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© 1999 American Society for Clinical Oncology CNS Involvement in Primary Mediastinal Large B-Cell LymphomaFrom the Division of Clinical Science, Medicine Branch, National Cancer Institute, Bethesda, MD. Address reprint requests to Patrick C. Elwood, MD, National Cancer Institute, 9000 Rockville Pike, Bldg 10/12N226, Bethesda, MD 20892.
PURPOSE: The risk of CNS involvement by non-Hodgkin's Lymphoma (NHL) has been associated with bone marrow and/or testicular involvement; however, it was recently reported that the number of extranodal sites is a more reliable predictor of CNS disease. Because primary mediastinal thymic large B-cell lymphoma (PMLCL) has a high propensity for involving extranodal sites, we investigated the frequency and pattern of CNS involvement in PMLCL. PATIENTS AND METHODS: The medical records of 219 patients with aggressive NHL, consecutively entered onto protocols at the National Cancer Institute between 1987 and 1998, were retrospectively reviewed. RESULTS: Twenty-three patients (11%) had clinical and pathologic features of PMLCL. These patients were young (median age, 29 years), female (61%), and presented with massive mediastinal adenopathy (70%). Extranodal disease occurred at presentation in 70% and at relapse in 93% of patients and involved contiguous intrathoracic structures and/or distant sites, including the lungs, kidneys, liver, adrenals, ovaries, pancreas, and bone. Six patients (26%) developed CNS involvement, two (9%) at presentation and four (27%) at relapse. All had extranodal disease, but only one had bone marrow involvement. Parenchymal and leptomeningeal CNS disease occurred in four and three patients, respectively. CONCLUSION: CNS involvement in PMLCL is associated with extranodal involvement other than bone marrow and may reflect the unique biology of this disease. The propensity to involve the CNS parenchyma raises the concern that intrathecal prophylaxis may not be effective and suggests that CNS imaging should be considered in patients with extranodal disease.
CNS INVOLVEMENT BY lymphoma is a poor prognostic event, particularly when it occurs at relapse.1-4 In hematopoietic malignancies with a high incidence of CNS involvement, such as acute lymphoid leukemia, prophylaxis and early diagnosis of CNS disease has led to major increases in survival. Similar benefits may be seen in patients at high risk of developing CNS involvement by lymphoma.5,6 Indeed, these benefits may be even greater in the future as more effective treatment is developed for systemic disease. Unlike other aggressive lymphoid malignancies, however, most patients with large-cell lymphomas are not uniformly at risk of developing CNS disease, so it is necessary to identify the subset of patients who will benefit from CNS prophylaxis. Earlier studies have shown that patients with involvement of bone marrow, testicles, and/or paranasal sinuses are at high risk of developing CNS disease, and intrathecal chemotherapy prophylaxis is usually considered in such patients.7 Unfortunately, the conclusions from many of these studies are unsatisfying because they include multiple different histologies and/or therapies.1-4 Recently, van Besien et al6 performed a multivariate analysis of risk factors for CNS recurrence in patients with large-cell lymphoma and identified involvement of more than one extranodal site and increased lactate dehydrogenase (LDH) as independent predictors. On the basis of this report, we were interested in examining the incidence of CNS involvement in primary mediastinal (thymic) large B-cell lymphoma (PMLCL) because of its propensity to affect extranodal tissues.8 A striking clinical feature of PMLCL is its proclivity to involve multiple extranodal tissues such as the lungs, kidneys, adrenals, liver, and/or ovaries.9,14-17 In contrast to other large B-cell lymphomas, PMLCL tends to affect young women and often presents as an anterior mediastinal mass arising from the thymus with invasion of adjacent tissue.9-15 Although 50% to 80% of patients with limited-stage disease achieve long-term survival with cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, and bleomycin (CHOP)–based therapy, high-risk patients with bulky mediastinal masses and/or extranodal disease tend to relapse and salvage therapy, including high-dose therapy with stem-cell transplantation, is often unsuccessful.9,13,14,16-21 To investigate the frequency and pattern of CNS involvement in PMLCL, we reviewed the cases of adult patients with aggressive non-Hodgkin's lymphoma (NHL) treated in the Medicine Branch of the National Cancer Institute (NCI) over an 11-year period and identified 23 cases with clinical and pathologic features diagnostic of PMLCL. Herein, we present our findings of CNS involvement in PMLCL and discuss clinical recommendations.
