Non-Hodgkin Lymphoma
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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Risk factors
- Immunosuppression: HIV (DLBCL, primary CNS, Burkitt), post-transplant (PTLD), congenital immunodeficiency
- Autoimmune disease (Sjögren — MALT salivary lymphoma; Hashimoto — thyroid MALT; SLE — DLBCL)
- Chronic infection: H. pylori (gastric MALT), HCV (splenic marginal zone), HHV-8 (primary effusion lymphoma, Kaposi-associated), HTLV-1 (adult T-cell leukemia/lymphoma — Japan, Caribbean), EBV (Burkitt, post-transplant, immune-deficient), Chlamydia psittaci (ocular adnexal MALT), Borrelia burgdorferi (cutaneous MALT)
- Environmental: agricultural exposures, pesticides, organic solvents, hair dyes (limited evidence)
- Prior chemotherapy/radiation
- 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
- Hepatosplenomegaly
- Compressive symptoms from bulky mass: SVC syndrome, spinal cord compression, ureteral obstruction
- Cytopenia symptoms from marrow involvement
- Burkitt: massive abdominal mass with rapid growth, tumor lysis at diagnosis
- DLBCL: rapidly enlarging nodal mass, often with B symptoms and extranodal involvement
Signs / physical exam
- Lymphadenopathy — often generalized, asymmetric, non-tender, firm, rubbery to hard
- Hepatosplenomegaly
- Pallor (anemia), petechiae (thrombocytopenia)
- Skin lesions (cutaneous T-cell lymphomas, B-cell skin lymphomas)
- 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
- Sarcoidosis — Bilateral hilar lymphadenopathy, non-caseating granulomas, elevated ACE
- Castleman disease — Hyaline-vascular or plasma cell variants; HHV-8 in multicentric; can mimic NHL
- Tuberculosis — Caseating granulomas, AFB stain/culture positive
- Autoimmune lymphoproliferation (ALPS) — Childhood-onset chronic adenopathy, double-negative T cells, FAS mutation
Diagnostic workup
Diagnostic criteria
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
- Immunohistochemistry: B-cell (CD19, CD20, CD79a, PAX5), T-cell (CD2, CD3, CD5, CD7), plasma cell (CD138), Ki-67 (proliferation index)
- FISH for translocations: t(14;18) BCL2 (follicular), t(11;14) CCND1 (mantle cell), t(8;14) MYC (Burkitt), MYC + BCL2 +/- BCL6 (double/triple-hit lymphoma — DLBCL high-grade)
- Cell-of-origin classification in DLBCL (GCB vs ABC) by Hans algorithm
- CBC, CMP, LDH (prognostic — high LDH worse), uric acid, beta-2 microglobulin
- HIV, hepatitis B and C (reactivation with rituximab), HTLV-1 in selected cases
- SPEP if marginal zone or other low-grade B-cell lymphoma
- Beta-HCG in women of reproductive age
- Bone marrow biopsy for staging (sometimes omitted if PET shows marrow involvement)
- LP if high-risk features (testicular, paranasal sinus, breast, epidural, double-hit, ≥2 extranodal sites + high LDH)
Imaging
- PET/CT — staging and response assessment (Deauville 5-point score)
- CT chest/abdomen/pelvis with contrast
- MRI brain for primary CNS lymphoma or suspected CNS involvement
- Echocardiogram (MUGA) before anthracycline
- Endoscopy if GI involvement suspected
Diagnostic algorithm
| Subtype | Cell of Origin | Characteristic Genetics | Key Treatment |
|---|---|---|---|
| DLBCL | Germinal center or post-GC B cell | BCL6, BCL2, MYC (double/triple-hit) | R-CHOP × 6; CAR-T if relapsed |
| Follicular lymphoma | Germinal center B cell | t(14;18) BCL2 | Observation if indolent; BR or R-CHOP |
| Mantle cell lymphoma | Pre-germinal center B cell | t(11;14) CCND1; CD5+ CD23- | BR + auto-HSCT; BTK inhibitors |
| Burkitt lymphoma | Germinal center B cell | t(8;14) MYC | Intensive R-EPOCH/CODOX-M; TLS prophylaxis |
| MALT (gastric) | Marginal zone B cell | t(11;18) API2-MALT1 | H. pylori eradication first |
| Mycosis fungoides / Sézary | Mature T cell (skin) | Variable | Topical therapy, photopheresis |
| PTCL-NOS | Mature peripheral T cell | Heterogeneous | CHOP-based; brentuximab if CD30+ |
| Primary CNS lymphoma | DLBCL of CNS | MYD88, CD79B mutations common | High-dose methotrexate |
Treatment
First-line
- DLBCL: R-CHOP × 6 cycles (rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone); polatuzumab vedotin + R-CHP (POLARIX trial) improves PFS in higher-risk patients; cure rate ~60-70%
- 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
- Primary CNS lymphoma: high-dose methotrexate-based regimen (R-MPV); avoid whole-brain RT in elderly (neurotoxicity)
- T-cell lymphomas: CHOP-based regimens with brentuximab vedotin for CD30+ disease; ALK+ ALCL has favorable prognosis
Second-line / adjunct
- Relapsed/refractory DLBCL: salvage chemotherapy (R-ICE, R-DHAP) + autologous HSCT for chemosensitive disease; CAR-T cell therapy (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) for refractory or relapsed after 2+ lines; bispecific antibodies (epcoritamab, glofitamab) emerging
- Polatuzumab vedotin + bendamustine + rituximab for relapsed DLBCL
- Tafasitamab + lenalidomide for transplant-ineligible relapsed DLBCL
- Rituximab maintenance for follicular lymphoma after induction
- Lenalidomide ± rituximab (R2) for follicular lymphoma
- PI3K inhibitors (copanlisib, duvelisib, idelalisib — limited use due to toxicity)
- EZH2 inhibitor tazemetostat for relapsed follicular lymphoma
- Bispecific antibodies: mosunetuzumab (relapsed FL), glofitamab and epcoritamab (relapsed DLBCL)
- Allogeneic HSCT for selected refractory or transformed disease
- Tumor lysis prophylaxis and CNS prophylaxis (intrathecal methotrexate) for high-risk patients
Complications
- Tumor lysis syndrome — high in Burkitt, double-hit DLBCL, bulky aggressive lymphoma; prophylax with hydration, allopurinol/rasburicase (avoid in G6PD)
- Treatment toxicities: rituximab infusion reactions, HBV reactivation, JC virus/PML; anthracycline cardiotoxicity; vincristine neuropathy
- CAR-T related: cytokine release syndrome, ICANS (neurotoxicity), prolonged cytopenia, hypogammaglobulinemia
- 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.
- Follicular lymphoma t(14;18) BCL2 translocation; mantle cell t(11;14) CCND1; Burkitt t(8;14) MYC.
- 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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