Diseases of The Spleen, Thymus, and White Blood Cells: Pathology
Diseases of The Spleen, Thymus, and White Blood Cells: Pathology
Diseases of The Spleen, Thymus, and White Blood Cells: Pathology
YL6: 04.12a Transcribed by TG 19: Ang, Bolong, Dagdag, de Leon, Igasan, Ong, R Pineda, Tiangco 1 of 7
B. SPLENOMEGALY Splenic Infarcts
• Spleen enlargement causes a dragging sensation in the left • The spleen, along with kidneys and brain, ranks as one of the most
upper quadrant and discomfort after eating common locations where emboli form
• Can be caused by hypersplenism → Emboli mostly arise from the heart
→ Characterized by anemia, thrombocytopenia, and ▪ It cannot receive thrombus from brain because of the
leukopenia, or a combination of the three called circulation
pancytopenia (depression of all hematopoietic stem cells) ▪ Prone to rupture
▪ Possibly due to sequestration of formed elements inside → If the embolus is infective or secondary to endocarditis,
the spleen and enhanced phagocytosis by macrophages suppuration may be evident
• Can also be caused by:
→ Infections
→ Immunologic/inflammatory conditions
→ Tumors from the spleen (lymphomas)
→ Lymphohematogenous disorders
→ Storage diseases (Gaucher’s disease)
• Can be either acute or chronic in form
Acute
• Acute congestion of the spleen is non-specific and happens over
the course of a few days
→ Recall: Congestion: accumulation or pooling of blood
• Characteristics: Figure 4. Splenic infarcts
→ Pooling of the blood leading to the enlargement of spleen –
400- 500g (3-4x normal weight) Other Diseases
→ Grossly, the spleen looks very beefy, moist, red and heavier • Lymphohematogenous Disorders
because of congestion → E.g. Leukemias and lymphomas
▪ The white pulp is lost • Storage Disease
→ Thin splenic capsule has several important implications: → E.g. Mucopolysaccharidoses, Niemann-Pick disease
▪ Spleen may rupture or burst due to fast growth and thin
size that may cause a pooling of blood in the C. OTHER ASSOCIATED CONDITIONS
retroperitoneum Rupture
o This is considered a medical emergency • Usually secondary to blunt trauma (e.g. during vehicular
• Happens because of: accidents)
→ Infections such as malaria and infectious mononucleosis • Most common predisposing conditions are infectious
→ Immunologic/inflammatory conditions mononucleosis, malaria, typhoid fever, and lymphoid
neoplasms
→ May cause the spleen to enlarge rapidly, producing a thin,
tense capsule that is susceptible to rupture
• This event often precipitates intraperitoneal hemorrhage, which
must be treated by prompt splenectomy to prevent death from
blood loss
Congenital Anomalies
• Hypoplasia
→ Absence of the spleen is very rare, hypoplasia is a more
Figure 2. Acute congestion
common finding
→ If this is present, look for other congenital abnormalities
Chronic
• Spleniculi (accessory spleens)
• Chronic congestion happens over a long period of time
→ There is generally no pathology, but overlooking an accessory
• Characteristics:
spleen during splenectomy is bad because you want all the
→ Enlargement is much bigger at 1000-2000 g (1000-5000 g
spleen to be removed
based on Kumar et al., 2015) ▪ If you don’t take out the problematic spleen, it would
→ Mainly characterized by fibrosis allowing growth to big size result in the hemolysis and sequestration of RBCs
▪ Does not rupture because it is made from fibrous ▪ Accessory spleen can also enlarge
deposits
→ This is only important in splenectomy with diseases like
▪ Sign of chronic, long-standing disease
leukemias
▪ There is no fibrosis in acute disease
▪ The disease will not be cured if accessory spleen is still
▪ The sluggish flow of blood triggers collagen deposition present
