Hodgkin Lymphoma

• Reed-Sternberg Cell Transformation and Immune Evasion: Reed-Sternberg cells arise from B cells that have undergone somatic hypermutation in the germinal center but paradoxically escape apoptosis despite acquiring non-functional immunoglobulin genes—a process that would normally trigger death in healthy B cells. These cells employ multiple immune evasion strategies: they downregulate major histocompatibility complex (MHC) class I and class II expression through selective loss of β2-microglobulin and transactivator of transcription (TAP), thereby evading cytotoxic T lymphocyte recognition; they constitutively activate the NF-κB pathway through mutations in NFKBIA (inhibitor of κB alpha) and A20, driving proliferation and survival; and they upregulate expression of immunosuppressive molecules including programmed death ligand 1 (PD-L1) and PD-L2 that engage PD-1 on infiltrating T cells, creating an immunosuppressive tumor microenvironment. Approximately 90% of classical Hodgkin lymphoma cases show PD-L1/PD-L2 amplification due to 9p24.1 chromosome gains, explaining the remarkable efficacy of checkpoint inhibitors in this disease.

• Epstein-Barr Virus Integration and Viral Oncogenesis: Epstein-Barr virus (EBV) integrates into the genome of Reed-Sternberg cells in approximately 40% of classical Hodgkin lymphoma cases and up to 100% of nodular lymphocyte-predominant Hodgkin lymphoma in certain populations. EBV latent membrane proteins (LMP-1 and LMP-2) constitutively activate both the NF-κB and Wnt/β-catenin pathways, promoting survival of otherwise apoptosis-prone cells; LMP-1 mimics CD40 signaling, providing crucial survival signals. Additionally, EBV-encoded BHRF1 inhibits pro-apoptotic proteins Bax and Bak, and EBNA-3A/3C inactivate tumor suppressor p53. In immunocompromised patients (HIV/AIDS with CD4 <50 cells/μL, solid organ transplant recipients), EBV-associated Hodgkin lymphoma occurs with markedly increased frequency, demonstrating the critical role of intact T cell immunity in preventing EBV-driven lymphomagenesis.

• Chronic Inflammatory Microenvironment and Th2 Polarization: Unlike most lymphomas where neoplastic cells comprise the bulk of the tumor mass, classical Hodgkin lymphoma is characterized by a sparse population of malignant cells (typically <1-10% of the cellular infiltrate) surrounded by abundant non-neoplastic inflammatory cells including T lymphocytes, macrophages, eosinophils, and mast cells. Reed-Sternberg cells secrete thymus-derived factor (TDF), thymus and activation-regulated chemokine (TARC), and macrophage inflammatory protein-1β (MIP-1β), recruiting predominantly CD4+ helper T cells and polarizing them toward Th2 differentiation through secretion of interleukin-10 (IL-10) and thyroid-stimulating hormone (TSH). This creates a microenvironment that actively suppresses anti-tumor immunity: infiltrating T cells are dysfunctional with reduced interferon-gamma production, and macrophages differentiate into alternatively-activated M2 phenotype that promotes tumor growth rather than immunity. The inflammatory milieu itself drives constitutional symptoms through IL-6 and TNF-α secretion, explaining the pathophysiology of fever, night sweats, and weight loss.

• Chromosomal Instability and Recurrent Genetic Alterations: Classical Hodgkin lymphoma typically exhibits complex karyotypes with gains and losses affecting multiple chromosomes, though translocations are relatively uncommon unlike other lymphomas. The most frequent genetic alterations include 9p24.1 gains (PD-L1/PD-L2 amplification, ~90%), 2p16 gains (REL amplification, ~30%), chromosome 12 gains (MDM2 amplification), and 17p deletions (TP53 loss, variable frequency). These alterations collectively drive constitutive NF-κB activation, impair p53-mediated apoptosis, and promote immune evasion. Additionally, mutations in JAK2 occur in approximately 20% of cases, leading to STAT3 phosphorylation and IL-6 signaling that promotes both survival and Th2 polarization. PTEN loss and PIK3CA mutations activate PI3K/AKT signaling, contributing to metabolic reprogramming and survival signals.

