B-Cell Lymphoma

Updated: Mar 31, 2023
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Practice Essentials

B-cell lymphomas are clonal tumors of mature and immature B cells that constitute the majority (80-85%) of non-Hodgkin lymphomas (NHLs). NHLs are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. [1] NHL usually originates in the lymphoid tissues and can spread to other organs.

NHL must be distinguished from Hodgkin lymphoma with certainty before therapy is initiated. Compared with Hodgkin lymphoma, NHL is much less predictable and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment.



NHL can be divided into two general prognostic groups: indolent lymphomas and aggressive lymphomas. Indolent lymphomas carry a relatively good prognosis, with median survival as long as 10 years, but those that have progressed to advanced stages are not usually curable. Early-stage (stage I and II) indolent NHL can be treated effectively with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology. The aggressive type of NHL has a shorter natural history, but a significant number of cases are curable with combination chemotherapy regimens.

With modern treatment of patients with NHL, the overall survival rate at 5 years is 73.8%. [2] Although relapse is common in advanced-stage NHL, patients can often be retreated with considerable success as long as the disease histology remains low grade. Most relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients with a divergent histology of both indolent and aggressive disease.

Patients who present with aggressive forms of NHL, or whose disease converts to an aggressive form, may achieve complete remission with combination chemotherapy regimens, with or without aggressive high-dose consolidation therapy with marrow or stem cell support. Aggressive lymphomas are increasingly observed in patients who are HIV positive, and treatment of these patients requires special consideration.



B-cell neoplasms are clonal tumors of mature and immature B cells at various stages of differentiation. B-cell neoplasms tend to mimic stages of normal B-cell differentiation, and the resemblance to normal cell stages is a major basis for their classification and nomenclature. [3]

The World Health Organization (WHO) classification divides B-cell malignancies into two broad categories [3] : (1) precursor B-cell neoplasms, which include B lymphoblastic leukemia/lymphoma with or without recurrent genetic abnormalities, and (2) mature B-cell neoplasms.

The following classification deals with only the mature B-cell neoplasms. Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For instance, B-cell chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma (SLL) are different manifestations of the same neoplasm, as are lymphoblastic lymphomas and T-cell acute lymphocytic leukemias.

The WHO classification of mature B-cell neoplasms is as follows [3] :

  • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
  • Monoclonal B-cell lymphocytosis
  • B-cell prolymphocytic leukemia
  • Splenic marginal zone lymphoma
  • Hairy cell leukemia
  • Splenic B-cell lymphoma/leukemia, unclassifiable
  • Splenic diffuse red pulp small B-cell lymphoma
  • Hairy cell leukemia–variant
  • Lymphoplasmacytic lymphoma
  • Waldenström macroglobulinemia
  • Monoclonal gammopathy of undetermined significance (MGUS), IgM
  • Heavy-chain diseases (μ, γ, α)
  • MGUS, IgG/A
  • Plasma cell myeloma
  • Solitary plasmacytoma of bone
  • Extraosseous plasmacytoma
  • Monoclonal immunoglobulin deposition diseases
  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
  • Nodal marginal zone lymphoma
  • Pediatric nodal marginal zone lymphoma
  • Follicular lymphoma
  • In situ follicular neoplasia
  • Duodenal-type follicular lymphoma
  • Pediatric-type follicular lymphoma
  • Large B-cell lymphoma with IRF4 rearrangement
  • Primary cutaneous follicle center cell lymphoma
  • Mantle cell lymphoma
  • In situ mantle cell neoplasia
  • Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
  • Germinal center B-cell type
  • Activated B-cell type
  • T-cell/histiocyte-rich large B-cell lymphoma
  • Primary DLBCL of the central nervous system (CNS)
  • Primary cutaneous DLBCL, leg type
  • Epstein-Barr virus (EBV)–positive DLBCL, NOS
  • EBV-positive mucocutaneous ulcer
  • DLBCL associated with chronic inflammation
  • Lymphomatoid granulomatosis
  • Primary mediastinal (thymic) large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma
  • Plasmablastic lymphoma
  • Primary effusion lymphoma
  • Human herpesvirus 8 (HHV-8)–associated DLBCL, NOS
  • Burkitt lymphoma
  • Burkitt-like lymphoma with 11q aberration
  • High-grade B-cell lymphoma with MYC and BLC2 and/or BCL6 rearrangements
  • High-grade B-cell lymphoma, NOS
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Pathophysiology and Etiology

Any of the following may play a role in the etiology of non-Hodgkin lymphoma (NHL) in a particular patient:

  • Genetic abnormalities
  • Environmental factors
  • Viral infections
  • Immunodeficiency states
  • Connective-tissue disorders

Chromosomal translocations and molecular rearrangements

Non-random chromosomal and molecular rearrangements (see the table below) play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype.

