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Types of Cancer   /   Pediatric Cancers   /   Lymphomas: Non-Hodgkin's Lymphoma (Childhood)   /   NCI Resources

NCI/PDQ® Health professionals: Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

National Cancer Institute
Last Modified: December 28, 2012

TABLE OF CONTENTS


General Information About Adult Non-Hodgkin Lymphoma (NHL)

Back Up

The NHLs are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. 1

Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment.


Incidence and Mortality

Estimated new cases and deaths from NHL in the United States in 2012: 2

  • New cases: 70,130.
  • Deaths: 18,940.


Anatomy

NHL usually originates in lymphoid tissues.


Prognosis and Survival

The NHLs can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas.

Indolent NHL types have a relatively good prognosis with a median survival as long as 10 to 20 years, but they usually are not curable in advanced clinical stages. Early-stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology.

The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.

In general, with modern treatment of patients with NHL, overall survival at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. The vast majority of relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies. 3

While indolent NHL is responsive to immunotherapy, radiation therapy, and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. Patients, however, can often be re-treated with considerable success as long as the disease histology remains low grade. Patients who present with or convert to aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support. 4 5

References:

  1. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012. [PUBMED Abstract]
  2. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
  3. Cabanillas F, Velasquez WS, Hagemeister FB, et al.: Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma. Blood 79 (4): 1024-8, 1992. [PUBMED Abstract]
  4. Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997. [PUBMED Abstract]
  5. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995. [PUBMED Abstract]


Late Effects of Treatment for Adult NHL

Back Up

Late effects of treatment for non-Hodgkin lymphoma (NHL) have been observed. Pelvic radiation therapy and large cumulative doses of cyclophosphamide have been associated with a high risk of permanent sterility. 1 For as many as three decades after diagnosis, patients are at a significantly elevated risk for second primary cancers, especially the following: 1 2 3

  • Lung cancer.
  • Brain cancer.
  • Kidney cancer.
  • Bladder cancer.
  • Melanoma.
  • Hodgkin lymphoma.
  • Acute nonlymphocytic leukemia.

Left ventricular dysfunction was a significant late effect in long-term survivors of high-grade NHL who received more than 200 mg/m of doxorubicin. 4 5

Myelodysplastic syndrome and acute myelogenous leukemia are late complications of myeloablative therapy with autologous bone marrow or peripheral blood stem cell support, as well as conventional chemotherapy-containing alkylating agents. 1 6 7 8 9 10 11 12 13 Most of these patients show clonal hematopoiesis even before the transplantation, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy. 8 14 15 With a median 10-year follow-up after autologous bone marrow transplantation (BMT) with conditioning using cyclophosphamide and total-body radiation therapy, in a series of 605 patients, the incidence of a second malignancy was 21%, and 10% of those were solid tumors. 16 Successful pregnancies with children born free of congenital abnormalities have been reported in young women after autologous BMT. 17

References:

