Cerebrospinal Fluid Spread of Anaplastic Glioma
Authors: Ozden Narin, Jan Drappatz, Lisa M. Doherty, Patrick Y. Wen, Santosh Kesari
Journal: Journal of Clinical Oncology (2007)

A 35-year-old woman presented with complex partial seizures that progressed to generalized tonic-clonic seizures in March 2002 and was found to have an infiltrating temporal lobe lesion upon receiving magnetic resonance imaging (MRI). Initial concern was for encephalitis or neoplasm. Biopsy of the lesion showed infiltrating glioma with possible neuronal component with a MIB-1 proliferation index focally of 4%. The tumor consisted of a uniformly dense population of mildly pleomorphic nuclei with little visible cytoplasm and no mitotic activity, no vascular cell proliferation, and no necrosis. Subsequent MRIs were stable until the December 2003 scan which showed increased signal on T2-weighted sequences MRI and increased enhancement. A repeat resection was consistent with a fibrillary glioma with anaplastic features— pleomorphic hyperchromatic nuclei with scant cytoplasm, nuclear molding and apoptosis, frequent bizarre multinucleated cells, frequent mitoses, and vascular proliferation with a MIB-1 index of greater than 50%; synaptophysin and pan-keratin stains were negative. The patient underwent treatment with involved field radiation and concurrent temozolomide therapy followed by adjuvant monthly temozolomide for 24 cycles with stable MRIs throughout treatment. After finishing the last cycle in February 2006, the patient developed dizziness and unsteadiness. A repeat brain MRI showed new enhancement in the right temporal resection cavity and also new enhancement surrounding the brainstem and cerebellar folia concerning for leptomeningeal gliomatosis (Figs 1A, 1B, and 1C; postcontrast T1-weighted, arrows). Pre-contrast (Fig 2 thoracic spine; A-T1-weighted; B-T2-weighted) and postcontrast (Fig 2 thoracic spine; C-T1-weighted) images of spine MRI showed marked, diffuse enhancement of subarachnoid space with nodular deposits of tumor (Fig 2C; arrow) nearly resembling a T2-weighted scan. A lumbar puncture for cerebrospinal fluid (CSF) was obtained and showed protein of 1,958, glucose of 66, WBC 333 (71% lymphocytes), and RBC (280,000). Cytology was positive for sheets of malignant cells with pleomorphic nuclei with high cytoplasmic to nuclear ratio consistent with glial origin (Fig 3). This constellation of findings is consistent with leptomeningeal seeding of glioma. The patient underwent an Ommaya reservoir placement and received intrathecal chemotherapy in addition to systemic chemotherapy. Despite several chemotherapy regimens, the leptomeningeal gliomatosis progressed on imaging and CSF cytology and the patient died 5 months later. CSF spread is recognized as a terminal pattern of progression in high-grade glioma patients. As new treatments improve local tumor control (24 months in this case), leptomeningeal seeding of gliomas appears to be increasingly evident. CNS parenchymal and blood-brain-barrier penetrating drugs, such as temozolomide, have improved the outcome of high-grade gliomas, but the penetration and distribution throughout the whole CSF system is an important issue that has yet to be addressed, especially with novel targeted agents. This issue was recently highlighted in a report of epidermal growth factor receptor inhibitor (gefitinib) for non– small-cell lung cancer with leptomeningeal metastases. Furthermore, the biologic underpinnings of this pattern should be investigated as they may provide insight into why such tumors are refractory to current treatments.