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Hodgkin Lymphoma — Complete Guide

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1. Definition & Cell of Origin

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2. WHO Classification (5 Subtypes)

— Goldman-Cecil Medicine, Table 172-1; Robbins & Kumar Basic Pathology

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3. Reed-Sternberg Cell — The Hallmark

• Classic RS cell: Large binucleated (or multi-nucleated) cell with prominent "owl-eye" nucleoli (large, eosinophilic, inclusion-like)
• Lacunar cell: RS variant in nodular sclerosis; artifact of formalin fixation causes cytoplasmic retraction into a "lacuna"
• L&H (lymphocytic and histiocytic) cell / "Popcorn cell": Seen in NLPHL — multilobated nucleus resembling popcorn

Immunophenotype of RS cells:

— Goldman-Cecil Medicine

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4. Clinical Features

Presentation

• Painless lymphadenopathy — most commonly cervical (60–70%), then mediastinal, axillary
• Mediastinal mass — especially in nodular sclerosis (young women); can cause SVC syndrome
• B symptoms (present in ~40%):
  • Fever >38°C (Pel-Ebstein fever — cyclical, pathognomonic)
  • Drenching night sweats
  • Weight loss >10% in 6 months
• Pruritus — generalized, may precede diagnosis
• Alcohol-induced pain at lymph node sites — classic but uncommon (pathognomonic when present)

Epidemiology

• Bimodal age distribution: Peak 1 at 25–30 years (young adults); Peak 2 at >50 years
• Slightly more common in males; more common in Whites than Blacks
• Higher incidence in higher socioeconomic classes (Western world)
• In the Indian subcontinent, peak is strongly shifted into childhood

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5. HL vs Non-Hodgkin Lymphoma (NHL) — Key Differences

— Robbins, Cotran & Kumar Pathologic Basis of Disease, Table 13.7

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6. Pathogenesis & EBV Association

• EBV is the leading suspect: present in RS cells in ~70% of mixed cellularity and ~50% of all classic HL cases
• History of infectious mononucleosis increases HL risk 3-fold
• EBV genome is monoclonal in RS cells of a given patient (infection precedes transformation)
• Immune escape mechanisms:
  • Loss of β2-microglobulin → failure to express class I MHC
  • High expression of PD-L1 → inhibits T-cell responses (therapeutic target)
• RS cells secrete cytokines: IL-5 (eosinophil attraction), TGF-β (fibrosis), IL-13 (autocrine growth)

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7. Staging — Ann Arbor / Lugano Classification

• A = No B symptoms; B = B symptoms present
• E = Extranodal contiguous extension; S = Spleen involved
• X = Bulky disease (mediastinal mass >1/3 thoracic diameter or >10 cm)

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8. Histopathology of Each Subtype (Exam Focus)

Nodular Sclerosis (most common — 60%)

• Collagen bands divide lymph node into nodules
• Lacunar cells (RS variants) in nodules
• Background: lymphocytes, eosinophils, plasma cells
• Young women, mediastinal involvement

Mixed Cellularity (~9%)

• Classic RS cells scattered among mixed inflammatory background
• Most strongly associated with EBV (up to 70%)
• Older males, advanced stage at presentation

Lymphocyte Rich (~3%)

• Abundant reactive lymphocytes, rare RS cells
• Best prognosis among classic HL
• Resembles NLPHL but RS cells are CD30+, CD15+

Lymphocyte Depleted (~1%)

• Numerous RS cells, depleted lymphocytes
• Worst prognosis; elderly, HIV+ patients
• High association with EBV and advanced stage

Nodular Lymphocyte Predominant (NLPHL, ~8%)

• Popcorn/L&H cells — large neoplastic cells with multilobated nuclei
• Background: predominantly small B lymphocytes and histiocytes
• CD20+, CD79a+, CD45+; CD30−, CD15− ← key distinction
• Indolent course; risk of transformation to diffuse large B-cell lymphoma

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9. Treatment

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10. Viva & Exam High-Yield Points

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Mutations in Hodgkin Lymphoma

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1. Why RS Cells are Genetically Abnormal B Cells

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2. Key Signaling Pathways & Mutations

NF-κB Pathway (Most Important)

• Constitutive NF-κB activation is the central oncogenic mechanism in RS cells
• NF-κB promotes RS cell survival, proliferation, and cytokine secretion
• Mechanisms of activation:
  • EBV LMP-1 (latent membrane protein-1) directly activates NF-κB in EBV+ cases
  • Mutations in TNFAIP3 (A20) — A20 is a negative regulator of NF-κB; loss-of-function mutations in A20 found in ~30–40% of cHL cases
  • REL gene amplification — REL encodes a NF-κB subunit; amplified on chromosome 2p

