B-Cell Lymphoma 

  • Author: Ajeet Gajra, MD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Jan 20, 2012
 

Overview

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 disease with certainty before therapy is initiated.

NHL usually originates in the lymphoid tissues and can spread to other organs. However, compared with 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. 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 2 general prognostic groups: indolent lymphomas and 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 (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 50-60%, and 30% 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.

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.

Classification

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.[2]

Per the 2008 revised World Health Organization (WHO) classification, B-cell malignancies are divided into 2 broad categories: (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[2] :

  • CLL/SLL
  • 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

There are several known associations and genetic abnormalities that may play a role in the etiology of non-Hodgkin lymphoma (NHL) in a particular patient. These include genetic abnormalities, environmental factors, viruses, immunodeficiency states, and 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 AbnormalityHistologyAntigen RearrangementOncogene Expression
t(14;18)(q32;q21)Follicular, diffuse large cellIgH*bcl- 2
t(11;14)(q13;q32)Mantle cellIgHcyclin-D1/bcl-1
t(1;14)(p22;q32)MALT lymphomaIgHbcl- 10
t(11;18)(q21;q21)MALT lymphomaIgHUnknown
t(9;14)(p13;q32)Lymphoplasmacytic lymphomaIgHPAX-5
8q24 translocations



t(8;14)(q24;q32)



t(2;8)(p11-12;q24)



t(8;22)(q24;q11)



Burkitt lymphomaIgH



Ig-8



Ig-6



c-myc
Trisomy 12, deletion 11q22-23, 17p13, and 6q21CLL
*Immunoglobulin H (IgH)



MALT = Mucosa-associated lymphoid tissue.



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 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.

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.

Viruses

Several viruses have been implicated in the pathogenesis of NHL, including the Epstein-Barr virus (EBV) in 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) in adult T-cell lymphoma/leukemia; and human herpesvirus 8 (HHV-8) in body cavity–based lymphomas in patients with HIV infection.

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).

Connective-tissue disorders

Certain connective-tissue disorders are also associated with an increased risk of NHL. These include Sjögren syndrome, rheumatoid arthritis, chronic lymphocytic thyroiditis, and 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.

Epidemiology

United States statistics

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. In 2001, an estimated 56,200 new cases of non-Hodgkin lymphoma (NHL) were diagnosed, with 26,300 deaths. NHL accounts for 5% of new cancers in men and 4% of new cancers in women.

Several hypotheses have been put forward to address the increasing incidence of NHL. One is that 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.

Another hypothesis is that better imaging techniques and improved biopsy techniques have contributed to the apparent increase in incidence. Finally, the aging population, the increasing number of immunosuppressive drugs, transplantation medicine, and the AIDS epidemic are believed to have contributed to the increased incidence of NHL.

International statistics

Certain endemic geographical factors appear to influence the development of NHL in specific areas. For example, in Africa, the incidence of Burkitt lymphoma is 5.7-7.6 per 100,000 population, compared with 0.1 per 100,000 population in the United States.

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.

Human T-lymphotropic virus 1 (HTLV-1)–associated adult T-cell lymphoma/leukemia occurs commonly in Japan and in the Caribbean.

Age-associated differences in incidence

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.

Sex-associated differences in incidence

NHL is more common in male subjects: the reported incidence is 19.2 cases per 100,000 population in men, 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.

Race-associated differences in incidence

The incidence of NHL is highest in white people: it is reported to be 15.9 per cases 100,000 population in white men, compared with 12 cases per 100,000 population in African American people. The incidence rates are 54% higher among white males than among 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.

Prognosis

Non-Hodgkin lymphoma (NHL) has been found to cause 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.

Overall, the prognosis for 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. To calculate the IPI for a given patient, a score of 1 is assigned for the presence of each of 5 factors, and the summed scores defines the IPI. The 5 factors assessed are as follows:

  • Age older than 60 years
  • Performance status greater than 1
  • Lactate dehydrogenase (LDH) level greater than 1 times the reference range
  • More than 1 extranodal site
  • Stage III or IV disease

In addition to the IPI, an age-adjusted IPI is commonly used. This uses only 3 risk factors: performance status greater than 1, LDH level greater than 1 times the reference range, and stage III or IV disease (age and extranodal sites are excluded). Risk groups based on the IPI and the age-adjusted IPI have been correlated with outcomes in patients with aggressive NHL (see the table below).

Table 2. Outcome According to Risk Groups for Patients With Aggressive NHL (Open Table in a new window)

Risk GroupRisk Factors (#)Complete Response (%)2-Year Survival (%)
IPI, all patients (n=2031)
Low0 or 18784
Low-intermediate26766
High-intermediate35554
High4 or 54434
Age-adjusted IPI, patients = 60 years (n=1274)
Low09290
Low-intermediate17879
High-intermediate25759
High34637

Patients with 2 or more IPI risk factors have a less than 50% chance of relapse-free and overall survival at 5 years. The IPI score also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system (CNS), liver, lung, and spleen. Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.

Molecular profiling has been used to predict survival of patients with diffuse large B-cell lymphoma (DLBCL) after chemotherapy. In a study the biopsy samples of 240 patients with DLBCL that used DNA microarrays and defined subgroups based on hierarchical clustering, Rosenwald et al noted 2 common oncogenic events, bcl -2 translocation and c-Rel amplification, only in the germinal center B-cell–like (GCB) subgroup.[3] The patients in this subgroup had the highest 5-year survival rate.

A study by Curry et al also indicated that overall survival is better in patients in the GCB phenotype subgroup than in those with a non-GCB phenotype.[4] However, the investigators also found evidence that among the patients with the GCB phenotype, the survival rate is better for those with negative c-Rel nuclear expression than for patients with positive c-Rel nuclear expression.

In the first group, 1 of 9 patients died within 8 years (median follow-up, 72 mo), whereas in the positive c-Rel group, 6 of 16 patients died within a 1- to 46-month period (median 18 mo).[4] Curry et al therefore suggested that c-Rel expression could aid in risk stratification for patients with DLBCL.

Lossos et al identified 6 genes (LMO2, BCL6, FN1, CCND2, SCAY3, and BCL2) that are strong predictors of survival in DLBCL.[5] Dunphy et al published a study on the detection of BCL2 gene arrangements by means of polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH).[6]

Dave et al, using gene-expression profiles of tumor biopsy specimens obtained at diagnosis to develop a predictor for survival in follicular lymphoma, concluded that the length of survival in patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.[7]

Clinical Presentation

Patient history

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. In addition, pruritus has been observed in patients with lymphoma.

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. Organ-specific symptoms, such as shortness of breath, chest pain, cough, abdominal pain and distention, or bone pain, may lead to identification of specific sites of involvement. Careful evaluation for neurologic symptoms is also appropriate because central nervous system (CNS) involvement may occur with aggressive histologies.

A 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 non-Hodgkin lymphoma (NHL).

A family history and a history of prior radiation therapy should be obtained; a history of exposure to other putative risk factors (see Pathophysiology and Etiology) is important as well. Although allogeneic bone marrow transplantation is rarely used in NHL, ascertaining the number of siblings that share both parents with the patient may be useful. Most lymphomas do not have a familial pattern; however, coexistence of multiple breast cancers, ovarian cancer, sarcomas, and lymphomas in a family may suggest an inherited abnormality in tumor suppressor genes.

Physical examination

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, and 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 (GI) 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 1 testicle involved are likely to relapse in the contralateral testis.

Complications

Complications of NHL include the following:

  • Lymphomatous meningitis
  • Superior vena cava syndrome
  • Other compression syndromes arising from compression of neighboring structures by bulky lymphadenopathy (eg, bilateral ureteric obstruction leading to obstructive uropathy, subacute intestinal obstruction due to compression of the bowel, pain or paraparesis secondary to compression of the nerve roots)
  • Spinal cord compression either from extradural compression from large masses or secondary to bony compression, especially in the setting of vertebral collapse
  • Pathologic fractures of long bones - May occur secondary to involvement by B-cell lymphoma

Differential Diagnosis

Hodgkin Disease

Infectious Mononucleosis

Metastatic Cancer, Unknown Primary Site

Sarcoidosis

Other problems to be considered include the following:

  • Pseudolymphoma syndrome
  • Carcinoma of unknown primary may be a differential diagnosis, especially if it presents with significant lymphadenopathy in the mediastinum 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.

Laboratory Studies

Complete blood count

A complete blood count with differential and examination of a peripheral smear is essential. This will assess bone marrow function and rule out the presence of abnormal circulating cells in the peripheral blood.

Screening chemistries

Screening chemistries to assess renal and hepatic function and measure serum glucose, calcium, albumin, lactate dehydrogenase (LDH), and beta2-microglobulin are essential. A serum protein electrophoresis is frequently appropriate.

HIV serology

HIV serology is appropriate for any patient with lymphoma that has risk factors for this disease. It should especially be considered in patients with large cell or small noncleaved-cell histologies.

Radiography and Computed Tomography

Chest radiography and computed tomography (CT) scans of the thorax, abdomen, and pelvis should be performed at initial evaluation in almost all patients with non-Hodgkin lymphoma (NHL). CT scanning can identify both nodal and extranodal sites of involvement and can provide an important approach to monitoring response to therapy.

Magnetic Resonance Imaging

The value of magnetic resonance imaging (MRI) in staging of NHL is limited. It is particularly useful in identifying bone and central nervous system (CNS) involvement. MRI can reveal meningeal involvement when gadolinium is used.

Gallium Scanning

Gallium scans provide functional, rather than purely anatomic, information and thus have potential value in resolving difficulties in determining response to therapy. To be maximally valuable, high doses of gallium must be administered, and single-photon emission CT (SPECT) scanning must be used.

Gallium scans are more accurate in evaluating supradiaphragmatic rather than infradiaphragmatic sites because of colon uptake of the gallium. Unfortunately, this test is most often needed to define intra-abdominal sites of involvement.

Positron Emission Tomography

Positron emission tomography (PET) scanning seems to have at least the same sensitivity and specificity as gallium scanning. In the initial reports, PET scanning appears to be a promising radiologic modality in the diagnosis and staging of non-Hodgkin lymphoma (NHL). However, larger comparative trials assessing the relative merits of PET scanning, gallium scanning, and computed tomography (CT) scanning must be completed before PET replaces various tests.

