Lymphomas — Hodgkin and Non-Hodgkin

Non-modifiable host factors

• Age and sex: Hodgkin lymphoma follows the bimodal curve described above; most non-Hodgkin lymphomas (NHL) rise steadily with age, with a modest male predominance.
• Inherited immunodeficiency: Ataxia-telangiectasia, Wiskott-Aldrich, common variable immunodeficiency, and X-linked lymphoproliferative syndrome — defective DNA repair or failure of cytotoxic T-cell control of EBV permits clonal B-cell outgrowth.
• Family history: First-degree relative with lymphoma modestly increases risk of both HL and NHL.

Infection-driven (antigen-drive or direct viral transformation)

• EBV: Latent membrane protein 1 mimics constitutive CD40 signaling → NF-κB activation. Underlies a large share of classical HL, endemic Burkitt, post-transplant lymphoproliferative disorder, and EBV+ primary CNS lymphoma.
• HTLV-1: Tax protein drives adult T-cell leukemia/lymphoma; endemic in Japan, the Caribbean, and West Africa.
• HHV-8: Primary effusion lymphoma, typically in advanced HIV.
• Chronic antigenic stimulation: H. pylori → gastric MALT lymphoma; HCV → splenic marginal zone lymphoma; Chlamydia psittaci → ocular adnexal MALT; Borrelia → cutaneous MALT. These are the potentially reversible causes — antimicrobial or antiviral eradication alone can induce remission.

Immune dysregulation

• HIV/AIDS: Risk of DLBCL, Burkitt, and primary CNS lymphoma; primary CNS lymphoma clusters at very low CD4 counts.
• Iatrogenic immunosuppression: Solid-organ or stem-cell transplant, TNF-α inhibitors, chronic methotrexate.
• Autoimmune disease: Sjögren (parotid MALT), Hashimoto (thyroid MALT), celiac disease (enteropathy-associated T-cell lymphoma), rheumatoid arthritis.

Modifiable/environmental exposures

• Prior cytotoxic therapy or radiation: Alkylating agents and topoisomerase II inhibitors cause secondary hematologic malignancy.
• Occupational: Benzene, herbicides, and pesticides are the classic stem details.
• Prevention leverage: USPSTF recommends one-time HIV screening for ages 15–65 and hepatitis C screening for adults 18–79, and effective treatment of both reduces downstream lymphoma risk.

Hodgkin Lymphoma

• Reed-Sternberg cells (diagnostic hallmark): Large multinucleated cells with "owl's eye" or "mirror-image" nuclei arising from B-cell lineage; represent <1% of cellular infiltrate but surrounded by reactive inflammatory cells (T cells, eosinophils, histiocytes)
• EBV association: 40% of HL cases contain EBV; particularly strong in nodular sclerosis subtype and in immunocompromised patients (HIV, post-transplant)
• Chromosomal abnormalities: Frequent gains of chromosome 9p (including JAK2 and STAT6 genes) leading to constitutive signaling; loss of MHC class I expression allows immune evasion
• Lymphocyte-predominant variant: Lacks true RS cells but has similar biology; arises from germinal center B cells

Non-Hodgkin Lymphoma

• B-cell lymphomas (80% of NHL): Arise from germinal center or post-germinal center B cells; include follicular (t(14;18) BCL2 translocation), diffuse large B-cell (DLBCL, t(14;18) or t(3;8) MYC translocations), small lymphocytic (SLL/CLL with del(13q), del(11q), or del(17p)), Burkitt (t(8;14) MYC/immunoglobulin H), mantle cell (t(11;14) cyclin D1), and marginal zone types
• T-cell lymphomas (15-20% of NHL): Include peripheral T-cell NOS, angioimmunoblastic, cutaneous (mycosis fungoides/Sézary), anaplastic large cell (ALK+ or ALK-), and natural killer/T-cell types
• Molecular drivers: Mutations in TP53, MYC, BCL2, BCL6, NOTCH1, and others drive transformation; different translocations define specific subtypes with distinct biology and prognosis
• Microenvironment dependence: NHL cells often depend on stromal support and cytokine signaling (unlike HL which overwhelmingly involves reactive cells)

Common to Both HL and NHL

• B symptoms (seen in 30-40% at presentation): Fever, night sweats, unintentional weight loss (>10% body weight in 6 months); presence indicates advanced stage and worse prognosis
• Lymphadenopathy: Painless, firm, rubbery, mobile lymph nodes; can be localized or generalized depending on type and stage
• Mediastinal involvement: Particularly common in HL (70%) and primary mediastinal large B-cell lymphoma; may present with chest pain, cough, dyspnea, or SVC syndrome