JAK-STAT Pathway

• RS cells show constitutive JAK2 amplification (chromosome 9p24.1)
• JAK2 amplification also co-amplifies PD-L1 and PD-L2 genes on the same locus → immune evasion
• STAT6 activating mutations — found in a subset; STAT6 drives IL-13 autocrine signaling
• SOCS1 mutations — SOCS1 normally inhibits JAK-STAT; loss-of-function mutations lead to sustained STAT activation

PI3K Pathway

• Activated downstream of JAK2 and receptor signaling; contributes to RS cell survival

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3. Chromosome 9p24.1 Amplification — High-Yield

This is why anti-PD-1 agents (nivolumab, pembrolizumab) work so well in relapsed/refractory HL — the tumor is genomically wired to overexpress PD-L1.

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4. β2-Microglobulin (B2M) Mutations

• Loss-of-function mutations in B2M → failure to assemble MHC class I molecules
• RS cells become invisible to CD8+ cytotoxic T cells
• A major immune escape mechanism

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5. EBV-Driven Oncogenesis (in EBV+ cases)

• LMP-1 mimics a constitutively active CD40 receptor → activates NF-κB and PI3K
• LMP-2A mimics a tonically active B-cell receptor → survival signals without BCR
• Together, LMP-1 and LMP-2A rescue the crippled B cell from apoptosis and drive clonal expansion

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6. NLPHL-Specific Mutations

• Unlike classic HL, NLPHL popcorn cells retain functional BCR signaling
• Frequent mutations in TNFRSF14 and RHOA
• Activation of BCR/PI3K pathway — basis for sensitivity to rituximab (anti-CD20)

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Summary Table — Viva-Ready

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Numerical & Structural Chromosomal Mutations (Genetics)

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PART 1 — NUMERICAL CHROMOSOMAL MUTATIONS

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A. Aneuploidy

— The Developing Human: Clinically Oriented Embryology

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B. Polyploidy

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C. Mechanism — Nondisjunction

Normal Meiosis:     Pair → one to each daughter cell
Nondisjunction:     Both go to ONE cell → other gets NONE
Result:             One gamete = n+1 (disomic)
                    Other gamete = n-1 (nullisomic)
Fertilization with normal gamete (n):
   n+1 + n = 47 (trisomy)
   n-1 + n = 45 (monosomy)

• Can occur in Meiosis I (more common) or Meiosis II
• Can also occur during early mitotic divisions of the zygote → Mosaicism (two or more cell lines with different karyotypes)

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D. Clinical Examples of Aneuploidy

Autosomal Trisomies

Sex Chromosome Aneuploidies

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E. Mosaicism

• Nondisjunction during early mitotic divisions post-fertilization
• Results in two cell populations with different karyotypes (e.g., 46,XX / 45,X)
• Phenotype is milder than full monosomy/trisomy
• True hermaphroditism likely due to XX/XY mosaicism

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PART 2 — STRUCTURAL CHROMOSOMAL MUTATIONS

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1. Translocation

• Balanced translocation carrier: Phenotypically normal, but produces abnormal gametes → risk of offspring with unbalanced karyotype
• 3–4% of Down syndrome cases are due to translocation trisomy 21 (not age-related — can recur in family)
• Most common structural abnormality: 1:1000

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2. Deletion

• Cat-like cry (from which the syndrome is named)
• Microcephaly, severe intellectual disability
• Congenital heart disease, hypertelorism

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3. Inversion

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4. Duplication

• More common than deletions
• Less harmful than deletions (no genetic material lost)
• Can still cause cognitive impairment or birth defects
• May involve part of a gene, a whole gene, or multiple contiguous genes

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5. Isochromosome

• Most common: i(Xq) — isochromosome of long arm of X → one of the causes of Turner syndrome
• Results in monosomy for one arm + trisomy for the other

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6. Microdeletion & Microduplication (Contiguous Gene Syndromes)

• Same deletion, different parent of origin → different syndrome
• Maternal chromosome 15 deleted → Angelman syndrome
• Paternal chromosome 15 deleted → Prader-Willi syndrome
• This is genomic imprinting — differential expression based on parental origin

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SUMMARY TABLE — Viva Quick Reference

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