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Non-Hodgkin
lymphomas are a heterogeneous group of disorders involving malignant
monoclonal proliferation of lymphoid cells in lymphoreticular sites,
including lymph nodes, bone marrow, the spleen, the liver, and the
GI tract. Presenting symptoms usually include peripheral lymphadenopathy.
However, some patients present without adenopathy but with abnormal
lymphocytes in circulation. Compared with Hodgkin lymphoma, there
is a greater likelihood of disseminated disease at the time of diagnosis.
Diagnosis is usually based on lymph node or bone marrow biopsy or
both. Treatment involves radiation therapy, chemotherapy, or both.
Stem cell transplantation is usually reserved for salvage therapy
after incomplete remission or relapse.
Non-Hodgkin lymphoma (NHL) is more common than Hodgkin lymphoma. It is the 6th most common cancer in the US; about 65,000 new cases are diagnosed annually in all age groups. However, NHL is not one disease but rather a category of lymphocyte cancers. Incidence increases with age (median age, 50 yr).
Etiology
The cause of NHL is unknown, although, as with the leukemias, substantial evidence suggests a viral cause (eg, human T-cell leukemia-lymphoma virus, Epstein-Barr virus, hepatitis C virus, HIV). Risk factors for NHL include immunodeficiency (secondary to posttransplant immunosuppression, AIDS, primary immune disorders, sicca syndrome, RA), Helicobacter
pylori infection, certain chemical exposures, and previous treatment for Hodgkin lymphoma. NHL is the 2nd most common cancer in HIV-infected patients (see Human Immunodeficiency Virus (HIV): Non-Hodgkin lymphoma), and some AIDS patients present with lymphoma. C-myc gene rearrangements are characteristic of some AIDS-associated lymphomas.
Pathophysiology
Most (80 to 85%) NHLs arise from B cells; the remainder arise from T cells or natural killer cells. Either precursor or mature cells may be involved. Overlap exists between leukemia and NHL because both involve proliferation of lymphocytes or their precursors. A leukemia-like picture with peripheral lymphocytosis and bone marrow involvement may be present in up to 50% of children and in about 20% of adults with some types of NHL. Differentiation can be difficult, but generally patients with more extensive nodal involvement (especially mediastinal), fewer circulating abnormal cells, and fewer blast forms in the marrow (< 25%) are considered to have lymphoma. A prominent leukemic phase is less common in aggressive lymphomas, except Burkitt's and lymphoblastic lymphomas.
Hypogammaglobulinemia caused by a progressive decrease in immunoglobulin production occurs in 15% of patients and may predispose to serious bacterial infection.
Classification
Pathologic classification of NHLs continues to evolve, reflecting new insights into the cells of origin and the biologic bases of these heterogeneous diseases. The WHO classification (see Table 5: Lymphomas: Subtypes of Non-Hodgkin Lymphoma (WHO Classification) ) is valuable because it incorporates immunophenotype, genotype, and cytogenetics, but numerous other systems exist (eg, Lyon classification). Among the most important new lymphomas recognized by the WHO system are mucosa-associated lymphoid tumors (MALT—see Gastritis and Peptic Ulcer Disease: Mucosa-associated lymphoid tissue (MALT) lymphoma); mantle cell lymphoma (previously diffuse small cleaved cell lymphoma); and anaplastic large cell lymphoma, a heterogeneous disorder with 75% of cases of T-cell origin, 15% of B-cell origin, and 10% unclassified. However, despite the plethora of entities, treatment is often similar except in certain T-cell lymphomas.
