Lymphoma Subtypes & Treatment Principles

Diagnosis, staging, and pretreatment testing

Tissue first. Lymphoma is diagnosed on an excisional biopsy (or a generous core when excision is impractical) because classification depends on nodal architecture plus immunophenotype. Flow cytometry and immunohistochemistry define lineage and subtype (CD20 for B cells, CD3 for T cells, CD5, CD10, CD15, CD30, cyclin D1), and FISH or cytogenetics identifies defining translocations. Fine-needle aspiration, a blood smear, or serum markers cannot classify a lymphoma.

Staging. FDG PET-CT stages Hodgkin lymphoma and the FDG-avid non-Hodgkin lymphomas and has largely replaced routine bone marrow biopsy in Hodgkin lymphoma and DLBCL. The Lugano (modified Ann Arbor) system is anatomic: stage I is one nodal region or a single extranodal lesion, stage II is two or more regions on the same side of the diaphragm, stage III involves nodes above and below the diaphragm, and stage IV is diffuse extralymphatic disease such as marrow, liver, or lung. In Hodgkin lymphoma the suffix B marks fever, drenching night sweats, or loss of more than 10% of body weight in 6 months, and bulky disease raises treatment intensity. LDH is a key prognostic marker.

Hodgkin lymphoma

Pathology. Classic Hodgkin lymphoma contains scattered large binucleate "owl-eye" Reed–Sternberg cells that are CD15+ and CD30+ and usually CD20− and CD45−, surrounded by reactive lymphocytes, eosinophils, and histiocytes. Nodular sclerosis is the most common subtype and classically affects young women with a mediastinal mass; mixed cellularity is associated with EBV. Nodular lymphocyte-predominant Hodgkin lymphoma is the exception, with "popcorn" cells that are CD20+ and CD15−/CD30−.

Presentation. Painless cervical or supraclavicular nodes and a mediastinal mass (cough, chest fullness) are typical. Spread to contiguous node groups is predictable, which is why involved-site radiation works in early disease. B symptoms, generalized pruritus, and cyclic Pel–Ebstein fevers occur, and pain in involved nodes after drinking alcohol is rare but highly suggestive.

Treatment. Early-stage disease receives ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for 2–4 cycles with or without involved-site radiation, adapted to the interim PET response. Advanced-stage disease receives brentuximab vedotin (anti-CD30 drug conjugate) plus AVD or nivolumab plus AVD, both of which drop bleomycin. Relapsed disease is treated with salvage chemotherapy and autologous stem cell transplant, brentuximab, or PD-1 blockade (Reed–Sternberg cells overexpress PD-L1).

Bleomycin causes dose-related pulmonary fibrosis, so baseline PFTs with DLCO are obtained; doxorubicin causes cumulative cardiomyopathy; mediastinal radiation later causes breast cancer, hypothyroidism, and premature coronary disease.

Aggressive B-cell lymphomas

Diffuse large B-cell lymphoma. DLBCL is the most common non-Hodgkin lymphoma (about 30%). The typical patient is in their 60s with a rapidly enlarging nodal or extranodal mass (the GI tract is the most common extranodal site), B symptoms, and a high LDH. Biopsy shows diffuse sheets of large CD20+ B cells. It arises de novo or by transformation of follicular lymphoma or CLL (Richter transformation).

Treating DLBCL. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for 6 cycles is given with curative intent and cures roughly 60–70%. Pola-R-CHP, in which the anti-CD79b drug conjugate polatuzumab vedotin replaces vincristine, improves progression-free survival in patients with higher IPI scores. The International Prognostic Index counts age over 60, elevated LDH, ECOG performance status of 2 or more, stage III–IV, and more than one extranodal site. An end-of-treatment PET showing complete metabolic response defines remission. Primary refractory disease or relapse within 12 months is treated with CD19-directed CAR-T cells; later chemosensitive relapse is treated with salvage chemotherapy and autologous transplant.

Burkitt lymphoma. The t(8;14) translocation places MYC beside the immunoglobulin heavy-chain enhancer (variants involve the light-chain loci). Sheets of medium-sized CD10+, BCL6+, BCL2− B cells with a Ki-67 index near 100% are interrupted by tingible-body macrophages, the "starry sky" pattern. The endemic form (equatorial Africa, nearly always EBV-positive) involves the jaw and facial bones; the sporadic form presents as an ileocecal or abdominal mass; the immunodeficiency form accompanies HIV.

Treating Burkitt. Treatment starts urgently with short, intensive rituximab-containing multiagent regimens such as CODOX-M/IVAC, DA-EPOCH-R, or hyper-CVAD, plus CNS prophylaxis with intrathecal methotrexate or cytarabine; most patients are cured. Burkitt has the highest tumor lysis risk of any lymphoma, so aggressive IV hydration, rasburicase, and frequent potassium, phosphate, calcium, uric acid, and creatinine checks are mandatory.

