Hodgkin lymphoma

Epidemiology

• Incidence: ~9,000 new cases/year in the US; ~1,200 deaths/year. Roughly 10% of all lymphomas and 0.4% of all cancers.
• Bimodal age distribution: peaks in the 20s and again in the mid-70s. Slight male predominance (1.3:1).
• Risk factors: viral infection (EBV, HIV); immunosuppression after solid-organ or stem-cell transplant (PTLD spectrum); autoimmune disease.

Clinical Presentation

• Painless lymphadenopathy: classical HL spreads in a contiguous nodal pattern, neck/chest > axillary > abdomen/pelvis/inguinal.
• B symptoms: unexplained fever (>38 °C, 100.4 °F), drenching night sweats, weight loss (>10% of baseline over 6 months).
• Other: pruritus, fatigue/malaise, alcohol-induced nodal pain (rare), and organ-compression symptoms (cough, dyspnea, chest pain, SVC syndrome).

Diagnosis

• Biopsy is required. Excisional biopsy when possible.
• Core needle biopsy is sometimes insufficient because Reed-Sternberg cells are rare within the tumor.
• Fine-needle aspiration is inadequate: it does not preserve tissue architecture.

Pathology

• Classical HL (cHL): ~95% of HL. Hodgkin Reed-Sternberg (HRS) cells (multinucleated, "owl-eye" nucleoli) are surrounded by a reactive inflammatory infiltrate; HRS cells release cytokines that recruit inflammatory cells, with feedback between HRS cells and surrounding immune cells. HRS cells make up only 0.1 to 10% of cells in the tumor. EBV positive in ~30 to 40% of cases.
• cHL subtypes: nodular sclerosis (~70%; young, mediastinal), mixed cellularity (~20%; older, EBV+), lymphocyte rich (~5%), lymphocyte depleted (~1%; worst).
• NLPHL / NLPBL: nodular lymphocyte-predominant HL, ~5%, is NOT classical HL. Renamed in the ICC 2022 as nodular lymphocyte-predominant B-cell lymphoma (NLPBL) (WHO 5th edition retains the NLPHL name), recognized as a B-cell NHL. Tumor cells are "popcorn" (LP) cells with lobulated vesicular nuclei and small peripheral nucleoli.
• Mediastinal gray zone lymphoma: features intermediate between cHL and primary mediastinal large B-cell lymphoma (WHO-HAEM5/ICC 2022); most nonmediastinal cases are now reclassified as DLBCL, NOS.

Tumor Microenvironment (TME) by Subtype

Immunophenotype: Classical HRS Cells vs NLPHL LP Cells

• NLPHL / NLPBL clinical features: median age ~37 (older than cHL), male > female, ~80% early stage. Rarely B symptoms, bulk, or extranodal disease. Peripheral adenopathy (axillary, inguinal), whereas cHL favors central nodes. Transforms to NHL in 5 to 10%; late relapses are more common. Also expresses CD19, CD79a, OCT2.

Pathogenesis of Classical HL

• Cell of origin: HRS cells derive from germinal-center B cells and carry clonally rearranged, somatically hypermutated Ig genes (often with crippling mutations), but lose the B-cell program and do not express immunoglobulin.
• Signaling: constitutive NF-κB and JAK-STAT pathway activation.
• PD-1 axis (near universal): 9p24.1 (PD-L1/PD-L2 genes) alteration → PD-L1/2 expression on HRS cells; 9p24.1 also increases JAK2 → further PD-L1/2 expression; EBV LMP1 → PD-L1 expression on RS cells; tumor-associated macrophages express PD-L1 in the TME. This underpins checkpoint-inhibitor sensitivity.

Workup

• Labs: CBC with differential, ESR, LDH, comprehensive metabolic panel including LFTs, albumin, creatinine; pregnancy test; HIV, hepatitis B and C testing.
• Imaging: PET/CT (with or without diagnostic IV-contrast CT).
• Bone marrow: routine biopsy NOT indicated (PET is sensitive for bony disease); consider only if cytopenias.
• Organ function: echocardiogram or MUGA for anthracyclines; pulmonary function testing for bleomycin.
• Counseling: fertility discussion, smoking cessation.

Staging

• Ann Arbor staging by PET/CT. Early stage = I to II; advanced stage = III to IV (both sides of the diaphragm and beyond).
• A vs B: A = no constitutional symptoms; B = fever, night sweats, >10% weight loss.
• Bulk: defined as ≥10 cm or >1/3 of the maximum intrathoracic diameter (thresholds vary by classification; modified Hasenclever in some).