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Table 5
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Subtypes of Non-Hodgkin
Lymphoma (WHO Classification)
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Cell Origin
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Tumor
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Precursor B-cell tumor
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Precursor B-lymphoblastic leukemia/lymphoma*
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Mature B-cell tumors
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B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma†
B-cell prolymphocytic leukemia†
Lymphoplasmacytic lymphoma†
Splenic marginal zone B-cell lymphoma (± villous lymphocytes) †
Hairy cell leukemia†
Plasma cell myeloma/plasmacytoma†
Extranodal marginal zone B-cell lymphoma of the MALT type†
Nodal marginal zone B-cell lymphoma (± monocytoid B cells)†
Follicular lymphoma†
Mantle cell lymphoma‡
Diffuse large B-cell lymphomas* (including mediastinal large B-cell lymphoma and primary effusion lymphoma)
Burkitt's lymphoma*
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Precursor T-cell tumor
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Precursor T-lymphoblastic lymphoma/leukemia*
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Mature T-cell tumors
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T-cell prolymphocytic leukemia†
T-cell granular lymphocytic leukemia*
Aggressive NK cell leukemia*
Adult T-cell lymphoma/leukemia* (HTLV 1-positive)
Extranodal NK/T-cell lymphoma, nasal type*
Enteropathy-type T-cell lymphoma*
Hepatosplenic γ-δ T-cell lymphoma*
Subcutaneous panniculitis-like T-cell lymphoma*
Mycosis fungoides/Sézary syndrome†
Anaplastic large cell lymphoma, T/null cell, primary cutaneous type*
Anaplastic large cell lymphoma, T-/null-cell, primary systemic type*
Peripheral T-cell lymphoma, not otherwise characterized*
Angioimmunoblastic T-cell lymphoma*
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*Aggressive.
†Indolent.
‡Indolent but more rapidly progressive.
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HTLV = human T-cell leukemia virus 1; MALT = mucosa-associated lymphoid tissue; NK = natural killer; ± = with or without.
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Lymphomas are commonly also categorized as indolent or aggressive. Indolent lymphomas are slowly progressive and responsive to therapy but are not curable with standard approaches. Aggressive lymphomas are rapidly progressive but responsive to therapy and often curable.
In children, NHL is almost always aggressive. Follicular and other indolent lymphomas are very rare. The treatment of these aggressive lymphomas (Burkitt's, diffuse large B cell, and lymphoblastic lymphoma) presents special concerns, including GI tract involvement (particularly in the terminal ileum); meningeal spread (requiring CSF prophylaxis or treatment); and other sanctuary sites of involvement (such as testis or brain). In addition, with these potentially curable lymphomas, treatment adverse effects as well as outcome must be considered, including late risks of secondary cancer, cardiorespiratory sequelae, fertility preservation, and developmental consequences. Current research is focused on these areas as well as on the molecular events and predictors of lymphoma in children.
Symptoms and Signs
Many patients present with asymptomatic peripheral lymphadenopathy. Enlarged lymph nodes are rubbery and discrete and later become matted. Disease is localized in some patients, but most patients have several areas of involvement. Mediastinal and retroperitoneal lymphadenopathy may cause pressure symptoms on various organs. Extranodal sites may dominate clinically (eg, gastric involvement can simulate GI carcinoma; intestinal lymphoma may cause a malabsorption syndrome; HIV patients who develop NHL often present with CNS involvement).
The skin and bones are initially involved in 15% of patients with aggressive lymphoma and in 7% with indolent lymphoma. Occasionally, patients with extensive abdominal or thoracic disease develop chylous ascites or pleural effusion because of lymphatic obstruction. Weight loss, fever, night sweats, and asthenia indicate disseminated disease. Patients may have hepatomegaly and splenomegaly as well.
Two problems are common in NHL but rare in Hodgkin lymphoma: Congestion and edema of the face and neck from pressure on the superior vena cava (superior vena cava or superior mediastinal syndrome) may occur. Also, ureters may be compressed by retroperitoneal or pelvic lymph nodes or both; this compression may interfere with urinary flow and cause secondary renal failure.
Anemia is initially present in about 33% of patients and eventually develops in most. It may be caused by bleeding from GI lymphoma, with or without low platelet levels; hemolysis from hypersplenism or Coombs'-positive hemolytic anemia; bone marrow infiltration from lymphoma; or marrow suppression from chemotherapy or radiation therapy.
