PATHOLOGY

4.02
Finals Reviewer – WBCs, Lymph Nodes, Spleen & Thymus

H.A. Saguil, MD
I. BASIC TERMINOLOGIES

A marked reduction in the number of circulating WBCs, due to a variety of causes

A WBC count of 500-1000 / mm3 is considered a red flag sign
Leukocytosis can either be due to increased destruction, or inadequate production of WBCs (see causes below)

Inadequate Production (most common cause – drugs)

 Due to myelosuppression (e.g. aplastic anemia w/ Increased Destruction
Leukopenia pancytopenia)  Immune-mediated mechanisms, either primary
 Drugs – especially chemotherapeutics & antibiotics idiopathic, or secondary to other diseases (e.g. SLE)
such as amiopyrene, thiouracil, phenylbutazone, etc.  Increased splenic sequestration (hypersplenism)
 DNA suppression due to megaloblastic /  Increased peripheral demand (n the setting of
myelodysplastic states bacterial & fungal infections)
 Kostmann syndrome – congenital neutropenia  The bone marrow will feature granulocytic
 The bone marrow will feature granulocytic hyperplasia
hypoplasia

An increase in the number of circulating WBCs, which is influenced by the ff. factors:
 The size of the precursor & storage cell pools in the bone marrow, thymus, circulation & peripheral tissues
 Rate of release of cells from the storage pools, into the circulation.
 The marginal pool – the proportion of cells adherent to the blood vessel walls at any time.
 Rate of extravasation of cells from the blood into the tissues.
There are specific types of leukocytosis, each corresponding to a different type of WBC.

Neutrophilia – secondary to acute bacterial infections (especially pyogenic types) or sterile inflammation of tissues (such
as myocardial infarctions, burns).
Leukocytosis
Eosinophilia – seen in allergic disorders, parasitic infections, adverse drug reactions

Basophilia – rare, and if seen, it is often indicative of myeloproliferative disease

Monocytosis – seen in chronic infections (tuberculosis), autoimmune disorders (SLE) and inflammatory bowel diseases

Lymphocytosis – may accompany monocytosis in the setting of chronic inflammation; also seen in viral infections and
pertussis

II. REACTIVE PROLIFERATION OF WHITE BLOOD CELLS

 Caused by stimuli that triggers the humoral immune response – thus, B-lymphocytes are involved
 Defined by the presence of germinal centers / secondary follicles surrounded by a mantle zone (collar of naive,
resting B-cells) in the lymph nodes.
 Tingible-body macrophages are present – they phagocytose B-cells that cannot produce antibodies.
Follicular Hyperplasia
 Differentiated from neoplasms by these distinct features:
o Preserved architecture of the lymph node
o Marked variation in the shape & size of the follicles
o Presence of frequent mitotic figures, tingible-body macrophages, and well-defined light & dark zones

 Caused by stimuli that triggers the cell-mediated immune response – thus, T-lymphocytes are involved
Paracortical  Expanded T-cell zones / paracortical areas may efface the lymphoid follicles.
Hyperplasia  Often accompanied by hypertrophy of sinusoidal & vascular endothelial cells, as well as infiltrating
macrophages & eosinophils

Reticular
 Increase in the number & size of cells lining the lymphatic sinusoids – leads to expansion & distension of the sinuses.
Hyperplasia / Sinus
 Nonspecific, but may be prominent in lymph nodes draining certain cancers (e.g. carcinoma of the breast)
Histiocytosis

III. DEVELOPMENTAL ABNORMALITIES OF WHITE BLOOD CELLS

 Genetic abnormality, arising from a mutation in the CHS1 gene (aka LYST gene) → defective microtubule
Chediak-Higashi polymerization in WBCs → impaired lysosomal digestion of bacteria (and all that it entails...)
Syndrome  Characterized by abnormal, large, irregular neutrophil granules
 Associated with pigment & bleeding disorders

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PATHOLOGY
Finals Reviewer – WBCs, Lymph Nodes, Spleen & Thymus

 Genetic abnormality, resulting from a laminin B receptor mutation; can be sometimes acquired (Pseudo-Pelger-Huet)
Pelger-Huet Anomaly  Not serious, and is usually an incidental finding on PBS.
 All neutrophils have a “pince-nez” appearance (neutrophils only have 2 nuclear lobes)