Medical records from 219 patients with intermediate or high-grade (Working Formulation D, E, F, G, and H) lymphoma treated at the NCI between 1987 and 1998 were retrospectively reviewed to identify patients with PMLCL.23 All patients had been referred to the NCI for treatment of primary or relapsed NHL on a protocol approved by the NCI institutional review board. Informed consent was obtained from all patients. For patients referred for the treatment of relapsed disease, medical records including prior therapeutic interventions were obtained from the outside institution. Before protocol treatment, all patients at a minimum had a complete medical history, physical examination, routine laboratory tests, and staging with whole-body computerized tomography. Additionally, relevant tissues, including bone marrow biopsy samples, were reviewed by an NCI hematopathologist. Among the 219 patients, six carried a pathologic diagnosis of PMLCL. For the remaining 213 cases, pathologic material was re-reviewed from the subset who had a pathologic diagnosis of large B-cell lymphoma and had a clinical presentation consistent with PMLCL (eg, anterior mediastinal mass and/or extranodal disease). The pathology from these patients was reviewed because PMLCL had only recently been recognized as a distinct entity and such patients were often classified as having diffuse large B-cell lymphoma. From this review, an additional 17 patients with clinical and pathologic features consistent with PMLCL were identified, for a total of 23 patients (11%) included in this report. Standard response definitions were used.24 A pathologic confirmation of CNS lymphoma was attempted in all patients by CSF cytology and/or brain biopsy. However, in those patients in whom a pathologic diagnosis could not be confirmed, a diagnosis of CNS lymphoma was clinically established if the patient had active lymphoma, signs and symptoms consistent with CNS disease, and radiographic abnormalities by computerized tomography or magnetic resonance imaging (MRI) that responded to therapy.25 For all patients, survival and disease-free survival were calculated by the Kaplan-Meier method from the time of initial diagnosis to the time of death or first event, respectively.
Patient Characteristics and Treatment Outcome The characteristics of the 23 patients with PMLCL on initial presentation are listed in Table 1. It is important to note that because our series included patients who had been referred to the NCI for relapsed disease as well as for initial treatment, the distribution of patient characteristics might be biased toward worse prognostic features. Despite this potential bias, the patients in the present series had characteristics similar to previous reports; the patients were young (median age, 29 years), female (61%), and often presented with B symptoms (48%), bulky mediastinal masses (> 10 cm, 70%) and increased LDH (89%).9-14 Additionally, advanced stage III/IV disease (43%) and extranodal involvement (70%) were quite frequent, and patients with stage I/II (n = 13) often presented with B symptoms and/or extranodal disease (62%) resulting from direct extension of the mediastinal mass.9-14
All patients received a regimen containing doxorubicin with or without involved field radiotherapy as initial therapy. Primary treatment regimens included etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH)24 in 11 patients (48%); CHOP27 in six patients (26%); prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, and folinic acid (ProMACE-CytaBOM)28 in three patients (13%); and cyclophosphamide, etoposide, doxorubicin, vincristine, bleomycin, methotrexate with leucovorin rescue, and prednisone (the Vanderbilt sequential regimen)26; methotrexate, bleomycin, cyclophosphamide, and etoposide (m-BACOD)14; and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD)29 in one patient each. Additionally, seven patients received involved-field radiotherapy for bulky disease and/or residual mediastinal abnormalities. With initial therapy, 13 patients (57%) achieved a complete response, seven patients (30%) achieved a partial response, two patients did not respond, and it is too early to evaluate one patient. Relative to the entire group, 15 patients (65%) ultimately progressed at a median of 8.3 months (range, 3.1 to 21.8 months). With a median follow-up of 3.9 years (range, 0.1 to 6.3 years), nine patients are alive and seven of these are currently free of disease.
