Lymphoma, B-Cell

Author: Ajeet Gajra, MD, Staff Oncologist, Clinical Assistant Professor, SUNY Upstate Medical University, Syracuse, Department of Internal Medicine, Division of Hematology and Oncology, VA Medical Center.

Coauthor(s): Neerja Vajpayee, MD, Clinical Assistant Professor, Clinical Assistant Professor, Hematopathology Division, Department of Pathology, State University of New York, Upstate Medical University, Syracuse; Sara Grethlein, MD, Associate Dean for Graduate Medical Education, Associate Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York at Upstate.

Ajeet Gajra, MD, is a member of the following medical societies: American Association for Cancer Research, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology.

Editor(s): Michael Paul Kosty, MD, Associate Director, Associate Professor, Department of Internal Medicine, Divisions of Supportive Care Services and Hematology and Oncology, Ida M and Cecil H Green Cancer Center, Scripps Clinic; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Wendy Hu, MD, Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center; Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems; and Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Thomas Jefferson University, Jefferson Medical College.

Background: Non-Hodgkin lymphoma (NHL) is a heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment (Armitage, 1993). NHL usually originates in the lymphoid tissues and can spread to other organs. However, unlike Hodgkin disease, 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 (ie, 80-90%) NHLs are of B-cell origin. 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 2 general prognostic groups: the indolent lymphomas and the aggressive lymphomas. Indolent lymphomas have a relatively good prognosis, with median survival time as long as 10 years, but they are not usually curable in advanced stages. Early-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 these patients can be cured with combination chemotherapy regimens.

In general, with modern treatment of patients with NHL, the overall survival rate at 5 years is approximately 50-60%. Thirty percent of patients with aggressive NHL can be cured. 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 (Cabanillas, 1992). A subset of aggressive lymphomas, Burkitt lymphoma and lymphoblastic lymphoma, are designated as high grade by the International Working Formulation (IWF) to reflect the rapidly progressive behavior of these subtypes.

While 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 re-treated 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 (CR) 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.


Pathophysiology: The World Health Organization (WHO) modification of the Revised European-American Lymphoma (REAL) Classification recognizes 3 major categories of lymphoid malignancies based on morphology and cell lineage. The categories include B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma. 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 are different manifestations of the same neoplasm, as are lymphoblastic lymphomas and T-cell acute lymphocytic leukemias. Within B- and T-cell categories, 2 subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.

WHO classification of lymphomas


  • B-cell neoplasms


    • Precursor B-cell neoplasms


      • Precursor B-cell acute lymphoblastic leukemia (B ALL)
      • Lymphoblastic lymphoma


    • Peripheral B-cell neoplasms


      • B-cell CLL/small lymphocytic lymphoma
      • B-cell prolymphocytic leukemia
      • Lymphoplasmacytic lymphoma/immunocytoma
      • Mantle cell lymphoma
      • Follicular lymphoma
      • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type
      • Nodal marginal zone lymphoma (with or without monocytoid B-cells)
      • Splenic marginal zone lymphoma (with or without villous lymphocytes)
      • Hairy cell leukemia
      • Plasmacytoma/plasma cell myeloma
      • Diffuse large B-cell lymphoma
      • Burkitt lymphoma


  • T-cell and putative NK-cell neoplasms


    • Precursor T-cell neoplasms


      • Precursor T-cell acute lymphoblastic leukemia (T-ALL)
      • Lymphoblastic lymphoma


    • Peripheral T-cell and NK-cell neoplasms


      • T-cell CLL/prolymphocytic lymphoma
      • T-cell granular lymphocytic leukemia
      • Mycosis fungoides/Sézary syndrome
      • Peripheral T-cell lymphoma, not otherwise characterized
      • Hepatosplenic gamma/delta T-cell lymphoma
      • Subcutaneous panniculitislike T-cell lymphoma
      • Angioimmunoblastic T-cell lymphoma
      • Extranodal T-cell/NK-cell lymphoma, nasal type
      • Enteropathy-type intestinal T-cell lymphoma
      • Adult T-cell lymphoma/leukemia (with human T-cell leukemia virus type 1 [HTLV-1])
      • Anaplastic large cell lymphoma, primary systemic type
      • Anaplastic large cell lymphoma, primary cutaneous type
      • Aggressive NK-cell leukemia


  • Hodgkin lymphoma (Hodgkin disease)


