Hodgkin Lymphoma

Overview
Epidemiology and Risk Factors
Pathology and Reed-Sternberg Cells
Histologic Subtypes
Clinical Presentation
Staging: Ann Arbor and PET-CT
Treatment: Chemotherapy and Targeted Therapy
Relapsed and Refractory Disease
Late Effects and Long-Term Survivorship
References & Research
Research Papers
Connections
Featured Videos

1. Overview

Hodgkin lymphoma (HL) is one of the great success stories of modern oncology — a cancer that was nearly universally fatal a century ago and is now curable in the majority of patients, even those with advanced disease. It is also one of the cancers most likely to strike young adults in the prime of life: its distinctive bimodal age distribution peaks between ages 15–35 and again after 55, making it the most common cancer in young people aged 15–30 in the United States. With overall cure rates exceeding 85–90% for early-stage disease and 70–75% for advanced disease, most people diagnosed with Hodgkin lymphoma will survive it. The challenge today is not just curing the disease but doing so with the least possible long-term toxicity — because patients who survive their lymphoma at 25 must live with the cardiovascular, pulmonary, and oncologic consequences of their treatment for the next 50 years.

The defining feature of HL is the Reed-Sternberg cell — a large, binucleated or multinucleated malignant cell that gives the disease its unique histologic appearance. These cells arise from germinal center B lymphocytes but have, in a strange twist, largely silenced their B-cell gene expression program while remaining surrounded by a dense inflammatory infiltrate of reactive T cells, eosinophils, plasma cells, and macrophages that paradoxically protect and support the malignant cells rather than destroying them. This tumor microenvironment is now understood to be central to HL biology and has become a target for new immunotherapies.

2. Epidemiology and Risk Factors

Approximately 9,000 new cases of Hodgkin lymphoma are diagnosed each year in the United States. The bimodal age distribution is one of the most distinctive features in oncology epidemiology: a large young-adult peak in the second and third decades and a smaller older-adult peak after age 55. The two peaks are not identical in biology — the older peak is more often associated with EBV positivity, immunosenescence, and mixed cellularity histology, while the young-adult peak is dominated by nodular sclerosis subtype.

Established and probable risk factors include:

Epstein-Barr virus (EBV) — the best-established environmental risk factor. EBV is detected in Reed-Sternberg cells in approximately 30–40% of cases (higher in mixed cellularity and lower in nodular sclerosis). Prior infectious mononucleosis (EBV primary infection) increases subsequent HL risk approximately 3-fold. EBV-associated HL is more common in lower-income settings and in older patients.
HIV infection — immunosuppression increases HL risk approximately 5–10-fold; HIV-associated HL is typically EBV-positive and presents with advanced-stage mixed cellularity histology.
Immunosuppression — solid organ transplant recipients and patients on long-term immunosuppressive therapy have elevated risk.
Family history — first-degree relatives of HL patients have 3–9 times higher risk; identical twins of affected individuals have very high concordance, suggesting genetic susceptibility.

3. Pathology and Reed-Sternberg Cells

The Reed-Sternberg (RS) cell is pathognomonic for classical Hodgkin lymphoma. These cells are large (15–45 micrometers), often binucleated or multinucleated, with large "owl-eye" eosinophilic nucleoli. Mononuclear variants (Hodgkin cells or "lacunar cells") are common, particularly in nodular sclerosis subtype. RS cells constitute only 0.1–10% of the tumor mass; the remainder is the reactive inflammatory infiltrate.

Immunohistochemistry is essential for diagnosis and subtype classification:

CD30 positive — expressed by virtually all RS cells in classical HL; the target of brentuximab vedotin antibody-drug conjugate.
CD15 positive — present in most classical HL cases; helpful for distinction from primary mediastinal B-cell lymphoma and anaplastic large-cell lymphoma.
CD20 negative (or dim) — in contrast to nodular lymphocyte-predominant HL (NLPHL), which is CD20-positive; CD20 status matters because NLPHL responds to rituximab.
PAX5 weakly positive — confirms B-cell lineage despite the loss of most other B-cell markers.

