1

GIT Pathology
ORAL CAVITY

1. Leukoplakia:
- Well defined white plaques caused by epidermal proliferations
- Cannot be scraped off
- Chronic irritation such as tobacco use, HPV & ill fitting dentures are predisposing factors
- 3-6% undergo malignant transformation
2. Oral Hairy Leukoplakia:
- Fluffy or hairy hyperkaratotic thickenings
- Seen in HIV+ pts; Majority have EBV
- No malignancy potential
3. Erythroplakia:
- Red plaque velvety eroded area with much more atypical epithelial changes
- Malignancy rate > 50%

Clinical:
Squamous Cell Carcinoma of the Tongue:
- HPV16 & 18, alcohol, tobacco
- Chronic mucosal irritation: metaplasia ! epithelial dysplasia !squamous cell carcinoma
- Moderately well-differentiated keratinized tumors; keratin pearls, epithelial thickening
- 50% mortality in 5yrs

ESOPHAGUS
- 4 layers the wall: (normally pale pink appearance)
o Mucosa(epithelium, lamina propria, muscularis mucosa, Sub-mucosa (Meissner’s Plexus & glands),
Muscularis propria/externa (Auerbach’s Plexus, long & circular muscles), Adventitia (NO serosa)
- Stratified squamous epithelium

Congenital Non-neoplastic Neoplasms

Atresia Hiatal Hernia Benign
Stenosis Achalasia Malignant
Mallory Weiss Tear
Esophagitis
Barrett’s Esophagus
varices

Congenital

1. Esophageal Atresia
- The esophagus fails to develop
- A portion of the esophagus is replaced by a non-canalized cord
o Associated with: Tracheo-esophageal fistula

Clinical:
- Newborn NOT able to swallow: Excess drooling, regurgitation
- Choking and cyanosis occurs with 1st feed
- Maternal polyhydroamnios & single umbilical artery

Non Neoplastic Conditions

1. Hiatal Hernia:
- Herniation of stomach through enlarged esophageal hiatus in the diaphragm
- There is separation of the diaphragmatic crura
- Incompetence of lower esophageal sphincter (LES)
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Sliding Type: “Sliding” 95% of cases

- Commonly occurs in patients that have severe reflux esophagitis
- The LES is non-functional
- Will be a “Bell-like” dilation of the stomach into the thoracic cavity
- Gastric reflux: Epigastric pain, heartburn

Paraesophageal Type: “Rolling”

- The greater curvature enters into the thorax
- That part of the stomach can be pinched off by the diaphragm:
o Volvulus ! strangulation ! leading to ischemia and perforation
- Surgery to repair

2. Achalasia/Cardiospasm:
- Lower esophageal sphincter fails to relax during swallowing response.
- Causes:
o Aperistalsis, partial relaxation of LES or ⇑ LES tone
Primary: Loss of inhibitory innervation on LES and smooth muscle
Secondary: Pseudoachalasia: Chaga’s Disease (Trypansoma cruzi), Sarcoidosis, paraneoplastic, Polio
o This causes a loss of ganglion cells in the myenteric plexus (found post-mortem)
Clinical:
- Gradual onset of dysphagia, Odynophagia (pain swallowing)
- Substernal discomfort
- Reflux of contents, vomiting
- Aspiration pneumonia, ⇑ risk of squamous cell carcinoma (toxins in the food bc ⇑ exposure to food)
- Proximal dilation

3. Mallory Weiss Syndrome: Lacerations

- Longitudinal mucosal tears: in the esophagus
o Mucosal or transmural
o Span the esophago-gastric junction
- They are caused by episodes of excessive vomiting without LES relaxation
o Common in alcoholics
- Hematemesis

4. Esophagitis:
- Inflammation of esophagus: many causes
o infections (CMV, HSV, Candidiasis) , Uremia
o Allergic: eosinophilic esophagitis
o Irritants: alcohol, acids: depression of CNS !reflux esophagitis (most common)

Reflux Esophagitis: (commonest esophagitis)

