Lymphomas

Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma and non-Hodgkin lymphoma (NHL—see Table 1: Lymphomas: Comparison of Hodgkin Lymphoma and Non-Hodgkin Lymphoma).

Lymphoma

Classification and external resources

Gastric MALT lymphoma

ICD-10
C81.-C96. ICD-O:
9590-9999

Lymphomas were once thought to be absolutely distinct from leukemias. However, better understanding of cell markers and tools with which to evaluate those markers now show that the differentiation between these 2 cancers is often vague. The notion that lymphoma is relatively restricted to the lymphatic system and leukemia to the bone marrow, at least in early stages, is also not always true.

 

Hodgkin Lymphoma(Hodgkin's Disease)

Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms include painless lymphadenopathy, sometimes with fever, night sweats, unintentional weight loss, pruritus, splenomegaly, and hepatomegaly. Diagnosis is based on lymph node biopsy. Treatment is curative in about 75% of cases and consists of chemotherapy with or without radiation therapy.

In the US, about 8000 new cases of Hodgkin lymphoma are diagnosed annually. The male:female ratio is 1.4:1. Hodgkin lymphoma is rare before age 10 and is most common between ages 15 and 40; a 2nd peak occurs in people > 50 to 60.

Pathophysiology

Hodgkin lymphoma results from the clonal transformation of cells of B-cell origin, giving rise to pathognomic binucleated Reed-Sternberg cells. The cause is unknown, but genetic susceptibility and environmental associations (eg, occupation, such as woodworking; history of treatment with phenytoin Some Trade Names
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, radiation therapy, or chemotherapy; infection with Epstein-Barr virus, Mycobacterium tuberculosis, herpesvirus type 6, HIV) play a role. Risk is slightly increased in people with certain types of immunosuppression (eg, posttransplant patients taking immunosuppressants); in people with congenital immunodeficiency states (eg, ataxia-telangiectasia, Klinefelter's syndrome, Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome); and in people with certain autoimmune disorders (RA, celiac sprue, Sjögren's syndrome, SLE).

Most patients also develop a slowly progressive defect in cell-mediated immunity (T-cell function) that in advanced disease contributes to common bacterial and unusual fungal, viral, and protozoal infections. Humoral immunity (antibody production) is depressed in advanced disease. Death often results from sepsis.

Symptoms and Signs

Most patients present with painless cervical adenopathy. Although the mechanism is unclear, pain may occur in diseased areas immediately after drinking alcoholic beverages, thereby providing an early indication of the diagnosis.

Other manifestations develop as the disease spreads through the reticuloendothelial system, generally to contiguous sites. Intense pruritus may occur early. Constitutional symptoms include fever, night sweats, and unintentional weight loss (> 10% of body weight in previous 6 mo), which may signify involvement of internal nodes (mediastinal or retroperitoneal), viscera (liver), or bone marrow. Splenomegaly is often present; hepatomegaly may be present. Pel-Ebstein fever (a few days of high fever regularly alternating with a few days to several weeks of normal or below-normal temperature) occasionally occurs. Cachexia is common as disease advances.

Bone involvement is often asymptomatic but may produce vertebral osteoblastic lesions (ivory vertebrae) and, rarely, pain with osteolytic lesions and compression fracture. Intracranial, gastric, and cutaneous lesions are rare and when present suggest HIV-associated Hodgkin lymphoma.

Local compression by tumor masses often causes symptoms, including

• Jaundice secondary to intrahepatic or extrahepatic bile duct obstruction

• Leg edema secondary to lymphatic obstruction in the pelvis or groin

• Severe dyspnea and wheezing secondary to tracheobronchial compression

• Lung cavitation or abscess secondary to infiltration of lung parenchyma, which may simulate lobar consolidation or bronchopneumonia

Epidural invasion that compresses the spinal cord may result in paraplegia. Horner's syndrome and laryngeal paralysis may result when enlarged lymph nodes compress the cervical sympathetic and recurrent laryngeal nerves. Neuralgic pain follows nerve root compression.

Diagnosis

• Chest x-ray

• CT of chest, abdomen, and pelvis

• CBC, ESR, alkaline phosphatase, LDH, liver function tests, albumin, Ca, BUN, and creatinine

• Lymph node biopsy

• Bone marrow biopsy

• Possibly PET for staging, bone scanning if bone pain present, or MRI if neurologic symptoms

Hodgkin lymphoma is usually suspected in patients with painless lymphadenopathy or mediastinal adenopathy detected on routine chest x-ray. Similar lymphadenopathy can result from infectious mononucleosis, toxoplasmosis, cytomegalovirus infection, non-Hodgkin lymphoma, or leukemia. Similar chest x-ray findings can result from lung cancer, sarcoidosis, or TB (for evaluation of a mediastinal mass, see Mediastinal and Pleural Disorders: Diagnosis).

