Lymphomas

• Definition: Lymphomas are clonal malignancies of lymphocytes (B, T, or NK lineage) that arise in and expand lymphoid tissue — nodes, spleen, thymus, Waldeyer's ring, gut-associated lymphoid tissue — as opposed to leukemias, which are defined by marrow and peripheral blood dominance. The distinction is one of compartment, not biology; the same clone (e.g., lymphoblastic, CLL/SLL) can present either way.
• Classification: The World Health Organization classification is the framework used in US practice and by the National Comprehensive Cancer Network (NCCN). It integrates morphology, immunophenotype, cytogenetics, and clinical features rather than morphology alone.

Why it matters clinically

• Curability: Unlike most solid tumors, several aggressive lymphomas are curable even at advanced stage. Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) are treated with curative intent at every stage, so accurate subtyping and staging change intent of therapy, not just regimen.
• Oncologic emergencies: Bulky, rapidly proliferating disease presents with superior vena cava syndrome, airway compromise, cord compression, or tumor lysis — recognition precedes any oncologic workup.
• Survivorship burden: Because cure rates are high and patients are often young, late effects of therapy (second cancers, cardiomyopathy, infertility) drive long-term management.

Epidemiology worth recalling

• Non-Hodgkin lymphoma is one of the more common malignancies in the United States, with incidence rising steeply with age; median age at diagnosis is in the sixth to seventh decade. DLBCL is the single most common subtype, followed by follicular lymphoma.
• Hodgkin lymphoma is uncommon overall but is a leading cancer of adolescents and young adults; nodular sclerosis is the dominant subtype in this group and skews toward young women with mediastinal disease.
• Male predominance is seen in most NHL subtypes and in Hodgkin lymphoma outside the nodular sclerosis subtype.
• No screening test exists; the USPSTF makes no lymphoma screening recommendation, so diagnosis is symptom-driven.

Mechanism 1 — Chronic antigenic stimulation (drives clonal selection)

• Infectious: Helicobacter pylori → gastric MALT lymphoma; Chlamydia psittaci → ocular adnexal MALT; Borrelia burgdorferi → cutaneous MALT; Campylobacter jejuni → immunoproliferative small intestinal disease. Hepatitis C virus drives splenic marginal zone lymphoma.
• Autoimmune: Sjögren syndrome → parotid MALT; Hashimoto thyroiditis → thyroid MALT; celiac disease → enteropathy-associated T-cell lymphoma. Persistent germinal center activity increases the odds of a mutational hit.

Mechanism 2 — Direct viral transformation

• EBV: latent membrane protein 1 mimics constitutive CD40 signaling, activating NF-κB. Linked to Hodgkin lymphoma, Burkitt (endemic form), post-transplant lymphoproliferative disorder, and primary CNS lymphoma.
• HTLV-1: Tax protein → adult T-cell leukemia/lymphoma; endemic to Japan and the Caribbean.
• HHV-8: primary effusion lymphoma.

Mechanism 3 — Loss of immune surveillance

• HIV/AIDS: risk rises as CD4 count falls; DLBCL, Burkitt, and primary CNS lymphoma are AIDS-defining.
• Iatrogenic immunosuppression: solid organ or stem cell transplant (PTLD), calcineurin inhibitors, methotrexate, TNF-α inhibitors.
• Primary immunodeficiency: ataxia-telangiectasia, Wiskott-Aldrich, common variable immunodeficiency — defective DNA repair or lymphocyte regulation.

Non-modifiable

• Age (NHL) and the bimodal age curve of Hodgkin lymphoma
• Male sex, white race (Hodgkin), family history in a first-degree relative
• Inherited DNA-repair defects as above

Modifiable / exposure-related

• Treatable infections: eradicating H. pylori can cause regression of early gastric MALT lymphoma — the classic exam point that antibiotics are cancer therapy here.
• Prior cytotoxic therapy or radiation for another malignancy
• Occupational: benzene, pesticides and herbicides, agricultural work
• Cigarette smoking (modest, subtype-dependent) and obesity

Step 2 — The translocation dictates behavior.