- Reflux of contents: Hyperemia ! inflammatory cells (eosinophils, PMNs) ! elongation of lamina propria
papillae ! basal zone hyperplasia

Complications:
o Hematemesis, stricture formation, aspiration pneumonia
o Barrett’s esophagus & adenocarcinoma
Clinical:
o Dyspepsia (indigestion), heart burn, symptoms ⇑ when lying down
o Regurgitation of gastric acid into the esophagus due to loss of LES
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5. Barrett’s Esophagus

- Esophageal mucosa replaced by metaplastic

Columnar epithelium (basal cell reprogramming)

Etiology:
- GERD: prolonged injury: GE reflux
- Prolonged reflux esophagitis
- M>F US Caucasian

Pathogenesis:
- Injury (reflux): inflammation & ulceration ! damaged ! basal stem cells reprogram
o ⇓ pH in stomach: Basal cells differentiate into gastric or intestinal type epithelium
- The new epithelium of the esophagus is better equipped to handle the acidic environment
- Z-line: Moves up; Red looking epithelium (intestinal metaplasia with goblet cells)
- Lack of absorptive eneterocytes

Endoscopy:
- Salmon-pink, velvety mucosa
o Exists as “tongues” extending up from the GE junction

Clinical:
- Heart burn
- epigastric pain, dysphagia, stenosis, hematemesis
- 30-40X ⇑ dysplasia of the columnar epithelium ! Esophageal adenocarcinoma
- Antacids: Relieve pain

6. Esophageal Varices:
- Lower esophagus: Dilated tortuous dilated vessel in submucosa
- Portal Hypertension: Left gastric (portal) anastimoses with esophageal (systemic); Sup. Rectal (portal) -
Mid/Inf rectal (caval) [hemorrhoids]; Paraumbilical (portal) - Sup epigastric (caval) [caput medusae]

Portal Hypertension:
o Alcoholic cirrhosis: varices, Ascities, jaundice
o Portal congestion forces blood into systemic system
o Flow: Plexus of esophageal veins ! azygos ! SVC
Clinical:
- Ascities; can be asymptomatic until rupture
- Varices can rupture and produce massive hemorrhage into the lumen
o Hemetemesis (vomit blood) ! possible death

Neoplasms
Benign Tumors Malignant (more common than benign)
Leiomyoma, Fibroma, Lipoma, Hemangioma 1. Squamous Cell Carcinoma
Neurofibroma, lymphangioma 2. Adenocarcinoma

1. Squamous Cell Carcinoma of the Esophagus: malignant tumor of the GI tract

keratin pearls = squamos cell
Etiology:
- >50yo Males>Female Blacks>Whites (Asians)
- Diet: Vitamin deficiency, nitrites
- Social: Alcohol, tobacco failure of LES to relax
- Esophageal disturbances: Achalasia, chronic gastritis, Plummer Vinson syndrome
- Genetic: Celiac Disease, Ectodermal dysplasia (Tylosis) iron deficiency causes esoph
web and squam cell in FEM
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Pathogenesis:
- Potential Carcinogens !chronic esophagitis !epithelial dysplasia ! carcinoma in situ ! neoplasm
- Early onset lesion:
o Small, gray/white, plaque-like thickening & mucosal elevation
o Locally invasive
o Lesions become tumor-like years later
- Middle third: 50%, Upper third: 20%, Lower third: 30% (more adenocarcinomas)
- Lymphatic spread: Survival ⇓ 20%

- 2 associated gene abnormalities

o p16 / INK4 tumor suppressor gene
o EGFR

- 3 forms of tumor:
o Exophytic: Polypoid masses protruding into the lumen
o Excavated: Necrotizing ulcerations; Can erode into respiratory tree or aorta
o Infiltrative: Lead to thickening of the wall; desmoplasia = constriction

Clinical:
- Dysphasia = progressive due to esophageal problems can get aspiration pneumonia b/c tumor burrows
- weight loss into trachea and leaves hole for pathogens
- coughing up small amounts of blood
- cervical lymphadenopathy, hepatomegaly, hoarseness of voice
mediastinal lymph nodes