Hodgkin Lymphoma Specifics

• Pruritus: Severe itching, particularly after bathing (classic but only 10-15%); pathognomonic when present
• Alcohol-induced pain: Pleuritic chest or abdominal pain within minutes of alcohol consumption (extremely rare but highly specific)
• Stage I-II disease common: 60-70% present with early-stage disease; inguinal and mediastinal involvement frequent

Non-Hodgkin Lymphoma Specifics

• Extranodal presentations: Common (30-40% at diagnosis); can involve GI tract (abdominal pain, bleeding), bone marrow (cytopenias), CNS (headache, confusion), liver, lungs, or virtually any organ
• Bulky disease: More common than in HL; may present with mass effect symptoms
• Cytopenias: More prominent at presentation due to bone marrow involvement; may present with anemia, thrombocytopenia, or infection
• Lytic lesions: Some subtypes (especially mantle cell, Burkitt) cause bone destruction rather than sclerosis
• Hypercalcemia: Seen in ~5-10% of NHL (PTCL and some high-grade lymphomas); caused by osteolytic cytokine production

Initial Evaluation

• Excisional lymph node biopsy (gold standard): Fine needle aspiration and core needle biopsy often insufficient; architectural pattern critical for subtype diagnosis; avoid inguinal nodes if possible (reactive changes)
• Flow cytometry: For rapid assessment of cell type; identifies aberrant antigen expression; essential for B- and T-cell classification
• Immunohistochemistry: Determines lineage (CD20 for B-cell, CD3 for T-cell); identifies specific subtypes; CD30/CD15 positive RS cells in HL

HL-Specific Diagnostic Features

• Histologic subtypes: Nodular sclerosis (60%, collagen fibrosis, mediastinal involvement), mixed cellularity (20%, numerous RS cells), lymphocyte-rich (5%), lymphocyte-predominant (5%, PD1+ LP cells, best prognosis)
• WHO/AJCC criteria: Presence of diagnostic neoplastic cells (RS cells in classical HL, LP cells in nodular lymphocyte-predominant)

NHL-Specific Diagnostic Features

• Cytology and flow: Small lymphocytic lymphoma shows CD5+CD19+CD23+ B cells (coexpression of T-cell marker CD5 is hallmark); follicular shows CD10+BCL2+
• Cytogenetics and molecular testing: t(14;18) in follicular and 30% of DLBCL; t(8;14) and high Ki-67 in Burkitt; t(11;14) in mantle cell; complex karyotype or del(17p)/TP53 mutation indicate poor prognosis
• LDH and beta-2 microglobulin: Prognostic markers; elevated in aggressive disease and high tumor burden

Staging Studies

• CT chest/abdomen/pelvis: Standard for both; assess node size (>1.5 cm short axis), extranodal disease, organ involvement
• PET-CT: Highly sensitive (90%+) for both HL and NHL; FDG-avid lesions more common in HL and aggressive NHL; crucial for prognosis and treatment planning; less useful in low-grade NHL
• Bone marrow biopsy: Indicated for staging in HL and some NHL; less critical since PET-CT has improved accuracy
• CSF examination: If any CNS involvement suspected or high risk (Burkitt, lymphoblastic, primary CNS lymphoma)

Stage Definition

• Stage I: Single lymph node region OR single extranodal site
• Stage II: Two or more lymph node regions on same side of diaphragm OR Stage I + extranodal
• Stage III: Lymph node involvement both sides of diaphragm ± extranodal
• Stage IV: Diffuse extranodal involvement (bone marrow, liver, lungs)
• A/B suffix: A = no B symptoms; B = B symptoms present (fever >38°C, night sweats, weight loss >10%)

Hodgkin Lymphoma

• Early-stage (I-IIA) favorable: 2-4 cycles ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) + involved field radiation therapy (20-30 Gy); cure rates >90%
• Early-stage unfavorable or IIB-IVA: 4 cycles ABVD + radiation; alternatively 6 cycles ABVD alone in selected patients
• **Advanced (IVB) or

