---

Lymphomas - Comprehensive Overview

---

Normal Counterparts - Origin of Lymphomas

---

I. CLASSIFICATION

WHO Classification (2016/Updated)

1. Cell of origin: B-cell vs. T/NK-cell
2. Maturity: Precursor (immature) vs. peripheral (mature/post-thymic)

• In the US and Europe, 85-90% of NHLs are B-cell in origin
• Most frequent NHL worldwide: Diffuse Large B-Cell Lymphoma (DLBCL) ~30%
• Second most frequent: Follicular Lymphoma ~20%
• Less common types (~5-10% each): Extranodal marginal zone/MALT, Peripheral T-cell, Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma
• Goldman-Cecil Medicine, p. 1951

---

II. EPIDEMIOLOGY & RISK FACTORS

Autoimmune and Inflammatory Conditions

• Rheumatoid arthritis: 2-fold increased NHL risk
• Sjögren syndrome: 30-40 fold increased marginal zone lymphoma risk
• Hashimoto thyroiditis: increased thyroid lymphoma risk
• Celiac disease: associated with enteropathy-type T-cell lymphoma

Infectious Agents

Environmental Factors

• Agricultural chemicals (phenoxy herbicides/Agent Orange), ionizing radiation, organic solvents, high-fat diet, ultraviolet radiation
• Prior treatment for Hodgkin lymphoma: 20-fold increased NHL risk
• Heavy smoking: increased follicular lymphoma risk
• Goldman-Cecil Medicine, pp. 845-864

---

III. NON-HODGKIN LYMPHOMAS (NHL)

A. B-Cell NHLs

1. Follicular Lymphoma

• ~20% of all NHLs; more common in North America and Western Europe
• Cell of origin: Germinal center B cells (centrocytes + centroblasts)
• Key genetic lesion: t(14;18) translocation → BCL2 overexpression → blocks apoptosis
• Morphology: Nodular (follicular) growth pattern; mixture of small centrocytes (cleaved nuclei) and larger centroblasts

• Immunophenotype: CD20+, BCL2+ (unlike reactive germinal centers), CD10+
• BCL2 immunostain: positive in neoplastic follicles (negative in reactive germinal centers) - key diagnostic feature
• Clinical behavior: Indolent, waxing and waning; median survival 7-9 years; NOT improved by aggressive therapy - palliated with anti-CD20 (rituximab) + gentle chemotherapy
• Histologic transformation: 30-50% transform to DLBCL; if MYC is acquired, prognosis is particularly poor (median survival 3-5 years)
• EZH2 inhibitors are active in the subset with EZH2 gain-of-function mutations

2. Diffuse Large B-Cell Lymphoma (DLBCL)

• Most common NHL (~30%)
• Aggressive but potentially curable
• Includes several distinct subtypes: primary CNS lymphoma, primary mediastinal (thymic) large B-cell lymphoma, leg-type cutaneous DLBCL, plasmablastic lymphoma, double/triple-hit lymphomas
• Double-hit lymphoma: MYC rearrangement + BCL2 and/or BCL6 rearrangements - now classified as "high-grade B-cell lymphoma with MYC and BCL2/BCL6 rearrangements"; requires aggressive regimens (DA-R-EPOCH)
• Primary CNS lymphoma: very sensitive to corticosteroids; treated with high-dose methotrexate ± rituximab; whole-brain RT adds toxicity without benefit
• Plasmablastic lymphoma: Most common in HIV+ patients; CD20 negative, so does NOT benefit from rituximab

3. Mantle Cell Lymphoma

• Cell of origin: Naive B cells in the mantle zone
• Moderately aggressive course
• Key genetic lesion: t(11;14) → cyclin D1 overexpression → confirmed by FISH; CD5+
• Distinct from CLL/SLL by cyclin D1

4. Marginal Zone Lymphoma / MALT Lymphoma

• Indolent tumors of antigen-primed B cells at sites of chronic immune stimulation
• Gastric MALT lymphoma: driven by H. pylori; eradication of H. pylori can induce regression
• Often remain localized for long periods

