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© 1999 American Society for Clinical Oncology Comparison of Lumbar and Shunt Cerebrospinal Fluid Specimens for Cytologic Detection of Leptomeningeal Disease in Pediatric Patients With Brain TumorsFrom the Departments of Hematology-Oncology, Radiation Oncology, Pathology and Laboratory Medicine, and Biostatistics and Epidemiology, St Jude Children's Research Hospital; and Departments of Pediatrics and Radiation Oncology, University of Tennessee College of Medicine, Memphis, TN. Address reprint requests to Amar Gajjar, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105; email amar.gajjar{at}stjude.org
PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary CNS tumors. Cytologic examination of lumbar CSF is routinely used to detect LMD. To determine whether examination of CSF obtained from ventricular shunt taps is a more sensitive method of detecting LMD in these patients, we designed a prospective study to compare the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal (VP) shunt taps. PATIENTS AND METHODS: As a part of diagnostic staging, follow-up testing, or both, 52 consecutive patients underwent concurrent lumbar and shunt taps on 90 separate occasions, ranging from the time of diagnosis to treatment follow-up. CSF from both sites was examined cytologically for malignant cells. RESULTS: The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n = 29), astrocytoma (n = 10), ependymoma (n = 5), germinoma (n = 3), atypical teratoid rhabdoid tumor (n = 2), choroid plexus carcinoma (n = 2), and pineoblastoma (n = 1). Each site yielded a median CSF volume of 1.0 mL. Fourteen of 90 paired CSF test results were discordant: in 12, the cytologic findings from shunt CSF were negative for malignant cells, but those from lumbar CSF were positive; in two, the reverse was true. Malignant cells were detected at a higher rate in lumbar CSF than in shunt CSF (P = .0018). When repeat analyses were excluded, examination of lumbar CSF remained significantly more sensitive in detecting malignant cells (P = .011). Analysis of the subset of patients with embryonal tumors showed similar results (P = .0008). CONCLUSION: Cytologic examination of lumbar CSF is clearly superior to cytologic examination of VP shunt CSF for detecting leptomeningeal metastases in pediatric patients with primary CNS tumors.
LEPTOMENINGEAL DISEASE (LMD) is found in as many as 32% of children at the time of diagnosis or recurrence of primary CNS tumors.1 Metastatic spread along the leptomeninges has been reported for virtually all types of CNS tumors, including primitive neuroectodermal tumors,2-4 germ cell tumors, ependymomas,5,6 and both high-7 and low-grade gliomas.1,8 Patients who have LMD at the time of diagnosis have a poorer prognosis and thus require more aggressive radiotherapy and chemotherapy.9-12 Consequently, the definitive diagnosis and careful staging of metastatic disease are of great prognostic significance for pediatric patients with brain tumors and are crucial for the selection of effective treatment strategies. At present, the diagnosis of LMD is based on the use of gadolinium-enhanced spinal magnetic resonance imaging (MRI) and on the cytologic examination of lumbar CSF samples obtained within 2 to 3 weeks after surgery. The cytologic detection of malignant cells is subject to false-positive results because of the morphologic resemblance of ependymal cells and malignant cells, the small number of cells that can be evaluated,13,14 and the differences in samples obtained at various levels of the neuraxis.15 Some studies have suggested that CSF cytology obtained from cisternal or shunt taps may be more sensitive than CSF obtained from lumbar punctures in detecting LMD.16,17 To answer this question definitively, we designed a prospective study to compare the sensitivity of cytologic examinations of CSF obtained concurrently from ventriculoperitoneal (VP) shunt taps and lumbar punctures in detecting LMD in children with primary CNS malignancies.
