlates well to subsequent stump healing.

14
n) Duplex Ultrasonography : It combines B mode imaging which provide information about
vessel wall and Doppler spectral analysis which provide information about velocity of flow
over a segment. Peak systolic velocity is measured and change in peak systolic velocity
across a stenotic segment can tell about degree of obstruction. Ratio of PSV at stenosis
to proximal segment of 2 denotes 50% obstruction and a value of 4 represents 70%
reduction.
 This modality is non invasive, cheap and has now become the mainstay of assessment of
arterial insufficiency, and has largely replaced routine use of conventional arteriography.
This requires detailed assessment of each major arterial segment i.e. Aorta, Iliac,
Femoropopliteal and infra popliteal segments.
Indications:
 This investigation has virtually become the first line investigation to localize the
level of block with a great deal of accuracy.
 It is used for post revascularization surveillance
 In case of autologous venous graft harvesting, it is used to assess vein.

o) Angiography: Conventional intra arterial contrast angiography is done through

contralateral common femoral or left brachial artery. All the regions which are required to
be assessed can be seen. To decrease the load of contrast, selective assessment or
assessment in conjunction with duplex Ultrasonography can be done.
Risks associated with it are contrast nephropathy, groin hematoma, infection,
retroperitoneal bleeding, dissection, pseudoaneurysm etc.
Indication: It is an invasive procedure and in presence of all these morbidities,
angiography is used only when need and possibility of endovascular intervention is
decided. It is superseded by newer non invasive investigation.

p) Magnetic Resonance Angiography (MRA): Gadolinium enhanced MRA can visualize

entire arterial tree without need for arterial puncture. It is better for distal small and pedal
vessels as compared to angiography. It has a sensitivity of 81% and specificity of 92%6.
Disadvantage:
 MRA requires patient cooperation as it is a longer study
 It could not be done in patients with metallic implants.
 Gadolinium can worsen renal condition of chronic kidney patients and precipitates
nephrogenic systemic fibrosis in patients with GFR <30/min.

Its advantage lies in the fact that it is completely non-invasive and does not use ionizing
radiation and visualizes proximal large and peripheral small vessels. Thus it is used when
arterial is to be mapped for a decision for revascularization.

q) CT angiography (CTA): Newer multidetector CT allows visualization of arterial tree

including small tibial vessels with an advantage of 3D reconstruction which is not possible
with conventional angiography.
Advantage:
 It can also be used in place of MRA in patients with metallic implants, claustrophobia.
 CTA allows better delineation of plaques ant thrombus.
Disadvantages include high radio exposure, contrast load and heavily calcified small
vessels can be misinterpreted as normal.

Treatment

A. Risk Factor modification: Since patients with PAD are at risk of cardiac and cerebral morbidity,
treatment aims at modifying risk factors to decrease risk of systemic disease. Thus patients with
asymptomatic PAD diagnosed on basis of ABI, should also be started on treatment.
1. Smoking: Smoking cessation is very important in treatment of PAD. This is because smoking
is associated with progression of atherosclerosis, PAD, cardiac morbidity and 3-4times risk of
graft failure as compared to non smoker5. Smoking cessation can be encouraged with patient
education, family support and pharmacological aids like nicotine gums/patch, bupropion etc.
 2. Diabetes Mellitus: Association between DM and PAD is well documented. Each 1% rise in
HbA1c is associated with 28% risk for PAD. Whereas microvascular complication respond to
5
sugar control, not much benefit has been reported for macro vascular complications . Still, a
strict sugar control is recommended. American Diabetes Association recommend HbA1c < 7%
as treatment goal.

3. Hypertension: goal is to maintain a BP < 140/90 in patient with PAD and <130/80 who also
have diabetes and renal insufficiency4,5. There is no recommendation for agents to be used
but use of ACE inhibitors is associated with decreased cardiac morbidity.

4. Hyperlipidemia: Diet modification is the first step. Avoiding saturated and trans saturated fats
are important. Statins should be given in patients with increased cholesterol levels. Statins
also stabilizes existing plaques, decreases oxidative stress and decreases vascular
inflammation. Current guideline4,5 :

Symptomatic/ asymptomatic PAD LDL < 100mg/dl

PAD + other involvement LDL < 70mg/dl

Elevated Triglycerides(LDL could not be Non-HDL cholesterol<130mg/dl

calculated exactly)

In patients with deranged HDL levels, niacin or fibrates should be added to increase HDL
levels. Niacin also acts by regression of already formed plaques.

5. Antiplatelet therapy: cardio vascular diseases are major source of morbidity in patients with
PAD. Thus Aspirin in a dose of 75-325mg/day or clopidogrel are associated with reduced risk
ok of MI or stroke. In high risk [patients, both can be started. These drugs do not alter
claudication distance or rest pain but help in enhancing graft patency rates when started pre
operatively.

B. Exercise Therapy5: In presence of claudication, patient generally restricts their activity to

decrease occurrence of pain. It increases morbidity due to increased risk of cardiac events
because of further derangement in metabolism. Exercise therapy aids in improvement in pain
free ambulation, overall working performance and regular exercises improves cardiac status.
According to guidelines, walking exercises should be performed for minimum 30-45min/session,
3-4times/week, for at least 12 weeks. In each session patient walks until limit of pain, then rest
then walk. As pain free ambulation increases, level of exercises should be increased. If during
exercise, cardiac symptoms like chest pain or ECG changes occur, cardiac re evaluation should
be done.

C. Pantoxifylline: It is methylxanthine derivative. It has a rheolytic effects on red blood cell wall
deformability and flexibility, thus reducing blood viscosity and improving oxygen delivery. It also
decreases platelets aggregation. Although, it shows improvement in claudication distance in trials,
its action is subjective in patients with some showing improvement and some showing no
improvement.
Dose: 400 mg TDS( max of 1800mg/day)
Side effects: it interferes with blood clotting especially if taken with warfarin/aspirin. It causes
nausea, anorexia, headache, drowsiness etc
D. Cilostazol: It is a phosphodiesterase III inhibitors that increases cAMP levels. It acts by:
 Inhibiting smooth muscle cell proliferation and contraction.
 It inhibits platelet aggregation.
 It decreases triglycerides levels and increases HDL.
Several trials has been done to compare pantoxifyline versus cilastozol. Dawson and colleague
reported increase in maximal walking distance by 54% on cilostazol than 30% increase shown by
pantoxifyline15.
Dose: 50 mg/day X 1week, then 50 mg BD X 1week then achieving a dose of 100 mg bd. This is
done to minimize side effects.
Side effects: headache, diarrhoea, nausea and vomiting. It is contra indicated in heart failure.

E. Naftidrofuryl: it is a serotonin antagonist. It acts by improving aerobic metabolism by stimulating

carbohydrates and fat in kerb’s cycle and promoting vasodilatation. It has been in use in Europe
but not approved in USA. Other drugs under trial and not approved are like Levocartinine,
Buflomedil (α1 and α2 antagonist), prostaglandins and L-Arginine.

F. Intermittent Pneumatic Compression: It is a useful treatment option with appropriate risk

modification technique in patients with:
 Non-reconstructable disease
 Patient unfit for surgery
 Patients not willing for surgery.

It involves sequential inflation and deflation of pneumatic pressure cuff positioned at foot or calf.
Pressure is applied for 2-3 sec and sequence is continued at rate of 3 cycle/min. studies have
shown improved limb salvage rates with IPC(54%) then without IPC(17%)16.

According to data provided by ACC/AHA, limb amputation rate for intermittent Claudication patient is
1%/yr whereas risk of cardiac death is 3-5%/yr. Thus according to Trans Atlantic Inter-Society
Consensus for Management of Peripheral Arterial Diseases (TASCII) document, medical
management against cardiovascular morbidity is the best management in claudication group.

Revascularization in claudication is recommended only if:

a) Failed medical therapy

b) Severe claudication
c) If a proximal stenotic lesion is present.

Whereas prognosis in CLI is very worse, 25% patient require amputation/ yr and 25% die within 1 yr
due to cardiovascular complication. Therefore TASC II document recommends together with risk
factor modification, some revascularization is required or amputation for better quality of life.

Revascularization can be done by open surgery or endovascular technique. Surgical repair can be
anatomic and extra anatomic repair and can be done by open or laparoscopic. Extra anatomic repair
is defined as any bypass graft that is placed in a site different from arterial segment being bypassed17.

Surgical repair option for aorto iliac disease

18
Endarterectomy : this is based on the fact that atherosclerosis is intimal and medial disease and
plane can be develop between plaque and outer layers of wall. It involves opening of diseased
segment and removing plaque.
Indications:
 In case of infection, endarterectomy is preferred as no grafts need to be placed.
 Small vessels which are not amenable for endovascular or graft repair.
 Patients with erectile dysfunction. In such cases endarterectomy with removal of plaques up to
iliac arteries and re establishing internal iliac supply is better than aorto bifemoral bypass.
Disadvantages:
 More blood loss.
 Difficult to perform.
 Higher incidence of failure as compared to aorto bifemoral bypass.

Aorto Bifemoral Bypass (ABFB): using PTFE grafts or Dacron grafts (knitted/woven), iliac, distal
aortic segment and proximal femoral segment can be bypassed by placing graft between infra renal
aorta and B/L femoral. There is not much benefit of one type of graft over another.

Open repair can be done by midline laparotomy or retroperitoneal approach by left flank incision.
Using flank in incision prevents bowel handling, decreases ileus , decreased losses whereas midline
approach preferred in cases with right renal artery involvement which is not assessed from flank
incision. Proximal aorto graft anastomosis done at infra renal level can be “end to end” or “end to
side”. End to end anastomosis is beneficial because it creates a straight conduit thus decreases
turbulence and delimitates risk of steal through iliac arteries6,18. Also end to end anastomosis lies
comfortably in retroperitoneum with less chances of bowel erosion.

End to side anastomosis is performed in cases with large IMA with poor back flow suggestive of poor
collaterals or occlusion of B/L external iliac disease because end to end anastomosis in such cases
disconnects antegrade flow and retrograde flow is not there to hypogastric arteries and pelvic
circulation. But end to side anastomosis, places distal circulation at risk for embolism or occlusion by
atherosclerotic plaques.

According to data available, patency rates with ABFB are 90% at 5yrs and 75-85% at 10 yrs18. This
patency rate is more in old age as compared to young with no effect of sex. Thus it is preferred
bypass procedure.

Complications:
a) Intra operative: due to extensive dissection required, there can be damage to ureter, vessels
or bowel.
b) Early complications like cardiac failure, pulmonary complications like pneumonia etc. Cardiac
complications are most common cause of mortality.
c) Bleeding
d) Intestinal and spinal cord ischemia: this occurs due to post operative hypotension or due to
loss of IMA flow or flow to hypogastric arteries as in end to end anastomosis.
e) Graft thrombosis: it is most common late complication. Generally it is occlusion of 1 limb
which can be managed by endovascular technique.
f) Graft infection: treatment is removal of graft.
g) Aorto enteric fistula: most commonly it is erosion of suture line in duodenum but can also be
seen with colon. Patients present with pain abdomen, bleeding per rectum and shock.
Treatment involves primary repair of gut with removal of graft.

Axillo-bifemoral Bypass1,17: it is an extra anatomic repair which is done in patients with CLI
a) with co morbidities that makes it difficult for them to undergo ABFB.
b) in case of previous ABFB with graft infection or aorto enteric fistula, it is done after graft
removal
It involves placing a sub cutaneous graft between axillary artery and ipsilateral femoral artery and
then opposite limb is vascularised by femoro-femoral bypass.

Although it is less complex procedure than ABFB, mortality is higher may be due to poor underlying
condition of patients. Graft patency rate is also low.
Complications: haemorrhage, local infection, brachial plexus injury, disruption of axillary graft
anastomosis and graft thrombosis with thrombosis of proximal and distal arteries.

Femoro femoral bypass: this is done in U/L iliac artery involvement with no distal involvement. It is
bases on principle that 1 iliac artery can support both limbs. A subcutaneous graft is placed between
two femoral arteries coursing suprapubic region. It is a good alternative for patients who are not fit to
undergo ABFB. Mortality rate is <5% with patency rates of 60-70% at 5 yrs1,17.

Obturator bypass: this a bypass which is done through obturator membrane and a graft is place
between CIA/EIA or limb of ABFB graft and femoral artery. It is done in cases in which arterial
reconstruction is required in groin but local graft cannot be placed:
a) Infected femoral pseudoaneurysm after angiographic puncture or drug abuse.
b) Infected femoral dialysis sheath.
c) Groin neoplasm requiring en bloc removal of artery.
d) Previous radiotherapy to groin.

This bypass aims at reconstructing vascular anatomy in groin after proper debridement of infected
tissue. 5 yr patency rates are 70-80%1,17.
Complications: groin sepsis, infection, injury to obturator nerve and artery.

Graft material for extra anatomic bypass can be autologous vein like saphenous or PTFE grafts. In
obturator Bypass, autologous vein is preferred graft since local tissues are already infected.

Axillopopliteal Bypass: indication for this includes:

a) Axillofemoral bypass being extended to popliteal due to groin infection
b) if bypass to groin will not increase distal supply due to distal occlusive disease as well.
Very poor patency rates due to long length of graft.

Thoraco Femoral Bypass: this is an alternative to ABFB in patients with infected ABFB graft or with
previous abdominal operation that makes ABFB difficult. Graft is placed between supra renal aorta
and femoral /iliac artery as required. Although patency rated of this procedure are exciting, but
morbidity of this procedure is high because it require sternotomy/thoracotomy and extensive
dissection for graft placement.

Surgical repair option for infra inguinal disease:

Grafts available for infra inguinal bypass are autogenous grafts such as GSV, short saphenous vein
or arm veins. GSV is preferred but if unavailable other veins can be used. Leg veins can be taken
from same limb or opposite limb if necessary and can be used in situ or reversed to place valve
endothelium outside. Cryopreserved vein grafts are cadaveric veins that have been preservd1,19.
These are expensive and prone to thrombosis due to intimal loss or aneurysm formation due to media
damage. But it is a good option if autologous vein is not available. Human Umbilical vein can also be
used. Ptfe (heparin covalently bonded) or Dacron grafts are also available.

According to patient data available, Vein grafts are superior to all other grafts whether above knee or
below knee bypass6,13,19. Thus recommendations are to use autogenous vein graft for infrainguinal
disease. If vein is not available, PTFE/Dacron can be used for above knee cases with not much
difference in patency rates between two. 5 patency rate is 60-70% both in above or below knee
cases.

Bypass is placed between a proximal artery which can be common femoral/SFA or can be more
proximal. If require, endarterectomy can be done. General principle in leg is to bypass all significant
diseased segment and distal anastomosis is made to artery with one branch supplying pedal arteries.
Shorter is channel, better is result. Thus distal limb could be popliteal artery, tibial or peroneal artery
which ever is in continuity with pedal arch.
In Diabetes, it has been seen that restoring pedal pulse or foot perfusion is most important factor, thus
anastomosis to pedal vessels is preferred. This can be a long bypass from CFA to paramalleolar or
from popliteal artery to pedal arch depending on level of obstruction and proximal flow.

Endovascular approach1,20

Stents available are Balloon expandable and self expanding. Balloon expandable have high precision
of placement but are less flexible. Self expanding stents are more flexible. Thus Short segment,
eccentric involvement, at level of bifurcation of aorta is treated with Balloon expansion whereas
tortuous arteries are stented with self expanding.

In Aorto iliac disease, endovascular access can be done from ipsilateral side but it is associated with
false tract through intima when we try to pass across plaque. If CIA artery involvement is not flush
with aorta, contralateral femoral artery approach with antegrade passage through plaque is
preferable. If CIA artery is involved flush with aorta, ipsilateral approach or brachial artery approach is
better.

Use of endovascular approach for iliac disease is associated with good patency rates of 90% at 5 or
10 yrs in cases with TASC A, B lesions and a patency rates of 70% at 4yrs in TASC C and D lesions.

Complications:

a) Contrast: contrast used in angiography places patient at risk for nephropathy especially if
underlying insufficiency is present. If creatinine >1.5mg%, use of preoperative N acetyl
cysteine and pre and intraoperative bicarbonate is defined.
b) Sheath site related: haemorrhage or pseudo aneurysm formation can be seen. These are
decreased by closure using a suture like device.
c) Arterial dissection
d) Embolization

In Femoro popliteal disease, endovascular approach with or without stent placement is used based on
disease severity. Patency rates as compared to open bypass are similar with less morbidity. In
Popliteal and infra popliteal disease, results with endovascular approach are few.

Endovascular approach vs Surgical

Use of endovascular approach is associated with:

a) Less morbidity,
b) Shorter hospital stay and
c) Less interference with daily life.

Surgical approach is associated with longer perioperative stay and also complication like bowel injury,
impotence, ureteric injury etc. but superior patency rates. Thus it becomes difficult to decide which
modality to choose.

TASC II document has given classification of obstructive lesions and has classified both aorto Iliac
and femoral disease as Type A,B,C and D lesion to aid in decision making. TYPE A and B lesions are
treated with endovascular approach and Type D with surgical. Type C lesions are generally amenable
to surgical approach. TASC II document prefers endovascular approach wherever it is possible. But it
does not consider outcome of treatment or any other factor before deciding treatment.
Lower Extremity Grading Score (LEGS)1,6,13 was proposed in 2002 to recommend treatment
considering outcome. It is based on % objective criteria- angiographic pattern of disease (TASC II),
presenting complaints, functional status, medical co morbidities and technical factors. Based on this,
a score is calculated and whether patient should be given medical therapy, surgical or endovascular
treatment is decided. LEGS score has been studied and outcomes in patients treated according to
and contrary to LEGS score were compared retrospectively. Patient treated according to LEGS score
were found to have better reconstruction patency, better ambulation and limb salvage. Thus LEGS
score is better guide to treatment.

BASIL trial (Bypass versus Angioplasty in Severe ischemia of Legs) 6,13,21 was done in UK to
compare surgery versus endovascular in severe limb ischemia. 450 patients were included and
amputation free survival was taken as endpoint. At 6 months, results were comparable in both group.
Also crossover treatment was also common. But at 2 yrs, both amputation free survival and overall
survival was better in surgery group.

a) Thus although TASC II recommends angioplasty over surgery, but if disease process is expected
to extend beyond 6months, surgery is better option.
b) Also endovascular and surgery are not stand alone therapies but could supplement each other.
Many TASC C and D lesion can be managed by combination of both.
c) Short segment disease in a large or medium size vessel is amenable to endovascular approach
whereas large segment / multi level disease is better dealt by surgical bypass.

Situational Perfusion Enhncement6,13: there are patients with decreased perfusion but
asymptomatic either because of their lifestyle requiring less mobilization of restricted mobility due to
cardiac/ orthopaedic reason. Such patient, if develop ulceration due to trauma or other reason, these
may not heal. Such patients require temporary boost to circulation till the time ulceration heals. Thus
endovascular therapy with inferior patency rates can be beneficial for such patients with very few
morbidity. Once ulcer heals, stent may close with recurrence of ischemia and patient is still
asymptomatic.

Amputation: it is recommended in:

a) patients with severe symptoms, who are not amenable to or failed revascularization
b) gangrenous tissue.
c) life threatening infection

Amputation should be done at level as distal as possible for a proper healing and rehabilitation. Post
rehabilitation, a majority of patients can resume their life better than with a non-functional painful limb.

REFERENCES

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Billiar TR, Matthews JB, Anderson DK, editors. Schwartz’s principles of surgery. 9 edition. New York: McGraw-
Hill;2010.p.701-76
2. Olin JW, Lie JT. Thromboangiitis obliterans (Buerger’s disease). In : Loscalzo J, Creager MA, Dzau VJ, eds.
Vascular Medicine. 2nd ed. Boston:LittleBrown;1996.p.1033-1049.
3. Schoen FJ. Blood Vessels. In: Kumar V, Abbas AK, Fausto N editors. Robbins and Cotran Pathologic Basis of
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Disease. 7 edition. Philadelphia: Saunders;2005.p.511-54
4. Silva MB, Choi L, Cheng CC. Peripheral Arterial Occlusive Disease. In: Townsend CM, Beauchamp RD, Evers BM,
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Mattox KL, editors. Sabiston textbook of surgery. 19 edition. Philadelphia: Elsevier;2012.p.1725-84
5. York JW, Taylor SM. Lower Extremity Arterial Disease: Decision Making And Medical Treatment. In: Gonenwett
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JC, Johnston WK, Cambria RP, Gloviczki P, Messina LM, Mills JL, editors. Ruthrerford’s Vascular surgery. 7
edition. Philadelphia: Saunders; 2010.p.1593-612
6. White JV. Lower Extremity Arterial Disease: General Considerations. In: Gonenwett JC, Johnston WK, Cambria
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RP, Gloviczki P, Messina LM, Mills JL, editors. Ruthrerford’s Vascular surgery. 7 edition. Philadelphia: Saunders;
2010.p.1576-92
7. Boyd AM. The natural course of atherosclerosis of the lower extremities. Angiology 1960;11:10-14.
8. Tenant WG, Ruckley CV. The critically ischaemic limb. In: Taylor I, Johnson CD (eds). Recent advances in
surgery. Churchill Livingston:Edinburgh;1995.p.117-39.
9. Longo GM, Lynch TG. Patient Clinical Evaluation. In: Gonenwett JC, Johnston WK, Cambria RP, Gloviczki P,
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Messina LM, Mills JL, editors. Ruthrerford’s Vascular surgery. 7 edition. Philadelphia: Saunders; 2010.p.204-15
10. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S et al. Recommended standards for reports
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11. Murie JA. Arterial disorders. In: Williams NS, Bulstrode CJK, O’Connell PR. Bailey & Love’s Short Practice of
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Surgery. 25 edition. London: Hodder Arnold; 2008.p.899-924
12. Kohler TR, Summer DS. Vascular laboratory: Arterial Physiologic Assessment In: Gonenwett JC, Johnston WK,
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Cambria RP, Gloviczki P, Messina LM, Mills JL, editors. Ruthrerford’s Vascular surgery. 7 edition. Philadelphia:
Saunders; 2010.p.217-33
13. Slovut DP, Sullivan TM. Critical limb ischemia: medical and surgical management. Vascular Medicine 2008; 13:
281–91
14. Armstrong PA, Bandyk DF. Vascular laboratory: Arterial Duplex scanning. In: Gonenwett JC, Johnston WK,
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Cambria RP, Gloviczki P, Messina LM, Mills JL, editors. Ruthrerford’s Vascular surgery. 7 edition. Philadelphia:
Saunders; 2010.p.235-56
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Cardiol. 2001;87:19D–27D
16. Kavros, SJ, Delis, KT, Turner, NS, et al. Improving limb salvage in critical limb ischemia with intermittent
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17. Schneider JR. Aortoilliac Disease: Extra- anatomic Bypass. In: Gonenwett JC, Johnston WK, Cambria RP,
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2010.p.1613-32
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 Radiofrequency Ablation in Surgical Practice
Anubhav Vindal, Bipin Singh

Ablation is removal of material from an object by vaporization, chipping, or other erosive processes. It
denotes complete removal or extinction, not merely mitigation or reduction. A variety of local ablative
methods, including chemical (ethanol, acetic acid, hot saline) and thermal (radiofrequency,
microwave, laser and cryo) are available for ablating body cells in situ.

Principle of Radio Frequency Ablation

Radio Frequency Ablation (RFA) uses the heat generated from high frequency alternating electric
current oscillating between 200 and 1200 kHz, usually in the range of 460-480 kHz and long
wavelength1, 2. RFA differs from other local methods of ablation in that the electrode itself does not
supply the heat. Needle electrodes supply an alternating electric current, which travels from the
electrode to a grounding pad (monopolar) or between two electrodes (bipolar). As the ions within the
tissue attempt to follow the alternating path of the current, ionic agitation creates frictional heat. This
friction heats the surrounding tissue to 50-100°C, inducing instantaneous coagulative necrosis with
irreversible damage1- 4. In addition to the frictional heat, conduction heat from the ablated area can
result in relatively slower damage of the tissue remote from the electrode tip2.

Temperatures greater than 100– 110°C result in tissue vaporization and carbonization with loss of
ions thus stopping current flow. This carbonized tissue then serves as an insulator to prevent heat
spread and thus limits the process of thermal damage1, 2. The efficacy of RFA can be reduced due to
factors like:

a) Heterogeneous nature of the target tissue in the presence of fibrosis or calcification, by

altering electrical and heat conduction, or
b) Adjacent blood flow, by perfusion-mediated tissue cooling.

