Lymphoma is a cancer of the lymphatic system—a vital part of the immune system that includes lymph nodes, the spleen, thymus gland, and bone marrow. The American Cancer Society estimates approximately 89,380 new cases of lymphoma are diagnosed in the United States each year: roughly 8,570 cases of Hodgkin lymphoma (HL) and 80,810 cases of non-Hodgkin lymphoma (NHL). Lymphoma is the most common blood cancer in the U.S. and the third most common childhood cancer.
The two main categories—Hodgkin lymphoma and non-Hodgkin lymphoma—differ fundamentally in their pathology, behavior, and treatment approaches. NHL is itself a diverse group comprising over 60 distinct subtypes. Advances in immunotherapy, targeted agents, and CAR-T cell therapy have dramatically improved outcomes across many lymphoma types.
Hodgkin Lymphoma (HL)
Hodgkin lymphoma is characterized by the presence of Reed-Sternberg cells—large, abnormal B-lymphocyte derivatives with a distinctive bilobed nucleus (often described as "owl eyes"). HL has a bimodal age distribution, with peaks in young adults (15–35) and older adults (over 55). It typically presents with painless lymphadenopathy, often in the cervical or mediastinal regions, and tends to spread in a contiguous, predictable pattern through adjacent lymph node groups.
Risk factors for Hodgkin lymphoma include prior Epstein-Barr virus infection (infectious mononucleosis), immunosuppression (particularly HIV/AIDS), and family history. HL is slightly more common in males and in individuals of higher socioeconomic status in developed countries.
Classical Hodgkin Lymphoma (cHL)
Accounts for approximately 95% of HL cases and includes four subtypes: nodular sclerosis (most common, ~70%), mixed cellularity (~20%), lymphocyte-rich, and lymphocyte-depleted. Nearly all cHL cases are associated with an inflammatory microenvironment driven by cytokines from Reed-Sternberg cells. Epstein-Barr virus (EBV) is detected in approximately 30–40% of cases.
Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)
Accounts for approximately 5% of HL cases and has a distinct biology featuring "popcorn cells" (lymphocyte-predominant cells) rather than classic Reed-Sternberg cells. NLPHL typically has an indolent course and excellent prognosis but can rarely transform into aggressive NHL.
Symptoms of Lymphoma
Common presenting symptoms include painless lymphadenopathy (swollen lymph nodes), B symptoms (unexplained fever above 38°C, drenching night sweats, and unintentional weight loss exceeding 10% of body weight in 6 months), fatigue, and pruritus (itching). Some patients experience pain in affected lymph nodes after consuming alcohol, which is a classic but uncommon symptom specific to Hodgkin lymphoma. Extranodal NHL can present with site-specific symptoms depending on the organ involved (e.g., abdominal pain, skin lesions, neurological symptoms).
Treatment of Hodgkin Lymphoma
- ABVD chemotherapy — Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine. The standard first-line regimen for most stages of cHL. Early-stage favorable HL typically receives 2 cycles of ABVD plus involved-site radiation therapy (ISRT), achieving cure rates exceeding 90%.
- Brentuximab vedotin (Adcetris) — An antibody-drug conjugate targeting CD30. Used in combination with AVD (A+AVD) as an alternative first-line regimen for advanced-stage cHL (ECHELON-1 trial) and for relapsed/refractory disease.
- PET-adapted therapy — Interim PET scans after 2 cycles guide treatment de-escalation or intensification, reducing unnecessary toxicity for patients with early metabolic response.
- Checkpoint inhibitors — Pembrolizumab and nivolumab are approved for relapsed/refractory cHL, exploiting the characteristic PD-L1 overexpression of Reed-Sternberg cells. Response rates exceed 65–70%.
- Autologous stem cell transplant (ASCT) — Standard for relapsed/refractory HL that responds to salvage chemotherapy.
Non-Hodgkin Lymphoma (NHL)
NHL comprises a heterogeneous group of lymphoid malignancies arising from B cells (~85%), T cells (~15%), or natural killer (NK) cells. NHL subtypes are classified by the WHO based on cell of origin, morphology, immunophenotype, genetic features, and clinical behavior. The most important clinical distinction is between aggressive (rapidly growing) and indolent (slowly growing) lymphomas.
Diffuse Large B-Cell Lymphoma (DLBCL)
The most common NHL subtype, accounting for approximately 30–35% of all NHL cases. DLBCL is an aggressive lymphoma that requires prompt treatment. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) remains the standard first-line therapy, curing approximately 60% of patients. Gene expression profiling distinguishes germinal center B-cell (GCB) and activated B-cell (ABC) subtypes, which have different biologies and may respond differently to targeted agents.
Follicular Lymphoma (FL)
The most common indolent NHL, representing approximately 20–25% of NHL cases. Characterized by the t(14;18) translocation causing BCL2 overexpression. FL typically follows a waxing-and-waning course over many years and is generally considered incurable with conventional therapy but has an excellent long-term prognosis. Treatment ranges from observation ("watch and wait") for asymptomatic low-tumor-burden disease to rituximab-based chemoimmunotherapy for symptomatic or advanced disease.