Fluorescence In Situ Hybridization

Fluorescence in situ hybridization (FISH) is useful in the accurate diagnosis of some categories of B-cell lymphoma. Characteristic immunophenotypes are associated with major types of lymphoma (see the table below).

Table 3. Characteristic Immunophenotypes of Major Subtypes of Lymphoma (Open Table in a new window)

LymphomaImmunophenotype
FollicularCD20+, CD3-, CD10+, CD5-
Small lymphocyticCD 20+, CD3-, CD10-, CD5+, CD23+
MALTCD20+, CD3-, CD 10-, CD5-, CD23-/+
Marginal zoneCD20+, CD3-, CD 10-, CD5-, CD23-/+
Mantle cellCD20+, CD3-, CD10-, CD5+, CD23-, cyclinD-1+
Mediastinal large B-cellCD20+, CD30+, MUM-1+
BurkittCD20+, Tdt-, CD10+, CD5-, bcl-2 -
B-lymphoblasticCD19+, CD10+, CD79a+
MALT = mucosa-associated lymphoid tissue.

Other Tests

Echocardiography/ventriculography

Left ventricular ejection fraction is assessed by using a 2-dimensional echocardiogram. Alternatively, a cardiac ventriculogram may be obtained.

Immunoglobulin gene rearrangement

Immunoglobulin (Ig) gene rearrangement is useful for differentiating a B-cell lymphoproliferative process from a monoclonal or reactive proliferation of lymphocytes. This technique not only provides a specific marker for B cells but also is a true marker for monoclonality.

Polymerase chain reaction

Polymerase chain reaction (PCR) is used to assess minimal residual disease. This technique has generally been applied to the t(14;18) translocation and the associated bcl -2 gene.

Whereas PCR positivity for bcl -2 gene rearrangements can be found in healthy individuals, patients with lymphoma in remission who show positive results for bcl -2 gene rearrangements by PCR in the blood or bone marrow are more likely to experience relapse than patients who do not have this abnormality. However, the correlation between relapse and PCR positivity is not perfect, and, at present, PCR is still considered a research tool.

Diagnostic Procedures

Biopsy

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 whenever lymphoma is suspected to confirm the diagnosis and for accurate subtyping. When possible, a fresh sample should be saved for flow cytometry. When possible, a hematopathologist should be consulted before the biopsy to ascertain the appropriate method of processing and handling the tissue sample obtained. This is especially true for patients who have had biopsies with negative results in the past.

Thoracentesis/paracentesis

The presence of a significant pleural effusion warrants thoracentesis, and the presence of ascites warrants paracentesis. These procedures help ascertain involvement of these body cavities by lymphoma; occasionally, the effusion or ascites may be chylous in nature. In addition to diagnosis and staging, these procedures are therapeutic for larger collections that are causing symptoms.

Histologic Findings

The histologic findings in B-cell non-Hodgkin lymphoma (NHL) are varied. The salient features of the most common subtypes are described below.

Chronic lymphocytic leukemia/small lymphocytic lymphoma

Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) is a neoplasm composed of monomorphic small, round to slightly irregular B lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes, admixed with prolymphocytes and paraimmunoblasts forming proliferation centers in tissue infiltrates.

The lymph node architecture is effaced, with a pseudofollicular pattern of regularly distributed pale areas corresponding to proliferation centers containing larger cells in a dark background of small cells. The predominant cell type is the small lymphocyte. Mitotic activity is usually low. The size of proliferation centers and the number of paraimmunoblasts vary from case to case, but there is no correlation between lymph node histology and clinical course.

On peripheral blood smears and bone marrow aspirate smears the CLL/SLL cells are small lymphocytes with clumped chromatin and scant cytoplasm (see the image below). Smudge or basket cells are typically seen in peripheral blood smears.

Monotonous small round lymphoid cells with clumpedMonotonous small round lymphoid cells with clumped chromatin admixed with a few larger paraimmunoblasts (prolymphocytes).

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

Mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal lymphoma composed of morphologically heterogeneous small B cells, including marginal zone (centrocytelike) cells, small lymphocytes, and scattered immunoblast and centroblastlike cells.

The lymphoma cells infiltrate around reactive B-cell follicles, external to a preserved follicle mantle, in a marginal zone distribution and spread out to form larger confluent areas that eventually overrun some or most of the follicles. There is plasma cell differentiation in a proportion of the cases. In epithelial tissues, the neoplastic cells typically infiltrate the epithelium, forming lymphoepithelial lesions.

Nodal marginal zone lymphoma

Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell neoplasm that morphologically resembles lymph nodes involved by marginal zone lymphoma of extranodal or splenic types, but without evidence of extranodal or splenic disease (see the image below).

Small neoplastic marginal zone lymphocytes with slSmall neoplastic marginal zone lymphocytes with slightly irregular nuclear borders and moderate clear cytoplasm (monocytoid appearance).

Follicular lymphoma

Follicular lymphoma is a neoplasm composed of follicle center B cells (typically both centrocytes and centroblasts) that usually has at least a partially follicular pattern (see the images below). It is graded by counting or estimating the absolute number of centroblasts in 10 neoplastic follicles, expressed per 40× high-power microscopic field (hpf). Grade 1 and grade 2 cases have a marked predominance of centrocytes and only a few centroblasts (grade 1, 0-5 centroblasts/hpf; grade 2, 6-15 centroblasts/hpf; grade 3, >15 centroblasts/hpf).

Expansile follicles of varying sizes and complete Expansile follicles of varying sizes and complete effacement of the normal lymph node architecture. Neoplastic follicles (40×). Neoplastic follicles (40×). Neoplastic follicles comprising cleaved cells (cenNeoplastic follicles comprising cleaved cells (centrocytes) and larger cells with vesicular nuclei and prominent 2-3 nucleoli (centroblasts).

If diffuse areas of any size composed predominantly or entirely of blastic cells are present in any case of follicular lymphoma, a diagnosis of diffuse large B-cell lymphoma (DLBCL) is also made. Peripheral blood involvement sufficient to produce lymphocytosis (usually < 20,000/µL) is observed in about 10% of patients. Bone marrow involvement occurs in 65% of patients and characteristically takes the form of paratrabecular lymphoid aggregates. Splenic white pulp and hepatic portal triads are also frequently involved.

Mantle cell lymphoma

Mantle cell lymphoma is a B-cell neoplasm generally composed of monomorphic small to medium-sized lymphoid cells with irregular nuclear contours and a cyclin-D1 translocation (see the image below). Neoplastic transformed cells resembling centroblasts, immunoblasts, or paraimmunoblasts and proliferation centers are absent. Hyalinized small vessels are commonly seen.

Mantle cell lymphoma. Small lymphoid cells with ovMantle cell lymphoma. Small lymphoid cells with oval to slightly irregular nuclei and clumped chromatin and rare admixed pink histiocytes.

A spectrum of morphologic variants is recognized. The blastoid and pleomorphic variants are considered to have poorer prognosis and to be of important clinical significance. Further evaluation of the proliferation fraction, either by counting mitotic figures or estimating the proportion of Ki67-positive nuclei, is important because of its prognostic impact.

Diffuse large B-cell lymphoma

The common morphologic features that unite the various forms of DLBCL are the relatively large cell size (usually 4-5 times that of a small lymphocyte) and a diffuse pattern of growth.[8] In other respects, a fair degree of morphologic variation exists.

In most cases, the tumor cells have a round or oval nucleus that appears vesicular because of margination of chromatin at the nuclear membrane, but large multilobed or cleaved nuclei predominate in some cases (see the image below). Nucleoli may be 2-3 in number and located adjacent to the nuclear membrane, or they may be single and centrally placed. Cytoplasm is usually present in moderate abundance and may be pale or basophilic.

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

Other more anaplastic tumors may contain multinucleated cells with large inclusionlike nucleoli that closely resemble Reed-Sternberg cells, and phenotyping is often necessary to distinguish these 2 entities.

An immunophenotypical subdivision of DLBCL has been proposed that uses a combination of antibodies to CD10, bcl-6, and MUM-1 to divide DLBCL into germinal center B cell-like (GCB) and nongerminal center B cell-like (non-GCB) varieties. Cases that are CD10 positive or CD10 negative and bcl-6 positive but MUM-1 negative are regarded as GCB type, whereas all others are regarded as non-GCB or activated B-cell (ABC) type.

This immunophenotypical subdivision does not completely correlate with gene expression-based subgrouping of DLBCL. In the non-GCB or the ABC, bcl-2 expression is known to be associated with poor patient outcome.

DLBCL may be classified in several different ways. Common morphologic variants of DLBCL, not otherwise specified, include centroblastic, immunoblastic, anaplastic, and rare morphologic variants. Molecular subgroups include GCB and ABC. Immunohistochemical subgroups include CD5-positive DLBCL, GCB, and non-GCB.

DLBCL subtypes include the following:

  • T-cell/histiocyte rich large B-cell lymphoma
  • Primary DLBCL of the central nervous system (CNS)
  • Primary cutaneous DLBCL, leg
  • Epstein-Barr virus (EBV)–positive DLBCL of the elderly

Other lymphomas of large B cells include the following:

  • Primary mediastinal (thymic) large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • DLBCL associated with chronic inflammation
  • Lymphomatoid granulomatosis
  • 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

Borderline cases include the following:

  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin disease

Burkitt lymphoma

Burkitt lymphoma is a B-cell lymphoma with an extremely short doubling time that often presents in extranodal sites or as an acute leukemia. Involved tissues are effaced by a diffuse infiltrate of monomorphic, medium-sized (nuclei similar or smaller to those of histiocytes) transformed lymphoid cells.

The nuclei are round with finely clumped and dispersed chromatin, with multiple basophilic medium-sized paracentrically situated nucleoli. The cytoplasm is deeply basophilic and usually contains lipid vacuoles (see the images below). A high mitotic index is typical, as is apoptotic tumor cell death, accounting for the presence of numerous tissue macrophages with their ingested tissue debris. These macrophages are often surrounded by a clear space, creating the characteristic starry sky pattern.

Burkitt lymphoma. Normal architecture is entirely Burkitt lymphoma. Normal architecture is entirely replaced by lymphoma cells and evenly dispersed macrophages, starry sky (250×). Burkitt lymphoma cells with round noncleaved nucleBurkitt lymphoma cells with round noncleaved nuclei and strongly basophilic cytoplasm (1000×).