Components of RFA system

RFA system consists of:

a) A Radiofrequency generator
b) RF electrode, which is placed in the target zone, and
c) Ground pads (dispersive electrodes), usually applied to the skin of the thigh.

RF Generators
The RF generators can be of two types – monopolar system and bipolar system. The bipolar RF
system is considered a safer form of treatment compared to the monopolar system, since placement
5
of grounding pads is eliminated, precluding the risk of skin burns . Additionally, the applied RF energy
is confined to the treatment area in the bipolar system in contrast to the monopolar system where the
energy streams out through the body in all directions, increasing the body temperature by 1-2 °C. For
the same reason, metallic implants are a contraindication to the use of the monopolar system since
they may be included in the electrical circuit leading to undesirable effects and burns. Since current
flow is restricted to the probe tip, the bipolar system allows the use of higher current densities
resulting in more uniform heating of tissues and the production of larger volumes of ablation.

RF electrodes
There are three types of commercially available RFA electrodes1:

i. Multi probe array electrodes

 These are also called Umbrella – shaped or Christmas tree – shaped electrodes due to the
shape of the tip of the electrodes. Multiple tines apply current simultaneously to the tissue to
be ablated, achieving coagulation zones of 3-5 cm.
ii. Internally cooled (or Cool-tip) electrodes
These have an inbuilt mechanism to cool the electrode with a continuous infusion of fluid
within their lumen. This allows for greater ablation volumes as the cooling results in no local
charring around the uninsulated electrode tip, thus allowing for longer flow of current. Longer
duration of current flow allows for a larger volume of local tissue coagulation, compared to
non-internally cooled electrodes.
iii. Wet electrodes
These use saline (either isotonic or hypertonic) infused through the electrode into
surrounding tissue, thereby increasing the conductivity with greater amounts of infusion of
ions in the tissue. This in turn increases the current flow and thus allows a longer duration of
current flow and an increased volume of coagulation. It creates a larger “virtual” electrode
around the metal electrode tip.

In general, the ablation zone that can be achieved using the currently available RFA devices is limited
to 4–5 cm in maximum diameter. For obtaining a larger ablative margin, the employment of multiple
electrodes or overlapping ablations with a single electrode is useful 3.

RFA technique1

RFA can be performed percutaneously, or during laparoscopic or open surgery. In a study comparing
open, laparoscopic, and percutaneous approaches for liver tumors, there was no difference in
mortality, major complications, or overall survival; but open compared to percutaneous approach
resulted in improved disease free survival and decreased local tumour recurrence.

Percutaneous approach
The percutaneous approach has the advantage of being performed under conscious or deep
sedation, providing an option for patients who are higher surgical risks. This can usually be done as
an outpatient or with a very short hospital stay, and can be performed multiple times if needed. Other
advantages of this technique are the use of sonography, computed tomography (CT) or magnetic
resonance imaging (MRI) to guide precise electrode placement. A contrast enhanced sonography or
contrast enhanced CT can be done during the procedure to check for adequacy of ablation.
Disadvantages of the percutaneous technique are lack of visualization of small surface tumours or
deeper tumours, which can be better identified with the open technique. Percutaneous RFA has
shown excellent results for small < 3 cm neoplasms in the liver, lung or kidney. However, higher local
recurrence has been shown with this approach for larger tumours and tumours in close proximity to
major vessels, such as the portal vein.

Open approach
Open RFA allows for better visualization of the lesion, and the ability to manipulate adjacent
structures. It has the advantage of being able to detect occult metastatic disease with use of intra-
operative ultrasound (IUS) and allows for treatment within a greater anatomic range. With hepatic
RFA, another advantage is the ability to occlude portal inflow (Pringle manoeuver), which reduces
heat dissipation and, therefore, increases the volume of tissue ablated. This technique is particularly
valuable when tumors are located in proximity to vascular structures.

Laparoscopic approach
Laparoscopic RFA combines many of the benefits of both the percutaneous and open approaches. It
is minimally invasive with less morbidity than that of a large incision while still allowing better
visualization of the tumor and of adjacent structures to optimize staging and treatment.
Clinical applications of RFA

A. Surgical Oncology
Surgical resection of all malignant cells remains the gold standard for treatment of most solid tumours.
However, surgical resection is not always an option in patients with coexistent morbidities or poor
functional status where resection would be associated with high morbidity and mortality. This
minimally invasive technique can serve both as a treatment for patients who are not surgical
candidates, as well as an adjunct to surgery, facilitating resection or in combination with surgery
achieving total tumour burden control.

a) Thyroid2, 6
Radiofrequency ablation can be used to treat both benign thyroid nodules and inoperable,
recurrent thyroid cancers in the operation bed as well as the lymph nodes. RF ablation for
follicular neoplasms or primary thyroid cancers is not recommended as there is no evidence
of treatment benefit by RF ablation in these malignancies.
Indications for RF ablation of benign thyroid nodules include patients with nodule-related
clinical problems like symptoms (neck pain, dysphasia, foreign body sensation, discomfort,
and cough); cosmetic reasons and patients with autonomously functioning thyroid nodules
causing problems related to thyrotoxicosis. Only nodules with a maximum diameter > 2 cm
may be considered for thyroid RF ablation as smaller nodules often prove difficult to target.
The electrode tip is initially positioned in the deepest and most remote portion of the nodule,
after which it is moved to the superficial and nearer portion of the nodule so as to prevent
visual disturbance caused by echogenic bubbles as a result of tissue ablation.

b) Barrett’s oesophagus7
Currently, RFA is a first-line treatment option for patients with high-grade dysplasia after
mucosal abnormalities have been removed by endoscopic mucosal resection. It is also useful
in patients with early intramucosal cancer, after the cancer has been completely resected. In
patients with high-grade dysplasia, it is clear that radiofrequency ablation is preferred over
oesophagectomy, given the encouraging results of this technology to date, the morbidity of
oesophagectomy, and the marked decrease in finding unsuspected cancer in these patients
with the advent of high-definition white light endoscopy and endoscopic mucosal resection.
Low-grade dysplasia is still an evolving area because of the difficulty associated with its
pathologic diagnosis.
What makes this technology exciting, compared with older technologies such as
photodynamic therapy, is that it is performed in a controlled manner to a specified depth. The
disadvantage of RFA is that tissue confirmation of the epithelial lining being ablated is not
possible.

c) Lung1, 8
RFA is increasingly being applied for primary as well as metastatic malignant lung nodules for
local control and palliation. Percutaneous CT-guided RFA of lung metastases is an effective
tool for local tumour destruction, with reported complete response rates of 100 % in tumours
less than 3–3.5 cm in diameter. In patients with pulmonary metastasis, multiple lesions and
advanced stage usually precludes curative surgical resection. Moreover, resectability, patient
tolerance, and pulmonary reserve decrease with each thoracotomy. RFA is minimally
invasive, with a low morbidity and with usually no or at most a minimal long-term reduction in
pulmonary reserve.
d) Breast1, 9
The role of RFA in breast cancer is still emerging. Complete coagulative necrosis is achieved
in 80%-100% of the patients with invasive tumors less than 2 cm in size. RFA may be useful
in sterilizing the tumor bed margins after percutaneous cytoreduction or complete excision.
RFA is usually followed by lumpectomy or mastectomy, either immediately or in a delayed
fashion. Skin burn is a common complication in a very small subset of patients. Various
strategies to minimize skin burns have been employed including cooling the breast with sterile
ice packs and subcutaneous injection of sterile saline or a high resistance solution to displace
the tumor away from the skin.

Limitations

a. Percutaneous ablation does not allow for full assessment of the lesion and therefore can
never be used for in situ carcinoma.
b. Lack of methodology or imaging to assure complete ablation of the lesion.
c. Follow-up imaging remains problematic in detecting residual or recurrent disease.
d. Oestrogen and progesterone receptor status, her 2 neu status, grade, histology, and
need for chemotherapy has to be known prior to RFA since no residual tumor cells would
be available post-procedure if complete ablation is achieved.

Contraindications

a. Superficial tumors within 1 cm of the skin due to increased risk for skin burns.
b. The presence of extensive intraductal component
c. Preoperative chemotherapy as it can lead to an underestimation of tumor size and leave
occult foci of residual carcinoma.

e) Liver1, 3, 4
RFA is considered a first line treatment modality for local control of hepatocellular carcinoma
in patients with Child-Pugh B or higher cirrhosis where resection would have a higher
associated mortality. Patients with three or fewer tumours with a diameter of 3 cm or less, no
extrahepatic lesions, with well-preserved liver function, no intractable ascites, and no vascular
invasion are considered as candidates for RFA therapy. RFA for HCC is mainly
accomplished by a percutaneous approach, although open or laparoscopic approaches can
also be used.
These days, RFA is also being used for unresectable primary hepatic carcinoma, metastatic
hepatic carcinoma and recurrent hepatic carcinoma after surgery, as well as for patients who
are unwilling to undergo hepatic resection. For patients who are not candidates for surgery,
RFA is a valuable alternative.
The “heat-sink” effect created by proximity of tumors to large vessels that can dissipate heat
is a primary mechanism by which the extent of thermal injury can be limited. The Pringle
maneuver is a well-known method for minimizing the heat sink effect when treating the
targeted HCC abutting a major vessel, although open laparotomy is needed for this method.
This has been shown to improve volume of tissue (tumour) coagulation by increasing local
heat deposition, rather than having heat being dissipated in the portal vein. Tissue damage
from chemotherapy and hypoxic injury to tumour cells from embolization have also been
shown to increase tumor sensitivity to hyperthermia. A synergistic effect between neoadjuvant
transarterial chemoembolization and RFA in the treatment of hepatocellular carcinoma has
also been demonstrated
To minimize intravascular tumour spread by intratumoral pressure during RFA, the multi-step
ablative method by incremental, stepwise expansion of the needle may be effective. Cooling
of bile ducts using an endoscopic nasobiliary drainage tube can prevent biliary complications
induced by RFA of HCC located in the hepatic hilar site close to major bile ducts.
 Limitations3
These include a limited ablation volume, technical limitations, and expected complications
dependent on tumour location, the heat-sink effect, intravascular tumour spreading by
intratumoral pressure during RFA, and tumour seeding.

f) Cholangiocarcinoma & malignant biliary obstruction10, 11

Endobiliary RFA therapy is feasible and safe for palliative treatment of malignant biliary
obstruction due to distal and Bismuth type I hilar extrahepatic cholangiocarcinoma. Self-
expanding metal stents can get occluded from tissue ingrowth or overgrowth, benign epithelial
hyperplasia or secondary to biofilm, and sludge formation within the lumen of the stent,
placed for effective drainage of bile. RFA reduces the tumour load, and thus prolongs stent
patency.

g) Kidneys1, 12
RFA as primary treatment for renal malignancy is limited to a select group of patients with
early T1a disease or for whom surgical resection is not an option. These include patients with
only one kidney, multifocal disease, Von Hippel Lindau syndrome, limited renal function,
elderly patients or patients with comorbidities who are poor candidates for surgery. Studies
have consistently shown 91%-97% complete first ablation success for small (< 3-4 cm),
exophytic, peripherally located tumors.
Contraindications include a life expectancy less than one year, the presence of distant
metastases, tumors > 5 cm, or tumors in the hilum or central collecting system.

h) Bone tumors and metastatic bone lesions1, 5, 13, 14

RFA has been long proven efficacious for the treatment of osteoid osteomas and majority of
patients experience pain relief within the first 1-2 week of treatment. It has been demonstrated
to be comparable to surgical resection with regards to recurrence. RFA has also been
described in case reports for the treatment of other benign bone tumors such as small
chondroblastomas (<3cm).
More recently, RFA has been applied as a palliative modality for the treatment of painful
metastatic bone lesions. Complication rates are minimal with skin necrosis and burns being
the most common.

9, 11, 15
i) Other organs
RFA has been used for tumor ablation of head and neck tumours including tumours of floor of
mouth, tongue, maxillary sinus and tonsil, brain, pancreas, prostate and rectum.

B. Varicose Veins24, 25
Radiofrequency energy thermally denatures vein wall collagen, leading first to vein wall inflammation,
then fibrosis and finally to occlusion. Surrounding tissues are protected by tumescent local
anaesthesia, which acts both as a heat sink and as an anaesthetic. The vein lumen is compressed by
the tumescent solution around the tip of the catheter, improving energy transfer and reducing power
requirements. The ability of RFA to treat varicose veins under local anaesthetic has aided the
transformation of this treatment from an inpatient operation to outpatient or office based procedure.

16, 17
C. Cardiology and cardiac rhythm management
James L. Cox performed the first maze procedure for atrial fibrillation in 1987. The original maze
procedure involved cutting and sewing multiple incisions in the left and right atria to interrupt all macro
re-entrant atrial fibrillation circuit options in the atria. After several modifications, this surgery is now
known as the MAZE III procedure, and in its modern form most of the surgical incisions have been
replaced by surgically placed linear lesion lines created by alternative energy sources (cryotherapy,
radiofrequency, and high-intensity focussed ultrasound) using specially designed devices.
For AV nodal reentry tachycardias, AV reentry tachycardias, and atrial tachycardias, RFA therapy is
the treatment of choice. More recently, ablation treatments for atrial flutter and fibrillation have also
been developed.

D. Pain management18- 21
The principle behind RF is production of heat that damages some or all of the nerve fibers in the
target neural structure. Its target is to block pain stimuli transmission from peripheral receptors to the
central pain structures. Various studies have documented its effective use for spinal facet pain,
trigeminal neuralgia, cervical radicular pain, chronic shoulder pain, pelvic pain and painful brachial
plexopathy secondary to a metastatic breast tumour.

22
E. Gynaecology
RFA of endometrium is effective in menorrhagia and RF volumetric thermal ablation (RFVTA) system
is used for ablating uterine fibroids.

F. Resistant Hypertension23
Resistant hypertension is defined as blood pressure that remains above the goal pressure despite the
use of at least three antihypertensive drugs of different classes (one being a diuretic). Accumulated
evidence indicates that human sympathetic nervous system deregulation contributes to the
development of arterial hypertension. A higher sympathetic nervous activation was documented in
essential hypertension, obesity-related hypertension, end-stage renal disease hypertension and in
obstructive sleep apnea.
Percutaneous RFA renal denervation is beneficial in milder forms of hypertension or secondary forms
such as end-stage renal disease-related hypertension where sympathetic over activity has been
demonstrated. Insulin sensitivity was improved in essential hypertensive and obstructive sleep apnea-
related hypertension patients, revealing a potential role in metabolic syndrome management as well.

G. Cosmetology26
ThermaCool TC RF device is a capacitive coupling electrode used to improve the neck and cheek
laxity and periorbital rhytides and to elevate the eyebrows. Through capacitive coupling, deep,
uniform and volumetric heating is deployed to tighten and contour both the skin and underlying
tissues. At the same time cryogen cooling is applied to protect the epidermis. It induces tightening of
skin via deep dermis tightening, thereby, resulting in a “non- surgical facelift”.
Many skin lesions are increasingly excised with the help of RFA.

H. Haemostasis27, 28
Effective control of lower GI bleeding in patients with refractory chronic radiation proctitis and control
of arterial bleed in case of stab injury to liver using RFA has been reported.

Advantages of RFA

a) Repeatable procedure
b) Minimally invasive
c) Superior local control
d) Efficacy comparable to tumour resection
e) Can be safely performed in elderly patients with potentially co-morbid diseases
f) May be done under local anaesthesia
 g) Faster recovery
h) Lesser hospital stay

Complications

General
RFA has been shown to be a relatively safe procedure, with mortality between 0.3% and 0.8% and
morbidity between 2% to 10%. Complications include post-procedural pain, post-RFA syndrome with
fever and flu-like symptoms that usually resolve within the first 24 h, skin burns from improperly
placed grounding pads, thermal injury to adjacent structures, bleeding, secondary infection, and
tumour seeding, which can be prevented by cauterization of the needle tract on withdrawal of the
probe.
High frequency signals generated by RFA equipment may interfere with implanted pacemakers or
defibrillators.

Organ Specific:

1. Thyroid29
Major

 Voice change
 Nodule rupture
 Nodule rupture with abscess formation
 Hypothyroidism
 Brachial plexus injury
Minor

 Haematoma
 Vomiting
 Skin burns
Side effects

 Pain
 Vasovagal reaction
 Mild fever
 Coughing

2. Lung1
The majority of complications from thoracic RFA are minor with the most frequently encountered
being pneumothorax, pleural effusions and hemoptysis. Others include pain, fever and
pneumonia.

3. Liver3, 4
 Severe haemorrhage
 RFA needle-track seeding
 Abscess formation
 Perforation of Gastrointestinal tract
 Jaundice
 Liver failure
 Bilioma formation
 Biliary stricture
 Portal vein thrombosis
 Haemothorax or Pneumothorax requiring drainage
 Ascites
 Septicaemia
  Death

13
4. Bone
 Bleeding
 Pathologic fractures
 Skin and muscle burns
 Damage to adjacent neurovascular structures
In order to avoid damaging nerve structures, maintaining a safety distance of 10 mm between the
periosteum and the nearest nerve structure is recommended.

25
5. Varicose vein Surgery
Early

 Failure to ablate
 Pain
 Thrombophlebitis
 Endovenous heat-induced thrombosis
The thrombus can protrude into the common femoral vein (CFV) as well. For safety
purpose it is recommended that the tip of the ablation catheter should be at least 2 cm
from the sapheno femoral junction.
 Deep vein thrombosis
 Wound problems and skin burns
 Lignocaine toxicity
The routine use of tumescent anaesthesia in a clinic room setting has now become an
established way to treat varicose veins. Tumescent anaesthesia consists of lactated
Ringer’s or normal saline fluid combined with lignocaine, epinephrine and optionally
bicarbonate to form a 0.1% anaesthetic solution.

Late complications

 Skin pigmentation
 Nerve damage/paraesthesia
 Recurrence
Recanalization of a vein could be due to either reflux from a tributary or an incompetent
perforator. Similarly, if the main lumen is patent, reflux from the groin due to an accessory
vein can also lead to failure and recurrence.

Advanced techniques of RFA1, 3

1. Artificial ascites method: To avoid burns, artificial ascites is useful for creating a space between
the surface of the liver and the skin, or gastrointestinal tract or diaphragm. The artificial ascites
technique has advantages over artificial pleural effusion because it can avoid interference with the
lungs and gastrointestinal tract at the same time.

2. Pneumoperitoneum: This may also work in a similar manner to the Pringle maneuver and
decrease the heat sink effect in tumours in proximity to large vessels by decreasing portal flow. It
also allows resection or displacement of structures adjacent to tumours that cannot be performed
with the percutaneous technique.

3. Fusion imaging technique: The fusion imaging technique, which is referred to as real time
virtual sonography (RVS), a virtual CT sonography system with magnetic navigation can
synchronize images obtained using B-mode ultrasonography with those obtained using
 multiplanar reconstruction CT on the same screen in real time. This imaging technique is a useful
procedure for detecting unclear nodules on B-mode ultrasonography. The technical success rate
after a single RFA session was found to be significantly higher for patients treated with RVS
assisted RFA than for those treated with RFA using B-mode ultrasonography alone; the number
of treatment sessions was significantly lower for the RVS-assisted group.

4. Contrast-enhanced ultrasonography: Levovist and Sonazoid are contrast agents used in

ultrasonography. The detectability rate for tumour nodules is significantly higher using contrast-
enhanced ultrasonography (CEUS) than with conventional ultrasonography.
3
Future Perspectives of RFA and Emerging Ablative Techniques

1. Radiofrequency thermal ablation using lyso-thermosensitive liposomal doxorubicin (LTLD): Lyso-

thermosensitive liposomal doxorubicin consists of heat-enhanced cytotoxic doxorubicin within a
heat-activated liposome. LTLD is infused intravenously prior to performing RFA. When the
ablated area is heated to >39.50C, LTLD releases doxorubicin in high concentrations into the
targeted HCC and its margins, leading to a larger ablative margin in case of hepatocellular
carcinoma.
2. Irreversible electroporation (IRE): Irreversible electroporation is a non-thermal ablative technique.
IRE is a method for the induction of irreversible disruption of cell membrane integrity resulting in
cell death without the need for additional pharmacological injury. Because IRE is a non-thermal
technique, issues related to perfusion-mediated tissue cooling or heating are not relevant.
3. High-intensity focused ultrasound ablation (HIFU): High intensity focused ultrasound ablation is an
extracorporeal non-invasive ablation mode using focused ultrasound energy, which is capable of
causing coagulative necrosis of the targeted tissues via intact skin without the need for surgical
incision or insertion of instruments. HIFU can provide a potential therapeutic method for the
precise ablation of entire tumours without damaging vital structures.
4. Microwave ablation therapy: Microwaves are currently being developed which offer the
advantages of higher intratumoral temperatures, larger ablative volumes, and faster ablation
times while minimizing energy dissipation.
5. Oncolytic virus therapy
6. Robot-assisted ablation therapy
7. Laser ablation therapy.

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and efficacy of radiofrequency ablation in the management of unresectable bile duct and pancreatic cancer: a
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l) Hegg RM, Schmit GD, Kurup AN, Weisbrod AJ, Boorjian SA, Atwell TD. Ultrasound-Guided Transhepatic
Radiofrequency Ablation of Renal Tumors: A Safe and Effective Approach. Cardiovasc Intervent Radiol. 2013 Aug
9. [Epub ahead of print].
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percutaneous radiofrequency thermoablations of osteoid osteoma. Int Orthop. 2012 Apr; 36(4): 811-5. doi:
10.1007/s00264-011-1402-8. Epub 2011 Nov 4.
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and neck tumors. Arch Otolaryngol Head Neck Surg. 2004 Jan; 130(1): 52-6.
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5(4): 94-101. doi: 10.4330/wjc.v5.i4.94.
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 Robotic Surgery: Overview, Applications and Future Trends
Vivek Bindal

Abstract

Robotic technology is the most advanced development in minimally invasive surgery. There are
several limitations and drawbacks to conventional laparoscopy, including limited movement, the
inability to perform high precision sutures, unnatural positions for the surgeon, and two dimensional
vision. Robotic surgery may overcome these limitations and allows extension of minimally invasive
surgery to an increasing number of patients. The potential advantages of robotic system include its
greater precision, lower error rates, reduced bleeding, shorter hospital stays, more rapid patient
recovery, and reduced pain. It also has ergonomic advantages for the surgeon.

The surgeon directs the robotic arms of the system through a console by means of hand controls and
pedals, making use of a stereoscopic viewing system providing a 3 dimensional view. Robotic system
is currently being used in general, urological, gynaecologic, and cardiothoracic surgery.

However, many issues are still not resolved, such as the clinical feasibility and safety of robotic
surgery in a general surgical context, the length and difficulty of the learning curve, and clinical
applications and drawbacks.

The main aim of this article is to provide an overview of development of robotic surgery, components
of the available Da Vinci Surgical System (DVSS), its clinical applications especially in abdominal
surgery and future trends of development.

Introduction

The use of robotics has been emerging

for about 75 years, however it is only
during the past 5-10 years that the
potential of robotics has been recognized
by the surgical community as a whole.
Robot term was first described by the
Czech playwright Karel Capek in the
classic play "Rossum's Universal Robots
(RUR)". In its original Czech, robota
means forced labour.

Scott Fisher, PhD (at the National

Aeronautics and Space Administration
(NASA) Ames Research Center, Palo
Alto, CA) and Joseph Rosen, MD (Plastic
Surgery, Stanford University, Palo Alto,
CA) gave the earliest conceptions of
surgical robotics in the mid to late
1
1980's. They described the concept of
telepresence surgery in which surgeon
works on computer assisted system to
direct and manipulate robotic arms to
perform the designated function (Figure
1).1 The patient and the surgeon are separated in distance and the communication between surgeon
and robotic arms is either by cables or internet.
Figure 1: Concept of Telepresence Surgery (The surgeon
manipulates the robotic arms sitting at a distance).1
With the advent of Laparoscopic Cholecystectomy in late
1980’s, it was clear that laparoscopic surgery is of major
advantage to the patient. But it posed significant
difficulties to the surgeon like loss of 3D visualisation,
loss of sense of touch and impairment of dexterity due to
fulcrum effect of the instruments. It was immediately
evident that the telepresence system provided a number
of solutions to the laparoscopic surgery problems.

