Departments of 1 Hematology and 2 Pathology, 3 The Leslie and Michael Gaffin Center for Neuro-Oncology, and 4 School of Public Health, Hadassah-Hebrew University Hospital, Jerusalem, Israel
* Correspondence to: Dr G. Spectre, Department of Hematology, Hadassah, Jerusalem, Israel 12000. Tel: +972-51-874302; Fax: +972-2-6449145; Email: galiaspectre{at}hotmail.com
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Abstract |
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Patients and methods: We retrospectively reviewed the disease characteristics and clinical course in seven patients (six females, one male) with indolent B-cell lymphomas who developed CNS involvement during various stages of their illness.
Results: The median ages at diagnosis of systemic and CNS lymphoma were 60 and 63 years, respectively. Histologies were: small lymphocytic lymphoma (two), follicular lymphoma grade I (two), follicular lymphoma grade II (two) and unclear low-grade histology (one). There were diverse neurological symptoms. Two patients had parenchymal involvement, three had leptomeningial involvement and two had both. Systemic lymphoma was found in all patients, all but one having bone marrow involvement. Four patients had a transformation to high-grade histology. Six patients were treated with systemic and intra-cerebrospinal fluid chemotherapy, and two received radiotherapy as well. Five patients achieved CNS response. Survival was 19 years for treated patients (median 2 years). Three patients died of CNS disease.
Conclusions: CNS involvement is a rare and unexpected complication of indolent NHL, which should be considered in the differential diagnosis of patients presenting with new neurological signs. This condition is treatable and some patients have a long clinical course.
Key words: central nervous system, clinical course, indolent, non-Hodgkin's lymphoma
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Introduction |
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Very little is known about the characteristics of patients with indolent lymphomas, such as follicular lymphoma and small lymphocytic lymphoma, who develop brain or leptomeningeal involvement. There are only a few published reports of this complication and there are no published series exclusively devoted to CNS involvement in indolent lymphoma, except for a few reports on chronic lymphocytic leukemia (CLL) [1518
]. We present a series of patients with indolent B-cell lymphoma, not including mantle cell lymphoma, and CNS involvement who were diagnosed and treated in our hospital between 1993 and 2003. Our goals were to describe their clinical presentations, histologies, pattern of involvement, clinical course and outcome.
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Patients and results |
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Data regarding sex, age, histology of the systemic disease, bone marrow involvement, LDH at presentation and type of treatment are listed in Table 1. The time from diagnosis of systemic lymphoma to CNS involvement was between 0 and 9 years, and the clinical presentation of CNS involvement was diverse (Table 1).
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Cerebrospinal fluid (CSF) examination was performed in six patients (Table 1). Cytology of the CSF in four patients showed small lymphocytes, which resembled the peripheral indolent lymphoma and confirmed the diagnosis of CNS involvement in those patients. Two patients had a normal CSF examination and underwent a brain biopsy for diagnosis (patients 4 and 5); both patients had transformation to high-grade lymphoma in the CNS. One patient refused further invasive evaluation and treatment, and the diagnosis was based on clinical signs and a brain CT scan that showed strong periventricular enhancement compatible with brain involvement in lymphoma (patient 7).
In four patients, molecular examinations of the original lymphoma and the cells in the CNS were performed. Of these, one patient had evidence of a V3 immunoglobulin gene rearrangement in the CSF and J-H gene rearrangement of bone marrow, one was positive for Bcl-2 and J-H gene rearrangement of bone marrow only, and two were negative for both Bcl-2 and immunoglobulin gene rearrangement in both CSF and bone marrow.
At the time of diagnosis of brain lymphoma, evidence of active systemic indolent lymphoma was found in all the patients and LDH levels were mildly elevated in three patients (patients 3, 6 and 7). Bone marrow involvement on initial diagnosis of lymphoma was seen in all patients except one.
The time from diagnosis of systemic indolent lymphoma to diagnosis of CNS involvement was between 5 months and 9 years in six patients. In patient 1 the diagnosis of CNS involvement was simultaneous with the systemic disease; he initially presented 9 years ago with ataxia and dysarthria and was diagnosed as having parenchymal and leptomeningial involvement by small lymphocytic lymphoma, together with systemic bone marrow disease. He received combination chemotherapy [high-dose methotrexate (HDMTX), procarbazine and intrathecal injections of cytosine arabinoside], and then clinically deteriorated and whole-brain radiotherapy was added. The patient relapsed 2 years later and was retreated with fludarabine and intrathecal methotrexate. Since then he has remained in good partial remission for 7 years with stable lesions on MRI and an unchanged neurological examination. He is currently being followed clinically with no treatment.