  1. Mudie NY, Swerdlow AJ, Higgins CD, et al.: Risk of second malignancy after non-Hodgkin's lymphoma: a British Cohort Study. J Clin Oncol 24 (10): 1568-74, 2006. [PUBMED Abstract]
  2. Travis LB, Curtis RE, Glimelius B, et al.: Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 85 (23): 1932-7, 1993. [PUBMED Abstract]
  3. Hemminki K, Lenner P, Sundquist J, et al.: Risk of subsequent solid tumors after non-Hodgkin's lymphoma: effect of diagnostic age and time since diagnosis. J Clin Oncol 26 (11): 1850-7, 2008. [PUBMED Abstract]
  4. Haddy TB, Adde MA, McCalla J, et al.: Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas. J Clin Oncol 16 (6): 2070-9, 1998. [PUBMED Abstract]
  5. Moser EC, Noordijk EM, van Leeuwen FE, et al.: Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma. Blood 107 (7): 2912-9, 2006. [PUBMED Abstract]
  6. Darrington DL, Vose JM, Anderson JR, et al.: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12 (12): 2527-34, 1994. [PUBMED Abstract]
  7. Stone RM, Neuberg D, Soiffer R, et al.: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 12 (12): 2535-42, 1994. [PUBMED Abstract]
  8. Armitage JO, Carbone PP, Connors JM, et al.: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol 21 (5): 897-906, 2003. [PUBMED Abstract]
  9. André M, Mounier N, Leleu X, et al.: Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103 (4): 1222-8, 2004. [PUBMED Abstract]
  10. Oddou S, Vey N, Viens P, et al.: Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 31 (1-2): 187-94, 1998. [PUBMED Abstract]
  11. Lenz G, Dreyling M, Schiegnitz E, et al.: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22 (24): 4926-33, 2004. [PUBMED Abstract]
  12. McLaughlin P, Estey E, Glassman A, et al.: Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105 (12): 4573-5, 2005. [PUBMED Abstract]
  13. Morton LM, Curtis RE, Linet MS, et al.: Second malignancy risks after non-Hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 28 (33): 4935-44, 2010. [PUBMED Abstract]
  14. Mach-Pascual S, Legare RD, Lu D, et al.: Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: a single institution study. Blood 91 (12): 4496-503, 1998. [PUBMED Abstract]
  15. Lillington DM, Micallef IN, Carpenter E, et al.: Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma. J Clin Oncol 19 (9): 2472-81, 2001. [PUBMED Abstract]
  16. Brown JR, Yeckes H, Friedberg JW, et al.: Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 23 (10): 2208-14, 2005. [PUBMED Abstract]
  17. Jackson GH, Wood A, Taylor PR, et al.: Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK. Leuk Lymphoma 28 (1-2): 127-32, 1997. [PUBMED Abstract]


Cellular Classification of Adult NHL

Back Up

A pathologist should be consulted prior to a biopsy because some studies require special preparation of tissue (e.g., frozen tissue). Knowledge of cell surface markers and immunoglobulin and T-cell receptor gene rearrangements may help with diagnostic and therapeutic decisions. The clonal excess of light-chain immunoglobulin may differentiate malignant from reactive cells. Since the prognosis and the approach to treatment are influenced by histopathology, outside biopsy specimens should be carefully reviewed by a hematopathologist who is experienced in diagnosing lymphomas. Although lymph node biopsies are recommended whenever possible, sometimes immunophenotypic data are sufficient to allow diagnosis of lymphoma when fine-needle aspiration cytology is preferred. 1 2


Historical Classification Systems

Historically, uniform treatment of patients with non-Hodgkin lymphoma (NHL) has been hampered by the lack of a uniform classification system. In 1982, results of a consensus study were published as the Working Formulation. 3 The Working Formulation combined results from six major classification systems into one classification. This allowed comparison of studies from different institutions and countries. The Rappaport classification, which also follows, is no longer in common use.


Table 1. Historical Classification Systems for NHL

Working Formulation   Rappaport Classification  
Low grade   
A. Small lymphocytic, consistent with chronic lymphocytic leukemia  Diffuse lymphocytic, well-differentiated 
B. Follicular, predominantly small-cleaved cell  Nodular lymphocytic, poorly differentiated 
C. Follicular, mixed small-cleaved, and large cell  Nodular mixed, lymphocytic, and histiocytic 
Intermediate grade   
D. Follicular, predominantly large cell  Nodular histiocytic 
E. Diffuse, small-cleaved cell  Diffuse lymphocytic, poorly differentiated 
F. Diffuse mixed, small and large cell  Diffuse mixed, lymphocytic, and histiocytic 
G. Diffuse, large cell, cleaved, or noncleaved cell  Diffuse histiocytic 
High grade   
H. Immunoblastic, large cell  Diffuse histiocytic 
I. Lymphoblastic, convoluted, or nonconvoluted cell  Diffuse lymphoblastic 
J. Small noncleaved-cell, Burkitt, or non-Burkitt  Diffuse undifferentiated Burkitt or non-Burkitt 