• t(8;14) MYC: drives the cell cycle → the highest proliferative fraction of any human tumor, explaining doubling in days, spontaneous tumor lysis, and exquisite chemosensitivity.
• t(14;18) BCL2: blocks apoptosis rather than accelerating division → indolent, accumulative, incurable-but-slow follicular disease that responds then relapses.
• t(11;14) cyclin D1: mantle cell lymphoma, biologically aggressive yet often widely disseminated at presentation.

Nodal findings

• Painless, rubbery, non-tender, usually mobile lymphadenopathy: the node is expanded by clonal cells and stroma rather than by acute edema. Contrast with the tender, mobile nodes of reactive adenitis and the hard, fixed, matted nodes of metastatic carcinoma. Fixation and matting can occur with bulky or long-standing lymphoma but are not the typical description. Cervical and supraclavicular sites predominate in Hodgkin lymphoma; a Virchow node demands a workup.
• Adenopathy persisting beyond several weeks, >2 cm, or supraclavicular is the combination that mandates biopsy rather than observation.

Constitutional (B) symptoms — cytokine-mediated

• Fever >38°C, drenching night sweats, unintentional weight loss >10% of body weight over 6 months — the formal Ann Arbor "B" designation; caused by IL-6, IL-1, and TNF-α from tumor and reactive cells. Pel-Ebstein fever (cyclic fever over days to weeks) is the classic Hodgkin buzzword.
• Pruritus and fatigue: cytokine-driven, not part of the formal B criteria — a common distractor.

Mass-effect findings

• Superior vena cava syndrome: facial and upper-extremity swelling, plethora, distended neck veins, worse when supine — from an anterior mediastinal mass.
• Cough, dyspnea, orthopnea, stridor: tracheal compression; positional dyspnea signals impending airway loss.
• Early satiety, left upper quadrant fullness: splenomegaly.
• Back pain with focal neurologic deficit: epidural cord compression.

Extranodal findings (favor NHL)

• GI: abdominal mass, obstruction, perforation risk (gastric and intestinal lymphoma)
• CNS: focal deficits or a solitary ring-enhancing lesion in advanced HIV (primary CNS lymphoma)
• Skin: patches/plaques progressing to tumors in mycosis fungoides, with erythroderma and circulating Sézary cells in Sézary syndrome
• Marrow: anemia, thrombocytopenia, recurrent infection
• Testis, sinus, breast: sites with a high risk of CNS relapse

Step 3 — Immunophenotype assigns lineage.

• B-cell: CD19, CD20, CD79a; light-chain restriction (kappa or lambda) proves clonality on flow cytometry
• T-cell: CD3, CD5, CD4/CD8
• Classical Hodgkin: CD15+, CD30+, CD20−, CD45− (the inverse of essentially every B-NHL)
• Nodular lymphocyte-predominant Hodgkin: popcorn / LP cells, CD20+, CD45+, CD15−, CD30−
• Ki-67 proliferation index: near-100% in Burkitt lymphoma

Step 5 — Response and prognosis.

• Deauville 5-point scale: interim and end-of-treatment PET uptake graded against mediastinal blood pool and liver; scores 4–5 indicate inadequate response and trigger regimen escalation.
• IPI stratifies aggressive NHL; the Hasenclever/IPS score is used in advanced Hodgkin lymphoma.

Immediate stabilization (before oncologic therapy)

• Airway and SVC syndrome: elevate the head of the bed, provide oxygen, and obtain urgent tissue; a patient with positional dyspnea from an anterior mediastinal mass can lose the airway under sedation, so biopsy planning is anesthesia-critical. Endovascular stenting or emergent radiation is used when obstruction is life-threatening.
• Spinal cord compression: emergent MRI plus corticosteroids (dexamethasone) and urgent radiation or surgical decompression.
• Tumor lysis syndrome prophylaxis: aggressive IV hydration plus a xanthine oxidase inhibitor (allopurinol) for standard risk; rasburicase (recombinant urate oxidase) for high-risk disease such as Burkitt or markedly elevated LDH/uric acid. Rasburicase is contraindicated in G6PD deficiency (hemolysis and methemoglobinemia) and in patients with prior anaphylaxis, hemolysis, or methemoglobinemia from the drug; safety data in pregnancy and lactation are limited, so use with caution.