along the venous channels of the spleen causing the
→ Only around 10% of autopsy cases
fibrous appearance and congestion
• Secondary to chronic venous pressure
→ High venous pressure due to portal hypertension or liver
cirrhosis
▪ Something is blocking the blood flow
▪ The high pressure induces collagen deposition in the
blood vessels or sinusoids of the spleen
o The organ can be large because the collagen
depositions are very slow
Figure 5. Spleniculi
Neoplasm
Neoplastic involvement of the spleen is rare except in myeloid and
lymphoid tumors, which cause splenomegaly
• Benign tumors may arise, with lymphangiomas and hemangiomas
being the most common
• May also involve malignant tumors such as lymphoma and
Figure 3. Chronic congestive splenomegaly leukemia
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Table 1. Disorders Associated with Splenomegaly (Kumar et al., 2015)
Infections
Nonspecific splenitis of various The nonspecific reaction in
blood-borne infections these infections is cause by both
(infectious endocarditis) the microbiologic agents
Infectious mononucleosis themselves and by the
Tuberculosis cytokines that are released as
Typhoid fever part of the immune response
Brucellosis
Cytomegalovirus
Syphilis
Malaria
Histoplasmosis
Figure 6. Thymus
Toxoplasmosis
Kala-azar
Trypanosomiasis
Schistosomiasis
Leishmaniasis
Echinococcosis
Congestive States Related to Portal Hypertension
Cirrhosis of the liver Main cause of massive
congestive splenomegaly
Schistosomiosis
• “Pipe-stem” hepatic
fibrosis
• Severe congestive
splenomegaly
Alcoholic cirrhosis and Figure 7. Hassall’s corpuscles
pigment cirrhosis
• Diffuse fibrous scarring B. THYMIC PATHOLOGIES
Portal or splenic vein Can stem from spontaneous Developmental Disorders
thrombosis portal vein thrombosis, DiGeorge Syndrome
usually associated with some • Thymic hypoplasia is seen in this syndrome
intrahepatic obstructive disease, Marked by severe defects in cell-mediated immunity and variable
or inflammation of the portal abnormalities of parathyroid development associated with
vein (pylephlebitis) hypoparathyroidism
Infiltrating tumors arising in
neighboring organs (e.g. Thymic Cysts
stomach or pancreatic CA) • Benign
Cardiac failure Cardiac decompensation of the • If thymic cysts are present, patient may have underlying
right side of the heart – neoplasm
tricuspid or pulmonic valvular → Common approach: what is causing the cyst? There must
disease, chronic or be a mass somewhere in that area putting pressure on the
pulmonale, or following left- thymus, causing the cyst
sided heart failure Isolated thymic cysts are not clinically significant
Lymphohematogenous Disorders
Hodgkin lymphoma Rare, except in myeloid and Thymic Follicular Hyperplasia
Non-Hodgkin lymphomas and lymphoid tumors • Benign
lymphocytic leukemias Lymphangiomas and Refers to the appearance of reactive B-cell lymphoid follicles within
Multiple Myeloma hemangiomas are most the thymus
Myeloproliferative disorders common and often cavernous in • There are some conditions that would induce the proliferation of
Hemolytic anemias type T cells
Immunologic-Inflammatory Conditions • The thymus can be enlarged in infections, immunologic states, and
Rheumatoid arthritis autoimmune disorders (e.g. myasthenia gravis, systemic lupus
Systemic Lupus Erythematosus erythematosus, rheumatoid disease)
Storage Diseases • Can sometimes be mistaken for a goiter, resulting in unnecessary
Gaucher disease surgery
Niemann-Pick disease
Mucopolysaccharidoses Thymoma
Miscellaneous Disorders • Only tumor that can come from thymus
Amyloidosis • Benign tumor but becomes malignant when it invades the
Primary neoplasms and cysts contagious structures like the lungs, pericardial sac, etc.