The first robot to be used for surgery was Puma 560, a

passive robot used in 1985 by Kwoh et al to perform
2
neurosurgical biopsies with greater precision (Figure 2).

Integrated Surgical Supplies Ltd. of Sacramento, CA, Figure 2: PUMA 560, the first robot used
2
developed ROBODOC, a robotic system designed to to perform neurosurgical biopsies.
machine the femur with greater precision in hip replacement surgery (Figure 3).3 ROBODOC was the
first surgical robot approved by the FDA and also the first
robot to perform automated procedure on humans. It was
developed for primary total hip replacement, revision hip
replacement and total knee replacement.

The concept of telesurgery became one of the main driving

forces behind the development of surgical robots. The US
Army became interested in the possibility of decreasing
wartime mortality by “bringing the surgeon to the wounded
soldier—through telepresence.” Computer Motion, Inc. of
Santa Barbara, CA, used seed money provided by the Army to
develop the Automated Endoscopic System for Optimal
Positioning (AESOP), a robotic arm controlled by the surgeon
voice commands to manipulate an endoscopic camera.

Shortly after AESOP was marketed, Integrated Surgical

Systems (now Intuitive Surgical) of Mountain View, CA,
introduced the Da Vinci surgical system. Within a year,
Figure 3: Robodoc, the orthopaedic
Computer Motion put the Zeus system into production. The robot used for total hip
Zeus system is composed of a surgeon control console and 3 table-mounted
replacement. robotic arms. The right
3

and left robotic arms replicate the arms of the surgeon, and the third arm is an AESOP voice-
controlled robotic endoscope for visualization. The system uses both straight shafted endoscopic
instruments similar to conventional endoscopic instruments and jointed instruments with articulating
end-effectors and 7 degrees of freedom.

The ongoing patent disputes between the two leading companies ended with the merge of Computer
Motion Inc. and Intuitive Surgical Inc. in
2003. At present, Da Vinci is the only Master Console Patient Cart Vision Cart
surgical system commercially available
with FDA approval for use in clinical
surgery.

Da Vinci Surgical System

 4
Cadie`re and colleagues in April, 1997 performed the first telesurgical laparoscopic cholecystectomy
in human at Brussels, Belgium using da vinci surgical system (DVSS).

In the da Vinci system which evolved from the telepresence machines developed for NASA and the
US Army, there are essentially 3 components: a vision cart that holds a dual light source and dual 3-
chip cameras, a master console where the operating surgeon sits, and a moveable cart, where 2
instrument arms and the camera arm are mounted (Figure 4).

Master Console
This is the place where the surgeon sits comfortably and via hand manipulators controls the
EndoWrist instrument movements at the surgical site (Figure 5a). The Surgeon Console operator sits
outside of the sterile field and controls instruments and a 3D endoscope with his/her hands, using two
master controllers and with his/her feet, using foot pedals. It is also considered the control unit for the
rest of the parts.

The console is provided with a “Stereo Viewer” (Figure 5b) that translates the image of the surgical
site acquired by the endoscope and displays it in front of the surgeon's eyes (surgical immersion). A
3D video image is displayed by the stereo viewer’s integrated left and right video channels when the
endoscope is activated. Instrument tips appear to align with the surgeon's hands at the master
controllers (Figure 5c) as seen in the stereo viewer. This design simulates the natural eye, hand and
instrument alignment of open surgery. Natural alignment, in turn, helps to optimize hand—eye
coordination. This means that the robotic platform allows the surgeon to be as dexterous as in open
surgery while operating in a minimally invasive environment. Further control is provided by motion
scaling and tremor reduction, which minimizes the impact of natural hand tremor or inadvertent
movement. With the lack of tactile feedback provided, care must be taken to pay attention to visual
clues of tissue tension as well as position, tension, and grip strength of the robotic instruments.

Fig 5a: Master Console, the place where the surgeon sits and controls the
instruments and endoscope movements
Figure 5b: Stereo Viewer providing a 3 dimensional view of the surgical field using
dual camera photo system.
Figure 5c: Master Controllers which allow the wrist and finger movements of the
surgeon to be translated into instrument tip movements

The Surgeon Console operator also has the option to change

the view from full screen mode to a multi-image mode (TiIePro
Display), which displays the 3D image of the operative field
along with up to two additional images provided by auxiliary
inputs. This helps in simultaneously view the radiological
imaging during the surgery in the same screen. The footswitch
panel provides the user interface for instrument arm
repositioning, camera and focus control, and energy use during surgery.

Patient Cart

The Patient Cart (Figure 6) is the operative component of the da Vinci System. It is the slave unit of
the system and functions to support the instrument arms and camera arm.

Remote center technology is used in the robotic system. The remote center is a fixed point in space
around which the patient cart arms move. Remote center technology enables the System to
maneuver instruments and endoscopes in the surgical site while exerting minimal force on the
patient's body wall.

The assistant surgeon operates the patient cart, exchanges instruments and endoscopes, and
performs other patient-side activities. The patient cart operator can view the operative site using an
optional touchscreen monitor. To help ensure patient-safety, the actions of the assistant surgeon
operating the patient cart take precedence over actions of the Surgeon Console operator.

Figure 6: Patient Cart with instrument and camera arm to support endowrist instruments and
endoscope. The touchscreen monitor is optional.

EndoWrist instruments
In the robotic surgical system, the tips of the instruments are designed to mimic the dexterity of the
human hand and wrist. It allows seven degrees of freedom and 90 degrees of articulation even
though it cannot be exactly similar with the dexterity of the human hand (Fig. 7a). This is a very
different technology compared with conventional laparoscopic
instruments which have five degrees of freedom and is called an endowrist function. This allows for
greater precision when operating in a minimally invasive environment. These instruments help in the
most rapid and most precise suturing, dissection and tissue manipulation available with any surgical
platform. These instruments are multi-use instruments available in 8mm and being developed in 5mm
diameters. The da vinci 8 mm ports, camera port and endowrist instruments are shown in figure 7b.

Fig. 7a: EndoWrist instruments allowing seven degrees of freedom

Figure 7b: Instruments and ports used in robotic surgery with remote centre technology.

Vision cart
There are two types of vision systems available with the da Vinci System: The Standard Definition
(SD) vision System and a High Definition (HD) vision System. Vision Cart (Figure 8) houses the image
processing equipments of the system. It also provides for an optional touchscreen monitor and
ancillary surgical equipment.

Touchscreen monitor (with

telestration facility)

Illuminator

Camera Control Units

Figure 8: Vision Cart

containing the touchscreen monitor, camera control unit and
illuminator.

Advantages and Limitations

Robotic surgery provides the surgeon with many advantages which enable him / her to provide
minimal access advantage to the patient even for the procedures which are technically difficult to be
performed with laparoscopic means. It also provides him with the ergonomic advantage of sitting
comfortably while performing long procedures. Table 1 compares the advantages and disadvantages
of robot assisted surgery versus laparoscopic surgery giving the explanation for various features in
robotic surgery.

Table 1: Conventional Laparoscopic Surgery versus Robot assisted Surgery

Advantages
Conventional Laparoscopic Robot Assisted Surgery
Surgery
Well developed technology 3 D visualisation
Dual-camera photo system
Affordable & ubiquitous Improved Dexterity
Instruments simulate finger and wrist motion
Proven Efficacy Shorter learning curve
Easy to work in large spaces like Elimination of physiologic tremors
peritoneal cavity Computer smoothes hand movements
Can be done with less Elimination of fulcrum effect
experienced assistant Jointed multi-articulate instruments
Seven degrees of freedom
Ability to scale motion
Computer assisted navigation
Ergonomic position
Surgeon sitting comfortably on console
Telesurgical Ability
Instructions from computer console can be sent to remote
location
Micro anastomosis possible

Disadvantages
Conventional Laparoscopic Surgery Robot Assisted Surgery
Loss of touch sensation Absence of touch sensation
Loss of 3 D visualisation Expert assistant required by patient side
Longer learning curve Requires re-docking if patient position is
changed
Compromised dexterity High start up cost ( > $ 1 million)
Limited degrees of freedom Newer technology with unproven benefit
The fulcrum effect Increased time for OT set up
Amplification of physiologic tremors Bulky equipment

Applications of Robotic Surgery

Robotic surgical systems have been utilized in a wide variety of minimally invasive abdominal surgical
procedures. DVSS is now used in general, urological, gynecologic, and cardiothoracic surgery. It is
being used for radical prostatectomy, pyeloplasty, nephrectomy, cystectomy, esophageal surgery,
bariatric surgery, cholecystectomy, colorectal resection, heller myotomy, fundoplication, hysterectomy,
cardiac septum and valve surgery and gynaecologic surgery (Figure 9). The applications of robotic
system will be discussed in various specialities, especially digestive surgery.

Digestive Surgery
Robotic Heller Myotomy
In robotic-assisted laparoscopic Heller myotomy, the high-definition, three-dimensional visualization
helps a great deal. It is easier to see individual muscle fibers and to be certain that the myotomy is
complete. This is significant because incomplete myotomy is the most common reason for the failure
of a Heller myotomy. The use of a robotic surgical system in laparoscopic Heller myotomy may also
5
help decrease the incidence of esophageal mucosal perforation. This event occurs in approximately
4% to 5% of laparoscopic Heller myotomies and is a dreaded complication especially if not
recognized intra-operatively.

Iqbal etal in their series of 19 robotic myotomies found no intra-operative esophageal perforation.6
This was in comparison to a 7.8% mucosal perforation rate for standard laparoscopic heller myotomy
in 51 cases.

Horgan et al reported a significant postoperative difference in the pressure exerted by the inferior
7
esophageal sphincter (3 mm Hg in favor of DVSS).

In conclusion, with respect to Heller myotomy, DVSS appears to be associated with a much lower risk
of perforation and a better quality of life.

Robotic Fundoplication
Several studies have been published comparing robotic with conventional laparoscopic
fundoplication8-10.

Morino et al conducted a prospective randomized trial of robot-assisted vs. laparoscopic Nissen

fundoplication in 50 consecutive patients at the University of Turin, Italy. 10 Twenty-five patients
underwent robot-assisted surgery using the da Vinci surgical system and 25 patients had a standard
laparoscopic fundoplication. Total operating time and skin-to-skin time were significantly shorter for
conventional laparoscopy. The cost of a robot-assisted procedure was significantly higher than that
for standard laparoscopic fundoplication (3157 euros vs.1527 euros; P <0.001). There were no
significant differences in clinical, endoscopic, or functional outcomes between groups.

Giulianotti et al in their series found that the morbidity rate and mean postoperative hospital stay for
robotic and laparoscopic procedures were 4.8% and 4 days and 11.4% and 6 days, respectively.8
They found that there was an improvement in the surgery time in first 21 and last 20 patients (133
minutes compared to 92 minutes).

The relevant literature appears to demonstrate that robotic antireflux surgery is feasible and safe, but
there seems to be no major difference in clinical outcomes when compared to standard laparoscopic
antireflux surgery. Operating time and costs are increased for computer-assisted antireflux surgery
compared to the conventional laparoscopic approach. On the other hand, it increases the surgeon
comfort, dexterity and the precision of surgery. Because of a small, deep fixed operative field in
fundolication, there is a role of robotic surgery. But at the current level of technology, computer-
assisted antireflux surgery does not appear to offer major clinical advantages to patients with access
to skilled and experienced laparoscopic
surgeons. Fundolication along with
cholecystectomy act as good training
models for learning robotic digestive
surgery.

Robotic Bariatric Surgery

The use of multi-articulated instruments and
increased freedom of movements with
robotic device helps to make a hand sewn

Figure 9: Robotic Bariatric Surgery under progress

gastrojejunostomy in gastric bypass a more plausible approach. Intracorporeal suturing and knot tying
are ideally suited to a robotic approach. In a robotic-assisted gastric bypass, the robotic device is
used for suturing the gastrojejunostomy. The rest of the procedure is typically conducted with
standard laparoscopic techniques.

Mohr et al studied totally robotic RYGB procedures. The median surgical time (169 vs. 208 minutes; P
= 0.03) and median operative time divided by body mass index (BMI) (3.8 vs. 5.0; P = 0.04) were
significantly lower for the totally robotic procedures.11 The authors concluded that totally robotic RYGB
was superior to laparoscopic RYGB and that it is associated with a shorter learning curve.

Robotic surgical systems have also been successfully used in adjustable gastric band placement.
Horgan et al. reported operative outcomes for 32 robot-assisted adjustable gastric band placements.
Robotic gastric band placement was associated with a low complication rate and a similar length of
stay as gastric bands placed with conventional laparoscopy.

Robotic bariatric surgery has been shown to be feasible and safe. It is likely that robotic surgical
system may reduce the learning curve for procedures like RYGB as compared to standard
laparoscopic techniques. It may also be of help in higher BMI patients.

Colorectal Surgery
Robotic system in colorectal surgery is particularly helpful at specific stages including takedown of the
splenic flexure, dissection of a narrow pelvis, identification of nervous plexus, and hand-sewn
anastomosis. It helps in better visualisation and ease of working in a limited space as in pelvis.
Superior high definition three dimensional vision means easy identification of nervous plexus. On the
other hand, table repositioning as required in many colorectal procedures spanning multiple
quadrants of the abdomen is difficult. So, many surgeons use double docking technique in which
robot is docked twice in different table positions. As per the available literature, DVSS would appear
to take longer and be more expensive than conventional laparoscopic surgery but less risk of
conversion to open surgery, although there appears to be no difference in blood loss, number of
lymph nodes, number of complications, number of total conversions, or length of hospital stay. 12-14

Cholecystectomy / Solid organ surgery

Robot-assisted laparoscopic cholecystectomy is a safe and effective bridge to advanced robotics in
general surgery. There is a significant learning curve (around 20–30 cases) to gain experience for
setting up the robotic instrumentation, which appears to be much less steep for the actual use of the
15
machine. It can be of value in cases of acute and chronic cholecystitis, where vision is impaired by
inflammation, where there is an increased tendency for diffuse bleeding in the dissection field, and
edema and fibrosis make the dissection difficult. In cases of complex gallstone disease like CBD
exploration or choledochoenterostomy, robotic device has a beneficial role by providing much needed
dexterity, 3D visualisation and increased degrees of freedom.16

Robotic cholecystectomy may prove its value in cases of complex gallstone disease and is an
excellent procedure for teaching the basics of robotic surgery. With the advent of single site robotic
systems (not yet FDA approved), benefit is given to the surgeon in terms of better ergonomics while
doing single site surgery.17 Further studies are needed to identify the benefits to the patient and
compare it to the additional cost of robotic cholecystectomy before routine application of this
technique can be justified.

Use of DVSS has been described for splenectomy, pancreatic resections and adrenalectomies. There
are small published series and they find that these surgeries are technically feasible and safe. But
most investigators find that robotic procedure is associated with an increase in operative time and
cost.
Urologic Surgery

There are multiple large series of robotic prostatectomies published in the literature. Compared to
18
open prostatectomy, the robotic technique seems to be associated with a similar oncologic outcome.
Demonstrated benefits of robotic prostatectomy include a shorter hospital stay, less pain, less blood
loss and fewer transfusions, and even better erectile function outcomes than conventional open
nerve-sparing prostatectomy. The standard laparoscopic radical prostatectomy was not widely
popular among urologists due to the difficulty faced with an extensive learning curve.

Robotic approach is beneficial in prostatectomy as the operative site is in the narrow confines of the
male pelvis with limited working space, and increased degrees of freedom of the endowrist
instruments allow cystourethral anastomosis to be completed with relative ease. These advantages
have made robotic approach as the gold standard in radical prostatectomy.

Thoracic Surgery

The da Vinci Surgical System has been used successfully for thymectomy, lobectomy,
esophagectomy, and resection of mediastinal tumors. Robotic devices have proven to be particularly
beneficial in minimally invasive thymectomy as a treatment for myasthenia gravis or thymoma. The
thymus is located in the anterior mediastinum in an anatomic area difficult to access with traditional
thoracoscopy. Robotic instrumentation with a full 7 degrees of articulation can maneuver around
corners, vital vessels, and nerves (phrenic) encountered in the tight confines of the anterior
mediastinum.

Rea et al in Italy have utilized the da Vinci system in 33 thymectomies with good results and minimal
morbidity.19 These authors concluded that the robotic devices, when compared to traditional rigid
thoracoscopic instruments, allow easier and safer access to the thymus in the neck region and the
contralateral hemithorax.

Gynaecologic Surgery

Several series of robotically assisted laparoscopic surgical hysterectomies have been reported, with
generally good results. A recent study by Payne et al comparing straight laparoscopic hysterectomy to
RALH, noted that the robotic cohort was associated with significantly less blood loss, decreased
20
hospital stay, but longer operative time. The intra-operative conversion rate to abdominal route from
laparoscopic dropped from 9% to 4% when the robot assistance was introduced and there were no
post-operative exploratory laparotomy in the robotic cohort. In another similar study by Sakhel et al,
RALH was associated with less total operative room time, less blood loss and no conversion to
laparotomy as compared to 11% conversion rate with straight laparoscopic hysterectomy. 21

Advantage of robotic system has been seen in radical hysterectomy with associated lymph node
dissection. Minimally invasive tubal reanastomosis with a robotic surgical system has been reported in
small numbers of patients. The scaled motion and lack of tremor allow for precise suturing with
interrupted 8-0 sutures, similar to that used in open microsurgical tubal reanastomoses.

Cardiac Surgery

DVSS was originally designed for use in closed chest cardiac surgery, but is now mostly used in other
areas. It has been successfully used in minimally invasive mitral valve repair and replacement with
good results, including a shorter length of stay and fewer blood transfusions than in open surgery. In
the future, it is likely that multi-vessel or off-pump totally endoscopic robotic coronary artery bypass
will be possible.

Future Developments

There is a long delay between the idea and commercialization of products, and robotic surgery is only
in its infancy. Several fascinating new developments may change how we use the robotics in the near
future. Miniaturization of robotic technology appears to be the theme of the new generation of
devices. Robots that are smaller than current systems have a natural advantage because they are
easier to deploy and can be used in more settings. The University of Washington group has
developed a smaller prototype machine that has the capability of being mounted on the patient and
controlled remotely. This robot, named RAVEN, has been prototyped and tested in the field. Due to its
22
smaller size and updated enhancements it can be deployed in remote areas and teleoperated.

Other robotic technology allows the surgeon to make rounds while sitting in a remote location. This
device developed by Dr. Yulun Wang is called the RP-7 (In Touch Health, Santa Barbara, California)
and is a mobile robotic platform that enables the physician to be remotely present by controlling robot
movements via the internet.23

Robotics provides a unique possibility of separating the surgeon from the patient. This separation can
be measured in feet or in thousands of miles. Telesurgery along with telementoring has been now
been tested in several environments and has been shown to be feasible and beneficial. The removal
of a gallbladder across the Atlantic Ocean and the mentoring of surgeons in Canada are examples of
how technology is rapidly approaching the day when any surgeon can be connected to a number of
colleagues who may be able to consult and in some cases assist during complex surgical
procedures.24

Natural orifice translumenal endoscopic surgery (NOTES) is a new approach to abdominal surgery
that promises to further reduce invasiveness by accessing the peritoneal cavity from a natural orifice.
A first-generation device for teleoperated endoluminal surgery, the ViaCath System, has been
developed by EndoVia Medical (Norwood, Massachusetts). The device consists of a console and two
flexible instruments located alongside a standard endoscope. A four-channel platform scope
(TransPort, USGI Medical, San Capistrano, California) based on the ShapeLock locking overtube has
been developed.25

Miniaturization of robotic tools and the ability to place robots entirely inside the peritoneal cavity offers
significant benefits in natural orifice procedures. Once inserted, the robots can be used inside the
peritoneum without the typical constraints of an externally actuated flexible endoscopic device. The
robots can be positioned to provide visualization and tissue manipulation within each quadrant of the
peritoneal cavity. Multiple miniature robots can be placed inside the peritoneal cavity, with the number
of devices not limited by the small diameter of the natural orifice. Such robots equipped with
stereoscopic imaging could provide much needed depth perception for the surgeon and could allow
triangulation between the image plane and the motion of the tools. The feasibility of using in vivo
mobile robots for NOTES procedures has been successfully demonstrated in a porcine model. 26

New technologies are sure to follow along, and this field will not look the same in 10 to 15 years. It
can be expected that we will continue to move toward more automation, more computer interface, and
more mechanical assist and further away from the open surgical techniques that were pioneered in
the years before.
There is a long delay between the idea and commercialization of products, and robotic surgery is only
in its infancy. Several fascinating new developments may change how we use the robotics in the near
future. Miniaturization of robotic technology appears to be the theme of the new generation of
devices. Robots that are smaller than current systems have a natural advantage because they are
easier to deploy and can be used in more settings. The University of Washington group has
developed a smaller prototype machine that has the capability of being mounted on the patient and
controlled remotely. This robot, named RAVEN, has been prototyped and tested in the field. Due to its
22
smaller size and updated enhancements it can be deployed in remote areas and teleoperated.

Other robotic technology allows the surgeon to make rounds while sitting in a remote location. This
device developed by Dr. Yulun Wang is called the RP-7 (In Touch Health, Santa Barbara, California)
and is a mobile robotic platform that enables the physician to be remotely present by controlling robot
movements via the internet.23

Robotic Surgery at SGRH

Sir Ganga Ram Hospital is one of the premier centres in Minimal Access and Robotic Surgery.
Institute of Minimal Access, Metabolic & Bariatric Surgery (iMAS) is the leading department having
done more than 50 cases of Robotic Bariatric Surgery in last one year. We feel that use of Robot in
Bariatric Surgery is a great advantage in super-super obese patients as it adds to the dexterity of the
surgeon. It provides for better and precise movements in patients with very heavy liver and limited
working space. It provides advantage in suturing while doing Gastric Bypass and oversewing the
staple line in Sleeve Gastrectomy.

The faculty in iMAS, SGRH has been trained in Robotic Surgery at various places around the world
including University of Illinois at Chicago (Prof. PC Giulianotti), Florida Hospital Celebration Health
(Dr. Keith Kim), IRCAD (Strasbourg, France) and International Robotic Training School (Grosseto,
Italy).

Other specialities including Urology, Thoracic Surgery, Gynaecology and Vascular Surgery are also
using robotics for various procedures.