Extranodal Disease
CNS Disease
Four patients in this series presented with parenchymal CNS lesions that were suspicious for lymphoma. Of interest, multiple CSF cytologies failed to show involvement by lymphoma, despite leptomeningeal enhancement on a gadolinium MRI scan in three of these patients. A diagnosis of CNS lymphoma was confirmed by brain biopsy in two patients and by clinical criteria in two patients. Brain biopsy was not attempted in the latter two patients because it was believed to be unsafe in one and was clinically consistent with lymphoma in the other patient. Two patients in this series presented with cranial nerve (CN) deficits (CN VII and VIII in one and CN VI in the other). Like the first four patients, the latter two patients also had multiple negative CSF cytologies despite CN deficits that suggested leptomeningeal involvement. In one patient, there was also a meningeal mass on MRI. All six patients had a clinical and/or radiographic response to CNS-directed therapy for their disease. The pattern of CNS involvement observed in these patients with PMLCL is unusual because of the high frequency of parenchymal and/or CN involvement and the absence of cytologic evidence of leptomeningeal disease. One patient with meningeal and CN involvement had discreet nodular lesions seen on MRI that are unusual in diffuse leptomeningeal disease. Furthermore, among the four patients with parenchymal disease, two had multiple lesions widely dispersed throughout the CNS, and two had parenchymal lesions contiguous with osseous skull involvement. Thus, PMLCL involved the CNS by either infiltration from adjacent tissue or by distant dissemination, particularly at relapse, in a manner similar to its involvement of other extranodal sites. This clinical feature is in contrast to the pattern of CNS involvement observed in other large B-cell lymphomas where leptomeningeal involvement typically occurs.1-3,30,31 We were interested in examining whether there was a relationship between the various risk factors for CNS disease and its development in our patients. Unfortunately, the relatively small size of this series precludes an analysis with high power. Nevertheless, an accounting of the known risk factors, elevated LDH, extranodal disease, and bone marrow involvement, in the patients who developed CNS disease yields an expected result (Table 3). The two patients who presented at initial diagnosis with CNS involvement each had an elevated LDH and involvement of multiple extranodal sites, including bone marrow in one patient. Furthermore, in the four patients who relapsed with CNS disease, the LDH was elevated at initial diagnosis, and all four had extranodal disease, including multiple sites in two patients. An important clinical question is the ability of these risk factors to discriminate patients who are at increased risk of CNS disease. When considering the overall frequency of the risk factors for CNS disease in the six patients in this series, all six had increased LDH, and four of six had more than one extranodal site.6 By comparison, among the 17 patients who did not develop CNS disease, 85% had elevated LDH (based on 13 patients with available data) and 24% had more than one extranodal site, suggesting that the specificity and sensitivity of these risk factors may be relatively low in patients with PMLCL. Expectedly, the overall median survival for the patients with CNS involvement was shorter than for the entire group (18 versus 26 months, respectively). Only one patient with CNS disease achieved long-term disease-free survival, and in this case the patient initially presented with five extranodal sites of disease, B symptoms, and an elevated LDH. He achieved an initial complete response after EPOCH chemotherapy, but relapsed 8 months later with a parenchymal CNS lesion and leptomeningeal disease. He was retreated with intrathecal methotrexate, systemic cisplatin, and high-dose cytarabine chemotherapy. Despite improving neurologic symptoms, he developed liver and kidney involvement. He achieved a complete response with a single cycle of ProMACE-CytaBOM followed by high-dose chemotherapy and autologous bone marrow transplantation. The patient is currently disease-free 51 months after his initial diagnosis. None of the other five patients achieved a durable remission after development of CNS disease, despite aggressive CNS and systemic treatment, highlighting the poor clinical prognosis of CNS disease.
Involvement of the CNS is an important, albeit relatively infrequent, complication of large B-cell lymphomas. When CNS involvement does occur, it presents a difficult therapeutic challenge and usually portends a poor outcome. Indeed, the obvious clinical approach is to prevent its development, but this requires that the clinician be able to identify patients at risk. Over the years, numerous studies have attempted to correlate clinical factors with the development of CNS disease and have variably identified bone marrow, testicular, paranasal sinus, and gastrointestinal involvement, extranodal disease, advanced stage, and increased LDH as risk factors.2,3,6,7,31-33 In a recent study, van Besien et al6 analyzed risk factors for CNS recurrence in 605 adult patients with newly diagnosed large-cell lymphomas and, in a multivariate analysis, identified more than one extranodal site of disease and increased LDH as independent predictors of CNS recurrence. In the present series and other published reports, primary mediastinal large B-cell lymphoma has a high incidence of extranodal involvement and elevated LDH, which suggests that CNS recurrence may be particularly high when compared with other types of large B-cell lymphoma.6,16,17,20 Because of the unique natural history of this disease, we undertook the present study to assess whether there was an increased incidence of CNS disease in PMLCL and to describe the nature of that involvement. To our knowledge, no prior studies have suggested that PMLCL is associated with an increased incidence of CNS disease. In part, this may be because PMLCL has only relatively recently been recognized by a lymphoma pathology classification (Revised European-American Lymphoma classification) as a distinct subset