The acute illness of adult T-cell leukemia-lymphoma (associated with human T-lymphotrophic virus 1 [HTLV-1]) has a fulminating clinical course with skin infiltrates, lymphadenopathy, hepatosplenomegaly, and leukemia. The leukemic cells are malignant T cells, many with convoluted nuclei. Hypercalcemia often develops, related to humoral factors rather than to direct bone invasion.
Patients with anaplastic large cell lymphoma have rapidly progressive skin lesions, adenopathy, and visceral lesions. This disease may be mistaken for Hodgkin lymphoma or metastatic undifferentiated carcinoma.
Diagnosis
As with Hodgkin lymphoma, NHL is usually suspected in patients with painless lymphadenopathy or when mediastinal adenopathy is detected on routine chest x-ray. Painless lymphadenopathy can also result from infectious mononucleosis, toxoplasmosis, cytomegalovirus infection, primary HIV infection, or leukemia. Similar chest x-ray findings can result from lung carcinoma, sarcoidosis, or TB. Less commonly, patients present after a finding of peripheral lymphocytosis on CBC done for nonspecific symptoms. In such cases, the differential diagnosis includes leukemia, Epstein-Barr virus infection, and Duncan's syndrome (X-linked lymphoproliferative syndrome).
Chest x-ray is obtained if not done previously, and a lymph node biopsy is done if lymphadenopathy is confirmed on CT or PET scan. If only mediastinal nodes are enlarged, patients require CT-guided needle biopsy or mediastinoscopy. Usually, tests should include CBC, alkaline phosphatase, renal and liver function tests, LDH, and uric acid. Other tests are done depending on findings (eg, MRI for symptoms of cord compression or CNS abnormalities).
Histologic criteria on biopsy include destruction of normal lymph node architecture and invasion of the capsule and adjacent fat by characteristic neoplastic cells. Immunophenotyping studies to determine the cell of origin are of great value in identifying specific subtypes and helping define prognosis and management; these studies also can be done on peripheral cells. Demonstration of the leukocyte common antigen CD45 by immunoperoxidase rules out metastatic cancer, which is often in the differential diagnosis of “undifferentiated” cancers. The test for leukocyte common antigen, most surface marker studies, and gene rearrangement (to document B-cell or T-cell clonality) can be done on fixed tissues. Cytogenetics and flow cytometry require fresh tissue.
Staging:
Although localized NHL does occur, the disease is typically disseminated when first recognized. Staging procedures include CT of the chest, abdomen, and pelvis; PET; and bone marrow biopsy. The final staging of NHL (see Table 3: Lymphomas: Cotswold Modification of Ann Arbor Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma) is similar to that of Hodgkin lymphoma and is based on clinical and pathologic findings.
Prognosis
Patients with T-cell lymphomas generally have a worse prognosis than do those with B-cell types, although newer intensive treatment regimens may lessen this difference. Prognosis for each NHL variant is related to differences in tumor cell biology.
Survival also varies with other factors. The International Prognostic Index (IPI) is frequently used in aggressive lymphomas. It considers 5 risk factors:
Outcome is worse with an increasing number of risk factors. Survival, as determined by IPI factor, has improved with the addition of rituximab to the standard chemotherapeutic regimen. Patients in the highest risk groups (patients with 4 or 5 risk factors) now have a 50% 5-yr survival. Low-risk patients without any of the risk factors have a very high cure rate. A modified IPI (the FLIPI) is being used in follicular lymphomas and in DLBCL (the R-IPI).
Treatment
Treatment varies considerably with cell type, which are too numerous to permit detailed discussion. Generalizations can be made regarding localized vs advanced disease and aggressive vs indolent forms. Burkitt's lymphoma (see Lymphomas: Burkitt's Lymphoma) and mycosis fungoides (see Lymphomas: Mycosis Fungoides) are discussed separately.
Localized disease
(stages I and II):
Patients with indolent lymphomas rarely present with localized disease, but when they do, regional radiation therapy may offer long-term control. However, relapses may occur > 10 yr after radiation therapy.