2. Esophageal Adenocarcinoma:
- Mucin type tumor of glandular origin

Etiology:
- 50yo Caucasian
- 5-10% esophageal carcinomas
- Occurs in the lower 1/3 of the esophagus

Pathogenesis:
- Squamous cells of esophagus ! gastric reflux
! Barrett’s esophagus ! gastric/intestinal
cells metaplasia ! genetic mutations in cells :p53 over expression
- ⇑ HER-2/NEU and β-catenin

Morphology:
- Increased mucin secreting cell proliferation
- Large nodular masses
- Deeply ulcerative / diffusely infiltrative mass

Clinical:
- weight loss, anorexia, fatigue, weakness
- Dysphagia: pain when swallowing solid food initially
- Chest pain, cough due to local extension of tumor
- Poor prognosis
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STOMACH

Non neoplastic:

1. Pyloric Stenosis:
- Concentric hypertrophy of circular muscle coat (can be cancerous growth)
- 1st Male child
- M>F
- Regurgitation, projectile vomiting (no bile), palpable epigastric mass, visible peristalsis

2. Acute Gastritis:
- Acute, transient inflammation of the gastric mucosa (PMNs)
- Loss of surface epithelium ! Erosions (more superficial than ulcer)
- Acute Erosive Gastritis: Erosions with hemorrhage

Etiology:
- NSAIDs: Blocks PGE2 (role: ⇑ HCO3-, ⇑ blood to stomach & ⇑ mucin)
- EtOH, smoking, Chemo, Uremia, H.pylori, stress, ischemia, shock
- Burns (Curling ulcers: from hypoxia and systemic acidosis) & head injuries (Cushing ulcers)

Morphology:
- Rugae will look normal, with multiple small ulcers

Pathogenesis:
- Hyperemia, punctuate areas of hemorrhage
- Edema & congestion of lamina propria with PMNs

Clinical:
- Epigastric pain, nausea, vomiting, Hematemesis & melena

3. Chronic Gastritis:
- Chronic mucosal inflammation changes! atrophy/metaplasia

Etiology:
- EtOH, smoking, radiation, Granulomatous conditions (Crohn’s, sarcoidosis)
- H.Pylori: gram –, urease + , motile, noninvasive, located in the gastric mucus layer
o Induces proinflammatory state (IL6, TNF, IL8)
o Protease, Urease, Phospholipase
o Steiner silver stain
o Urea breathe test +
o ⇑ Gastric acid and ⇓ HCO3-; hyperacidity
Text Steiner Silver Stain

Morphology:
- Lymphocyte & plasma cell infiltrate into lamina propria, PMNs in neck region
- intestinal metaplasia: columnar with goblet cells with glandular atrophy
which is normal in intestines adenocarcinoma occurs as well
Clinical:
- Nausea, vomiting, epigastric pain, dyspepsia, normal gastrin levels
- Proliferation of lymphoid tissue: lead to MALToma or lymphoma (B cell)

Autoimmune variant
- Loss of parietal cells from autoAb ! gland destruction!mucosal atrophy
- Pernicious anemia: Loss of acid & IF ! megaloblastic anemia
- Achloridia (loss of acid), hypergatrinemia (redundant development of parts of stomach), ⇑ Gastrin
- Associated with other autoimmune diseases: Hashimoto’s Thryroiditis, Addison’s Disease
- Long term risk: gastric carcinoma & Carcinoid tumors
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4. Gastric Ulcers
- Loss of mucosa extending through muscularis mucosal layer
- Gastric and duodenal common

Acute Gastric Ulcers

Etiology:
- Severe trauma, Extensive burns (Curling ulcers) head injuries (Cushing ulcers)
Pathogenesis:
- Systemic acidosis and hypoxia (burns)
- Vagal stimulation (cranial lesions) ! ⇑ acid
Morphology:
- Multiple small circular ulcers with normal adjacent mucosa
- Rugae are normal with nonindurated bases

Peptic Ulcer Disease (chronic)