5. Burkitt Lymphoma

• t(8;14) - MYC translocation (or variants t(2;8) or t(8;22))
• Endemic form: African children, jaw tumors, nearly all EBV+
• Sporadic form: abdominal/ileocecal mass, ~15-35% EBV+
• AIDS-associated form: aggressive, often involves CNS
• "Starry sky" pattern on histology (macrophages phagocytosing apoptotic cells)

6. Small Lymphocytic Lymphoma (SLL) / CLL

• Tissue manifestation of CLL; indolent
• CD5+, CD23+, weak surface Ig

7. Lymphoplasmacytic Lymphoma (Waldenström's Macroglobulinemia)

• B-cell neoplasm with terminal differentiation to plasma cells
• Secretes monoclonal IgM → hyperviscosity syndrome
• Nearly all cases have MYD88 mutations
• No bone destruction (unlike myeloma)

---

B. T- and NK-Cell NHLs

• Peripheral T-cell lymphoma, NOS: Pleomorphic mixture of malignant T cells; reactive eosinophils and macrophages (cytokine-driven); express CD2, CD3, CD5; significantly worse prognosis than DLBCL
• Anaplastic Large Cell Lymphoma (ALCL): CD30+; ALK+ form has better prognosis; ALK- form has poor prognosis; distinct from Hodgkin lymphoma (CD15-negative)
• Adult T-cell leukemia/lymphoma: caused by HTLV-1; skin lesions, hypercalcemia, leukemia picture
• Mycosis fungoides / Sézary syndrome: Primary cutaneous T-cell lymphoma; starts as skin patches → plaques → tumors (Sézary syndrome = erythroderma + circulating atypical cells)
• Extranodal NK/T-cell lymphoma (nasal type): EBV-associated; midline destructive lesions of the nasopharynx; more common in Asia and Latin America
• Enteropathy-associated T-cell lymphoma: associated with celiac disease; intestinal involvement

---

C. Lymphoblastic Lymphoma / ALL

• Precursor B or T lymphoblasts
• T-cell LBL: mediastinal mass in young males; CNS involvement common
• B-cell LBL: solid tumors of skin and bones (~85% of ALL has B-cell phenotype)
• Treated with ALL-type regimens (cytarabine, high-dose methotrexate, maintenance therapy, CNS prophylaxis)

---

IV. HODGKIN LYMPHOMA (HL)

What Makes HL Distinct

1. Reed-Sternberg (RS) cells - the neoplastic element
2. Robust but ineffective host immune response; RS cells are only a small fraction of the tumor mass
3. Arises in a single node/chain and spreads in stepwise contiguous fashion - important for radiotherapy planning

• Robbins Basic Pathology, p. 417

Reed-Sternberg Cells

• Large cells (~45 µm diameter) with bilobed or multilobed nuclei, each with a large "owl-eye" nucleolus (~5-7 µm, size of a small lymphocyte)
• Diagnostic RS cells must have at least two nuclear lobes/nuclei each with a nucleolus

Pathogenesis of HL

• RS cells originate from germinal center B cells (proven by clonal IGH rearrangements + somatic hypermutation in microdissected RS cells)
• Classic HL RS cells paradoxically fail to express immunoglobulin genes - due to widespread epigenetic reprogramming
• NF-κB activation is the central molecular event:
  • EBV LMP-1 (in ~70% of mixed-cellularity subtype) activates NF-κB
  • EBV- tumors: loss-of-function mutations in IκB or TNFAIP3
• Immune evasion: RS cells express high levels of PD-L1 and PD-L2 (chromosome 9p amplification) → antagonizes cytotoxic T-cell responses
• Reactive background: RS cells secrete IL-5 (eosinophil chemoattractant), TGF-β (fibrogenic), IL-13 (autocrine growth)

