Definition and epidemiology
Lymphoma encompasses a diverse group of malignancies originating from lymphocytes. The two major categories are Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), distinguished by histopathology and clinical behavior.
Hodgkin lymphoma accounts for approximately 10% of all lymphomas. It exhibits a bimodal age distribution with peaks in the third decade and after age 55. The annual incidence is roughly 2-3 per 100,000 in developed countries. Classical HL (95% of cases) is characterized by Reed-Sternberg cells in an inflammatory background; nodular lymphocyte-predominant HL (5%) has a different cell of origin and behavior.
Non-Hodgkin lymphoma comprises more than 60 distinct subtypes. The most common include diffuse large B-cell lymphoma (DLBCL, ~30% of NHL), follicular lymphoma (20%), and marginal zone lymphomas. NHL incidence increases with age, with a median age at diagnosis around 65 years. Annual incidence is approximately 20 per 100,000. Risk is slightly higher in males. Certain subtypes show geographic variation: Burkitt lymphoma is endemic in equatorial Africa, while MALT lymphomas of the stomach are more common in regions with high Helicobacter pylori prevalence.
- Reed-Sternberg cells (CD15+, CD30+) are pathognomonic for classical Hodgkin lymphoma
- Hodgkin lymphoma spreads contiguously; non-Hodgkin lymphoma spreads non-contiguously
- B symptoms (fever, night sweats, weight loss >10%) worsen prognosis and upstage disease
- Excisional lymph node biopsy is required for diagnosis; FNA is insufficient
- Alcohol-induced lymph node pain is rare but specific for Hodgkin lymphoma
- Gastric MALT lymphoma regresses with H. pylori eradication in most early cases
- Burkitt lymphoma has t(8;14) translocation causing MYC overexpression; requires CNS prophylaxis
- EBV is associated with endemic Burkitt, some Hodgkin lymphoma, and post-transplant lymphoproliferative disorder
Etiology and risk factors
The etiology of lymphoma is multifactorial, involving genetic predisposition, immune dysfunction, infectious agents, and environmental exposures.
Immunodeficiency
- HIV/AIDS: Dramatically increases NHL risk, particularly primary CNS lymphoma and Burkitt lymphoma
- Organ transplantation: Immunosuppressive therapy increases risk of post-transplant lymphoproliferative disorder (PTLD)
- Congenital immunodeficiency syndromes: Ataxia-telangiectasia, Wiskott-Aldrich syndrome, common variable immunodeficiency
Infectious agents
- Epstein-Barr virus (EBV): Associated with Burkitt lymphoma, Hodgkin lymphoma (especially mixed cellularity subtype), PTLD, and some DLBCL subtypes
- Helicobacter pylori: Causative agent in gastric MALT lymphoma
- Human T-lymphotropic virus type 1 (HTLV-1): Causes adult T-cell leukemia/lymphoma
- Hepatitis C virus: Associated with splenic marginal zone lymphoma and lymphoplasmacytic lymphoma
- Human herpesvirus 8 (HHV-8): Linked to primary effusion lymphoma
Autoimmune conditions
- Sjögren syndrome: Increased risk of MALT lymphoma
- Celiac disease: Associated with enteropathy-associated T-cell lymphoma
- Rheumatoid arthritis and systemic lupus erythematosus: Modest increase in NHL risk
Chemical and occupational exposures
- Pesticides, herbicides (particularly phenoxyacetic acids)
- Organic solvents (benzene)
- Ionizing radiation
Genetic factors
Family history of lymphoma confers 2-4 fold increased risk. Specific genetic polymorphisms in immune regulation and DNA repair genes have been implicated.
Pathophysiology
Lymphomagenesis involves malignant transformation of lymphocytes at various stages of differentiation, leading to uncontrolled proliferation and impaired apoptosis.
Hodgkin lymphoma
Classical HL is characterized by rare malignant Reed-Sternberg (RS) cells and Hodgkin cells (mononuclear variants) within an abundant inflammatory infiltrate of reactive lymphocytes, eosinophils, plasma cells, and histiocytes. RS cells are typically clonal B cells that have lost most B-cell markers and express CD15 and CD30. The pathogenesis involves constitutive activation of NF-κB signaling. EBV is detected in RS cells in approximately 40% of cases in developed countries. The tumor cells secrete cytokines (IL-5, IL-13, TGF-β) that recruit the reactive infiltrate and may contribute to systemic symptoms.