Two patients developed symptoms of brain involvement while receiving chemotherapy for systemic lymphoma (patients 2 and 6), one following radiotherapy to a paravertebral mass (patient 7), and three patients were not receiving treatment despite the presence of systemic indolent lymphoma. Four patients had evidence of high-grade histological transformation at the time of CNS involvement; patients 4 and 5 had transformation in the CNS while patients 6 and 7 had systemic transformation.
Treatment received for CNS disease included intrathecal methotraxate and/or cytosine arabinoside in six patients, HDMTX in five patients, bloodbrain barrier disruption regimen (HDMTX, VP16, cyclophosphamide) in two patients, and fludarabine in one patient. Cranial irradiation was given in patients 1 and 2 as second-line therapy. Patient 7 refused chemotherapy, received dexamethasone only, and died from brain lymphoma 3 months after the diagnosis. Five patients achieved CNS remission (patients 1, 3, 4, 5 and 6). Patient 3 died 4 years after the diagnosis of brain lymphoma, from metastatic breast cancer; patient 6 had both systemic and leptomeningeal relapse 2 years after diagnosis of brain lymphoma and died of systemic lymphoma and pancytopenia. Patient 4 underwent autologous bone marrow transplantation for systemic relapse of transformed follicular lymphoma, but relapsed in the CNS 7 months after bone marrow transplantation and died of sepsis and active brain disease. Her case history is presented in Figures 13. Patients 1 and 5 are alive between 2 and 9 years after the diagnosis of brain involvement.
Patient 2 failed to achieve CNS remission and died from brain lymphoma and liver failure 11 months after the diagnosis of CNS disease.
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Discussion |
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The seven patients in our series represent a very small portion of B-cell malignancies treated at our institution (<1%), and <3% of those with indolent histologies. The clinical course was different in each case. For example, one patient presented with neurological symptoms at the time of the original diagnosis and two other patients developed brain lymphoma while receiving treatment for systemic lymphoma. Hollender et al. [4] reported an incidence of 2.8% of CNS involvement in low-grade lymphoma (although their series included mantle cell lymphoma according to the WHO classification). Multivariate analysis revealed that B symptoms, bone marrow involvement and skin involvement were risk factors for developing CNS involvement. These factors together carried a risk of 7% of developing brain lymphoma within 5 years of diagnosis. None of our patients had skin lymphoma, and B symptoms were reported in only one of the seven patients. The only common features we could find in our patients were bone marrow involvement at the time of lymphoma diagnosis (six of seven patients) and systemic or CNS high-grade histological transformation (four of seven patients). However, bone marrow involvement is a very common feature of indolent lymphoma and can be found in at least 70% of patients presenting with advanced-stage follicular lymphoma [26
]. Thus, we believe bone marrow involvement is of no predictive value in these patients. In the four patients with samples available for molecular analysis we did not find agreement between the gene rearrangement in the systemic lymphoma and the brain lymphoma. However, the sample size was too small to draw meaningful conclusions.
According to the literature, CNS involvement occurring as a complication of NHL carries a very poor prognosis. The median survival is reported to be 4 months among agressive histologies [1
, 2
, 6
, 27
]. Van Besien et al. [7
] described a 1 year survival of 25%. Our patients with indolent lymphoma and CNS involvement had a good response to treatment; the shortest survival of 3 months was documented in the only patient who refused treatment, five out of six patients who received treatment achieved CNS remission and only three patients died of brain lymphoma. The survival of six patients who received treatment was between 11 months and 9 years (median 2 years), and two patients are currently alive at 2 and 9 years after diagnosis of CNS lymphoma. Survival in our patients is relatively low for patients with indolent lymphomas, but is certainly longer compared with survival of patients with CNS relapse of aggressive lymphomas.
Initial treatment of brain lymphoma in our patients was based on chemotherapy and did not include initial radiotherapy. Nevertheless, a good response rate was achieved, and only two patients required radiotherapy as second-line treatment. We assume that this therapeutic approach is reasonable and can prevent the long-term CNS morbidity, including cognitive dysfunction, that occurs after brain irradiation.
CNS involvement in indolent lymphoma is a rare complication. A significant number of patients presenting with this complication may also present with disease transformation that can be either systemic or confined to the CNS. Considering the rarity of CNS involvement and the limited number of common features in our patients, we presume that this complication will continue to be an unexpected occurrence in indolent lymphoma. Given its rarity there will be no place for prophylactic CNS chemotherapy for patients with these disorders. However, this entity should be considered in the differential diagnosis of new neurological symptoms and signs in patients with indolent lymphoma, especially when disease transformation is diagnosed.
Received for publication April 3, 2004. Revision received July 29, 2004. Accepted for publication October 5, 2004.
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