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1. Fisher SS, McGreevy MM, Humphries J, and Robinett W. Virtual Environment Display System. In: Crow F and
Pizer S (Ed) Proceedings of the Workshop on Interactive 3-D Graphics 1:1-12, 1986.
2. Kwoh YS, Hou J, Jonckheere EA, et al. A robot with improved absolute positioning accuracy for CT guided
stereotactic brain surgery. IEEE Trans Biomed Eng. 1988;35:153–61.
3. Paul, HA, Bargar WL, Mittlestadt B, Musits B, Taylor RH, Kazanzides P, Zuhars J, Williamson B, Hanson W,
Development of a surgical robot for cementless total hip arthroplasty.Clin Orthop 1992 Dec;(285):57-66
4. Cadiere GB, Himpens J, Germay O, et al. Feasibility of robotic laparoscopic surgery: 146 cases. World J Surg
2001;25:1467-1477.
5. Melvin WS, Dundon JM, Talamini M, et al. Computer-enhanced robotic telesurgery minimizes esophageal
perforation during Heller myotomy. Surgery 2005;138:553-8.
6. Iqbal A, Haider M, Desai K, et al. Technique and follow-up of minimally invasive Heller myotomy for achalasia.
Surg Endosc. 2006;20:394–401.
7. Horgan S, Galvani C, Gorodner MV, et al. Robotic-assisted Heller myotomy versus laparoscopic Heller myotomy
for the treatment of esophageal achalasia: multicenter study. J Gastrointest Surg. 2005;9:1020 – 9.
8. Giulianotti PC, Coratti A, Angelini M, et al. Robotics in general surgery: personal experience in a large community
hospital. Arch Surg. 2003;138: 777–84.
9. Melvin WS, Krause KR, Needleman BJ, et al. A prospective trial of laparoscopic vs. computer assisted robotic
Nissen fundoplication. J Gastrointest Surg 2002;6:11-6.
10. Morino M, Pellegrino L, Giaccone C, et al. Randomized clinical trial of robot-assisted versus laparoscopic Nissen
fundoplication. Br J Surg 2006;93:553-8.
11. Mohr CJ, Nadzam GS, Curet MJ. Totally robotic Roux-en-Y gastric bypass. Arch Surg. 2005;140:779 –86.
12. Spinoglio G, Summa M, Priora F, et al. Robotic colorectal surgery: first 50 cases experience. Dis Colon Rectum.
2008;51:1627–32.
13. Rawlings AL, Woodland JH, Vegunta RK, et al. Robotic versus laparoscopic colectomy. Surg Endosc.
2007;21:1701–8.
14. Pigazzi A, Ellenhorn JD, Ballantyne GH, et al. Robotic-assisted laparoscopic low anterior resection with total
mesorectal excision for rectal cancer. Surg Endosc. 2006;20:1521–5.
15. Jayaraman S, Davies W, Schlachta CM. Getting started with robotics in general surgery with cholecystectomy:
the Canadian experience. J can chir. 2009;52(5):374-8.
16. Breitenstein S, Nocito A, Puhan M, et al. Robotic-assisted versus laparoscopic cholecystectomy: outcome and
cost analyses of a case-matched control study. Ann Surg. 2008;247:987–93.
17. Morel P, Hagen ME, Bucher P, Buchs NC, Pugin F. Robotic Single-Port Cholecystectomy Using a New Platform:
Initial Clinical Experience. J Gastrointest Surg [Epub Sep 27, 2011].
18. Kaul S, Bhandari A, Hemal A, et al. Robotic radical prostatectomy with preservation of the prostatic fascia: a
feasibility study. Urology 2005;66(6):1261-5.
19. Rea F, Marulli G, Bortolotti L, et al. Experience with the “daVinci” robotic system for thymectomy in patients with
myasthenia gravis: report of 33 cases. Ann Thorac Surg 2006;81(2):455-9.
20. Payne TN, Dauterive FR. A comparison of total laparoscopic hysterectomy to robotically assisted hysterectomy:
surgical outcomes in a community practice. J Minim Invasive Gynecol. 2008 May-Jun; 15 (3):286-91.
21. Sakhel K, Kirakosyan A, Lukban J, Hines J. Comparison between Robot-Assisted Laparoscopic Hysterectomy
and Total Laparoscopic Hysterectomy - A Cohort Study. Presented at the AAGL annual meeting, 38th Global
Congress, Orlando, November 17th 2009.
22. Oleynikov D. Robotic Surgery. Surg Clin N Am 88 (2008): 1121–1130
23. Ellison LM, Nguyen M, Fabrizio MD, et al. Postoperative robotic telerounding: a multicenter randomized
assessment of patient outcomes and satisfaction. Arch Surg 2007;142(12):177–81 [discussion: 1181].
24. Sebajang H, Trudeau P, Dougall A, et al. The role of telementoring and telerobotic assistance in the provision of
laparoscopic colorectal surgery in rural areas. Surg Endosc 2006;20(9):1389–93 [Epub 2006, Jul 3].
25. Swanstrom LL, Whiteford M, Khajanchee. Developing essential tools to enable transgastric surgery. Surg Endosc
2008;22:600–4.
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2007;21(7):1212–5.
Scientific Basis of Symptoms, Signs, Investigations and Treatment
of Chronic Arterial Insufficiency
Pawanindra Lal
liv
Overview of Chronic Arterial Insufficiency

Chronic Arterial Insufficiency of the lower limbs refers to slowly progressive peripheral arterial
occlusive disease wherein the patient suffers from symptoms of limited circulation over a period of
months or years. There is slow deterioration in function along with increase in symptoms and signs.
Due to the slow progression of disease, there is time for the limb to develop alternative circulation
through collateral vessels. Based on the duration of ailment, the following classification is helpful to
distinguish acute ischaemia from chronic ischaemia in the clinical setting. In acute arterial
insufficiency, the presentation is dramatic largely due to the absence of any alternative collateral
circulation. This chapter would mainly focus on various aspects of atherosclerotic chronic arterial
insufficiency of the lower limbs.

Table No 1: Classification of Limb Ischaemia

Terminology Definition or comment
Onset:
Acute Ischaemia <14 days
Acute on chronic Worsening symptoms and signs (<14 days)
Chronic Ischaemia stable for >14 days
Severity (acute, acute on chronic):
Incomplete Limb not threatened
Complete Limb threatened
Irreversible Limb non-viable

The symptoms and signs of chronic arterial insufficiency are

a) Claudication
b) Rest Pain
c) Ulceration
d) Gangrene

In contrast, the Symptoms and signs of acute limb ischaemia are as shown in Table 2.

Table No 2: Symptoms & Signs of Acute Ischaemia

Symptoms or signs Comment
Pain Occasionally absent in complete ischaemia
Pallor Also present in chronic ischaemia
Pulseless Also present in chronic ischaemia
Unreliable as ischaemic limb takes on ambient
Perishing cold
temperature
Leading to anaesthesia (unable to feel touch
Paraesthesia*
on foot or hand)
Paralysis* Unable to wiggle toes or fingers
*Anaesthesia and paralysis are the key to diagnosing complete ischaemia that requires emergency
surgical treatment

Aetiology of Chronic Arterial Insufficiency or Chronic Ischaemia:

Chronic ischaemia is related to progressive narrowing of the lumen of the artery supplying the limb.
The commonest causes are enumerated below:

1. Atherosclerosis – Affecting Large and Medium sized vessels. It is complex chronic inflammatory
process affecting the elastic and muscular arteries and the disease is systemic and segmental in
presentation.

Table No 3: Risk Factors for Atherosclerosislv

  Hypercholesterolemia - ↑ LDL & ↓ HDL
 Hypertension
 Cigarette Smoking – Tobacco metabolites on
vascular endothelium – 4X higher risk.
 Diabetes Mellitus (3-5X)

lvi
Table 4: Pathophysiological Effects of Smoking
Whole vessel effect Vasoconstriction
Hypertension
Endothelial effect Increased endothelial denudation
Increased endothelial cell turnover
Decreased endothelial PGI2 production
Platelets effects Increased platelet counts
Increased platelet aggregation
Increased platelet adhesiveness Increased TXA2 production
Lipid effect Decreased HDL
Coagulation effects Decreased fibrinolytic activity
Increased blood viscosity
Increased fibrinogen levels

The atheromatous plaque consists of smooth muscle cells, connective tissue (matrix), lipid and
macrophages. It tends to localise at the sites of bifurcations or bends where turbulence, sheer
stress, flow separation and stasis are known to occur.

2. Buergers Disease (Thromboangiitis obliterans): This is a disease involving medium and small
sized muscular arteries associated with smoking in a relatively young male with predilection for
tibial vessels. Rest pain, gangrene and ulceration are usual presentations with history of migratory
thrombophlebitis.

Table 5 - Diagnostic Criteria for Thromboangiitis Obliteranslvii

 Age younger than 45 years
 Current or recent history of tobacco use
 Presence of distal extremity ischemia (claudications, pain at rest, ischemic ulcers)
 Exclusion of autoimmune diseases, hypercoagulable states and diabetes mellitus
 Exclusion of a proximal source of embolization by echocardiography and arteriography
 Consistent arteriographic findings in the clinically involved and noninvolved limbs

3. Takayasu’s arteritis is a disease affecting the brachio-cephalic vessels in a young female

commonly referred to as pulse less disease.

4. Temporal arteritis or giant cell arteritis is a disease affecting the temporal vessels in females
after 50 years of age and presenting with headaches.

5. Raynaud’s phenomenon (RP) is a manifestation in the upper limbs – Primary (also referred to
as Raynaud’s disease – where RP is in the absence of any primary disease and Secondary
when it is associated with occupation/drugs/connective tissue disorders/thoracic outlet syndrome
etc. This is a condition of vasospasm which comprises of three stages namely, pallor
(vasoconstriction) which is followed by cyanosis (accumulation of deoxygenated blood) and lastly,
rubor (return of blood flow leading to reactive hyperemia) due to compensatory vasodilatation.

Clinical Features of Chronic Ischaemia

The hall mark clinical presentation of a chronically ischaemic limb is intermittent claudication
progressing gradually to constant rest pain which then leads to colour changes of pregangrene and
ultimately to frank gangrene and ulceration.

Intermittent Claudication
This is a special character of pain described for arterial disorders. This is a clinical condition where a
cramping, aching or tightness like severe pain appears in the leg affected during exercise, usually
16
after a fixed level of exercise and is promptly (within two to three minutes) relieved with rest . It Is
due to the accumulation of Substance P which fails to get washed away due to poor blood supply.
The site of claudication gives an important clue to the level of blockage. This vascular claudication
needs to be differentiated from spinal claudication which is due to compression of spinal nerves due
to spinal stenosis.

Table 6: Difference between Vascular & Spinal Claudication

Vascular Claudication Spinal Claudication
 Never present on standing or start of walking  Pain brought on by weight bearing or taking
or on first step first step.
 Pain is cramping/aching in a muscle group  Pain classically radiated down the back of
supplied by proximal vessels leg with associated numbness or tingling or
 Always brought on by walking and relieved altered sensation
on rest.  Is brought on by extension of spine and
relieved by flexion, “simian stance”

Table 7: Presentation according to site of block

Site of Blockage Clinical Presentation
Aorto-Iliac Disease Buttock, Thigh & calf claudication. Leriche
Syndrome
Common Femoral Disease Thigh & Calf Claudication
Superficial Femoral Disease Calf claudication
Popliteal Artery Disease Calf claudication
Crural Artery Disease Calf & Claudication

Table 8 : Boyd’s classification of intermittent claudicationlviii:

Grade I Pain starts but if the patient continues to walk the metabolites increase the muscle
blood flow and sweep away the P- substance produced by exercise and pain
disappears.
Grade 2 Pain continues but the patient can still walk with effort.
Grade 3 Pain compels the patient to take rest.
Grade 4 Rest pain

Table 9: Factors Affecting Claudication Distance

 Excess Weight
 Walking Uphill
 Walking against Wind
 Carrying Shopping/load

Rest pain
This is said to be the “cry of dying nerves”. It is a severe pain described as “agonizing” or “burning”
felt in the foot at rest, made worse by lying down or elevation of the foot. The pain is felt first in the
most distal part of the leg, in the toes and the instep of the foot. It is due to the ischaemia of the skin
and subcutaneous tissues, which are richly supplied by nerves. Characteristically, the pain is worse at
night largely due to absence of gravity effect in the supine position aiding blood flow to the limb and
partly due to lower blood pressure and heart rate while sleeping leading to decreased blood flow to
the limb. The patient might attempt to overcome this somewhat by using “gravity aid” and hanging the
foot out of the bed or by sleeping in chair. This attitude leads to pedal oedema and thereby worsening
of microvascular perfusion. Paradoxically, a limb with rest pain may appear bright red due to
accumulation of vasodilator metabolites. Rest pain is completely different from night cramps
commonly seen in the elderly.

Critical Limb Ischaemialix

It is defined as persistently recurring rest pain requiring regular analgesia for more than 2 weeks, or
ulceration or gangrene of the foot or toes, with an ankle systolic pressure of less than 50 mm Hg or a
toe systolic pressure of less than 30 mm Hg. This applies to both diabetic and non- diabetic patients.
It is imperative to determine whether the limb is critically ischemic or not so that appropriate
management can be instituted.

Pregangrene: This is an older terminology, which refers to the presence of two or more of clinical
findings, which are harbingers of imminent gangrene in a critically ischemic limb.

Table 8: PreGangrene
 Rest Pain
 Oedema
 Hyperaesthesia
 Colour Changes
 Ulceration

TABLE 9 - Fontaine classification of limb ischaemia

Stage 1 No clinical symptoms
Stage 2 Intermittent claudication
Stage 3 Ischaemic rest pain
Stage 4 Ischaemic ulcer, gangrene

Clinical Examination

Physical examination involves inspection of the extremities for signs of chronic ischaemia like thin,
shiny skin, loss of hair and subcutaneous fat, presence of brittle nails with transverse ridges and
areas of minor ulceration and differentiation from signs of acute arterial occlusion like pallor,
pulselessness, poikilothermia, pain, paraesthesia and paralysis. All the peripheral pulses have to be
palpated with care and recorded. It is important to know the site of palpation of each pulse and the
bony prominence against which it is palpated. It is important to note temperature difference between
two limbs if any, skin changes of ischemia, muscle wasting, Capillary and Venous Refilling, Buerger’s
Angle, perform Buerger’s Test, and differentiate an arterial ulcer from a venous ulcer. Similarly, dry
gangrene has to be differentiated from wet gangrene. It is possible for patients with proximal stenosis
to have a palpable distal pulse at rest and it is important to look for their disappearance on exercise. It
is also important to perform a detailed and appropriate neurological assessment to differentiate spinal
from vascular claudication.

Investigations

General
a) Blood: Routine examination of blood including a hemoglobin percent (low Hb% can decrease
claudication distances and aggravate rest pain), blood sugar examination as diabetics have worse
prognosis, are essential. Erythrocyte sedimentation rate (ESR) is usually raised in Buerger’s
disease. In patients with high suspicion of underlying connective tissue disorders, specific test like
RA factor, LE cell phenomenon etc. may be carried out. Lipid profile is mandatory in elderly
patients with atherosclerosis.
b) Urine examination for sugar.
c) Plain X-ray of the abdomen will show the presence of arterial calcification and flecks of calcium
may outline an aneurysm.
d) ECG: an abnormality in ECG may influence the decision for surgery, in patients with lower limb
disease.

Tests of global Vascular Status

lx
a) Hand Held Doppler ultrasound blood flow detection uses a continuous wave ultrasound signal,
beamed at an artery and a receiver picks up the reflected beam. The changes of frequency in the
reflected beam, as compared with the transmitted beam, are due to the “Doppler shift”, resulting
from passage of beam through moving blood. These frequency changes are converted to audio
signals. This investigation may be used effectively in cases where a differential diagnosis of
 atherosclerosis is entertained showing the site of block and extent of distal run-off. A 8-10 MHz
continuous waver Doppler ultrasound probe is used to assess the posterior tibial (PT), dorsalis
pedis (DP) and peroneal arteries. A normal pedal pulse produces a Doppler signal with 2 or 3
distinct phases with a clear sharp sounding systolic peak. The reduction in the pitch of this signal
and a lack of the phasic components is recognized as abnormal finding. In low arterial flow
conditions, it becomes difficult to differentiate between arterial from venous flow. In such a
situation, application of compression in the distal part of the limb would tend to augment in case of
a venous signal but will leave the arterial signal unaffected.
6:
b) Ankle Brachial systolic blood pressure index (ABPI) This measurement gives the
quantitative assessment of the global limb arterial perfusion. Patient lies supine, all
measurements are at the level of the heart and only after resting for 10-15 minutes. A standard
BP cuff of 15-20 cm width is positioned in the ankle just above the malleoli. A 8-10 MHz Doppler
ultrasound probe is used to hear the pedal Doppler signals and inflated above the systolic
pressure for the signals to disappear. The point at which the Doppler signals first returns on
gradually lowering the pressure marks the systolic pressure at the ankle level. Normally an
average of 2 measurement for each of the arteries namely dorsalis pedis and posterior tibial is
used to denote the ankle pressure. Similar procedure is done for brachial artery. The ratio of the
highest recorded systolic pressure at the ankle to the brachial systolic pressure at the arm forms
the ABPI. The ankle brachial index is interpreted in the manner as given in Table 4. As a thumb
rule, patients with ABPI of 0.8 or 0.9 have moderate peripheral vascular disease, those between
0.5 to 0.8 suffer from intermittent claudication and those with < 0.5 may suffer from rest pain,
ulceration or gangrene.

Table 10 – Ankle Brachial Pressure Index

ABI Interpretation
1.1 ± 0.1 Normal
0.6 ± 0.2 Intermittent claudication
0.3 ± 0.1 Ischaemic rest pain
0.1 ± 0.1 Ischaemic ulceration or gangrene

“Segmental pressures”, i.e. differences in arterial blood pressure between segments of limb can be
detected to give indication of the sites of stenosis, specially as Buerger’s is said to be a segmental
disease.

c) Toe Pressures Using Photoplethysmograph: These are used when the arterial disease is
suspected between the ankle and the toes. The measurement is done using a an occlusion cuff of
2-3 cm diameter placed around the great toe or 2nd or 3rd toe and the digital pulse is recorded by a
photoelectric cell placed on the toe. The measurements are recorded on a strip chart recorder
with cuff pressures being recorded simultaneously. Toe pressures are normally lower than the
brachial or the tibial arteries at the ankle due to high resistance created by small digital arteries.
Toe pressures are also indicated as a percentage of the brachial artery pressure referred to as
the Toe Brachial Index (TBI). Normal ratio is 0.8-0.9. Patients with claudication have TBI of 0.2-
0.5 and those with CLI have TBI<0.2

d) Pole Test: This is used to determine the adequacy of lower limb blood flow in patients with
incompressible vessels or who are unable to tolerate an ankle pressure cuff. It involves listening
to the pedal pulse using the hand held Doppler probe while the patient’s leg is raised against a
pole. The height at which the Doppler signal disappears is reflected by the markings in mm Hg in
a calibrated pole directly. A maximum of 60-70 mm Hg only can be recorded since the test is
limited by the height upto, which the patient is able to lift the leg.

e) Transcutaneous Oximetry (TcPO2): It is based on the principle that the partial pressure of the
oxygen, which diffuses through to the surface of the skin, reflects the oxygen tension of the
underlying tissues. It is time consuming and is best used in the selection of amputation sites since
it correlates well to subsequent stump healing.

f) Walk Test: The basis of this test is that measurement of ABPI before and after a patient has
walked can expose less severe or compensated peripheral vascular disease. The walk can be
standard or graded (incline) using a treadmill. A reduction in ABPI of >20% indicates presence of
 severe arterial disease. In normal limbs, there is a rise or status quo in the ABPI. As a rough
guide, post exercise ABPI of 0.8-0.9 confirms claudication caused by moderate disease, 0.5-0.7
indicates significant disease and <0.5 denote severe arterial insufficiency.

Tests for Disease Localisation

a) Duplex imaging6 gives accurate information on the size of artery, the flow rate, turbulence and the
presence of stenosis. The combination of Doppler and color mapping allows easy recognition of
stenotic sites. This has been achieved by the use of pulsed or continuous wave Doppler and the
two- dimensional images produced by the B- scan made either singly or in combination. Peak
systolic velocity at the site of stenosis is compared to that measured proximally to obtain a peak
systolic velocity ratio (PVR) and relates to the degree of stenosis. A 2x increase in PVR at a
stenosis corresponds to 50% reduction in diameter on arteriography. This modality is non invasive
and has now become the mainstay of assessment of arterial insufficiency, and has largely
replaced routine use of conventional arteriography. This requires detailed assessment of each
major arterial segment i.e Aorta, Iliacs, Femoropopliteal and infrapopliteal segments. This
investigation has virtually become the first line investigation to localize the level of block with a
great deal of accuracy.

b) Intravascular Ultrasound: Minute ultrasound probes with 10MHz transducers mounted on tips of
small 3-4 F catheters are placed directly in the lumen of the arteries over a guidewire and produce
intravascular ultrasound images which give details of arterial walls, luminal contents and
dimensions. This is not a routine investigation for peripheral arterial disease and as yet is not cost
effective.

c) Arteriography: This is an invasive technique which though has become much safer in the recent
years due to fine 3-4 F catheters, and remains the gold standard to provide a road map required
for vascualt surgeons expecially before surgery is planned. However, alternative modalities have
emerged which seem more attractive and safer largely because they are non invasive and lack
the potential hazards of arteriography like allergies to contrast agents, use of ionizing radiation,
and technique related problems like hematoma, arterial spasm, sub-intimal dissection, infection,
pseudoaneurysm, AV fistula and embolisation. Angiography remains still the preferred
investigation before percutaneous transluminal angioplasty or definitive bypass surgery is
performed but is slowly being pushed away by the following non invasive techniques as they are
improving with technology.

d) CT Angiography: The introduction of the helical (spiral) CT scanning and multidetector CT which
uses 2 or 4 helicals to scan the patient, CT imaging has been revolutionized for vascular imaging
wherein a single breathhold time is sufficient to generate the scans from the aortic arch to the
groins with imaging quality as good as conventional angiography. However, it still uses ionizing
radiation and iodinated contrast agents and therefore it has not yet gained usage for peripheral
arterial disease. It is however, the imaging of choice for pre-operatibe assessments of aneurysms.

e) MR Angiography: Increasing usage of Magentic Resonance Imaging in the last decade and
improvement in technology has seen a shift towards using this modality for assessment of
vascular system. Earlier, Time of Flight MRI and Phase Contrast MRI were used to visualize
moving blood as a white image but the definition and clarity of the vessels was found to be inferior
to angiograms. More recently, Gadolinium Enhanced MRI (Gd-MRI) has significantly improved
this quality of image and made it comparable to conventional angiography. The disadvantage is
the high cost of the contrast material and availability of the MRI technology. As of now Gd-MRI is
being used more often for assessment of peripheral limb ischaemia in combination with Dupleix
Scanning and Conventional catheter angiography has been reserved where findings of these two
investigations are discordant.

Treatment of Atherosclerotic Chronic Arterial Insufficiency

The management of atherosclerotic occlusive peripheral arterial disease is divided into three parts as
follows:
a) Modification of risk factors and medical management.
 b) Treatment of Intermittent claudication
c) Treatment critical limb ischemia.

The following flow chart1 is a useful aid memoire on the management of this condition.

FlowChart 1: Treatment Pathway for chronic lower limb ischemia. From: Beard JD, Gaines PA. Treatment of
chronic lower limb ischemia. In: Vascular & Endovascular surgery. Beard JD & Gaines PA (eds). 2 nd edition. WB
Saunders. London. . 2001:Pp 55-88.

A. Risk Factor modification

Table 11. Medical Management
 Cessation of smoking
 Treatment of Hyperlipidemia
 Control of Hypertension
 Management of Diabetes
 Use of anti-oxidants – treatment for homocystinemia
 Anti-platelet therapy

B. Treatment of Intermittent Claudication

Intervention is based on several factors which are “quality of life” issues more than claudication
distance. Also the presence of co-morbid conditions significantly alters intervention.

Table 12: Factors affecting intervention in Claudication

Favour of Intervention Against Intervention

  Severe symptoms  Short history
 Job affected  Still smoking
 No improvement with exercise  Other limiting conditions
 Aorto-iliac disease  Femoro-distal disease
 Stenosis/short occlusion  Long segment occlusion
 Unilateral Symptoms  Multi-level disease

a) Exercise programmes have shown that encouraging the patients to walk to near maximum pain
tolerance had beneficial results in more distal disease such a femoral block as compared to
angioplasty. In proximal disease, angioplasty has been found to be superior to exercise though
long term well controlled studies are limited in literature.

b) Use of drugs such as pentoxyfylline, naftidrofuryl, inositol and cinnarizine, which have vasodilator
as well as haemorheological properties remain debatable.

c) Endovascular treatmentlxi – Percutaneous techniques for treating arterial occlusions involves the
following procedures:
 Percutaneous Transluminal Balloon dilatation (Angioplasty) (PTA)
 Endovascular Stenting
 Endovascular atherectomy

Angioplasty. The mechanism of action of a balloon angioplasty involves fracture and

displacement of plaque along with over stretching of the media and the adventitia. The initial step
involves passage of a guide wire across the narrowed segment or area followed by proper
positioning of the balloon in the segment to be dilated.

Aorto-iliac interventions have the highest long-term success with normal distal vessels, especially
for focal stenoses in large high caliber and high flow arteries. The 5 yr patency rate for PTA of
common iliac artery is 70-80 %. Femoro-popliteal interventions have much lower success unless
there is focal disease with good distal run off.

Endovascular Stenting: This involves the use of self expanding metallic stents to keep the
constriction segment open after PTA. Stents are usually preferred for long segment stenoses in
combination with PTA. Studies comparing angioplasty alone versus angioplasty with stenting
have shown higher long term success in the latter group with similar complication rates.
Angioplasty is the first line of treatment for stenosis and occlusions less than 10 cm in length.