Deauville 5-Point Scale (PET response)

• Interpretation: DS 1 to 3 is generally treated as PET negative (complete metabolic response), DS 4 to 5 as PET positive; interim PET (after cycle 2) is strongly prognostic and drives PET-adapted therapy.

Prognosis and Risk Stratification

• Ann Arbor: early stage (I to II) cure rate ~85 to 90+%; advanced stage (III to IV) cure rate ~75+%.
• Early stage is split into "favorable" vs "unfavorable"; the EORTC criteria are most commonly used, and presence of any unfavorable/high-risk criterion classifies a patient as unfavorable. EORTC unfavorable factors: age ≥50, ≥4 involved nodal areas, large mediastinal mass (M/T ratio ≥0.35), and ESR ≥50 (no B symptoms) or ≥30 (with B symptoms). Bulk is typically ≥10 cm or the mediastinal ratio, not peripheral nodes >5 cm.
• Advanced stage: International Prognostic Score (IPS / Hasenclever), one point each (score 0 to 7 predicts prognosis):
  • Age ≥45
  • Male sex
  • Stage IV
  • Albumin <4.0 g/dL
  • Hemoglobin <10.5 g/dL
  • WBC ≥15,000/µL
  • Lymphopenia (absolute lymphocytes <600/µL or <8%)

Principles of Therapy

• Early stage (I to II): combined chemotherapy (ABVD, or BEACOPP in Europe) plus radiation, curing >85 to 90%. Chemotherapy allows progressive narrowing of RT fields (extended field → involved field → involved-site RT). Historically RT alone gave ~80% 10-year RFS; chemo + RT proved superior and raised cure to >85 to 90%.
• Advanced stage (III to IV): systemic therapy for systemic disease, curing ~75 to 85%. Historically ABVD in the US and BEACOPP in parts of Europe, but now outdated: N-AVD (SWOG S1826) is preferred US frontline for advanced cHL, and PET-adapted BrECADD (HD21) has largely replaced escBEACOPP in GHSG practice.
• ABVD = adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine.

Early-Stage cHL Treatment

• GHSG HD10: de-escalation established ABVD x 2 + 20 Gy as standard for favorable early-stage HL.
• CALGB 50604 (PET-adapted, chemo alone): ABVD x 2 → if DS 1 to 3, ABVD x 2 more (3-year PFS 91%); if DS 4 to 5, escBEACOPP x 2 + 30 Gy IFRT (3-year EFS 67%).
• RAPID (PET-adapted): ABVD x 3 → if DS 1 to 2, randomize observation vs RT; if DS 3 to 5, 4th ABVD then IFRT. 3-year PFS 94.6% vs 90.8% (risk difference 3.8 points favoring RT; noninferiority of omitting RT not shown); 3-year OS 97.1% vs 99.5% (favoring no further therapy, p=0.07). Omitting RT is problematic with larger tumors (>5 cm nodes); EORTC H10 similarly showed lower PFS with RT omission.
• GHSG HD11: ABVD x 4 + 30 Gy established for unfavorable early-stage. HD14: escBEACOPP x 2 + ABVD x 2 + RT (2+2) beat ABVD + RT.

Advanced-Stage cHL Treatment

• SWOG S0816 (PET-adapted ABVD): ABVD x 2 → if DS 1 to 3, ABVD x 4 (total ABVD x 6); if DS 4 to 5, escalate to BEACOPP x 6. 5-year PFS 76% (PET negative, ABVD x 6) vs 66% (PET positive, escalated).
• RATHL: stage IIB to IV, or stage IIA with adverse features (bulk or ≥3 involved sites). ABVD x 2 → if PET negative, AVD x 4 or ABVD x 4; if PET positive, escalated BEACOPP x 4 or BEACOPP-14 x 6. Dropping bleomycin (AVD) is non-inferior in PET2-negative patients (3-year PFS ~82% both arms in stage III to IV). PET-positive 3-year PFS ~67.5%.
• HD18: escBEACOPP x 2 → PET2. If DS 1 to 2, total 4 vs 6 to 8 cycles (fewer cycles adequate); if DS 3 to 5, 6 to 8 cycles +/- rituximab. PET-guided BrECADD improved PFS over escBEACOPP with less toxicity (HD21: 4-yr PFS 94.3% vs 90.9%, HR 0.66), so escBEACOPP is no longer the single best option.
• ABVD vs BEACOPP (stage IIB to IV or IPS >3): BEACOPP gives better disease control; individual trials show no consistent OS difference, but pooled/meta-analyses (Skoetz Cochrane 2017) favor BEACOPP for OS. ABVD remained common due to the efficacy/toxicity tradeoff. Frontline intensification also applies to PET2-positive disease, not only relapsed/refractory.
• AHL2011: PET-driven de-escalation, escBEACOPP x 2 → if PET2 negative, switch to ABVD; if PET2 positive, continue escBEACOPP. Confirms you can de-escalate to ABVD if PET negative after 2 cycles of escalated BEACOPP.
• ECHELON-1 (BV+AVD in stage III/IV cHL): brentuximab vedotin + AVD (BV-AVD) x 6 vs ABVD x 6. 2-year modified PFS 82.1% vs 77.2% (HR 0.77, 95% CI 0.60 to 0.98); 3-year PFS 83.1% vs 76%. 6-year OS 93.9% vs 89.4% (HR 0.59; Ansell NEJM 2022). Greatest benefit in age <60, stage IV, and >1 extranodal site. BV-AVD needs no PET adaptation. More toxic (grade 3+ AEs 83% vs 66%): febrile neutropenia, sepsis, infection, neutropenia, so G-CSF is mandatory. FDA approved March 2018.