Escalation and second line

• Anti-CD30 antibody-drug conjugate (brentuximab vedotin) and PD-1 checkpoint inhibitors (nivolumab, pembrolizumab) for relapsed/refractory classical Hodgkin lymphoma, exploiting CD30 expression and 9p24.1-driven PD-L1 overexpression.
• Salvage chemoimmunotherapy followed by autologous stem cell transplant for chemosensitive relapsed Hodgkin lymphoma or DLBCL.
• CD19-directed CAR T-cell therapy (axicabtagene ciloleucel, tisagenlecleucel) for relapsed/refractory large B-cell lymphoma.
• Anti-CD20 antibody plus antiviral prophylaxis: AASLD and NCCN recommend screening HBsAg and anti-HBc before rituximab and giving entecavir or tenofovir prophylaxis when positive, because rituximab causes fatal HBV reactivation.
• Antibiotic eradication of H. pylori is first-line for localized gastric MALT lymphoma.

Disease-related — emergencies flagged

• Superior vena cava syndrome (EMERGENCY): mediastinal mass obstructs venous return → facial plethora, neck vein distension, positional dyspnea. Airway compromise is the lethal component.
• Malignant spinal cord compression (EMERGENCY): epidural deposit → back pain preceding weakness, sensory level, urinary retention. MRI plus steroids without delay.
• Tumor lysis syndrome (EMERGENCY): massive cell lysis releases potassium, phosphate, and nucleic acids → hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia (calcium-phosphate precipitation) and acute kidney injury. Highest risk in Burkitt and high-LDH disease; may occur spontaneously before chemotherapy.
• Immune dysfunction: Hodgkin lymphoma impairs cell-mediated immunity → herpes zoster, fungal and mycobacterial infection. NHL causes hypogammaglobulinemia → encapsulated organism infection.
• Marrow failure and autoimmune cytopenias: warm autoimmune hemolytic anemia and immune thrombocytopenia, most classically with CLL/SLL.
• Histologic transformation: follicular lymphoma converting to DLBCL — signaled by sudden nodal growth, new B symptoms, and a rising LDH.

Treatment-related

• Febrile neutropenia (EMERGENCY): obtain cultures and give empiric broad-spectrum anti-pseudomonal beta-lactam therapy immediately per IDSA guidance; do not wait for a source.
• Anthracycline cardiotoxicity: doxorubicin generates free radicals and inhibits topoisomerase IIβ → dose-dependent dilated cardiomyopathy. Signaled by a falling LVEF or new heart failure; ASCO recommends baseline and surveillance cardiac imaging in at-risk survivors.
• Bleomycin pulmonary fibrosis: oxidative injury with low lung hydrolase → dry cough, dyspnea, falling DLCO, basilar crackles.
• Vincristine: peripheral neuropathy and constipation/ileus (microtubule disruption); fatal if given intrathecally.
• Cyclophosphamide: acrolein-mediated hemorrhagic cystitis (prevent with mesna and hydration) and later bladder cancer.
• Rituximab: infusion reactions, HBV reactivation, progressive multifocal leukoencephalopathy.
• CAR T-cell therapy: cytokine release syndrome (treat with tocilizumab) and ICANS.
• Late effects: secondary MDS/AML from alkylators and topoisomerase inhibitors; solid tumors and breast cancer after chest radiation — for women who received chest/mantle radiation between roughly ages 10 and 30, the American Cancer Society and NCCN Survivorship guidance recommend annual mammography plus breast MRI starting at age 25 or 8 years after radiation, whichever comes later (minor variation exists among ACS, NCCN Survivorship, and Children's Oncology Group long-term follow-up guidelines); hypothyroidism; infertility.