Current Classification Systems

As the understanding of NHL has improved and as the histopathologic diagnosis of NHL has become more sophisticated with the use of immunologic and genetic techniques, a number of new pathologic entities have been described. 4 In addition, the understanding and treatment of many of the previously described pathologic subtypes have changed. As a result, the Working Formulation has become outdated and less useful to clinicians and pathologists. Thus, European and American pathologists have proposed a new classification, the Revised European American Lymphoma (REAL) classification. 5 6 7 8 Since 1995, members of the European and American Hematopathology societies have been collaborating on a new World Health Organization (WHO) classification, which represents an updated version of the REAL system. 9 10

The WHO modification of the REAL classification recognizes three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma. Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For example, B-cell chronic lymphocytic leukemia and B-cell small lymphocytic lymphoma are simply different manifestations of the same neoplasm, as are lymphoblastic lymphomas and acute lymphocytic leukemias. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms. 9 10


Updated REAL/WHO classification

    B-cell neoplasms

  1. Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL).
  2. Peripheral B-cell neoplasms.
    1. B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.
    2. B-cell prolymphocytic leukemia.
    3. Lymphoplasmacytic lymphoma/immunocytoma.
    4. Mantle cell lymphoma.
    5. Follicular lymphoma.
    6. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type.
    7. Nodal marginal zone B-cell lymphoma ( monocytoid B-cells).
    8. Splenic marginal zone lymphoma ( villous lymphocytes).
    9. Hairy cell leukemia.
    10. Plasmacytoma/plasma cell myeloma.
    11. Diffuse large B-cell lymphoma.
    12. Burkitt lymphoma.

    T-cell and putative NK-cell neoplasms

  1. Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL.
  2. Peripheral T-cell and NK-cell neoplasms.
    1. T-cell chronic lymphocytic leukemia/prolymphocytic leukemia.
    2. T-cell granular lymphocytic leukemia.
    3. Mycosis fungoides/Sézary syndrome.
    4. Peripheral T-cell lymphoma, not otherwise characterized.
    5. Hepatosplenic gamma/delta T-cell lymphoma.
    6. Subcutaneous panniculitis-like T-cell lymphoma.
    7. Angioimmunoblastic T-cell lymphoma.
    8. Extranodal T-/NK-cell lymphoma, nasal type.
    9. Enteropathy-type intestinal T-cell lymphoma.
    10. Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+).
    11. Anaplastic large cell lymphoma, primary systemic type.
    12. Anaplastic large cell lymphoma, primary cutaneous type.
    13. Aggressive NK-cell leukemia.

    Hodgkin lymphoma

  1. Nodular lymphocyte-predominant Hodgkin lymphoma.
  2. Classical Hodgkin lymphoma.
    1. Nodular sclerosis Hodgkin lymphoma.
    2. Lymphocyte-rich classical Hodgkin lymphoma.
    3. Mixed-cellularity Hodgkin lymphoma.
    4. Lymphocyte-depleted Hodgkin lymphoma.

The REAL classification encompasses all the lymphoproliferative neoplasms. Refer to the following PDQ® summaries for more information:


PDQ® modification of REAL classification of lymphoproliferative diseases

  1. Plasma cell disorders. (Refer to the PDQ® summary on Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment for more information.)
    1. Bone.
    2. Extramedullary.
      1. Monoclonal gammopathy of undetermined significance.
      2. Plasmacytoma.
      3. Multiple myeloma.
      4. Amyloidosis.

  2. Hodgkin lymphoma. (Refer to the PDQ® summary on Adult Hodgkin Lymphoma Treatment for more information.)
    1. Nodular sclerosis Hodgkin lymphoma.
    2. Lymphocyte-rich classical Hodgkin lymphoma.
    3. Mixed-cellularity Hodgkin lymphoma.
    4. Lymphocyte-depleted Hodgkin lymphoma.