Screen for G6PD deficiency before rasburicase, which can cause hemolysis and methemoglobinemia in deficient patients.

Indolent B-cell lymphomas

Follicular lymphoma. The most common indolent lymphoma affects older adults with painless generalized nodes that wax and wane for years, usually advanced at diagnosis. The t(14;18) translocation overexpresses the antiapoptotic protein BCL2 (CD10+, BCL2+ follicles). Asymptomatic, low-burden disease is observed because early treatment does not prolong survival; symptoms, bulk, cytopenias, or organ threat prompt rituximab alone or with bendamustine or CHOP, and stage I–II disease can be cured with involved-site radiation. Transformation to DLBCL occurs at roughly 2–3% per year and is suspected when one node suddenly grows, LDH rises, or B symptoms appear; the most PET-avid site is biopsied.

Mantle cell lymphoma. The t(11;14) translocation overexpresses cyclin D1. Cells are CD5+ like CLL but CD23−. Typical patients are older men with advanced disease: generalized nodes, splenomegaly, marrow involvement, and GI involvement that may appear as lymphomatous polyposis. Treatment is chemoimmunotherapy (with autologous transplant for fit patients) followed by rituximab maintenance, and BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are key agents, especially at relapse.

Gastric MALT lymphoma. Chronic H. pylori gastritis drives this extranodal marginal zone lymphoma, and eradication therapy (bismuth quadruple therapy preferred; clarithromycin triple therapy only for a strain known to be susceptible) makes most localized cases regress, so gastrectomy is unnecessary. Persistent disease, H. pylori–negative tumors, and tumors with t(11;18) (API2–MALT1, which predicts resistance to eradication) receive involved-site radiation; disseminated disease receives rituximab. Other antigen-driven MALT lymphomas arise in the parotid in Sjögren syndrome, the thyroid in Hashimoto thyroiditis, the ocular adnexa with Chlamydia psittaci, and the small intestine with Campylobacter jejuni.

Waldenström macroglobulinemia. This lymphoplasmacytic lymphoma carries MYD88 L265P in more than 90% of cases and secretes monoclonal IgM. Large pentameric IgM stays mostly intravascular and raises serum viscosity, causing headache, blurred vision with "sausage-link" retinal veins, mucosal bleeding, and confusion. Lymphadenopathy, hepatosplenomegaly, neuropathy, and cryoglobulins are common, but lytic bone lesions, hypercalcemia, and renal failure point instead to myeloma. Symptomatic hyperviscosity is treated with emergent plasmapheresis, followed by a BTK inhibitor or bendamustine-rituximab.

Rituximab alone can transiently raise IgM (IgM flare), so patients with high IgM undergo plasmapheresis first; red-cell transfusion is delayed until viscosity falls because it thickens the blood further.

T-cell lymphomas and special settings

Adult T-cell leukemia/lymphoma. HTLV-1 is endemic in Japan, the Caribbean, and West Africa and spreads by breast milk, sex, and blood. Decades later, CD4+ T cells with multilobed "flower" nuclei cause hypercalcemia with lytic bone lesions (tumor PTHrP and osteoclast activation), skin lesions, lymphadenopathy, and hepatosplenomegaly; the acute form carries a poor prognosis.

Mycosis fungoides and Sézary syndrome. Mycosis fungoides is a lymphoma of CD4+ skin-homing T cells that produces itchy patches, then plaques, then tumors, often mistaken for eczema or psoriasis. Biopsy shows epidermotropism with Pautrier microabscesses. Early disease is managed with skin-directed therapy such as topical steroids and phototherapy. Sézary syndrome is the leukemic form: erythroderma, generalized lymphadenopathy, and circulating T cells with cerebriform nuclei.

Primary CNS lymphoma. Usually a DLBCL confined to the brain, eyes, or CSF, it affects immunocompetent older adults and patients with AIDS and CD4 counts below 50 (EBV-driven). MRI shows one or a few homogeneously enhancing periventricular lesions (ring-enhancing in AIDS), unlike the multiple ring-enhancing basal ganglia lesions of toxoplasmosis. Steroids are withheld until stereotactic biopsy because they shrink the tumor and spoil the histology; slit-lamp and CSF examination complete staging. High-dose methotrexate–based chemotherapy is the backbone (plus antiretroviral therapy in HIV); resection adds nothing, and radiation alone relapses and is neurotoxic.

Post-transplant lymphoproliferative disorder. Impaired T-cell surveillance lets EBV-infected B cells proliferate after solid-organ or stem-cell transplant, most often in the first year and in EBV-seronegative recipients of EBV-positive organs, typically children. Fever, lymphadenopathy, or a mass in the allograft or GI tract is typical. Reducing immunosuppression is the first step, allowing EBV-specific T cells to recover; rituximab is added next, and chemotherapy such as R-CHOP is reserved for nonresponders.