About ½ of patients with aggressive lymphomas present with localized disease, for which combination chemotherapy, with or without regional radiation, is usually curative. Patients with lymphoblastic lymphomas or Burkitt's lymphoma, even if apparently localized, must receive intensive combination chemotherapy with meningeal prophylaxis. Treatment may require maintenance chemotherapy (lymphoblastic), but cure is expected.
Advanced disease
(stages III and IV):
For indolent lymphomas, treatment varies considerably. A watch-and-wait approach, treatment with a single alkylating drug, or 2- or 3-drug regimens may be used. Criteria considered in selecting management options include age, general health, distribution of disease, tumor bulk, histology, and anticipated benefits of therapy. The B-cell specific anti-CD20 antibody rituximab and other biologic response modifiers appear to be of benefit; one of these drugs can be combined with chemotherapy or administered as single therapy. Radiolabeled-antibody therapy is also valuable.
In patients with the aggressive B-cell lymphomas (eg, diffuse large B cell), the standard drug combination is rituximab plus cyclophosphamide , hydroxydaunorubicin ( doxorubicin ), vincristine , prednisone (R-CHOP). Complete disease regression is expected in ≥ 70% of patients, depending on the IPI category. More than 70% of complete responders are cured, and relapses > 2 yr after treatment ceases are rare.
As cure rates have improved with the use of R-CHOP, autologous transplantation is reserved for patients with relapsed or refractory aggressive B-cell lymphomas, some younger patients with mantle cell lymphoma, and some patients with aggressive T-cell lymphomas.
Lymphoma relapse:
The first relapse after initial chemotherapy is almost always treated with autologous stem cell transplantation. Patients usually should be ≤ 70 yr or in equivalent health and have responsive disease, good performance status, a source of uncontaminated stem cells, and an adequate number of CD34+ stem cells (harvested from peripheral blood or bone marrow). Consolidation myeloablative therapy may include chemotherapy with or without irradiation. Posttreatment immunotherapy (eg, rituximab , vaccination, IL-2) is being studied.
An allogeneic transplant is the donation of stem cells from a compatible donor (brother, sister, or matched unrelated donor). The stem cells have a 2-fold effect: reconstituting normal blood counts and providing a possible graft-vs-tumor effect.
In aggressive lymphoma, a cure may be expected in 30 to 50% of eligible patients undergoing myeloablative therapy.
In indolent lymphomas, cure with autologous transplantation remains uncertain, although remission may be superior to that with secondary palliative therapy alone. Reduced intensity allotransplantation appears to offer a potentially curative option in some patients with indolent lymphoma.
The mortality rate of patients undergoing myeloablative transplantation has decreased dramatically to 2 to 5% for most autologous procedures and to < 15% for most allogeneic procedures.
Complications
of treatment:
A late sequela of standard and high-dose chemotherapy is the occurrence of 2nd tumors, especially myelodysplasias and acute myelogenous leukemia. Chemotherapy combined with radiation therapy increases this risk, although its incidence is still only about 3%.
Burkitt's
Lymphoma
Burkitt's
lymphoma is a B-cell lymphoma occurring primarily in children. Endemic
(African), sporadic (non-African), and immunodeficiency-related
forms exist.
Burkitt's lymphoma is endemic in central Africa and constitutes 30% of childhood lymphomas in the US. The form endemic to Africa often presents as enlargement of the jaw or facial bones. In non-African Burkitt's lymphoma, abdominal disease predominates, often arising in the region of the ileocecal valve or the mesentery. The kidneys, ovaries, or breasts may be involved as well, and in adults, disease may be bulky and generalized, often with massive involvement of liver, spleen, and bone marrow. CNS involvement is often present at diagnosis or with relapsing lymphoma.