    • Nodular lymphocyte-predominant Hodgkin lymphomas


    • Classic Hodgkin lymphomas


      • Nodular sclerosis Hodgkin lymphoma
      • Lymphocyte-rich classic Hodgkin lymphoma
      • Mixed cellularity Hodgkin lymphoma
      • Lymphocyte depletion Hodgkin lymphoma

The more than 20 clinicopathologic entities described here can be divided into more clinically useful indolent or aggressive lymphomas as follows:

Clinical classification of lymphoproliferative disorders (prescreening development questionnaire [PDQ] modification of REAL classification of lymphoproliferative diseases)


  • Plasma cell disorders


    • Monoclonal gammopathies of undetermined significance (MGUS)


    • Plasmacytoma (bone, extramedullary)


    • Multiple myeloma


    • Amyloidosis


  • Hodgkin lymphomas


  • Indolent lymphomas/leukemias


    • Follicular lymphomas


      • Follicular small cleaved cell
      • Follicular mixed small cleaved and large cell
      • diffuse small cleaved cell


    • Diffuse small lymphocytic lymphoma/CLL - Distinguish prolymphocytic leukemia (aggressive), T-cell granular lymphocytic leukemia


    • Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia


    • Marginal zone lymphomas


      • MALT (extranodal B-cell lymphoma)
      • Monocytoid B-cell lymphoma (nodal B-cell lymphoma)
      • Splenic lymphoma with villous lymphocytes (splenic lymphoma)


    • Hairy cell leukemia


    • Mycosis fungoides/Sézary syndrome


  • Aggressive lymphomas/leukemias


    • Diffuse large cell lymphomas - Distinguish primary mediastinal large B-cell lymphoma, follicular large cell lymphoma, anaplastic large cell lymphoma (nodal versus cutaneous only), extranodal NK-cell/T-cell lymphoma (nasal type), lymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma), angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (distinguish rare subtypes subcutaneous panniculitic and hepatosplenic gamma/delta T-cell lymphomas), enteropathy-type intestinal T-cell lymphoma, intravascular lymphomatosis


      • Diffuse mixed cell lymphoma
      • Diffuse large cell lymphoma
      • Immunoblastic lymphoma


    • Burkitt lymphoma/diffuse small noncleaved cell lymphoma


    • Lymphoblastic lymphoma


    • Central nervous system (CNS) lymphoma


    • Adult T-cell leukemia/lymphoma (with HTLV-1)


    • Mantle cell lymphoma


    • Posttransplantation lymphoproliferative disorder


    • AIDS-related lymphoma


    • True histiocytic lymphoma


    • Primary effusion lymphoma


    • Aggressive NK-cell leukemia



  • In the US: In 2001, an estimated 56,200 new cases of NHL were diagnosed, with 26,300 deaths. NHL accounts for 5% of new cancers in men and 4% of new cancers in women.

    A striking increase in NHL incidence rates has occurred over the last 4 decades, referred to as an epidemic of NHL. The lifetime risk of being diagnosed with NHL is 2.08%. The incidence rate is increasing approximately 3% per year and has increased more than 80% since 1973. Several hypotheses address the increasing incidence of NHL. New classification systems and techniques, such as gene rearrangement studies establishing clonality, have led to diagnoses of NHL in patients who would have previously been diagnosed with benign disorders such as pseudolymphoma or atypical lymphoid hyperplasia. Better imaging techniques and improved biopsy techniques are likely to have contributed to the apparent increase in incidence. The aging population, the increasing number of immunosuppressive drugs, transplantation medicine, and the AIDS epidemic have contributed to the increased incidence of NHL.

  • Internationally: Certain endemic geographical factors appear to influence the development of NHL in specific areas.

    In Africa, the incidence of Burkitt lymphoma is 5.7-7.6 per 100,000 population as compared to 0.1 per 100,000 population in the United States (see Burkitt Lymphoma).

    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 other than those 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 (see Lymphoma, Follicular).

    HTLV-1–associated adult T-cell lymphoma/leukemia occurs commonly in Japan and in the Caribbean (see Human T-Cell Lymphotrophic Viruses).

Mortality/Morbidity: NHL was responsible for 5% of cancer deaths in the United States. In 1997, NHL was the leading cause of death from cancer in men aged 20-39 years.

Race: Incidence is the highest in white people. It is reported at 15.9 per cases 100,000 population for white males, compared to 12.0 cases per 100,000 population for African American people. The incidence rates are 54% higher among white males than Japanese American people and 27% higher among white males than among Chinese American people. Incidence rates are also lower among Native American people and Hispanic people.