• Defective Apoptotic Pathways and Survival Signals: Reed-Sternberg cells should undergo apoptosis due to their non-functional B cell receptors and defective class switch recombination, yet they survive through convergent mechanisms. Besides PD-L1/PD-L2-mediated immune evasion, these cells employ direct anti-apoptotic strategies: they express high levels of anti-apoptotic BCL-2 family members (BCL-2, MCL-1, BCL-XL), express death receptor ligands including Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) that paradoxically promote survival through reverse signaling, and constitutively activate MAPK and PI3K/AKT pathways. Notably, Reed-Sternberg cells express CD30 and CD15 but typically lack CD45 and CD20—this immunophenotype drives their identification on flow cytometry and represents target molecules for novel therapeutics like brentuximab vedotin (anti-CD30 monoclonal antibody conjugated to microtubule-disrupting agent monomethyl auristatin E).

• Epstein-Barr Virus Infection: EBV is the most established etiologic agent, with seropositive status conferring approximately 2-4 fold increased risk and EBV integration found in 40% of classical Hodgkin lymphoma and up to 100% of certain subtypes. EBV-associated disease characteristically presents in very young children (<5 years) and in immunosuppressed populations (HIV/AIDS with CD4 <50 cells/μL where incidence increases 300-fold, post-solid organ transplant recipients, individuals with X-linked lymphoproliferative syndrome). The risk is particularly elevated in developing nations and regions with high EBV exposure, suggesting that chronic antigenic stimulation or delayed primary infection (versus early childhood infection in developed countries) may increase malignant transformation risk.

• Immunosuppression and Immune Deficiency: Patients with severe immunosuppression demonstrate markedly elevated Hodgkin lymphoma risk, particularly in the context of HIV infection with CD4 counts <50 cells/μL (100-300 fold increased incidence), organ transplantation requiring long-term immunosuppressive therapy, and primary immunodeficiency syndromes including Wiskott-Aldrich syndrome, ataxia-telangiectasia, and X-linked lymphoproliferative syndrome. These conditions predispose to EBV-driven lymphomagenesis and often present with EBV-associated disease. Notably, restoration of immune function through antiretroviral therapy (ART) in HIV-positive patients significantly reduces Hodgkin lymphoma incidence, though risk remains somewhat elevated compared to immunocompetent populations.

• Genetic Predisposition and Familial Clustering: Approximately 5-10% of Hodgkin lymphoma cases occur in familial clusters, suggesting inherited genetic predisposition. Twin studies demonstrate significantly higher concordance in monozygotic versus dizygotic twins, implicating genetic factors. Associations include HLA-A1 and HLA-B5 alleles, though these explain only modest proportions of heritability. Patients with a first-degree relative with Hodgkin lymphoma have 3-4 fold increased risk. Shared environmental exposures and EBV infection patterns within families may contribute to apparent familial clustering, and genetic association studies have identified susceptibility loci in immune regulation genes.

• Prior Lymphoid Malignancy or Atypical Lymphoid Proliferations: Patients with prior non-Hodgkin lymphoma demonstrate elevated Hodgkin lymphoma risk, as do patients with nodular lymphoid hyperplasia. These associations suggest underlying immune dysregulation predisposing to lymphoid neoplasia, though whether they represent true etiologic relationships or shared risk factors remains incompletely understood.

• Environmental and Occupational Exposures: Case-control studies have suggested associations between wood dust exposure, pesticide exposure, and previous infectious mononucleosis (typically EBV-related) and increased Hodgkin lymphoma risk, though these associations remain inconsistently reported and effect sizes are modest. The evidence for occupational chemical exposures is weaker than for non-Hodgkin lymphoma.

