Pathology of Lymphoma

1. General Principles

Diagnosis Requires Tissue

• Robbins Pathologic Basis of Disease, p. 555

Clonality and Antigen Receptors

Molecular Pathogenesis

• AID (activation-induced cytidine deaminase): expressed in germinal center B cells to drive class switching and somatic hypermutation. Misregulation causes translocations (e.g., MYC::IGH in Burkitt) and BCL6 mutations.
• V(D)J recombinase errors: can juxtapose proto-oncogenes to antigen receptor gene regulatory elements, underling rearrangements in both B- and T-cell neoplasms.
• Viruses: HTLV-1 (adult T-cell leukemia/lymphoma); EBV (30–40% of HL, Burkitt lymphoma — 90% endemic, 20% sporadic); HHV8 (primary effusion lymphoma).
• Chronic inflammation: H. pylori → gastric MALT lymphoma; gluten-sensitive enteropathy → intestinal T-cell lymphoma.
• Robbins, pp. 553–555

2. WHO Classification Overview

Hodgkin Lymphoma (HL)

Non-Hodgkin Lymphoma (NHL) — Mature B-Cell Neoplasms (selection)

• Chronic lymphocytic leukemia / Small lymphocytic lymphoma (CLL/SLL)
• Follicular lymphoma (FL)
• Mantle cell lymphoma (MCL)
• Marginal zone lymphoma (MZL) / MALT
• Diffuse large B-cell lymphoma (DLBCL)
• Burkitt lymphoma (BL)
• Lymphoplasmacytic lymphoma
• Plasma cell myeloma

NHL — Mature T-Cell & NK-Cell Neoplasms (selection)

• Peripheral T-cell lymphoma (NOS)
• Anaplastic large cell lymphoma (ALCL), ALK+/ALK−
• Adult T-cell leukemia/lymphoma (HTLV-1)
• Extranodal NK/T-cell lymphoma
• Hepatosplenic T-cell lymphoma

Precursor Neoplasms

• T/B-lymphoblastic lymphoma/leukemia (ALL)

3. Hodgkin Lymphoma

Histopathology — The Hallmark Cell

• Large (up to ~100 µm), with abundant slightly basophilic cytoplasm
• Binucleated or multinucleated with prominent, large eosinophilic nucleoli ("owl-eye" appearance)
• Mononuclear Hodgkin cells (variants) with similar nuclear features
• RS cells are the minority of cells; the bulk of the lesion is a reactive inflammatory background infiltrate of lymphocytes, eosinophils, plasma cells, and histiocytes

Immunophenotype

Classic HL Subtypes

• Broad collagen bands divide lymph node into cellular nodules
• RS cells in lacunar spaces ("lacunar cells" — artifact of formalin fixation)
• Predilection: lower cervical, supraclavicular, mediastinal nodes

• No fibrotic bands; polymorphic background (histiocytes, eosinophils, plasma cells)
• Classic RS cells are more easily identified
• Often EBV-positive

• Marked lymphocyte depletion; sheets of RS and pleomorphic cells
• Sparse inflammatory background; may have fibrosis
• Most aggressive; often advanced stage at presentation

• Abundant small reactive lymphocytes; classic RS cells present but infrequent

Staging (Ann Arbor)

• Cummings Otolaryngology, p. 3850; K.J. Lee's Essential Otolaryngology, p. 1050

4. Non-Hodgkin Lymphoma — Key Entities

CLL / Small Lymphocytic Lymphoma

• Most common leukemia of adults (Western world); median age 60; 2:1 male predominance
• Pathogenesis: deletions 13q14.3 (loss of miR-15a/miR-16-1 → BCL2 overexpression), del 11q, del 17p, trisomy 12q; NOTCH1 mutations (10–18%, poor prognosis)
• Morphology: small, round, mature-appearing lymphocytes with clumped chromatin; "proliferation centers" (pale-staining aggregates with larger prolymphocytes)
• Immunophenotype: CD5+, CD19+, CD20 (dim), CD23+, surface Ig (dim); CD5 co-expression distinguishes CLL from other B-cell lymphomas
• Genetics: unmutated IgVH genes = more aggressive course
• Robbins, p. 555

Follicular Lymphoma

• Second most common NHL in the West; derived from germinal center B cells
• Hallmark translocation: t(14;18) → BCL2::IGH → BCL2 overexpression → impaired apoptosis in follicular center cells
• Morphology: nodular/follicular architecture; centrocytes (small cleaved) and centroblasts (large noncleaved) in neoplastic follicles
• Immunophenotype: CD10+, CD19+, CD20+, BCL2+, BCL6+, CD5−, cyclin D1−
• Indolent but typically incurable with conventional therapy; ~30–40% transform to DLBCL (Richter-like transformation)