A chest x-ray is obtained if not already done. X-ray is usually followed by lymph node biopsy if findings are confirmed on CT or PET scan of the chest. If only mediastinal nodes are enlarged, mediastinoscopy or Chamberlain procedure (a limited left anterior thoracostomy allowing biopsy of mediastinal lymph nodes inaccessible by cervical mediastinoscopy) may be indicated. CT-guided biopsy may also be considered, but results of fine-needle aspiration are often inaccurate, so lymph node biopsy is preferred. CBC, ESR, alkaline phosphatase, and renal and liver function tests are generally done. Other tests are done depending on findings (eg, MRI for symptoms of cord compression, bone scan for evaluation of bone pain).

Biopsy reveals Reed-Sternberg cells (large binucleated cells) in a characteristically heterogeneous cellular infiltrate consisting of histiocytes, lymphocytes, monocytes, plasma cells, and eosinophils. Classic Hodgkin lymphoma has 4 histopathologic subtypes (see Table 2: Lymphomas: Histopathologic Subtypes of Hodgkin Lymphoma (WHO Classification)); there is also a lymphocyte-predominant type. Certain antigens on Reed-Sternberg cells may help differentiate Hodgkin lymphoma from non-Hodgkin lymphoma, and classic Hodgkin lymphoma from the lymphocyte-predominant type.

Other test results may be abnormal but are nondiagnostic. CBC may show slight polymorphonuclear leukocytosis. Lymphocytopenia may occur early and become pronounced with advanced disease. Eosinophilia is present in about 20% of patients, and thrombocytosis may be present. Anemia, often microcytic, usually develops with advanced disease. In advanced anemia, defective iron reutilization is characterized by low serum iron, low iron-binding capacity, and increased bone marrow iron. Pancytopenia is occasionally caused by bone marrow invasion, usually by the lymphocyte-depleted type. Hypersplenism (see Spleen Disorders: Hypersplenism) may appear in patients with marked splenomegaly. Elevated serum alkaline phosphatase levels may be present, but elevations do not always indicate bone marrow or liver involvement. Increases in leukocyte alkaline phosphatase, serum haptoglobin, ESR, and other acute-phase reactants usually reflect active disease.

Staging: After diagnosis, stage is determined to guide therapy. The commonly used Ann Arbor staging system (see Table 3: Lymphomas: Cotswold Modification of Ann Arbor Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma) incorporates symptoms; physical examination findings; results of imaging tests, including chest x-ray, CT of the chest, abdomen, and pelvis; and unilateral bone marrow biopsy. Laparotomy is not required for staging. Other staging tests may include PET scan and cardiac and pulmonary function tests in anticipation of therapy. The Cotswold modifications of the Ann Arbor staging system incorporate the prognostic implications of tumor bulkiness and numerous disease sites.

Designation of the letter A to any stage means that no systemic symptoms are being experienced. Designation of the letter B means that at least one systemic symptom is experienced. The presence of symptoms correlates with response to treatment.

Prognosis

In classic Hodgkin lymphoma, disease-free survival 5 yr after therapy is considered a cure. Relapse is very rare after 5 yr. Chemotherapy with or without radiation therapy achieves cure in 70 to 80% of patients. Increased potential for relapse depends on many factors, including male sex, age > 45 yr, involvement of multiple extranodal sites, and presence of constitutional symptoms at diagnosis. Patients who do not achieve complete remission or who relapse within 12 mo have a poor prognosis.

Treatment

• Chemotherapy

• Radiation therapy

• Surgery

• Sometimes hematopoietic stem cell transplantation

The choice of treatment modality is complex and depends on the precise stage of disease. Before treatment, men should be offered sperm banking, and women should discuss fertility options with their oncologists.

Stage IA, IIA, IB, or IIB disease is generally treated with an abbreviated chemotherapy regimen of doxorubicin Some Trade Names
ADRIAMYCIN
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(Adriamycin), bleomycin Some Trade Names
BLENOXANE
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, vinblastine Some Trade Names
VELBAN
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, and dacarbazine Some Trade Names
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(ABVD) plus radiation therapy, or longer course chemotherapy alone. Such treatment cures about 80% of patients. In patients with bulky mediastinal disease, chemotherapy may be of longer duration or of a different type, and radiation therapy is used routinely.