Non-Hodgkin lymphoma
NHL subtypes arise from B cells (85-90%), T cells (10-15%), or rarely NK cells. Pathogenesis varies by subtype:
- Chromosomal translocations: t(14;18) in follicular lymphoma leads to BCL2 overexpression and impaired apoptosis; t(8;14) in Burkitt lymphoma causes MYC deregulation and rapid proliferation
- Oncogene activation and tumor suppressor inactivation: TP53, BCL6, and MYC alterations are common in aggressive NHL
- Immune evasion: Tumor cells alter antigen presentation and express immune checkpoint ligands
- Microenvironment: Follicular lymphoma cells depend on interactions with follicular dendritic cells and T helper cells
Lymphomas are classified as indolent (slow-growing, often incurable but compatible with long survival) or aggressive (rapid growth, life-threatening without treatment but potentially curable). Indolent lymphomas may transform to aggressive forms over time.
Clinical features
Lymphadenopathy
The most common presentation is painless, persistent lymph node enlargement. In HL, lymphadenopathy typically begins in cervical or supraclavicular nodes and spreads in a predictable, contiguous pattern. NHL more often presents with widespread, non-contiguous nodal involvement. Nodes are usually firm, rubbery, and non-tender. Alcohol-induced pain in involved nodes (rare but specific for HL) is a classic but uncommon finding.
Extranodal disease
NHL more commonly involves extranodal sites than HL. Common sites include:
- Gastrointestinal tract: Stomach (MALT lymphoma), small bowel (enteropathy-associated T-cell lymphoma)
- Skin: Mycosis fungoides, primary cutaneous B-cell lymphoma
- Central nervous system: Primary CNS lymphoma in immunocompromised patients
- Bone marrow: Follicular lymphoma, mantle cell lymphoma
- Waldeyer ring: Tonsils and nasopharynx
Systemic (B) symptoms
Present in approximately 30-40% of patients and more common in advanced disease:
- Fever: Temperature >38°C without infection
- Drenching night sweats: Requiring change of clothing or bedding
- Unintentional weight loss: >10% of body weight over 6 months
B symptoms are more common in HL than NHL and indicate a worse prognosis. Pruritus is common in HL but is not a B symptom.
Mass effects and organ dysfunction
- Mediastinal mass: Superior vena cava syndrome, cough, dyspnea (common in nodular sclerosis HL and primary mediastinal large B-cell lymphoma)
- Abdominal mass: Early satiety, bowel obstruction
- Splenomegaly: Left upper quadrant fullness, early satiety
- Bone marrow involvement: Cytopenias
Other manifestations
- Immunologic phenomena: Autoimmune hemolytic anemia, immune thrombocytopenia (warm AIHA in NHL)
- Hyperviscosity syndrome: In lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)
- Paraneoplastic neurologic syndromes: Rare
Diagnosis
Excisional lymph node biopsy
The gold standard for diagnosis. Fine-needle aspiration is inadequate because lymphoma diagnosis requires assessment of architecture. Core needle biopsy may be acceptable if excisional biopsy is not feasible. The pathologist evaluates morphology, immunophenotype (via immunohistochemistry and/or flow cytometry), and genetic/molecular features.
Histopathology
Hodgkin lymphoma: Reed-Sternberg cells (large binucleate or multinucleate cells with prominent nucleoli giving an "owl's eye" appearance) and Hodgkin cells in a reactive background. Classical HL subtypes: nodular sclerosis (most common, collagen bands), mixed cellularity (EBV association), lymphocyte-rich, lymphocyte-depleted. Immunophenotype: CD15+, CD30+, CD20−/weak.
Non-Hodgkin lymphoma: Architecture (follicular, diffuse, nodular) and cytology (small vs large cells) guide subtype classification. Immunophenotyping distinguishes B-cell (CD19, CD20, CD79a) from T-cell (CD3, CD5, CD7) origin. Specific markers aid subtype diagnosis: CD10 and BCL6 in follicular lymphoma, cyclin D1 in mantle cell lymphoma.
