Hodgkin Lymphoma - Complete Notes for MBBS

Note on Harsh Mohan: Harsh Mohan's Textbook of Pathology is not available in my medical library database, so this answer draws exclusively from Robbins (both Pathologic Basis of Disease and Basic Pathology), which covers the same content in depth and is the most widely used pathology reference for MBBS examinations.

1. DEFINITION AND OVERVIEW

• Incidence: ~0.7% of all new cancers; ~9000 cases/year in the US
• Age: Bimodal distribution - first peak in young adults (15-35 years), second peak in adults >55 years
• Historical significance: First human cancer successfully cured with radiation therapy and chemotherapy

2. PATHOGENESIS

Cell of Origin

• Clonal IGH gene rearrangements in every RS cell from a given case
• Evidence of somatic hypermutation in these rearranged immunoglobulin genes

Role of EBV

• EBV is present in RS cells in up to 70% of mixed-cellularity subtype cases
• Present in a smaller fraction of other classic forms
• Integration site of EBV genome is identical in all RS cells within a given case - indicating infection precedes (and may be related to) transformation
• EBV-encoded Latent Membrane Protein 1 (LMP-1) transmits signals that upregulate NF-κB

NF-κB Activation (Central Mechanism)

1. EBV+ tumors: LMP-1 activates NF-κB
2. EBV- tumors: Acquired loss-of-function mutations in IκB or TNF-α-induced protein 3 (negative regulators of NF-κB)
3. Copy number gains in the REL proto-oncogene (chromosome 2p)

Immune Evasion

• RS cells often have mutations causing loss of β2-microglobulin → failure to express Class I MHC molecules
• RS cells express high levels of PD-L1 and PD-L2 (immune checkpoint proteins) - genes on chromosome 9p are frequently amplified
• This stifles cytotoxic T-cell responses - which is why anti-PD-1 antibodies (e.g., pembrolizumab) produce excellent responses even in treatment-resistant cases

Cytokine Milieu - The Reactive Infiltrate

• IL-5 - chemoattractant for eosinophils
• IL-10 - suppresses Th1 immune responses → cutaneous anergy
• TGF-β - fibrogenic factor (responsible for fibrosis in nodular sclerosis)
• IL-13 - may stimulate RS cell growth (autocrine)
• Eotaxin - attracts eosinophils

3. MORPHOLOGY

Reed-Sternberg Cell - The Diagnostic Cell

Classic binucleate Reed-Sternberg cell with owl-eye appearance (Robbins & Kumar Basic Pathology)

• Very large cell: 15-45 μm in diameter
• Multiple nuclei OR single nucleus with multiple nuclear lobes
• Each lobe contains a large, inclusion-like acidophilic nucleolus (5-7 μm, about the size of a small lymphocyte) surrounded by a clear halo
• "Owl-eye" appearance - two mirror-image nuclei/lobes with prominent nucleoli
• Abundant, slightly eosinophilic cytoplasm
• Immunophenotype: CD15+, CD30+, CD45-, B-cell markers-, T-cell markers-

RS Cell Variants

4. WHO CLASSIFICATION - FIVE SUBTYPES

Subtype 1: NODULAR SCLEROSIS (Most Common - ~65-70%)

Nodular Sclerosis - pink collagen bands subdivide tumor cells into nodules (Robbins)

• Morphology: Lacunar cells + collagen bands dividing lymphoid tissue into circumscribed cellular nodules. Background of T lymphocytes, eosinophils, macrophages, plasma cells.
• Immunophenotype: CD15+, CD30+; usually EBV negative
• Demographics: Most common in adolescents and young adults; equal in males and females
• Sites: Lower cervical, supraclavicular, mediastinal lymph nodes (characteristic)
• Stage at presentation: Usually stage I or II
• Prognosis: Excellent

Subtype 2: MIXED CELLULARITY (~25%)

Mixed cellularity - classic binucleate RS cell surrounded by eosinophils, lymphocytes, and macrophages (Robbins)

• Morphology: Frequent classic RS cells (most abundant here) + heterogeneous inflammatory infiltrate (lymphocytes, eosinophils, plasma cells, macrophages)
• Immunophenotype: CD15+, CD30+; 70% EBV positive (highest EBV association)
• Demographics: Most common in patients >50 years; male predominance; bimodal incidence
• Stage at presentation: More than 50% present as stage III or IV
• Features: More likely to be disseminated; more systemic symptoms
• Prognosis: Still very good overall

Subtype 3: LYMPHOCYTE-RICH (Uncommon)

• Frequent mononuclear and classic RS cells; background rich in T lymphocytes
• CD15+, CD30+; ~40% EBV positive
• Greater in males; tends to occur in older adults
• Uncommon but favorable prognosis

Subtype 4: LYMPHOCYTE-DEPLETED (Uncommon, Most Aggressive Classic)