Burkitt's lymphoma is the most rapidly growing human tumor, and pathology reveals a high mitotic rate, a monoclonal proliferation of B cells, and a “starry-sky” pattern of benign macrophages that have engulfed apoptotic malignant lymphocytes. There is a distinctive genetic translocation involving the C-myc gene on chromosome 8 and the immunoglobulin heavy chain of chromosome 14. The disease is closely associated with Epstein-Barr virus infection in endemic lymphoma; however, it is uncertain whether Epstein-Barr virus plays an etiologic role. Burkitt's lymphoma occurs frequently in patients with AIDS and may be an AIDS-defining disease.
Diagnosis
Diagnosis is based on biopsy of lymph node or tissue from another suspected disease site. Staging includes CT of the chest, abdomen, and pelvis, bone marrow biopsy, CSF cytology, and PET scan.
Treatment
Treatment must be initiated rapidly and staging studies expedited because of rapid tumor growth. An intensive alternating regimen– cyclophosphamide , vincristine , doxorubicin , methotrexate , ifosfamide , etoposide , and cytarabine (CODOX-M/IVAC)–results in a cure rate of > 90% for children and adults. Meningeal prophylaxis is essential. With treatment, tumor lysis syndrome (see Principles of Cancer Therapy: Tumor Lysis Syndrome) is common, and patients must receive IV hydration, allopurinol or rasburicase , alkalinization, and close attention to electrolytes (particularly K and Ca).
If the patient presents with bowel obstruction secondary to tumor and the tumor is completely resected at initial diagnostic-therapeutic laparotomy, then aggressive therapy is still indicated. Salvage therapy for treatment failures is generally unsuccessful, underscoring the importance of very aggressive initial therapy.
Mycosis
Fungoides
Mycosis fungoides
is an uncommon chronic T-cell lymphoma primarily affecting the skin
and occasionally the internal organs.
Mycosis fungoides is rare compared with Hodgkin lymphoma and NHL. Unlike most other lymphomas, it is insidious in onset, sometimes appearing as a chronic, pruritic rash that is difficult to diagnose. It begins focally but may spread to involve most of the skin. Lesions are plaquelike but may become nodular or ulcerated. Eventually, systemic involvement of lymph nodes, liver, spleen, and lungs occurs, resulting in the advent of symptoms, which include fever, night sweats, and unintentional weight loss.
Diagnosis
Diagnosis is based on skin biopsy, but histology may be equivocal early in the course because of insufficient quantities of lymphoma cells. The malignant cells are mature T cells (T4+, T11+, T12+). Characteristic Pautrier's microabscesses are present in the epidermis. In some cases, a leukemic phase called Sézary syndrome is characterized by the appearance of malignant T cells with serpentine nuclei in the peripheral blood.
Once mycosis fungoides has been confirmed, the stage (see Table 3: Lymphomas: Cotswold Modification of Ann Arbor Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma) is determined by CT scan of the chest, abdomen, and pelvis and by bone marrow biopsy for blood or lymph node involvement. PET scan may also be used for suspected visceral involvement.
Prognosis
Most patients are > 50 yr at diagnosis; average life expectancy is 7 to 10 yr after diagnosis, even without treatment. However, survival rates vary markedly depending on stage at diagnosis. Patients who receive treatment for stage IA disease have a life expectancy analogous to that of similar people without mycosis fungoides. Patients who receive treatment for stage IIB disease survive for about 3 yr. Patients treated for stage III disease survive an average of 4 to 6 yr. Patients treated for stage IVA or IVB disease (extracutaneous disease) survive < 1.5 yr.
Treatment
Electron beam radiation therapy, in which most of the energy is absorbed in the first 5 to 10 mm of tissue, and topical nitrogen mustard have proved highly effective. Plaques may also be treated with sunlight and topical corticosteroids. Systemic treatment with alkylating drugs and folic acid antagonists produces transient tumor regression, but systemic treatment is primarily used when other therapies have failed, after relapse, or in patients with documented extranodal or extracutaneous disease. Extracorporeal phototherapy with a chemosensitive drug has shown modest success. The adenosine deaminase inhibitors fludarabine and 2-chlorodeoxyadenosine show promise.
Last full review/revision July 2008 by Carol S. Portlock, MD
Content last modified July 2008
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