Staging investigations
Ann Arbor staging system (I-IV based on number and location of involved nodal regions, with A/B suffix for absence/presence of B symptoms):
- CT chest, abdomen, and pelvis with contrast: Assess nodal and extranodal involvement
- PET-CT: Standard for HL and aggressive NHL (DLBCL, Burkitt); provides baseline for response assessment. Fluorodeoxyglucose (FDG) avidity varies by subtype; indolent lymphomas may have low uptake
- Bone marrow biopsy: Indicated in most NHL and stage I-II HL if it would change management; less commonly needed with routine PET-CT use
- Laboratory tests: Complete blood count, comprehensive metabolic panel, LDH (prognostic marker), uric acid, hepatitis B and C serology, HIV testing
- Additional tests as indicated: Lumbar puncture for CNS prophylaxis consideration (Burkitt, lymphoblastic lymphoma, testicular DLBCL), echocardiogram or MUGA scan (baseline cardiac function before anthracyclines)
Prognostic indices
- International Prognostic Score (IPS) for HL: Age ≥45, male sex, stage IV, albumin <4 g/dL, hemoglobin <10.5 g/dL, WBC ≥15,000, lymphocytes <600 or <8% of WBC
- International Prognostic Index (IPI) for aggressive NHL: Age >60, elevated LDH, ECOG performance status ≥2, Ann Arbor stage III-IV, >1 extranodal site
- Follicular Lymphoma IPI (FLIPI): Age, stage, hemoglobin, LDH, number of nodal areas
Differential diagnosis
Infectious lymphadenopathy
- Infectious mononucleosis: Young patient, fever, pharyngitis, atypical lymphocytosis, positive monospot or EBV serology
- Tuberculosis: Chronic symptoms, risk factors, caseating granulomas on biopsy
- Toxoplasmosis: Posterior cervical nodes, exposure to cats, positive serology
- HIV acute retroviral syndrome: Generalized lymphadenopathy, fever, rash
- Cat-scratch disease: History of cat scratch, regional lymphadenopathy
Other malignancies
- Metastatic carcinoma: Hard, fixed nodes; primary tumor may be evident; epithelial markers on immunohistochemistry
- Acute leukemia: Pancytopenia, circulating blasts, bone marrow involvement
Autoimmune and inflammatory
- Sarcoidosis: Bilateral hilar lymphadenopathy, non-caseating granulomas, elevated ACE
- Castleman disease: Localized or multicentric lymphadenopathy, systemic inflammation; HHV-8 association in HIV patients
Benign lymphoid proliferations
- Reactive lymphoid hyperplasia: Recent infection, tender nodes that resolve
- Kikuchi disease: Necrotizing lymphadenitis, young Asian females, fever
Management
Treatment is highly subtype-specific. General principles include accurate histologic classification, appropriate staging, and risk stratification.
Hodgkin lymphoma
Early-stage favorable (IA-IIA without risk factors): Combined modality therapy with abbreviated chemotherapy (ABVD for 2-4 cycles) followed by involved-site radiotherapy. Some protocols use chemotherapy alone with PET-adapted approach.
Early-stage unfavorable and advanced-stage (IIB-IV): ABVD chemotherapy for 6 cycles remains standard. BEACOPPescalated (more toxic but potentially more effective) is used in some centers for advanced disease. PET-CT after 2 cycles guides treatment intensification or de-escalation. Consolidative radiotherapy for initial bulky disease or residual PET-positive lesions.
Relapsed/refractory: Salvage chemotherapy followed by autologous stem cell transplant for chemotherapy-sensitive disease. Brentuximab vedotin (anti-CD30 antibody-drug conjugate) and checkpoint inhibitors (nivolumab, pembrolizumab) have activity in relapsed HL.
Non-Hodgkin lymphoma
Indolent lymphomas (follicular, marginal zone): "Watch and wait" is appropriate for asymptomatic, low-burden disease. Treatment indications include symptomatic disease, organ compromise, cytopenias, rapid progression, or patient preference. First-line therapy typically combines anti-CD20 monoclonal antibody (rituximab or obinutuzumab) with chemotherapy (bendamustine, CHOP, or CVP). Rituximab maintenance after induction improves progression-free survival. Radiotherapy is curative for localized stage I disease.
