Dr. Connors provides an excellent overview of several sites of extranodal lymphoma, which represent an unusual presentation of non-Hodgkins lymphoma. He outlines an organized, phased approach to diagnosis, staging, and treatment, emphasizing interdisciplinary management. In this review, we will add some perspectives from the Stanford experience.
With the adoption of the Revised European and American Lymphoma (REAL) classification scheme, our understanding of low-grade extranodal lymphomas continues to evolve. Low- grade lymphoma of mucosa-associated lymphoid tissue (MALT), is included within the REAL classification and consequently has become an increasingly common diagnosis among extranodal lymphomas. Given its relatively recent description, the clinicopathologic significance of this entity requires further study in order to be understood more fully.
Orbital Malt Lymphoma
Among orbital lymphomas, only small case series of MALT lymphomas have been reported.[2,3] We reviewed the Stanford University experience with stage I extranodal lymphoma, applying the diagnostic criteria outlined in the REAL system. Among 92 extranodal lymphomas reviewed, 22 cases of low- grade orbital MALT lymphoma were identified. Patients were routinely staged with orbital computed tomographic (CT) scan, chest x-ray, abdominopelvic CT scan, and bone marrow biopsy. Patients with conjunctival lymphoma (15 patients) were irradiated using anterior low-energy x-rays or 9- to 12- MeV electron beams. Special care was taken to avoid cataract formation by employing a central eye bar to shield the lens.
Patients with retrobulbar lymphoma (seven patients) were treated with an isocentric technique using megavoltage photons. Mean radiation dose was 34 Gy (range, 30 to 40 Gy) given in daily fractions of 1.8 to 2 Gy.
This technique yielded a projected 10-year local control rate of 100% and an actuarial rate of freedom from any relapse of 71% with a mean follow-up of 7.7 years. Interestingly, in all four patients who relapsed, treatment failure occurred in extranodal sites where MALT lymphomas have been described. No failure occurred in a nodal site. This natural history and pattern of failure may imply a possible homing mechanism for MALT lymphoma cells. Based on this experience, our current recommended radiation dose for low-grade orbital MALT lymphoma is 30.6 Gy in 1.8 by fractions.
Gastric MALT Lymphoma
Another extranodal lymphoma that has generated tremendous interest is low-grade gastric MALT lymphoma. The emerging role of H pylori in the development of gastric MALT lymphoma has been articulately summarized by Dr. Connors. Although historically gastric lymphoma has been managed by subtotal or total gastrectomy, it has become increasingly common to treat gastric MALT lymphoma with an antibiotic regimen. This approach has resulted in complete pathologic re- mission, and although this may be an intellectually satisfying treatment strategy, our enthusiasm must be tempered by the report of early local relapse after antibiotic therapy.
Some have advocated the use of protracted, single-agent, orally active chemotherapy regimens, such as cyclophosphamide (Cytoxan, Neosar) or chlorambucil (Leukeran), for 12 to 24 months. However, these regimens have resulted in only a 48% disease-free survival rate at 5 years, while subtotal gastrectomy and postoperative radiotherapy yielded a 5-year disease-free survival rate of 100%.
Given the rather localized natural history of gastric MALT lymphoma and the considerable morbidity of gastrectomy, this extranodal disease site is an ideal target for a primary radiotherapeutic approach. At Stanford, we have evaluated a total of 27 patients with stage IE gastric lymphoma. Of these, 11 were diagnosed with low-grade gastric MALT lymphoma. These patients were staged with upper endoscopy, chest x-ray, abdominopelvic CT scan, and bone marrow biopsy. Five were treated with systemic chemotherapy (three patients) or antibiotic therapy (two patients); all subsequently experienced recurrence of disease. However, one patient managed by subtotal gastrectomy alone and five patients treated with 36 to 40 Gy of definitive gastric radiotherapy remained disease-free with a mean follow-up of 46 months.
Based on our limited experience, we currently treat stage IE gastric MALT lymphoma patients with multiagent antibiotic therapy for 4 weeks followed by 36 Gy of gastric radiotherapy via isocentric technique. Regional nodal radiotherapy is safely omitted, as regional lymph nodes are seldom involved in low-grade lesions. By reducing the irradiated volume, we have found this treatment to be well tolerated. Follow-up endoscopy is scheduled 1 to 2 months after completion of therapy in order to document H pylori eradication and pathologic complete response.
Primary CNS Lymphoma
Unlike the previously discussed gastric and orbital MALT lymphomas, primary CNS lymphoma portends an ominous prognosis, with historical 5- year survival rates of only 3% to 4%. Traditionally, treatment centers around whole-brain radiotherapy to a dose of at least 40 Gy and oral dexamethasone. With this approach, patients often achieve a radiographic response only to suffer early central and neuraxis relapse.
Given the high risk of CNS relapse, some have advocated a combined modality approach for the treatment of immunocompetent patients with high performance scores. By utilizing intravenous and intraventricular methotrexate followed by 40 Gy of whole-brain radiotherapy and a 14.4-Gy localized radiation boost, as well as high-dose ara-C, median time to recurrence was extended to 41 months with a median survival of 42 months.
Based on these and other data, the Radiation Therapy Oncology Group (RTOG) has launched an intergroup phase II trial of combined-modality therapy for primary CNS lymphoma, with patients receiving IV methotrexate, procarbazine (Matulane), and vincristine and intraventricular methotrexate. After radiographic reevaluation, patients with residual disease receive 45 Gy of whole-brain radiotherapy, while those with no residual disease receive 36 Gy in twice-daily fractions of 1.2 Gy. Radiotherapy is followed by two cycles of high-dose ara-C. We currently offer this protocol to our primary CNS lymphoma patients who are immunocompetent and have high performance scores.
Extranodal lymphomas remain an unusual subtype of non-Hodgkins lymphoma. Based on the peculiar natural history and anatomic considerations of the various sites of presentation, extranodal lymphomas pose management challenges to the clinician. However, by applying an organized approach to diagnosis, staging, and treatment, excellent care can be rendered. We agree with Dr. Connors that aggressive, multidisciplinary management, specific to each type and site of lymphoma, optimizes patient outcome.
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