Secondary neoplasms → Benign: considered non-descript which means that when
you look at them in the microscope, they look the same,
(polygonal or spindle cells)
II. THYMUS
Well encapsulated
A. ANATOMY The neoplastic epithelial cells are arranged in a swirling
• Similar to your appendix, in the sense that they aren’t functional pattern and have bland, oval to elongated nuclei with
before, but becoming more important now inconspicuous nucleoli
• Where T cells develop and originate Only a few small, reactive lymphoid cells are
• Only palpable in childhood and adolescence interspersed
→ As you grow older, it atrophies → Malignant: rarer, cortical type
• Composed of two well-encapsulated fused lobes: ▪ Remember: for malignant neoplasm, invasion tells you
→ Epithelial component (Hassall’s corpuscles/Thymic when it’s malignant
corpuscles) ▪ Arise in the form of squamous cell carcinoma or
Whorls of medullary epithelial cells with their keratinized lymphoepithelioma-like carcinoma
cores o Looks like a squamous cell with a lot of reactive T
→ T lymphocytes (lymphoid component) lymphocytes
▪ Surrounds epithelial component ▪ Can only be seen surgically
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The neoplastic epithelial cells are polygonal and have Disorders of the WBCs can be classified into two broad categories,
round to oval, bland nuclei with inconspicuous nucleoli proliferative disorders and leukopenias
Numerous small, reactive lymphoid cells are
interspersed Proliferative Disorders (Leukocytosis)
• Increase in white blood cells
• Can be reactive or neoplastic
Reactive proliferations: common in the setting of infections
or inflammatory processes or when leukocytes are needed for
an effective host response
Neoplastic disorders: less frequent but much more
important clinically
Leukopenia
• Decrease in white blood cells
• Less frequent but more important clinically
Figure 8. A: Benign thymoma (medullary type), B: Malignant thymoma • Can indicate an infection or a tumor
(type I) • Sometimes used interchangeably with neutropenia in clinics
because for WBCs in peripheral blood, most are neutrophils
NICE TO KNOW Associated with rare congenital immunodeficiency diseases,
Note that WHO staging is different according to Robbins advanced HIV infection, and treatment with high doses of
→ In clinical practice: WHO is used more often corticosteroids
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• Congenital Anomalies • Bacterial endocarditis
→ Rare congenital condition (e.g. Kostmann syndrome, which • Rickettsiosis
is seen in Swedish population) • Malaria
Inherited defects in specific genes impair granulocyte • Autoimmune disorders
differentiation → Systemic lupus erythematosus
• Inflammatory bowel diseases
Accelerated Removal or Destruction of Neutrophils Ulcerative colitis
• Immunologically mediated injury to neutrophils Lymphocytosis • Rare
→ Increased tissue migration, thus low peripheral blood count • Atypical lymphocytes in infectious
Can be seen in autoimmune diseases or caused by exposure mononucleosis or other types of
to drugs viral infections can mimic
• Splenomegaly due to sequestration of neutrophils leukemia.
• Increased peripheral utilization due to overwhelming sepsis • They may look similar to your
lymphoblasts
C. LEUKOCYTOSIS • Accompanies monocytosis in many
An increase in the number of white cells in the blood disorders associated with chronic
Common reaction to a variety of inflammatory states immunologic stimulation
• The most important and common cause of leukocytosis is → Tuberculosis
infection → Brucellosis
• Viral infections
Table 2. Major Mechanisms of Neutrophilic Leukocytosis → Hepatitis A
Type of Leukocytosis Cause → Cytomegalovirus
Increased Production in the Chronic infection or → Epstein-Barr virus
Marrow inflammation (growth factor-
• Bordetella pertussis infection
dependent)
Paraneoplastic (e.g. Hodgkin
Note on lymphocytes: Sometimes, an increase in WBC could
lymphoma; growth factor-
produce a leukemoid reaction because of high count of WBC in
dependent)
leukemia. There can also be leukemoid reactions in certain cancers
Myeloproliferative disorders
or infections. They have a lot of neutrophils in varying stages of
(e.g., chronic myeloid leukemia;
maturation. So you may see some immature forms of granulocytes.
growth factor-independent)
(Ledesma, 2019)
Increased release from marrow Endotoxemia
stores Infection
Reactive Changes in Neutrophils
Hypoxia
• Toxic granules
Decreased margination Exercise
→ Seen in infections or sepsis.