WHO Classification of HL Subtypes

Key HL Subtypes

• Young adults; mediastinal involvement common
• Collagen bands divide lymph node into nodules
• Lacunar cells (RS variants with retracted cytoplasm due to formalin fixation)
• Background: lymphocytes, eosinophils, plasma cells, neutrophils

• Older adults; EBV present in ~70%
• Diagnostic RS cells easily found
• Background: lymphocytes, eosinophils, plasma cells, histiocytes

• Rarest; most aggressive; older/HIV patients
• Few lymphocytes; sheets of RS cells

• Distinct entity; neoplastic cells are "popcorn cells" (LP cells/lymphocytic and histiocytic cells)
• CD20+, CD79a+, CD45+ (unlike classic HL)
• CD30-, CD15- (unlike classic HL)
• More indolent course; associated with late relapse

Immunophenotype of Classic HL RS Cells

---

V. STAGING - ANN ARBOR SYSTEM (Modified Cotswolds)

• Goldman-Cecil Medicine, Table 172-3

---

VI. WORKUP & STAGING INVESTIGATIONS

1. Biopsy: Excisional lymph node biopsy (gold standard); fine needle aspiration is inadequate
2. Laboratory: CBC, chemistry including LDH, uric acid
3. Imaging: CT chest/abdomen/pelvis; FDG-PET/CT is now mandatory for HL and most aggressive NHLs - more sensitive than CT for staging and residual disease assessment; PET can replace bone marrow biopsy in HL
4. Bone marrow biopsy: In NHL if results will change management (not needed if PET positive)
5. Lumbar puncture: If CNS involvement suspected (DLBCL with high IPI, Burkitt, etc.)

---

VII. INTERNATIONAL PROGNOSTIC INDEX (IPI) - for aggressive NHLs

1. Age > 60 years
2. Elevated LDH
3. Performance status 2-4
4. More than 1 extranodal site
5. Ann Arbor stage III or IV

• Goldman-Cecil Medicine, Table 171-8

---

VIII. TREATMENT OVERVIEW

Hodgkin Lymphoma

• Limited stage (I-II, favorable): 2-4 cycles ABVD + involved-site radiotherapy
• Advanced stage (III-IV): 6-8 cycles ABVD or escalated BEACOPP
  • BEACOPP: superior response rates but more toxicity (infertility with alkylating agents; not seen with ABVD)
• Brentuximab vedotin (anti-CD30 ADC): used in refractory/relapsed HL and upfront with AVD in stage III-IV
• PD-1 checkpoint inhibitors (nivolumab, pembrolizumab): active in relapsed/refractory HL (exploiting PD-L1 overexpression on RS cells)
• Relapsed/refractory HL: Second-line chemo → autologous hematopoietic stem cell transplant (HSCT) for chemosensitive disease

Non-Hodgkin Lymphoma - Key Treatments

Special Situations

• AIDS-associated NHL: Treat same as non-immunocompromised; add CNS prophylaxis; prognosis has improved with HAART
• Post-transplant lymphoproliferative disorder (PTLD): Reduce immunosuppression first; rituximab; chemotherapy for refractory cases
• Elderly patients: Dose-adjusted regimens; careful assessment of cardiac function for anthracyclines

---

IX. KEY GENETIC LESIONS SUMMARY

---

X. CLINICAL PEARLS

• Lymphoma spreads stepwise and contiguously in HL but skips nodes more often in NHL
• "B symptoms" (fever >38°C, night sweats, >10% weight loss) are adverse prognostic signs and affect staging (A vs. B designation)
• RS cells in classic HL: CD15+, CD30+ - the hallmark immunoprofile
• RS-like cells can appear in infectious mononucleosis, solid tumors, and some NHLs - diagnosis requires clinicopathologic correlation
• Follicular lymphoma is incurable with standard therapy but follows an indolent course; transformation to DLBCL occurs in 30-50%
• Gastric MALT lymphoma often regresses with H. pylori eradication alone
• High macrophage infiltrate in HL is a predictor of treatment resistance
• PET/CT has replaced gallium scanning and is now the gold standard for staging and response assessment in HL and aggressive NHLs

---