Primary mediastinal (thymic) large B-cell lymphoma

Primary mediastinal large B-cell lymphoma is a diffuse large B-cell lymphoma that arises in the mediastinum from a putative thymic B-cell origin and has distinctive clinical, phenotypic, and genotypic features. Histologically, it is commonly associated with compartmentalizing alveolar fibrosis (see the image below). The cells are medium-sized to large and have abundant clear/pale cytoplasm and round to oval nuclei. A few cases have multilobated and pleomorphic nuclei resembling the Reed-Sternberg cells of Hodgkin lymphoma.

Compartmentalizing fibrosis and infiltrate of mediCompartmentalizing fibrosis and infiltrate of medium-sized to large lymphoid cells.

Staging

Ann Arbor staging system

The Ann Arbor staging system is commonly used for patients with non-Hodgkin lymphoma (NHL).[9] In this system, stages I, II, III, and IV adult NHL can be subclassified into A and B categories. The B designation is applied to individuals with any of the following well-defined generalized symptoms: unexplained loss of greater than 10% of body weight in the 6 months before diagnosis, unexplained fever with temperature higher than 38°C, and drenching night sweats.

Stage I NHL denotes involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE).

Stage II NHL indicates the involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE). The number of lymph node regions involved may be indicated by a subscript (eg, II3).

Stage III NHL implies involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIISE).

Stage IV NHL is disseminated (multifocal) involvement of 1 or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement. The designation E is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver.

If pathologic proof of involvement of 1 or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus (+) sign is listed. Sites are identified by the following notations: N=nodes, H=liver, L=lung, M=bone marrow, S=spleen, P=pleura, O=bone, and D=skin.

Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on findings made as a result of invasive procedures beyond the initial biopsy. For example, a patient with enlarged cervical lymph nodes on palpation and enlarged mediastinal lymph nodes on computed tomography (CT) scanning of the thorax without systemic symptoms might be found to have involvement of the bone marrow upon percutaneous biopsy. The precise stage of such a patient would be CSII2 A, PSIVA(M+).

Other staging considerations

A number of other factors that are not a part of the Ann Arbor staging system have important prognostic value in B-cell NHL. These factors include age, performance status, tumor size, lactate dehydrogenase (LDH) values, and the number of extranodal sites involved. To identify subgroups of patients most likely to relapse, the International Prognostic Index (IPI) was compiled for 2031 patients with aggressive NHL.[10] The IPI has been validated by several cancer centers and has been incorporated into new trials designed by various cooperative groups. (See Prognosis.)

Modalities of Antilymphoma Therapy

Radiation therapy

Because patients with B-cell lymphoma often have disseminated disease, radiation therapy plays a limited role. It is used in early-stage limited disease (see Medical Therapy for Different Stages of B-Cell Lymphoma); it also has a role as consolidative therapy in aggressive lymphomas that respond to chemotherapy.

With most histologic types of follicular lymphoma, doses of 44 cGy can achieve local control of disease. In large cell lymphoma, the dose-response curve of radiation therapy is less well established. In addition, radiation has a role in managing some of the complications (eg, superior vena cava syndrome and bone involvement with lymphoma with impending pathologic fracture).

Chemotherapy

Chemotherapy forms the cornerstone of therapy in lymphoma and has a curative, as well as a palliative, role in this disease. It is discussed in greater detail below. (See Medical Therapy for Different Stages of B-Cell Lymphoma and Treatment of Specific Lymphoma Subtypes.)

Biologic therapy

Biologic therapy comprises interferon therapy and monoclonal antibody (mAb) therapy. Interferon therapy was the first biologic treatment studied in non-Hodgkin lymphoma (NHL). It is widely used in Europe for the treatment of indolent lymphomas but is seldom used in the United States. This difference is based on 2 studies, one from France and the other from the United States.

The French trial demonstrated benefits in overall survival and progression-free survival (PFS) when interferon followed a doxorubicin-containing chemotherapy regimen to treat patients with poor prognosis.[11] However, the US-based trial demonstrated no advantage to interferon therapy for treatment of patients with indolent lymphomas.[12]

Although initial studies reported an increase in disease-free survival (DFS) and overall survival rates compared with those observed for combination chemotherapy alone,[11] more mature data from one of these studies did not support any significant difference in overall survival.[13] Data on the use of interferon maintenance therapy suggest prolonged DFS but no consistent overall survival benefit. The role for interferon therapy in patients with indolent lymphomas, therefore, remains under clinical evaluation.

The use of mAbs is the latest addition to the armamentarium against B-cell lymphoma. Various mAbs currently are either in use or under investigation for the treatment of B-cell lymphoma (see the table below).

Table 4. Monoclonal Antibodies for Treatment of NHL (Open Table in a new window)

AntibodyAntigenConjugate
Rituximab (Rituxan)*



(IDEC Pharmaceuticals/Genentech)



CD20None
CAMPATH-1H*



(Humanized IgG1† ; Millennium Pharmaceuticals, Inc)



CD52None
Tositumomab (Bexxar)*



(GlaxoSmithKline/Corixa Corporation)



CD20131 I‡
Ibritumomab tiuxetan (Zevalin)



(IDEC Pharmaceuticals)



CD20CD20,90
Epratuzumab



(Immunomedics, Inc)



CD22131 I,90?
Hu1D10HLA-DRIINone
Bevacizumab



(IDEC Pharmaceuticals)



VEGF¶None
Lym-1 (Oncolym)



(Berlex Laboratories, Inc/Peregrine Pharmaceuticals, Inc)



HLA-DR131 I
* Food and Drug Administration (FDA) approved



† Immunoglobulin G



‡ Iodine I 131



§ Yttrium ? 90



II Human leukocyte antigen



¶ Vascular endothelial cell growth factor



The role of monoclonal antibodies is discussed in greater detail below. (See Medical Therapy for Different Stages of B-Cell Lymphoma and Treatment of Specific Lymphoma Subtypes.)

Medical Therapy for Different Stages of B-Cell Lymphoma

Indolent stage I and contiguous stage II adult NHL

Encountering localized presentations is unusual in most indolent subtypes of B-cell non-Hodgkin lymphoma (NHL). However, the goal of treatment should be cure in patients who are shown to have truly localized disease after undergoing appropriate staging procedures.

Long-term disease control within radiation fields can be achieved in a significant number of patients with indolent stage I or stage II NHL by using doses of radiation that usually range from 2500-4000 cGy to involved sites or to extended fields that cover the adjacent nodal sites.[14, 15] Early-stage disease treated with radiation alone has a 10-year overall survival of 60-80%.[16, 17]

The value of adjuvant chemotherapy (ie, single-agent chlorambucil, doxorubicin [Adriamycin]-based combination chemotherapy) has not been proven conclusively.[18, 19]

In the rare circumstance when radiation therapy is contraindicated in a patient who is asymptomatic, chemotherapy as used for patients with advanced disease can be employed, or watchful waiting can be considered. Patients with involvement that cannot be encompassed by radiation therapy are treated as patients with stage III or IV indolent lymphoma. Follicular large cell and mantle cell NHL are often treated as aggressive lymphomas.

Aggressive stage I and contiguous stage II adult NHL

Radiation therapy alone can achieve long-term disease control in 90% of treated patients when a dose of 3500-5000 cGy is used. However, the disease-free survival (DFS) rate using radiation alone ranges from 60-70% at 5 years.[20]

The success of combination chemotherapy in early-stage disease has led to comparison of chemotherapy and radiation therapy with chemotherapy alone. In 2 large randomized prospective trials, chemotherapy (ie, cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], prednisone, and bleomycin [CHOP]) with radiation therapy yielded a better outcome than CHOP alone.[21, 22] Adjuvant radiation therapy is discussed further in connection with diffuse large B-cell lymphoma (DLBCL; see Treatment of Specific Lymphoma Subtypes).

Extranodal sites, including the gastrointestinal (GI) tract, thyroid, and bone, may be involved with aggressive NHL. Because extranodal site presentations frequently have an unpredictable pattern of relapse, chemotherapy is often used as the primary treatment modality. However, adjuvant radiation to the regions of disease involvement after chemotherapy appears to yield the same improvement in DFS and overall survival rates as for nodal disease.[22]

Indolent, noncontiguous stage II/III/IV adult NHL

Optimal treatment of advanced stages of indolent B-cell NHL remains controversial. The reasons for controversy include the fact that the vast majority of patients with advanced stages of indolent NHL are not cured with the current therapeutic options. The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. Hence, deferred treatment must be considered.

The role of interferon alfa in this patient population remains unclear. Standard therapy includes alkylating agents (as single agents or as components of combination chemotherapy) or purine nucleosides (eg, fludarabine and 2-chlorodeoxyadenosine [cladribine; 2-CDA]). The purine analogues have excellent activity in the small lymphocytic subtype and now constitute the standard treatment for that variant.

Because none of these therapies is curative for advanced-stage disease, innovative approaches are under clinical evaluation. These include intensive therapy with chemotherapy and total-body irradiation followed by autologous or allogeneic bone marrow or peripheral stem cell transplantation and the use of monoclonal antibodies (mAbs), including rituximab and other radiolabeled mAbs.[23]

Data support rituximab maintenance therapy in patients with indolent lymphoma.[24, 25] In this trial, patients who were treated with chemotherapy in the past were treated with rituximab and randomized to receive maintenance rituximab at 6-month intervals for 2 years or to retreatment with rituximab at progression; progression-free survival (PFS) was prolonged in the maintenance group (31.3 vs 7.4 mo). However, the duration of rituximab benefit (ie, the time to the need for the next lymphoma therapy) and overall survival were not significantly different.

The Swiss Group for Clinical Cancer Research has evaluated an alternative schedule of rituximab maintenance. Patients who had stable disease after 4 weekly doses of weekly rituximab were randomized to receipt of a single infusion of rituximab at 3, 5, 7, and 9 months or to observation alone. The event-free survival was 23 months for the maintenance arm compared with 12 months for the observation arm after a median observation time of 35 months.[26]

In patients with relapsed follicular lymphoma, the role of rituximab maintenance has been elucidated by the European Organisation for Research and Treatment of Cancer (EORTC) 20981 trial, which randomly assigned patients to CHOP with rituximab (R-CHOP) or CHOP alone followed by a second randomization to rituximab maintenance or observation alone. PFS was 51.8 months for patients receiving rituximab maintenance after RCHOP and 23 months in the observation arm after R-CHOP. However, overall survival was not statistically significant.[27]

Because most patients requiring treatment for indolent lymphomas are treated at the present time with chemoimmunotherapy, the role of first-line rituximab maintenance is not clear. Many oncologists look forward to the results of the PRIMA (Primary Rituximab and Maintenance) trial, in which patients were randomized to rituximab maintenance or observation after first-line chemoimmunotherapy.