Sex: NHL is more common in male subjects, with a reported incidence of 19.2 cases per 100,000 population as compared with 12.2 cases per 100,000 population in women. However, in some sites, such as the thyroid, the incidence may be higher in women.

Age: The median age at presentation for all subtypes of NHL is older than 50 years. 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.

  • Lymphadenopathy is the most common manifestation of lymphoma. Symptoms can include fevers, night sweats, weight loss, and fatigue. In addition, symptoms related to mass effect are common. The duration of symptoms and the pace of progression should be documented. The possibility that waxing and waning lymphadenopathy may be due to lymphoma should not be discounted. Spontaneous remissions have been documented in some patients with lymphoma. This most commonly occurs in low-grade lymphomas.
  • Systemic symptoms known to be associated with adverse prognosis include unexplained fevers, night sweats, and weight loss. The initial evaluation of a patient with known or suspected lymphoma should include an assessment for these B symptoms. In addition, pruritus has been observed in patients with lymphoma.
  • Organ-specific symptoms, such as shortness of breath, chest pain, cough, abdominal pain and distension, or bone pain, may lead to identification of specific sites of involvement. Careful evaluation for neurologic symptoms is also appropriate because CNS involvement may occur with aggressive histologies.
  • History of concurrent illness, such as diabetes or congestive heart failure, might modify therapeutic decisions. In addition, organ transplantation or HIV may provide diagnostic and prognostic insight in cases of NHL.

Physical: The physical examination of a patient with an advanced high-grade lymphoma may reveal high fever, tachycardia, and respiratory distress. However, the physical examination more typically reveals pallor (suggesting anemia) or purpura, petechiae, or ecchymoses (suggesting thrombocytopenia). Examination should include palpation of all lymph node–bearing areas as well as assessment of hepatomegaly and splenomegaly. Pharyngeal involvement, a thyroid mass, evidence of pleural effusion, abdominal mass, testicular mass, or cutaneous lesions are examples of findings that might direct further investigations and subsequent therapy. A neurologic examination is appropriate at diagnosis.

Certain associations of involvement between various organ sites are noteworthy. Approximately 25% of patients with involvement of Waldeyer ring have involvement of the gastrointestinal tract, and the converse is also true. This finding occurs most commonly in mantle cell lymphoma. Patients with paranasal sinus involvement, testicular involvement, and epidural lymphoma are particularly prone to have meningeal involvement and thus require a diagnostic lumbar puncture. One quarter of patients with bone marrow involvement by large cell lymphoma also have CNS disease. Patients with one testicle involved are likely to relapse in the contralateral testis.

Causes: Several known associations and genetic abnormalities that may play a role in the etiology of NHL in a particular patient exist.

  • Chromosomal translocations and molecular rearrangements
    • The most common chromosomal abnormality associated with NHL is the t(14;18)(q32;q21) translocation that 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 chromosome band 18q21 to the heavy-chain region of the immunoglobulin (Ig) locus within chromosome 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 chromosome band 11q13, and is diagnostic of mantle cell lymphoma.
  • Environmental factors also seem to play a role in the development of NHL
    • 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 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 and/or radiation therapy are at increased risk of developing NHL.
  • Several viruses have been implicated in the pathogenesis of NHL, including the Epstein-Barr virus in Burkitt lymphoma (especially in endemic areas of Africa), sinonasal lymphoma in Asia and South America, and lymphomas in immunocompromised patients; HTLV-1 in adult T-cell lymphoma/leukemia; and human herpesvirus 8 (HHV 8) in body cavity–based lymphomas in patients with HIV infection.
  • Immunodeficiency states that seem to predispose to NHL include congenital immunodeficiency states (eg, ataxia telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia, severe combined immunodeficiency) as well as acquired immunodeficiency states (eg, HIV infection, iatrogenic immunosuppression for solid organ or bone marrow transplant recipients).
  • Connective-tissue disorders, including Sjögren syndrome, rheumatoid arthritis, chronic lymphocytic thyroiditis, and systemic lupus erythematosus (SLE), are also associated with increased risk of NHL.
Other Problems to be Considered:

Pseudolymphoma syndrome

Carcinoma of unknown primary may be a differential diagnosis, especially if it presents with significant lymphadenopathy in the mediastinum and/or abdomen.

Mycobacterial infections, especially in patients with immune compromise, may manifest as fever, weight loss, and lymphadenopathy and, therefore, clinically mimic lymphoma.

Fungal infections (eg, histoplasmosis, cryptococcosis in the acute phase) can similarly manifest as lymphadenopathy, fever, and (occasionally) weight loss, simulating lymphoma.