Atherectomy: This technique involves the use of a specially designed catheter, which can
remove the atherosclerotic plaque from the arterial wall by shaving, cutting or high-speed
rotational ablation. Laser energy has also been used to vaporize and debulk the plaque where the
stenosis is thick before PTA is attempted. Atherectomy has been used extensively in the last few
years for the treatment of CLI either as a stand-alone treatment or in lesions at bifurcations or
trifurcations as also in stent restenoses. However, prospective comparative data is limited.

d) Surgical treatment – i) Infra-inguinal bypass: Above knee and below knee femoropopliteal
bypass grafting has been used using saphenous vein and PTFE as the graft material.
Comparative have shown that while saphenous is superior to PTFE in graft patency at 2 years for
below knee level, the results are equivocal for above knee level but favour the use of vein. ii)
Supra-inguinal bypass – Aorto-bifemoral bypass has >90% patency at 1 year but higher mortality.
Cross femoral or ilio-femoral by pass have similar success rates for unilateral disease with lower
mortality rates. Axillo-bifemoral grafts have a lower patency rate and are not justifiable for
claudication.
Fig 1: Types of Supra-inguinal Bypass surgery. From: Beard JD, Gaines PA. Treatment of chronic
lower limb ischemia. In: Vascular & Endovascular surgery. Beard JD & Gaines PA (eds). 2nd edition.
WB Saunders. London. 2001: Pp 55-88.

Fig 2: Types of Infra-inguinal Bypass surgery. From: Beard JD, Gaines PA. Treatment of chronic
lower limb ischemia. In: Vascular & Endovascular surgery. Beard JD & Gaines PA (eds). 2nd edition..
WB Saunders. London. 2001:Pp 55-88

C. Treatment of Critical Limb Ischemia (CLI)

Most patients with CLI would need intervention unless there are severe co-morbid conditions and has
limited survival.

a) Endovascular Therapy: 50-75% of patients tend to benefit from endovascular intervention and
this should be offered as the first choice. Although, the benefits of angioplasty with or without
stenting are not as prolonged in infra-inguinal disease as compared to supra-inguinal disease, yet
the short-term benefits are sufficient to induce healing of the threatened limb. However it is prone
to higher complication rate as compared to claudicants due to risk of embolization and dissection.

The Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL) trial compared PTA with
surgery in 452 patients with rest pain, ulceration or gangrene of the leg secondary to infra-inguinal
diseaselxii. The primary end-point, amputation-free survival, was similar for PTA and surgery at 1
year (71% vs 68%, p = NS) and 3 years (52% vs57%, p = NS). Although there was no significant
difference in mortality between the groups at 30 days, surgery was associated with a higher post-
procedure morbidity.

BASIL demonstrated that endovascular therapy and surgery were comparable as first-choice
therapy for CLI, but that PTA was less expensive and did not preclude subsequent treatment with
surgery. Therefore, PTA should be chosen first if a patient is a candidate for either procedure,
lxiii
particularly if the patient’s life expectancy is less than 2 years .

Stents: Despite favorable limb salvage rates, endovascular interventions for the treatment of CLI
are associated with modest, 60–80%, 1-year primary patency rates10. Several stent technologies
have been introduced in an effort to prolong the durability of percutaneous interventions by
minimizing late stent failure from restenosis. Stent types currently being investigated include: self-
expanding stents, covered stents (i.e. stent grafts), Drug Eluting stents (DES), and bioabsorbable
stents.

Cutting balloon angioplasty (CBA): The cutting balloon catheter (Boston Scientific
Corporation,Natick, MA, USA) is a device in which razor blades (atherotomes) are embedded on
the exterior of the balloon. These atherotomes, whichare arranged longitudinally, score the plaque
surface during balloon expansion (Figure 6). Proponents of the device claim that cutting balloons
are less traumatic to the vessel wall and can limit the extent of dissection following angioplasty,
which has yet to be demonstrated in a convincing mannerlxiv.

Cryoplasty: The PolarCath™ (Boston Scientific Corporation) is a device that combines balloon
angioplasty with the delivery of cold thermal energy to the vessel wall. It consists of a specialized
balloon catheter attached to a source of pressurized nitrous oxide (N2O) that is used to inflate the
cryoplasty balloon. As the balloon volume increases, the N2O contained within it expands, and its
temperature falls below freezing. Proponents of the technique theorize that application of
cryoplasty leads to apoptosis and reduced restenosis. However, a recent study in humans
showed no difference for cryoplasty compared with PTA for release of the growth factors and
cytokines that initiate neo-intimal hyperplasialxv.

Excimer laser-assisted angioplasty (ELA): The proposed mechanism by which the laser
debulks atheromatous plaque is ‘photoablation’ (i.e. destruction of plaque material by
photochemical energy contained within the UV pulses). One advantage of excimer laser over prior
laser technologies is that it causes minimal thermal injury to the surrounding tissue. Successful
recanalization using excimer laser does not eliminate the need for subsequent balloon
angioplasty because the diameter of even the largest catheter (2.5 mm) is smaller than the typical
diameter of the femoral arteries where it is commonly used. The shallow penetration depth of the
UV pulses limits the speed at which the catheter can be advanced, and therefore ELA is a time-
consuming endeavor by defaultlxvi. The costs of the catheter, approximately $1500 per device, as
well as the price of the laser unit make it a very expensive option. In summary, ELA is an
 expensive therapeutic modality that has not been shown to improve outcomes compared to
conventional PTA for the treatment of CLI. Without evidence of superiority compared to
conventional therapies, it cannot be recommended for routine use in CLI.

Atherectomy: Atherectomy is an adjunct, or alternative, to angioplasty for the treatment of

peripheral artery obstruction. The SilverHawk™ Excision System (Fox Hollow Technologies,
Redwood City, CA, USA) is a directional atherectomy catheter. Plaque is shaved off as the
atherectomy blade rotates, and debris is collected inside a nose cone at the tip. At present there
are no randomized data to show that this device is superior to PTA.One disadvantage of the
SilverHawk catheter is its limited ability to treat heavily calcified lesions, which reduces it
usefulness in patients with CLI. Complications of excisional atherectomy include distal
embolization, thrombosis and vessel wall perforation. In one study, the authors concluded that
while immediate results of excisional atherectomy in this cohort were ‘good’, the midterm
lxvii
restenosis rates were high . Another study concluded that patency rates and limb salvage rates
lxviii
with excisional atherectomy were similar, but not superior, to other endovascular modalities .

b) Both supra and infra inguinal bypass surgery is possible in this group of patients where co-
existent morbid conditions are absent. Whereas, PTFE is preferred for the former, autologous
saphenous vein is preferred for the latter. The patency rates for femoro-popliteal bypass are 10%
lower for CLI as compared to claudicants.

c) Drugs: Prostacycline analogues are expensive and when used have shown significant reduction
in death and amputation in short term (6 months).

d) Chemical Sympathectomy is an option in non-diabetics, which is useful for improving rest pain or
minimal tissue loss. 2 ml of 10% phenol is injected using a translumbar approach under image
intensifier control at L3 level and then L4 level.

e) Pain Relief – Morphine sulphate has been used for chronic pain relief.

f) Amputations – These are ideal for those with extensive tissue loss, poor case for
revascularization and presence of severe co-morbid conditions along with the above.

D. Treatment of Buerger’s Disease

Up to two- thirds of patients first presenting in vascular clinic with intermittent claudication, can be
treated by conservative methods.

Abstinence from tobacco: The only proven treatment guideline to prevent disease progression and
avoiding an amputation is complete cessation of smoking or other forms of tobacco. Shionoya et al lxix
stated that abstinence from tobacco is important cornerstone of treatment of Buerger’s disease.
Goodman et allxx confirmed that if the patients of Buerger’s disease cease smoking completely, their
disease, in most cases, may reach a plateau and in some improvement may be noted. They however
pointed out that the beneficial effects from cessation of smoking often cannot be expected in late
stages of disease, hence smoking should be stopped early in disease. Also the treatment of the
disease is useless if smoking is continued. In a series of 120 patients, it was observed that if there
was no gangrene when the patient discontinued smoking, amputation did not occur in 94% cases
whereas 43% of those who continued smoking required one or more amputationslxxi. Any form of
lxxii
continued usage of tobacco keeps the disease active . Repeated education and counseling is
required for these patients. Raynaud’s phenomenon or claudication may continue even after complete
discontinuation of tobacco.

Explanation and advice: Many patients are worried by the presence of pain while walking. Once told
about the nature of disease and advice regarding methods to improve their claudication distance e.g.
by walking slowly or by improving underlying systemic disorder like, anemia, congestive failure, the
claudication distance can be increased.
 Adjustment of lifestyle: Adjustments to everyday habits of transport can increase mobility within
the claudication distance, e.g use of a bicycle etc.
 Exercise & Diet: Taking regular exercise within limits of pain and control of weight in case of
obesity.
 Care of feet, avoiding socks with holes and amateur chiropody, which can spark off gangrene in
the toes and heels, particularly in diabetic patients.
 Heel raise: claudication distance may be improved by raising the heels of shoes by 1 cm. The
work of the calf muscles is reduced thereby.
 Analgesics and position: rest pain can be relieved to some extent in some patients by use of
analgesics, elevation of the head end of the bed (Buerger’s position) and Buerger’s exercises
(repeated 2 minute elevation and dependency of limb).

Drugs: Despite the clear presence of inflammation in this disorder, anti-inflammatory agents such as
steroids have not been shown to be beneficial. Similarly, strategies of anticoagulation (thinning of the
blood with aspirin or other agents to prevent clots) have not proven effective. Vasodilator drugs are
usually started in these patients but their role is equivocal. Abramsonlxxiii found that vasodilators
increased cutaneous blood supply only and had no role in increasing muscle blood supply. Some of
the drugs used are:

Prostaglandins: Prostacylin or PGI2 (Iloprost) has forty times antiplatelet and vasodilator activity as
compared to PGE1. They are effective in both cutaneous and muscular vessels. Intravenous infusion
of prostacyclin (Iloprost) has been demonstrated in some studies to relieve rest pain for up to a month
and in some upto 6 monthslxxiv. Low molecular weight dextrans: dextrans of molecular weight 50000
are used during acute attack of thromboangitis. They cause hemodilution, decrease viscosity of blood
and improve microcirculation. Intra-arterial infusion is said to be more effective than intravenous
infusion therapy.

Intra-arterial Thrombolytic therapy: Selective low dose intrarterial streptokinase (Bolus 10,000 Units
followed by 5,000 units per hour) have been used in a very small group of patients with alteration of
level of amputation or it’s avoidance in 58% patientslxxv.

Praxiline: (niftidrofuryl oxalate) may alter tissue metabolism, increasing the claudication distance by
allowing a greater oxygen debt to be incurred. No proven benefit.

Trental: (oxypentifylline) has some effect on whole blood viscosity by reducing rouleaux formation.
No proven benefit.

Aspirin in dispersible form may be prescribed for its anti-adhesive effect on platelets. No proven
benefit.

Direct Arterial Surgery: Surgical bypass or revascularization is rarely feasible in patients with
Buerger’s disease because of occlusion of small and medium sized vessels, presence of segmental
and skips lesions and absence of a distal target vessel for by pass. Shionoya et al lxxvi undertook
arterial reconstruction in 23 of 148 patients of thromboangitis obliterans and performed 22 bypass
procedures and 5 thromboendarterectomies. The overall success rates were around 26%. But even
this rate has not been duplicated in later studies. Reddy et allxxvii found that in south Indian patients,
there was involvement of arteries with little pathology in veins, and therefore attempted arterialization
of veins by creating arterio-venous fistula between the artery proximal to the site of block and the
adjacent vein. They reported a success rate of 72%. Saasjima et al reported a five-year primary
patency rate of 49% and secondary patency rate of 62% in 61 patients after infra-inguinal
bypasslxxviii.

Sympathectomy: Sympathectomy is not beneficial in intermittent claudication, but can relieve rest
pain and ulceration because the effect is mainly on skin and subcutaneous blood vessels and its use
is limited to buying time before definitive amputation. For the same reason it helps in the healing of
superficial ischaemic ulcerations. It might aggravate claudication by stealing the blood from ischaemic
muscles and diverting it to the skin and therefore is a contraindication for sympathectomy. In vessel
wall, sympathectomy is done with following objective.
 To cause vasodilatation by decreasing sympathetic vasomotor tone.
 To abolish pain impulses carried by sympathetic fibers.
Nakata et allxxix reported ulcer healing in 58% and relief of rest pain in 64% after lumbar
sympathectomy and concluded that the clinical effects of sympathectomy were because of increased
blood flow to the skin. Methods of conducting sympathectomy are:
lxxx
1. Surgical sympathectomy :

Lumbar sympathectomy: Open sympathectomy is done preferably through the extraperitoneal

approach.The sympathetic chain lies on the side of the body of vertebrae, sometimes inside the
psoas muscle sheath. In unilateral surgeries, sympathetic ganglia, L1, L2, L3 and sometimes L4 are
removed. In bilateral cases, L1 of one side is preserved (to avoid retrograde ejaculation). A
transperitoneal approach may also be used, especially in patients where bilateral lumbar
sympathectomy is planned (but used less often in view of its increased morbidity). The complications
of this surgery include paralytic ileus, injury to genitofemoral nerve, ureteric injury, hemorrhage
(because of major vessel injury e.g injury to aorta, inferior vena cava or avulsion of lumbar veins), and
rarely bowel injury. With the advent of minimally invasive surgery, lumbar sympathectomy is being
done laparoscopically through the retroperitoneal route and has decreased the morbidity of access, to
32
a large extent .

The draw back of lumbar sympathectomy is that it is a temporary procedure and the effect rarely lasts
beyond a period of six months. The reasons for failure include:

 Technical- failure to identify the lumbar chain. (Lumbar chain can often be mistaken with
lymphatic chain genitofemoral nerve, psoas sheath, psoas minor etc.).
 Cross connections of the chain from the opposite lumbar chain
 Regeneration of the cut ends of the chain causing reformation of the chain.
 Hypersensitivity of the end organ receptors to the circulating noradrenaline.
 Responsiveness of the sympathetic plexus around the vessels.

For upper limb Beurger’s disease, cervical sympathectomy is done where; T1 (lower portion of stellate
ganglion), T2 and T3 are removed. Cervical sympathectomy can be done through:

a) Supraclavicular route- less morbid but accessibility to the T3 ganglion is slightly difficult.
(b) Axillary route- accessibility to the ganglion is best but requires opening of the thoracic cavity and
increases the morbidity.
(c) Posterior approach- this is the shortest possible route, but the presence of bulky paravertebral
muscles make this a difficult proposition and is rarely used.
(d) Transthoracic laparoscopic sympathectomy is now the standard treatment of choice for the upper
limb disease.
21
2. Chemical sympathectomy :

This is an alternative to surgical sympathectomy but is contraindicated in patients on anticoagulant

therapy. A long 15 cm needle is inserted with local infiltration, first to seek the side of the vertebral
body and secondly to pass alongside it to reach the lumbar sympathetic chain. 5 ml of phenol solution
in water is injected beside the bodies of 2nd, 3rd and 4th vertebrae. The procedure is done preferably
under fluoroscopic or ultrasound guidance and care is taken to avoid penetrating the aorta or inferior
vena cava.

Omental transposition

Casten and Alday first described Omental transposition to the lower extremity in atherosclerotic
lxxxi lxxxii
occlusive disease . Hoshino et al classified omentum according to the number of arterial
branches in the omentum. Type 1 has a single layer of vessels and is more common than Type 2,
which has a double layer. Hoshino et al, have expressed their results in terms of improvement of five
symptoms namely, rest pain, coldness, cyanosis, intermittent claudication and ulcer healing. They
classified their results as excellent (if 4-5 symptoms were relieved-71%), good (if 2-3 symptoms were
relieved-19%) and fair (if 1 symptom was relieved-10%).
In India, omental transposition has been done more frequently and with encouraging results, since
there are limited options for limb salvage. The procedure is based on the arterial arcade formed by
the anastomosis of right and left gastroepiploic arteries. For unilateral procedures, the omental
pedicle is based on the right gastroepiploic artery as it is a dominant artery and has a longer length.
For bilateral procedures, both epiploics may be used, though sometimes a single vessel is used, as
there is risk of gastric devasularization if both arteries are used. A subfascial tunnel is made from the
inferior end of the laparotomy incision to the inguinal and further down to the ankle medially. The
omentum is lengthened based on the dominant artery in the pedicle as shown (Fig 3, 4 & 5) and
brought down to the distal most portion of the affected limb through the subcutaneous tunnel.
Complications of this procedure include:,gastric devascularization and necrosis, paralytic ileus, gastric
hemorrhage, omental necrosis and wound infection.

Singh et al, using pedicled omental transposition, reported ulcer healing in 88%, decrease in rest pain
in 72%, increase in claudication distance in 96% and improvement in skin temperature in all the 50
patientslxxxiii. Others have reported no significant difference in these parameters when pedicled grafts
were compared with free omental graftslxxxiv. The effect of omental transposition is said to be because
of its rich vascular supply which directly improves tissue perfusion and secondly omentum is said to
cause neovascularization in the affected limb.

Fig 3 – Diagram depicting technique of omental tranfer and lengthening. Numbers 1 represents
division of left gastroepiploc vessel and mobilization of omentum preserving the gastro-epiploic
arcade, division of arcade proximal to rt. Omental vessel (2), ligation of mid omental vessel distally (3)
and extended further to gain length (4). [From: Singh I, Ramteke VK. The role of omental tranfer in
buerger’s disease; New Delhi’s experience. Aust N Z J Surg. 1996;66:372-6.]
Fig 4 – Alternative technique for omental tranfer and lengthening. Number 1 is same as in Fig 1.
Number 2 shows division of and right and mid omental vessels and sparing the left omental vessel.
[From: Singh I, Ramteke VK. The role of omental tranfer in buerger’s disease; New Delhi’s
experience. Aust N Z J Surg. 1996;66:372-6.]
Fig 5 – Steps used for bilateral omental transfer. [From: Singh I, Ramteke VK. The role of omental
tranfer in buerger’s disease; New Delhi’s experience. Aust N Z J Surg. 1996;66:372-6.]

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 Reduced Port Surgery
Vinod K Malik, Ashish Dey, Vijay Singh
Introduction

Nothing is untouched by evolution and that applies to surgery as well. Since time immemorial,
mankind has been trying to develop and improve upon their surgical skills. A major leap in this
direction was the introduction of laparoscopy in early 1900’s (1). Although for a few decades, the
progress was slow but with the application of laparoscopy to cholecystectomy in 1980’s, the world
saw a rapid spread, acceptance and adoption by surgeons everywhere. In the following years,
application of laparoscopy spread so much that today almost all surgeries could be performed
laparoscopically. Introduction of NOTES (Natural Orifices Transluminal Endoscopic Surgery) (2)
renewed the enthusiasm to develop techniques that would allow further reduction of the number of
incisions/ports to achieve the ultimate aim of being able to successfully and safely perform incision-
less / scar-less surgeries improving the patient reported outcome (PRO) even further. Single Port
Access (SPA) Surgery was introduced in 2007 (3, 4) and brought Port-reduction (from conventional
multiport surgery) into the limelight. Several instruments and techniques have since been developed
in the past 6 years to increase the efficiency and safety of the procedures. Currently these techniques
are safe in the hands of their pioneers. However, their success would depend on these techniques
being accepted, adopted and mastered by surgeons all over the world.

Types of Reduced Port Surgery

Aiming to achieve scarless surgery gave birth to reduced port surgeries that included: Three-Port
Laparoscopic Surgeries, Two-Port Laparoscopic Surgeries and Single-Port Laparoscopic Surgeries or
Single Incision Laparoscopic Surgeries (SILS). There have been many other names used for single
port/single site surgery including SILS (Single Incision Laparoscopic Surgery), E-NOTES (Embryonic
– Natural Orifice Transumbilical Endoscopic Surgery), OPUS (One Port Umbilical Surgery), SIMPLE
(Single Incision Multiport Laparo-Endoscopic Surgery), SPS (Single Port Surgery, SIL (Single Incision
Laparoscopy), SPL (Single Port Laparoscopy), SLaPP (Single Laparoscopic Port Procedure), SLiPP
(Single Laparoscopic Incision and Port Procedure), and more (5). Laparo-endoscopic single-site
surgery (LESS) is, a term coined by a multidisciplinary consortium called Laparo-Endoscopic Single-
Site Surgery Consortium for Assessment and Research (LESSCAR) in July 2008 for single-incision
laparoscopic surgery (5).

Patient Selection for Reduced Port Surgery

The ideal patients are the ones whose main concern is cosmesis, who are non-obese, medium height
and with no previous abdominal surgery (6, 7, 8). It has been reported that SILC (Single Incision
Laparoscopic Cholecystectomy) is feasible and safe in patients with uncomplicated gallstone disease
and gallbladder polyps (9, 10). SILC is not recommended in patients who have a high BMI or acute
cholecystitis because of high complication rate (bile leak by gall bladder rupture, wound infection),
increased operative time and high rate of conversion (11). For urological procedures, ideal cases
would be surgeries like renal, adrenal cyst marsupialization, pyeloplasty, renal tumor ablative
techniques, or simple nephrectomy for small nonfunctioning kidney (6).

Advantages and Limitations of Reduced Port Surgery

Reduced port surgery definitely has some potential advantages like better cosmetic outcome, reduced
post-operative pain leading to reduced analgesic requirement, faster recovery and hence, reduced
hospital stay when compared to conventional four-port laparoscopic (6, 12). However, concrete
evidence is lacking due to the limited number of randomized control trials and more so the ones with
large study groups (13).

Cosmesis
Reduced port-surgeries definitely have an advantage over conventional four-port laparoscopy due to
a virtually scarless surgery in case of SILS via umbilical port and lesser number of scars in case of
two-port and three-port surgeries. A recent study reported higher cosmetic satisfaction of patients with
LESSC (Laparo-endoscopic Single Site Cholecystectomy) as compared to Standard Laparoscopy
(SL) technique (98% vs 85%) (14). There have been more studies with similar conclusions (15, 16,
17). However, there are other studies that have reported otherwise especially because patients are
more worried about post-operative pain and risk of complications while choosing which procedure to
go through (18, 19). Another study with a 12-month follow-up of 99 patients reported significantly
better cosmetic outcome in the SILC group at 6 months as compared to CLC (Conventional
Laparoscopic Cholecystectomy) but no difference at 12 months. Thus, as far as overall post-operative
outcome is concerned, Reduced Port Surgeries, especially SILS, is not ranked higher than the
conventional four-port laparoscopic technique (20).

Safety and Complications

Conventional Laparoscopy has become the gold standard for many procedures in the last two
decades. To establish a new technique and prove that it’s better than the gold standard, it needs to be
as safe and have added advantages over the gold standard (21). Various studies comparing three-
port and two-port surgeries to four port surgeries have indicated that the three-port and two-port
techniques are as safe as four-port surgeries in elective cases. For instance while comparing
cholecystectomies with these techniques, similar statistics have been found for CBD injuries and
conversion rate to open surgery (22, 23, 24, 25, 26). Many authors have reported that SILC was
feasible and safe in selected patients with uncomplicated benign gallbladder disease (9, 14). Current
studies show that SPLC is has a low rate of conversion to 4-Port conventional laparoscopic
cholecystectomy (2 to 9.3%) and the main reason for conversion was the presence of acute
inflammation (27, 28). Bile duct injuries, hemorrhage, subhepatic abscesses, etc. constitute the major
complications of SILC (and other reduced port surgeries) and have been reported to occur in about
2.7% cases and intervention by either ERCP-stenting or surgery have been reported to be needed in
about 1.7% (10). Recent studies have shown an incidence of biliary tract injury between 0.09 and
0.7% (27, 28, 29). Port-site bleeding has been reported to be due to the placement of secondary
trocars and not due to dilatation of port-site done for retrieving the excised specimen (30, 31).

A recent study reported the incidence of port-site complications in laparoscopic surgeries to be

around 3% of which the highest percentage was in case of laparoscopic cholecystectomies (52.9%).
Umbilical ports were the ones most commonly involved (47%) and in general, more the number of
ports more the complications, was found to be true in most studies (17, 31). Another study reported a
similar rate of port-site complications for both SILC (Single Incision Laparoscopic Cholecystectomy)
and CLC (Conventional Laparoscopic Cholecystectomy) groups (17).

Cost
Cost is one of the main concerns for patients while choosing between surgical procedures and one of
the main reasons for not choosing laparoscopic procedures over open procedures especially in
developing countries. Reducing the number of ports required for a surgery is likely to reduce the cost
of surgery (32). Two-port cholecystectomies have been reported to be more cost-effective compared
to standard four-port cholecystectomies (33). However, procedures like SILS could be more
expensive compared to SL with the need for special instruments and special ports for SILS (6, 17). A
recent study compared the cost of surgery of SILS cholecystectomy (1933.7 ± 64.4 USD) to
Conventional Four-Port Laparoscopic Cholecystectomy (1874.7 ± 46.2 USD) (14).