  3. Indolent lymphoma/leukemia.
    1. Follicular lymphoma (follicular small-cleaved cell [grade 1], follicular mixed small-cleaved, and large cell [grade 2], and diffuse small-cleaved cell).
    2. Chronic lymphocytic leukemia/small lymphocytic lymphoma. (Refer to the PDQ® summary on Chronic Lymphocytic Leukemia Treatment for more information.)
    3. Lymphoplasmacytic lymphoma (Waldenstrím macroglobulinemia).
    4. Extranodal marginal zone B-cell lymphoma (MALT lymphoma).
    5. Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma).
    6. Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes).
    7. Hairy cell leukemia. (Refer to the PDQ® summary on Hairy Cell Leukemia Treatment for more information.)
    8. Mycosis fungoides/Sézary syndrome. (Refer to the PDQ® summary on Mycosis Fungoides/Sézary Syndrome Treatment for more information.)
    9. T-cell granular lymphocytic leukemia. (Refer to the PDQ® summary on Chronic Lymphocytic Leukemia Treatment for more information.)
    10. Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30+).
    11. Nodular lymphocytepredominant Hodgkin lymphoma. (Refer to the PDQ® summary on Adult Hodgkin Lymphoma Treatment for more information.)

  4. Aggressive lymphoma/leukemia.
    1. Diffuse large cell lymphoma (includes diffuse mixed-cell, diffuse large cell, immunoblastic, and T-cell rich large B-cell lymphoma).

      Distinguish:

      1. Mediastinal large B-cell lymphoma.
      2. Follicular large cell lymphoma (grade 3).
      3. Anaplastic large cell lymphoma (CD30+).
      4. Extranodal NK-/T-cell lymphoma, nasal type/aggressive NK-cell leukemia/blastic NK-cell lymphoma.
      5. Lymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma).
      6. Angioimmunoblastic T-cell lymphoma.
      7. Peripheral T-cell lymphoma, unspecified.
        • Subcutaneous panniculitis-like T-cell lymphoma.
        • Hepatosplenic T-cell lymphoma.

      8. Enteropathy-type T-cell lymphoma.
      9. Intravascular large B-cell lymphoma.

    2. Burkitt lymphoma/Burkitt cell leukemia/Burkitt-like lymphoma.
    3. Precursor B-cell or T-cell lymphoblastic lymphoma/leukemia. (Refer to the PDQ® summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
    4. Primary central nervous system (CNS) lymphoma. (Refer to the PDQ® summary on Primary CNS Lymphoma Treatment for more information.)
    5. Adult T-cell leukemia/lymphoma (HTLV 1+).
    6. Mantle cell lymphoma.
    7. Polymorphic posttransplantation lymphoproliferative disorder.
    8. AIDS-related lymphoma. (Refer to the PDQ® summary on AIDS-Related Lymphoma Treatment for more information.)
    9. True histiocytic lymphoma.
    10. Primary effusion lymphoma.
    11. B-cell or T-cell prolymphocytic leukemia. (Refer to the PDQ® summary on Chronic Lymphocytic Leukemia Treatment for more information.)

References:

  1. Zeppa P, Marino G, Troncone G, et al.: Fine-needle cytology and flow cytometry immunophenotyping and subclassification of non-Hodgkin lymphoma: a critical review of 307 cases with technical suggestions. Cancer 102 (1): 55-65, 2004. [PUBMED Abstract]
  2. Young NA, Al-Saleem T: Diagnosis of lymphoma by fine-needle aspiration cytology using the revised European-American classification of lymphoid neoplasms. Cancer 87 (6): 325-45, 1999. [PUBMED Abstract]
  3. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982. [PUBMED Abstract]
  4. Pugh WC: Is the working formulation adequate for the classification of the low grade lymphomas? Leuk Lymphoma 10(Suppl): 1-8, 1993. [PUBMED Abstract]
  5. Harris NL, Jaffe ES, Stein H, et al.: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84 (5): 1361-92, 1994. [PUBMED Abstract]
  6. Pittaluga S, Bijnens L, Teodorovic I, et al.: Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation. Blood 87 (10): 4358-67, 1996. [PUBMED Abstract]
  7. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998. [PUBMED Abstract]
  8. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997. [PUBMED Abstract]
  9. Pileri SA, Milani M, Fraternali-Orcioni G, et al.: From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities? Ann Oncol 9 (6): 607-12, 1998. [PUBMED Abstract]
  10. Society for Hematopathology Program.: Society for Hematopathology Program. Am J Surg Pathol 21(1): 114-121, 1997. [PUBMED Abstract]


Indolent NHL

Back Up

Indolent non-Hodgkin lymphoma (NHL) includes the following subtypes:


Follicular Lymphoma

Follicular lymphoma comprises 20% of all NHLs and as many as 70% of the indolent lymphomas reported in American and European clinical trials. 1 2 3 Most patients with follicular lymphoma are age 50 years and older and present with widespread disease at diagnosis. Nodal involvement is most common and is often accompanied by splenic and bone marrow disease. Rearrangement of the bcl-2 gene is present in more than 90% of patients with follicular lymphoma; overexpression of the bcl-2 protein is associated with the inability to eradicate the lymphoma by inhibiting apoptosis. 4


Prognosis

Despite the advanced stage, the median survival ranges from 8 to 15 years, leading to the designation of being indolent. 5 6 7 Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. 8 The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment. 9 Watchful waiting, i.e., the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma. 10 An international index for follicular lymphoma (i.e., the Follicular Lymphoma International Prognostic Index [FLIPI]) 11 12 13 identified five significant risk factors prognostic of overall survival (OS):

  1. Age (60 years vs. >60 years).
  2. Serum lactate dehydrogenase (LDH) (normal vs. elevated).
  3. Stage (stage I or stage II vs. stage III or stage IV).
  4. Hemoglobin level (120 g/L vs. <120 g/L).
  5. Number of nodal areas (4 vs. >4).

Patients with none or one risk factor have an 85% 10-year survival rate, while three or more risk factors confer a 40% 10-year survival rate. 11 As a revised FLIPI, an elevated beta-2-microglobulin and lymph node size of more than 6 cm are proposed prognostic factors instead of serum LDH and the number of nodal areas. 14 Gene expression profiles of tumor biopsy specimens suggest that follicular lymphoma that is surrounded by infiltrating T-lymphocytes has a much longer median survival (13.6 years) than follicular lymphoma that is surrounded by dendritic and monocytic cells (3.9 years) (P < .001). 15

Follicular small-cleaved cell lymphoma and follicular mixed small-cleaved and large cell lymphoma do not have reproducibly different disease-free survival or OS.


Therapeutic approaches

Therapeutic options include watchful waiting; rituximab, an anti-CD20 monoclonal antibody, alone or with purine nucleoside analogs; oral alkylating agents; and combination chemotherapy. 16 Radiolabeled monoclonal antibodies, vaccines, and autologous or allogeneic bone marrow or peripheral stem cell transplantation are also under clinical evaluation. 16 Currently, no randomized trials guide clinicians about the initial choice of rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options. On a comparative basis, it is difficult to prove benefit when relapsing disease is followed with watchful waiting, or when the median survival is more than 10 years. Follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress and rarely require therapy. 17 18

Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to a therapy applicable to that histologic type. 19 Rapid growth or discordant growth between various disease sites may indicate a histologic conversion. The risk of histologic transformation was 30% by 10 years in a retrospective review of 325 patients from diagnosis between 1972 and 1999. 20 In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk FLIPI, and expectant management. The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after re-treatment. 21 (Refer to the Treatment for Aggressive, Recurrent Adult NHL section of this summary for a description of the regimens used to treat histologic conversions.) The durability of the second remission may be short, and clinical trials should be considered. 21 22 23


Lymphoplasmacytic Lymphoma (Waldenstrím Macroglobulinemia)

Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenstrím macroglobulinemia). 24 25 26 Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Other lymphomas may also be associated with serum paraproteins.

Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy. 10 27 28

Prognostic factors associated with symptoms requiring therapy include the following:

  • Age 70 or older.
  • Beta-2-microglobulin of 3 mg/dL or more.
  • Increased serum LDH. 27


Therapeutic approaches

The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia. 25 26 27 29 30 31 If the viscosity relative to water is greater than four, the patient may have manifestations of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms (such as retinopathy, congestive heart failure, and central nervous system [CNS] dysfunction) but should be combined with chemotherapy for prolonged control of the disease. Symptomatic patients with a serum viscosity of not more than four are usually started directly on chemotherapy. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; rituximab, cyclophosphamide, and steroids are often employed. 28 Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.

First-line regimens include rituximab, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy. 32 33 34 Rituximab shows 60% to 80% response rates in previously untreated patients, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy. 32 35 36[Level of evidence: 3iiiDiv] The rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent such as cyclophosphamide or the proteosome inhibitor bortezomib. 28 37 The nucleoside analogs 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma. 38 39[Level of evidence: 3iiiDiv] Single-agent alkylators, bortezomib, and combination chemotherapy with or without rituximab also show similar response rates. 37 40 41 42[Level of evidence: 3iiiDiv] Currently, no randomized trials guide clinicians about the initial choice of rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, or combinations of these options. 25 26 32 A combination of bortezomib, dexamethasone, and rituximab has been proposed for its high response rate, rapidity of action, and avoidance of an IgM rebound. 43

Interferon-alpha also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma. 44 Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation. 45 46 47 48 Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogs, which can deplete hematopoietic stem cells or predispose patients to myelodysplasia or acute leukemia. 32 49 After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomly assigned to either fludarabine or cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration of 19 months vs. 3 months, P < .01), no difference was observed in OS. 50[Level of evidence: 1iiDii] Among patients with concomitant hepatitis C virus (HCV) infection, some will attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin. 51[Level of evidence: 3iiiDiv]


Marginal Zone Lymphoma

Marginal zone lymphomas were previously included among the diffuse small lymphocytic lymphomas. When marginal zone lymphomas involve the nodes, they are called monocytoid B-cell lymphomas or nodal marginal zone B-cell lymphomas, and when they involve extranodal sites (e.g., gastrointestinal tract, thyroid, lung, breast, orbit, and skin), they are called mucosa-associated lymphatic tissue (MALT) lymphomas. 52 53 54 55 56 57 58 59 60


Gastric MALT

Many patients have a history of autoimmune disease, such as Hashimoto thyroiditis or Sjígren syndrome, or of Helicobacter gastritis. Most patients present with stage I or stage II extranodal disease, which is most often in the stomach. Treatment of Helicobacter pylori infection may resolve most cases of localized gastric involvement. 61 62 After standard antibiotic regimens, 50% of patients show resolution of gastric MALT by endoscopy after 3 months. Other patients may show resolution after 12 to 18 months of observation. Of the patients who attain complete remission, 30% demonstrate monoclonality by immunoglobulin heavy chain rearrangement on stomach biopsies with a 5-year median follow-up. 63 The clinical implication of this finding is unknown. Translocation t(11;18) in patients with gastric MALT predicts for poor response to antibiotic therapy, for H. pylorinegative testing, and for poor response to oral alkylator chemotherapy. 64 65 66 Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression. 62 Patients who progress are treated with radiation therapy, 67 68 69 70 rituximab, 71 surgery (total gastrectomy or partial gastrectomy plus radiation therapy), 72 chemotherapy, 58 or combinedmodality therapy. 73 The use of endoscopic ultrasonography may help clinicians to follow responses in these patients. 74 Three small case series (two retrospective and one prospective) reported durable complete remissions after treatment of H. pylori in patients with aggressive lymphoma (complete remission rate of 35%88% and a median duration of 2160 months). 75 76 77


