Hodgkin Lymphoma

Overview

• Goldman-Cecil Medicine, p. 1964

Epidemiology

• ~30,000 new cases/year in North America and Europe
• Incidence: ~2.7 per 100,000; mortality: ~0.5 per 100,000
• Bimodal age distribution: early peak at 25-30 years, second peak at >50 years
• Slightly more common in men; higher incidence in Whites vs. Blacks; very rare in Asian populations
• Highest incidence in the US, Canada, Switzerland, and northern Europe
• Cumulative lifetime risk: ~1 in 250-300 in North America
• Goldman-Cecil Medicine, p. 1964

Pathobiology and Etiology

• EBV DNA and proteins are detected in RS cells in up to 70% of mixed-cellularity cases and a smaller fraction of other classic subtypes
• The EBV integration site is identical in all RS cells within a given patient, indicating infection precedes clonal transformation
• A history of infectious mononucleosis raises the risk of HL 2-3x; this elevated risk persists for >20 years after the EBV illness
• EBV likely is one of several steps in transformation, particularly for mixed-cellularity subtype

• Robbins & Kumar Basic Pathology, p. 416; Goldman-Cecil Medicine, p. 1964

Cell of Origin

Reed-Sternberg Cell

• Large cell, 15-45 μm in diameter
• Enormous multilobate nucleus with exceptionally prominent nucleoli
• Binucleate cells with mirror-image lobes, each with a large acidophilic nucleolus surrounded by a clear zone - the classic "owl-eye" appearance
• Abundant, slightly eosinophilic cytoplasm

• Robbins & Kumar Basic Pathology, p. 417-418; Goldman-Cecil Medicine, p. 1964-1965

Classification: Five Subtypes

1. Nodular Sclerosis (most common, ~70%)

• Equally frequent in men and women
• Typical age: adolescents and young adults
• Predilection for lower cervical, supraclavicular, and mediastinal lymph nodes
• Morphology: lacunar cells (RS variant with pale cytoplasm that retracts in formalin-fixed tissue, leaving nucleus in an empty space/lacune); broad bands of collagen subdivide tumor into nodules
• Prognosis: excellent

2. Mixed Cellularity (~20-25%)

• More common in men; median age slightly older
• Strongly associated with EBV (up to 70%)
• Classic binucleate RS cells in a mixed background of eosinophils, lymphocytes, plasma cells, and histiocytes
• Often presents at a more advanced stage

3. Lymphocyte-Rich (<5%)

• Must be distinguished from NLPHL
• Good prognosis; RS cells set in a predominantly lymphocytic background

4. Lymphocyte Depletion (rare, <1%)

• Older patients; often HIV-associated
• Paucity of lymphocytes; abundant RS cells or fibrosis
• Poorest prognosis among the classic subtypes; often presents in advanced stage

5. Nodular Lymphocyte Predominant (NLPHL, ~10%)

• Separate entity from classic HL
• Characteristic "popcorn" L&H cells expressing CD20, CD79a, BCL6
• CD15-negative; indolent course; late relapses can occur
• Robbins & Kumar Basic Pathology, p. 417-419; Goldman-Cecil Medicine, p. 1964-1965

Immune Evasion Mechanism

• Loss of β2-microglobulin function → failure to express class I MHC → CD8+ T cells cannot recognize tumor
• High expression of PD-L1 and PD-L2 (encoded on chromosome 9q24, which is often amplified) → engagement of PD-1 on T cells suppresses anti-tumor immune response
• This is the mechanistic basis for the remarkable clinical efficacy of anti-PD-1 antibodies (pembrolizumab, nivolumab) in relapsed/refractory HL
• Robbins & Kumar Basic Pathology, p. 417-419

Clinical Features

• Painless lymphadenopathy is the cardinal feature (often cervical, supraclavicular)
• Mediastinal involvement is common in the nodular sclerosis subtype and may cause cough, dyspnea, or SVC syndrome
• Alcohol-induced pain at sites of disease (classic but uncommon)

• Unexplained fever >38°C (recurrent)
• Drenching night sweats
• Unexplained weight loss >10% body weight over 6 months

• Pruritus (can be severe)
• Anemia
• Pel-Ebstein fever (cyclical high fevers, characteristic but rare)

Staging: Modified Ann Arbor System

• Goldman-Cecil Medicine, p. 1965

Workup and Staging Investigations

• Full history and physical examination (lymphadenopathy, organomegaly)
• Complete blood count, ESR
• LFTs, renal function, LDH, alkaline phosphatase, serum albumin, protein electrophoresis
• HIV, hepatitis B and C serology
• Chest X-ray (PA and lateral)
• CT scan of neck, thorax, abdomen, and pelvis with contrast
• FDG-PET/CT - now mandatory; more sensitive and specific than CT alone for staging and response assessment; has replaced bone marrow biopsy for staging purposes
• Goldman-Cecil Medicine, p. 1965-1966

Treatment

Limited Stage (Stages I and II, favorable)

• Brief combination chemotherapy (typically 2-4 cycles) is the cornerstone
• Standard regimen: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for 3-4 months
• Involved-site radiation therapy (ISRT) may be added in selected patients (bulky disease or inadequate PET response after chemotherapy)
• PET/CT after 2 cycles guides further therapy (response-adapted approach)
• 5-year OS: >90% for stage IA/IIA

Advanced Stage (Stages III and IV)

• 6 months of ABVD or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)
• Escalated BEACOPP gives higher complete remission rate but more toxicity; ABVD remains standard in most centers
• Brentuximab vedotin (anti-CD30 antibody-drug conjugate) + AVD is an alternative first-line regimen for advanced disease
• Interim PET/CT after 2-4 cycles stratifies subsequent treatment intensity
• 5-year disease-free survival for stage IVA/IVB: ~50%

Relapsed/Refractory Disease

• High-dose chemotherapy + autologous hematopoietic stem cell transplantation (auto-HSCT) can cure ~50% of relapsed patients
• Brentuximab vedotin (anti-CD30): effective in relapsed/refractory cHL post-transplant; approved as maintenance post-auto-HSCT
• Anti-PD-1 checkpoint inhibitors - nivolumab and pembrolizumab: highly effective in relapsed/refractory HL (response rates ~65-87%); even tumors resistant to all other therapies often respond; now being integrated into earlier lines of therapy
• Goldman-Cecil Medicine, p. 1966-1968; Robbins & Kumar Basic Pathology, p. 419

Prognosis and Long-Term Complications

• Secondary malignancies: lung cancer, breast cancer (especially after mantle field radiation), and other solid tumors
• Cardiovascular disease: accelerated coronary artery disease, valvular disease, pericarditis

• Pulmonary toxicity (bleomycin)
• Cardiotoxicity (doxorubicin)
• Secondary leukemia and myelodysplasia (especially alkylating agents in BEACOPP)
• Infertility

• Goldman-Cecil Medicine, p. 1966-1968; Robbins & Kumar Basic Pathology, p. 419

Key Summary Table