Post-Operative Pain and Analgesic Requirement

Post-operative pain and hence, analgesic requirement were less after three-port and two-port surgery
(12, 15, 22). Some recent studies have suggested that patients undergoing SILC had similar pain
score and analgesic requirement within 24 hours after operation when compared with conventional
four-port laparoscopic cholecystectomy (9, 34). Even though less number of ports should result in less
pain, increased pain scores could be explained by the need for larger incision in cases of Single port
laparoscopic surgeries (35). However, some studies have also reported better pain profiles and lower
analgesia requirements in the SILC group compared to standard 4-port laparoscopic cholecystectomy
(17).

Duration of Hospital Stay

Even though various studies have reported differences in the duration of hospital stay, on an average
it has been reported to be similar for conventional 4-port laparoscopic cholecystectomies, 3-port, 2-
port and single-port laparoscopic cholecystectomies (16, 36, 37). Mean postoperative hospital stay for
three-port laparoscopic cholecystectomies has been reported to be 1.19 days as compared to 1.44
days for conventional four-port laparoscopic cholecystectomies (36). Another study reported mean
hospital stay for LESSC (Laparo-Endoscopic Single Site Cholecystectomy) to be 1.4 +/- 0.2 days as
compared to 1.4 +/- 0.7 days for three-port laparoscopic cholecystectomy (14).
Operative Time
The operative time of SILC in several studies reported no statistically significant difference compared
to CLC (17, 38). Another study has a longer operative time for SILC as compared to CLC (20). A
recent study reported the average operative time for LESSC to be 46.9 ± 14.6 min which is shorter
than the operative time reported for conventional four-port laparoscopic cholecystectomies by most
studies (39).

Learning Curve
Reducing the number of ports also means making the maneuverability of instruments more difficult.
Limited operating fields, clashing of instruments, lack of triangulation and difficulty to attain critical
view of safety in SILC result in a learning curve during which complications are more likely (10, 20,
40). A learning curve of 20-25 cases has been suggested for the safe adoption of SILC (41, 42). The
learning curve of the SILC procedures suggests that for experienced laparoscopic surgeons, SILC is
an easy and safe procedure in case of benign diseases (39).

Rate of Conversion
The presence of acute inflammation has been the main cause of conversion in SILC procedures. A
study including 298 LESSC cases and 315 TPLC (Three port Laparoscopic cholecystectomy) cases,
reported that 4 patients of LESSC required addition of extra ports and 2 patients required conversion
to open surgery. In the same study, 2 patients of TPLC also required conversion to open surgery (14).
Recent studies suggest that SILC is feasible with a low rate of conversion between 2 to 9.3% (27, 28).

Modifications of/ for Reduced Port Surgery

With increase in experience in reduced port surgeries several new tools have been developed like
transvaginal access, needlescopic instruments and robot assistance which can enhance the safety
and feasibility of reduced port surgeries without diminishing its advantages (43). Application of da
Vinci surgical robot for single port surgery seems very promising and could help overcome some of
the difficulties of single port surgeries by way of improved ergonomics (44).

The Alligator Forceps (Covidien, USA), (Fig 1)

have been in use for quite a while (45) and has
found use among the recent developments with
reduced port surgeries. The 2 mm port obviates
the need of an extra port and can be used to
grasp the fundus as well as the Hartman’s Pouch
in lieu of the lateral ports as in CLC. Fig 1- Alligator Forceps (Covidien, USA)

Several devices have been developed for single port surgeries including SILS® port (Fig 2) and
Dexide Port (by Covidien, Norwalk, CT, USA), The X-cone® (KARL STORZ GmbH and Co. KG,
®
Tuttlingen, Germany), (Fig 3), Cuschieri Endocone (KARL STORZ GmbH and Co. KG, Tuttlingen,
® ®
Germany), GelPOINT (Applied Medical, Rancho Santa Margarita, CA, USA), Triport and
®
Quadport (by Advanced Surgical Concepts, Bray, Ireland; distributed by Olympus),
®
AirSeal (Surgiquest, Orange, CT, USA) and OCTO-port by Dalim Surgnet from South Korea to name
a few (46).
 Fig 2- SILS Port, (Covidien USA) Fig 3- X-Cone, (Karl Storz , Germany)

A modified reduced port procedure for cholecystectomy was proposed where sutures were attached
to the gallbladder and two regular trocars were inserted through umbilical incision. This procedure
reported a lower cost than the conventional laparoscopic surgery as well as the SILC procedure using
commercially available ports for SILC (47). Concerns have been raised regarding bile spillage
particularly in those gallbladders that may harbor malignancies.

Another promising technique that can improve LESS surgery is the use of Magnetic anchoring and
guidance system (MAGS) technology (using magnetically controlled and anchored intracorporeal
surgical instruments) (48).

There have been many more developments and many are en route. Mentioning all of them is out of
scope of this article. However, this does assure us that scarless surgeries could soon become a
reality.

Future of Reduced Port Surgery

Currently, reduced port surgeries are safe in the hands of the pioneers. However, their feasibility and
safety needs to be established before considering their obvious benefits of cosmesis, reduced post-
operative pain, etc. We believe that for any new surgical technique to be approved and accepted, the
first requirement is to establish its safety not just in the hands of its pioneers but with surgeons
worldwide. This would require more prospective randomized control trials with larger study groups.
Reduced port surgery is in an immature state at present with several limitations hidden behind the
obvious advantages.

Another important factor is cost. Currently, many patients choose open surgery instead of
laparoscopic surgery solely due to high cost even though the safety and efficacy of most conventional
laparoscopic procedures have been proven many times over. Reduced port surgeries are also
technically challenging and demand enhanced skills and ambidexterity, hence the learning curve.
Several modifications of techniques and instruments are under evaluation which could shorten the
learning curve and make reduced port surgery a feasible, safe and affordable alternative not just to
CLC but to open surgery as well. Simulation systems can go a long way in training of surgical
residents in laparoscopic surgery while ensuring safety of the patients and needs to be inducted in the
training curriculum.

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 Fundoplication for GERD — Current Status
Pawanindra Lal, Anubhav Vindal

Introduction

Gastro-oesophageal reflux disease (GERD) is one of the most common chronic disorders of the
gastrointestinal tract, and its incidence has increased all over the world over the last few years.1 The
prevalence of GERD has been found to be much higher in Asia than quoted in earlier studies and
Indian race has been found to be at an increased risk for the development of GERD and its
2
sequalae. Forty percent of symptomatic GERD patients develop erosive reflux oesophagitis, with the
potential sequelae of impaired quality of life, haemorrhage, peptic stricture formation, and Barrett’s
oesophagus.3 After diagnosis of GERD, patients generally require lifelong treatment. With the advent
of proton pump inhibitors, some patients are able to heal oesophagitis, and those who cannot;
antireflux surgery is a satisfactory maintenance therapy, and potentially the only option for patients
who have medically refractory GERD.

Indications for surgery

Guidelines of the Society of American Gastrointestinal Endoscopic Surgeons provide specific

4
indications for antireflux surgery:
1. Patients who have failed medical management.
2. Patients who opt for surgery despite successful medical management (due to lifestyle
consideration including age, time or expense of medication etc).
3. Patients who have complication of GERD (Barrett’s, stricture, grade 3 or 4 oesophagitis).
4. Patients who have atypical symptoms (asthma, hoarseness, cough, chest pain, aspiration)
and reflux documented on 24 hour pH monitoring.

Requirements to proceed with an antireflux procedure in such patients are:5

1. Increased oesophageal exposure to gastric juice documented by 24 hour oesophageal pH
monitoring.
2. Presence of a mechanically defective lower sphincter on manometric studies.
3. Adequate oesophageal body motor function on manometric studies.

More recently, the Society of American Gastrointestinal and Endoscopic Surgeons Guidelines
Committee has published guidelines for surgical treatment of gastroesophageal reflux disease.6
According to these guidelines, when the diagnosis of reflux is objectively confirmed, surgical therapy
should be considered in individuals who:
a) Have failed medical management (inadequate symptom control, severe regurgitation not
controlled with acid suppression, or medication side-effects)
OR
b) Opt for surgery despite successful medical management (due to quality-of-life considerations,
lifelong need for medication intake, expense of medications, etc.)
OR
c) Have complications of GERD (e.g., Barrett’s oesophagus, peptic stricture) OR
d) Have extra-esophageal manifestations (asthma, hoarseness, cough, chest pain, aspiration)

Coexistence of Barrett’s oesophagus with gastroesophageal reflux symptoms is considered by many

a clear indication for antireflux surgery.6 Surgical intervention for asymptomatic Barrett’s oesophagus
is more controversial, however.

It is important to note that the preoperative workup of these patients including history, symptom
scoring, endoscopy, pH- and mano-metry and other laboratory investigations be taken up in a
dedicated way. This ensures that the diagnosis and the decision to go ahead with surgical treatment
are based on a sound footing. This is one of the main reasons why different canters and different
investigators have widely varying success rates performing similar surgeries on a matched subset of
patients.
The aim of preoperative investigations is to select reflux patients appropriate for surgical treatment to
optimize outcomes. There is currently no consensus, and significant variability, among surgeons
regarding which studies should be obtained before surgery, and in what order.
a) Oesophagogastroduodenoscopy (OGD): Is likely the one study that all patients should have
preoperatively, as it can confirm the diagnosis of GERD or identify other etiologies of
esophagogastric mucosal abnormalities and allows biopsies to be taken.
b) pH-metry: Important for patients when the diagnosis of GERD cannot be confirmed on OGD
or diagnostic uncertainty exists. A normal 24-h intraesophageal pH study after an H2-blocker-
and proton pump inhibitor (PPI)-free interval should strongly suggest an alternate diagnosis
and lead to additional diagnostic investigations.
c) Oesophageal manometry: Frequently performed before surgery and advocated by many
experts in order to identify conditions that might contraindicate fundoplication (such as
achalasia) or modify the type of fundoplication according to a tailored approach based on
esophageal motility. Nevertheless, there is no support in the literature for mandatory
preoperative manometry6, and there are numerous studies refuting the need for a tailored
approach to fundoplication.
d) Barium swallow: Frequently obtained test for better delineation of the anatomy. May be
particularly valuable in patients with large hiatal hernias who have a shortened oesophagus.
6
Other preoperative tests have been examined, such as gastric emptying studies , but there are no
data to support a correlation between their results and postoperative outcomes. This test may be
important, however, in patients who require reoperation, as it may provide indirect evidence for vagal
nerve injury during the original surgery.

Surgical management
Surgery for gastro-oesophageal reflux disease (GERD) has been in a state of evolution over the last
70 years. Nissen’s fundoplication, Belsey’s wrap, and Hill’s gastropexy have all been introduced,
studied, and modified. Different approaches have been used, including thoracotomy, laparotomy,
thoracoscopy, laparoscopy, and robotic-assisted techniques.

Historical Aspects
Surgery for GERD has evolved from anatomical repair of hiatal hernia to physiological restoration of
gastroesophageal junction. In 1919, Angelo Soresi published the first treatise describing elective
surgical repair of hiatus hernia.7 This operation consisted of reduction of the hernia and closure of the
opening of the diaphragm. In 1950, Richard Sweet from Massachusetts General Hospital published
the transthoracic technique.8 These surgeons of the first half of the 20th century had focused on
correcting an anatomic defect. To their dismay, many patients had successful restoration of anatomy
but persisting symptoms.

Allison should be credited for initiating the modern era of antireflux surgery. 9 In 1951 Philip Allison
reported a technique for repair of hiatal hernia in the treatment of GERD. He described left
thoracotomy, restoration of the abdominal length of the oesophagus, posterior crural repair, and left
phrenic nerve crush. The long-term results of this operation, however, were unsatisfactory. Allison
reported a 20-year retrospective survey of 553 patients operated on for various types of hiatal
10
hernia. Only 66% of the patients had symptomatic relief, and 49% had recurrence of the hiatal
hernia.

Another important contributor was Lucius Hill. He demonstrated that the antireflux barrier consisted of
the gastroesophageal valve, the lower oesophageal sphincter (LES), the diaphragm, and posterior
fixation of the gastroesophageal junction.11 His technique aimed to re-establish the 180º fold that was
lost in patients who have severe reflux. Using an upper midline incision, he placed sutures between
the proximal lesser curvature of the stomach, the median arcuate ligament, and the anterior and
posterior phrenoesophageal fascial bundles. He included placement of cardio-diaphragmatic sutures
for fixation of the GE junction, along with closure of the hiatus.

The identification of the lower oesophageal sphincter and use of manometry were reported in 1956. 12
Osophageal pH monitoring would come 2 decades later. These tools linked anatomy and physiology
to permit accurate diagnosis of reflux disease and provided an objective standard for evaluation of
surgery. In the midst of this physiologic revolution, Rudolph Nissen and Ronald Belsey developed the
operations used by most surgeons in the 21st century.13
The Belsey procedure was developed by Ronald Belsey in late 1940s in Bristol, England. 14 His initial
15
operation underwent multiple modifications before the final version, Mark IV, in 1967. His repair
emphasized physiology over anatomy. It was designed to restore all the normal functions of a
competent cardia. It is a partial fundoplication or an enveloping of distal oesophagus with the gastric
fundus over 270°. The Belsey procedure is difficult to teach and communicate and has fewer margins
for error.16

In 1936, Rudolph Nissen excised the cardia of the stomach in a patient who had an esophageal ulcer,
and anastomosed the oesophagus to the stomach. He buttressed the suture line by wrapping the
fundus of the stomach around it and the lower oesophagus. 17 Years later Nissen astutely noted that
the patient had no heartburn, and rightfully attributed that to the ‘‘wrap’’ used at his surgery. In 1955,
18
Nissen performed “gastroplication” surgery on 2 patients with excellent clinical outcome. It involved
wrapping both anterior and posterior walls of the stomach around the lower 6 cm of the oesophagus
using 4 or 5 interrupted sutures, 1 or more of which also incorporated part of the anterior wall of the
oesophagus. The wrap was performed around a large-bore indwelling intraesophageal stent.
Although this provided good control of reflux, it was associated with a number of side effects that have
encouraged modification.

Fundoplication in the Open Era

In the 1970s, Nissen's fundoplication was rapidly adopted worldwide and became the most popular
antireflux operation. The original operation underwent modifications by Nissen himself, as well as by
other surgeons. These include taking care to use only the gastric fundus to envelope the oesophagus
in performing the fundoplication, sizing the fundoplication with a 60-Fr bougie and limiting the length
of the fundoplication to 1-2 cm.19 With wider application of the Nissen procedure, it became evident
that a successful Nissen fundoplication is not simply a matter of wrapping the stomach around the
lower oesophagus and sewing it in place. Rather, a good deal of judgement and experience is
required to determine, how tight and how long to make the fundoplicatioon, what portion of the
stomach should be used and what conditions preclude the use of the operation. Consequently, Nissen
fundoplication has contributed to a number of severe postoperative complications. Most can be
attributed to surgical technique and inaccurate selection of patients for operation. If the fundoplication
is constructed too long or performed as a wrap rather than an enveloping of the oesophagus by the
fundus, permanent dysphagia may result. Such a fundoplication precludes physiologic belching and
vomiting.

In the United States, Donahue et al.20 and Demeester and Johnson21 worked to improve on Nissen's
operation. They were the first to truly understand the physiologic mechanism of Nissen's and modified
it by division of short gastric vessels and the creation of a loose floppy wrap. Demeester and Johnson
evaluated the optimal length of the wrap and convincingly showed that a loose wrap of just 2 cm was
sufficient for reflux suppression and reduced the incidence of troublesome postoperative bloating and
dysphagia. It is this modification of the original Nissen fundoplication that is most commonly
performed today in the laparoscopic era.

Due to the complexity of the variables determining the success of Nissen’s fundoplication and the
22
multitude of postoperative problems associated with an improper procedure, Dor et al. and Andre
23
Toupet proposed construction of a partial wrap (less than 360°) in an effort to minimize the
postoperative symptoms plaguing patients who underwent Nissen fundoplication. The partial
fundoplications are usually constructed by covering either the anterior or posterior wall of the distal
oesophagus with the stomach. This necessitates suturing the fundus of the stomach to the
oesophagus as the primary and most important portion of the procedure. This suture line is subject to
a great deal of stress and as a consequence has a limited durability. Although the partial
fundoplication operations are successful in preventing reflux and permitting physiologic belching when
they remain intact, they disrupt with a distressing frequency.

Following four decades of experience with open antireflux procedures, long-term outcomes following
open surgery have been well described. Postoperative hospital stay ranges from 7 to 14 days 24,25,
26,27
short-term morbidity is acceptable , and long-term success is achieved in the majority of
26,28 29
patients. Rossetti and Hell reported that 87.5% of patients, followed for more than 10 years after
a 360° fundoplication without short gastric vessel division, were free from reflux symptoms and
adverse sequelae. Similarly, DeMeester et al.26 reported a 91 per cent success rate for the Nissen
fundoplication procedure at mean follow-up of 45 months. Adverse outcomes following open Nissen
26.27.30
fundoplication include persistent dysphagia and gas bloat syndrome. Many patients also have
31
troublesome early dysphagia which resolves as follow-up matures.

Uncontrolled reports suggest that the performance of a partial fundoplication variant may reduce the
incidence of postoperative dysphagia.24 However, this proposal has not been supported by the results
15,30-33
of published randomized trials. Three trials have compared Nissen fundoplication with posterior
31-34
partial fundoplication , and none of these found any significant increase in the likelihood or severity
of dysphagia following Nissen fundoplication.

An overall assessment of all of these randomized trials has failed to demonstrate important
25
advantages to support the routine application of a posterior partial fundoplication. However, this
cannot be extrapolated to the alternative technique of anterior partial fundoplication; it is possible, but
certainly not proven, that this modification could result in outcome improvements. 24,36

Laparoscopic Era
There has been increasing interest in the surgical management of gastroesophageal reflux disease,
37
particularly after the introduction of minimal invasive techniques in 1991. Since laparoscopic Nissen
37
fundoplication was first described in 1991 by Dallemagne et al. laparoscopic antireflux surgery has
1,38-43
been embraced enthusiastically in many centres. The laparoscopic approach to antireflux
surgery now offers a potentially more acceptable surgical option for patients with gastro-oesophageal
reflux because of the reduced postoperative pain and more rapid recovery. This has led many
symptomatic patients, who previously did not wish to undergo open antireflux surgery, now to request
a laparoscopic fundoplication.44,45

Laparoscopic antireflux surgery (LARS) requires surgeons to learn a new range of operating skills.
There is a definable learning curve, during which procedures are associated with extended operating
times and an increased risk of complications. 46 With increased experience and improvements of
advanced laparoscopic and esophageal surgical skills, there has been a significant decline in early
and long-term complications. In a review of more than 10,000 reported laparoscopic antireflux
procedures, morbidity was uncommon (6%), mortality was rare (0.08%), and the reoperation rate was
low (4%).47 In addition to symptomatic improvement, the effectiveness of LARS has been objectively
confirmed with 24-h pH monitoring, which clearly demonstrates excellent control of esophageal acid
exposure more than five years after surgery.48

Initial nonrandomized studies comparing open and laparoscopic approaches to fundoplication

suggested that although the laparoscopic approach took more time to perform, the incidence of
postoperative complications such as incisional pain and respiratory compromise was lower, and
postoperative disability and hospital stay were shorter. Since then, multiple randomized studies also
have been performed.49-53 In 1997, Laine and coworkers53 reported a randomized trial of 110 patients
comparing laparoscopic versus open Nissen fundoplication. During the 3-month follow-up period, 24-
hour pH tracing was normal in 97% of the patients in the laparoscopic Nissen fundoplication group
and 68% of the patients in the open group. Likewise, LES pressure had increased by 80% in the
laparoscopic group and only 40% in the open group. The mean duration of the operation was 88
minutes in the laparoscopic group and 57 minutes in the open group. The average hospital stay was
3.2 days in the laparoscopic group, versus an average 6.4-day stay in the open group. Similarly in
2002, Chrysos and colleagues51 reported a randomized trial of laparoscopic versus open Nissen
fundoplication in 106 patients. This showed the open group to have more pain as well as more
frequent respiratory complications. At 12-month follow-up, both open and laparoscopic groups were
shown to have increased lower LES tone. Follow-up pH monitoring confirmed reduction of reflux in
both groups as well.

The promising early outcome studies for laparoscopic antireflux surgery are now supported by the
initial results of randomized trials, confirming that this approach reduces the early morbidity of surgery
for gastrooesophageal reflux. Further medium-term outcome studies also confirm that the
laparoscopic method controls pathological reflux as effectively as the traditional open operation. All
published studies report that laparoscopic antireflux surgery reduces hospital treatment costs and
early surgical morbidity.54-60
To achieve good results, however, surgeons should be aware of the potential for certain
complications which are commoner following laparoscopic surgery and the need to adopt strategies to
avoid them. At present, a short loose Nissen fundoplication performed laparoscopically, with or
without division of the short gastric vessels, is an appropriate surgical treatment for gastro-
oesophageal reflux disease.

Until the results of long-term studies are available, the true outcome of laparoscopic antireflux surgery
and its status compared with open antireflux surgery must remain uncertain.

Based on the available level 1 evidence, laparoscopic fundoplication should be preferred over its
open alternative as it is associated with superior early outcomes (shorter hospital stay and return to
normal activities, and fewer complications) and no significant differences in late outcomes (failure
6
rates). Nevertheless, antireflux surgeons should be aware that laparoscopic fundoplication takes
longer to perform and has a higher incidence of reoperations, at least in the short term.

Modifications of Laparoscopic Nissen’s Procedure

The postoperative problems associated with a classical Nissen’s procedure have led to the
investigation of a range of modifications that seek to improve outcome in patients after antireflux
61
surgery. Watson et al. investigated whether division of the short gastric vessels during laparoscopic
Nissen’s fundoplication affected postoperative outcome. They do not suggest significant outcome
differences.

For a long time, the use of a large bougie in the oesophagus has been advocated to avoid the
construction of a too-tight total wrap. Philip Donahue introduced the ‘‘floppy Nissen fundoplication’’ in
a dog model.62 Using a 15 Hegar dilator underneath the fundoplication and a 50 French oesophageal
bougie during the creation of the fundoplication, he ensured a standard, large diameter to the wrap.
Dr. Tom DeMeester further modified this technique in his landmark study in 1986. 26 He used a 60
French oesophageal bougie, shortened the fundoplication length to 1 cm, and performed complete
mobilization of the gastric fundus with division of the short gastric vessels. Objective data have now
been attained to support the use of a similar indwelling device to reduce obstructive side effects. 63
The consensus that has seemed to have emerged is to ensure a short loose wrap, irrespective of
whether the short gastric vessels are divided or not. Recently, a number of surgeons have advocated
tailoring the antireflux procedure according to various features assessed before operation.64-67

Laparoscopic Partial Fundoplication

Nissen fundoplication has undergone many modifications in the form of partial fundoplication. These
partial fundoplications have been found to be effective, well tolerated, leading to improved quality of
life with acceptable rate of long term side effects in GERD. 31,68-70

There is a paucity of information available on the comparison of a laparoscopic complete wrap versus
a laparoscopic partial wrap. In the largest series with significant numbers of each operation, a partial
wrap appeared to be chosen by surgeon preference or when there was impaired esophageal
71-73
motility. Studies done to compare laparoscopic Nissen fundoplication and laparoscopic partial
74-77
fundoplication have failed to find the advantage of one wrap over the other. Studies have shown
that laparoscopic Nissen fundoplication is associated with higher incidence of dysphagia and lesser
incidence of recurrence as compared to laparoscopic partial fundoplication. 51,56,78,79 Another study has
shown more incidence of recurrence in laparoscopic partial fundoplication with similar dysphagia. 80
Fibbe et al.81 compared laparoscopic partial and total fundoplications in 200 patients with esophageal
motility disorders and found no difference in postoperative recurrence of reflux and concluded that no
tailoring of the surgical management is necessary. Similarly, Laws et al. 82 found no clear advantage of
one wrap over the other in their prospective, randomized study comparing these two groups.
Moreover, in a meta-analysis of 9 prospective randomized trials including open and laparoscopic total
versus partial fundoplications in 793 patients, no statistical difference was found in new onset
76
dysphagia or recurrence of reflux.