Catecholamines
→ Granules are bigger, numerous, and coarser
Decreased extravasation into Glucocorticoid
tissues → The body’s way of trying to fight off infection.
• Döhle bodies
In steroids, the number is actually normal in the peripheral blood, → A small bluish dot in the cytoplasm that is not connected to
but the problem is, your WBCs don’t go to the sites of inflammation. the nucleus of your neutrophil
That’s why steroids are a good way to keep the inflammation at the ▪ Small bluish dot: enlargement of the endoplasmic
very low level. (Ledesma, 2019) reticulum
• Leukemoid reaction
Types of Leukocytosis → Increase in the number of WBC with varying forms of
maturity (i.e. from the myeloid lineage: promyelocyte,
NOTE metamyelocytes)
For this section, the highlighted words are those mentioned during the ▪ Different stages of maturity that may mimic your chronic
lecture myeloid leukemia
▪ Important note: You shouldn’t see an increase in
Table 3. Types of leukocytosis basophils here
o If you have an increase of basophils, you think of
Leukocytosis Type Cause
Chronic Myeloid Leukemia (CML)
Neutrophilia • Increase in neutrophils
→ CML is not seen in leukemoid reaction
• Acute bacterial infections
→ E.g. from pyogenic organisms
• Sterile inflammation such as necrosis
→ Myocardial infarction
• Burns
Eosinophilia • Allergic disorders
→ Asthma
→ Hay fever
→ Parasitic infections
• Drug reactions
• Malignancies
→ Hodgkin lymphoma
→ Some Non-Hodgkin lymphoma
• Autoimmune disorders
→ Pemphigus
Figure 10. Neutrophils with purple cytoplasmic granules (toxic
→ Dermatitis herpetiformis
granulations) and blue cytoplasmic patches of dilated endoplasmic
• Vasculitides
reticulum (Döhle bodies, black arrow)
• Atheroembolic disease
Induces transient eosinophilia
D. LYMPHADENITIS
Basophilia • Rare
• Inflammation of lymph nodes
Often indicative of myeloproliferative
• May be acute or chronic
disease (e.g. Chronic myelogenous
leukemia or CML)
Monocytosis • Increase in monocytes
• Chronic infections
→ Tuberculosis
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Table 4. Acute and Chronic Lymphadenitis Others
Acute Chronic • Lymphoid follicle formation in non-lymphoid tissues
Expect to see many neutrophils May take some time for → E.g. Colon/Gastrointestinal Tract (aside from Peyer's Patch),
changes to be seen joint spaces (in Rheumatoid arthritis)
Tender and large due to Non tender lymph nodes • Due to chronic infection
sudden enlargement of lymph → Common denominator for all these things in order for
nodes lymphoid follicle to be formed in these areas
Due to infection Due to immunologic stimuli
(have undergone a vaccine or QUICK REVIEW
exposure to certain diseases SUMMARY OF TERMS
• The spleen is a site of immune responses
Chronic Lymphadenitis produces 3 different patterns of lymph node → Acts like a sieve to filter the blood and particulate matter
reaction: (1) Follicular Hyperplasia (2) Paracortical Hyperplasia → The major organ for the mononuclear lymphatic system
(3) Sinus Histiocytosis
• Splenic macrophages: responsible for “pitting” of RBC
→ Heinz bodies: inclusions of denatured hemoglobin
Follicular Hyperplasia
→ Howell-Jolly bodies: nuclear remnants (mostly RNA)
Caused by antigenic stimuli that activate humoral immune
response • Extramedullary hematopoiesis: the spleen produces RBCs and
other cellular elements during fetal development and certain
• You should see these 3 things in the germinal center of Follicular
disease states
Hyperplasia, which are absent in Follicular lymphoma: (1) Mantle
Zone (2) Germinal Center: Light and Dark Zones (3) Tingible- • Sequestration: the harboring of the spleen of RBCs and WBCs
body Macrophage from the peripheral blood