• Single best next step for persistent painless adenopathy: excisional lymph node biopsy, not FNA and not empiric antibiotics. Architecture is required for classification, and steroids given before biopsy can obliterate the diagnosis.
• CD15+/CD30+/CD20−/CD45− is classical Hodgkin lymphoma; CD20+/CD45+/CD15−/CD30− popcorn cells are nodular lymphocyte-predominant Hodgkin. The inverted CD20/CD45 status is the discriminator examiners love.
• Spread pattern is a free discriminator: Hodgkin lymphoma spreads contiguously from one nodal group to the adjacent one; NHL spreads non-contiguously with frequent extranodal and marrow involvement.
• The one association to know cold: nodular sclerosis Hodgkin lymphoma in a young woman with an anterior mediastinal mass, lacunar cells, and collagen banding — and its complication, superior vena cava syndrome.
• Antibiotics as cancer therapy: H. pylori eradication is first-line for localized gastric MALT lymphoma. If lymphoma persists after eradication, suspect t(11;18), which predicts antibiotic non-responsiveness.
• Tumor lysis before treatment starts: Burkitt lymphoma can lyse spontaneously. Expect hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia — the low calcium is the value most often missed. Rasburicase is contraindicated in G6PD deficiency.
• Distinguish the toxicities of ABVD by organ: Adriamycin → heart (echo/LVEF), Bleomycin → lung (DLCO), Vinblastine → neuropathy/myelosuppression, Dacarbazine → nausea. New dyspnea in a treated Hodgkin patient is bleomycin toxicity until proven otherwise, not simply pneumonia.
• Common distractor: Reed-Sternberg-*like* cells appear in infectious mononucleosis and other reactive states. Reed-Sternberg cells are diagnostic only in the correct architectural and immunophenotypic context — and mononuclear Hodgkin cell variants are sufficient when the background is right.
• Screen before rituximab: hepatitis B serologies (HBsAg and anti-HBc), because reactivation can be fulminant.

• Hodgkin lymphoma (HL): 10% of lymphomas; bimodal age distribution (peaks at 20s and 55+); better prognosis than NHL
• Non-Hodgkin lymphoma (NHL): 90% of lymphomas; increases with age, immunosuppression, autoimmune disease
• Reed-Sternberg cells (owl-eye nuclei) are pathognomonic for Hodgkin lymphoma
• B-cell lymphomas account for 85% of NHL; T-cell lymphomas are 15%
• Mediastinal involvement more common in HL; extranodal disease more common in NHL

1. 1.Confusing HL and NHL prognosis: HL has better overall prognosis (~90% 5-yr survival); NHL prognosis varies widely by subtype (indolent vs. aggressive)
2. 2.Missing extranodal disease in NHL: Always check imaging, CBC, LDH, and consider bone marrow biopsy; NHL frequently involves organs outside nodes at diagnosis
3. 3.Misidentifying Reed-Sternberg cells: They are diagnostic of HL but not always present; look for Hodgkin cells (mononuclear variants) which are sufficient for diagnosis; must exclude benign mimics (viral infection, reactive lymph nodes)

Hodgkin Lymphoma

• Early-stage (Stage I-II): Radiation ± chemotherapy (ABVD)
• Advanced (Stage III-IV): ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) × 6-8 cycles ± radiation; PET-CT guides response
• Newer regimens: Stanford V, escalated BEACOPP for high-risk disease

Non-Hodgkin Lymphoma

• Indolent (e.g., follicular): Observation ("watch and wait") vs. R-bendamustine or rituximab monotherapy; transforms require aggressive treatment
• Aggressive (e.g., DLBCL, Burkitt): R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) ± intrathecal prophylaxis (Burkitt, high LDH)
• CNS prophylaxis: Required for Burkitt and high-grade lymphomas at risk for CNS involvement