B-Cell Lymphoma

Updated: Sep 25, 2017
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Practice Essentials

Non-Hodgkin lymphoma (NHL) is a collective term for a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. [1] Most NHLs (80-85%) are of B-cell origin. See the image below.

Diffuse large B-cell non-Hodgkin lymphoma. Large c Diffuse large B-cell non-Hodgkin lymphoma. Large cells with abundant cytoplasm and large round-ovoid nuclei with thick nuclear membrane and multiple prominent nucleoli.

Signs and symptoms

Lymphadenopathy is the most common manifestation of lymphoma. Lymphadenopathy may wax and wane. Spontaneous remissions have been documented, most commonly in patients with low-grade lymphomas.

Systemic symptoms known to be associated with adverse prognosis include the following:

  • Unexplained fevers
  • Night sweats
  • Weight loss

Organ-specific symptoms that may lead to identification of specific sites of involvement include the following:

  • Shortness of breath, chest pain, cough
  • Abdominal pain and distention
  • Bone pain
  • CNS symptoms

Typical physical examination findings include the following:

  • Pallor (suggesting anemia)
  • Purpura, petechiae, or ecchymoses (suggesting thrombocytopenia)

Findings in patients with an advanced high-grade lymphoma may include the following:

  • High fever
  • Tachycardia
  • Respiratory distress

Examples of findings that might direct further investigations and subsequent therapy include the following:

  • Pharyngeal involvement
  • Thyroid mass
  • Evidence of pleural effusion
  • Abdominal mass
  • Testicular mass
  • Cutaneous lesions


Laboratory studies are as follows:

  • CBC with differential and examination of a peripheral smear – To assess bone marrow function and rule out the presence of abnormal circulating cells in the peripheral blood
  • Screening chemistries – To assess renal and hepatic function and measure serum glucose, calcium, albumin, lactate dehydrogenase (LDH), and beta2-microglobulin
  • Serum protein electrophoresis – Frequently appropriate
  • HIV serology – Appropriate for patients with risk factors, especially those with large cell or small noncleaved-cell histologies

Imaging studies

  • Chest radiography and CT scans of the thorax, abdomen, and pelvis should be performed at initial evaluation in almost all patients with NHL; CT scanning can identify both nodal and extranodal sites of involvement and can provide an important approach to monitoring response to therapy
  • MRI is useful in identifying bone and CNS involvement and can reveal meningeal involvement when gadolinium is used
  • Gallium scans provide functional information and thus have potential value in resolving difficulties in determining response to therapy

Diagnostic procedures

  • In addition to a diagnostic biopsy, almost all patients should have a bone marrow aspirate and biopsy performed
  • Flow cytometry and immunohistochemical stains of the biopsied material should be performed to confirm the diagnosis and for accurate subtyping
  • Thoracentesis – In patients with a significant pleural effusion
  • Paracentesis – In patients with ascites

Histologic findings

The most common subtypes of B-cell NHL are as follows:

  • Chronic lymphocytic leukemia/small lymphocytic lymphoma
  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
  • Nodal marginal zone lymphoma
  • Follicular lymphoma
  • Mantle cell lymphoma
  • Diffuse large B-cell lymphoma
  • Burkitt lymphoma
  • Primary mediastinal (thymic) large B-cell lymphoma


Modalities of antilymphoma therapy are as follows:

  • Radiation therapy – Used in early-stage limited disease, as consolidative therapy in aggressive lymphomas that respond to chemotherapy, and to manage some complications (eg, superior vena cava syndrome, impending pathologic fracture)
  • Chemotherapy – Curative as well as palliative
  • Biologic therapy – Monoclonal antibody (mAb) therapy (eg, rituximab)

Typical medical therapy by stage is as follows:

  • Indolent stage I and contiguous stage II adult NHL – Radiation therapy
  • Aggressive stage I and contiguous stage II adult NHL – Radiation therapy, chemotherapy with adjuvant radiation therapy
  • Indolent, noncontiguous stage II/III/IV adult NHL – Controversial; treatment options range from watchful waiting to aggressive myeloablative therapy with hematopoietic precursor cell rescue
  • Aggressive noncontiguous stage II/III/IV adult B-cell lymphoma – Doxorubicin-based combination chemotherapy, with or without supplemental local field radiation

Typical therapy for specific subtypes of lymphoma is as follows:

  • Follicular lymphoma - Watchful waiting, for asymptomatic patients with normal blood cell counts and no critical visceral involvement; medical treatments include alkylating agents (eg, chlorambucil or cyclophosphamide; cornerstone of treatment) and rituximab
  • Splenic marginal zone lymphoma – Splenectomy
  • Extranodal B-cell lymphoma of MALT – Antibiotic treatment of Helicobacter pylori infection; surgical excision; systemic chemotherapy for widespread disease
  • Mantle cell lymphoma – Combination chemotherapy; bortezomib for relapsed disease
  • Diffuse large B-cell lymphoma – Current standard therapy is rituximab with cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), prednisone, and bleomycin (R-CHOP)
  • Mediastinal diffuse large B-cell lymphoma – CHOP with adjuvant field radiation therapy
  • Burkitt lymphoma – Most adult treatment regimens include brief high-dose combination chemotherapy with CNS prophylaxis with and without cranial irradiation


Non-Hodgkin lymphoma (NHL) is a collective term for a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. [1] NHL must be distinguished from Hodgkin lymphoma with certainty before therapy is initiated.