Mantle Cell Lymphoma

• Hallmark translocation: t(11;14) → cyclin D1 (CCND1)::IGH → cyclin D1 overexpression → cell cycle dysregulation
• Morphology: monomorphic small-medium lymphocytes with irregular nuclear contours; diffuse or vaguely nodular pattern; no RS cells, no proliferation centers
• Immunophenotype: CD5+, CD19+, CD20+, cyclin D1+, CD23−, CD10−
• Aggressive; median survival ~3–5 years without modern therapy

MALT Lymphoma (Extranodal Marginal Zone)

• Low-grade B-cell lymphoma arising in mucosa-associated lymphoid tissue
• Driven by chronic antigenic stimulation: H. pylori (gastric MALT); Sjögren syndrome (salivary gland); Hashimoto thyroiditis (thyroid)
• H. pylori eradication alone can induce remission in early gastric MALT lymphoma
• Morphology: heterogeneous small lymphocytes, monocytoid B cells, plasma cells; lymphoepithelial lesions (tumor cells invading glandular epithelium)
• Key translocations: t(11;18), t(14;18) (BCL10::IGH), t(3;14)

Diffuse Large B-Cell Lymphoma (DLBCL)

• Most common NHL (~30–40% of all NHL)
• Morphology: large cells, vesicular nuclei, prominent nucleoli, diffuse growth pattern; no residual follicular architecture
• Molecular subgroups (cell of origin):
  • Germinal Center B-cell (GCB): BCL2 rearrangement, EZH2 mutations; better prognosis
  • Activated B-cell (ABC): NF-κB pathway activation, MYD88 mutations; worse prognosis
• Immunophenotype: CD19+, CD20+, CD79a+; BCL6 and/or MUM1 for subclassification
• Aggressive but potentially curable with R-CHOP

Burkitt Lymphoma

• Extremely aggressive; one of the fastest growing human tumors (Ki-67 ~100%)
• Three clinical forms: Endemic (jaw mass, African children; >90% EBV+), Sporadic (abdominal, young adults; 20% EBV+), Immunodeficiency-associated (HIV; ~40% EBV+)
• Hallmark translocation: t(8;14) → MYC::IGH (or t(2;8), t(8;22) variants) → MYC overexpression → dysregulated cell cycle, increased proliferation
• Morphology: medium-sized monomorphic cells, round nuclei, multiple small nucleoli, scant cytoplasm; brisk mitotic activity + apoptosis → phagocytosis by macrophages = "starry sky" pattern (pale macrophages against dark blue lymphoid background)
• Immunophenotype: CD20+, CD10+, BCL6+, BCL2−, surface IgM+; Ki-67 ~100%

Anaplastic Large Cell Lymphoma (ALCL)

• T-cell lymphoma; two forms: ALK+ (younger patients, better prognosis) and ALK− (older, worse)
• ALK+ driven by t(2;5) → NPM1::ALK fusion → constitutive ALK tyrosine kinase signaling
• Morphology: large pleomorphic cells with eccentric horseshoe-shaped nuclei ("hallmark cells"), sometimes sinusoidal spread
• Immunophenotype: CD30+++ (strong), ALK+ (in ALK+ form), CD3 often lost, EMA+

Adult T-Cell Leukemia/Lymphoma (ATLL)

• Caused by HTLV-1 retrovirus (endemic Japan, Caribbean)
• Morphology: "flower cells" — T cells with multilobated, clover-leaf nuclei
• Highly aggressive; often presents with hypercalcemia, lytic bone lesions, skin involvement

5. Key Immunohistochemistry Panel

6. Clinical Features Shared Across Lymphomas

• Painless lymphadenopathy (most common presentation)
• B symptoms: fever, night sweats, ≥10% weight loss
• Mediastinal mass: particularly NS-CHL, T-lymphoblastic lymphoma, DLBCL
• Extranodal disease: stomach (MALT), CNS (DLBCL), skin (mycosis fungoides, ALCL), liver/spleen, bone marrow
• Staging: CT chest/abdomen/pelvis; whole-body PET-CT; bone marrow biopsy selectively
• Prognosis: HL has ~95% overall survival; DLBCL curable in ~60% with R-CHOP; Burkitt lymphoma >90% cure rates in pediatric stages I–III with intensive chemotherapy