IV. MYELOID NEOPLASMS

A. Myeloproliferative Disorders

 The common pathogenic feature of these disorders is the presence of mutated, constitutively-active tyrosine kinases, or other aberrations in
the signalling pathways, leading to growth factor independence.
 Other common features include:
o Increased proliferative drive in the bone marrow
o Homing of neoplastic cells to secondary hematopoietic organs, leading to extramedullary hematopoiesis
o Variable progression to a “spent phase” (marrow fibrosis, cytopenia)
o Variable progression to acute leukemia

 Characterized by the presence of the Philadelphia chromosome (BCR-ABL fusion product), formed from the BCR
gene of chromosome 22 & ABL gene of chromosome 9 → promotes growth-factor independent hematopoiesis
 The bone marrow becomes 100% cellular with an increased myeloid:erythroid ratio
Chronic Myelogenous o Massive increase is seen in neutrophils in PBS
Leukemia  There is also splenomegaly, secondary to extramedullary hematopoiesis
 Progresses into an “accelerated phase” characterized by anemia & thrombocytopenia, which terminates in a so-called
“blast crisis” (30% or more of the blood is composed of immature blast cells)
 Occurs at any age, but more common in adults

 Caused by JAK2 point mutations → tyrosine kinase activation → growth factor independent hematopoiesis.
 Produces the so-called panmyelosis – an increase in all cell lines of the bone marrow; the bone marrow is also
frequently hypercellular.
Polycythemia Vera o However, most of the clinical symptoms are d/t increased red cell mass, hence, polycythemia.
o Platelet function is frequently abnormal as well.
o Abnormal platelets + abnormal blood flow d/t inc RBCs → high risk for major bleeding & thrombotic episodes
 No blast crisis; instead, it progresses to a “spent phase” with myelofibrosis and splenomegaly

 Caused by JAK2 & MPL point mutations.

 Hallmark of this disorder is rapid, progressive, obliterative bone marrow fibrosis → bone marrow failure
Primary Myelofibrosis
 Marrow failure leads to the premature release of precursor cells (leukoerythroblastosis); dacryocytes (“tear-drop
RBCs”) are also frequently seen.

 Rarest myeloproliferative disorder, frequently a diagnosis of exclusion; caused by JAK2 & MPL mutations
Essential
 Giant platelets are often seen, and there is an increased number of megakaryocytes in the bone marrow
Thrombocytosis
 Platelet count often approaches 1 million / mm3

B. Acute Myeloid Leukemia

 A tumor of hematopoietic precursors; the genetic mutations causing this tumor are known to disrupt genes related to important transcription
factors, leading to the failure of differentiation.
o AML is diagnosed when the bone marrow is composed of >20% blasts (Normal: 1-2%)
 Clinically, AML produces anemia, thrombocytopenia, fever, fatigue & lymphadenopathy; it is considered worse than ALL (see below)

C. Myelodysplastic Syndrome

 Clonal stem cell disorder, characterized by maturation defects, leading to ineffective hematopoiesis and a high risk of AML (by 25%)
 The bone marrow is hypercellular, but this is not always the case (Not hypercellular accdg. to Doc Saguil)
 Characteristic feature: Dysplastic differentiation affecting all cell lines
o Erythroid precursors – ring sideroblasts (erythroblasts w/ iron-laden granules) & megaloblasts; refractory anemias
o Neutrophils – pseudo-Pelger-Huet abnormality
o Megakaryocytes – “pawn-ball” abnormality (cells w/ multiple, separate nuclei)
o Myeloid blasts – increased, but less than 20% - compare w/ AML

V. LYMPHOID NEOPLASMS

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PATHOLOGY
Finals Reviewer – WBCs, Lymph Nodes, Spleen & Thymus
Some generalities from Doc Saguil & Robbins:

 WBC malignancies, but the term leukemia refers to neoplasms with widespread bone marrow & occassional peripheral blood involvement,
while lymphoma refers to neoplasms that arise as discrete tissue masses.
o All leukemias of lymphocytes have lymphoma counterparts; meanwhile, primary lymphomas can have “leukemic” phases
 Any myeloid leukemia can infiltrate a lymph node or another tissue (granulocytic sarcoma / chloroma)

 All lymphomas are malignant proliferations of lymphocytes

 All leukemias involve bone marrow changes and can suppress normal hematopoiesis
 Many have a strong viral relationship (HTLV-1, EBV, HHV-8)
 Many have chromosomal translocations & can arise in inherited diseases (Trisomy 21 / Downs Syndrome, Fanconi anemia, ataxia
telangiectasia)
 Can be caused by H. pylori infections (gastric B-cell lymphomas), or can follow celiac disease / gluten-sensitive enteropathy (T-cell lymphomas)