Table 1. Chromosomal Abnormalities in B-Cell Non-Hodgkin Lymphoma (Open Table in a new window)

Cytogenetic Abnormality


Antigen Rearrangement

Oncogene Expression


Follicular, diffuse large cell


bcl- 2


Mantle cell




MALT lymphoma


bcl- 10


MALT lymphoma




Lymphoplasmacytic lymphoma



8q24 translocations




Burkitt lymphoma





Trisomy 12, deletion 11q22-23, 17p13, and 6q21


*Immunoglobulin H (IgH)

MALT = Mucosa-associated lymphoid tissue.

The most common chromosomal abnormality associated with NHL is the t(14;18)(q32;q21) translocation, which is found in 85% of follicular lymphomas and 25-30% of intermediate-grade NHLs. This translocation results in the juxtaposition of the bcl-2 apoptotic inhibitor oncogene at band 18q21 to the heavy-chain region of the immunoglobulin (Ig) locus within band 14q32, resulting in its overexpression.

The t(11;14)(q13;q32) translocation results in overexpression of bcl -1 (cyclin-D1/PRAD1), a cell cycle control gene on band 11q13, and is diagnostic of mantle cell lymphoma.

For the workup of any high-grade B-cell lymphoma of germinal center origin, fluorescence in situ hybridization (FISH) studies for evaluation of myc, bcl-6, and bcl-2 rearrangements should typically be ordered, in order to establish classification of "double hit" lymphomas. Double hit B-cell lymphomas are a specific subtype of diffuse large B-cell lymphoma (DLBCL) that have a much more aggressive clinical course and are associated with translocations of two of the three oncogenes (myc, bcl-2, and bcl-6).

Environmental factors

The risk of NHL is increased in certain workers, including the following:

  • Farmers
  • Pesticide applicators
  • Flour millers
  • Meat workers
  • Painters
  • Mechanics
  • Workers in the petroleum, rubber, plastics, and synthetics industries

Chemicals that have been linked to the development of NHL include the following:

  • Pesticides and herbicides (eg, organophosphates, chlorophenols)
  • Solvents and organic chemicals (eg, benzene, carbon tetrachloride)
  • Wood preservatives

Patients who receive cancer chemotherapy, radiation therapy, or both are at increased risk of developing NHL.


Several viruses have been implicated in the pathogenesis of NHL. Epstein-Barr virus (EBV) is linked to Burkitt lymphoma (especially in endemic areas of Africa), sinonasal lymphoma in Asia and South America, and lymphomas in immunocompromised patients. Human T-lymphotropic virus 1 (HTLV-1) is linked to adult T-cell lymphoma/leukemia. Human herpesvirus 8 (HHV-8) is implicated in body cavity–based lymphomas in patients with HIV infection.

Results of an Italian study support a role for chronic hepatitis C virus infection in NHL, and suggest involvement of hepatitis B virus infection. Associations were clearest for B-cell NHL and diffuse large B-cell lymphoma. [4]

Immunodeficiency states

Immunodeficiency states that seem to predispose to NHL include congenital immunodeficiency states (eg, ataxia telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia, and severe combined immunodeficiency), as well as acquired immunodeficiency states (eg, HIV infection and iatrogenic immunosuppression for solid organ or bone marrow transplant recipients). [5]

Connective-tissue disorders

Connective-tissue disorders associated with an increased risk of NHL include the following:

  • Sjögren syndrome
  • Rheumatoid arthritis
  • Chronic lymphocytic thyroiditis
  • Systemic lupus erythematosus (SLE)

Other disease states

Increased incidence of gastrointestinal (GI) lymphomas is observed in patients with celiac sprue and inflammatory bowel disease. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is observed most frequently, but not exclusively, in association with Helicobacter pylori infection.