Total wrap supporters acknowledge the fact that the wrap needs to be “floppy” to minimize
postoperative dysphagia. It should also be noted that a floppy Nissen fundoplication is safe and
effective in patients suffering from a defective esophageal peristalsis. Finally, proponents of the total
fundoplication note the decreased the effectiveness of a partial fundoplication in controlling reflux.
Advocates of partial fundoplication claim that it results in fewer side effects than a 360° fundoplication.
Complications such as gas bloat and persistent dysphagia appear to be less frequent. Partial
fundoplication was recommended as the initial procedure of choice for patients who have poor
esophageal motility.83 Patients suffering from postoperative dysphagia had their 360° wraps revised to
84
partial fundoplication. Some authors propose partial wraps as the operation of choice, regardless of
85
esophageal motility. Unfortunately, long-term follow-up revealed a high failure rate of partial wraps in
86
terms of control of acid reflux. Jobe and coworkers showed a worse outcome with a partial
fundoplication than with total fundoplication. Other authors noted that as many as 50% of the patients
who had partial fundoplication had evidence of reflux when studied postoperatively. 87

A large randomized trial with open antireflux surgery has reported that posterior partial fundoplications
31
are associated with less troublesome complaints of gas–bloat and rectal flatus. In addition, another
trial comparing a total with a partial anterior fundoplication performed laparoscopically suggested
similar advantages with this partial fundoplication.88 It has been argued that some partial
fundoplication procedures augment various constituents of the valvuloplasty components of the
competence in the gastroesophageal junction and as a consequence were associated with a very low
89
incidence of mechanical complications.

Based on the available level 1 evidence, partial fundoplication is associated with less postoperative
dysphagia, fewer reoperations, and similar patient satisfaction and effectiveness in controlling GERD
compared with total fundoplication up to 5 years after surgery.6 Nevertheless, the paucity of long-term
follow-up data that compare the effectiveness of the procedures makes it hard to recommend one
type of fundoplication over the other, especially in an era when the long-term effectiveness of surgical
treatment for GERD is questioned. It should also be noted that a body of literature suggests that
anterior partial fundoplication may be less effective in the long term, and retrospective data suggest
that partial fundoplication may not be as effective as total in the long run. 6 Nonetheless, the evidence
suggests that surgeons appropriately trained in minimally invasive techniques who perform surgery
for GERD may minimize postoperative dysphagia by choosing partial fundoplication or short total
fundoplication (1–2 cm) over a large bougie (56 French) and maximize the effectiveness of the
procedure by choosing total fundoplication or longer (at least 3 cm) posterior fundoplication.6
Controlled studies that take into account these guidelines are needed.

Anterior versus Posterior partial fundoplication

A randomized, controlled clinical trial addressed the question of whether there are important
differences between the anterior and the posterior partial fundoplication in terms of reflux control and
side effects.90 It found significant differences in favour of the posterior fundoplication regarding the
level of reflux control. The reasons that were postulated for this observation are that the buttressing
effect of an anterior versus a posterior wrap might differ. The posterior fundoplication elevates the
abdominal portion of the oesophagus from its native bed in the hiatus and by necessity angulates the
gastroesophageal junction. This angulation might have the potential to cause some oesophageal
outflow obstruction.

Hence, a posterior partial fundoplication performed laparoscopically was followed by adequate reflux
control assessed both objectively and subjectively but an anterior partial fundoplication gave
unacceptable results both in terms of reflux control and esophageal acid reflux variables. 90

270° Partial Anterior fundoplication

Various case series suggest that the 270° anterior partial fundoplication is associated with less
postoperative dysphagia, improved ability to belch and less risk of gas bloat symptoms. 24,91 Although
this technique has been less widely applied than the posterior variant, the outcomes of uncontrolled
prospective assessment have suggested advantages.

Recently, the results of a trial comparing a laparoscopic 270° anterior partial fundoplication with a
Nissen’s total fundoplication showed a reduced incidence of dysphagia and gas-related problems in
the former group 13 yet equivalent control of reflux in both at 6 months follow-up. A subsequent
longer follow-up of patients having a similar 270° anterior partial fundoplication suggested reassuring
outcomes.92
The way the anterior fundoplication is constructed is different from the posterior fundoplication
variants, as the fundus sits in front rather than behind the oesophagus.

A 270° anterior partial fundoplication may not be as effective for the prevention of reflux as Nissen’s
fundoplication. The Nissen’s technique creates an over competent valve whilst anterior fundoplication
36
restores the GEJ to a more physiological state. If the durability of anterior fundoplication is proven to
be as good as that of the Nissen fundoplication, there can be a strong case for its routine application
in patients with GERD requiring surgery.

180° Partial Anterior fundoplication

As a modification of the 270° anterior partial fundoplication, another variant in the form of 180° partial
anterior fundoplication has been advocated. A more anatomical reconstruction of the antireflux
mechanism by anterior 180° partial fundoplication has been shown to have a lower incidence of
dysphagia and other side effects, such as flatulence, than Nissen’s fundoplication. 88

A possible explanation for the reduced incidence of dysphagia following 180° anterior fundoplication
may be the more “physiological” manometric profile of the lower oesophagus seen after 180° anterior
fundoplication. Anterior 180° fundoplication reduces the resistance to bolus transport seen after
88
Nissen’s fundoplication.

90° Partial Anterior fundoplication

Further modification of anterior fundoplication leading to the development of a 90° anterior

fundoplication has also been tried.93 Various comparisons between 90° anterior fundoplication and
Nissen’s fundoplication have been reported. In one series only 18% of patients reported postoperative
inability to belch, which is lower than the 60% to 80% reported after 270° anterior or Nissen’s
fundoplication.93 The early outcome of the 90° anterior fundoplication suggests that the reduction in
postoperative dysphagia is even more pronounced than that seen after Nissen’s or 180° anterior
fundoplication.93

It is unlikely that the 90° fundoplication will replace Nissen’s fundoplication in the majority of patients
requiring antireflux surgery, however, there are some patients for whom this procedure might be
preferable: patients with an adynamic oesophagus, patients with a giant paraesophageal hernia or
intra-thoracic stomach, where there is no certain disorder of the reflux mechanism, and patients
(typically women) for whom the avoidance of excessive flatus is important.

Laparoscopic fundoplication versus medical treatment

Several recent randomized controlled trials comparing laparoscopic fundoplication to medical

treatment have been published. The LOTUS trial, a large European multi-center trial comparing
maintenance therapy of esomeprazole (PPI) to a standardized laparoscopic Nissen fundoplication
94
reported 5-year outcomes of 372 patients in 2011. Relief of GERD symptoms at 5 years was higher
in the PPI group (92% vs. 85%), however limited by the fact that the trial design required pre-
enrollment symptomatic response to PPI use. Nearly a quarter (23%) of patients in the PPI group
required an increase in their dosage to maintain symptom control. While heartburn and regurgitation
improved in the surgery group, they remained stable in the PPI group over time with regurgitation
being significantly worse in the PPI group. Perioperative mortality and morbidity was low, 0% and 3%
respectively.

Anvari reported the 3-year outcomes of 93 patients in a Canadian randomized controlled trial of
laparoscopic Nissen versus PPI.95 Outcome was assessed via a GERD symptom scale, visual analog
scale (VAS) for overall symptom control and 24 h pH monitoring at baseline and 3 years. Primary
treatment failure (redofundoplication or PPI use) occurred in 12% of patients in the surgical arm and
16% in the PPI arm (inadequate reflux control despite maximal PPI dosage). Antireflux surgery was
superior to PPI for heartburn-free days, overall VAS control of symptoms and quality of life. Gastro-
esophageal reflux score was significantly improved in both groups after 3 years and although the
percent time of pH <4 on 24-h pH study was less in the surgical group (mean 2.1% vs. 4.3%),
although the difference did not reach statistical significance.
Another recent systematic review showed that surgical management of GERD is more effective than
medical management with respect to patient-relevant outcomes in the short and medium term.96 The
authors concluded that the review of patient-relevant outcomes in the short and medium terms
support the recommendation that fundoplication be evaluated as a treatment alternative for long-term
medical therapy or for patients with chronic GERD and insufficient symptom control under medical
treatment. However, given the scarcity of long-term data, the relationship between the benefit and
harm of antireflux surgery compared with permanent medical treatment still is unclear, and
fundoplication should be considered very cautiously for selected patients.

Fundoplication and Barrett’s Oesophagus

An expanded role for surgical management has been proposed, with some surgeons now claiming
that earlier surgical correction of pathological reflux may prevent progression to the complications of
Barrett’s oesophagus and stricture formation.45,64,97 With more and more evidence suggesting that
antireflux surgery may affect the natural history of Barrett’s oesophagus, and ultimately the risk of
esophageal cancer, surgical therapy may be considered for patients with Barrett’s oesophagus,
especially for young patients and those with symptomatic Barrett’s oesophagus.

However, it must be remembered that the evidence in this regard is circumstantial and more studies
evaluating the natural history of Barrett’s oesophagus after antireflux surgery are needed to arrive at a
definite conclusion.

Endoscopic Modalities for GERD

These treatment modalities are primarily designed for patients with little or no significant hiatal hernia
and are delivered trans-orally, via upper endoscopy. There are principally three different types of
these new treatment options.

First, radiofrequency energy delivered to the lower oesophageal sphincter (LES) theoretically adds
bulk to the LES and changes the sphincter’s compliance.98

A second endoscopic therapy for GERD involves the creation of a mechanical barrier at the
gastroesophageal junction (GEJ). An ethylene vinyl alcohol copolymer is endoscopically injected
within the submucosa or muscular layers of the oesophageal wall 1-2 mm caudal to the Z line.
Another system entails the submucosal placement of a poly-acrylo-nitrile based hydrogel prosthesis
(1.5 mm × 18 mm) above the GEJ.99

The third category of endoluminal procedures employs direct, endoscopic tightening of the LES. This
can be achieved by either sewing or plicating the LES.100

EsophyX (Endogastric Solutions, Redwood City, WA), is a device to create an incisionless

fundoplication (Transoral incisionless fundoplication (TIF)) and is the only such device which is FDA
approved. Long-term data are not yet available for EsophyX. In short term follow-up, from 6 months to
2 years, EsophyX may be effective in patients with a hiatus hernia ≤ 2 cm with typical and atypical
101
GERD. Further studies are required to define optimal techniques and the most appropriate patient
selection criteria, and to further evaluate device and technique safety.

Stretta system (Mederi Therapeutics Inc. Greenwich, CT) is currently the only FDA approved system
for the radiofrequency treatment of GERD. The Stretta procedure is considered appropriate therapy
for patients being treated for GERD who are 18 years of age or older, who have had symptoms of
heartburn, regurgitation, or both for 6 months or more, who have been partially or completely
responsive to antisecretory pharmacologic therapy, and who have declined laparoscopic
101
fundoplication.

Robotic fundoplication

The use of robotic surgery has been reported to be safe and feasible with similar outcomes during up
102-105
to 1-year follow up compared with laparoscopic antireflux surgery. Most of the available
randomized controlled trials have reported a significant increase in operating times and cost when the
robot is used.102,104,106 While robotic assistance can be safely and effectively used for fundoplication,
its higher cost compared with conventional laparoscopy and similar short-term patient outcomes make
it a less than ideal initial choice. Nevertheless, further study regarding learning curves and surgeon
workload with the robotic technique are needed before stronger recommendations can be made.

Our Experience at MAMC (India)

Our own experience in laparoscopic fundoplication has been quite favourable. In all 125 patients with
confirmed diagnosis of GERD and with indications for surgical therapy were operated in the last
decade. The follow-up of all of these patients is available and ranges from 6 months to 10 years.

Each of the patients underwent extensive preoperative diagnostic work-up both to confirm the
diagnosis of GERD, as well as to gauge its severity. A total of 75 patients underwent laparoscopic
Nissen fundoplication (LNF), while 50 were chosen for laparoscopic Toupet fundoplication (LTF),
based on the merits of each case.

The mean duration of surgery in the LNF group was 99 minutes (range 80-140) while it was 115
minutes (range 90-150) in the LTF group (due to the larger number of sutures that need to be applied
in the latter). The average duration of hospital stay in LNF patients was 3.31 days and in LTF patients
was 3.17 days. Likewise, time taken to return to routine work post operatively was also similar in the
two groups, 12.6 days for LNF, and 11.5 days for LTF group.

Postoperatively there was found to be a significant decrease in GERD symptoms, Demeester score
and Modified Visick grade in all the patients, regardless of the type of procedure performed. This may
be due to the extensive and diligent pre-operative workup and characterization of the patients’
symptoms and tailoring the therapy accordingly. Only 10 patients of LTF (20%) complained of
temporary post operative dysphagia that lasted for only 2 weeks. There were no such complaints in
the LNF group. The post operative Quality of Life (assessed using VAS) was also found to be similar
in both the groups – LNF: 2.31 to 8.33 and LTF – 2.58 to 8.58.

A study performed by the first author compared LNF with LTF and found that both the procedures are
effective in the management of GERD, and show comparable improvements in symptoms and
objective assessment of patients in the short term (6 weeks). 107 They further noted that LTF was
technically more demanding and took longer to perform than LNF, which was however associated
with a higher incidence of transient post operative dysphagia. All patients showed an objective and
significant increase in LES pressures, LES length and normal pH with sustained beneficial effects on
long term studies carried out 6 month to 4 years post operatively.

Summary

As was stressed earlier, the preoperative workup of patients with suspected GERD is very important
and should be performed in all cases. Under no instance should this surgery be taken lightly as a
surgery performed incorrectly or in an undeserving patient can spell disaster. It is a highly specialized
treatment modality and should be carried out in a dedicated center by an experienced surgeon to
ensure the best results.

The question of which fundoplication technique offers the best outcomes for patients undergoing
surgery for GERD is controversial.11,24,26 Whilst uncontrolled studies have reported good results
following laparoscopic or open surgery for floppy Nissen’s, anterior or posterior fundoplication, 24,91,108-
113
they have done little to resolve this controversy. Indian patients seem to do very well with a floppy
Nissen Fundoplication and benefits are sustained and objectively proven.

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METASTATIC BREAST CANCER
Durgatosh Pandey, Jyoti Sharma, Paras Khanna, Ajay Gogia

INTRODUCTION

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer
death in females’ worldwide, accounting for 23% (1.38 million) of the total new cancer cases
and 14% (458,400) of the total cancer deaths each year [1]. About half the breast cancer
cases and 60% of the deaths are estimated to occur in economically developing countries, a
shift from the previous decade during which the most common cause of cancer death was
cervical cancer. It is the commonest cancer in females in most of the cancer registries in
India [2].
Metastatic breast cancer i.e. stage IV, is a complex multi-step process defined by the
expansion of tumorigenic cells beyond the breast, chest wall, and regional lymph nodes to
other areas of the body. It is a serious complication of breast cancer, as metastatic disease
in breast cancer is often fatal. Strategies targeting the primary tumor have markedly
improved, but systemic treatments to prevent metastasis are less effective; metastatic
disease remains the underlying cause of death in the majority of patients. Western studies
report that 3-10 % of patients of cancer initially present with distant metastasis [3].
Nevertheless, nearly 30% of women initially diagnosed with early-stage disease will
ultimately develop metastatic lesions, often months or even years later [4].
The recommended primary treatment approach for women with metastatic breast cancer
and an intact primary tumor is the use of systemic therapy. Local therapy of the primary
tumor is recommended only for palliation of symptoms. However, a series of retrospective
studies have revealed that surgical removal of the primary breast tumor has a favorable
impact on the prognosis of selected stage IV breast cancer patients with oligometastatic
disease.

THEORIES ON THE NATURAL HISTORY OF BREAST CANCER-

1. The Halsted theory : Spread from one source
Breast cancer was seen to be a disease that arose in one location (the breast) and, if
left untreated, spread through the lymphatic system first to regional lymph nodes and
subsequently to other organs in the body. This theory of “contiguous” development of
metastasis was articulated by Dr. W.S Halsted and was the basis of extensive
locoregional surgery like radical mastectomy. [5]

2. The Alternative theory : Systemic disease

Dr. Bernard Fisher stated that breast cancer is a systemic disease and that variations
in effective locoregional treatment are unlikely to affect survival substantially. This
theory implicated that distant metastasis of any significance have already occurred at
the time a breast tumor is detected clinically or by imaging [6].

3. The Spectrum theory : Combined theory

Dr Hellman suggested that metastasis is a function of tumor growth and progression.
Lymph node involvement is of prognostic importance not only because it indicates
more malignant tumor biology, but also because persistent disease in the nodes can
be the source of distant disease. Therefore, in contrast to the systemic therapy,
locoregional therapy is important [7].

NEWER CONCEPTS- Metastatic progression at the cellular and molecular level (8)
Molecular –based hypothesis –

1. Parallel evolution model – suggests that CTC’s (circulating tumor cells,found in

blood) or DTC’s (disseminated tumor cells,found in bone marrow or and
 secondary organs such as liver, lung, or bone) are found early in tumorigenesis
and are independent of primary tumor characteristics.
2. Gene expression of primary tumor predicts metastasis model- suggests that
intrinsic molecular characteristics of the primary tumor predict risk of subsequent
metastasis. Therefore, resection of the primary tumor with systemic therapy to
target the CTC’s burden should be the treatment goal for these patients.
3. Stem cell theory- states that specialized tumor-initiating cancer cells have the
potential to proliferate and form new sites of tumor metastasis. Extirpation of the
primary tumor followed by targeted therapy to wipe out the stem cell population
should be the treatment goal.

Metastasis and host interactions: feedback regulatory mechanisms

1. Metastasis and immunologic effects- as per this theory, surgical removal of

primary tumor reverses tumor induced immunosuppression, restoring both T
and B cell mediated immunity, in the presence of disseminated disease.
2. Tumor dormancy theory- proposes that removal of primary tumor results in
proliferation of macrometastasis by increasing angiogenesis and reducing
apoptosis. This theory argues against the resection of intact primary in stage
IV patients [9].

PRESENTATION OF MBC

A patient may present with metastatic breast carcinoma or develop a systemic recurrence
after treatment for an apparently localized breast cancer.

Most common sites for breast cancer metastasis include- bone, lung, liver, lymph nodes,
chest wall and brain, with the most common site being the bone. However, case reports
have documented dissemination to almost every organ in the body [10, 11]. A recent study
revealed the patterns of metastatic failure following BCT. The most common exclusive first
site of metastasis was bone (5.9% at 15 years). The 4 most common anatomic sites of
distant metastases as the first exclusive event were bone (41.1%), lung (22.4%), liver
(7.3%), and brain (7.3%) [12].

Extensive evaluation to identify metastasis is not required in asymptomatic patients with

stage I and II cancer because of low likelihood of metastatic disease. In patients with stage
III disease, occult metastasis is found in up to 20% of cases and staging studies are
recommended [13]. Symptoms are related to the location and extent of the tumor. These are
nonspecific, appropriate evaluation is warranted in cancer patients with new or evolving
symptoms. Tissue biopsy is imperative when clinical or radiological findings are equivocal.

In two recent studies, it was demonstrated that the ER, PR or HER2 status of a biopsy-
proven metastatic lesion does not match the pathology of the primary tumor in a substantial
fraction of patients (ranging from 15% to 40% of the patient cohort) ,which would
dramatically alter the treatment . This suggests that biopsies of relapsed and metastatic
breast cancers should be performed routinely in clinical practice [14, 15].

PROGNOSTIC FACTORS IN MBC

The average period of survival after diagnosis of metastatic disease is 18–24 months, but
this varies between patients depending on various factors. These include-
Tumor biology (grade, estrogen receptor status, HER-2 status)
Performance status
 Cancer related symptoms
Sites of recurrence
Number of sites of recurrence
Prior adjuvant therapy
Disease-free interval
Prior therapy for metastatic disease
Response/duration of treatment with prior therapy for metastatic disease

Hormone-receptor positive tumors are more likely to spread to bone as the initial site of
metastasis; hormone-receptor negative and/or HER-2-positive tumors are more likely to
recur initially in viscera. Lobular (as opposed to ductal) cancers are more often associated
with serosal metastases to the pleura and abdomen [16]. Studies have correlated location of
disease recurrence with differing 5-year survival rates: soft tissue-41%; bone-23%; visceral
metastasis-13% [17]. Patients who have received less therapy, have a longer disease-free
interval since initial diagnosis, soft tissue or bone metastases, fewer symptoms and better
performance status, and tumors that are hormone-receptor positive are likely to experience
longer survival with metastatic disease than more heavily treated patients with shorter
intervals since treatment, visceral metastases, and greater symptomatology.

Triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen

receptor, progesterone receptor, and HER2, comprises approximately 15% of
incident breast cancers and is over-represented among those with metastatic disease[18]. A
retrospective analysis of one hundred and thirty-four patients with metastatic TNBC treated
at Cancer Hospital of China from January 1999 to December 2007 concluded
that recurrence risk and mortality are considerably higher in TNBC patients within the early
years of follow-up. TNBC patients have a higher risk of multiple and visceral metastases,
and poorer survival, which might attribute to its aggressive clinical behavior and lack of
effective regimens [19]. Assessment of ER, PR and Her-2/neu expression in South Indian
patients showed that 46% were triple negative and these patients are at an increased risk for
metastatic disease [20].

A distinctive subset of metastatic breast cancer (MBC) is oligometastatic disease (OMBC),

which is characterized by single or few (3-4) clinically detectable metastatic lesions. Studies
on OMBC showed overall survival rates of 35-73% at 10 years and 26-52% at 20 years, and
relapse free rates of 27-42% at 10 years and 26-42% at 20 years[21].

One to 10% of women with metastatic breast cancer have a recurrence of their disease as
an isolated lesion (local, regional, or distant) which may be treated by surgical resection,
irradiation, or both. These are patients with stage IV breast cancer with no evidence of
disease, or stage IV-NED. A retrospective analysis of ninety-six patients concluded that
patients with stage IV-NED have poor prognosis due to early development
of metastatic disease. Absence of axillary nodal involvement at the time of mastectomy and
systemic therapy following local management is associated with improved disease free
survival and overall survival [22].

The frequency of bilateral breast cancer is 1.4-11.0% among all breast cancers. It can
present as synchronous (SC) or metachronous (MC). MC breast cancer is different from
SC breast cancer in having more advanced grade, stage, less ER expression, more frequent
rates of local relapse and distant metastasis and better response to chemotherapy in case of
relapse/metastasis [23].

MANAGEMENT OF MBC
Treatment goals in patients with advanced breast cancer include-
 Prolongation of life
 Control of tumor burden
  Reduction in cancer related symptoms or complications
 Maintenance of quality of life and function

Factors guiding treatment include-

 Tumor biology- ER, PR, and HER 2 status
 Clinical history- menopausal status, previous therapies, patient symptoms, functional
assessment

Treatment options include-

ENDOCRINE THERAPY- In the case of hormone receptor positivity and in the absence of
visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Single
agent therapy is the standard approach. First-line endocrine therapy by estrogen antagonism
or suppression of estrogen achieves objective responses (ORs) and clinical benefit (CB) in
around 30% and 50% of estrogen receptor-positive metastatic breast cancer patients,
respectively. [24]

For postmenopausal women- following agents can be used in a sequential manner:

a. “Third generation” Aromatase inhibitors
1. Anastrozole, (non-steroidal) 1 mg PO daily
2. Letrozole,(non-steroidal) 2.5 mg PO daily
3. Exemestane,(steroidal) 25 mg PO daily
b. Selective estrogen receptor modulators
1. Tamoxifen, 20 mg PO daily
2. Toremifene, 60 mg PO daily
c. Antiestrogens
1. Fulvestrant, 500 mg IM monthly
d. Progestins
1. Megestrol acetate
2. Medroxyprogesterone
e. Estrogens-
1. Diethylstilbestrol, 5 mg PO tid
2. Ethinyl estradiol

Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation
aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in
translating these findings into clinical practice stems from the influence of prior
adjuvant endocrine therapy [25]. Options for first line therapy include an AI for women who
have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant
anastrozole. For patients relapsing more than an year following termination of adjuvant
therapy, re-implementation of the aromatase inhibitor may be a reasonable choice. In
contrast, patients relapsing on treatment or shortly after terminating adjuvant therapy need
alternative treatment options.Tamoxifen [26] as well as fulvestrant [27] may have antitumor
effects in patients where aromatase inhibitors fail, and the steroidal compound exemestane
has been shown effective among patients becoming resistant to a non-steroidal aromatase
inhibitor [28].