Escalated BEACOPP: Key Toxicities

• Infertility: males ~90% azoospermia; females premature menopause.
• Secondary MDS/AML: pooled analysis of 8 RCTs (5,357 patients) put MDS risk at ~4.4% with BEACOPP.

N+AVD: New Frontline Standard (Advanced Stage)

• Nivolumab + AVD (N-AVD): NEW STANDARD; FDA approved March 20, 2026 for previously untreated stage III to IV cHL in adults and pediatric patients ≥12 years, based on SWOG S1826 (Herrera AF et al, NEJM 2024). N-AVD vs BV-AVD: 2-year PFS 92% vs 83% (HR 0.45, 95% CI 0.30 to 0.65), with markedly less peripheral sensory neuropathy (any-grade 29% vs 56%). Replaces BV-AVD as first-line in advanced cHL.

Elderly Patients with HL

• Represent ~15 to 25% of HL. Poor chemotherapy tolerance (comorbidity, frailty) and increased risk of bleomycin lung toxicity; toxicity limits treatment delivery.
• Sequential BV x 2 → AVD x 6 → BV x 4: 2-year EFS 80%, PFS 84%, OS 93%, ORR 95%.
• BV doublets (older/frail HL): BV + dacarbazine (ORR ~90 to 100%) or BV + nivolumab. Avoid frontline BV + bendamustine: the ≥60 cohort was stopped for excessive toxicity (serious AEs 65%, 2 on-study deaths).

Relapsed / Refractory cHL

• Standard second line: salvage chemotherapy (ICE, DHAP, GDP) +/- brentuximab, then ASCT in chemosensitive patients (salvage CR ~50 to 70%). ASCT cures ~50% of patients; PET status after salvage is prognostic of ASCT outcome.
• Brentuximab vedotin (CD30 ADC): after CD30 binding, the ADC-CD30 complex is internalized to the lysosome, releasing MMAE (monomethyl auristatin E), which disrupts microtubules → G2/M arrest and apoptosis. Pivotal phase 2 in HL relapsed after ASCT (n=102): ORR 75%, CR 34%; median PFS 9.3 months; 5-year PFS 22% overall, 52% in CR patients (Younes JCO 2012; Chen Blood 2016).
• AETHERA (BV consolidation after ASCT, before relapse): high-risk R/R HL (n=329; primary refractory, relapse within 1 year, or extranodal disease at relapse). BV x 16 vs placebo starting day +30 to 45: 5-year PFS 59% vs 41% (HR 0.521); no OS benefit (Moskowitz Blood 2018).
• PD-1 blockade in late R/R HL (rationale: 9p24.1 amplification, JAK2, EBV LMP1, macrophage PD-L1):
  • Nivolumab (CheckMate 205, n=243, all post-ASCT; BV exposure varied by cohort: A BV-naive, B BV after ASCT, C BV before and/or after ASCT): ORR 69%, CR 16%, median DOR 16.6 months.
  • Pembrolizumab (KEYNOTE-087, n=210): ORR 69%, CR 22%, median DOR 16.5 months. Highly effective but high relapse rate.
  • KEYNOTE-204 (pembrolizumab vs BV in R/R HL): 12-month PFS 53.9% vs 35.6% (median PFS 13.2 vs 8.3 months), favoring pembrolizumab (using PD-1 ahead of BV may be preferable).
• Brentuximab + nivolumab: active combination in the relapsed/salvage setting.
• Allo-HSCT: considered for chemorefractory disease or post-PD-1 progression in young, fit patients; PD-1 can bridge to allo-HSCT; complete response before allo confers the best outcomes.