Disease-related — emergencies first

• Tumor lysis syndrome (EMERGENCY): Massive release of intracellular contents from rapidly dividing tumor → hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia (phosphate binds calcium) with urate/calcium-phosphate nephropathy. Signaled by rising creatinine and potassium after the first chemotherapy dose; highest risk in Burkitt and lymphoblastic lymphoma with markedly elevated LDH. NCCN recommends risk-stratified prophylaxis with aggressive IV hydration plus allopurinol (low risk) or rasburicase (high risk) — rasburicase is contraindicated in G6PD deficiency because hydrogen peroxide generation causes hemolysis and methemoglobinemia.
• Superior vena cava syndrome and airway compression (EMERGENCY): Bulky mediastinal mass; facial/arm swelling, distended neck veins, orthopnea. Sedation or general anesthesia can precipitate complete airway collapse — obtain imaging and consider tissue diagnosis under local anesthesia first.
• Malignant spinal cord compression (EMERGENCY): Epidural deposit or vertebral involvement; back pain preceding weakness or sphincter dysfunction. Urgent MRI of the whole spine plus corticosteroids before definitive radiation or surgery.
• CNS/leptomeningeal spread: Cranial neuropathies or altered mentation; classic in Burkitt, lymphoblastic, and high CNS-IPI DLBCL — prompts CSF sampling and CNS-directed prophylaxis.
• Histologic transformation: Indolent follicular lymphoma evolving to DLBCL — heralded by rapid asymmetric nodal growth, new B symptoms, and a sharply rising LDH with a focally intense PET lesion.
• Marrow failure and immune cytopenias: Infiltration causes cytopenias; SLL/CLL classically produces warm autoimmune hemolytic anemia (positive direct antiglobulin test).

Treatment-related

• Febrile neutropenia (EMERGENCY): IDSA guidance is blood cultures then immediate empiric antipseudomonal beta-lactam (e.g., cefepime) — do not wait for a source.
• Anthracycline cardiomyopathy: Cumulative, dose-dependent free-radical and topoisomerase-IIβ injury; ASCO survivorship guidance supports baseline and surveillance echocardiography, with falling LVEF or global longitudinal strain as the signal.
• Bleomycin pneumonitis: Dry cough, dyspnea, and a falling DLCO; avoid high inspired oxygen.
• Vincristine neuropathy; cyclophosphamide hemorrhagic cystitis from acrolein (mesna prophylaxis), infertility, and later bladder cancer.
• Rituximab: Hepatitis B reactivation — AASLD advises HBsAg and anti-HBc screening with antiviral prophylaxis before anti-CD20 therapy; rarely PML.
• CAR-T therapy: Cytokine release syndrome (tocilizumab) and ICANS.
• Late effects: Secondary MDS/AML and, after mediastinal radiation, breast and lung cancer, hypothyroidism, and premature coronary disease.

• Immunophenotype decides the case: Reed-Sternberg cells are CD15+/CD30+ and CD45-negative; the popcorn LP cells of nodular lymphocyte-predominant HL are the mirror image — CD20+/CD45+ but CD15/CD30-negative. Reversing these is the single most common trap.
• Single best next step for painless lymphadenopathy: excisional lymph node biopsy. Fine-needle aspiration destroys the architecture needed for subtyping and is the wrong answer even when the stem says the node is easily accessible.
• Starry sky = Burkitt: Sheets of monomorphic B cells with tingible-body macrophages, Ki-67 approaching 100%, t(8;14) MYC–IgH. Because doubling time is the fastest of any human tumor, tumor lysis prophylaxis must start before chemotherapy, not after the potassium rises.
• The translocation table examiners actually test: t(14;18) BCL2 → follicular (apoptosis blocked); t(11;14) cyclin D1 → mantle cell; t(8;14) MYC → Burkitt; t(11;18) → MALT lymphoma that will not respond to H. pylori eradication alone.
• Gastric MALT: If H. pylori is positive and t(11;18) is absent, eradication therapy alone can induce remission — antibiotics as cancer therapy is the classic question.
• Indolent does not mean treat: Asymptomatic, low-burden follicular lymphoma is managed with observation per NCCN; it is highly treatable but not curable, whereas advanced DLBCL and HL are curable with combination chemoimmunotherapy. Choosing "start chemotherapy now" for an asymptomatic follicular patient is the planted distractor.
• Buzzwords worth memorizing: pruritus after a hot shower and alcohol-induced nodal pain point to Hodgkin lymphoma; cerebriform Sézary cells and erythroderma point to cutaneous T-cell lymphoma; drenching night sweats plus >10% weight loss define B symptoms and upstage the letter, not the number.
• Mediastinal mass caution: In a young patient with a large anterior mediastinal mass, assess the airway before sedation — a stem describing orthopnea that worsens when supine is warning you, not describing anxiety.