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© 1999 American Society for Clinical Oncology Comparison of CSF Cytology and Spinal Magnetic Resonance Imaging in the Detection of Leptomeningeal Disease in Pediatric Medulloblastoma or Primitive Neuroectodermal TumorFrom the Departments of Hematology-Oncology, Radiation Oncology, Pathology and Laboratory Medicine, Biostatistics and Epidemiology, and Radiology, St Jude Children's Research Hospital; and Departments of Pediatrics, Radiation Oncology, and Radiology, University of Tennessee, College of Medicine, Memphis, TN. Address reprint requests to Maryam Fouladi, MD, St Jude Children's Research Hospital; Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105; email maryam.fouladi{at}stjude.org
PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Examination of CSF for malignant cells, detection of LMD on spinal magnetic resonance imaging (MRI), or both are the methods routinely used to diagnose LMD. A recent study suggested 100% correlation between CSF and MRI findings in children with medulloblastoma. To determine the validity of this hypothesis, we compared the rate of detection of LMD between concurrent lumbar CSF cytology and spinal MRI performed at diagnosis in patients with medulloblastoma or PNET. PATIENTS AND METHODS: As a part of diagnostic staging, 106 consecutive patients newly diagnosed with medulloblastoma or PNET were evaluated with concurrent lumbar CSF cytology and spinal MRI. CSF cytology was examined for the presence of malignant cells and spinal MRI was reviewed independently for the presence of LMD. RESULTS: Thirty-four patients (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. There were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bounds on the proportion of patients with LMD whose disease would have gone undetected using either CSF cytology or MRI as the only diagnostic modality were calculated at 14.4% and 17.7%, respectively. CONCLUSION: With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET. Thus, both CSF cytology and spinal MRI should routinely be used to diagnose LMD in patients with medulloblastoma or PNET.
LEPTOMENINGEAL disease (LMD) occurs in up to 32% of children with primary CNS tumors at diagnosis.1 Metastatic spread along the leptomeninges has been reported for virtually all types of CNS tumors but is most frequent in embryonal tumors such as medulloblastoma and primitive neuroectodermal tumor (PNET).2-4 Patients with CNS tumors who have LMD at diagnosis have a worse prognosis and require more aggressive therapy.5-8 Consequently, the definitive diagnosis and careful staging of metastatic disease are of great prognostic importance in childhood brain tumors and are crucial for the selection of effective treatment. At present, the diagnosis of LMD is based on the use of gadolinium (Gd)-enhanced spinal magnetic resonance imaging (MRI) and the cytologic examination of CSF for malignant cells, which were obtained 2 to 3 weeks after surgery. In retrospective analyses of adult patients with a variety of primary or secondary CNS tumors and positive lumbar CSF cytology, MRI revealed abnormalities consistent with LMD in up to 70% of patients at some point in their clinical course.9-13 Although a recent pediatric study reported 100% correlation between MRI and lumbar CSF cytology in patients with medulloblastoma,14 the number of patients was small and the studies were not contemporaneous. To determine the relative roles of cytology and MRI for the diagnosis of LMD, we investigated the impact of using only one of the two modalities to diagnose LMD in a large cohort of patients with PNET and medulloblastoma who had undergone both diagnostic procedures.
Between December 1989 and August 1998, 106 consecutively accrued pediatric patients with primary CNS PNET or medulloblastoma had concurrent lumbar punctures and Gd-enhanced spinal MRI as part of their initial diagnostic work-up for the presence of LMD. Patients eligible for the study were younger than 21 years of age, with a histologically proven diagnosis of medulloblastoma or PNET. Two to three weeks after the initial surgery, CSF cytology by lumbar puncture was obtained up to 48 hours post–Gd-enhanced MRI as part of the initial staging evaluation. CSF samples were mixed with one drop of 22% bovine albumin (Organon Teknika, Durham, NC), placed in a cytospin sample chamber, and centrifuged at 1,000 revolutions per minute for 5 minutes (Shandon centrifuge; Shandon, Cheshire, United Kingdom). A pathologist reviewed all slides for the detection of malignant cells. Both cytologic studies and spinal MRIs were interpreted independently of each other. Spinal MRI examinations were performed on three different Siemens MRI machines over the 10-year period of this study, with software provided by the same vendor. The software underwent a slow evolution over this period. During the first 9 years, the examinations relied primarily on postcontrast imaging, with contiguous 4- or 5-mm sagittal images of the entire spine followed by routine transverse imaging below the conus. During the last year, the examination consisted of 3- or 4-mm overlapping sagittal images at 1- and 1.5- or 2-mm intervals, without routine transverse images.
Statistical Considerations
Among the 106 patients, there were 68 males and 38 females. The median age was 7.3 years (range, 0.3 to 19.8 years). Twenty-five patients had positive CSF cytology for malignant cells at diagnosis, and 81 had negative cytology. There were 22 patients with MRI evidence of LMD and 84 without. As listed in Table 1, 34 children (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. Overall, among the 106 patients, there were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. The exact 95% upper bound on the proportion of patients with LMD who would have gone undetected using CSF cytology alone is 14.4%. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bound on the proportion of patients who would have gone undetected using only MRI of the spine is 17.7%.
