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Cerebrospinal Fluid Dissemination and Neoplastic Meningitis in Primary Brain Tumors Sajeel Chowdhary, MD, Sherri Damlo, and Marc C

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Cerebrospinal Fluid Dissemination and Neoplastic Meningitis in Primary Brain Tumors Sajeel Chowdhary, MD, Sherri Damlo, and Marc C Special Report Cerebrospinal Fluid Dissemination and Neoplastic Meningitis in Primary Brain Tumors Sajeel Chowdhary, MD, Sherri Damlo, and Marc C. Chamberlain, MD Background: Neoplastic meningitis, also known as leptomeningeal disease, affects the entire neuraxis. The clinical manifestations of the disease may affect the cranial nerves, cerebral hemispheres, or the spine. Because of the extent of disease involvement, treatment options and disease staging should involve all compartments of the cerebrospinal fluid (CSF) and subarachnoid space. Few studies of patients with primary brain tumors have specifically addressed treatment for the secondary complication of neoplastic meningitis. Therapy for neoplastic meningitis is palliative in nature and, rarely, may have a curative intent. Methods: A review of the medical literature pertinent to neoplastic meningitis in primary brain tumors was performed. The complication of neoplastic meningitis is described in detail for the various types of primary brain tumors. Results: Treatment of neoplastic meningitis is complicated because determining who should receive ag- gressive, central nervous system (CNS)–directed therapy is difficult. In general, the therapeutic response of neoplastic meningitis is a function of CSF cytology and, secondarily, of the clinical improvement in neuro- logical manifestations related to the disease. CSF cytology may manifest a rostrocaudal disassociation; thus, consecutive, negative findings require that both lumbar and ventricular cytological testing are performed to confirm the complete response. Based on data from several prospective, randomized trials extrapolated to primary brain tumors, the median rate of survival for neoplastic meningitis is several months. Oftentimes, therapy directed at palliation may improve quality of life by protecting patients from experiencing continued neurological deterioration. Conclusions: Neoplastic meningitis is a complicated disease in which response to therapy varies by histology. Thus, survival rates after CNS-directed therapy will differ by the underlying primary tumor. Optimal therapy of neoplastic meningitis is poorly defined, and few guidelines exist to guide clinicians on the most appropri- ate choice of therapy. Introduction methotrexate, rituximab, thiotepa, and trastuzumab. Neoplastic meningitis is a disease that affects the ce- Chamberlain et al1 proposed an evaluation for as- rebral hemispheres, the spine, and the cranial nerves. sessing response in neoplastic meningitis that includes All cerebrospinal fluid (CSF) compartments (ventricles, CSF cytology/flow cytometry, radiographic evaluation, basal cisterns, cerebral and spinal subarachnoid space) and a standardized neurological examination. The need to be assessed during staging and considered with proposal (Response Assessment in Neuro-Oncology) respect to treatment. Most often, treatment involves ra- recommended that CSF analysis be performed for all diotherapy and the intra-CSF administration of chemo- patients, as well as complete, contrast-enhanced neur- therapy. For many patients, concomitant, systemic axis magnetic resonance imaging (MRI), and, when therapy is required because of systemic tumor recur- the intra-CSF administration of therapy is planned, rence. Therapeutic agents for intra-CSF administration radioisotope CSF flow studies should be obtained.1 A include cytosine arabinoside, liposomal cytarabine, standardized instrument was created to assess a neuro- logical examination that does not require neurological 1 From the Lynn Cancer Institute (SC), Marcus Neuroscience Institute, consultation. Because the majority of radiographic le- Boca Raton, Florida, Damlo Does (SD), and Seattle Cancer Care Alli- sions that occur in the setting of neoplastic meningitis ance (MCC), Cascadian Therapeutics, Seattle, Washington. cannot be measured, the working group proposed that Submitted January 30, 2017; accepted April 26, 2017. clinicians use a novel, radiological response scorecard Address correspondence to Sajeel Chowdhary, MD, Marcus Neuro- science Institute, 800 Meadows Road, First Floor, Boca Raton, to grade neuroimaging as improved, stable, or progres- FL 33486. E-mail: [email protected]. sive. Isolated progression based on radiographic evi- Dr Chamberlain has received funding for research, is a consultant dence was defined as sufficient to determine disease for, and holds stock in Pharmaco-Kinesis, Nativis, Roche, and progression of neoplastic meningitis.1 The proposal by Tocagen. No significant relationships exist between the remaining 1 authors and the companies/organizations whose