Lymphoma: An Overview of the B-Cell Lymphomas

What it is

Lymphoma is a cancer of the lymphocytes, the white blood cells that patrol the immune system. Rather than a single disease, it is a large family of related malignancies that arise when a lymphocyte acquires genetic changes that let it grow and survive abnormally. The B-cell lymphomas, which make up the large majority of cases, originate from B lymphocytes at various points in their normal maturation. Because B cells pass through distinct developmental stages in lymph nodes and other tissues, the resulting tumors differ widely in behavior, some grow rapidly over weeks (aggressive lymphomas) while others smolder for years (indolent lymphomas).

Non-Hodgkin lymphoma (NHL) is the umbrella term that covers most of these entities. Within it, diffuse large B-cell lymphoma (DLBCL) is the most common aggressive subtype, and follicular lymphoma (FL) the most common indolent one [1][3].

How common it is

In the United States, NHL is projected to account for approximately 79,320 new cases in 2026, with B-cell lymphomas comprising the large majority [2]. The age-adjusted incidence is about 18.7 per 100,000 per year (2019, 2023), and the lifetime risk of developing NHL is roughly 2.0%, about 1 in 50 [1]. NHL represents approximately 3.8% of all new cancer diagnoses, placing it among the more common malignancies overall [1].

The trend is modestly favorable. NHL incidence has been falling slightly, about 0.6% per year over 2014, 2023 [1]. Projected deaths for 2026 number approximately 19,970, with a mortality rate near 4.8 per 100,000 per year (2020, 2024) [1][2]. Encouragingly, death rates have declined roughly 2.4% per year, a change widely attributed to the introduction of anti-CD20 antibody therapy (the rituximab era) and, more recently, cellular therapies [1].

Who's at risk

Most risk factors for lymphoma are not modifiable. Age is the dominant one: most NHL is diagnosed between 65 and 74 years, and incidence rises steadily with age [1]. Immune system status matters substantially, HIV infection, immunosuppression after organ transplantation, and inborn errors of immunity all increase risk and underlie a recognized category of immune deficiency/dysregulation-associated large B-cell lymphoma. Certain autoimmune diseases (Sjögren syndrome, Hashimoto thyroiditis, celiac disease) are linked to specific lymphoma types, particularly MALT lymphoma. A first-degree family history of hematologic malignancy modestly raises risk as well.

Some contributing factors are at least partly modifiable. Several chronic infections are causally associated with particular entities: Epstein-Barr virus (EBV), Helicobacter pylori (gastric MALT lymphoma), hepatitis C virus, HTLV-1, and HHV-8. Certain occupational and chemical exposures, some pesticides, herbicides, and solvents, have been implicated. The evidence linking individual exposures to risk varies in strength and remains an active area of study.

How it's found

There is no screening test for lymphoma, and NHL is not screened for in the general population. Diagnosis is tissue-based and prompted by symptoms or incidental findings rather than by routine testing. When a lymphoma is suspected, an adequate tissue sample, an excisional biopsy is preferred over a needle core, is needed because accurate classification requires assessment of tissue architecture alongside a full immunohistochemical and molecular workup [4].

Common presentations include painless, persistent enlargement of lymph nodes; "B symptoms" (unexplained fever, drenching night sweats, and weight loss); fatigue; and organ-specific or extranodal findings when lymphoma involves the stomach, central nervous system, or other sites. Aggressive subtypes tend to declare themselves rapidly, whereas indolent lymphomas are frequently discovered incidentally during imaging or evaluation for an unrelated problem.

Outlook

Across all NHL, five-year relative survival is approximately 74% (based on 2016, 2022 follow-up) [1]. This aggregate figure, however, conceals enormous variation between entities and is of limited value for any individual. These are population statistics, not individual predictions. They describe the average experience of large groups diagnosed in the past and cannot forecast what will happen to any one person, whose outcome depends on subtype, stage, biology, age, overall health, and treatment.

Prognosis is driven far more by entity and stage than by any single overall number. Indolent follicular lymphoma is often associated with prolonged survival, while aggressive subtypes carry a lower aggregate survival yet are curable in a substantial fraction of patients [1]. Within DLBCL, Ann Arbor stage, cell-of-origin, and "double-hit" status (concurrent MYC and BCL2 rearrangements) further stratify expected outcome [5][6][7][8][9]. Because of this heterogeneity, a single survival figure should be interpreted with caution and always in the context of a specific diagnosis.

How it's diagnosed and classified

Classification is the foundation of everything that follows, and it rests on integrating tissue architecture, immunophenotype, and molecular genetics. Under the current WHO classification of haematolymphoid tumours (WHO-HAEM5, 2022), the framework distinguishes many entities, among them DLBCL-NOS, high-grade B-cell lymphomas including those with MYC and BCL2 rearrangements, Burkitt lymphoma, primary mediastinal large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, MALT lymphoma, and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia [8]. Cell-of-origin assignment (for example, the Hans algorithm using CD10, BCL6, and MUM1) and FISH for MYC, BCL2, and BCL6 are central to placing a tumor accurately within this scheme [10][5][4].

How treatment is guided

Treatment selection follows directly from classification and from a panel of biomarkers that define both biology and therapeutic eligibility. Markers such as cyclin D1/t(11;14) and SOX11 (mantle cell lymphoma) [11], MYD88 L265P (lymphoplasmacytic lymphoma) [12], TP53/del(17p) and IGHV mutation status [13][14], Ki-67 proliferation index [15], and EBV (by EBER in situ hybridization) [16][17] refine diagnosis and risk. Surface markers including CD20, CD19, and the proliferation profile establish eligibility for specific drug classes, anti-CD20 antibodies, and CD19-directed CAR-T and bispecific agents, though the choice of any therapy for a given person is an individualized clinical decision made with the treating team [18].

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References

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4. National Complete Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. (Diagnostic workup: adequate tissue, immunophenotyping required; morphology alone insufficient.)

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9. El-Sharkawi D, et al. Outcomes of MYC-rearranged diffuse large B-cell lymphoma under the WHO 5th-edition and ICC classifications. Blood Cancer J. 2023;13(1):60. PMID 37072385. doi:10.1038/s41408-023-00827-5.

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18. Casan JML, Wong J, Northcott MJ, Opat S. Anti-CD20 monoclonal antibodies: reviewing a revolution. Hum Vaccin Immunother. 2018;14(12):2820-2841. PMID 30096012. doi:10.1080/21645515.2018.1508624.