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Problems in Lymphoma Management: Special Sites of Presentation

Problems in Lymphoma Management: Special Sites of Presentation

The article by Dr. Connors is an excellent overview of lymphomas involving five sites: the eye, central nervous system (CNS), sinuses, testes, and stomach. The author emphasizes that these lymphomas present unique management challenges even to the experienced oncologist. The tumors are difficult to diagnose, resistant to treatment, or, in the case of gastric lymphoma, occasionally associated with a causative organism that warrants antibiotic treatment.

Diagnostic Difficulties

The author states that although lymphoma is a common malignancy, it may be difficult to diagnose when it involves certain anatomic sites. Lymphomas limited to the eye, CNS, or stomach may escape diagnosis for months to years, often being mistaken for other diseases. Intraocular lymphoma is frequently misdiagnosed as an idiopathic intra-ocular inflammatory disease called uveitis. Many cases of intraocular lymphoma, we feel, actually represent a CNS lymphoma involving the eye, since spread to the CNS is common, but metastasis outside of the CNS is rare. In a series of 12 patients diagnosed with intraocular lymphoma at the National Eye Institute, the mean time from onset of symptoms to diagnosis was 21.4 months; intraocular lymphoma was not the initial diagnosis in any of these patients.[1]

Even when lymphoma is suspected, confirming the diagnosis can be difficult. Certain lymphomas may be histologically difficult to differentiate from other malignancies or, in more benign forms of the disease, from reactive lymphoid hyperplasia. In the case of primary CNS lymphoma, diagnosis is usually based on identification of malignant cells in a sample of vitreous fluid or cerebrospinal fluid (CSF). The malignant cells, however, are few in number and friable, and, unless the specimen is processed quickly, lymphoma cells degenerate. In addition, it is critical to have the specimen examined by a cytopathologist experienced in reading vitreous samples, since diagnosis of intraocular lymphoma is often based on only a handful of malignant cells.

The author states that the symptoms of primary CNS lymphoma and lymphoma of the stomach can be mild, non-specific, and responsive temporarily to nonspecific therapy. Furthermore, it may be difficult not only to initially diagnose a site-specific lymphoma but also to promptly detect recurrence.

In collaboration with the National Cancer Institute, we have been looking for new diagnostic tests to improve our ability to diagnose primary CNS lymphoma. Interleukin-10 (IL-10), a growth factor for B-lymphocytes, has been associated with the presence of lymphoid malignancies.[2] More recently, we demonstrated that IL-10 was elevated in the vitreous fluid of all 5 patients with intraocular lymphoma but was normal in 0 of 13 patients with idiopathic ocular inflammatory disease.[3] Also, the risk of malignant involvement of the CSF was eight times higher when elevated levels of IL-10 were detected.

Therapeutic Dilemmas

The article points out the importance of understanding the special characteristics of these lymphomas in order to optimize therapy. Dr. Connors illustrates that the lymphomas discussed have unique natural histories and responses to therapy, which should guide the choice of a treatment plan. The author notes that localized and advanced-stage testicular lymphomas follow disparate clinical courses and mandate different approaches. Unfortunately, some of these lymphomas are rare, and few randomized clinical trials examining appropriate therapy for these malignancies have been conducted. Some are so rare that large, randomized clinical trials to compare therapies are infeasible. As a result, many therapies currently being used remain controversial.

For example, Dr. Connors states that irradiation is a mainstay in the treatment of intraocular lymphoma, but most patients relapse within the eye or brain. This has led to the use of eye and whole-brain radiation followed by systemic and/or intrathecal chemotherapy.

We found that the radiation followed by chemotherapy is associated with both treatment-related morbidity and mortality from leukoencephalopathy. The National Cancer Institute and National Eye Institute are completing a phase II trial of combination intrathecal and systemic chemotherapy without radiation for primary CNS lymphoma involving the brain or eye. Fourteen patients were treated with intravenously administered thiotepa (Thiotepa), high-dose methotrexate, vincristine, and intrathecally administered methotrexate and cytarabine (ara-C).[4] The response rate was 100%, with a 79% complete response rate. Median progression-free survival was 16 months; median overall survival has not been reached. Although the therapy was generally well tolerated, two patients over 60 years of age experienced severe leukoencephalopathy.

Other investigators have successfully treated older patients with primary CNS lymphoma with chemotherapy alone,[5] and promising results have been reported with the use of salvage high-dose chemotherapy with autologous bone marrow transplantation.[6] Clearly, larger trials are needed to more definitively determine the safety and efficacy of this therapeutic approach and to compare this therapy with other regimens.

The problem of determining optimal therapy for rare malignancies is also illustrated by Dr. Connors’ data from the British Columbia Cancer Agency. The author states that patients with site-specific lymphoma need a phased treatment plan. In the case of lymphoma of the paranasal sinus, the author outlines the use of systemic, local, and finally prophylactic treatment to prevent spread to the CNS and emphasizes that intrathecal chemotherapy is essential for successful treatment. However, other studies have shown 5-year survival rates of at least 80% without intrathecal chemotherapy.[7] Again, only larger randomized clinical trials can accurately determine the ideal therapy for these lymphomas, but given their rarity, these trials are difficult to conduct.

The benefit of understanding the unique features of a lymphoma limited to a specific anatomic site is best illustrated in the section on lymphoma of the stomach. The author notes that Helicobacter pylori can cause a low- grade B-cell mucosa-associated lymphoid tumor (MALT) that may be responsible for some higher-grade gastric lymphomas. In these cases, appropriate antibiotics should be used, and in the case of low-grade MALT and H pylori infection, antibiotics may cause regression of the lymphoma. However, again, because of the small number of patients, optimal therapy will be difficult to delineate.


1. Whitcup SM, de Smet MD, Rubin BI, et al: Intraocular lymphoma: Clinical and histopathologic diagnosis. Ophthalmology 100:1399-1406, 1993.

2. Benjamin D, Kuobloch TJ, Dayton MA: Human interleukin 10: B cell lines derived from patients with AIDS and Burkitt’s lymphoma constitutively secrete large quantities of interleukin 10. Blood 80:1289-1298, 1992.

3. Whitcup SM, Stark-Vancs V, Wittes RE, et al: Association of interleukin-10 in the vitreous and cerebrospinal fluid in primary central nervous system lymphoma. Arch Ophthalmol, 1997 (in press).

4. Sandor VA, Stark-Vancs V, Setser A, et al: Phase II trial of chemotherapy alone for primary central nervous system lymphoma (PCNSL) (abstract). Proc Am Soc Clin Oncol 16:25a, 1997.

5. Freilich RJ, Delattre JY, Monjour A, et al: Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology 46:435-439, 1996.

6. Soussain C, Merle-Beral H, Reux I, et al: A single-center study of 11 patients with intraocular lymphoma treated with conventional chemotherapy followed by high-dose chemotherapy and autologous bone marrow transplantation in 5 cases. Leuk Lymphoma 23:339-345, 1996.

7. Nakamura K, Uehara S, Omagari J, et al: Primary non-Hodgkin’s lymphoma of the maxillary sinus. Am J Clin Oncol 20:272-275, 1997.

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