Mantle Cell Lymphoma (MCL)
Marginal Zone Lymphoma (MZL)
An indolent B-cell lymphoma representing approximately 8% of NHL. The three subtypes—extranodal (MALT), nodal, and splenic—differ in presentation and management. Gastric MALT lymphoma caused by H. pylori infection can be cured with antibiotic therapy alone in approximately 75% of early-stage cases. Non-gastric MALT lymphomas are treated with radiation therapy (for localized disease) or rituximab-based therapy.
Mantle Cell Lymphoma (MCL)
Accounts for approximately 5–7% of NHL. Characterized by the t(11;14) translocation causing cyclin D1 overexpression. MCL is generally aggressive and has historically had the worst prognosis among common B-cell lymphomas. Treatment for younger patients involves intensive chemoimmunotherapy with cytarabine-containing regimens followed by autologous transplant. BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) have transformed treatment of relapsed MCL.
T-Cell Lymphomas
T-cell lymphomas represent approximately 10–15% of all NHL and include peripheral T-cell lymphoma NOS, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma (ALK-positive and ALK-negative), and extranodal NK/T-cell lymphoma (nasal type, strongly associated with EBV). T-cell lymphomas generally have a worse prognosis than B-cell lymphomas and are treated with CHOP-based chemotherapy, with the addition of brentuximab vedotin for CD30-positive subtypes. Romidepsin, belinostat, and pralatrexate are approved for relapsed peripheral T-cell lymphoma.
Burkitt Lymphoma
A highly aggressive B-cell lymphoma characterized by MYC translocation t(8;14). It is the fastest-growing human tumor, with a doubling time of 24–48 hours. Endemic Burkitt lymphoma (associated with EBV and malaria) is the most common childhood cancer in equatorial Africa. Sporadic Burkitt lymphoma in developed countries often presents with abdominal masses. Despite its aggressiveness, Burkitt lymphoma is curable in 70–90% of cases with intensive chemoimmunotherapy regimens.
Lymphoma Staging (Lugano Classification)
| Stage | Description | Key Notes |
|---|---|---|
| Stage I | Single lymph node region or single extralymphatic organ | Limited stage |
| Stage II | Two or more lymph node regions on the same side of the diaphragm | Limited stage; bulky disease may be treated as advanced |
| Stage III | Lymph node regions on both sides of the diaphragm | Advanced stage |
| Stage IV | Diffuse or disseminated involvement of one or more extralymphatic organs (liver, bone marrow, lung) | Advanced stage |
The Lugano classification (2014) replaces the Ann Arbor staging system. PET-CT is the standard staging modality for FDG-avid lymphomas. "A" and "B" suffixes indicate absence or presence of systemic symptoms (fever, night sweats, weight loss).
Risk Factors
- Immunodeficiency — HIV/AIDS, organ transplant recipients on immunosuppressive therapy, and inherited immunodeficiency syndromes have markedly increased NHL risk, particularly for aggressive subtypes and primary CNS lymphoma.
- Autoimmune diseases — Sjögren syndrome, rheumatoid arthritis, celiac disease, and systemic lupus erythematosus are associated with increased NHL risk, likely due to chronic immune stimulation.
- Infections — EBV (Burkitt lymphoma, post-transplant lymphoproliferative disorder), H. pylori (gastric MALT lymphoma), HCV (splenic marginal zone lymphoma), HTLV-1 (adult T-cell leukemia/lymphoma).
- Prior chemotherapy or radiation — Alkylating agents and radiation therapy increase the risk of secondary NHL.
- Family history — First-degree relatives of HL patients have a 3–5 fold increased risk. Familial clustering is also observed in some NHL subtypes.
- Age — HL has a bimodal distribution (young adults and over 55). NHL incidence increases with age, with a median age at diagnosis of approximately 67.
- Chemical exposures — Herbicides (Agent Orange/2,4-D), pesticides, and organic solvents have been linked to increased NHL risk.
CAR-T Cell Therapy
Chimeric antigen receptor T-cell (CAR-T) therapy represents a groundbreaking advance in lymphoma treatment. FDA-approved CAR-T products for lymphoma include:
- Axicabtagene ciloleucel (Yescarta) — Approved for relapsed/refractory DLBCL and follicular lymphoma. The ZUMA-7 trial showed superiority over standard salvage chemotherapy and transplant as second-line therapy for DLBCL.
- Tisagenlecleucel (Kymriah) — Approved for relapsed/refractory DLBCL and follicular lymphoma.
- Lisocabtagene maraleucel (Breyanzi) — Approved for relapsed/refractory large B-cell lymphoma, including as second-line therapy (TRANSFORM trial).
The manufacturing process involves collecting the patient's T cells via leukapheresis, genetically engineering them to express a chimeric antigen receptor targeting CD19 on B-cell lymphomas, expanding the cells in a laboratory, and infusing them back into the patient after lymphodepleting chemotherapy. The process typically takes 3–4 weeks from collection to infusion.
CAR-T therapy achieves complete remission in approximately 40–50% of patients with relapsed/refractory DLBCL, many of whom appear to be cured at long-term follow-up. Cytokine release syndrome (CRS) and neurotoxicity are important but manageable side effects.