Lymphoma: Types, Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Lymphoma is a malignancy of lymphocytes — B-cells, T-cells, or NK cells — arising from any stage of lymphocyte development and capable of involving lymph nodes, spleen, bone marrow, and extranodal organs. Lymphomas are classified into two broad categories: Hodgkin lymphoma (HL, approximately 8,500 US cases/year, characterized by Reed-Sternberg cells) and non-Hodgkin lymphoma (NHL, approximately 80,000 US cases/year). NHL encompasses over 60 distinct biological entities defined by the WHO classification system based on cell of origin, molecular genetics, and clinical behavior. B-cell NHLs (approximately 85% of NHL) include Diffuse Large B-Cell Lymphoma (DLBCL, 25-30% of all NHL, the most common aggressive subtype), Follicular Lymphoma (20-25%, most common indolent subtype), Mantle Cell Lymphoma (6%), Marginal Zone Lymphoma (8%), Burkitt Lymphoma (3%), and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL, 7%). T-cell NHLs (approximately 10% of NHL) include peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), and cutaneous T-cell lymphomas. NHL incidence has increased approximately 3-4-fold since the 1970s, partly due to HIV epidemic and aging population. Survival has improved dramatically with rituximab, targeted agents, and CAR-T cell therapy.

Risk factors for lymphoma vary substantially by subtype. Immunosuppression is the strongest general risk factor: HIV infection increases NHL risk 50-100-fold (primarily aggressive NHL subtypes: DLBCL, primary CNS lymphoma, Burkitt lymphoma), and post-transplant immunosuppression causes post-transplant lymphoproliferative disorder (PTLD) predominantly EBV-driven. Chronic infections drive specific lymphoma subtypes: EBV causes endemic Burkitt lymphoma (African children), EBV-positive DLBCL, HL, and NK/T-cell lymphoma; Helicobacter pylori chronic gastritis causes gastric MALT lymphoma (eradication of H. pylori cures early-stage gastric MALT); HTLV-1 causes adult T-cell leukemia/lymphoma in endemic regions (Japan, Caribbean). Hepatitis C virus is associated with splenic marginal zone lymphoma and cryoglobulinemic lymphoma. Autoimmune diseases — Sjogren syndrome, systemic lupus erythematosus, rheumatoid arthritis — confer 2-5-fold elevated NHL risk. Celiac disease predisposes to enteropathy-associated T-cell lymphoma (EATL). Obesity and specific occupational chemical exposures (herbicides, particularly phenoxyacetic acids; pesticides) modestly increase NHL risk. Age is a risk factor for most NHL subtypes (median age 60-70 years), while HL has a bimodal distribution with peak in young adults aged 20-34.

The most common presenting feature of lymphoma is lymphadenopathy — painless, progressive enlargement of lymph nodes, most commonly cervical, supraclavicular, axillary, or inguinal. Nodes are typically firm, rubbery, non-tender, and do not regress after antibiotics. Mediastinal lymphadenopathy (particularly in HL and primary mediastinal large B-cell lymphoma, PMBL) causes cough, dyspnea, and superior vena cava syndrome. B-symptoms — unexplained fever exceeding 38°C, drenching night sweats, and weight loss exceeding 10% of body weight over 6 months — occur in approximately 30-40% of HL and aggressive NHL patients and indicate a worse prognosis. Splenomegaly causes left upper quadrant fullness, early satiety, and left shoulder pain; massive splenomegaly with cytopenia is characteristic of splenic marginal zone lymphoma. Extranodal disease may affect the gastrointestinal tract (abdominal pain, GI bleeding, bowel obstruction), CNS (headache, focal neurological deficits, cranial nerve palsies), skin (CTCL, other NHLs), bone marrow (cytopenias), lungs, or orbit. Primary CNS lymphoma presents with rapidly progressive cognitive changes, focal deficits, or personality change in immunocompromised patients.

Excisional lymph node biopsy is strongly preferred over core needle biopsy to preserve lymph node architecture essential for WHO classification. Where excision is not feasible (mediastinal, retroperitoneal nodes), CT-guided core needle biopsy with ancillary flow cytometry, immunohistochemistry, and FISH is acceptable. Mandatory workup includes complete immunophenotyping (CD markers, BCL2/BCL6/MYC by IHC and FISH for DLBCL), cytogenetics (karyotype, FISH for specific translocations: t(14;18) in FL, t(8;14) in Burkitt, t(11;14) in MCL, MYC, BCL2, BCL6 double/triple-hit status in DLBCL), and molecular pathology (clonality, MYD88 L265P in lymphoplasmacytic lymphoma, NOTCH1 in MCL). PET-CT with 18F-FDG is the gold standard for staging FDG-avid lymphomas (all aggressive B-cell, HL, MALT); CT chest-abdomen-pelvis without PET for CLL/SLL and some indolent NHLs. Ann Arbor/Lugano staging (I-IV) guides treatment. Bone marrow trephine biopsy is required for staging many NHLs. DLBCL: IPI (International Prognostic Index, 0-5 based on age, performance status, LDH, stage, extranodal sites) stratifies treatment. MYC/BCL2 double-hit or MYC/BCL2/BCL6 triple-hit DLBCL (high-grade B-cell lymphoma by WHO) requires dose-escalated induction (DA-EPOCH-R).