• Splenomegaly: characterized by anemia, thrombocytopenia,
Mantle zone and leukopenia, or a combination of the three called
pancytopenia
• Encompassing your germinal center
→ Acute congestion: non-specific and happens over the
• Composed of naïve B cells
course of a few days, 400- 500g (3-4x normal weight)
→ Recall: Naïve B cells are B cells that have not been exposed
→ Chronic congestion: happens over a long period of time,
to an antigen
1000-2000 g
• Splenic infarct: common infarct caused by occlusion of the major
Inside the Germinal Center (Light and Dark zones)
splenic artery or any of its branches
• Light zone: composed of centrocytes • Other associated conditions of the spleen
Centrocytes: B cells with irregular or cleaved nuclear
→ Rupture: often precipitates intraperitoneal hemorrhage
contours
→ Congenital anomalies: hypoplasia, spleniculi
• Dark zone: composed of centroblasts
→ Neoplasm: may either be benign (lymphangiomas and
→ Centroblasts: B cells that have been presented with antigens
hemangiomas) or malignant (lymphoma and leukemia)
by the APCs within the germinal center
• Thymus: only palpable in childhood and adolescence, as you grow
→ As the B cells mature and produce high affinity antibodies,
older, it atrophies
they undergo somatic hypermutations (change the heavy
• Composed of two well-encapsulated fused lobes:
chains of the immunoglobulins) in order to find a specific
antibody for these antigens → Epithelial component (Hassall’s corpuscles/Thymic
corpuscles)
• Sequence of events:
1. B cells go to the dark zone to develop the antibody → T lymphocytes (lymphoid component): surrounds epithelial
component
2. Once they developed an antibody, the B cells go to the light
zone where they are presented with the antigen • DiGeorge Syndrome: thymic hypoplasia, marked by severe
3. If the antibody that they developed is not specific to that defects in cell-mediated immunity
antigen, they go back again to the dark zone until they find the • Thymic Cyst: uncommon lesions lined by stratified or columnar
specific antibody epithelium
• Thymic Follicular Hyperplasia: appearance of reactive B-cell
Tingible- Body Macrophages lymphoid follicles within the thymus
• Found in the middle of germinal centers • Thymoma: only tumor that can come from thymus
• "Tingible-body” because it contains many apoptotic debris • Leukocytosis: increase in white blood cells
→ Apoptotic debris: remnants of B lymphocytes that did not • Leukopenia: decrease in white blood cells
produce the correct antibody or are self-reactive • Neutropenia: reduction in the number of neutrophils in the blood
→ Neutropenia and leukopenia are used interchangeably in
Paracortical Hyperplasia the clinics because WBCs in peripheral blood are mostly
• “Para” – beside the cortical area neutrophils
→ Increase in the cells of paracortical area • Agranulocytosis: a clinically significant reduction in neutrophils
• Paracortical area: houses T lymphocytes • Common causes of neutropenia:
→ Recall: T lymphocytes produce cytokines to encourage the → Exposure to drugs (i.e., you don’t give chloramphenicol to
proliferation and differentiation of B lymphocytes children)
• Usually virus induced → Chemotherapeutic drugs that depress WBCs
→ Vaccines: notorious for producing this benign hyperplasia → Myelodisplastic syndromes
→ Stimulation of T lymphocytes found in paracortical region → Inadequate or ineffective granulopoiesis
→ Increased destruction or sequestration of neutrophils in the
Sinus Histiocytes periphery
• Old name: Reticular Hyperplasia • Toxic granules: granules are bigger, numerous, and coarser,
• Expansion of sinusoids at the center of the lymph node seen in infections or sepsis.
