Hodgkin's Lymphoma

Reed-Sternberg cell biology, Ann Arbor staging, BV-AVD frontline standard, and curative salvage with ASCT and checkpoint immunotherapy

Key Points

• Hodgkin's lymphoma (HL) is one of oncology's greatest success stories — overall cure rates exceed 85–90% across all stages with modern therapy.
• Classic HL is defined by the Reed-Sternberg cell: a CD15+, CD30+, CD45− germinal-center B cell that has lost its B-cell identity; it constitutes <1% of the tumor mass yet drives the inflammatory microenvironment.
• HL has a bimodal age distribution with a predominant peak in young adults (15–35 years) and a smaller second peak after age 55; EBV is detected in ~30–40% of classic HL in developed countries.
• BV-AVD (brentuximab vedotin + doxorubicin, vinblastine, dacarbazine) is the preferred frontline regimen for advanced-stage (III–IV) HL, demonstrating superior 6-year PFS over ABVD in the ECHELON-1 trial.
• PET-adapted therapy using Deauville criteria after 2 cycles guides de-escalation (omit radiation in PET-negative early-stage) or escalation (switch to BEACOPP in PET-positive advanced-stage).
• Nivolumab and pembrolizumab exploit 9p24.1 amplification-driven PD-L1 overexpression on Reed-Sternberg cells, achieving ORRs of 65–70% in relapsed/refractory HL — transforming salvage options.

Epidemiology, Classification, and Biology

Hodgkin's lymphoma accounts for approximately 8,500–9,000 new cases and 900 deaths annually in the United States. Despite its rarity, it is the most common cancer in adolescents and young adults aged 15–30 and is among the most curable of all cancers. The 2022 WHO classification divides HL into two major entities: **Classic Hodgkin Lymphoma (cHL, ~95%):** Four histologic subtypes — Nodular Sclerosis (NS, most common ~70%, young women, mediastinal disease), Mixed Cellularity (MC, ~25%, older adults, EBV+, HIV-associated), Lymphocyte-Rich (LR, rare, good prognosis), and Lymphocyte-Depleted…

Clinical Presentation

The hallmark of HL is painless, rubbery lymphadenopathy. Cervical and supraclavicular nodes are most commonly involved; anterior mediastinal adenopathy (present in ~60% of NS-HL) may cause cough, dyspnea, or SVC syndrome. Axillary and inguinal involvement is less common; infradiaphragmatic or mesenteric involvement is rare in classic HL. **B symptoms** are present in ~35% at diagnosis and are a formal staging suffix (suffix B): fever >38°C, drenching night sweats, and ≥10% unintentional weight loss over 6 months. Their presence upstages prognosis and influences treatment decisions. Other…

Staging and Risk Stratification

Staging follows the Lugano Classification (modified Ann Arbor): - **Stage I:** Single nodal region or single extralymphatic site (IE) - **Stage II:** Two or more nodal regions, same side of diaphragm; IIE = contiguous extranodal extension - **Stage III:** Nodal regions both sides of diaphragm; IIIS = splenic involvement - **Stage IV:** Diffuse extralymphatic involvement (bone marrow, liver, lung parenchyma) - **Suffixes:** A (no B symptoms), B (B symptoms present), X (bulky disease: mediastinal mass ≥1/3 chest diameter or nodal mass ≥10 cm) Staging workup: PET/CT (gold standard — FDG-avid in…

Treatment

**Early-Stage Favorable (I–II, no adverse features):** ABVD × 2–4 cycles + involved-site radiation therapy (ISRT) 20–30 Gy remains standard. PET-guided de-escalation (HD16, H10 trials): PET2-negative patients may omit RT in some protocols, though this increases relapse risk vs. combined modality. 5-year PFS >90%, OS >95%. **Early-Stage Unfavorable (I–II with adverse features):** ABVD × 4–6 cycles + ISRT 30 Gy; or 2 cycles BEACOPP-esc → 2 ABVD + ISRT for very high-risk patients per GHSG HD14. **Advanced-Stage (III–IV):** BV-AVD (brentuximab vedotin + doxorubicin + vinblastine + dacarbazine) ×…

Relapsed / Refractory HL

Approximately 15–20% of HL patients relapse after first-line therapy, and ~5% are primary refractory. The standard approach is salvage platinum-based chemotherapy to establish chemosensitivity, followed by high-dose therapy and autologous stem cell transplantation (ASCT) in eligible patients. Checkpoint inhibitors have transformed the R/R landscape by exploiting constitutive PD-L1 overexpression on Reed-Sternberg cells driven by 9p24.1 amplification. **Salvage chemotherapy (bridge to ASCT):** - ICE (ifosfamide + carboplatin + etoposide): ORR ~65–70%; most widely used in the US - DHAP…

Late Effects and Survivorship

Given the young age at diagnosis and high cure rates, long-term toxicity of treatment is a dominant concern in HL survivorship. The late effects of ABVD and mediastinal radiation have shaped decades of trial design aimed at treatment de-escalation. **Cardiovascular toxicity:** Mediastinal radiation significantly increases risk of coronary artery disease, valvular disease, and pericardial disease — risks that emerge 10–20 years after treatment. Anthracycline-related cardiomyopathy adds to this burden. Cardiac screening (echocardiography, stress testing) every 5–10 years is recommended for…