United States statistics

After a striking increase in incidence rates between 1970 and 1995 (which may in part have reflected improved diagnosis), the rates of new non-Hodgkin lymphoma (NHL) cases stabilzed. From 2010-2019, rates of new cases fell on average 1.0% each year, and from 2011-2020, death rates fell on average 2.2% each year. [2]

The lifetime risk of being diagnosed with NHL is 2.1%. [2] The American Cancer Society estimates that 80,550 new cases of NHL will be diagnosed in 2023, with 20,180 deaths. In US males, NHL is the seventh most common cancer, accounting for 4% of new cancers and cancer-related deaths; in females it is the sixth most common cancer, accounting for 4% of new cancers and 3% of cancer deaths. [6]

International statistics

Perry and colleagues identified the following significant differences in the epidemiology of NHL in developing countries, compared with the developed countries [7] :

  • Higher percentage of males
  • Lower median age at diagnosis for both low- and high-grade B-cell lymphoma
  • Lower frequency of B-cell lymphoma and a higher frequency of T- and NK-cell lymphoma
  • Approximately 20% more cases of high-grade B-cell lymphoma and 10% fewer cases of low-grade B-cell lymphoma

In developing regions, diffuse large B-cell lymphoma was the most common subtype (42.5%) Other subtypes seen more frequently were Burkitt lymphoma (2.2%), precursor B- and T-lymphoblastic leukemia/lymphoma (1.1% and 2.9%) and extranodal natural killer (NK)/T-cell lymphoma (2.2%). [7]

In Europe, NHL is the 11th most common cancer, representing 3% of the total cancer diagnoses in 2012. [8]

Certain endemic geographic factors appear to influence the development of NHL in specific areas. For example, in equatorial Africa, a variant of Burkitt lymphoma associated with Epstein-Barr virus (EBV) is the most common childhood malignancy.

In the Middle East, heavy-chain disease (alpha) is a disorder of B-lymphoid cells that is characterized by diffuse thickening of the small intestine caused by a lymphoplasmacytic infiltrate with secretion of incomplete immunoglobulin A (IgA) heavy chains. This clinicopathologic entity is rarely encountered in individuals who are not of Mediterranean ethnicity.

Follicular lymphomas are more common in North America and Europe but are rare in the Caribbean, Africa, China, Japan, and the Middle East.

Age-, sex-, and race-associated differences in incidence

NHL is most frequently diagnosed in  persons 65-74 years old. High-grade lymphoblastic and small noncleaved-cell lymphomas are the only subtypes of B-cell NHL that are observed more commonly in children and young adults.

NHL is more common in men: the reported incidence is 23.0 cases per 100,000 population in men, compared with 15.8 cases per 100,000 population in women. However, the incidence of NHL in some anatomic sites, such as the thyroid, may be higher in women. [2]

The incidence of NHL is highest in Whites: it is reported to be 24.7 cases per 100,000 population in White men, compared with 20.2 and 17.4 cases per 100,000 population in Hispanic and African-American men, respectively. The incidence rates are lowest among Asians, Pacific Islanders, and Native Americans. [2]



Overall, the prognosis for non-Hodgkin lymphoma (NHL) varies with the histology, the stage of disease at diagnosis, the response of disease to therapy, and other factors as listed in the International Prognostic Index (IPI) score.

 The IPI was originally designed as a prognostic factor model for aggressive NHL, but can be useful for predicting the outcome of patients with low-grade lymphoma. This index is also used to identify patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system, liver, testis, lung, and spleen. [9] Separate indices have been developed for follicular and mantle cell lymphoma. [10, 11, 12]

The IPI includes the following risk factors (for each factor that is present, the patient receives 1 point) [9] :

  • Age ≥60 y
  • Elevated lactate dehydrogenase (LDH) level
  • Stage III or IV disease
  • Eastern Cooperative Oncology Group (ECOG) performance status ≥2
  • Two or more extranodal sites

Based on the IPI score, patients can be categorized as follows:

  • Low risk (0-1)
  • Low-intermediate risk (2)
  • High-intermediate risk (3)
  • High risk (4-5)

With this model, relapse-free and overall survival rates at 5 years are as follows:

  • 0-1 risk factors - 75%
  • 2-3 risk factors - 50%
  • 4-5 risk factors - 25%