• Two morphologic variants:
  • Reticular variant: Frequent RS cells and variants, paucity of reactive background
  • Diffuse fibrosis variant: Few RS cells, prominent fibrosis
• CD15+, CD30+; most cases EBV positive
• More common in older males, HIV-infected individuals, and people in low-resource countries
• Often presents with advanced disease (stage III/IV)
• Worst prognosis among classic subtypes

Subtype 5: NODULAR LYMPHOCYTE PREDOMINANT (Nonclassic, ~5%)

Nodular lymphocyte predominant - scattered large pale L&H (popcorn) cells among small lymphocytes (Robbins)

• Morphology: Nodules of small lymphocytes + macrophages; "popcorn" L&H variant RS cells; classic RS cells absent; eosinophils and plasma cells scanty
• Immunophenotype: CD20+, BCL6+ (B-cell markers positive); CD15-, CD30- (unlike classic forms); EBV negative
• Shows ongoing somatic hypermutation in IGH genes → confirmed germinal center B-cell origin
• Demographics: Majority are young males (<35 years); cervical or axillary lymphadenopathy
• Sites: Mediastinal and bone marrow involvement rare
• Risk: 3-5% cases transform to diffuse large B-cell lymphoma
• In ICC classification, renamed: "Nodular lymphocyte-predominant B-cell lymphoma"
• Prognosis: Excellent; may recur more than classic subtypes but survival remains excellent

5. ANN ARBOR STAGING SYSTEM

• A = No systemic ("B") symptoms
• B = Presence of B symptoms: fever (>38°C), drenching night sweats, unexplained weight loss (>10% body weight in 6 months)

6. CLINICAL FEATURES

Presentation

• Painless lymphadenopathy - the most common presenting feature
• Most frequent nodes: cervical > mediastinal > axillary
• Pel-Ebstein fever - characteristic cyclical fever (periods of high fever alternating with afebrile periods)
• Alcohol-induced pain - pain in involved lymph nodes after drinking alcohol (classic and unusual symptom)
• Pruritis (itching) - common
• Mediastinal mass - can cause cough, dyspnea, superior vena cava syndrome

B Symptoms (Constitutional)

• Fever
• Night sweats
• Weight loss >10% of body weight

Staging-Related Features

• Stage I/II (nodular sclerosis, lymphocyte predominant): Usually no B symptoms
• Stage III/IV (mixed cellularity, lymphocyte depleted): B symptoms common; anemia present

Spread Pattern (Stereotypic)

Immune Dysfunction

• Cutaneous anergy (impaired cell-mediated immunity) in most cases of classic HL due to IL-10 secretion by RS cells suppressing Th1 responses
• Risk of opportunistic infections (e.g., herpes zoster reactivation)

7. IMMUNOPHENOTYPE SUMMARY

8. DIAGNOSIS

• Excisional lymph node biopsy - essential; must identify RS cells or variants in appropriate reactive background
• Immunohistochemistry (IHC) - critical to distinguish from NHL and reactive conditions
• Staging workup:
  • Physical examination
  • CT scan of chest, abdomen, pelvis
  • PET scan (increasingly used)
  • Bone marrow biopsy

9. TREATMENT AND PROGNOSIS

Treatment

• Early-stage (I, II): Combination chemotherapy (ABVD regimen: Adriamycin/doxorubicin, Bleomycin, Vinblastine, Dacarbazine) ± involved-field radiotherapy
• Advanced stage (III, IV): Chemotherapy (ABVD or escalated BEACOPP)
• Relapsed/refractory disease: Anti-PD-1 antibodies (pembrolizumab, nivolumab) - highly effective because PD-L1/L2 overexpression is a key immune escape mechanism in HL

Historical note: Low-stage HL was one of the early success stories in oncology - curable with involved-field radiotherapy. However, long-term survivors treated with radiotherapy showed higher rates of secondary malignancies (lung cancer, breast cancer, melanoma) and cardiovascular disease, leading to current chemotherapy-first approaches.

Prognosis

• Stage is the most important prognostic variable (not histologic subtype) with current treatment protocols
• Hodgkin lymphoma is one of the most curable cancers, even in advanced stages

10. QUICK MEMORY AIDS (for MBBS Exams)

• "Owl-eye" RS cell = diagnostic hallmark
• CD15+ CD30+ CD45- = classic RS cell immunophenotype
• Nodular sclerosis = most common subtype; young adults; mediastinal involvement; lacunar cells + collagen bands
• Mixed cellularity = most classic RS cells; highest EBV association (70%); males >50 years
• Lymphocyte predominant = popcorn cells; CD20+ CD15- CD30-; best prognosis
• Lymphocyte depleted = worst prognosis classic; HIV patients; elderly
• EBV = especially mixed cellularity (70%)
• Spread = contiguous, stepwise (unlike NHL)
• Extranodal = rare (unlike NHL)
• Alcohol pain = pathognomonic symptom
• B symptoms = fever + night sweats + >10% weight loss
• Anergy = impaired cell-mediated immunity (IL-10 from RS cells)
• PD-L1/L2 = immune evasion target; anti-PD-1 therapy works excellently