CSF volume was available in 103 of the 106 patients in the study; three patients did not have CSF volume data available. Only three patients had CSF volumes less than 0.5 mL. The median CSF volume was 1.3 mL. The quartile range for CSF volume (ie, 25% to 75%) was 1 mL to 2 mL. There was no evidence of an association between the volume of the CSF sample and the probability that the sample was positive (P > .7). Furthermore, the discordant rates between CSF cytology and MRI did not differ significantly when CSF volume was greater than 0.5 mL and less than 2.0 mL versus a CSF volume greater than or equal to 2.0 mL.
Up to 32% of patients with PNET or medulloblastoma have metastatic disease at diagnosis.1 The diagnosis of LMD generally requires the detection of malignant cells in lumbar CSF or the presence of metastatic disease by Gd-enhanced MRI or computed tomography (CT) myelogram. The sensitivity and specificity of each diagnostic method is difficult to estimate because there is no diagnostic standard short of detection of LMD at autopsy. Some series have suggested that CSF cytology obtained from cisternal or shunt taps may be more sensitive than CSF obtained from lumbar punctures in detecting LMD.15,16 In contrast to largely retrospective studies of adults with a variety of malignancies, we recently completed a prospective study that compared the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal shunt taps in 52 pediatric patients with primary CNS tumors as part of an initial diagnostic work-up or during follow-up testing to detect LMD.17 A total of 90 paired shunt and lumbar CSF samples were analyzed. Among the 90 paired samples in that study, malignant cells were detected at a significantly higher rate in lumbar CSF than in shunt CSF (P = .0018, one-sided). When the analysis was confined to only those patients with embryonal tumors, malignant cells continued to be detected at a higher rate in lumbar CSF samples than in shunt samples (P = .0008, one-sided). Thus, we concluded that lumbar CSF should remain the specimen of choice for the routine cytologic detection of malignant cells in the CSF of children with LMD. In recent studies, Gd-enhanced MRI has been found to be more sensitive than CT myelogram in the detection of LMD.18,19 Heinz et al18 reported the results of a prospective study of 33 patients with primary CNS tumors who had Gd-enhanced MRI within 2 weeks of a CT myelogram. Seven patients were found to have metastatic disease. Although both MRI and CT myelogram detected metastases in patients, the number of lesions detected by MRI was 24 compared with 15 detected by CT myelogram. These results lead to the conclusion that MRI may be more sensitive than CT myelogram in detecting LMD.18 This data has also been confirmed in a larger study of 61 patients by Chamberlain.19 Most studies of the role of neuroimaging and CSF cytology in the diagnosis of LMD have been retrospective and have primarily reported the incidence of MRI or CT abnormalities in patients with positive CSF cytologic results. In these early studies, which involved adults with a variety of metastatic solid tumors, MRI revealed abnormalities in 23% to 71% of patients with positive results on CSF cytology.9-13 The only study to address the correlation between CSF cytology and demonstration of spinal metastases by Gd-enhanced MRI in medulloblastomas is by Harrison et al.14 Of 26 patients with medulloblastoma, 10 patients had been investigated with both CSF cytology and MRI of the spine up to 8 months after diagnosis. Seven of these samples were lumbar, seven were obtained intraoperatively from cisterna magna, and three were from both. When comparing lumbar CSF with spinal MRI, three cases demonstrated involvement by both routes, and four were negative by both routes. The authors concluded that there was a 100% correlation between lumbar CSF and spinal MRI. A significant limitation to Harrison's study is that the sample size is too small to draw a meaningful conclusion regarding the sensitivity of these two modalities; among the 26 patients, only seven had both lumbar CSF cytology and spinal MRI. Furthermore, the CSF samples and spinal MRIs were not concurrent. The interval between the two studies ranged from 6 to 198 days (average, 65 days). Finally, the timing of the MRI was not uniform, ranging from preoperative to postoperative (range, 8 days to 8 months). In contrast, the current study involved 106 consecutive patients with PNETs or medulloblastomas who had both CSF cytology and Gd-enhanced MRI of the spine performed as part of their initial staging evaluation in the early postoperative period. There was no selection of patients by symptoms of leptomeningeal disease, and the two diagnostic methods were performed concurrently (within 48 hours of each other), 2 to 3 weeks postsurgery. Based on our findings, if CSF cytology had been the only diagnostic procedure used, we estimate that up to 14.4% of patients with LMD would have been missed. If only MRI of the spine had been used to diagnose LMD, up to 17.7% of patients with LMD would have been missed. Thus, the use of either diagnostic modality alone could result in missing the diagnosis of LMD in up to 14% to 18% of patients, which, in turn, could lead to the potential under-treatment of a patient. There was no association noted in this study between the volume of CSF and the probability that the sample was positive (P > .7). Furthermore, the discordant rates between CSF cytology and MRI did not differ significantly when CSF volume was greater than 0.5 mL and less than 2.0 mL compared with volumes greater than or equal to 2.0 mL. However, it must be pointed out that the CSF volume was not standardized because the data were collected retrospectively. A prospective study that uses larger volumes of CSF needs to be performed to assess this question more accurately and in a more standardized fashion. In conclusion, this study strongly suggests that neither spinal MRI nor CSF cytology alone is sufficient for the definitive diagnosis of LMD. We conclude that both CSF cytology and spinal Gd-enhanced MRI are necessary to maximize the potential identification of the presence of LMD in patients with medulloblastoma or PNET.
Supported in part by Cancer Center support grants no. PA30CA 21765 and P01 CA 23099 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). The authors thank Jennifer Havens and Annemarie Fraga for assistance in data collection and Wei Wang for assistance with the statistical analysis.
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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