 Most common cancer among children; it is a neoplastic proliferation of lymphoblasts (either pre-T or pre-B-cells)
 Most have chromosomal changes (translocations, hyperploidy, Philadelphia chromosome)
 Clinical symptoms include the sudden onset of anemia, bleeding, fever, bone pain, adenopathy & splenomegaly.
Acute Lymphoblastic
o May be accompanied by CNS symptoms (headache, vomiting, nerve palsies)
Leukemia / Lymphoma
 Histologically characterized by the following:
o Hypercellular bone marrow, packed with lymphoblasts.
o Lymphoblasts – cells with condensed chromatin, inconspicuous nucleolus, scant cytoplasm and lacks granules

 Most common leukemia of adults in the Western world

 It is the primary suspect when there is unexplained lymphocytosis reaching counts >4000 / mm3 over several months
 Chromosomal translocations are rare; rather, trisomies and deletions are common.
Chronic Lymphocytic
 The liver may be involved, either in the portal tracts, or within the sinusoids.
Leukemia / Lymphoma
 Usually asymptomatic; if symptoms are present, they are non-specific (easy fatigability, anorexia)
aka Small Lymphocytic  Histologically characterized by:
Lymphoma (SLL) o Proliferation centers – loose aggregates of lymphocytes, tends to efface normal lymph node architecture.
o Malignant cells closely resemble normal lymphocytes – compare with ALL
 May develop immune dysfunction – either hypogammaglobulinemia (low antibodies) or autoantibodies to RBCs &
platelets.

 Malignant proliferation of plasma cells, usually originating from the bone marrow; can have a leukemic phase.
 High levels of IL-6, a cytokine that promotes plasma cell growth, is a marker of poor prognosis.
 Can upregulate RANKL → stimulates osteoclasts → frequent lytic bone lesions (“punched-out” defects in X-rays)
o Can lead to hypercalcemia (and assoc. SSx) and renal failure
 Malignant plasma cells – oval, with nucleus at the periphery, “cartwheel” / “clock-face” chromatin & prominent
Multiple Myeloma
golgi bodies.
o 20% of the bone marrow is composed of sheets of plasma cells (Normal: 1-3%)
 Known for producing monoclonal gammopathies – seen as a monoclonal spike on SPE (serum protein
electrophoresis)
o Increased antibody production → Bence-Jones proteinuria (light chains in the urine)

Solitary
 Solitary plasma cell tumor, usually in bone or in soft tissue; may progress to multiple myeloma in 10-20 years.
Plasmacytoma

Monoclonal  Most common plasma cell dyscrasia, occurring in individuals aged 50 (3%) up to 70 (5%).
Gammopathy of  Generally follows a benign course, with no plasma cell proliferation.
Unknown Significance  However, 1% of patients have a chance to progress to multiple myeloma

 Waldenström macroglobulinemia – hyperviscosity syndrome d/t excess IgM secretion by malignant plasma cells
Other Gammopathies  Heavy chain disease
 Amyloidosis – usually secondary to multiple myeloma

 Arises from germinal center B-cells, and is characterized by BCL2 mutations (chromosomal translocation)
 Histologically, presents with a nodular to diffuse growth pattern within the lymph nodes, with two main cell types:
Follicular Lymphoma o Centrocytes – small cells w/ irregular / cleaved nuclei & scant cytoplasm
o Centroblasts – larger cells w/ open chromatin, several nucleoli & modest cytoplasm
 Bone marrow involvement is frequent; splenic white pulp & hepatic portal triads may also be involved.

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PATHOLOGY
Finals Reviewer – WBCs, Lymph Nodes, Spleen & Thymus
 Characterized by the presence of Reed-Sternberg cells (multinucleate, or with a multi-lobed nuclei, each lobe/nucleus
has a prominent nucleolus, giving it an “owl’s eyes” appearance).
o R-S cells are also CD30 (+)
 The tumor is generally composed of R-S cells mixed with reactive lymphocytes, macrophages, eosinophils, plasma
cells and stromal cells.
 Clinically, it most commonly presents as painless lymphadenopathy.
 Has several distinct subtypes:
Hodgkin Lymphoma
o Nodular sclerosis – characterized by lacunar RS cells & fibrous bands dividing the cellular areas into nodules;
most common variant
o Mixed cellularity – RS cells present, mixed with T-cells, eosinophils, macrophages & plasma cells
o Lymphocyte-rich – RS cells present background infiltrate is mostly T-cells
o Lymphocyte depletion – RS cells present, reduced background infiltrate of cells
o Lymphocyte predominance – characterized by lymphohistiocytic (“popcorn”) cells, with a background
infiltrate of dendritic cells & reactive B-cells