Aggressive B-cell lymphomas (DLBCL): R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for 6 cycles is standard. CNS prophylaxis (intrathecal or high-dose methotrexate) for high-risk patients. Interim PET-CT after 2-4 cycles assesses response. Consolidative radiotherapy for initial bulky disease in some protocols.
Burkitt lymphoma: Intensive, short-duration chemotherapy with CNS prophylaxis. Regimens include dose-adjusted EPOCH-R or CODOX-M/IVAC. High cure rates but significant toxicity.
Mantle cell lymphoma: Combination immunochemotherapy (R-CHOP or more intensive regimens like R-HyperCVAD) followed by autologous stem cell transplant in eligible patients. Rituximab maintenance improves outcomes.
Peripheral T-cell lymphomas: CHOP-based chemotherapy; outcomes generally worse than B-cell lymphomas. Autologous transplant consolidation in first remission for eligible patients.
Primary CNS lymphoma: High-dose methotrexate-based chemotherapy (with or without rituximab) followed by consolidation (whole-brain radiotherapy or autologous transplant). Avoid steroids before biopsy as they rapidly lyse lymphoma cells.
Gastric MALT lymphoma: H. pylori eradication with antibiotics achieves remission in 60-80% of cases when localized and H. pylori-positive. Radiotherapy or rituximab for H. pylori-negative or persistent disease.
Supportive care
- Tumor lysis syndrome prophylaxis: Allopurinol or rasburicase, hydration, monitoring electrolytes for high-burden or rapidly proliferative lymphomas
- Antimicrobial prophylaxis: PCP prophylaxis during chemotherapy; antiviral prophylaxis if hepatitis B positive
- Growth factors: G-CSF to prevent febrile neutropenia in high-risk regimens
- Fertility preservation: Discuss before treatment in patients of reproductive age
Complications and prognosis
Prognosis
Hodgkin lymphoma: Overall highly curable. Five-year survival exceeds 85% for all stages combined. Early-stage favorable disease has >95% cure rate. Advanced-stage disease has 70-80% cure rate with modern therapy. Relapsed HL after autologous transplant has cure rates of 40-60%.
Non-Hodgkin lymphoma: Outcomes vary dramatically by subtype. Indolent lymphomas have median survival of 10-20 years but are generally incurable; treatment provides disease control. Aggressive lymphomas are potentially curable: DLBCL has 60-70% cure rate with R-CHOP. Burkitt lymphoma has >80% cure in children and young adults. Primary CNS lymphoma has median survival of 3-5 years with modern therapy. Peripheral T-cell lymphomas have poorer outcomes than most B-cell lymphomas.
Treatment-related complications
Acute: Myelosuppression (infection, bleeding), nausea/vomiting, mucositis, tumor lysis syndrome, infusion reactions, peripheral neuropathy (vincristine), hemorrhagic cystitis (cyclophosphamide).
Long-term: Secondary malignancies (acute leukemia, solid tumors), cardiovascular disease (anthracycline cardiomyopathy, radiation-induced heart disease), pulmonary fibrosis (bleomycin), infertility, hypothyroidism (neck irradiation), premature menopause.
Disease-related complications
- Immunosuppression: Both disease and treatment increase infection risk
- Bone marrow failure: Cytopenias from marrow involvement
- Organ infiltration: Liver dysfunction, renal impairment, neurologic deficits
- Transformation: Indolent lymphomas may transform to aggressive subtypes (Richter transformation in CLL, high-grade transformation of follicular lymphoma), with poor prognosis
- Autoimmune phenomena: Hemolytic anemia, thrombocytopenia
Surveillance
Regular follow-up includes physical examination, blood tests, and imaging. PET-CT is used for end-of-treatment assessment in FDG-avid lymphomas but routine surveillance imaging is controversial due to false positives and radiation exposure. Follow-up focuses on detecting relapse, monitoring for late effects, and screening for secondary malignancies.
ABVD chemotherapy for Hodgkin lymphoma: Adriamycin (doxorubicin), Bleomycin, Vinblastine, Dacarbazine. CHOP for aggressive NHL: Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), Prednisone.