• Lymphadenopathy (Most Common Presenting Finding): Painless lymphadenopathy is the initial presenting symptom in approximately 80% of patients, with involvement of supradiaphragmatic nodes (cervical, supraclavicular, axillary) occurring in approximately 60-70% of cases. The lymph nodes are characteristically firm, rubbery, non-tender on palpation, and may form matted masses. Mediastinal involvement occurs in approximately 50-60% of early-stage disease and can be massive; anterior mediastinal masses may compress airways, causing cough, dyspnea, or superior vena cava syndrome. Inguinal and pelvic lymphadenopathy occur in 15-20% of cases. Notably, Pel-Ebstein fever (cyclical fever with alternating hot and cold periods lasting days to weeks) is pathognomonic when present, though only occurs in approximately 5% of patients; non-cyclical fever is far more common. The inflammatory milieu generated by Reed-Sternberg cells' secretion of IL-6, TNF-α, and other cytokines directly drives nodal enlargement through recruitment of inflammatory cells.

• B Symptoms (Systemic Constitutional Symptoms): Approximately 20-30% of patients present with B symptoms, defined as fever (temperature >38°C), night sweats (requiring change of clothing/bedding), and unintentional weight loss (>10% body weight over 6 months). These symptoms directly result from TNF-α and IL-6 secretion by both Reed-Sternberg cells and activated macrophages; fever occurs through TNF-α and IL-1 effects on the hypothalamic thermoregulatory center, and night sweats represent dysregulation of thermoregulation coupled with autonomic dysfunction. Presence of B symptoms is highly prognostic—B symptom status drives staging (stage A versus B) and significantly impacts treatment recommendations and prognosis. Patients with B symptoms generally have more advanced disease and worse prognosis.

• Pruritus and Other Paraneoplastic Symptoms: Pruritus (severe itching, often intractable and preceding other symptoms by months) occurs in approximately 10-15% of patients and is a paraneoplastic phenomenon mediated by IL-6 and other cytokine-driven mast cell degranulation in skin. While non-specific, pruritus in the context of lymphadenopathy should raise suspicion for Hodgkin lymphoma. Alcohol-induced pain in involved lymph nodes occurs in approximately 5-10% of patients and is pathognomonic when present; patients report sharp pain in nodal regions 10-30 minutes after alcohol consumption, likely reflecting chemokine release by Reed-Sternberg cells upon ethanol exposure.

• Constitutional Symptoms and Systemic Effects: Patients frequently report fatigue, malaise, anorexia, and generalized weakness related to the systemic inflammatory state. Patients may appear acutely or chronically ill depending on disease extent and duration. Some patients present with complications of advanced disease including jaundice from hepatic infiltration, ascites from peritoneal involvement, or respiratory symptoms from pulmonary involvement.

• Physical Examination Findings: Beyond lymphadenopathy, findings vary with disease extent. Hepatomegaly occurs in approximately 5-10% at presentation and indicates hepatic parenchymal infiltration (liver involvement occurs in approximately 5% of stage I-II disease but up to 15-20% of advanced disease). Splenomegaly is present in approximately 5-10% at diagnosis and portends more advanced disease (splenic involvement occurs in 10-15% of stage II-III disease, up to 25% of stage IV). Superior vena cava syndrome may present with facial plethora, upper extremity edema, and venous distension from massive anterior mediastinal mass. Patients with advanced disease may have lymphedema from inguinal/pelvic node involvement obstructing lymphatic drainage.

• Important Clinical Variants and Atypical Presentations: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), representing approximately 5% of Hodgkin lymphoma cases, typically presents with early-stage localized disease, excellent prognosis, and may have indolent course with prolonged survival even without treatment in some cases. In contrast, nodular sclerosis subtype (60-70% of cases) typically presents with mediastinal involvement and may have more aggressive course. Lymphocyte-rich classical Hodgkin lymphoma (5%) has intermediate prognosis. Mixed cellularity (15-20%) and lymphocyte-depleted (<5%) subtypes tend to present with advanced disease. Primary mediastinal Hodgkin lymphoma, accounting for approximately 6-10% of cases, presents with large anterior mediastinal masses that can cause respiratory compromise, superior vena cava obstruction, or cardiac involvement; requires expedited evaluation and treatment initiation.