The optimal maintenance schedule and dose are also under study. Ongoing trials, including Eastern Cooperative Oncology Group (ECOG) 4402 and the Swiss group, are evaluating dose schedules and the optimal duration of maintenance treatment.

Thus, treatment options include an entire spectrum from watchful waiting to aggressive myeloablative therapy with hematopoietic precursor cell rescue. Any specific option should be chosen only after a detailed and open discussion with the patient, and the treatment selected should be based on patient factors, including age, life expectancy, comorbidities, patient preferences, and goals of therapy. Considerations for treatment include the following:

  • For asymptomatic patients, deferred therapy with careful observation
  • Oral alkylating agents (with or without steroids) - Cyclophosphamide, chlorambucil
  • Purine nucleoside analogue - Fludarabine, 2-CDA
  • Combination chemotherapy alone - Cyclophosphamide plus vincristine plus prednisone (CVP), cyclophosphamide plus vincristine plus procarbazine plus prednisone (C[M]OPP), fludarabine plus mitoxantrone plus dexamethasone (FND)
  • Anti-CD20 mAb - May be considered as first-line therapy either alone or with combination chemotherapy[28] (radiolabeled mAbs are being studied in patients with minimal [< 20%] or no marrow involvement)
  • Intensive therapy with chemotherapy and total-body radiation followed by autologous or allogeneic bone marrow or peripheral stem cell transplantation - Under clinical evaluation
  • Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine

Aggressive noncontiguous stage II/III/IV adult B-cell lymphoma

The treatment of choice for patients with advanced stages of aggressive B-cell lymphoma is combination chemotherapy, either alone or supplemented by local field radiation.

Chemotherapy is doxorubicin-based and can provide long-term disease-free survival rates in 35-45% of patients.[29, 30, 31]

A prospective trial of 4 regimens—(1) CHOP; (2) prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and leucovorin (ProMACE-CytaBOM); (3) moderate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD); and (4) methotrexate-leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B)—for patients with diffuse large-cell lymphoma showed no difference in overall survival rates or time to treatment failure at 3 years.[31]

Other randomized trials have confirmed no advantage among standard doxorubicin-based combinations versus CHOP. In B-cell lymphomas, the addition of rituximab to CHOP chemotherapy increases both remission rates and overall survival. R-CHOP is the current standard of care.[25]

No benefit of adjuvant radiation therapy was observed in advanced-stage aggressive NHL. In patients aged 60 years and older, several randomized trials have confirmed the superiority of CHOP over other less toxic regimens in PFS and overall survival rates. Thus, unless obvious contraindications to the use of one or more of these agents exist, age itself is not considered a reason to preclude CHOP chemotherapy in elderly patients.

On the basis of current evidence, patients with aggressive NHL with high International Prognostic Index (IPI) scores seem likely to benefit from high-dose chemotherapy with autologous hematopoietic precursor cell rescue. Results from ongoing trials will identify the subsets of patients who consistently benefit from this approach.

Treatment of Specific Lymphoma Subtypes

Follicular lymphoma

Follicular lymphoma is the second most common subtype of NHL, representing 20% to 25% of all new NHL cases. It usually has an indolent clinical course; however, relapses are very common, and as the number of relapses increases, the duration between them decreases. Follicular lymphoma can be graded according to the percentage of blasts (grade I-III); follicular lymphoma grade III has a more aggressive course and is often treated similarly to diffuse large B-cell lymphoma (DLBCL). The median survival of patients with follicular lymphoma exceeds 9 years.[32]

The Follicular Lymphoma International Prognostic Index (FLIPI) is based on 5 independent risk factors: hemoglobin concentration lower than 12 g/dL, serum lactate dehydrogenase exceeding the upper normal value, Ann Arbor stage III–IV, more than 4 nodal sites, and age greater than 60 years. By means of the FLIPI, patients can be classified into 3 groups with distinct survival probabilities (see the table below).[33]

Table 5. Follicular Lymphoma International Prognostic Index and Overall Survival (Open Table in a new window)

No. of risk factorsFLIPI score% of PatientsOverall survival



5 y, % 10 y,%



0-1Low3691 71
2Intermediate3778 51
3 or moreHigh2753 36

The FLIPI score is an important prognostic tool. However, clinicians should bear in mind that it may over- or underestimate the prognosis with respect to age.

There have been advances in understanding the biologic prognostic factors in follicular lymphoma.[34] The International Leukaemia Lymphoma Molecular Profiling Project (LLMPP) consortium identified 2 main gene signatures that were independently associated with follicular lymphoma patient survival.[7]

The first signature, called immune response 1, encodes T cell markers and was associated with a favorable outcome. The second signature, immune response 2, was characterized by the presence of genes expressed in macrophages. A molecular predictor based on these signatures was able to segregate the patient population into 4 strata with markedly distinct clinical outcomes.

A watch-and-wait strategy in follicular lymphoma is appropriate (standard treatment) for patients who are asymptomatic and have blood cell counts within the reference range and no critical visceral involvement—though most patients ultimately develop progressive disease and require therapy, commonly within 12-18 months.

Alkylating agents (eg, chlorambucil or cyclophosphamide) remain the cornerstone of treatment. Most patients (ie, approximately 75%) respond to such agents; however, only a minority (25-35%) achieve a complete response, and relapse is inevitable. The median duration of first response is 2.5 years.[35] More intensive therapy (eg, with cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], prednisone, and bleomycin [CHOP]) can induce a higher rate of complete response (~65%) but has not been shown to alter the natural history of the disease.[36]

After relapse, significant palliation can be achieved with repeated therapy with alkylating agents, though response rates are somewhat lower and remissions are generally shorter.[35] Therefore, patients die from the effects of progressive lymphoma or its treatment.

Transformation to aggressive histology (eg, DLBCL) also remains a significant problem. Transformation is often heralded by the onset of rapid progression at one site in association with B symptoms, and transformation can occur in as many as 40% of patients.[37] Transformation portends poor short-term prognosis in most series, with median survival less than 1 year, although the aggressive lymphoma may be curable with intensive chemotherapy, especially in those patients who present with limited disease.

Molecular remission in follicular lymphoma refers to the conversion to negativity by polymerase chain reaction (PCR) assay for the t(14;18) in peripheral blood or bone marrow following therapy, and molecular remission implies a lower disease burden in those patients in clinical remission. Molecular remission after chemotherapy or autologous bone marrow transplantation following in vitro B-cell purging has been associated with improved DFS in some reports.[38]

As a single agent, fludarabine phosphate can induce remission in 40-50% of patients with relapsed or refractory indolent B-cell NHL, though complete response is uncommon (about 10%). Fludarabine appears to be particularly active in the subset of B-cell small lymphocytic lymphoma (SLL). Its superiority to chlorambucil in chronic lymphocytic leukemia (CLL) has been convincingly demonstrated.[39] In newly diagnosed follicular lymphoma, the overall response rate is 65% (37% complete response), with a median duration of response of 16 months.[40]

In a randomized study of 309 patients with newly diagnosed B-cell NHL, the overall response rate (69%) and the complete response rate (39%) were significantly higher with fludarabine than with standard CVP chemotherapy, which produced a response rate of 53% and a complete response rate of 17%. Myelosuppression was more common after fludarabine, but no difference in the frequency of serious infections occurred between the 2 groups.

Although the increased remission rate in the fludarabine arm is encouraging, in the short-term follow-up, no significant difference in survival existed. Furthermore, in another randomized study of previously treated patients, fludarabine achieved response rates and survival similar to those of CVP. Therefore, fludarabine does not clearly alter the natural history of relapsed disease.[41]

A new oral formulation of fludarabine has been developed and seems to have adequate plasma concentrations with predictable bioavailability. Once established, this would further simplify the use and administration of this agent for indolent B-cell lymphomas.

The concept of mAb therapy is not new. More than 20 years ago, murine antibodies against B1 (CD20) were demonstrated to induce remission in patients with relapsed B-cell NHL. However, the development of humanized mAbs has significantly increased their clinical activity. In addition to direct cytotoxic effects, humanized mAbs can induce both complement-dependent cytotoxicity and cellular immune response.

Rituximab is a chimeric (mouse/human) monoclonal anti-CD20 and the first mAb approved in the treatment of cancer. It induces remission in approximately 50% of patients with relapsed and refractory follicular lymphoma, though most responses are not complete.[42, 43] The response rate is significantly lower in patients with nonfollicular indolent B-cell NHL, such as lymphoplasmacytic or B-cell SLL. However, the median duration of remission in patients with follicular lymphoma is in the range of 1 year, with no evidence of a plateau in PFS.[42, 43]

Rituximab also seems active in the treatment of bulky disease.[44] Re-treatment of those who had a prior response induces another response in 40% of patients, with a projected median duration of 16 months or longer. Whether a longer course of therapy (ie, 8 wk) improves the response rate is not yet known.

With the exception of some infusion-related toxicity, rituximab is well tolerated. Infusion-related toxicity, including tumor lysis syndrome and cytokine release syndrome, can occur in patients with circulating tumor cells or an elevated white blood cell (WBC) count, particularly with the initial administration of rituximab. Consider other modes of cytoreduction in patients with circulating disease, and administer rituximab cautiously.

When administered to patients newly diagnosed with follicular lymphoma with low tumor burden, rituximab induced a remission in 73% of patients, including a complete response in 26%. Relapses were noted, with a median duration of response of 12 months or longer.[45]

In another report (involving patients not selected for low tumor burden), 54% of patients receiving rituximab as initial therapy achieved a response, although complete response was rare (only 5%).[46] In the latter study, maintenance rituximab was administered; therefore, ascertaining its impact on relapse is difficult. Single-agent rituximab evidently is not curative, although it is an important palliative treatment with relatively low short-term toxicity.

