Hematology · PANCE / PANRE

Hodgkin Lymphoma

B-cell lymphoma defined by Reed-Sternberg cells in a reactive inflammatory background — highly curable with combined modality therapy.

Also known as: Hodgkin lymphoma, Hodgkin disease, HL, classical Hodgkin lymphoma, nodular lymphocyte predominant Hodgkin

Overview

B-cell-derived lymphoid neoplasm characterized by malignant Reed-Sternberg cells (multinucleated, owl-eye appearance) and Hodgkin/lacunar cell variants embedded in a reactive infiltrate of lymphocytes, eosinophils, plasma cells, and macrophages. Two main categories: classical Hodgkin lymphoma (95%; subtypes nodular sclerosing, mixed cellularity, lymphocyte-rich, lymphocyte-depleted) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL, 5%).

Epidemiology

Bimodal age distribution: peaks at ages 15-35 and >55 years. Annual US incidence ~2.5 per 100,000. Nodular sclerosing subtype most common in young adults; mixed cellularity more common in older adults and HIV-associated. Slight male predominance overall.

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Risk factors

EBV infection — strongly associated with mixed cellularity and lymphocyte-depleted subtypes; ~40-50% of classical HL has EBV in tumor cells
HIV infection — increased risk despite reduced T-cell immunity (paradoxically); EBV-driven
Immunosuppression: post-transplant, autoimmune disease on immunosuppressants
Family history (slight increase in first-degree relatives)
Western/affluent socioeconomic background associated with young adult presentations

Pathophysiology

Reed-Sternberg cells arise from germinal center B cells that have escaped apoptosis. They constitute only ~1% of the tumor mass but drive recruitment of a reactive inflammatory infiltrate via cytokine production (IL-5, IL-10, IL-13, TGF-beta, CCL17/TARC). NF-κB and JAK-STAT signaling are constitutively active. Disease typically spreads contiguously from one lymph node region to adjacent regions (distinct from the often non-contiguous spread of non-Hodgkin lymphoma).

Clinical presentation

Symptoms

Painless cervical or supraclavicular lymphadenopathy (most common presentation)
Mediastinal mass — dyspnea, cough, chest discomfort, SVC syndrome (typical of nodular sclerosing in young adults)
B SYMPTOMS (defined): fever >38°C, drenching night sweats, unintentional weight loss >10% in 6 months
Pel-Ebstein fever — cyclical, classical (rare in practice)
Pruritus (paraneoplastic), alcohol-induced pain at involved nodes (rare but classic)
Fatigue, malaise

Signs / physical exam

Lymphadenopathy: cervical, supraclavicular, axillary; non-tender, rubbery, fixed in advanced disease
Mediastinal mass on physical exam (rare findings: tracheal deviation, SVC syndrome — facial plethora, neck/upper extremity edema)
Hepatosplenomegaly in advanced stages
Fever, cachexia

Classic findings

Young adult (15-35) with painless cervical lymphadenopathy, mediastinal mass on CXR, and nodular sclerosing histology with Reed-Sternberg cells.

Differential diagnosis

Non-Hodgkin lymphoma — No Reed-Sternberg cells; immunophenotype CD20+ CD45+ (HL is CD30+ CD15+ CD20-/+ CD45-)
Infectious mononucleosis (EBV) — Acute lymphadenopathy with atypical lymphocytes; positive Monospot/EBV VCA IgM; self-limited
Tuberculosis — Mediastinal/hilar lymphadenopathy with granulomatous inflammation; positive PPD/IGRA; AFB stain/culture
Sarcoidosis — Bilateral hilar lymphadenopathy, non-caseating granulomas, elevated ACE; young Black adults
Cat-scratch disease — Localized tender lymphadenopathy after cat exposure; Bartonella henselae serology
Metastatic carcinoma — Hard, fixed nodes; primary site identifiable
HIV-related lymphadenopathy — Generalized adenopathy; serologic workup

Diagnostic workup

Diagnostic criteria

Histologic identification of Reed-Sternberg cells (or lymphocyte-predominant variants in NLPHL) with characteristic immunophenotype on excisional biopsy.

Labs

Excisional lymph node biopsy is essential for diagnosis (fine-needle aspiration is INSUFFICIENT — Reed-Sternberg cells need architectural context)
Immunohistochemistry: classical HL — CD30+, CD15+, CD20 weak/negative, CD45 negative, PAX5 weak; NLPHL — CD20+, CD45+, CD30 negative, CD15 negative
EBV testing on tumor (EBER ISH)
CBC, CMP, LDH, ESR (incorporated in IPS score), albumin
HIV, hepatitis B/C testing
Beta-HCG in women of reproductive age
Cardiac echocardiogram and pulmonary function tests before anthracyclines and chest radiotherapy
Fertility counseling and gamete preservation discussion before chemotherapy

Imaging

PET/CT — gold standard for staging and response assessment (Deauville 5-point score)
CT chest/abdomen/pelvis if PET unavailable
Bone marrow biopsy NO LONGER routinely required if PET is performed (PET detects marrow involvement)
Ann Arbor staging with Cotswolds modification: I (single nodal region), II (≥2 regions same side of diaphragm), III (both sides of diaphragm), IV (disseminated extranodal involvement); A = no B symptoms, B = B symptoms present; X = bulky disease (mediastinal mass >1/3 thoracic diameter or any mass >10 cm)