Etiology:
- Text
H.pylori, NSAIDs, Smoking, EtOH, stress, Zollenger Ellison Syndrome
gastrin secreting tumor
Morphology:
- Sites: Duodenum (no malignancy potential) (1), Stomach (2), GE junction (3)
- 50%<2cm round to oval punched out with straight walls
- Raised margins with smooth clean base, radiating surrounding mucosal folds
4 zones:
- Necrotic fibrinoid debris, Inflammatory cell layer, Granulation layer, Scar tissue layer

Clinical:
- Burning epigastric pain 1-3hrs post meal, alkali foods relieve, worse at night, weight loss
- Complications: Bleeding, perforation, gastric outlet obstruction,
- Malignant transformation
- Duodenal ulcers: Pt eats all the time ! ⇑ weight. eating alleviates pain here

Zollenger Ellison Syndrome

- Neuroendocrine tumor: ⇑ gastrin
- Multiple ulcers in stomach duodenum, jejunum & ileum

Neoplastic

5. Gastric Adenocarcinoma
- Exophytic, flat, or excavated mucin producing tumors

Etiology:
- common in Japanese and S. Koreans
- Intestinal Type: 50yo M>F 2:1, Chronic Gastritis, H.pylori, nitrate (smoked foods) signet cells (mucin)
o Amplification of HER2/NEU and ⇑ β-Catenin
- Diffuse Type: Young female, E-Cadherin and FGR2 risk factors

Pathogenesis:
- Intestinal Type: H.pylori: release ROS ! DNA damage
o Intestinal metaplasia
- Excavated tumor: resemble ulcer however has heaped-up margins

Morphology:
excavated diffuse
- Intestinal Type: Neoplastic glands resemble colonic epithelium
- Diffuse Type: No gland formation; Signet-Ring Cells (mucin vacuole w n. in periphery)
o Linitis plastica appearance: leather bottle stomach ! Desmoplasia
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Clinical:
- Asymptomatic early, then weight loss and abdominal pain later very common symptoms of cancer
- Virchow’s Node, pyloric obstruction, Krukenberg tumor- ovary met with signet ring cells from any origin
- Depth of tumor most prognostic factor Virchow node = supra-clavicular nodes most likely in ovaries
Sister Mary Joseph node = periumbilical
6. Gastrointestinal Stroma Tumors (GIST)
- Tumor of the gastric mesenchyme; Benign or malignant
o Anywhere in GIT; stomach most prominent
- Neoplastic Interstitial Cells of Cajal – (pacemaker cells): stomach for motility
o Usually in submucosa
- Creates Swirls and bundles of Spindle Shaped Cells
- Tumor Marker: C-Kit (CD 117)
- Mutation of CH4
- Tx: GLEEVEC (tyrosine kinase mutation)

SMALL INTESTINE

Congenital abnormalities

1. Meckel’s Diverticulum
- Incomplete involution of vitelline duct/yolk stalk/omphalomesenteric duct (connects gut to yolk sac)
- True Diverticulum: blind out pouching of GI
o Consists of 4 wall layers: mucosa, submucosa, muscularis propria & serosa
- Sometimes lined by gastric mucosa or pancreatic tissue (any path of those tissues can manifest here)

Rule of 2’s:
- 2in, 2ft from ileocecal valve, 2% population, 2% symptoms, 2:1 M>F 2 types of cells: gastric or pancreatic

Clinical:
- Asymptomatic or GI bleed, ulceration, fistula, perforation
- Pernicious anemia: IF diverticula has bacteria (deplete B12)
- Technetium 99m: test for Meckel’s

Complications:
- Hemorrhage, intussception, ulceration, obstruction

Malabsorption Syndromes:

1. Celiac Disease: (Gluten Sensitive Enteropathy or Nontropical Sprue)

Etiology:
- Exposure to Gluten products at young age!
- Common in twins & trisomy 21 (DS)
- HLA-DQ2 (95%), HLADQ8 (5%)
Pathogenesis:
- Immunological sensitivity to Gliadin (in gluten)
- Lamina Propria:
o CD4+Tcells, Lymphocytes, MACs & plasma cell infiltrate
o CH8+ Tcells: NKG2DR (NKcellR): recongnizes stressed epithelial cells & kills them
Morphology:
- Elongated hyperplastic crypts, with atrophy & loss of villi (flattened) in duodenum
Clinical:
- Diarrhea, steatorrhea, Fe deficiency anemia & Ca++
- Serology: Anti-tissue transglutaminase (tTG) Ab, anti-gliadin Ab, Anti-endomysial Ab
Complications:
- Tcell lymphomas (increased risk)
- Dermatitis Herpetiformis
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2. Tropical Sprue:
- Living or visiting tropics
- Bacterial infection superimposed on small intestine injury
- All SI involved equally (Ileum absorbs bile and B12)
Clinical:
- Symptoms appear months to yrs after exposure
- Responds to antibiotics

3. Whipple’s Disease:
Etiology:
- gram (+) sickle shaped Trepophyrema whippeli
- Commonly in older men!
Pathogenesis:
- Whippeli invade MACs in the lamina propria of the SI: ! systemic disease
- Malabsorption 2o to disruption of normal villi function
- MACs obstruct lymphatics and reabsoption of chylomicrons
Morphology:
- Distended, foamy PAS + inclusion MACs in lamina propria and LNs
- Prominent fat within intestinal mucosa
DDX: Entamoeba Histolitica: Histologically look similar
Clinical:
PAS+ stain of MACs filled with T. whippeli
- Steatorrhea, weight loss anorexia,
- Polyarthritis, hyperpigmentation, CNS complaints (dementia/SZ), lymphadenopathy

LARGE INTESTINE

Congenital Malformation

1. Hirschsprung’s disease
- Commonest cause of congenital intestinal obstruction
Etiology:
- M4:1F, 10% Down Syndrome
- Defects in migration of neuroblasts ! Absence of ganglion cells in Meissner & Auerbach’s plexus
Morphology:
- Megacolon: Dilation & hypertrophy proximal to aganglionic segment
- Rectum always affected
Clinical:
- Delayed meconium passage (constipation), Abdominal distention
- Stercoral ulcers: shallow; produced by impacted, inspissated (removal of water) feces
Complications:
- Enterocolitis, perforation & peritonitis

Non congenital

2. Diverticular Disease:
- Not true diverticula
Etiology:
- Elderly, normally asymptomatic from poor fiber intake
- Lack of fiber leads to sustained bowel contractions & ⇑ intraluminal pressure
Pathogenesis:
- Weakening of circular muscle with longitudinal muscle in teaniae coli! diverticula
- Can become infected ! diverticulitis
- Flask-like structures (95% sigmoid colon)
Clinical:
- Usually asymptomatic, GI bleeding, lower abdominal pain, fever (if -itis), constipation, flatulence, diarrhea
- diverticulOSIS=bleeding, diverticulITIS=pain
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Colitis
- Inflammation of colon from many underlying causes:
- Infections, necrotizing Enterocolitis, pneudomembranous, ischemia, Inflammatory bowel disease
Clinical:
- Diarrhea, (mucoid or bloody)
- Lower abdominal pain & cramps
- Tenesmus: painful defecation!

1. Pseudomembranous Colitis
- Broad spectrum antibiotic allows C. difficile to take over colonic environment
- #1 nosocominal diarrhea
- C. difficile toxin: causes ribosylation of GTPases (Rho) ! apoptosis of epithelium
Morphology:
- Raised yellow plaques in colon
- Pseudomembrane: fibrin, inflammatory cells and debris (⇑PMNs)
o Surface epithelium denuded !Damaged crypts
o Mucopurulent exudate!forming a cloudy pseudomembrane
- Clinical:
- Fever, leukocytosis, abdominal pain, watery diarrhea, toxin in stool