Practice questions
1. A 28-year-old man presents with a 3-month history of painless right cervical lymphadenopathy. He reports intermittent fevers and night sweats requiring him to change his clothes. He has lost 7 kg unintentionally. Examination reveals a 4 cm firm, non-tender right cervical lymph node and a 3 cm left supraclavicular node. Excisional biopsy shows large binucleate cells with prominent eosinophilic nucleoli in a background of lymphocytes, eosinophils, and fibrosis. Immunohistochemistry is positive for CD15 and CD30. What is the most likely diagnosis?
2. A 68-year-old woman with a 2-year history of painless waxing and waning cervical and axillary lymphadenopathy now develops worsening fatigue, early satiety, and a 6 kg weight loss over 2 months. Examination reveals diffuse lymphadenopathy and splenomegaly. CT shows extensive lymphadenopathy above and below the diaphragm. Excisional lymph node biopsy shows sheets of large cells with high mitotic rate destroying normal architecture. She was previously diagnosed with follicular lymphoma. What is the most likely explanation?
3. A 45-year-old man with HIV (CD4 count 80 cells/μL, not on antiretroviral therapy) presents with 3 weeks of confusion, headache, and right-sided weakness. MRI brain shows a solitary ring-enhancing lesion in the left frontal lobe. Toxoplasma serology is negative. Stereotactic biopsy reveals a lymphoid infiltrate with large atypical cells that are CD20+ and CD10+. CSF cytology is positive for malignant lymphocytes. What is the most appropriate initial treatment?
Frequently asked questions
What causes lymphoma?
Lymphoma results from malignant transformation of lymphocytes due to a combination of genetic mutations, immune dysfunction, infections, and environmental factors. Specific causes include immunodeficiency states (HIV, immunosuppressive therapy), viral infections (EBV, HTLV-1, HHV-8), bacterial infection (H. pylori in gastric MALT lymphoma), autoimmune diseases, and chemical exposures. Many cases have no identifiable cause. Family history modestly increases risk.
What are the first symptoms of lymphoma?
The most common initial symptom is painless, progressive enlargement of lymph nodes, typically in the neck, armpits, or groin. Lymph nodes are usually firm and rubbery. Some patients develop systemic B symptoms: fevers, drenching night sweats, or unintentional weight loss exceeding 10% of body weight. Others may notice a mediastinal mass causing cough or shortness of breath, or abdominal fullness from splenomegaly or mesenteric nodes. Many patients are asymptomatic and lymphadenopathy is discovered incidentally.
How is lymphoma diagnosed?
Lymphoma is diagnosed by excisional lymph node biopsy, which is the gold standard. The entire node or a large piece is removed surgically and analyzed by a pathologist who examines tissue architecture, cell morphology, and performs immunohistochemistry to determine lymphoma subtype. Fine-needle aspiration is inadequate. After diagnosis, staging involves CT and PET-CT scans, bone marrow biopsy in many cases, and blood tests including LDH and complete blood count to assess disease extent and prognosis.
Is lymphoma curable?
Curability depends on the lymphoma subtype. Hodgkin lymphoma is highly curable, with over 85% long-term survival across all stages using chemotherapy and/or radiotherapy. Aggressive non-Hodgkin lymphomas like diffuse large B-cell lymphoma and Burkitt lymphoma are also potentially curable, with 60-80% cure rates. Indolent lymphomas like follicular lymphoma are generally incurable but compatible with long survival (median 10-20 years), managed with intermittent treatment. Relapsed or refractory disease may still achieve cure with stem cell transplant or newer therapies.
Hodgkin vs non-Hodgkin lymphoma — what is the difference?
Hodgkin lymphoma is distinguished by the presence of Reed-Sternberg cells on pathology and represents about 10% of lymphomas. It typically spreads contiguously between adjacent lymph node groups, has a bimodal age distribution, often starts in cervical nodes, and is highly curable. Non-Hodgkin lymphoma comprises over 60 different subtypes of lymphoid malignancies, spreads non-contiguously, accounts for 90% of lymphomas, increases with age, more commonly involves extranodal sites, and has variable prognosis depending on subtype ranging from indolent to aggressive.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: C85.9
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.