• Histopathologic Diagnosis with Reed-Sternberg Cell Identification: Definitive diagnosis requires tissue diagnosis (excisional lymph node biopsy or core needle biopsy) demonstrating classic Reed-Sternberg cells and/or Hodgkin cells within appropriate cellular background. Reed-Sternberg cells are large multinucleated giant cells (diameter >45 μm) with multiple nuclei or multilobated nuclei, each containing a prominent eosinophilic nucleolus described as an "owl's eye" appearance; they have abundant cytoplasm and typically show mitotic figures. Hodgkin cells are mononuclear variants with similar cytologic features. In classical Hodgkin lymphoma, these cells comprise <10% of cellular infiltrate, surrounded by background lymphocytes (predominantly T cells), macrophages, eosinophils, and plasma cells. Fine needle aspiration biopsy is inadequate for diagnosis due to limited cellularity; excisional biopsy is strongly preferred over core needle biopsy for accurate subtyping and assessment of fibrosis. Immunohistochemistry shows Reed-Sternberg cells positive for CD30 and CD15, negative for CD45 (common leukocyte antigen) and CD20 (B cell antigen)—this immunophenotype (CD30+ CD15+ CD45- CD20-) is highly characteristic. Detection of EBV

Immediate stabilisation (before any chemotherapy)

• Airway/SVC emergencies: a bulky anterior mediastinal mass with stridor, orthopnea, or superior vena cava syndrome takes precedence — head-of-bed elevation, oxygen, urgent tissue acquisition, and in true compromise empiric corticosteroids or emergent radiation. Avoid general anesthesia/sedation for biopsy when possible (loss of negative intrathoracic pressure can cause total airway collapse); obtain the biopsy first if safe, since steroids can render nodal tissue non-diagnostic.
• Pre-treatment workup mandated by NCCN Hodgkin Lymphoma guidelines: PET-CT for Lugano staging, echocardiogram (anthracycline), pulmonary function testing with DLCO (bleomycin), hepatitis B/C and HIV serology, and — per ASCO fertility preservation guidance — sperm banking or oocyte/embryo cryopreservation offered before the first cycle.

First-line therapy (NCCN)

• Combination cytotoxic chemotherapy — ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is the backbone for classical HL. Early-stage favorable disease receives abbreviated ABVD plus involved-site radiation therapy (ISRT); advanced stage receives full-course systemic therapy.
• Response-adapted escalation/de-escalation: interim PET after cycle 2 scored by the Deauville 5-point scale. A negative interim scan permits dropping bleomycin (AVD) to spare lung toxicity; a positive scan prompts intensification (e.g., escalated BEACOPP).
• Antibody-drug conjugate and checkpoint blockade up front: brentuximab vedotin (anti-CD30–MMAE) plus AVD, or a PD-1 inhibitor (nivolumab) plus AVD, are guideline-endorsed options for advanced-stage disease, exploiting CD30 expression and 9p24.1 PD-L1 amplification.
• NLPHL is CD20-positive: excision alone or ISRT for stage IA, rituximab-based therapy for more extensive disease.

Relapsed/refractory disease

• Salvage chemotherapy (e.g., ifosfamide/carboplatin/etoposide) followed by high-dose therapy with autologous stem cell transplant, with brentuximab vedotin maintenance in high-risk patients; PD-1 inhibitors (nivolumab, pembrolizumab) for post-transplant or chemorefractory disease; allogeneic transplant is reserved for selected relapses.

Contraindicated / avoid

• Bleomycin with brentuximab vedotin — prohibitive pulmonary toxicity; also avoid bleomycin in significant baseline DLCO impairment.
• Anthracyclines with markedly reduced ejection fraction; live vaccines during immunosuppression; staging laparotomy/splenectomy, obsolete since PET-CT.

Disease-related (some emergent)

• Superior vena cava syndrome / airway obstruction (emergency): bulky anterior mediastinal mass compresses the SVC and trachea — facial plethora, jugular distension, orthopnea, stridor. Signals need for urgent imaging and expedited therapy.
• Impaired cell-mediated immunity: Th2 polarization and dysfunctional T cells predispose to herpes zoster, and to fungal and mycobacterial infection even before chemotherapy.
• Cytopenias and organ infiltration: marrow involvement causes anemia and thrombocytopenia; hepatic infiltration causes cholestatic liver enzyme elevation. Autoimmune hemolytic anemia and immune thrombocytopenia occur as paraneoplastic phenomena.
• Tumor lysis syndrome (emergency): uncommon in HL because tumor burden of malignant cells is low, but consider with bulky disease — hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, acute kidney injury.