2. Amebic Colitis
- Caused by Entamoeba histolytica parasite
- Amoebae invade the crypts of colonic glands and burrow down into the submucosa
o inflammation & necrosis of submucosa
o Eat RBCs
- Form Flask shaped ulcers
Clinical:
- amebic dysentery: bloody diarrhea
- Produce amebic liver abscess ! FEVER
- Resembles inflammatory bowel disease on biopsy
- Hystolysin released: kills PMNs
- Rule out IBD (steroids will ⇑ Ameobic growth)

Idiopathic Inflammatory Bowel Disease: (Crohn’s & Ulcerative colitis)

- Common in Young Females of Jewish decent (more associated with Crohn’s)
- Chronic relapsing inflammatory disorders
- Cause malabsorption
- Chronic delayed type inflammatory reaction caused by CD+4 T-cells secreting IL-17
- Extraintestinal associated diseases that can develop before the onset of GI symptoms (More common in UC)
o Migratory Polyarthritis
o ankylosing spondylitis
o erythema nodosum (tender, red nodules on the shins)
o Primary Sclerosing cholangitis (involvement of the biliary tract)
o Aphthous ulcers, gall stones

1. Crohn’s Disease:
Etiology:
- Systemic inflammatory disease affecting any part of GI tract
o Primarily in the Ileum (B12 deficiency)
- Body makes antibodies against cell in the Ileum ! inflammation
- HLA-DR allele associated
- Common in Females and Jews young adults
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Morphology:
- Transmural involvement of the bowel due to inflammation & mucosal damage
- Non-Caseating Granulomas (40-60% of cases)
- Fistula formation: can perforate
- Bowel wall thickens narrowing lumen ! fibrosis & inflammation in muscularis propria
- Creeping Fat: Omentum wraps around inflamed intestine
- Skip Lesions: due to several segments that are randomly involved.
- Crypt Abscesses: neutrophilic infiltration into the crypts
- Serpentine Ulcers: hemorrhaging separated by discontinuous healthy tissue
- Chronic mucosal damage
o Cobblestone Appearance: Transmural cracks ! can form fistulas (perianal)

Clinical:
- Recurrent episodes of non-bloody diarrhea
- crampy lower right abdominal pain fever lasting days to weeks
- Increased risk of bowel cancer but reduced because parts are resected
- Obstructive Megacolon from stenosis
- String Sign: on Barium swallow small ring from stenosis

2.) Ulcerative Colitis:

- Nongranulomatous inflammatory disease limited to the colon QuickTime™ and a
TIFF (Uncompressed) decompressor

o mucosa & submucosa only; NORMAL serosa

ar e needed to see this picture.

- Always starts at rectum

- Pseudopolyps: Islands of regenerating mucosa bulging upward
- HLA-DRB1

Morphology:
- NO skip lesion, NO granulomas, NO fibrosis, Thin intestinal wall
- Mucosa of Rectum: inflammatory pseudopolyps
- Superficial Ulcers
- Predominately mononuclear infiltrate into lamina propria
- PMN infiltrate into epithelial layer ! form crypt abscesses
- In rare cases: the ulcers can damage neural plexus !neuromuscular
dysfunction ! severe gangrenous TOXIC MEGACOLON

Ulcerative Colitis Clinical:

- Attacks of bloody mucoid diarrhea
- Flare-ups w/stress
- Dysplasia of cells ⇒ Risk of carcinoma
- Extraintestinal associated diseases:
o Primary Sclerosing Cholangitis (p-ANCA)
o Uveitis:
o Ankylosing spondylosis
o Migratory Polyarthritis
o Erythema nodosum: red nodules on shins

Vascular disorders

1. Ischemic Bowel Disease:

Etiology:
- Transmural infarct: Occlusion of M aa (Celiac, S./I. mes.)
- Mural or mucosal infarcts: Hypoperfusion
Predisposing factors of occlusion:
- Systemic atherosclerosis: leads to arterial thrombosis
- Cardiac vegetation: leads to arterial embolism
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- Hypercoagulable states : venous thrombosis

Non-occlusive :
- Cardiac failure, shock, volvulus, herniation
- Splenic flexure commonest site for Watershed infarcts.