Hodgkin vs. Non-Hodgkin Lymphoma

Hodgkin Lymphoma Non-Hodgkin Lymphoma

 Often localized to a single group of lymph nodes  More frequent involvement of multiple peripheral nodes
 Orderly spread by contiguity  Noncontiguous spread
 Mesenteric lymph nodes & Waldeyer ring is rarely involved  Waldeyer ring and mesenteric nodes commonly involved
 Extranodal presentation is rare  Extranodal presentation common

 Most common form of Non-Hodgkin lymphoma

Diffuse Large B-cell  Characterized by enlarged malignant cells (4-5 times the normal lymphocyte) and diffuse growth pattern
Lymphoma  The tumor cells have large nuclei, open chromatin and prominent nucleoli
 Tumor cells may be admixed with normal B-cells – from the lab manual

 Frequently associated with MYC oncogene translocation to chromosome 8 → increased MYC expression
 Also frequently associated with EBV infections (essentially, all endemic Burkitt lymphomas are d/t latent EBV
Burkitt Lymphoma infections)
 Histologically shows a “starry-sky” pattern – numerous malignant lymphoid cells, with interspersed, benign
macrophages

 Rare, but distinctive B-cell neoplasm, associated with activating mutations in the serine / threonine kinase BRAF
Hairy Cell Leukemia
 Characterized by leukemic cells with fine, hair-like projections.

VI. DISEASES OF THE SPLEEN

 One of the main causes of splenomegaly; occurs in any blood-borne infection, either due to the pathogens themselves,
Non-specific Acute or the cytokines released as part of the immune response.
Splenitis  Grossly, the spleen is enlarged, weighing 200-400 grams (Normal – 150 grams)
 Histologic features: acute congestion of the red pulp, neutrophil & plasma cell infiltrates.

 A result of chronic venous outflow obstruction (the most common cause is cirrhosis)
 Compared to acute splenitis, the spleen can weigh 1000-5000 grams in long-standing congestion.
Congestive
 Red pulp is initially congested, but undergoes fibrosis over time.
Splenomegaly
 Congestion → slow blood flow → increased exposure of blood to macrophages → hypersplenism → anemia,
leukopenia & thrombocytopenia

Splenic Infarcts  Caused by splenic artery occlusion; since the spleen has no collateral circulation, it is especially prone to infarcts.

Primary Splenic  Rare, except in the setting of myeloid & lymphoid tumors.
Tumors  Most common primary tumors – lymphangioma & hemangioma; Others include fibroma, osteoma & chondroma.

 Asplenism – congenital absence of the spleen is rare; Splenic hypoplasia is more common
Congenital Anomalies
 Spleniculi – formation of accessory spleens in the abdominal cavity

 Usually involves blunt trauma to the spleen; less commonly, it can occur spontaneously in a spleen with compromised
Splenic Rupture
structure (e.g. infectious mononucleosis, typhoid fever, malaria)

VII. DISEASES OF THE THYMUS

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 PATHOLOGY
Finals Reviewer – WBCs, Lymph Nodes, Spleen & Thymus

Developmental  Thymic hypoplasia & aplasia – frequently encountered in DiGeorge syndrome

Abnormalities  Thymic cysts – uncommon lesions, usually incidental findings

 A morphologically-normal thymus is large for the patient’s age – mistaken for thymoma
Thymic Hyperplasia
 At other times, there is the appearance of B-cell germinal centers in the thymus (thymic follicular hyperplasia)

 This term is restricted to tumors of thymic epithelial cells – if the WBCs are involved, then it’s a lymphoma...
o Benign thymoma – neoplastic cells are spindle-shaped, arranged in a swirling pattern; often encapsulated.
Thymoma o Invasive thymoma – cytologically benign, but the tumor has now penetrated the capsule to invade surrounding
tissues.
o Thymic carcinoma – squamous cell carcinoma of the thymus

ADDENDUM: Identifying lymphoid neoplasms based on origin

So to use this figure, tignan kung aling cell ang involved, ang kung saan siya galing – more or less you can narrow down yung diagnosis and
thus answer the question :)

B-cell Acronyms: CLP – common lymphoid precursor; BLB – B-lymphoblast; NBC – naive B-cell; MC – Mantle B-cell; GC – Germinal center B-cell; MZ
– marginal zone B-cell

T-cell Acronyms: DN – double-negative pro-T-cell; DP – double-positive pro-T-cell (CD4+ & CD8+); PTC – peripheral T-cell

Smile... you’re finished...

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