Rituximab has also been administered in combination with cytotoxic chemotherapy and other biologic agents. It appears to be fairly well tolerated, although significant hematologic toxicity was noted in combination with fludarabine, requiring a dose reduction in some cases.

In a phase II study, R-CHOP and rituximab achieved a 100% response rate, including complete response in 22 of 38 patients (58%). Seventy-four percent of the patients remained in remission at a median of 2.5 years of follow-up.[47] However, no randomized data are currently available in indolent B-cell NHL, and careful study is required to determine if these combinations result in improved survival.

Radioimmunotherapy is a novel therapeutic approach to combating follicular B-cell NHL that is currently awaiting approval from the US Food and Drug Administration (FDA). It exploits the sensitivity of lymphoma cells to radiation and the natural properties of mAbs.

The mAb is labeled with gamma- and beta-emitting radioactive isotope (eg,131 I) in order to enhance the antibody’s capacity to kill tumor cells. The radiolabeled mAb binds to the CD20 antigen while emitting cytotoxic beta particles; the gamma emissions are used to scan the patient and to adjust the radiation dose. This process produces a crossfire effect, whereby the destruction of tumor cells is enhanced by radiation emissions from different directions.

An anti-CD20 mAb radiolabeled with131 I is tositumomab, which has been studied extensively via the dosimetric approach. In the original schedule, a total whole-body radiation dose of 75 cGy is delivered.[48] Early results have been encouraging, with objective response rates of 65% (17% complete response) in the heavily pretreated regimen versus 28% (3% complete response) for the previous chemotherapy regimen.[49]

131 I tositumomab is associated with the development of human anti-mouse antibodies (HAMAs) in about two thirds of the patients. However, the development of HAMAs with131 I tositumomab does not seem to preclude later treatment with chimeric mAbs such as rituximab.[50]

90 Y ibritumomab (Zevalin) is another radiolabeled mAb that has demonstrated high response rates (82% with 26% complete response) in follicular lymphoma.[51] At interim analysis in a randomized study including 143 patients, the response rate was higher with90 Y ibritumomab (80%) than with rituximab, which produced a 44% response rate.[52]

Note that these radiolabeled antibodies are capable of inducing profound myelosuppression, particularly in patients with significant preexisting bone marrow infiltration by lymphoma. Furthermore, they are expensive, and whether they result in superior survival is not yet known.

High-dose therapy with autologous bone marrow transplantation is feasible and has been evaluated as consolidation in patients with follicular lymphoma.[38, 53] Approximately 30-40% of those treated after relapse achieved long-term DFS, although late relapses can occur. In one cohort of patients treated in first remission, the projected risk of relapse rate at 10 years was only 30%, although in another study the median duration of remission was shorter, at approximately 4 years.[54]

High-dose therapy may improve the remission duration in comparison with historical controls but has not yet been demonstrated to improve survival, possibly on the basis of early treatment-related toxicity and the development of secondary myelodysplasia. Patients with histologic transformation, a group with historically poor prognosis, may have an improved outcome after high-dose consolidation (particularly those patients with chemosensitive disease).

Allogeneic stem cell transplantation is associated with a relatively high mortality rate that is attributable predominantly to the complications of graft versus host disease. However, it appears to have a low risk of subsequent relapse, possibly because of graft versus lymphoma effect. An apparent plateau in failure-free survival rates suggests that allogeneic stem cell transplantation may offer cure to some patients with follicular lymphoma and may be appropriate for selected younger patients.[55]

With the advent of nonmyeloablative allogeneic stem cell transplants, this modality may be available to a larger group of patients because it does not carry the risks of acute early toxicity and mortality, unlike the myeloablative stem cell transplant.

A patient-specific vaccine engineered from lymphoma-associated idiotype coupled with an immune-stimulating keyhole limpet hemocyanin adjuvant may lower the risk of subsequent relapse in those patients who generate a response.[56] Whereas constructing these patient-specific vaccines with the original hybridoma rescue technique is laborious and time consuming, it can now be accomplished much more quickly using a recombinant/PCR-based technology, making this a feasible strategy.

Therefore, recombinant idiotype vaccination is now being tested in a randomized trial including patients in first remission of follicular lymphoma to determine if an anti-idiotype response can indeed decrease the risk of relapse.

Small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia

Treatment of SLL and CLL is discussed in more detail in Chronic Lymphocytic Leukemia.

Splenic marginal zone lymphoma

Typically, patients with splenic marginal zone lymphoma present with splenomegaly without lymphadenopathy, though bone marrow involvement is common. Cytopenias secondary to hypersplenism are also common. A splenectomy is often required to establish the diagnosis, and remission afterwards may be prolonged. After splenectomy, symptoms or signs of progressive disease may occur; however, the progression-free interval may be substantial. Systemic therapy at this point is similar to that used for CLL.

Extranodal B-cell lymphoma of MALT

Mucosa-associated lymphoid tissue (MALT) lymphomas are usually localized and are most often observed in the stomach, lung, salivary gland, thyroid, orbit, conjunctiva, and lacrimal gland. An association of MALT lymphomas with autoimmune disease is well known. The development of gastric MALT lymphomas has been attributed to antigenic stimulation associated with chronic H pylori gastritis. Indeed, the current standard initial treatment for early-stage disease is antibiotic therapy to eradicate the infection; regression of lymphoma occurs in some patients.

Surgical excision is the primary treatment (and in most cases is required to make the diagnosis). Further treatment may not be needed. When the tumor is incompletely excised, radiotherapy may be appropriate. In the minority of patients presenting with a more widespread disease, systemic chemotherapy is effective. The majority of MALT lymphomas respond to treatment similar to that for follicular lymphoma. However, evolution to DLBCL necessitates an anthracycline-containing regimen.

Mantle cell lymphoma

Mantle cell lymphoma accounts for about 5% of adult NHLs in the United States and Europe. In the past, these lymphoid neoplasms were frequently included in International Working Formulation (IWF) category E (diffuse small cleaved cell lymphomas).

Mantle cell lymphoma is a tumor of older adults, with a male predominance in a ratio of 4:1. Patients usually have stage III or IV disease at diagnosis with widespread lymphadenopathy; other involved sites include spleen, Waldeyer ring, and, often, bone marrow and extranodal sites such as the GI tract (lymphomatous polyposis). B symptoms are present in about 30% of cases, and leukemic phase of disease is seen in 20-30% of cases.

Involvement of the GI tract is very common, though routine endoscopy as part of diagnostic workup is not recommended. In the presence of GI symptoms, however, endoscopy is recommended. The course is moderately aggressive, with a median survival of 3-5 years. A more aggressive blastoid variant has been described with a median survival of 3 years.[57] Prognosis can be determined by biologic and clinical features.

Data reveal that the expression of 4 genes is associated with an increase in proliferation of malignant cells and hence with a poor prognosis. These include CDC-2, ASPM, tubulin-alpha and CENP-F.[3] The IPI and FLIPI scores did not correlate well with survival in patients with mantle cell lymphoma. Therefore, the Mantle Cell Lymphoma International Prognostic Index (MIPI) was proposed. MIPI includes age, performance status, lactate dehydrogenase (LDH) and white blood cell (WBC) count (see the table below).[58]

Table 6. Mantle Cell Lymphoma International Prognostic Index (Open Table in a new window)

PointsAge, YECOG PSLDH ULNWBC 109/L
0< 500-1< 0.67< 6.7
150-590.67-0.996.7-9.9
260-692-41.0-1.4910-14.9
3=70=1.5=15
ECOG=Eastern Cooperative Oncology Group; PS=performance status; ULN=upper limit of normal.

Patients with 0-3 points are classified as low risk, those with 4-5 points are classified as intermediate risk, and those with 6 to 11 points are classified as high risk. The 5-year overall survival for low-, intermediate- and high-risk groups was 60%, 35% and 21% respectively.

Initial studies of newly diagnosed mantle cell lymphoma treated with rituximab plus CHOP (R-CHOP) led to a median PFS of 16 to 22 months.[59, 60] More intensive regimens like rituximab plus cyclophosphamide, vincristine, doxorubicin (Adriamycin) and dexamethasone (R-HyperCVAD) are associated with an overall response rate of greater than 95% with 87% complete remissions. The 5-year overall survival rate with this regimen is 65%.[61]

The Southwest Oncology Group (SWOG) conducted a phase II multicenter trial (S0213) in newly diagnosed patients younger than 70 years. R-HyperCVAD alternating every 21 days with rituximab plus high-dose methotrexate-cytarabine was given for a total of 8 cycles. Overall response rate was 88%, with 40% complete response, 18% complete response unconfirmed, and 30% partial response. PFS was 89% at 1 year and 64% at 2 years. Overall survival was 91% at 1 year and 76% at 2 years. There was significant hematologic toxicity (87% grade IV).

Hence, HyperCVAD remains an active regimen in this disease. However, it is associated with significant toxicity especially in older patients.

In patients with relapsed disease, bortezomib (Velcade) has been approved by the FDA on the basis of the results of the PINNACLE study.[62] Bortezomib 1.3 mg/m2 was administered on days 1, 4, 8, and 11 of a 21-day cycle for up to 17 cycles. The response rate was 33%, and the median duration of response was 9.2 months. The most common grade 3 or higher adverse events were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). Treatment-related death occurred in 3% of patients.

Ongoing trials from SWOG and ECOG have incorporated bortezomib with standard chemotherapy as first line agents. The results of these trials will better clarify the role of these agents as first line therapy.

90 Y ibritumomab has increased response rates, complete remission rates and event-free survival when given after R-CHOP.[63] Phase II data on temsirolimus in patients with relapsed or refractory disease have shown an overall response rate of 38%. The median duration of response was 6.9 months. The median time to progression in all patients was 6.5 months. The most common adverse effect was thrombocytopenia.[64]

There is evidence that the use of the mammalian target of rapamycin (mTOR) inhibitor everolimus, in combination with conventional chemotherapy agents such as doxorubicin, vincristine, and rituximab, in mantle cell lymphoma results in a synergistic increase in cytotoxicity in lymphoma cells.[65]

Revlimid has also shown to have response in relapsed disease.

In early retrospective analyses, SWOG investigators found that patients with advanced-stage mantle cell lymphoma who were treated with CHOP chemotherapy had lower failure-free survival rates and overall survival times than patients with other lymphoma subtypes did.[57]

The European Organization for Research and Treatment of Cancer (EORTC) also reported that patients with mantle cell lymphoma who were treated with aggressive doxorubicin-containing combination therapy had response rates similar to those of patients with IWF intermediate-grade disease, but no evidence of a curable mantle cell lymphoma subset was present.