of large B-cell lymphoma with unique clinical and biologic features. The prominent clinical features of the patients in this study are similar to those described in other series and included increased LDH (95%) and extranodal disease (70%) but rarely included bone marrow infiltration, which is classically associated with CNS recurrence (Tables 1 and 2).9-14,7 In the present study, CNS involvement occurred in six (26%) of 23 patients over the course of disease, most often at the time of first relapse. This incidence of CNS involvement is equivalent to that seen in high-grade lymphomas, such as lymphoblastic, Burkitt, and atypical Burkitt lymphomas, where the incidence of CNS disease ranges from 30% to 60%.1,4,30,34,35 In contrast, it is significantly higher than reported in other series of PMLCL as well as in series of unselected cases of intermediate-grade lymphoma.1,3,39-39 A tabulation (Table 4) of 389 cases of PMLCL extracted from 13 reported series, in which the incidence of CNS infiltration was noted, reveals a 4% (range, 0% to 35%) incidence of CNS disease when considering the entire disease course and an 11% (range, 0% to 58%) incidence in relapsed patients. Additionally, a review of reports on the incidence of CNS disease in intermediate-grade lymphomas indicates a range between 3% and 22%.1,3,4,30,34
A number of potential explanations exist for the high incidence of CNS disease found in the present series. It is possible that, because this is a retrospective analysis involving both previously untreated and relapsed patients, the resulting bias has led to a significant overestimate of CNS disease. We believe this is a less likely explanation because the clinical behavior of PMLCL is consistent with a high incidence of CNS disease and would be predicted by the prognostic model from van Besien et al.6 Indeed, it is possible that the absence of previous reports noting a high incidence of CNS disease in PMLCL is more likely related to its recent recognition as a unique pathologic entity and its prior inclusion with other histologic subtypes less likely to infiltrate the CNS. The incidence of CNS disease may also be affected by the use of CNS prophylaxis or systemic agents with CNS penetration in some of the reported series (Table 4). These latter two variables may explain to some extent why there is such a wide variation in the reported incidence of CNS involvement in the various clinical series. If the results of the present report are correct, they raise some interesting biologic questions regarding the natural history of PMLCL and its propensity to involve extranodal sites including the CNS. By morphology and immunophenotype, the malignant cell of PMLCL is a large B cell that is difficult to distinguish from other large B-cell lymphomas. However, unlike these latter lymphomas, the malignant cell of PMLCL is believed to originate from a unique thymic B cell and usually lacks many of the molecular hallmarks of the other aggressive B-cell lymphomas, such as rearrangements and/or mutations in bcl-2, bcl-6, and c-myc.8,40 Clinically, this tumor initially grows in the mediastinum, often to a large size, and has the propensity to invade local extranodal structures. The tumor readily spreads to distant extranodal areas, including the kidney, liver, adrenals, and pancreas (Table 2). This clinical pattern of spread and the aggressiveness of PMLCL are quite consistent with our observed high incidence of CNS disease and indicate a biologic basis for extranodal tropism; however, the mechanisms for this tropism are unknown at present. Further analysis of the genotype and phenotype of PMCL may help elucidate these mechanisms and suggest future therapeutic strategies. The nature of the CNS spread in PMLCL seems to be significantly different from other large B-cell lymphomas, further highlighting the unique character of this lymphoma subtype. Characteristically, large B-cell lymphomas typically involve the leptomeninges and less commonly spread to the parenchyma (Table 5).1-3,30-32,35 A tabulation of sites of CNS involvement in large-cell lymphoma from multiple series shows that 65% involved the leptomeningeal and dural surfaces, 26% involved the brain parenchyma, and only 9% involved both sites (Table 5). By contrast, in the present series, all but one patient had a mass lesion involving the parenchyma, and four patients also had evidence by MRI of leptomeningeal disease. Of interest, unlike other large B-cell lymphomas with leptomeningeal involvement, there was no cytologic evidence of suspended lymphoma cells within the CSF of any patient from this series.6 This suggests that although PMLCL may involve the leptomeninges, the tumor cells are adherent to the tissue surfaces and do not readily circulate in the CSF.
The results of this study raise some necessary clinical questions regarding the management of these patients. The high incidence of CNS disease in PMLCL indicates that prophylaxis should be considered for patients at high risk. However, the unique propensity of this lymphoma to involve extranodal sites raises the issue of how reliable current risk factors are in discriminating patients at high risk and suggests that this question should be studied in a larger cohort of PMLCL patients. In the absence of such a study, we suggest that doctors use practical medical judgment in selecting patients for CNS prophylaxis and consider patients with either multiple extranodal sites or one extranodal site and elevated LDH for treatment. Perhaps a more difficult question is the choice of CNS prophylaxis. The high incidence of parenchymal involvement in PMLCL raises the concern that intrathecal therapy alone would not be adequate and suggests that whole-brain radiation or high-dose systemic methotrexate or cytarabine would be needed. We are not prepared, however, to make this recommendation based on the limited number of patients in this series because of the increased morbidity associated with these approaches. Instead, we suggest that patients at risk be carefully evaluated by brain MRI and lumbar puncture for CSF cytology and laboratory tests, and receive standard therapy as medically indicated.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