Classical HL originates from a germinal center B cell that has undergone crippling mutations in its immunoglobulin genes, making the cell unable to undergo normal B-cell selection and differentiation — cells that should undergo apoptosis instead survive, driven by constitutive activation of NF-κB, JAK-STAT, and PI3K signaling pathways.

4. Histologic Subtypes

The WHO classification divides Hodgkin lymphoma into classical HL (cHL) with four subtypes, and the biologically distinct nodular lymphocyte-predominant HL (NLPHL):

Nodular sclerosis (NSCHL) — 70% of all cHL. The most common subtype in high-income countries and in young adults. Characterized by broad collagen bands that divide lymphoid tissue into nodules containing RS cells ("lacunar cells" variant) in fibrous stroma. Strongly associated with mediastinal involvement. Generally favorable prognosis when treated with current regimens.
Mixed cellularity (MCCHL) — 20%. The predominant subtype in developing countries and the EBV-associated form. No sclerosis; heterogeneous infiltrate of plasma cells, eosinophils, and lymphocytes. More common in children and older adults. Often presents at a more advanced stage but is highly responsive to ABVD.
Lymphocyte-rich cHL — 5%. Abundant background lymphocytes with scattered RS cells. Best prognosis among cHL subtypes; often early-stage at presentation.
Lymphocyte-depleted cHL — <1%. RS cells predominate, background lymphocytes depleted. Associated with HIV and EBV. Advanced stage at presentation; poorest prognosis of the cHL subtypes.
Nodular lymphocyte-predominant HL (NLPHL) — 5%. A distinct entity with "popcorn cells" (LP cells or lymphocytic and histiocytic variants) that are CD20-positive, CD30-negative, CD15-negative. Indolent behavior, frequent late relapses but rarely fatal. Treatment differs from cHL; rituximab is active. Risk of transformation to DLBCL exists.

5. Clinical Presentation

The classic presentation is a young adult with painless, rubbery lymphadenopathy, most commonly in the cervical, supraclavicular, or mediastinal nodes. Mediastinal involvement (bulky disease in the anterior/superior mediastinum) is highly characteristic of nodular sclerosis HL and is the reason HL commonly presents with an anterior mediastinal mass on chest imaging. The alcohol-pain phenomenon — pain in affected lymph nodes shortly after drinking alcohol — is pathognomonic when it occurs, though present in only 10–15% of patients.

B symptoms are constitutional symptoms defined as:

Unexplained fever >38°C on multiple occasions.
Drenching night sweats requiring change of bedclothes.
Unexplained weight loss >10% of body weight in the preceding 6 months.

The presence of any B symptom changes Ann Arbor staging from "A" to "B" (e.g., Stage IIIA vs. Stage IIIB) and is associated with more advanced disease and higher-risk features. Pruritus and fatigue are common but are not formal B symptoms.

6. Staging: Ann Arbor and PET-CT

The Ann Arbor staging system (modified Cotswolds) classifies HL by the number and location of involved nodal regions and the presence of extranodal involvement:

Stage I: Single lymph node region or single extranodal site.
Stage II: Two or more lymph node regions on the same side of the diaphragm.
Stage III: Lymph node regions on both sides of the diaphragm.
Stage IV: Diffuse extranodal involvement (bone marrow, liver, lung parenchyma, etc.).

Each stage is modified by A (no B symptoms) or B (B symptoms present), and by X (bulky disease — typically a mediastinal mass >1/3 of the maximum intrathoracic diameter or a single node mass >10 cm).

PET-CT (FDG-PET combined with CT) has transformed HL staging and response assessment. PET-CT is significantly more sensitive than CT alone for nodal and extranodal disease, upstages approximately 15–20% of patients compared with CT staging, and is now mandatory for all HL staging. The Deauville criteria (5-point scale comparing lesion FDG uptake to mediastinal blood pool and liver) provide a standardized PET response assessment used for interim and end-of-treatment evaluation. An interim PET after 2 cycles of ABVD (after cycles 1–2) has become the cornerstone of response-adapted therapy approaches.