Diagnostic algorithm

Ann Arbor Stage	Definition	Approach
I	Single lymph node region or single extranodal site (IE)	ABVD × 2-4 + ISRT
II	≥2 lymph node regions same side of diaphragm	ABVD × 4 + ISRT (favorable) or × 6 (unfavorable)
III	Lymph node regions on both sides of diaphragm	ABVD or A+AVD × 6 (no radiation if PET negative)
IV	Disseminated extranodal involvement (liver, marrow, lung)	ABVD or A+AVD × 6
Modifiers	A: no B symptoms / B: fever, sweats, weight loss / X: bulky (>10 cm or mediastinum >1/3)	B symptoms and bulk worsen prognosis

Ann Arbor staging with Cotswolds modifications guides treatment intensity in Hodgkin lymphoma.

Treatment

First-line

Early-stage (I-II) favorable: 2-4 cycles ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) + involved-site radiation (ISRT); response-adapted approach using interim PET to minimize toxicity
Early-stage unfavorable: 4-6 cycles ABVD + ISRT
Advanced-stage (III-IV): 6 cycles ABVD or escalated BEACOPP (more intensive, more toxic); brentuximab vedotin (anti-CD30 ADC) + AVD (without bleomycin) — improved progression-free survival in advanced-stage (ECHELON-1)
PET-adapted therapy: interim PET after 2 cycles directs intensification or de-escalation
Highly curable: ~85-90% long-term survival in early stage, 70-80% in advanced stage
NLPHL: rituximab (CD20+) ± involved-site radiation; observation possible for stage I/II low-volume disease after complete excision

Second-line / adjunct

Relapsed/refractory: salvage chemotherapy (ICE — ifosfamide, carboplatin, etoposide; or DHAP) followed by high-dose chemo + autologous HSCT for chemosensitive disease
Brentuximab vedotin (anti-CD30 antibody-drug conjugate) — single-agent or maintenance post-transplant (AETHERA trial)
Checkpoint inhibitors: nivolumab, pembrolizumab — highly active in relapsed/refractory HL (high tumor PD-L1 expression from 9p24.1 amplification)
Allogeneic HSCT for selected relapsed disease after autologous failure
Targeted therapies: pembrolizumab + GVD (gemcitabine, vinorelbine, doxorubicin) as bridge to HSCT
Pregnancy management: ABVD generally safe in 2nd/3rd trimesters; delay therapy if early stage and not progressing in 1st trimester

Complications

Treatment-related: anthracycline cardiotoxicity (cumulative), bleomycin pulmonary fibrosis (risk with G-CSF), infertility (especially BEACOPP, alkylators)
Secondary malignancies: solid tumors (breast in young women after chest radiation, lung, thyroid) and secondary AML/MDS (especially with alkylator-containing regimens); risk persists decades
Cardiovascular disease from mediastinal radiation: premature CAD, valvular disease, restrictive pericarditis
Hypothyroidism from neck radiation
Pulmonary fibrosis from bleomycin
Endocrine dysfunction, premature menopause
Psychosocial: survivorship, fertility, body image
Long-term breast cancer screening starting 8-10 years after chest radiation in women treated <30 years old

PANCE pearls

Reed-Sternberg cells (large, binucleated, owl-eye nucleoli) are the defining feature; positive CD30 and CD15, negative CD20 and CD45 in classical HL.
Hodgkin lymphoma classically spreads CONTIGUOUSLY to adjacent nodal regions — contrasts with the often non-contiguous spread of non-Hodgkin lymphoma.
Mediastinal mass in a young adult woman → nodular sclerosing Hodgkin lymphoma is high on the differential.
Alcohol-induced pain at nodal sites is a classic but rare and unreliable finding.
ABVD remains standard first-line; brentuximab vedotin + AVD (A+AVD) improves outcomes in advanced disease but adds peripheral neuropathy.
Hodgkin lymphoma is one of the most curable malignancies — focus has shifted from cure to MINIMIZING LATE TOXICITY (secondary cancers, cardiovascular disease, infertility).
Mediastinal radiation in young women increases breast cancer risk dramatically; annual mammogram + MRI starting 8-10 years after radiation, or age 25, whichever later.
Checkpoint inhibitors are exceptionally active in HL because tumor cells overexpress PD-L1 due to 9p24.1 chromosomal amplification.
B symptoms (fever, drenching sweats, weight loss >10%) carry prognostic weight and are part of staging (A vs B suffix).

References

NCCN 2024 — NCCN Clinical Practice Guidelines in Oncology: Hodgkin Lymphoma (NCCN.org)
ECHELON-1 — Brentuximab Vedotin with Chemotherapy for Stage III/IV Hodgkin's Lymphoma (Connors et al., NEJM 2018)
RATHL — Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma (Johnson et al., NEJM 2016)
KEYNOTE-204 — Pembrolizumab versus brentuximab vedotin in relapsed/refractory Hodgkin lymphoma (Kuruvilla et al., Lancet Oncol 2021)
AETHERA — Brentuximab vedotin as consolidation therapy after autologous HSCT (Moskowitz et al., Lancet 2015)

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