Extragastric MALT

Localized involvement of other sites can be treated with radiation or surgery. 68 69 70 78 79 80 Patients with extragastric MALT lymphoma have a higher relapse rate than patients with gastric MALT lymphoma in some series, with relapses many years and even decades later. 81 Many of these recurrences involve different MALT sites than the original location. 82 When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas. 59 83 For patients with ocular adnexal MALT, antibiotic therapy using doxycycline targeting Chlamydia psittaci resulted in durable remissions for half of the patients in a small series of 27 patients. 84[Level of evidence: 3iiiDiv] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas. 85


Monocytoid B cell lymphoma (Nodal marginal zone lymphoma)

Patients with nodal marginal zone lymphoma (monocytoid B-cell lymphoma) are treated with the same paradigm of watchful waiting or therapies as described for follicular lymphoma. Among patients with concomitant HCV infection, the majority attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin. 51[Level of evidence: 3iiiDiv]


Mediterranean abdominal lymphoma

The disease variously known as Mediterranean abdominal lymphoma, heavychain disease, or immunoproliferative small intestinal disease (IPSID), which occurs in young adults in eastern Mediterranean countries, is another version of MALT lymphoma, which responds to antibiotics in its early stages. 86 Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease. 87


Splenic marginal zone lymphoma

Splenic marginal zone lymphoma is an indolent lymphoma that is marked by massive splenomegaly and peripheral blood and bone marrow involvement, usually without adenopathy. 88 89 90 This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission. 60 91

Management is similar to that of other low-grade lymphomas and usually involves rituximab alone or rituximab in combination with purine analogs or alkylating agent chemotherapy. 92 Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia. 89 90 92 Among small numbers of patients with splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes) and infection with HCV, the majority attained a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin. 51 93; 94[Level of evidence: 3iiiDiv] In contrast, no responses to interferon were seen in six HCV-negative patients.


Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous anaplastic large cell lymphoma presents in the skin only with no pre-existing lymphoproliferative disease and no extracutaneous sites of involvement. 95 96 97 Patients with this type of lymphoma encompass a spectrum ranging from clinically benign lymphomatoid papulosis, marked by localized nodules that may regress spontaneously, to a progressive and systemic disease requiring aggressive doxorubicin-based combination chemotherapy. This spectrum has been called the primary cutaneous CD30-positive T-cell lymphoproliferative disorder.

Patients with localized disease usually undergo radiation therapy. With more disseminated involvement, watchful waiting or doxorubicin-based combination chemotherapy is applied. 95 96 97

(Refer to the PDQ® summaries on Chronic Lymphocytic Leukemia Treatment; Mycosis Fungoides/Sézary Syndrome Treatment; Hairy Cell Leukemia Treatment; and Adult Hodgkin Lymphoma Treatment for more information.)

References:

  1. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998. [PUBMED Abstract]
  2. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997. [PUBMED Abstract]
  3. Society for Hematopathology Program.: Society for Hematopathology Program. Am J Surg Pathol 21(1): 114-121, 1997. [PUBMED Abstract]
  4. López-Guillermo A, Cabanillas F, McDonnell TI, et al.: Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood 93 (9): 3081-7, 1999. [PUBMED Abstract]
  5. Peterson BA, Petroni GR, Frizzera G, et al.: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 21 (1): 5-15, 2003. [PUBMED Abstract]
  6. Swenson WT, Wooldridge JE, Lynch CF, et al.: Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 23 (22): 5019-26, 2005. [PUBMED Abstract]
  7. Liu Q, Fayad L, Cabanillas F, et al.: Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of t

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