Lymphocyte Disorders - Pathology

Normal Lymphocyte Morphology (Quick Reference)

Classification of Lymphocyte Disorders

1. Reactive/Quantitative disorders - non-neoplastic changes in number or morphology
2. Neoplastic (lymphoid) disorders - malignant clonal proliferations

I. Reactive Lymphocyte Disorders

Lymphocytosis

• Absolute lymphocyte count > 4 × 10⁹/L
• Causes: viral infections (EBV, CMV, pertussis, hepatitis), stress responses
• Atypical (reactive) lymphocytes are large, with abundant cytoplasm, indented by surrounding RBCs - characteristic of infectious mononucleosis

Lymphocytopenia

• Count < 1.5 × 10⁹/L
• Causes: corticosteroids, HIV infection, immunosuppressive therapy, autoimmune diseases (SLE), radiation

Hemophagocytic Lymphohistiocytosis (HLH)

• Pathogenesis: Familial forms have mutations in CTL/NK cytotoxic granule machinery (perforin, granzymes), impairing killing of infected cells. This triggers persistent T-cell/NK activation with IFN-γ secretion, causing macrophage hyperactivation ("cytokine storm" with IFN-γ, TNF-α, IL-6, IL-12).
• Clinical: Acute febrile illness, splenomegaly/hepatomegaly, cytopenias, hyperferritinemia, elevated soluble IL-2R, high triglycerides, DIC.
• Common trigger: EBV infection; also complicates peripheral T-cell lymphoma.
• Treatment: Glucocorticoids + etoposide; HSC transplantation for familial/refractory cases. Without treatment, median survival < 2 months. - Robbins, p. 553

II. Neoplastic Lymphocyte Disorders (Lymphoid Neoplasms)

General Principles of Pathogenesis

• Most white cell neoplasms carry nonrandom chromosomal translocations or mutations that serve as driver events.
• Oncoproteins block normal maturation (differentiation arrest) or activate pro-survival/growth pathways (RAS/PI3K/AKT).
• Environmental contributors: radiation, chemical carcinogens, viruses (EBV, HTLV-1, H. pylori), immunosuppression.
• Hematologic malignancies are genetically simpler than solid tumors, partly explaining their higher curability. - Robbins, p. 553-554

A. Precursor (Immature) Lymphoid Neoplasms

Acute Lymphoblastic Leukemia/Lymphoma (ALL/LBL)

• Most common cancer in children; ~75-80% are B-cell origin (B-ALL), remainder T-cell.
• Tumor cells are lymphoblasts with arrested differentiation that accumulate as nonfunctional blasts in bone marrow.
• Key genetic lesions:
  • t(12;21) - ETV6-RUNX1 fusion (most common in childhood B-ALL, favorable)
  • t(9;22) - BCR-ABL (Philadelphia chromosome; 190 kDa protein with stronger tyrosine kinase than the 210 kDa CML form; worse prognosis but responds to TKIs)
  • Other cryptic TK rearrangements ("Ph-like ALL") in adults
• Clinical: Bone marrow failure (anemia, thrombocytopenia, neutropenia), rapidly growing masses, CNS involvement
• Treatment: Intensive chemotherapy; CAR-T cells directed against CD19 for relapsed B-ALL; TKI combinations for Ph+ ALL.
• Prognosis is generally excellent in children (>90% cure rate); more guarded in adults. - Robbins, p. 558-559

B. Peripheral (Mature) B-Cell Neoplasms

1. Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL)

• Most common adult leukemia in the Western world; ~15,000 new cases/year in the US.
• Median age at diagnosis: 60 years; male predominance (2:1).
• CLL = peripheral blood lymphocytosis > 5000/mm³; SLL = same clone but primarily nodal.

• Chromosomal translocations are rare; dominant anomalies: del(13q14.3), del(11q), del(17p), trisomy 12q.
• Del(13q) targets miR-15a/miR-16-1 (tumor suppressor miRNAs) → BCL2 overexpression → anti-apoptosis.
• NOTCH1 gain-of-function mutations in 10-18% → worse prognosis.
• Unmutated Ig genes (naive B-cell origin) = more aggressive than somatic hypermutated cases.
• Growth depends on BTK signaling via the B-cell receptor → BTK inhibitors (ibrutinib) are highly effective.

• Lymph nodes diffusely effaced by small round lymphocytes (6-12 µm), condensed chromatin, scant cytoplasm.
• Characteristic "proliferation centers" (pale-staining aggregates of larger activated cells) - pathognomonic for CLL/SLL.
• "Smudge cells" in peripheral blood smear (fragile CLL cells disrupted during smear preparation).
• Bone marrow, spleen, and liver almost always involved.