Treatment-related, acute

• Febrile neutropenia (emergency): chemotherapy-induced marrow suppression; single fever in a neutropenic patient mandates immediate blood cultures and empiric antipseudomonal beta-lactam per IDSA febrile neutropenia guidance.
• Bleomycin pulmonary toxicity (potentially fatal): free-radical–mediated alveolar injury; dry cough, exertional dyspnea, bibasilar crackles, falling DLCO on surveillance PFTs, reticular infiltrates on CT. Stop bleomycin; steroids for pneumonitis.
• Anthracycline cardiotoxicity: topoisomerase-IIβ/free-radical myocyte injury producing dilated cardiomyopathy; falling ejection fraction on echocardiography.
• Vinca neuropathy and brentuximab vedotin neuropathy: microtubule disruption causing length-dependent sensory neuropathy; brentuximab also carries a risk of progressive multifocal leukoencephalopathy.
• Checkpoint inhibitor immune-related adverse events: thyroiditis, colitis, hepatitis, pneumonitis, hypophysitis — managed with corticosteroids and drug hold.

Late effects (the classic survivorship testable point)

• Second malignancies: alkylator/topoisomerase exposure → therapy-related MDS/AML (typically within a decade); chest radiation → breast cancer in women irradiated as adolescents/young adults, plus lung cancer (synergistic with smoking) and thyroid cancer.
• Radiation late toxicity: accelerated coronary disease and valvular disease, hypothyroidism after neck irradiation, and functional asplenia after splenic irradiation with risk of encapsulated-organism sepsis.
• Infertility and premature ovarian insufficiency: far greater with escalated BEACOPP than with ABVD.

• The single best next step for painless firm cervical/supraclavicular adenopathy in a young adult: excisional lymph node biopsy. FNA is inadequate — it cannot show architecture or the inflammatory background. Do not give empiric corticosteroids first; they can lyse the tumor and make the biopsy non-diagnostic.
• Immunophenotype is the one association examiners test: classical HL Reed-Sternberg cells are CD15+ CD30+, CD45− CD20− with owl-eye nucleoli. Nodular lymphocyte-predominant HL is the mirror image — popcorn (LP) cells that are CD20+ CD45+, CD15− CD30−, which is why rituximab works there and not in classical HL.
• Reed-Sternberg-like cells are not pathognomonic — they appear in infectious mononucleosis, other lymphomas, and carbamazepine reactions. Diagnosis requires the cells plus the appropriate background and immunophenotype.
• Spread pattern distractor: HL spreads contiguously from one nodal group to the next and is usually supradiaphragmatic; non-Hodgkin lymphoma spreads noncontiguously and more often involves extranodal sites and Waldeyer's ring.
• Buzzwords worth memorizing: alcohol-induced nodal pain and Pel-Ebstein fever are rare but essentially diagnostic; intractable pruritus can precede adenopathy by months. Nodular sclerosis (young woman, mediastinal mass, lacunar cells) is the most common subtype; EBV associates most strongly with mixed cellularity and lymphocyte-depleted disease.
• Know the regimen toxicities cold — ABVD: Adriamycin (doxorubicin) → cardiomyopathy, get a baseline echo; Bleomycin → pulmonary fibrosis, get baseline PFTs with DLCO; Vinblastine → peripheral neuropathy and myelosuppression; Dacarbazine → nausea. A survivor with a new dry cough and falling DLCO is bleomycin lung until proven otherwise.
• Survivorship stem: a woman in her 30s who received mediastinal radiation as a teenager needs early breast cancer surveillance (annual mammography plus breast MRI beginning roughly 8–10 years after radiation, per NCCN survivorship recommendations), plus thyroid and cardiovascular screening.
• Response assessment: PET-CT with Deauville scoring, not CT size criteria alone — interim PET drives whether bleomycin is dropped or therapy is escalated.