In the study, patients with mantle cell lymphoma treated with CVP, with or without interferon, had rates of relapse similar to those of IWF low-grade disease; however, patients with mantle cell lymphoma had a significantly shorter overall survival time than patients with IWF low-grade disease.

Considered together, these data confirm the uniquely unfavorable natural history of mantle cell lymphoma and suggest the need for innovative approaches in its management. High-dose therapy with autologous stem cell rescue alone does not seem to significantly impact the disease based on results from early clinical trials.

Diffuse large B-cell lymphoma

Historically, patients with early stage (localized disease [stage I and II disease]) aggressive lymphomas were treated with radiation therapy alone. However, more recently, patients with localized disease have been treated with combination chemotherapy alone or in combination with localized radiation therapy. The current standard therapy for patients with DLBCL is R-CHOP.

A 1995 ECOG randomized phase III trial of 8 cycles of CHOP with or without radiation therapy for early stage intermediate-grade NHL found that the use of low-dose radiation (3000 cGy) as consolidation for patients achieving complete response after CHOP yielded significantly better results than CHOP alone in terms of DFS. This study excluded stage I patients with favorable features and did not address the issue of how much chemotherapy is necessary when used as a component of combined modality therapy.[22]

A SWOG study further supported the use of radiation therapy with abbreviated chemotherapy in this setting.[21] In this study, 401 patients with localized intermediate- or high-grade NHL were randomized to receive 3 cycles of CHOP followed by involved field radiation therapy or to receive 8 cycles of CHOP alone. A minimum of 4000 cGy was administered to all sites of initial disease, with an addition boost to 5500 cGy for residual overt disease.

Patients treated with abbreviated CHOP and radiation had significantly better PFS (77% vs 64%) and overall survival rates (82% versus 72%) than patients treated with CHOP alone. A subset analysis of 127 patients younger than 60 years with stage I disease and normal Karnofsky performance score indicated a 4-year survival rate of 97% (4 deaths). This study concluded that CHOP (3 cycles) plus radiation is more effective and less toxic than CHOP (8 cycles) alone for early-stage diffuse large B-cell lymphoma.

Future studies should focus on patients who are symptomatic, patients older than 60 years, or those with bulky stage II disease.

The role of consolidative radiation therapy in the setting of R-CHOP chemotherapy in early-stage (stage I-II) disease is not well reported. Phan et al report a retrospective analysis in 469 patients with histologically confirmed DLBCL treated with R-CHOP. Of the 190 patients with stage I or II disease, 103 (54%) received consolidative radiation therapy. The 5-year overall survival and PFS for stage I and II disease treated with radiation therapy were 92% and 82%, respectively; whereas without radiation therapy, OS and PFS were 73% and 68%, respectively.[66]

It remains unclear what criteria were used to select those patients with advanced-stage disease to receive radiation therapy and how the sites for radiation therapy were determined. Even though retrospective in nature, these data are in line with other US trials from the era before rituximab.

In patients with early-stage disease, chemotherapy alone may be considered in certain special situations (eg, young females in whom the radiation port will include breasts and patients requiring treatment to the salivary glands, which may lead to dry mouth).

Other special situations of limited-stage disease include testicular lymphoma, which has a predisposition to spread to the other testis and to the central nervous system (CNS). In such patients, chemotherapy with R-CHOP and intrathecal methotrexate and cytarabine is considered standard. Scrotal irradiation is recommended after chemotherapy.[67]

Primary CNS lymphoma is being seen in both HIV-positive and HIV-negative patients. The cornerstone of therapy involves systemic methotrexate in such patients. The role of radiation remains controversial, in that it is associated with a high incidence of neurocognitive deficits, especially in patients older than 60 years.[68]

Several chemotherapy regimens are commonly used for aggressive lymphoma (see the table below).

Table 7. Combination Chemotherapy Regimens Useful as Primary Treatment of Aggressive Lymphoma (Open Table in a new window)

RegimenDrugs and Dosages
CHOPCyclophosphamide 750 mg/m2 IV on day 1



Doxorubicin 50 mg/m2 IV on day 1



Vincristine 1.4 mg IV on day 1; not to exceed 2 mg



Prednisone 100 mg PO on days 1-5



Repeat q21d



BACOPBleomycin 5 U/m2 IV on days 15, 22



Doxorubicin 25 mg/m2 IV on days 1, 8



Cyclophosphamide 650 mg/m2 IV on days 1, 8



Vincristine 1.4 mg/m2 IV on days 1, 8; not to exceed 2 mg



Prednisone 60 mg/m2 PO on days 15-28



Repeat q28d



m-BACODMethotrexate 200 mg/m2 IV on days 1, 8



Leucovorin 10 mg/m2 PO q6h for 8 doses starting 24 h after methotrexate



Bleomycin 4 U/m2 IV on day 1



Cyclophosphamide 600 mg/m2 IV on day 1



Vincristine 1 mg/m2 IV on day 1



Dexamethasone 6 mg/m2 PO on days 1-5



Repeat q21d



ProMACE/MOPPPrednisone 60 mg/m2 PO on days 1-14



Methotrexate 1500 mg/m2 IV on day 14



Leucovorin 50 mg/m2 IV q6h for 5 doses starting 24 h after methotrexate



Doxorubicin 25 mg/m2 IV on days 1, 8



Cyclophosphamide 650 mg/m2 IV on days 1, 8



Etoposide 120 mg/m2 IV on days 1, 8



Repeat q28d



ProMACE is administered for a variable number of cycles, based on tumor response, then MOPP therapy is administered for the same number of cycles.



MACOP-BMethotrexate 400 mg/m2 IV on weeks 2, 6, 10; one-fourth dose is administered as IV bolus, the remaining is administered over 4 h



Leucovorin 15 mg PO q6h for 6 doses starting 24 h after methotrexate



Doxorubicin 50 mg/m2 IV on weeks 1, 3, 5, 7, 9, 11



Cyclophosphamide 350 mg/m2 IV on weeks 1, 3, 5 , 7, 9, 11



Vincristine 1.4 mg/m2 IV on weeks 2, 4, 6, 8, 10, 12



Bleomycin 10 U/m2 IV on weeks 2, 4, 6, 8, 10, 12



Prednisone 75 mg/d PO for 12 wk, taper to 0 during weeks 10-12



Trimethoprim-sulfamethoxazole 1 double-strength tablet bid daily for 12 wk



From 1986 to 1991, 1138 previously untreated patients with stage II (bulky), III, or IV intermediate-grade or high-grade NHL were randomized to receive either standard chemotherapy (ie, CHOP) or 1 of the third-generation regimens (ie, m-BACOD, ProMACE-CytaBOM, MACOP-B). No difference in response rate, time to treatment failure, or overall survival rate was noted between CHOP and the newer regimens. Moreover, the newer regimens were more toxic and expensive.

Other randomized comparisons have failed to show an advantage of the third-generation regimens over CHOP.

Although CHOP (in combination with rituximab) remains the best available standard therapy, it is curative in less than 50% of patients, indicating the need for new treatment approaches. The following recommended treatment strategies should be adjusted according to the level of risk, as defined by the prognostic factors validated by the IPI.

Younger patients (ie, ≤60 y) at low or intermediate risk have 5-year survival rates higher than 50%. They should be treated with 6-8 cycles of a standard doxorubicin-containing regimen such as CHOP.

The 5-year survival rate in younger patients (ie, ≤60 y) deemed to be at high-intermediate or high risk is lower than 50%. Because the clinical features that correlate with relapse are also associated with a decreased likelihood of achieving an initial remission, these patients should be offered participation in clinical trials of dose-intensive treatment strategies aimed at improving the rates and durability of complete responses.

Efforts to augment dose intensity of induction and consolidation therapy include the use of colony-stimulating factors and infusion of chemotherapy, as well as conventional and repetitive high-dose therapy with hematopoietic stem cell support. The current status of such an approach is addressed below.

All patients older than 60 years should undergo evaluation of cardiac, pulmonary, and renal function and coexistent illness, which may complicate therapy. Most older patients with advanced-stage aggressive NHL have 5-year survival rates lower than 50% as a result of decreased initial response, poor tolerance to therapy, and the need for dose reduction because of age.

Approaches to elderly patients should include interventions aimed at preserving or increasing dose intensity and improving tolerance to chemotherapy with the use of cytokines and infusion chemotherapy. Selected physiologically younger patients may be eligible for consolidation with high-dose therapy and hematopoietic stem cell support.

A French group (Groupe d’Etude des Lymphomes de l’Adulte) was the first to demonstrate that the addition of rituximab to the CHOP regimen improved disease-free survival in elderly patients.[69] A subsequent trial demonstrated an advantage to R-CHOP over CHOP alone in good-risk patients younger than 60 years.[70]

The same group also determined in a randomized trial that the addition of etoposide to CHOP improved response rate and event-free survival at 5 years in patients less than 60 years with good-prognosis NHL.[71] They also determined that CHOP plus etoposide is more toxic than CHOP in patients older than 60 years. In this age group, CHOP administered every 2 weeks yielded a better complete response rate, greater 5-year event-free survival, and longer overall survival than CHOP given every 3 weeks.[72]

The French group also demonstrated the merits of the ACVBP regimen (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) in patients with low-risk aggressive disease.[73]

Récher et al compared the addition of rituximab to the ACVBP regimen (R-ACVBP) to R-CHOP and found significant improvement in survival among patients with diffuse large B-cell lymphoma with low-intermediate risk aged 18-59 years on the R-ACVBP regimen.[74]

Patients with compromised cardiac function require individualized approaches, such as the use of a regimen that does not contain an anthracycline (eg, CVP; cyclophosphamide, vincristine, procarbazine, and prednisone [C-MOPP]; cyclophosphamide, etoposide, and prednisone [CEPP]). Alternatively, a reduction in the total anthracycline dose may be attempted (eg, by alternating CHOP with C-MOPP or CEPP), or dexrazoxane (Zinecard) may be administered by a continuous infusion along with the anthracycline because the former is shown to exert cardioprotective effect when used with an anthracycline.