NHL usually originates in the lymphoid tissues and can spread to other organs. However, 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.

Most NHLs (80-85%) are of B-cell origin. Accordingly, the following discussion pertains to B-cell NHL, although the classification as outlined below includes all lymphoproliferative diseases. Furthermore, management discussed in this article refers only to B-cell NHL in previously healthy individuals and is not applicable to patients with HIV or other immunocompromised conditions.

NHL can be divided into two general prognostic groups: indolent lymphomas and aggressive lymphomas. Indolent lymphomas carry a relatively good prognosis, with median survival time as long as 10 years, but they are not usually curable in advanced stages. 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.

Special care is necessary when multiagent chemotherapy is administered. The specific regimen should be clearly documented and the plan outlined in the patient’s chart. The dosage should be calculated carefully and always cross-checked by the pharmacist. The total and cumulative anthracycline dose should be clearly charted.

Oncologic emergencies, such as tumor lysis syndrome, spinal cord compression, ureteric obstruction, lymphomatous meningitis, and superior vena cava syndrome, though infrequent in terms of overall incidence, are observed relatively commonly in NHL as compared with other malignancies. A high index of clinical suspicion and early confirmatory tests are essential.

In general, with modern treatment of patients with NHL, the overall survival rate at 5 years is approximately 70%. [2] 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.

Whereas indolent NHL is responsive to radiation therapy and chemotherapy, a continuous rate of relapse is usually observed in advanced stages. However, patients can often be retreated with considerable success as long as the disease histology remains low grade.

Patients who present with or convert to aggressive forms of NHL 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.

Go to Non-Hodgkin Lymphoma and Cutaneous B-Cell Lymphoma  for complete information on these topics.

For patient education resources, see the Blood and Lymphatic System Center, as well as Lymphoma.



B-cell and T/natural killer (NK)-cell neoplasms are clonal tumors of mature and immature B cells, T cells, or NK 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]

Per the 2008 revised World Health Organization (WHO) classification, B-cell malignancies are divided 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] :

  • B-cell prolymphocytic leukemia
  • Splenic marginal zone lymphoma
  • Hairy cell leukemia
  • Splenic lymphoma/leukemia, unclassifiable
  • Lymphoplasmacytic lymphoma
  • Heavy chain diseases
  • Plasma cell neoplasms
  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
  • Nodal marginal zone lymphoma
  • Follicular lymphoma
  • Primary cutaneous follicle center cell lymphoma
  • Mantle cell lymphoma
  • Diffuse large B-cell lymphoma (DLBCL), not otherwise specified
  • T-cell/histiocyte rich large B-cell lymphoma
  • Primary DLBCL of the central nervous system (CNS)
  • Epstein-Barr virus (EBV)-positive DLBCL of the elderly
  • 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
  • Large B-cell lymphoma arising in human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease
  • Primary effusion lymphoma
  • Burkitt lymphoma
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
  • 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

Nonrandom 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 Histology Antigen Rearrangement Oncogene Expression
t(14;18)(q32;q21) Follicular, diffuse large cell IgH* bcl- 2
t(11;14)(q13;q32) Mantle cell IgH cyclin-D1/bcl-1
t(1;14)(p22;q32) MALT lymphoma IgH bcl- 10
t(11;18)(q21;q21) MALT lymphoma IgH Unknown
t(9;14)(p13;q32) Lymphoplasmacytic lymphoma IgH PAX-5
8q24 translocations




Burkitt lymphoma IgH



Trisomy 12, deletion 11q22-23, 17p13, and 6q21 CLL
*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 lymphomas that have a much more aggressive clinical course and are assocaited with translocations of two of the three oncogenes ( myc, bcl-2, and bcl-6).

Environmental factors

Certain workers have a slightly increased risk of NHL, including farmers; pesticide applicators; flour millers; meat workers; painters; mechanics; and workers in the petroleum, rubber, plastics, and synthetics industries.

Chemicals that have been linked to the development of NHL include a variety of pesticides and herbicides (eg, organophosphates, chlorophenols), solvents and organic chemicals (eg, benzene, carbon tetrachloride), and 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 i n 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 BV 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 for new cases of non-Hodgkin lymphoma (NHL) have remained stable for more than a decade, and death rates have not changed significantly since 2002. The lifetime risk of being diagnosed with NHL is 2.1%. It has been estimated that in 2016, 72,580 new cases of NHL will be diagnosed, with 20,150 deaths. NHL is the seventh most common cancer in the US, accounting for 4.3% of new cancers and 3.4% of all cancer-related deaths. [2]

International statistics

Perry and colleagues identified the following significant differences in the epidemiology of NHL in developing countries, compared with the developed countries [6] :

  • 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 NK/T-cell lymphoma (2.2%). [6]

In Europe, NHL is the 11th most common cancer, representing 3% of the total cancer diagnoses in 2012. [7]

Certain endemic geographical 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 23.7 cases per 100,000 population in men, compared with 16.1 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 white people: it is reported to be 24.8 cases per 100,000 population in white men, compared with 20.7 and 17.6 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. [8] Separate indices have been developed for follicular and mantle cell lymphoma. [9, 10, 11]

The IPI includes the following risk factors (for each factor that is present, the patient receives 1 point) [8] :

  • 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%