7. Treatment: Chemotherapy and Targeted Therapy

Early-stage favorable HL

For early-stage (I–IIA) favorable HL without bulky disease, the standard is combined modality therapy: 2–4 cycles of ABVD chemotherapy followed by involved-site radiation therapy (ISRT) at 20–30 Gy. Chemotherapy-alone approaches (omitting radiation) are preferred in some centers to reduce late effects, particularly for young women (breast cancer risk from chest irradiation) and those with mediastinal involvement (cardiac and pulmonary toxicity). PET-adapted strategies allow radiation to be omitted safely in PET-negative patients after 2 cycles of ABVD in some guidelines.

Advanced-stage HL (IIB with bulky disease, III–IV)

ABVD (Adriamycin/doxorubicin, Bleomycin, Vinblastine, Dacarbazine) has been the standard backbone for advanced HL for over three decades. It achieves complete remission in approximately 75% of advanced-stage patients with overall 5-year progression-free survival of 70–75%.

The ECHELON-1 trial (PMID 29641226) established BV-AVD (brentuximab vedotin replacing bleomycin in ABVD) as a new standard of care for stage III–IV HL. Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that delivers the microtubule toxin MMAE selectively to CD30-positive RS cells. BV-AVD demonstrated a significant improvement in modified progression-free survival compared with ABVD (hazard ratio 0.77) and, critically, eliminated bleomycin-related pulmonary toxicity — a major source of treatment morbidity and mortality. BV-AVD is now preferred over ABVD for stage III–IV HL by NCCN guidelines.

Response-adapted therapy with interim PET allows intensification or de-escalation based on mid-treatment response. In the UK RATHL trial (PMID 26257744), patients who were PET-negative after 2 cycles of ABVD were safely de-escalated by omitting bleomycin for the remainder of treatment (reducing pulmonary toxicity) without compromising outcomes. Conversely, PET-positive patients can be escalated to BEACOPP.

Escalated BEACOPP (Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin/vincristine, Procarbazine, Prednisone) achieves higher complete remission rates and better PFS than ABVD in head-to-head trials, but at the cost of substantially higher acute toxicity (febrile neutropenia, treatment-related mortality) and late effects (secondary myeloid malignancies, infertility). Its use is generally reserved for high-risk advanced disease or as escalation in interim PET-positive patients; it is more widely used in Europe than North America.

8. Relapsed and Refractory Disease

Approximately 15–30% of patients with advanced-stage HL will relapse or have refractory disease after first-line chemotherapy. Salvage therapy followed by high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) remains the standard curative approach for fit patients with chemosensitive relapse:

Salvage chemotherapy (ICE, DHAP, IGEV, GDP) is given for 2–3 cycles to assess chemosensitivity and mobilize stem cells.
PET-negative status after salvage predicts far better outcomes with ASCT than PET-positive disease.
Brentuximab vedotin maintenance post-ASCT significantly improves progression-free survival in high-risk patients (AETHERA trial, PMID 25796459).

For relapsed/refractory disease after ASCT, PD-1 checkpoint inhibitors have transformed the treatment landscape. Both nivolumab (PMID 27248927) and pembrolizumab achieve overall response rates of 65–87% in heavily pretreated R/R HL. HL uniquely over-expresses PD-L1 on RS cells due to 9p24.1 amplification encoding the PD-L1/PD-L2 genes — making it one of the most PD-1-responsive tumors in oncology. Both agents are approved for this indication. Long-term remissions are seen in some patients, and PD-1 blockade is increasingly being explored in earlier lines.

Allogeneic stem cell transplant (alloSCT) can provide graft-versus-lymphoma benefit and long-term remission in carefully selected patients who have failed ASCT, at the cost of significant transplant-related morbidity and mortality.

9. Late Effects and Long-Term Survivorship

The extraordinary curability of HL, particularly in young adults, means that millions of long-term survivors now live with the cumulative toxicity of treatments received decades earlier. Late effects are one of the most important and underappreciated aspects of HL management — in long-term follow-up, late effects-related mortality actually exceeds lymphoma-related mortality after the first decade.