Patients who are not cured with initial chemotherapy represent a relatively unfavorable group. With salvage chemotherapy regimens (see the table below), response rates near 50% have been reported. However, complete response rates are generally in the 20-30% range, and long-term relapse-free survival has been observed in fewer than 5% of patients treated with salvage chemotherapy.

Table 8. Salvage Chemotherapy Regimens Used Commonly in Recurrent Aggressive NHL (Open Table in a new window)

RegimenDrugs and Dosages
DHAPDexamethasone 40 mg PO/IV on days 1-4



Cytarabine 2 g/m2 over 3 h q12h for 2 doses on day 2, start after completing cisplatin infusion, reduce to 1 g/m2 for age >70 y



Cisplatin 100 mg/m2 continuous IV infusion over 24 h on day 1



Repeat q3-4wk



ESHAPEtoposide 60 mg/m2 IV on days 1-4



Methylprednisolone 500 mg IV on days 1-4



Cytarabine 2 g/m2 over 2 h on day 5 after completing cisplatin



Cisplatin 25 mg/m2/d continuous IV infusion on days 1-4



Repeat q3-4wk



EPOCHEtoposide 50 mg/m2/24 h continuous IV infusion on days 1-4



Vincristine 0.4 mg/m2/24h continuous IV infusion on days 1-4



Doxorubicin 10 mg/m2/24h continuous IV infusion on days 1-4



Cyclophosphamide 750 mg/m2 IV on day 6



Prednisone 60 mg/m2 PO on days 1-6



Repeat q21d



MINEMesna 1.33 g/m2 mixed with ifosfamide over 1 h on days 1-3, followed by 500 mg IV 4 h after the ifosfamide



Ifosfamide 1.33 g/m2 IV over 1 h on days 1-3



Mitoxantrone 8 mg/m2 IV over 15 min on day 1



Etoposide 65 mg/m2 IV over 1 h on days 1-3



Repeat q21d



Because of the limited long-term DFS achieved with salvage combination chemotherapy, the major approach to salvage therapy has become high-dose chemotherapy, with or without total-body irradiation, in conjunction with autologous peripheral blood stem cell transplantation. Among patients younger than 60 years, advances in supportive care, such as the use of colony-stimulating factor, have reduced the mortality rate associated with this therapy to 5%.

Several preparative regimens are commonly used in the treatment of NHL (see the table below).

Table 9. Preparative Regimens Commonly Used Before High-Dose Chemotherapy in NHL (Open Table in a new window)

RegimenDrugs and Dosages
Cy-TBICyclophosphamide 60 mg/kg/d on days 6, 5



Total-body irradiation 12 Gy administered in 6 fractions of 2 Gy each, 2 fractions daily on days 4, 3, 2



Cy-VP-TBIEtoposide 1800 mg/m2 on day 7



Cyclophosphamide 50 mg/kg/d on days 6, 5, 4



Total-body irradiation 10 Gy administered in 5 fractions of 2 Gy each, 2 fractions daily on days 3, 2, 1 fraction on day 1



CBVCyclophosphamide 1800 mg/m2 on days 6, 5, 4, 3



Carmustine (BCNU) 400 mg/m2 on day 2



Etoposide 2400 mg/m2 on day 7



BEAMCarmustine (BCNU) 300 mg/m2 on day 6



Etoposide 200 mg/m2 on days 5, 4, 3, 2



Ara-C 200 mg/m2 on days 5, 4, 3, 2



Melphalan 140 mg/m2 on day 1



Mediastinal diffuse large B-cell lymphoma

Primary mediastinal B-cell lymphoma is a distinct clinicopathologic entity, requiring knowledge of both morphology, immunophenotype, and presenting site for diagnosis. It accounts for approximately 7% of DLBCLs. These patients are treated with 4-6 cycles of CHOP chemotherapy followed by involved field radiation therapy. The presence of bulky disease, pleural effusion at presentation, and a positive gallium scan after CHOP chemotherapy are poor prognostic factors.

Burkitt lymphoma

Although Burkitt and Burkitt-like lymphomas account for fewer than 10% of adult diffuse lymphomas, they account for the majority of childhood B-cell lymphomas. Histologic criteria have been used to differentiate Burkitt from Burkitt-like lymphomas. Whereas Burkitt lymphomas are notable for remarkable uniformity of nuclear size and contour, Burkitt-like variants have greater variability in nuclear size and shape.

Differences also appear to exist in the molecular genetics of Burkitt and Burkitt-like lymphomas. For example, c-myc rearrangements were detectable in 94% of the former but not in the latter. Clinical features also tend to vary because patients with Burkitt lymphoma are younger (median age 31 y) than patients with Burkitt variants (median age 56 y), and the former group more commonly presents with extranodal (primarily GI) disease.

Despite these differences, there seem to be no significant differences in the response to therapy or in the previously identified prognostic factors. In both subtypes, localized disease, serum LDH levels within the reference range, and normal performance status are favorable prognostic features.

Many of the treatment regimens for adult Burkitt lymphoma are based on pediatric protocols. An intensive clinical trial using aggressive combination chemotherapy patterned after that used in childhood Burkitt lymphoma has been described and has been very successful for adult patients.[75, 76, 77] There is no role for local radiation therapy in the treatment of patients with Burkitt lymphoma or Burkitt-like lymphoma.

Most adult treatment regimens include brief high-dose combination chemotherapy with CNS prophylaxis with and without cranial irradiation. For example, a high-dose brief-duration combination chemotherapy program including cyclophosphamide, doxorubicin, etoposide, vincristine, bleomycin, methotrexate, and prednisone was associated with a response rate of 85% and a disease-free survival rate of 65% (median follow-up, 29 mo) in patients with advanced-stage disease.[78]

Patients with diffuse small noncleaved-cell/Burkitt lymphoma have a 20-30% lifetime risk of CNS involvement. CNS prophylaxis (usually 4-6 injections of methotrexate intrathecally) is recommended for all patients. In a series of 41 patients treated with systemic and intrathecal therapy, 44% of those who presented with CNS disease and 13% of those who relapsed with CNS involvement became long-term disease-free survivors.[79] CNS relapse patterns were similar regardless of irradiation, but increased neurologic deficits were noted among those irradiated.

The Cancer and Leukemia Group B (CALGB) 9251 study, which compared an extensive regimen of intrathecal chemotherapy with cranial irradiation (cohort 1) with a less intensive regimen of intrathecal chemotherapy and cranial radiation to only high-risk patients (cohort 2), found no significant differences in response rate and event-free survival. However, there was a marked decrease in neurologic toxicity in cohort 2 (61% vs 26%).[80]

The utility of high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell rescue remains a topic of active investigation in Burkitt lymphoma. In some institutions, treatment includes the use of consolidative bone marrow transplantation. The early encouraging results obtained with more intensive approaches underscore the need to enroll these patients in clinical trials.

Surgical Therapy

Surgical interventions rarely are required in B-cell non-Hodgkin lymphoma and are usually limited to diagnostic procedures, such as excisional biopsy. In the unusual event of a pathologic fracture of a bone secondary to involvement by lymphoma, orthopedic surgery may be necessary to stabilize the bone.

Consultations

Radiation oncologists are often consulted because radiation plays a role in management of B-cell lymphoma; it is considered the treatment of choice in early stage indolent lymphoma and has a role in consolidation of treatment in localized aggressive lymphoma.

A surgical consultation is indicated when central venous access devices are employed, especially when stem cell or bone marrow transplantation is considered.

Restrictions on Diet and Activity

Typically, no dietary restrictions exist for patients with non-Hodgkin lymphoma (NHL). Patients with prolonged neutropenia following chemotherapy, especially if undergoing high-dose chemotherapy with hematopoietic precursor cell rescue, are provided with a reduced-bacteria diet. Patients with high tumor burden undergoing chemotherapy may be at risk for tumor lysis syndrome and sometimes require a diet low in uric acid and potassium. No restrictions on the activity of NHL patients are necessary.

Follow-Up

Complications of therapy

Several common complications arise from therapy. Neutropenic fever after chemotherapy is not uncommon and can be life-threatening if associated with sepsis. Tumor lysis syndrome after chemotherapy is possible in patients with bulky disease. Severe hemorrhagic cystitis, as is sometimes observed after high-dose cyclophosphamide therapy, may develop.

Further inpatient care

The management of B-cell lymphoma is largely conducted on an outpatient basis. Patients are admitted to the hospital only they are scheduled to receive some of the more intensive chemotherapy regimens or if they are undergoing bone marrow or stem cell transplantation.

Patients require admission for complications that may arise from the disease or its therapy (eg, lymphomatous meningitis, severe superior vena cava compression, tumor lysis syndrome, neutropenic fever).

Further outpatient care

Most chemotherapy is administered in the outpatient/ambulatory setting. As is essential for any patient receiving chemotherapy, hematologic and biochemical values should be checked before the administration of chemotherapy. A thorough history and physical examination are helpful in early diagnosis of infections, cancer progression, and chemotherapy-induced toxicity.

In/out patient medications

In addition to the chemotherapeutic agents used to treat lymphoma, commonly prescribed outpatient medications include antiemetics (eg, prochlorperazine, ondansetron, granisetron). The choice of these individual agents depends on the emetogenic potential of the chemotherapy regimen used; sometimes steroids (eg, dexamethasone) and benzodiazepines (eg, lorazepam) are used as adjuncts to manage nausea and vomiting.

Similarly, pain medications are frequently prescribed to manage any cancer-associated pain; often, narcotic agents are used. These are prescribed on the basis of need and are titrated and tapered in accordance with the individual patient’s requirements. The stepwise pain management protocol recommended by the World Health Organization is commonly followed.

Transfer

Patients with lymphoma who are being managed at peripheral health care facilities may require their care to be transferred to a tertiary care or research institute for access to clinical trials and investigational agents.

Patients who are profoundly ill or are experiencing significant complications from either the disease or its therapy also warrant transfer to a facility that is better equipped to handle such emergencies.

 
Contributor Information and Disclosures
Author

Ajeet Gajra, MD  Associate Professor of Medicine, Director of Hematology/Oncology Fellowship Program, State University of New York Upstate Medical University; Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Veterans Affairs Medical Center

Ajeet Gajra, MD, is a member of the following medical societies: American Association for Cancer Research, American Medical Association, and American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Neerja Vajpayee, MD  Associate Professor, Department of Pathology, State University of New York Upstate Medical University

Neerja Vajpayee, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, and United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Sara J Grethlein, MD, and Uzma Athar, MD, to the development and writing of the source article.

