Heterogeneous group of lymphoid malignancies (mostly B-cell) — DLBCL most common aggressive type, follicular lymphoma most common indolent.
Also known as: NHL, non-Hodgkin lymphoma, DLBCL, follicular lymphoma, Burkitt lymphoma, MALT, mantle cell lymphoma
Overview
Diverse group of lymphoid neoplasms arising from B cells (~85%), T cells, or NK cells, distinct from Hodgkin lymphoma by absence of Reed-Sternberg cells. Includes >60 WHO-defined entities ranging from indolent (follicular lymphoma, marginal zone, MALT, CLL/SLL) to aggressive (DLBCL, mantle cell, Burkitt, primary CNS lymphoma) and very aggressive (Burkitt, lymphoblastic lymphoma).
Epidemiology
Sixth most common cancer in US adults; annual incidence ~20 per 100,000. Median age at diagnosis ~67. DLBCL is the most common type (~30%), followed by follicular lymphoma (~20%). Slight male predominance. Incidence has risen over recent decades partly from improved diagnosis and aging population.
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Inherited: variants in HLA, TNFSF13B, RHOA, others
Pathophysiology
B-cell lymphomas arise from various stages of B-cell differentiation: pre-germinal center (mantle cell), germinal center (follicular, Burkitt, GCB-DLBCL), post-germinal center (ABC-DLBCL, plasmablastic, multiple myeloma), and marginal zone (MALT, splenic). Characteristic translocations involve juxtaposition of oncogenes (BCL2, BCL6, MYC, CCND1) to immunoglobulin enhancers, deregulating expression. T-cell lymphomas often involve mature peripheral T cells (PTCL, AITL, ALK+ ALCL) and tend to be more aggressive.
Clinical presentation
Symptoms
Lymphadenopathy — painless, peripheral or central; often progressive over weeks to months
B symptoms — fever, drenching night sweats, weight loss >10% (especially in aggressive lymphomas)
Extranodal disease (more common in NHL than Hodgkin): GI tract (MALT in stomach, intestinal involvement), CNS (primary CNS lymphoma, leptomeningeal), skin (cutaneous T-cell lymphomas mycosis fungoides/Sézary), bone marrow, testis, sinuses
Testicular mass (testicular lymphoma, often DLBCL)
Waldeyer's ring involvement (tonsillar enlargement, especially marginal zone, DLBCL)
Classic findings
Rapidly enlarging supradiaphragmatic node in an older adult with B symptoms — biopsy reveals diffuse large B-cell lymphoma. Burkitt: jaw mass in pediatric African patient (endemic) or abdominal mass in immunodeficient host (sporadic).
Differential diagnosis
Hodgkin lymphoma — Reed-Sternberg cells, CD30+ CD15+ CD20- CD45-, contiguous spread, bimodal age distribution
Reactive lymphadenopathy (viral, bacterial) — Tender, mobile nodes <1-2 cm, identifiable cause; resolves within weeks
Metastatic carcinoma — Hard, fixed nodes; primary site identifiable; characteristic histology and IHC
Tissue diagnosis with WHO-defined histologic and immunophenotypic criteria specific to subtype. Ann Arbor staging used; International Prognostic Index (IPI) prognosticates DLBCL and other aggressive lymphomas (age, stage, LDH, performance status, extranodal sites).
Labs
Excisional lymph node biopsy ESSENTIAL — needle biopsy may miss architecture; flow cytometry, IHC, cytogenetics, FISH on fresh tissue
Follicular lymphoma (low grade, indolent): observation if asymptomatic and low burden; bendamustine + rituximab or R-CHOP if symptomatic; rituximab maintenance
Mantle cell lymphoma: bendamustine-rituximab; for younger fit patients, intensive induction (R-CHOP/R-DHAP or Nordic regimen) followed by autologous HSCT consolidation; BTK inhibitors (acalabrutinib, ibrutinib, zanubrutinib) for relapsed/refractory; chemo-free regimens (BTK inhibitor + rituximab + venetoclax) emerging
Burkitt lymphoma: intensive multi-agent regimen (R-EPOCH dose-adjusted, or CODOX-M/IVAC) with aggressive tumor lysis prophylaxis (rasburicase, hyperhydration) and CNS prophylaxis
MALT lymphoma (gastric, H. pylori-positive): H. pylori eradication ALONE achieves regression in ~75-80% of localized cases; rituximab ± involved-site radiation if no response
Marginal zone (splenic): rituximab; splenectomy if symptomatic and HCV-negative
Secondary malignancies: AML/MDS (especially with alkylators); other solid tumors
Infection from immunosuppression (PJP, fungal, viral reactivation)
Bowel perforation from rapidly responding GI lymphoma
CNS relapse — devastating in DLBCL with high-risk features
Transformation of indolent lymphoma (follicular → DLBCL ~3%/year cumulative)
PANCE pearls
Indolent vs aggressive distinction drives management: indolent = often observed initially, may not be curable; aggressive = treated immediately, often curable. (Paradox: aggressive lymphomas are more curable than indolent because they respond to chemotherapy.)
DLBCL = most common NHL; R-CHOP × 6 cures ~60-70%; subtype refinement (GCB vs ABC, double/triple-hit) guides intensification.
Gastric MALT lymphoma: treat H. PYLORI FIRST — eradication alone produces remission in most localized cases. This is one of the few cancers cured by antibiotics.
Burkitt lymphoma is the FASTEST-GROWING human tumor (doubling time ~24 hours) — initiate treatment urgently and prophylax against severe tumor lysis.
Mantle cell lymphoma is a CD5+ B-cell lymphoma that lacks CD23 (distinguishing it from CLL); CD23 is positive in CLL and negative in mantle cell.
International Prognostic Index (IPI): age >60, stage III/IV, LDH elevated, ECOG ≥2, ≥2 extranodal sites — each scores 1 point.
CAR-T cell therapy has revolutionized relapsed/refractory aggressive B-cell lymphomas — axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel induce durable remissions in ~40% of chemo-refractory disease.
Primary CNS lymphoma is almost always DLBCL; treat with high-dose methotrexate-based regimens. AVOID upfront whole-brain radiation in elderly due to severe neurocognitive toxicity.
References
NCCN 2024 — NCCN Clinical Practice Guidelines in Oncology: B-Cell and T-Cell Lymphomas (NCCN.org)
POLARIX — Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma (Tilly et al., NEJM 2022)
ZUMA-1 — Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma (Neelapu et al., NEJM 2017)
GALLIUM — Obinutuzumab for First-Line Treatment of Follicular Lymphoma (Marcus et al., NEJM 2017)
WHO 5th edition — WHO Classification of Haematolymphoid Tumours, 5th edition (2022)
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