Study Design and Population Between July 1994 and October 1998, 52 consecutive pediatric patients with primary CNS tumors and VP shunts underwent concurrent shunt taps and lumbar punctures as part of the diagnostic work-up or during follow-up testing to detect LMD. Data were prospectively collected on these 52 patients over the study period. A total of 90 paired shunt and lumbar CSF samples were available for analysis. Patients eligible for the study had a histologically proven diagnosis of primary CNS tumor and a VP shunt in place. CSF for cytologic analysis was obtained from both shunt taps and lumbar punctures on the same day. The St Jude Children's Research Hospital institutional review board approved all treatment protocols. Informed consent was obtained from patients, parents, or guardians, as appropriate, at the time of protocol enrollment. Samples of CSF were mixed with one drop of 22% bovine albumin (Organon Teknika, Durham, NC), placed in a cytospin sample chamber, and centrifuged at 1,000 rpm for 5 minutes (Shandon centrifuge; Shandon, Cheshire, United Kingdom). Slides were stained using a Wright Giemsa stain and were reviewed by a institutional neuropathologist for the detection of malignant cells.
Statistical Considerations
The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n = 29), astrocytoma (n =10), ependymoma (n = 5), germinoma (n = 3), choroid plexus carcinoma (n = 2), atypical teratoid rhabdoid tumor (n = 2), and pineoblastoma (n = 1). The median number of paired CSF samples from each patient was one (range, one to six). Twenty-one of the paired samples were obtained at the time of diagnosis. The median amount of CSF obtained from each site was 1 mL. The locations of the tumors were posterior fossa (n = 38), pineal (n = 3), thalamic (n = 2), bithalamic (n = 2), suprasellar (n = 1), cerebellar (n = 1), cerebral (n = 1), hypothalamic (n = 1), lateral ventricle (n = 1), pontine (n = 1), and parietal (n = 1). Overall, 23 of 90 lumbar samples and 13 of 90 shunt samples tested positive for malignant cells. Among the 90 pairs of CSF samples, 11 had positive cytology at both sites, and 65 had negative cytology. Fourteen pairs were discordant: in 12, the cytologic findings from shunt CSF were negative, but those from lumbar CSF were positive; in two, the reverse was true (Table 1). Malignant cells were detected at a significantly higher rate in lumbar CSF than in shunt CSF (P = .0018).
When only the 52 initial samples taken from the patients were analyzed, the results of 10 were discordant: in nine, the cytologic findings from shunt CSF were negative, but those from lumbar CSF were positive; in one, the reverse was true (Table 2). Thus, cytologic examination of CSF from the lumbar site remained significantly more sensitive in detecting LMD (P = .011).
Data from the subgroup of patients with embryonal tumors were analyzed separately. This subgroup included 32 patients and 67 pairs of results. Among the 67 pairs of CSF samples, eight had positive cytology at both sites, and 48 had negative cytology. Eleven pairs were discordant: in 10, the cytologic findings from shunt CSF were negative, but those from lumbar CSF were positive; in one, the reverse was true. Malignant cells were detected at a significantly higher rate in lumbar CSF than in shunt CSF (P = .0008, one-sided). When the analysis was confined to the initial samples from each patient in this subgroup, seven of the 32 pairs were discordant. In all seven, the cytologic findings from shunt CSF were negative, but those from lumbar CSF were positive. Cytologic examination of CSF from the lumbar site remained significantly more sensitive in detecting LMD (P = .0078, one-sided).