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Expansile follicles of varying sizes and complete effacement of the normal lymph node architecture.
Neoplastic follicles (40×).
Neoplastic follicles comprising cleaved cells (centrocytes) and larger cells with vesicular nuclei and prominent 2-3 nucleoli (centroblasts).
Monotonous small round lymphoid cells with clumped chromatin admixed with a few larger paraimmunoblasts (prolymphocytes).
Mantle cell lymphoma. Small lymphoid cells with oval to slightly irregular nuclei and clumped chromatin and rare admixed pink histiocytes.
Small neoplastic marginal zone lymphocytes with slightly irregular nuclear borders and moderate clear cytoplasm (monocytoid appearance).
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.
Burkitt lymphoma. Normal architecture is entirely replaced by lymphoma cells and evenly dispersed macrophages, starry sky (250×).
Burkitt lymphoma cells with round noncleaved nuclei and strongly basophilic cytoplasm (1000×).
Compartmentalizing fibrosis and infiltrate of medium-sized to large lymphoid cells.
Lymphoma cells show strong membranous positivity with CD20 indicative of B-cell origin.
Table 1. Chromosomal Abnormalities in B-Cell Non-Hodgkin Lymphoma
Cytogenetic AbnormalityHistologyAntigen RearrangementOncogene Expression
t(14;18)(q32;q21)Follicular, diffuse large cellIgH*bcl- 2
t(11;14)(q13;q32)Mantle cellIgHcyclin-D1/bcl-1
t(1;14)(p22;q32)MALT lymphomaIgHbcl- 10
t(11;18)(q21;q21)MALT lymphomaIgHUnknown
t(9;14)(p13;q32)Lymphoplasmacytic lymphomaIgHPAX-5
8q24 translocations



t(8;14)(q24;q32)



t(2;8)(p11-12;q24)



t(8;22)(q24;q11)



Burkitt lymphomaIgH



Ig-8



Ig-6



c-myc
Trisomy 12, deletion 11q22-23, 17p13, and 6q21CLL
*Immunoglobulin H (IgH)



MALT = Mucosa-associated lymphoid tissue.



Table 2. Outcome According to Risk Groups for Patients With Aggressive NHL
Risk GroupRisk Factors (#)Complete Response (%)2-Year Survival (%)
IPI, all patients (n=2031)
Low0 or 18784
Low-intermediate26766
High-intermediate35554
High4 or 54434
Age-adjusted IPI, patients = 60 years (n=1274)
Low09290
Low-intermediate17879
High-intermediate25759
High34637
Table 3. Characteristic Immunophenotypes of Major Subtypes of Lymphoma
LymphomaImmunophenotype
FollicularCD20+, CD3-, CD10+, CD5-
Small lymphocyticCD 20+, CD3-, CD10-, CD5+, CD23+
MALTCD20+, CD3-, CD 10-, CD5-, CD23-/+
Marginal zoneCD20+, CD3-, CD 10-, CD5-, CD23-/+
Mantle cellCD20+, CD3-, CD10-, CD5+, CD23-, cyclinD-1+
Mediastinal large B-cellCD20+, CD30+, MUM-1+
BurkittCD20+, Tdt-, CD10+, CD5-, bcl-2 -
B-lymphoblasticCD19+, CD10+, CD79a+
MALT = mucosa-associated lymphoid tissue.
Table 4. Monoclonal Antibodies for Treatment of NHL
AntibodyAntigenConjugate
Rituximab (Rituxan)*



(IDEC Pharmaceuticals/Genentech)



CD20None
CAMPATH-1H*



(Humanized IgG1† ; Millennium Pharmaceuticals, Inc)



CD52None
Tositumomab (Bexxar)*



(GlaxoSmithKline/Corixa Corporation)



CD20131 I‡
Ibritumomab tiuxetan (Zevalin)



(IDEC Pharmaceuticals)



CD20CD20,90
Epratuzumab



(Immunomedics, Inc)



CD22131 I,90?
Hu1D10HLA-DRIINone
Bevacizumab



(IDEC Pharmaceuticals)



VEGF¶None
Lym-1 (Oncolym)



(Berlex Laboratories, Inc/Peregrine Pharmaceuticals, Inc)



HLA-DR131 I
* Food and Drug Administration (FDA) approved



† Immunoglobulin G



‡ Iodine I 131



§ Yttrium ? 90



II Human leukocyte antigen



¶ Vascular endothelial cell growth factor



Table 5. Follicular Lymphoma International Prognostic Index and Overall Survival
No. of risk factorsFLIPI score% of PatientsOverall survival



5 y, % 10 y,%



0-1Low3691 71
2Intermediate3778 51
3 or moreHigh2753 36
Table 6. Mantle Cell Lymphoma International Prognostic Index
PointsAge, YECOG PSLDH ULNWBC 109/L
0< 500-1< 0.67< 6.7
150-590.67-0.996.7-9.9
260-692-41.0-1.4910-14.9
3=70=1.5=15
ECOG=Eastern Cooperative Oncology Group; PS=performance status; ULN=upper limit of normal.
Table 7. Combination Chemotherapy Regimens Useful as Primary Treatment of Aggressive Lymphoma
RegimenDrugs and Dosages
CHOPCyclophosphamide 750 mg/m2 IV on day 1



Doxorubicin 50 mg/m2 IV on day 1



Vincristine 1.4 mg IV on day 1; not to exceed 2 mg



Prednisone 100 mg PO on days 1-5



Repeat q21d



BACOPBleomycin 5 U/m2 IV on days 15, 22



Doxorubicin 25 mg/m2 IV on days 1, 8



Cyclophosphamide 650 mg/m2 IV on days 1, 8



Vincristine 1.4 mg/m2 IV on days 1, 8; not to exceed 2 mg



Prednisone 60 mg/m2 PO on days 15-28



Repeat q28d



m-BACODMethotrexate 200 mg/m2 IV on days 1, 8



Leucovorin 10 mg/m2 PO q6h for 8 doses starting 24 h after methotrexate



Bleomycin 4 U/m2 IV on day 1



Cyclophosphamide 600 mg/m2 IV on day 1



Vincristine 1 mg/m2 IV on day 1



Dexamethasone 6 mg/m2 PO on days 1-5



Repeat q21d



ProMACE/MOPPPrednisone 60 mg/m2 PO on days 1-14



Methotrexate 1500 mg/m2 IV on day 14



Leucovorin 50 mg/m2 IV q6h for 5 doses starting 24 h after methotrexate



Doxorubicin 25 mg/m2 IV on days 1, 8



Cyclophosphamide 650 mg/m2 IV on days 1, 8



Etoposide 120 mg/m2 IV on days 1, 8



Repeat q28d



ProMACE is administered for a variable number of cycles, based on tumor response, then MOPP therapy is administered for the same number of cycles.



MACOP-BMethotrexate 400 mg/m2 IV on weeks 2, 6, 10; one-fourth dose is administered as IV bolus, the remaining is administered over 4 h



Leucovorin 15 mg PO q6h for 6 doses starting 24 h after methotrexate



Doxorubicin 50 mg/m2 IV on weeks 1, 3, 5, 7, 9, 11



Cyclophosphamide 350 mg/m2 IV on weeks 1, 3, 5 , 7, 9, 11



Vincristine 1.4 mg/m2 IV on weeks 2, 4, 6, 8, 10, 12



Bleomycin 10 U/m2 IV on weeks 2, 4, 6, 8, 10, 12



Prednisone 75 mg/d PO for 12 wk, taper to 0 during weeks 10-12



Trimethoprim-sulfamethoxazole 1 double-strength tablet bid daily for 12 wk



Table 8. Salvage Chemotherapy Regimens Used Commonly in Recurrent Aggressive NHL
RegimenDrugs and Dosages
DHAPDexamethasone 40 mg PO/IV on days 1-4



Cytarabine 2 g/m2 over 3 h q12h for 2 doses on day 2, start after completing cisplatin infusion, reduce to 1 g/m2 for age >70 y



Cisplatin 100 mg/m2 continuous IV infusion over 24 h on day 1



Repeat q3-4wk



ESHAPEtoposide 60 mg/m2 IV on days 1-4



Methylprednisolone 500 mg IV on days 1-4



Cytarabine 2 g/m2 over 2 h on day 5 after completing cisplatin



Cisplatin 25 mg/m2/d continuous IV infusion on days 1-4



Repeat q3-4wk



EPOCHEtoposide 50 mg/m2/24 h continuous IV infusion on days 1-4



Vincristine 0.4 mg/m2/24h continuous IV infusion on days 1-4



Doxorubicin 10 mg/m2/24h continuous IV infusion on days 1-4



Cyclophosphamide 750 mg/m2 IV on day 6



Prednisone 60 mg/m2 PO on days 1-6



Repeat q21d



MINEMesna 1.33 g/m2 mixed with ifosfamide over 1 h on days 1-3, followed by 500 mg IV 4 h after the ifosfamide



Ifosfamide 1.33 g/m2 IV over 1 h on days 1-3



Mitoxantrone 8 mg/m2 IV over 15 min on day 1



Etoposide 65 mg/m2 IV over 1 h on days 1-3



Repeat q21d



Table 9. Preparative Regimens Commonly Used Before High-Dose Chemotherapy in NHL
RegimenDrugs and Dosages
Cy-TBICyclophosphamide 60 mg/kg/d on days 6, 5



Total-body irradiation 12 Gy administered in 6 fractions of 2 Gy each, 2 fractions daily on days 4, 3, 2



Cy-VP-TBIEtoposide 1800 mg/m2 on day 7



Cyclophosphamide 50 mg/kg/d on days 6, 5, 4



Total-body irradiation 10 Gy administered in 5 fractions of 2 Gy each, 2 fractions daily on days 3, 2, 1 fraction on day 1



CBVCyclophosphamide 1800 mg/m2 on days 6, 5, 4, 3



Carmustine (BCNU) 400 mg/m2 on day 2



Etoposide 2400 mg/m2 on day 7



BEAMCarmustine (BCNU) 300 mg/m2 on day 6



Etoposide 200 mg/m2 on days 5, 4, 3, 2



Ara-C 200 mg/m2 on days 5, 4, 3, 2



Melphalan 140 mg/m2 on day 1



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