Second primary malignancies are the most feared late effect. Radiation-field cancers — most importantly breast cancer (in women who received mantle-field chest radiation before age 30), lung cancer (especially in smokers who received chest radiation), and mesothelioma — carry 2–8 times the general population risk. Alkylating agent and topoisomerase inhibitor exposure (BEACOPP) increases therapy-related myeloid neoplasm (t-MDS/t-AML) risk.
Cardiovascular disease is the leading non-malignant cause of excess mortality. Mediastinal radiation causes accelerated coronary artery disease, valvular disease (particularly aortic and mitral stenosis from radiation fibrosis), constrictive pericarditis, and carotid artery disease. Anthracycline-related cardiomyopathy adds additional cardiac risk. Cardiac surveillance with echocardiography beginning 10 years after treatment (or at age 40) is recommended.
Pulmonary toxicity from bleomycin (pneumonitis, pulmonary fibrosis) is an important acute complication of ABVD; radiation-induced pneumonitis and fibrosis add long-term risk.
Endocrine effects: hypothyroidism after neck irradiation (30–50% at 20 years); gonadal dysfunction and infertility from alkylating agents (BEACOPP carries high infertility risk); premature menopause in women.

Modern treatment design actively seeks to reduce late effects: smaller radiation fields (ISRT vs. mantle fields), lower radiation doses, PET-adapted approaches to omit radiation in responding patients, and BV-AVD replacing bleomycin all reflect this shift.

10. References & Research

Key Research Papers

Connors et al., 2018 (ECHELON-1) — PMID: 29641226 — BV-AVD vs. ABVD for stage III–IV HL: BV-AVD improved modified PFS and eliminated bleomycin pulmonary toxicity.
Johnson et al., 2016 (RATHL) — PMID: 26257744 — PET-adapted de-escalation (omitting bleomycin) after interim PET negativity; non-inferior outcomes with less pulmonary toxicity.
Ansell et al., 2015 — PMID: 27248927 — Nivolumab for relapsed/refractory HL: 87% overall response rate; PD-L1 overexpression via 9p24.1 amplification.
Moskowitz et al., 2015 (AETHERA) — PMID: 25796459 — Brentuximab vedotin maintenance post-ASCT: significantly improved PFS in high-risk HL.
Engert et al., 2012 — PMID: 22805950 — BEACOPP vs. ABVD for advanced HL: higher CR and PFS with BEACOPP, more toxicity; long-term outcomes meta-analysis.
Gallamini et al., 2007 — PMID: 19553647 — Interim PET after 2 cycles of ABVD as a predictor of treatment failure in advanced HL; Deauville criteria development.
Ansell et al., 2022 (CHECKMATE-205) — PMID: 32243120 — Long-term follow-up of nivolumab in R/R HL post-ASCT; durable remissions in a subset.
Borchmann et al., 2017 — PMID: 25168702 — GHSG HD18 trial: PET-adapted reduction of BEACOPP in advanced HL; non-inferior with reduced toxicity.
Hutchings et al., 2009 — PMID: 18252221 — PET-CT staging in HL: upstages 15–20% of patients and improves response assessment vs. CT alone.
van Leeuwen & Ng, 2016 — PMID: 27993830 — Late effects in HL survivors: cardiovascular disease, second malignancies, and emerging data on survivorship surveillance.
Younes et al., 2016 (KEYNOTE-087) — PMID: 29641225 — Pembrolizumab for R/R HL: 69% ORR, manageable safety; Phase II data supporting FDA approval.
Swerdlow et al., 2016 — PMID: 22493412 — WHO classification of HL subtypes; updated criteria for RS cell immunophenotyping and NLPHL distinction.

Research Papers

The links below run live searches on PubMed, the U.S. National Library of Medicine's database of biomedical literature.

Connections

Non-Hodgkin Lymphoma — the larger, more heterogeneous family of lymphomas; shares many staging, imaging, and treatment concepts with HL.
Leukemia — related hematologic malignancy; lymphocyte biology and bone marrow involvement bridge the two disease families.
Oncology — full cancer index on this site.
Autoimmune Disease — the inflammatory tumor microenvironment of HL mimics autoimmune tissue reactions; PD-1 inhibitors used in HL also drive autoimmune toxicity.
Mononucleosis — EBV primary infection (infectious mono) is a risk factor for subsequent Hodgkin lymphoma development.
Hematology — full list of blood and bone marrow conditions on this site.
Complete Blood Count — CBC with differential is part of HL staging workup; lymphopenia and eosinophilia are associated prognostic features.
All Conditions — complete disease index.

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