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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Question 1HematologyEasy
A 68-year-old man has progressive cervical, axillary, and inguinal lymphadenopathy with fever, drenching night sweats, and a 15-lb weight loss over 3 months. Lymph node biopsy shows Reed-Sternberg cells (binucleated cells with owl-eye nucleoli). Which of the following is the most likely diagnosis?
AChronic lymphocytic leukemia
BHodgkin lymphoma
CSarcoidosis
DNon-Hodgkin lymphoma
Reveal answer & full explanation
Correct answer: B — Hodgkin lymphoma
AChronic lymphocytic leukemia
BHodgkin lymphoma✓
CSarcoidosis
DNon-Hodgkin lymphoma
Why Hodgkin lymphoma is correct
Reed-Sternberg cells (binucleated cells with owl-eye nucleoli) are pathognomonic for classic Hodgkin lymphoma.
The contiguous painless lymphadenopathy plus B symptoms (fever, drenching night sweats, weight loss >10% of body weight) is the classic constitutional presentation.
Hodgkin lymphoma has a bimodal age distribution, with a second peak in older adults such as this man.
Early-stage disease is highly curable with ABVD chemotherapy with or without radiotherapy (5-year survival >85%).
Why the others are wrong
Chronic lymphocytic leukemia — CLL causes painless lymphadenopathy in older adults but is defined by an absolute peripheral lymphocytosis with smudge cells, not Reed-Sternberg cells; buzzword-matching age and adenopathy while ignoring the biopsy.
Sarcoidosis — Sarcoidosis produces non-caseating granulomas and bilateral hilar adenopathy, not Reed-Sternberg cells; premature closure on a granulomatous mimic.
Non-Hodgkin lymphoma — NHL can cause identical B symptoms and adenopathy, but Reed-Sternberg cells specifically distinguish Hodgkin from non-Hodgkin lymphoma; the classic confused-with trap.
Question 2HematologyMedium
A 30-year-old male with no significant history presents with 3 weeks of fever, night sweats, and 12-lb weight loss. Complete blood count (CBC) shows WBC 11K (normal differential), Hgb 9.8 (normocytic), and platelets 180K. Erythrocyte sedimentation rate (ESR) is 112. LDH is elevated. CT shows mediastinal and bilateral hilar lymphadenopathy. Excisional biopsy of a mediastinal node shows scattered large binucleated cells with prominent eosinophilic nucleoli in a mixed inflammatory background. Which of the following is the most likely diagnosis?
ANon-Hodgkin lymphoma
BSarcoidosis
CTuberculous lymphadenitis
DClassical Hodgkin lymphoma
Reveal answer & full explanation
Correct answer: D — Classical Hodgkin lymphoma
ANon-Hodgkin lymphoma
BSarcoidosis
CTuberculous lymphadenitis
DClassical Hodgkin lymphoma✓
Why Classical Hodgkin lymphoma is correct
Classical Hodgkin lymphoma (cHL) is the most common lymphoma in young adults (bimodal peak: 15-35 and above 55)
The large binucleated cells with prominent eosinophilic (owl-eye) nucleoli on the node biopsy are Reed-Sternberg cells: large CD30+/CD15+ B-cells in an inflammatory background (lymphocytes, eosinophils, plasma cells, neutrophils) — pathognomonic for cHL
B symptoms (fever, night sweats, weight loss), elevated LDH/ESR, and mediastinal/hilar adenopathy round out the classic presentation
Why the others are wrong
Non-Hodgkin lymphoma — lacks Reed-Sternberg cells; shows a clonal lymphoid population on biopsy rather than the mixed inflammatory background (confused-with lymphoma category)
Sarcoidosis — produces bilateral hilar adenopathy but shows non-caseating granulomas, not Reed-Sternberg cells (anchoring on hilar nodes)
Tuberculous lymphadenitis — fever, night sweats, weight loss, high ESR, and mediastinal/hilar adenopathy mimic this presentation, but biopsy would show caseating granulomas with acid-fast bacilli, not large binucleated cells in a mixed inflammatory background (anchoring on constitutional symptoms)
Treatment: (1) Early favorable (Stage I-IIA): doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) x2 cycles plus involved-site radiation; (2) Early unfavorable: ABVD x4 cycles plus radiation; (3) Advanced stage (III-IV): brentuximab vedotin-doxorubicin-vinblastine-dacarbazine (BV-AVD) (brentuximab vedotin replacing bleomycin to reduce pulmonary toxicity) or escalated bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisone (BEACOPP) (young fit patients)
PET-adapted therapy: interim PET-negative patients can de-escalate
Cure rate: overall 85-90%
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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-)
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)
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)
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
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
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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