Hodgkin Lymphoma
A rare malignant cell hiding in a crowd of reactive cells
Reed-Sternberg Cells and Pathogenesis
The malignant cell. Hodgkin lymphoma (HL) is defined by Reed-Sternberg (RS) cells: large cells with two nuclei or a bilobed nucleus, each lobe holding a prominent eosinophilic nucleolus, giving an "owl-eye" appearance. RS cells come from germinal-center B cells but have lost most of their B-cell program. They often carry crippling immunoglobulin gene mutations that would normally trigger apoptosis, and constitutive NF-κB signaling keeps them alive. They make up only a small minority of the tumor (often about 1%); the rest is a reactive infiltrate of T cells, eosinophils, plasma cells, and histiocytes.
Immunophenotype. Classic RS cells are CD30+ (a TNF receptor family member) and CD15+, weakly PAX5+, and usually CD20− and CD45−. They secrete cytokines that build their own niche: IL-5 recruits eosinophils, TGF-β stimulates fibrosis, and other chemokines attract T cells. RS cells often overexpress PD-L1 through amplification of chromosome 9p24.1, which helps them evade T cells.
EBV. EBV is present in RS cells in roughly 40% of classic HL in Western countries, most often in mixed cellularity, lymphocyte-depleted, and HIV-associated cases. Its latent membrane protein 1 (LMP1) behaves like a permanently active CD40 receptor, switching on NF-κB and rescuing crippled B cells from apoptosis.
Clinical Presentation
Who and where. Incidence is bimodal, peaking at about 15–35 years and again after 55. Patients present with painless, rubbery cervical or supraclavicular lymph nodes, often with an anterior mediastinal mass found on chest imaging. HL spreads contiguously from one node group to the next, so it is often localized at diagnosis, and extranodal disease is uncommon.
Symptoms. B symptoms (fever above 38 °C, drenching night sweats, and loss of more than 10% of body weight in 6 months) indicate more advanced disease and worse prognosis. Generalized pruritus is common, and pain in involved nodes after drinking alcohol is rare but characteristic. Pel-Ebstein fever cycles through days of fever and afebrile intervals. Eosinophilia reflects IL-5 secretion.
| Feature | Hodgkin lymphoma | Non-Hodgkin lymphoma |
|---|---|---|
| Malignant cells | Few RS cells in a reactive background | Sheets of malignant lymphocytes |
| Nodal pattern | Single axial group (cervical, mediastinal) | Multiple peripheral nodes |
| Spread | Contiguous, predictable | Noncontiguous, skips node groups |
| Extranodal disease | Rare | Common (GI tract, skin, CNS, marrow) |
| Age | Bimodal (young adults and >55) | Mostly older adults; varies by subtype |
Histologic Subtypes
Classic HL. Four subtypes share CD15+/CD30+ RS cells. As a rule, the more reactive lymphocytes, the better the outlook, and the more RS cells, the worse.
| Subtype | Frequency | Patients | Histology and clues |
|---|---|---|---|
| Nodular sclerosis | ~70% | Adolescents, young adults; the only subtype not favoring males | Collagen bands, lacunar cells, mediastinal mass; EBV+ in a minority |
| Mixed cellularity | ~20–25% | Older adults, men, HIV | Many RS cells among eosinophils and plasma cells; often EBV+ and advanced |
| Lymphocyte-rich | ~5% | Older men | Few RS cells in abundant small lymphocytes; best prognosis of classic HL |
| Lymphocyte-depleted | <1% | Elderly, HIV | Sheets of RS cells, few lymphocytes, EBV+, marrow involvement; worst prognosis |
| Nodular lymphocyte-predominant | ~5% of HL | Mostly men | Popcorn cells: CD20+, CD45+, BCL6+, CD15−, CD30−, EBV− |
Lacunar cells. In nodular sclerosis, RS variants have cytoplasm that retracts during formalin fixation, leaving each cell in a clear space. The collagen bands that divide the node into nodules reflect TGF-β secretion.
Nodular lymphocyte-predominant HL (NLPHL). This separate entity has lymphocyte-predominant (popcorn) cells with multilobed nuclei that keep their B-cell identity. It usually involves isolated peripheral nodes (cervical, axillary, or inguinal) rather than the mediastinum, follows an indolent course, can transform to diffuse large B-cell lymphoma, and responds to the anti-CD20 antibody rituximab.
Treatment and Late Effects
Chemotherapy. ABVD, with or without involved-site radiation, cures most patients. Its components and signature toxicities are Adriamycin (doxorubicin; dilated cardiomyopathy), Bleomycin (pulmonary fibrosis), Vinblastine (myelosuppression), and Dacarbazine. Bleomycin injures lung and skin because these tissues lack bleomycin hydrolase; risk rises with cumulative dose, older age, renal impairment, and high inspired oxygen.
Targeted therapy. Brentuximab vedotin, an anti-CD30 antibody linked to the microtubule toxin MMAE, can replace bleomycin in advanced disease; peripheral neuropathy is its main toxicity. PD-1 inhibitors (nivolumab, pembrolizumab) work well because RS cells overexpress PD-L1.
Late effects. Survivors carry lifelong risks from therapy:
- Secondary breast cancer after mediastinal radiation, especially in women irradiated before age 30, warranting early screening
- Lung cancer, particularly in smokers
- Coronary artery disease, valve disease, and constrictive pericarditis from radiation, plus anthracycline cardiomyopathy
- Hypothyroidism from neck radiation
- Therapy-related AML/MDS and infertility from alkylating agents and radiation
Early toxicities appear within months (bleomycin lung injury, radiation pneumonitis, anthracycline cardiotoxicity); hypothyroidism and secondary leukemia appear over years; solid tumors and cardiovascular disease emerge over decades.