For postmenopausal women with hormone receptor +ve and HER2 –ve advanced breast
cancer progressing on nonsteroidal aromatase inhibitors, four phase III trials involving 2876
patients—EFECT, SoFEA, CONFIRM, and BOLERO-2—have assessed the efficacy of various
treatment options. Data suggest that standard-dose fulvestrant (250 mg monthly) and
exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to
500 mg monthly results in a 15% reduction in the risk of progression, and that adding
everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in
the risk of progression, albeit with increased toxicity. Consideration should be given to the
patient’s age, functional status, and comorbidities during selection of an endocrine therapy
[29, 30]
.
2. For premenopausal women- options include:
a. SERM- Tamoxifen
b. Ovarian suppression / ablation-
1. LHRH agonist
2. Surgical oophorectomy
3. Radiotherapeutic oophorectomy
c. Progestin – Megesterol acetate
d. Androgen - Fluoxymesterone
e. Estrogens - Diethylstilbesterol

First intervention for premenopausal women is ovarian function suppression with initiation
of tamoxifen treatment as the combined endocrine therapy can improve survival as
compared to either treatment alone. AI is a viable option, if tamoxifen resistance is proven,
although it mandates the use of ovarian function suppression [31]

Currently, there is no general consensus regarding optimal sequencing of endocrine therapy

for metastatic breast cancer. However, for patients with metastatic ER+ breast cancer, it
remains important to extend endocrine treatment for as long as their disease responds, prior
to implementing chemotherapy.

CHEMOTHERAPY
Chemotherapy is the mainstay of treatment in patients with hormone- negative or hormone-
refractory tumors, short disease free interval, aggressive relapse, or recurrence in visceral
sites.
Single-agent chemotherapy facilitates better understanding of which drugs are contributing
to benefit or side effects, allowing appropriate treatment modification, and is generally
associated with less toxicity; therefore, it remains the preferred approach for most women
with metastatic breast cancer. However, combinations can be offered in cases where rapid
response is required or in younger patients with good performance status. Chemotherapy
treatment can be interrupted in patients who have had significant response or palliation
following initiation of therapy and reintroduced when there is tumor progression or
recrudescence of patient symptoms.

NCCN Guidelines Version 3.2013- chemotherapy regimens:

Preferred single agents-
Anthracyclines- Doxorubicin, Pegylated liposomal doxorubicin
Taxanes- Paclitaxel
Anti-metabolites- Capecitabine, Gemcitabine
Mitotic spindle inhibitors- Vinorelbine, Eribulin
Other single agents-
Cyclophosphamide, Carboplatin, Docetaxel, Cisplatin, Epirubicin, Ixabepilone
Chemotherapy combinations-
CAF (Cyclophosphamide, Adriamycin, 5-FU)
FEC (5- FU, Epirubicin, Cyclophosphamide)
AC (Adriamycin, Cyclophosphamide)
EC (Epirubicin, Cyclophosphamide)
CMF (Cyclophosphamide, Methotrexate, 5-FU)
Docetaxel/ capecitabine
GT (Gemcitabine/paclitaxel)
Paclitaxel/ Bevacizumab
No gold standard chemotherapy exists for stage IV cancer, therefore treatment needs to be
individualized and tailored according to patient’s response. Stem cell therapy has shown
promising results in few diseases but its role in breast cancer needs to be defined and is still
under clinical trials.

ANTI-HER2 THERAPY-

The gene c-erb B2 or neu or HER2 is amplified in 20-25% of breast cancers. This
amplification is associated with a more aggressive disease and a poor prognosis. Patients,
carrying a HER2-positive MBC, benefit from new therapies targeting the HER2 receptor.
These treatments have shown their efficacy as single agent, and have a synergistic effect
with chemotherapy. In first line metastatic disease, treatment should include a combination
based on trastuzumab and chemotherapy. However, primary and acquired resistance to
trastuzumab remains a significant problem. Pertuzumab, a humanized monoclonal antibody
that binds to a domain of the HER2 receptor separate from trastuzumab, may have the
potential to overcome trastuzumab resistance.

As per NCCN guidelines and recent trials-

Preferred first-line agents for HER2 psitive disease-

Pertuzumab + trastuzumab + docetaxel (CLEOPATRA study) [32]
Pertuzumab + trastuzumab + paclitaxel
Other first line agents- trastuzumab with
Paclitaxel+/- carboplatin
Docetaxel
Vinorelbine
Capecitabine
Preferred agents for trastuzumab exposed HER2 positive disease- Ado-trastuzumab
emtasine (T-DM1) [33]
Other agents for trastuzumab exposed HER2 positive disease-
Lapatinib + capecitabine
Trastuzumab + capecitabine
Trastuzumab + Lapatinib

ANTIANGIOGENESIS THERAPY

Vascular-endothelial-growth-factor (VEGF) is a key mediator of angiogenesis. The overall

patient benefit from adding Bevacizumab, a humanized monoclonal antibody against VEGF,
to first- and second-line chemotherapy in metastatic breast cancer so far has been modest.
It is dependent on the type of chemotherapy used and limited to a prolongation of
progression free survival and response rates in both first- and second-line therapy. In
contrast, Bevacizumab has no significant impact on the patient-related secondary outcomes
of overall survival or quality of life, which indicate a direct patient benefit. For this reason, the
clinical value of Bevacizumab for metastatic breast cancer remains controversial [34].

ROLE OF SURGERY-

Metastatic breast cancer is considered as incurable. Surgery of the primary tumor is usually
indicated for palliation of local complications like ulceration, fungation or hemorrhage.

A recent meta-analysis included 28,693 patients with stage IV disease of whom 52.8 %
underwent excision of the primary tumor. It showed that patients undergoing surgery had a
superior survival at 3 years (40 % (surgery) versus 22 % (no surgery) (odds ratio 2.32, 95 %
confidence interval 2.08-2.6, p < 0.01). Subgroup analyses for selection of patients
for surgery or not, favored smaller primary tumors, less competing medical comorbidities and
lower metastatic burden (p < 0.01). There was no statistical difference between the two
groups regarding location of metastatic disease, grade of tumor, or receptor status [35].

The current evidence is still not strong enough to advocate surgery for primary in all MBC
patients. However, there seems a subset of MBC patients who, when carefully selected have
a survival benefit from surgery of primary tumor. Further trials are needed to decide the
optimal treatment and its various aspects like the patient characteristics, timing of surgery,
the nature of surgery and extent of surgery etc.

Treatment of specific metastatic sites:

Skeletal metastasis- Most common site is dorsolumbar vertebrae followed by proximal
femur, pelvis, ribs, sternum, proximal humerus and skull.
A. Bisphosphonates- eg. Pamidronate, zoledronate. These are effective in reducing the
pain caused by bone lesions as well as in preventing complications of metastasis like
pathological fracture, hypercalcemia, spinal cord compression etc.
B. Denosumab – this is a human monoclonal antibody against the osteoclastogenic
cytokine- RANKL (Receptor activator of nuclear factor kappa B ligand) and is
comparable to bisphosphonates in the treatment of osteolytic metastasis.
C. Radiotherapy – external beam radiotherapy (EBRT) and highly conformal techniques
like stereotactic body radiotherapy (SBRT) and image guided radiotherapy (IGRT)
have been recommended for alleviation of focal bone pain and at sites of impending
pathological fractures.
D. Surgery – has a role in pathological fractures for stabilization or fixation of bone or
joint and surgical decompression of metastatic spinal cord compression.

Brain metastasis- treatment includes:

A. Solitary lesion- Surgical resection
Radiosurgery with cyber/ gamma knife
Whole brain radiation therapy (WBRT)
B. Multiple lesions- WBRT
Stereotactic radiosurgery
C. Leptomeningeal metastasis- WBRT
Intrathecal chemotherapy with methotrexate or cytarabine

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 Current management of Urolithiasis
R.C.M. Kaza

Introduction

Surgical management of urolithiasis has undergone fundamental changes since the advent of
extracorporeal shockwave (ESWL). The past decade has seen significant revolution in the
management of stone disease as open surgical removal was surplanted by endoscopy and
shockwave lithotripsy. Improved technology in ESWL and Percuteneous Nephrolithotripsy (PCNL) in
the 80,s and Ureteroscopy (URS) in the late 90’s has stimulated this revolution, which has been
readily embraced by both patients and urologists. These newer treatment modalities are well
tolerated by patients because of associated lower morbidity and decreased hospital stay.

The surgical treatment modalities for urolithiasis are the following:-

1. ESWL
2. Endoscopy
3. Retrograde ureteroscopic and cystoscopic approach
4. Percutaneous approach, and
5. Open surgical stone removal.

The purpose of this paper is to provide guidelines on the use of these various surgical treatment
modalities for urolithiasis today. The guidelines put forward in this report are not meant to be
exclusive and is up to the attending urologist to individualise the treatment for his patient. There are
geographical variations in the disease any guidelines will have to take this into account.

Indication for treatment of urolithiasis

The goal of treatment is to achieve a stone free status and at the same time to reduce the incidence
of unplanned secondary procedures and minimize complications. The most common indication for the
treatment of urolithiasis is occurrence of symptons and/or obstructive uropathy in a functioning
kidney. It is also essential to prevent recurrence of stones in a case who has been treated for
urolithiasis or has had a spontaneous expulsion of stone.

Classification of stones:

Knowledge of classification of stones has therapeutic implications.Stones can be classified into

various categories depending on different features.

Stone size: This is an important parameter for deciding treatment line. The size is assessed in one
or two dimensions and stratified into under 5, 5-10,10-20 and above20mm in largest diameter.

Stone Location: Stones can be located in different parts of the anatomy of urinary tract such as the
kidney, ureter and bladder. They can be further classified as pelvic, calyceal (upper, middle, lower) in
kidney and proximal, middle and distal ureter and bladder stones.

Xray characterstics: Stones can be radioopaque or radiolucent or poorly radioopaque. NCCT can
reveal stone characteristics such as internal structure, density etc.
 Radioopaque Poor radioopacity Radiolucent
Calcium Oxalate dihydrate Magnesium ammonium Uric Acid
phosphate
Calcium Oxalate Apatite Ammonium Urate
monohydrae
Calcium Phosphate cystine Xanthine
2,8 dihydroxyadenine
Drug stones

Etiology of stone formation:

Stones can be classified according to etiology.

Non Infection stones:

 Calcium Oxalate
 Calcium Phosphate
 Uric Acid
Infection Stone:
 Magnesium Ammonium phosphate
 Ammonium urate
 Carbon apatite
Genetic causes:
 Cystine
 Xanthine
 2,8 dihydroxy adenine
Drug stones

Stone composition
Composition of stone can critically impact on treatment decision and results. Many a time metabolic
evaluation is required to prevent recurrences. Stones are often formed from a mixture of substances.
Chemical Name Mineral Name
Calcium Oxalate mono hydrate Whewellite
Calcium Oxalate dehydrate wheddilite
Basic calcium phosphate apatite
Calcium Hydroxyl phosphate Hydroxylapatite
b-tricalcium phosphate Whitlockite
calcium apatite phosphate Dahlite
calcium hydrogen phosphate Brushite
Calcium carbonate Aragonite
Octacalcium phosphate
Uric acid dehydrate Uricite
Ammonium Urate
Sodium acid urate monohydrate
Magnesium Ammonium Phosphate Struvite
Magnesium Ammonium Phosphate Dittamrite
monohydrate newberite
Magnesium acid phosphate trihydrate
Cystine
Gypsum
Xanthine
2,8 dihydroxyadenine
Proteins
Cholesterol
Calcite
Potassium urate
Trimagnesium phosphate
Melamine
Matrix
 Drug stones
Foreign body calculi

Risk groups for stone formation: 50% of patients who have first episode of stone will recur agin.
10% of patients will have a propensity to form recurrent stones. Stone type and severity of disease
determine the probability of recurrence.

High risk stone formers:

Genetic factors:
Early stone formers
Family history
Brushite stones
Uric acid and urate stones
Infection stones
solitary kidney
Diseases associated with stone formation:
Hyperparathyroidism
Nephrocalcinosis
GI disorders such as patients with patients with jejuno ileal bypass, ileal resection,
crohns disease etc)
Genetically determined stone formation
Cystinuria
Oxaluria
Xanthin uria
2,8 hydroxiadenine
Cystic fibrosis
Drugs associated with stone formation
Indinavir
Anatomical abnormalities
Medullary sponge kidney
UPJ obstruction
Calyceal diverticulam
VU reflux
Horse shoe kidney
Ureterocele

Diagnosis:
The options that exist include USG,Plain xray KUB and NCCT. Low dose CT can also be used where
the BMI is less than 30. The sensitivity and specificity are as under.
Investigation sensitivity specificity
USG Stones >5mm 96% 100%
In all locations 78% 31%
KUB 44-77% 80-87%
NCCT 96% 100%
Low dose CT 96% 94%

In case of acute flank pain USG is most useful since it is reproducible, inexpensive and does not use
radiation. NCCT also helps in determining structure and composition of stone and in estimating the
skin to stone distance which is important for ESWL. Low doe CT reduces the radiation exposure.
IVU is helpful to delineate anatomy in case surgery is planned and enhaced CT with 3D vertical
reconstruction is also very useful as It also estimates skin to stone distance very well.

Metabolic work up:

It is indicated in the following conditions.
 Cases presenting with recurrent stones despite drug therapy
 With early recurrence after complete stone clearance.
  With late recurrence after a long stone free period because stone composition may change.

All the above conditions call for a detailed metabolic work up. First time stone formers should be
subjected to basic metabolic work up, particularly if a proceedure is being planned. It should include
urinalysis for cells and crystals and culture. Blood should be investigated for creatinine, uric acid,
ionized calcium, sodium, Potassium. Blood cell count and CRP.
Analysis of stone composition gives important information for long term management. The analysis
should be done with Xray diffraction or infrared spectroscopy. Wet chemistry is obsolete.

Treatment of Renal colic:

NSAIDs are the first drug of choice. Opioids like pethidine give rise to vomiting and they carry a
chance of recurrent colic. Administration of alpha blockers in suitable cases will help expulsion of
stones. Diclofenac suppositories help to reduce inflammation and prevent recurrent episodes. If
analgesia can not be achieved by this consideration should be given to stenting/percutaneous
nephrostomy. The indication for this becomes urgent if there is accompanying sepsis in the form UTI.

Stone relief spontaneous passage and medical expulsive therapy (MET)

Observation of ureteral stones:

Stones pass spontaneously particularly ureteral stones. Data on the size of stones and the time they
take to pass is inadequate.
Stone size Average time to pass Percentage of passages(
95% CI)
<5mm 68%
>5mm 47%
<2mm 31days
2-4mm 40days
4-6mm 39days

95% stones up to 4mm pass within 40 days. The passage can be assisted by medical expulsive
therapy.

Observation of Renal stones:

Only those kidney stones which are calyceal and asymptomatic may be suitable for follow up. Most of
the stones become symptomatic, cause infection and show growth. So they call for treatment along
established lines. Co morbidities need to be kept in mind while planning treatment.

Medical expulsive therapy: (MET)

This therapy is most suitable for distal ureteral stones although benefit has been seen even in ESWL
steistrasse in expelling the fragments. Alpha blockers are the most useful drugs for example
Tamsulosin. They relax the ureteral smooth muscle by blocking alpha receptors and reduce the
incidence of colics. Calcium channel blockers like Nefidipine is also useful in MET but it is less
effective as compared to Tamsulosin.

Patients on MET should have well controlled pain, no clinical evidence of infection, and adequate
renal reserve. They should be followed once every 14 days to ensure that the stone is moving and to
assess for hydronephrosis. Maximum therapy time is a month. Stone size and stone location are
important determinants of success in MET. Best results are seen in distal ureteral calculi. MET helps
in migration of proximal calculi downwards.
Management of a renal calculi

Size:- Stones with a maximal length of up to 2.0 cm in diameter can be considered for ESWL
monotherapy.
An alternative option is retrograde URS. Stones with a maximal length of more than 2.0 cm in
diameter should be counseled on the possible need for percutaneous nephrolithotripsy (PCNL) as a
primary modality and ESWL following PCNL as the secondary modality.
Stones with maximal length of more than 2.0 cm in diameter are sometimes treated by using ESWL
montherapy with a DJ stent in-stu. These patients need to be counseled that this approach with result
in a lower stone free rate as well as a possible protracted treatment duration due to numerous ESWL
sessions to treat this large stone. The optimal treatment for such stone should remain as PCNL with
or without ESWL combination therapy.

Location:- Renal stones located in the lower pole of the kidneys which are symptomatic and/or
increasing in size on follow-up can be considered to be treated with ESWL montherapy. However,
patients need to be counseled on the expected stone free rates of <50% of ESWL monotherapy vs
90% with PCNL.

An alternative option to manage lower pole stones is retrograde URS with success rate at 80%.

Composition

If stone composition is known beforehand, the calcium phosphate monohydrate (brushite) or cystine
(esp>1 cm in maximal length) then patients should be counseled on low stone free rates (.50%) with
ESWL monotherapy and PCNL should be considered as a first line treatment modality.

Use of stent

In general, stents should be considered by the attending urologists when dealing with sizeable stones
in patients with solitary kidney.

Staghorn Calculi
For the management of staghorn calculi, ESWL monotherapy should not be the first line treatment
choice, but the combination of PCNL and ESWL should be utilized. As most staghorn calculi are
struvite in nature with varying amounts of calcium, a more aggressive approach may be warranted.
Open surgery may be considered for large and complex staghorn calculi.

Calculi in calyceal diverticulum

Not all calyceal diverticulum with stones are symptomatic and require operative intervention.
Indications for operative intervention will include chronic pain secondary to diverticulum, recurrent
urinary tract infection, gross haematuria or evidence of progressive renal damage.
Percutaneous management of calyceal diverticulum is the most effective approach for rendering
patient with calyceal diverticulum stone free and for achieving diverticular ablation

Role of Laparoscopy
For renal pelvic stones, caliceal diverticulum stones, stones in anatomical variance laparoscopic
surgery offers another minimally invasive alternative to open surgery. It is however investigational at
present and limited to specialized laparoscopic centres.
Management of ureteric stone

Probability of Spontaneous Passage

Stones < 0.5 cm in transverse diameter that do not pass spontaneously within 4 to 6 weeks or a
reasonable period and /or are causing recurrent symptoms should be considered for ESWL
monotherapy.

Stones >0.5 cm in transverse diameter should be considered for treatment as the chance of
spontaneous passage is low in stones of this size.

Stone of 1 cm or less in proximal ureter

As a guideline ESWL monotherapy is recommended as first line treatment for most patients with this
stone. In event that the shockwave therapy fails, then the option of a PCNL or urteroscopy and
intracorporeal lithotripsy would be acceptable second line procedures. Open surgery should only be
considered in standard patients as a salvage procedure.

For stone > 1.0 cm in proximal ureter

In dealing with larger stones in upper ureter, ESWL, PCNL, and URS are all acceptable treatment
choices but URS may become less appropriate as the stone encountered becomes larger. However,
improvement in laser technology makes it more acceptable as first line modality in certain areas with
appropriate facilities. An open surgery should again not be a first line treatment in most patients with
large ureteral stones but may be appropriated for non standard patients and it is certainly an
acceptable alternative as a salvage procedure.

For Stone of 1 cm or less in the distal ureter

ESWL and URS are both acceptable treatment choices. Blind basketing without fluoroscopy
guidewire cannot be encouraged as a treatment option. Open Surgery should not be a first line
treatment but should be considered as a salvage procedure.

For stone larger than 1.0 cm in distal ureter

For larger stone in the ureter, ESWL monotherapy and / or URS are both acceptable for first line
treatment options. Blind basketing is again not recommended and open surgery should be reserved
as a salvage procedure.

Type of ESWL machine

Stone along the entire length of the ureter can be considered for ESWL if the lithotripter system with
high resolution fluoroscopy is available for reliable stone localization. If the lithotripter system has only
ultrasound facilities for stone localization, distal ureteric stones may have to be treated with URS as a
first line modality.

Use of Stents
In general, routine is not recommended as part of ESWL therapy and instead ureteric stone should be
treated in-situ and without stents. However, stents help in reducing colics although patients do
complain of dysuria and frequency.

Contra-indications in the use of ESWL for management of urolithiasis

Absolute contra-indications:-
 Pregnancy
 Untreated Urinary Tract Infection
 Distal obstruction to the stone that cannot be bypassed with a stent
  Untreated bleeding diatheses
 Non functioning kidney
Relative Contraindications
 High stone burden eg. Staghorn calculus
 Abnormal renal anatomy
e.g 1. Uretero-pelvic junction obstruction
2. calyceal diverticulum
3. Horseshoe kidney
Stone Composition – cystine or brushite
Uncontrolled hypertension
Morbid Obesity

Contra-indications to PCNL
The only absolute contra-indication is uncorrected bleeding diathesis
In some patients percutaneous access cannot be done safely. These are usually persons with gross
organo-megaly such as splenomegaly, or anatomical distortion secondary to such problems as
scoliosis, which make access dangerous. CT scan is suggested if PCNL is chosen to plan the access
route.

Open surgery
Open surgery in general should only be reserved as a salvage procedure for patients suffering from
urinary stone disease. However, when facilities and / or expertise is not available, open surgery
remains a viable treatment option with good outcome.

Selected References
1. Chaussy C. Schmiedt E, Jocham D, et al: First clinical experience with extracoreally induced destruction of
kidney stones by shock waves. J Urol 127:417, 1982
2. Lam HS, Limgeman JE, Mosbaugh PG, et al: Evolution of the technique of combination therapy for staghorn
calculi: A decreasing role for extracorporeal shock wave lithotripsy, J Urol 1992; 148:1058-1062
3. Winfield HN, Clayman RV, Chaaussy CG, et al: Monotherapy of Staghorn renal calculi: A comparative study
between percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy. J Urol 1988; 139:895-899.
4. Netto. N.R., Jr., Claro, J.F.A., Lemos, G.C. and cortado, P.L.: Renal calculi in lower pole claices: what is the best
method of treatment? J.Urol., 146:721,1991.
5. Lingemann., J.E. Smith, Evaluation and treatment of calculus disease of the urinary tract. Appropriate
Management of Staghorn Calculi. Problems in Urology - Vol 7, No.4, pp 493-502, 1993.
6. Beliman GC, Silverstein JI, Blickensderfer S, et al: Technique and follow up of percutaneous management of
caliceal diverticula. Urol 1993; 42(1):21-25.
7. Ueno A, Kawamura T, Ogawa A, et al: Relation of spontaneous passage of ureteral calculi to size. Urol 1977;
10:544-546.
8. Grasso M, Bagley D: small diameter, actively deflectable, flexible ureteropyeloscopy. J Urol Nov 1998 160 (M):
1648-1653
9. Taufiek ER, Bagley DH: Management of upper urinary tract calculi withureteroscopic techniques. Urology Jan
1999 53(1): 25-31
10. Grasso M, Ficazzola M: Retrograde ureteropyeloscopy for lower pole caliceal calculi. j Uro Dec 1999 162: 1904-
1908
11. Ramakumar S, Segura JW: Laparoscopic surgery for renal urolithiasis: pyelolithotomy, caliceal diverticulectomy
and treatment of stones in pelvic kidney. J Endourol Dec 2000 14(10):829-832.
12. Resim S, Ekerbicer H, Cifteti A. Effect of tamsulosin on the number and intensity of ureteral colic in patients with
lower ureteral calculus. Int J Urol 2005 Jul; 12(7):615-20
13. Walden M, Lahtinen J, Elvander E. Analgesic effect and tolerance of ketoprofen and diclofenac in acute uretarel
colic. Scand J Urol Nephrol 1993; 27(3):323-5.
14. Naja V, Agarwal MM, Mandal AK, et al. Tamsulosin facilitates earlier clearance of stone fragments and reduces
pain after shockwave lithotripsy for renalcalculi; results from an open label randomized study. Urology 2008 Nov;
72(5):100611.
15. Schuler TD, Shahani R, Honey RJ, et al. Medical explusive therapy as an adjunct to improve shockwave
lithotripsy outcomes: a systematic review and meta-analysis. j Endourol 2009 Mar;23 (3):387-93.
16. Parsons JK, Hergan LA, Sakamoto K, et al. Efficacy of alpha blockers for the treatment of ureteral stones. J
urol2007 Mar;177930:983-7.