Clinical:
- Elderly man; severe abdominal pain, nausea, bloody stools, absent bowel sounds
- Small bowel is most commonly by occlusion of the Superior mesenteric artery.
- Death is high with transmural
- Gangrene, perforation, peritonitis, shock & vascular collapse

Neoplasm of Small and Large Intestine:

Non-Neoplastic Polyps: no malignant potential Neoplastic Epithelial Lesion

Hyperplastic Polyps Benign Polyps:
Hamartomatous Polyps Adenomas: tubular, villous, tubulovillous
Juvenile Polyps Malignant Polyps:
Peutz-Jeghers Polyps: (FAP) Adenocarcinoma
Inflammatory polyps Squamous Cell Carcinoma of the Anus

1. Hyperplastic polyps:
- 90% of all epithelial polyps; NO malignant potential
- Occur sporadically in the intestine;50% more common in Rectosigmoid region
o Small, nipple like smooth protrusions of the mucosa
o Contain abundant crypts lined by well-differentiated goblet cells

2. Juvenile Polyps:
- Adults: called retention polyp
- found in children < 5y/o; usually 1-3cms
- Juvenile Polyposis Syndrome: ⇑ risk of malignancy
- Hamartomatous proliferations of the lamina propria (inflammation)
o Retention polyp: (dilated cystic glands) peduculated rounded
structure

3. Peutz Jegher’s Polyp:

- Autosomal dominant, LKB1 gene no real malignancy but risk of other cancers
- Multiple polyps in GIT
- Network of fribromuscular bands extending into the polyp and glands
- Hyperpigmentation in mucocutaneous areas (lips, face, genitalia)

4. Adenomas:
- Malignant potential; precursor lesions of carcinoma
- Risk ⇑: ⇑ size (2cm); dysplasia & loss of architecture
- Associated with APC gene mutation
- Tubular Adenoma
o Most common (90%)
o Smaller than villous; mainly found retrosignmoid
o Size: 0.3cm for sessile & 1-2cm for pedunculated
- Villous Adenoma
o Most malignant
o Cauliflower-like masses projecting into lumen; larger
o Patient will have a loss of fluid & proteins (needed to make mucin)
" Presents with: Hypoproteinemia and hypokalemia
" Anemia due to occult blood loss
- Tubulovillous Adenoma
o Contain both tubule and villi structures
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5. Familial Adenomatous Polyposis:

- Autosomal Dominant: APC gene mutation on CH 5q21
- Patient can develop up to 2500 polyps low fiber, high fat diets
o Minimum of 100 for diagnosis
- Most of the polyps are tubular adenomas
- The polyps arise in adolescence/ early adult
- 100% chance of colonic cancer by age 35; prophylactic colectomy

Clinical:
- Pt will be a 29 yo male whose father died of colorectal cancer at age 40
1. Gardner syndrome: APC gene defect
o Tubular adenomas with multiple osteomas and epidermal cysts
2. Turcot syndrome: APC gene defect
a. Adenomas and CNS gliomas
3. Peutz-Jeghers Syndrome: LKB1 gene mutation
a. causes hamartomatous peutz-jeghers polyps. cells are benign and dysplastic
b. Melanotic mucosal and cutaneous pigmentation
4. Cowden Syndrome: PTEN mutation
a. hamartomatous polyps in the GI tract

6. Colorectal Carcinoma:
- Commonly in the elderly or Ulcerative Colitis (younger)
- 90% of cases arise from an adenomatous polyp
- 15% of cases come from a defect in DNA mismatch repair genes
- Spread is to Regional LNs; stage is most important indicator
- Tumor marker: CEA, DCC then to liver —> lung —> bone
- Aspirin may inhibit tumor formation by inhibiting COX-2 enzyme
o COX-2 is expressed in cancers
- Patient will be an elderly man with Iron-deficiency anemia due to GIT malignancy

Two pathways for the development of carcinoma:

1. Mismatch Repair (microsatellite instability)

- HNPCC or acquired: Genetic lesion in mismatch repair genes
- HNPCC: (Warthin Lynch Syndrome) defect in MLH1
- DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS1, PMS2
- Second hit: LOH, mutation or promoter methylation
- mutation ! second hit! mutations accumulate in genes that regulate growth ! formation of repeat segments
called ‘microsatellites’ ! carcinoma
- Right Ascending (proximal) colon:
o Sessile serrated carcinoma Exophytic polypoid masses that grow along one wall
o Bulky and bleed easily (Melena) ! Fe deficiency anemia
o Patient will present with fatigue, weakness
o Mucinous and poorly differentiated carcinomas, Lymphocytic infiltrates

2. APC / β -catenin Pathway (adenoma-carcinoma)

- Inherited or acquired APC mutation (First hit)
- Methylation or inactivation of normal alleles (Second hit)
- β-catenin accumulates activating MYC & cyclin D ! proliferation
- Loss of both APC ! adenomas ! K-RAS ! p53, LOH ! carcinoma
- Left Descending (distal) colon:
o Annular, encircling lesions that produce “napkin-ring” constrictions of the bowel
o Margins of the “ring” are heaped up
o Altered bowel habits (diarrhea-constipation), lower left quadrant discomfort
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7. Carcinoid tumors:
- GI Neuroendocrine in origin (kulchitsky cells)
- Can metastasize

Stomach occurs in 3 settings:

- Type 1: Gastric atrophy and achlorhydria
o Hypergastrinemia leads to ECL cell hyperplasia
o Can be multiple foci with benign course
- Type 2: Gastrinoma (ZE syndrome)
o Usually MEN2 syndrome; hypergastrinemia
- Type 3: Sporadic
o Usually aggressive tumor with metastasis

Morphology:
- Tend to be yellow, tan, firm with desmoplasia
- Can cause bowel kinking or obstructions
- Dense core granules can be seen in cells on EM
- Cells are round/ oval with stippled nuclei; salt & pepper n.

Clinical:
- 5-HIAA found in urine
- Cutaneous flushing
- Diarrhea, vomiting
- asthma attacks, wheezing
Niacin deficiency
- Pellagra (4D’s)
o Diarrhea
o Dermitits
o Dementia
o Death
- cardiac involvement
o R sided plaques
- Appendix

Neuromarkers:
- Synaptophysin
- Neuron-specific enolase
- Chromogranin A
14

8. Primary GI Lymphomas:
- Represent 1-6% of GI neoplasms
- MALToma: H.pylori: causes Bcell hyperplasia
b. Monoclonal Bcell neoplasm CD5 CD10; t(11:18) common BCL2 + MLT genes
c. Tx: antibiotics
- Bcell: Immunoproliferative small intestinal disease
- Tcell neoplasms
d. Celiac Disease associated

Appendix

1. Acute Appendicitis

Pathogenesis:
- Obstruction ! ⇑ mucin secretion ! Pressure collapses veins ! ischemia ! Infection
- bacterial infection: inflammation, edema, pain, peritonitis, perforation, abscess, bacteremia
Morphology:
- Early Stage: congestion with PMN infiltrates beyond submucosa. Dull granular with red membrane
- Acute suppurative: ⇑ PMNs, fibropurulent reaction on serosa, abscess within wall, ulcerations
- Acute gangrenous: Hemorrhage green ulcerations, necrosis to serosa ! rupture
Clinical:
- Young adults
- Pain, rebound tenderness (peritoneal irritation) at McBurney’s point
- Mild fever, leukocytosis (PMNs) in lamina propria
differential = ectopic pregnancy
2. Appendiceal Mucocele
- Luminal dilation: excess mucin secretions
- Fecalith obstruction allowing mucin to fill
hard stool
3. Pseudomyxoma Peritonei:
- Rupture of adenomous or carcinomous mucocele into peritoneum
- Peritoneal studding of mucinous neoplastic implants
o Mucinous cystadenocarcinomas
- Mucin produced and needs to be drained ! Jelly Belly

Intestinal obstructions:

- Choleocystoduodenal Fistula: gallstone stuck in ileocecal valve ! obstruction; Air in biliary tract
- Meconium Ileus: Children with CF