DLBCL (aggressive B-cell): R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg) every 21 days for 6-8 cycles achieves cure in approximately 60-65% overall (80% for low-risk IPI 0-1). Pola-R-CHP (polatuzumab vedotin, an anti-CD79b antibody-drug conjugate, replacing vincristine in R-CHOP) improves 2-year PFS for all DLBCL per POLARIX trial. Double/triple-hit DLBCL: DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab). Relapsed/refractory DLBCL: second-line R-ICE or R-DHAP, then high-dose chemotherapy plus autologous SCT for chemosensitive disease. In early-relapsed DLBCL (within 12 months of R-CHOP), CAR-T cell therapy (axicabtagene ciloleucel, ZUMA-7 trial: superior EFS vs standard-of-care salvage+autoSCT; lisocabtagene maraleucel, TRANSFORM trial) is now preferred second-line therapy. Follicular lymphoma: watch-and-wait for asymptomatic low-tumor-burden; R-CVP or R-CHOP or obinutuzumab-CHOP for GELF-criteria disease; lenalidomide-rituximab (RELEVANCE trial); PI3K inhibitors (copanlisib, umbralisib) for relapsed. Mantle cell lymphoma: ibrutinib plus rituximab or VR-CAP; acalabrutinib or zanubrutinib (2nd-gen BTK inhibitors). HL: BV-AVD or ABVD (see Hodgkin lymphoma entry).

Prognosis varies dramatically by subtype and stage. HL (all stages): 5-year OS approximately 87%; Stage I-II exceeds 95%. DLBCL: overall cure rate approximately 60-65%; IPI 0-1 (low risk) 5-year OS greater than 80%; IPI 4-5 (high risk) 5-year OS approximately 40%; double-hit/triple-hit DLBCL approximately 30-40% 5-year OS with DA-EPOCH-R. Follicular lymphoma: indolent, median OS exceeds 15-20 years but rarely cured with standard therapy; transformation to DLBCL occurs in approximately 3% per year and worsens prognosis. Burkitt lymphoma: intensive chemotherapy (CODOX-M/IVAC) achieves cure in approximately 70-80% of limited-stage and 50-60% of advanced-stage adult patients. Primary CNS lymphoma: median OS approximately 3-5 years with methotrexate-based regimens plus autologous SCT in selected patients. Mantle cell lymphoma: incurable with standard therapy; median OS 5-7 years, improving with BTK inhibitors.

Prevention focuses on modifiable risk factors and infectious agent management. HIV prevention (condoms, PrEP with tenofovir/emtricitabine for high-risk individuals) and early effective ART reduces HIV-associated NHL risk substantially. Helicobacter pylori eradication with triple therapy (omeprazole, amoxicillin, clarithromycin, 14 days) is both therapeutic and preventive for gastric MALT lymphoma: it achieves complete remission in approximately 75% of early-stage HP-positive gastric MALT and prevents progression. HCV treatment with direct-acting antivirals achieves SVR and may cause regression of HCV-associated splenic marginal zone lymphoma and cryoglobulinemic lymphoma. Post-transplant lymphoproliferative disorder (PTLD) prevention includes minimizing immunosuppression, monitoring EBV viral load post-transplant, and using rituximab-based pre-emptive therapy for rising EBV titers. Celiac disease patients should strictly maintain a gluten-free diet to reduce EATL risk. There is no established population-based screening for lymphoma, but prompt evaluation of persistent lymphadenopathy enables earlier diagnosis. Maintaining healthy body weight, as obesity is a modest NHL risk factor.

Seek prompt medical evaluation for any lymph node swelling that persists beyond 4 weeks, does not respond to antibiotics, and is firm, rubbery, non-tender, and gradually increasing in size — this is the classical presentation of lymphoma. Multiple enlarged lymph nodes in different body regions appearing simultaneously warrant urgent evaluation. B-symptoms (unexplained fever, drenching night sweats requiring clothing change, and unintentional weight loss exceeding 10% of body weight over 6 months) combined with any lymphadenopathy require urgent hematology referral. New-onset progressive breathlessness or superior vena cava syndrome features (facial swelling, red face, distended neck veins, arm swelling) may indicate mediastinal lymphoma — a medical emergency requiring same-day evaluation. Abdominal swelling, early satiety, or palpable abdominal mass may indicate splenic or retroperitoneal lymphoma. HIV-positive individuals or immunosuppressed transplant recipients who develop lymphadenopathy or B-symptoms require urgent evaluation for HIV-associated or post-transplant lymphoma. Anyone previously treated for lymphoma who notices new lymph node swelling, B-symptoms, or the return of original symptoms should contact their oncology team promptly, as relapse requires timely assessment for salvage therapy including CAR-T cell eligibility.