Autopsy studies suggest that dissemination of tumor cells via the CSF pathways is probably the primary mechanism of metastases within the CSF.19 As tumors grow, they may breach the ependymal epithelium, gain entry to the circulating CSF, and be distributed over the surface of the brain and the spinal cord. Normal CSF flow would carry the tumor cells through the aqueduct of Sylvius, the fourth ventricle, and eventually through the foramina of Magendie and Luschka to the rest of the intracranial and spinal subarachnoid space. Viable tumor cells that penetrate the ependymal lining of the ventricle can become attached to the ependyma or leptomeninges at distant sites. Obstructive hydrocephalus is thought to favor ependymal implantation.19 The diagnosis of LMD generally requires the presence of malignant cells in CSF obtained from lumbar puncture, the detection of LMD by gadolinium-enhanced spinal MRI, computed tomographic myelography, or both.20 Gadolinium-enhanced MRI is diagnostically more sensitive and specific than computed tomographic myelography.21,22 However, even in patients with negative MRI studies, lumbar CSF cytology may be positive in 30%.22 The sensitivity and specificity of CSF cytology are difficult to determine because the existing literature contains primarily retrospective data from studies of adult patients with a variety of metastatic solid tumors. Wasserstrom et al16 reviewed 90 patients with either clinical findings typical of LMD or objective or radiologic evidence of LMD. The most common primary tumors were carcinoma of the breast (n = 46), carcinoma of the lung (n = 23), and melanoma (n = 11); no patients had primary CNS tumors. The investigators observed that, for LMD confirmed by autopsy, the initial cytologic findings from lumbar CSF were positive in only 54% of cases; positive findings had increased to 90% by the third lumbar puncture over the period from diagnosis to death. These results may reflect progression of disease over time. Similarly, in the largest analysis of patients with LMD (from Memorial Sloan-Kettering Cancer Center), Glass et al23 reviewed the correlation between premortem positive findings from CSF cytology and pathologic autopsy findings. Of 117 adult patients with either primary CNS tumors or metastatic CNS disease proven at autopsy, who had undergone premortem cytologic examination of CSF, 31 (26%) were positive and 86 (74%) were negative. Of 51 patients with leptomeningeal tumor at autopsy, cytology was positive in 30 (59%) and negative in 21 (41%). Two problems with these data are the uncertain time of cytologic evaluation before the patients' deaths and the degree to which disease progression during the interval between CSF examination and autopsy may have influenced the results. The variability of CSF findings was further addressed by Murray et al,15 who showed that CSF levels of protein, glucose, and malignant cells differ widely in samples obtained at various levels of the neuraxis, even when CSF flow is not obstructed. These investigators described adults with primary (n = 1) and secondary (n = 3) CNS tumors who had neurologic signs and symptoms of LMD. CSF was obtained from each patient by lumbar spinal puncture and from a ventricular Ommaya reservoir. There were marked disparities in the mean protein concentration of individual patients (1,110 mg/dL lumbar; 52 mg/dL ventricular), glucose concentration (10 mg/dL lumbar; 86 mg/dL ventricular), and neoplastic cell count (3,765 cells lumbar; 21 cells ventricular). The finding that ventricular CSF cytology may be positive in light of negative lumbar CSF cytology was first described by Wasserstrom et al.16 On the basis of this report, Rogers et al17 designed a study to compare cisternal and lumbar CSF of 14 patients with neurologic signs and symptoms suggestive of leptomeningeal metastases. Malignant cells were present in both cisternal and lumbar CSF in nine patients but only in cisternal CSF in three. These investigators concluded that cytologic examination of cisternal CSF should be considered routinely for patients believed to have LMD if cytologic findings from lumbar CSF are negative. In contrast to these largely retrospective studies of adults with a variety of malignancies, our prospective study clearly shows that examination of lumbar CSF is more sensitive than examination of shunt CSF for the routine detection of LMD in children with primary CNS tumors. Among the 90 paired samples in our study, 12 tested negative for malignant cells at the shunt site but positive at the lumbar site, and two tested positive at the shunt site but negative at the lumbar site. Of the latter two paired samples, one pair came from a patient with a fourth ventricular tumor and MRI evidence of CSF obstruction and the other from a patient with spinal MRI evidence of diffuse LMD. When the analysis was confined to only patients with embryonal tumors, malignant cells continued to be detected at a higher rate in lumbar CSF samples than in shunt samples. Cisternal or ventricular fluid may be useful to detect LMD in cases in which there is evidence of CSF flow obstruction. However, lumbar CSF should remain the specimen of choice for the routine cytologic detection of malignant cells in the CSF of children with LMD.
Supported in part by Cancer Center Support grants no. P30 CA 21765 and P01 CA 23099 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities. We thank Alberto Broniscer, Suradej Hongeng, Jennifer Havens, Theresa Boggs, and Myra Hazard for their assistance in data collection; Rezaul Karim for providing the SAS Macro program; Flo Witte for editorial review; and Patsy Burnside for typing the manuscript.
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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