NLPHL / NLPBL Treatment

• Stage IA: involved-site RT alone (often curative).
• Other early stage: rituximab alone (CD20+) or R-CVbP (rituximab, cyclophosphamide, vinblastine, prednisolone).
• Advanced stage: rituximab (+/- maintenance); ABVD or BEACOPP (+/- rituximab); R-CHOP, R-CVP, or other R-chemotherapy.
• Variant (THRLBCL-like) pattern: more aggressive, often treated with R-CHOP-like therapy, but it does not by itself equal transformation; correlate with full pathology and stage. Confirmed transformation to DLBCL/THRLBCL warrants aggressive B-cell therapy.

Survivorship and Late Effects

• No benefit to routine surveillance scans.
• Secondary malignancy: infertility and second cancers are far higher with BEACOPP than ABVD. Check CBC yearly for AML/MDS (≤1% risk with ABVD; alkylators drive t-MDS/AML). RT-related solid tumors: breast (mantle/mediastinal field), lung, thyroid, sarcoma.
• After RT: cardiovascular and second-cancer risk increase.
  • Breast: annual mammography after mediastinal/axillary RT; recommend annual breast MRI plus mammography if chest RT (esp. ≥10 Gy) given at age ≤30, beginning 8 years after RT or at age 25, whichever is later.
  • Thyroid: annual TSH screening for hypothyroidism (neck/mediastinal RT).
  • Cardiovascular: anthracycline cardiomyopathy; mediastinal RT causes CAD, valvular disease, pericarditis. Aggressive risk-factor modification (diabetes, hypertension, hyperlipidemia, smoking cessation); consider carotid ultrasound if neck RT and stress test/echo every ~10 years.
• Pulmonary: bleomycin causes pulmonary fibrosis; avoid hyperoxia later in life when possible.
• Endocrine/gonadal: hypothyroidism and gonadal failure; fertility preservation is crucial.

Treatment Algorithm Summary (PET-adapted)

• Early-stage favorable: ABVD x 2 → PET.
  • Deauville 1 to 2: 20 Gy RT, or ABVD x 2 more (CALGB 50604: 4 total cycles). Omitting RT (RAPID, 3 total cycles) required a negative PET after cycle 3, and RAPID did not show noninferiority of omitting RT.
  • Deauville 3: 20 Gy RT, or ABVD x 2 + RT, or drop bleomycin and AVD x 4.
• Early-stage unfavorable: ABVD x 2 → PET.
  • Deauville 1 to 3: ABVD x 2 + 30 Gy RT, or drop bleomycin and AVD x 4.
  • Deauville 4 to 5: escBEACOPP x 2 → PET; if DS 1 to 3, escBEACOPP x 2 or 30 Gy RT; if DS 4 to 5, escBEACOPP x 4 +/- RT.
• Advanced stage: preferred N-AVD x 6 (SWOG S1826; no PET adaptation). Alternative, PET-adapted ABVD: ABVD x 2 → PET.
  • Deauville 1 to 3: drop bleomycin and AVD x 4; consider RT if bulky.
  • Deauville 4 to 5: escalate to escBEACOPP (per RATHL, escBEACOPP x4 or BEACOPP-14 x6) and continue escalated; do not switch back to A(B)VD after PET2-positive ABVD.
  • Alternate: escBEACOPP x 2 → PET; if DS 1 to 3, continue escBEACOPP x 2 or transition to A(B)VD x 4.
  • Additional option: brentuximab vedotin + AVD x 6.

Key Conclusions

• ~9,000 US cases/year. cHL: CD30+ (near universal), CD15+ (~75 to 85%), PAX5 dim+, CD45-; CD20 weak/variable in a minority (does not mandate rituximab). NLPHL/NLPBL (5%): CD20+, CD19+, CD45+, CD79a+, CD15/CD30 negative.
• Near-universal 9p24.1 (PD-L1/2) alterations in cHL underpin immunotherapy sensitivity.
• PET/CT for staging and response; no routine bone marrow. Adverse factors: bulk, elevated ESR, increased involved sites.
• Frontline: early favorable ABVD x 2 + 20 Gy (GHSG-met) or ABVD x 3 to 4 +/- ISRT; early unfavorable ABVD x 4 + 30 Gy, 2+2 approach, or PET-adapted AVD; advanced A(B)VD x 6, BV+AVD, escBEACOPP, and now nivolumab + AVD.
• Novel agents: brentuximab vedotin (frontline BV-AVD, post-ASCT consolidation, post-ASCT relapse) and PD-1 blockade: pembrolizumab approved for adult R/R cHL (no 2-line minimum; the ≥2-line rule is the pediatric indication), nivolumab after auto-HSCT and BV, and now frontline with N-AVD.
• Survivorship: no routine surveillance scans; monitor for second cancers and mitigate cardiovascular risk.