Stage IIIA disease is usually treated with ABVD combination chemotherapy. Involved field irradiation is also sometimes added. Cure rates of 75 to 80% have been achieved.

Stage IIIB disease requires ABVD combination chemotherapy typically alone but sometimes with involved field irradiation. Survival rates range from 70 to 80%.

For stage IVA and IVB disease, ABVD combination chemotherapy is the standard regimen, producing complete remission in 70 to 80% of patients; > 50% remain disease-free at 5 yr. Other effective drugs include nitrosoureas, ifosfamide Some Trade Names
IFEX
MITOXANA
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, cisplatin Some Trade Names
PLATINOL
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or carboplatin Some Trade Names
PARAPLATIN
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, and etoposide Some Trade Names
ETOPOPHOS
VEPESID
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. A promising new drug combination, Stanford V, is a 12-wk regimen that incorporates involved field irradiation for consolidation.

Autologous transplantation using peripheral stem cell products should be considered for all physiologically eligible patients with relapsed or refractory Hodgkin lymphoma who respond to salvage chemotherapy.

Complications of treatment: Chemotherapy with mechlorethamine Some Trade Names
MUSTARGEN
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, vincristine Some Trade Names
ONCOVIN
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(Oncovin), procarbazine Some Trade Names
MATULANE
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, and prednisone Some Trade Names
DELTASONE
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(MOPP) and MOPP-like regimens increases the risk of leukemia, which generally develops after > 3 yr. Both chemotherapy and radiation therapy increase the risk of malignant solid tumors (eg, breast, GI, lung, soft tissue). Mediastinal radiation increases the risk of coronary atherosclerosis. Breast cancer risk is increased in women beginning about 7 yr after they have received radiation treatment to adjacent nodal regions.

Posttreatment surveillance: Routine testing is done to identify recurrence. For a schedule of posttreatment surveillance, see Table 4: Lymphomas: Hodgkin Lymphoma Posttreatment Surveillance

 

Non-Hodgkin Lymphomas

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.

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

• Chest x-ray

• CT of chest, abdomen, and pelvis (possibly integrated PET–CT)

• CBC, ESR, alkaline phosphatase, LDH, liver function tests, albumin, Ca, BUN, creatinine, electrolytes, and uric acid

• HIV, hepatitis B virus, and hepatitis C virus testing

• Lymph node and bone marrow biopsy

• MRI of spine if neurologic symptoms are present

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:

• Age > 60

• Poor performance status (can be measured using the Eastern Cooperative Oncology Group tool)

• Elevated LDH

• > 1 extranodal site

• Stage III or IV disease

Outcome is worse with an increasing number of risk factors. Survival, as determined by IPI factor, has improved with the addition of rituximab Some Trade Names
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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

• Chemotherapy, radiation therapy, or both

• Sometimes anti-CD20 monoclonal antibody

• Sometimes hematopoietic stem cell transplantation

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 Some Trade Names
RITUXAN
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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 Some Trade Names
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plus cyclophosphamide Some Trade Names
CYTOXAN
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, hydroxydaunorubicin ( doxorubicin Some Trade Names
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), vincristine Some Trade Names
ONCOVIN
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, prednisone Some Trade Names
DELTASONE
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(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 Some Trade Names
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, 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 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 Some Trade Names
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, vincristine Some Trade Names
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, doxorubicin Some Trade Names
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, methotrexate Some Trade Names
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, ifosfamide Some Trade Names
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MITOXANA
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, etoposide Some Trade Names
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, and cytarabine Some Trade Names
CYTOSAR-U
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(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 Some Trade Names
ZYLOPRIM
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or rasburicase Some Trade Names
ELITEK
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, 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.

Mycosis Fungoides

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

• Radiation therapy, topical chemotherapy, phototherapy, or topical corticosteroids

• Sometimes systemic chemotherapy

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 Some Trade Names
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deaminase inhibitors fludarabine Some Trade Names
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and 2-chlorodeoxyadenosine show promise.

See also

• Hodgkin's lymphoma
• Non-Hodgkin's lymphoma
• Follicular lymphoma
• Burkitt's lymphoma
• Mantle cell lymphoma
• Gastric lymphoma
• Cutaneous T Cell lymphoma
• Mycosis fungoides
• Anaplastic large cell lymphoma
• MALT lymphoma
• Primary central nervous system lymphoma
• BCP-1 cells
• Ann Arbor staging
• International Prognostic Index
• Terminal lymphatic cancer