products or ser- Chamberlain et al recognizes these instruments are vices may be referenced in this article. novel and will require validation in prospective clinical January 2017, Vol. 24, No. 1 Cancer Control S1 trials of neoplastic meningitis. Nearly one-half of patients with positive CSF cy- A paucity of literature exists relating to the treat- tology will have cytologically negative findings on an ment of primary brain tumors and the co-occurrence of initial CSF examination.7-11 That number increases to neoplastic meningitis. However, general principles have 80% when repeat CSF examination is performed; how- been established regarding neoplastic meningitis. Ther- ever, little benefit is achieved from more than 2 lumbar apy for neoplastic meningitis is palliative in nature with punctures.8-20 rare curative intent. Few guidelines exist for the treat- Wasserstrom et al3 reported on 90 patients with ment and response evaluation of neoplastic meningitis. carcinomatous meningitis, 5% of whom had positive The current effort reviewed the medical literature perti- results on CSF cytology from either the cisterna magna nent to neoplastic meningitis in primary brain tumors to or ventricles. Chamberlain et al10 found that positive assist clinicians in understanding existing therapies for findings on lumbar CSF cytology at diagnosis, absent and the evaluation of neoplastic meningitis. CSF flow obstruction, and simultaneously obtained ventricular and lumbar cytology samples were dis- Clinical Presentation cordant in 30% of cases. When spinal manifestations The classic presentation of neoplastic meningitis in- were present, the authors discovered that lumbar CSF cludes pleomorphic clinical manifestations relating to cytology was more likely to be positive; alternatively, neurological function in the spinal cord and its exiting ventricular CSF cytology was more likely to be positive nerve roots, the cerebral hemispheres, and the cranial when cranial signs or symptoms were present.10 Not nerves.2-7 Typically, a neurological examination will un- obtaining CSF from a site of radiographically demon- cover additional signs and symptoms beyond what pa- strable or symptomatic disease was associated with tients have reported. false-negative results on cytology in their prospective Changes in mental status and headache are the evaluation of 39 patients, as did withdrawing less than most common manifestations of dysfunction in the 10.6 mL of CSF, taking fewer than 2 samples, and de- cerebral hemisphere, although confusion, dementia, laying the processing of specimens.11 After the authors hemiparesis, and seizure can occur. Dysfunction of the corrected for these factors, they discovered several of cranial nerves, the most common being cranial nerve their study patients with neoplastic meningitis still had VI, can manifest as diplopia or trigeminal sensory or persistently negative findings on CSF cytology.11 motor loss; optic neuropathy and cochlear dysfunction Nearly 40% of cases with clinically suspected neo- are also common. Spinal manifestations can include plastic meningitis proven at the time of autopsy are lower- and upper-extremity weakness, segmental/der- cytologically negative, according to a study by Glass matomal sensory loss, pain, and nuchal rigidity.2-7 et al.9 This number was higher than 50% in patients Clinicians should have a high index of suspicion to with focal neoplastic meningitis.9 make the diagnosis of neoplastic meningitis. Discovery Low sensitivity rates of CSF cytology make diag- of multifocal neuraxis disease in a patient with malig- nosing neoplastic meningitis and assessing treatment nancy is suggestive of neoplastic meningitis; however, response difficult. Immunohistochemistry, molecular patients with neoplastic meningitis also commonly biology techniques, and several biochemical mark- present with isolated syndromes, including cranial ers have been explored to discern a reliable biologi- neuropathy and cauda equina syndrome. cal marker of disease; however, in general, use of bio- New manifestations of a neurological nature may markers has been limited by poor rates of specificity represent disease progression; however, the clinician and sensitivity.8-20 Using monoclonal antibodies for the must distinguish these from the signs and symptoms analysis of immunohistochemistry in the setting of of parenchymal disease and treatment-related ad- neoplastic meningitis does not significantly increase verse events.2-7 the sensitivity rate of cytology alone.8-20 However, for cases of leukemia and lymphoma, antibodies against Diagnosis surface markers can distinguish between neoplastic Examination of the Cerebrospinal Fluid and reactive lymphocytes in the CSF.8-20 Examination of the CSF is considered the most use- Researchers have studied the use of cytogenetics ful laboratory study to aid in the diagnosis of neoplas- to help improve the rate of diagnostic accuracy for
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