• Hypogammaglobulinemia → recurrent infections (most common cause of death)
• Autoimmune hemolytic anemia
• Transformation to diffuse large B-cell lymphoma (Richter syndrome, ~5% of cases)

2. Follicular Lymphoma

• Second most common NHL in adults (US); arises from germinal center B cells.
• Hallmark: t(14;18) translocation → BCL2 overexpression (BCL2 normally suppresses apoptosis; inappropriately expressed in follicular lymphoma, conferring survival advantage)
• Morphology: Nodular (follicular) growth pattern; cells resemble centrocytes (small, cleaved) and centroblasts (large, noncleaved).
• Immunophenotype: CD10+, BCL6+, BCL2+, CD20+, CD19+ (unlike normal reactive germinal center B cells, which are BCL2 negative)
• Typically indolent but incurable with standard therapy; may transform to DLBCL (~30-40% over time). - Robbins, p. 562

3. Diffuse Large B-Cell Lymphoma (DLBCL)

• Most common NHL (~25-30% of all NHLs in adults).
• Clinically aggressive; arises de novo or via transformation from indolent lymphomas.
• Two major molecular subtypes (gene expression profiling):
  • Germinal center B-cell (GCB) type - better prognosis
  • Activated B-cell (ABC) type - worse prognosis; depends on constitutive NF-κB activation
• Morphology: Diffuse sheets of large lymphoid cells with vesicular nuclei and prominent nucleoli.
• Treatment: R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone); ~60-70% cure rate.

4. Burkitt Lymphoma

• Highly aggressive; associated with t(8;14) translocation → MYC overactivation.
• Three forms: endemic (Africa, EBV-driven, jaw/facial bones), sporadic (abdomen), immunodeficiency-associated (HIV).
• Morphology: Medium-sized cells with basophilic cytoplasm; classic "starry-sky" pattern (macrophages engulfing apoptotic tumor cells give light areas amid dark tumor cells).
• Fastest-dividing human tumor (near 100% Ki-67 proliferation index).
• Curable with intensive chemotherapy if caught early.

5. Marginal Zone Lymphomas / MALToma

• Arise within lymph nodes, spleen, or extranodal tissues (mucosa-associated lymphoid tissue).
• Extranodal MALToma is special:
  • Arises at sites of chronic inflammation (autoimmune or infectious): stomach (H. pylori), salivary gland (Sjögren syndrome), thyroid (Hashimoto thyroiditis)
  • Remains localized for prolonged periods
  • May regress with eradication of the inciting agent (e.g., antibiotic treatment of H. pylori can lead to gastric MALToma regression)
  • Progression involves chromosomal translocations activating NF-κB via BCL10/MALT1 upregulation: t(11;18), t(14;18), t(1;14)
  • Cells of origin: memory B cells (somatically hypermutated Ig genes)

6. Hairy Cell Leukemia

• Rare B-cell neoplasm; ~2% of leukemias; predominantly middle-aged White males (median age 55; M:F = 5:1).
• Pathogenesis: >90% harbor BRAF V600E activating mutation (same mutation as in melanoma and Langerhans cell histiocytosis).
• Morphology: Tumor cells have fine hair-like cytoplasmic projections (best seen on phase-contrast microscopy or electron microscopy); tartrate-resistant acid phosphatase (TRAP) stain positive.
• Presents with massive splenomegaly, pancytopenia, and "dry tap" on bone marrow aspiration (fibrosis).
• Highly responsive to purine analogs (cladribine, pentostatin); BRAF inhibitors (vemurafenib) for refractory cases.

C. Plasma Cell Neoplasms (Terminal B-Cell Differentiation)

Multiple Myeloma

• Clonal expansion of plasma cells in bone marrow, producing monoclonal immunoglobulin (M protein).
• Pathogenesis: Primary translocations involving Ig heavy-chain locus (14q32) with partners including FGFR3 (t(4;14)), Cyclin D1 (t(11;14)), MMSET.
• Clinical features (mnemonic CRAB): hyperCalcemia, Renal failure, Anemia, Bone lesions (punched-out lytic lesions).
• Secondary infections due to hypogammaglobulinemia of normal Ig isotypes.
• Bence-Jones proteins (free light chains in urine) cause cast nephropathy.
• Bone marrow: >10% plasma cells; abnormal plasma cells with "clock-face" chromatin.

D. Mature T-Cell and NK-Cell Neoplasms

Peripheral T-Cell Lymphoma (PTCL), Unspecified

• Most common mature T-cell lymphoma; aggressive; median age ~60 years.
• Diffuse nodal infiltrate of atypical T cells with variable size; CD3+, CD4+ or CD8+.
• Associated with systemic symptoms, eosinophilia, HLH.
• Poor prognosis; responds poorly to R-CHOP.

Adult T-Cell Leukemia/Lymphoma (ATLL)

• Caused by HTLV-1 retrovirus (endemic in Japan, Caribbean, Central Africa).
• Highly aggressive; skin lesions, hypercalcemia, lytic bone lesions.
• Hallmark cell: "flower cell" (multilobated nucleus) in peripheral blood.

Mycosis Fungoides / Sézary Syndrome

• Primary cutaneous T-cell lymphoma; presents as chronic skin rash progressing through patch → plaque → tumor stages.
• Sézary syndrome = leukemic form (Sézary cells = large lymphocytes with cerebriform/convoluted nuclei in blood).
• Neoplastic cells are CD4+ skin-homing T cells.

Anaplastic Large Cell Lymphoma (ALCL)

• Large anaplastic T cells (or null phenotype); characteristic "hallmark cells" - horseshoe or kidney-shaped nuclei.
• ALK-positive ALCL: harbors t(2;5) producing NPM-ALK fusion protein; primarily young patients; excellent prognosis.
• ALK-negative ALCL: older patients; worse prognosis.
• Strongly CD30+. Treatment includes brentuximab vedotin (anti-CD30 antibody-drug conjugate).

E. Hodgkin Lymphoma (HL)

WHO Classification of Hodgkin Lymphoma

Summary Table - Key Distinguishing Features