• Endothelial cells, lining the sinusoids, proliferate and increase in body’s way of trying to fight off infection
the number of macrophages • Döhle bodies: small bluish dot in the cytoplasm that is not
→ Reason why it looks pale pink (because of cytoplasm of connected to the nucleus of your neutrophil
macrophages) • Small bluish dot: enlargement of endoplasmic reticulum
• Most lymph nodes that drain cancers have this pattern • Leukemoid reaction: increase in the number of WBC with varying
→ E.g. Axillary lymph nodes of Breast CA patients will have this forms of maturity
pattern → You shouldn’t see an increase in basophils here
• Benign form of lymphadenitis • Lymphadenitis: inflammation of lymph nodes
→ Acute: tender and large lymph nodes due to an infection
→ Chronic: non tender lymph nodes due to immunologic stimuli
• 3 Different Patterns of Chronic Lymphadenitis: (1) Follicular
Hyperplasia (2) Paracortical Hyperplasia (3) Sinus
Histiocytosis
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• Follicular Hyperplasia should have: (1) Mantle Zone (2) Germinal IMPORTANT LINKS
Center: Light and Dark Zones (3) Tingible-body Macrophage
• Mantle Zone: encompassing the germinal center with naïve B cells Trans feedback: https://tinyurl.com/AcadsTransFeedback
• Light zone: composed of centrocytes Errata submission: https://tinyurl.com/ContentErrataSubmission
• Dark zone: composed of centroblasts Errata tracker: https://tinyurl.com/ErrataTracker
• Tingible-Body Macrophages: found in the middle of germinal
centers
• Paracortical hyperplasia: increase in the cells of paracortical
APPENDIX
area, usually virus- induced
• Sinus histiocytes: expansion of sinusoids at the center of the
lymph node due to the proliferation and expansion of
macrophages, producing pale pink color
• Common denominator for lymphoid follicle formation: chronic
inflammation
REVIEW QUESTIONS
1. T/F. The spleen, like a huge lymph node, is the major organ for the
multinuclear lymphatic system.
2. Which of the following is true regarding splenomegaly?
a) Causes a dragging sensation in the left upper quadrant and
discomfort after eating
b) Characterized by anemia, thrombocytopenia, and leukopenia
c) Characterized by pancytopenia
d) Only A & B
e) All of the above
3. Which congenital anomaly has generally no pathology but can be
bad when overlooked during a splenectomy?
a) Hypoplasia
b) Spleniculi
c) Neoplasm
d) Splenomegaly
4. The following are normal components of the thymus EXCEPT for:
a) Hassall's corpuscles
b) T lymphocytes
c) B lymphocytes
d) Thymic corpuscles
5. A developmental disorder which is always benign and may indicate
an underlying neoplasm.
a) DiGeorge Syndrome
b) Thymic Follicular Hyperplasia
c) Thymoma
d) Thymic Cysts
6. Which of the following is INCORRECTLY matched?
a) Leukopenia: increase in white blood cells
b) Leukocytosis: increase in white blood cells
c) Lymphocytosis: increase in lymphocytes
d) None of the above
7. An end result of infection is due to a neutrophil count of
a) <250/mm3
b) <300/mm3
c) <500/mm3
d) >600/mm3
8. Leukocytosis with an increased release from marrow stores is
caused by the following EXCEPT:
a) Endotoxemia
b) Catecholamines
c) Hypoxia
d) Infection
9. One can expect to see many neutrophils in acute lymphadenitis.
The most common cause of chronic lymphadenitis is infection.
a) Statement 1 is true. Statement 2 is false.
b) Statement 1 is false. Statement 2 is true.
c) Both statements are true.
d) Both statements are false.
10. Benign hyperplasia which houses T lymphocytes and is usually
virus induced
a) Follicular Hyperplasia
b) Paracortical Hyperplasia
c) Sinus Histiocytosis
REFERENCES
REQUIRED
(1) Ledesma, J.D. October 08, 2019. Diseases of the Spleen, Thymus,
and White Blood Cell [Lecture slides].
(2) Kumar, V., Abbas, A.K., & Aster, J.C. 2015. Robbins and Cotran
Pathological Basis of Disease Ninth Edition.
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