Neoplastic Meningitis Due to Lung, Breast, and Melanoma Metastases

Emilie Le Rhun, MD; Sophie Taillibert, MD; Marc C. Chamberlain, MD

Disclosures

Cancer Control. 2017;24(1):22-32. 

In This Article

Diagnosis

According to guidelines published by the National Comprehensive Cancer Network (NCCN), the diagnosis of neoplastic meningitis may be determined by the presence of CTCs in the CSF.[21] In the absence of CTCs in the CSF, neoplastic meningitis has been defined as the presence of neuroradiological findings consistent with neoplastic meningitis and associated with characteristic symptoms and signs of neoplastic meningitis in the setting of cancer.[4,7,21] A diagnosis of probable neoplastic meningitis can also be made in those with cancer who present with symptoms and signs consistent with neoplastic meningitis, CSF abnormalities (although nonspecific), and inconclusive findings on magnetic resonance imaging (MRI).[1] Underdiagnosis remains a challenge because establishing a diagnosis of neoplastic meningitis requires specific assessments (analysis of CSF and imaging of the CNS) based on a clinical suspicion of neoplastic meningitis; those challenges notwithstanding, corroborative test results may also be normal.[7]

Clinical Symptoms and Signs

Patients with neoplastic meningitis frequently present with multifocal neurological symptoms and signs related to specific domains of the CNS involved with CTCs. Clinical manifestations may have a subtle presentation in some patients. Neurological symptoms and signs are classically categorized as belonging to 1 of 3 CNS domains: (1) cerebral hemispheres, (2) cranial nerves, and (3) spinal cord/nerve roots.[3,22] Shown in Table 1, the most frequent manifestations of neoplastic meningitis are headache, change in mental status, gait abnormality, vomiting (cerebral hemisphere dysfunction), diplopia and facial paresis (cranial nerve involvement), lower extremity weakness and paresthesias, back or neck pain, and radiculopathy (spinal cord/exiting nerve-root manifestations).[23–28] Clinical manifestations suggestive of neoplastic meningitis are the development of cauda equina syndrome, communicating hydrocephalus, or cranial neuropathy.[1] Typically, neurological signs exceed the number of symptoms, so a careful neurological examination is required to assist in the diagnosis and management of neoplastic meningitis.[4,29] Meningismus (neck stiffness) is uncommon and presents in fewer than 15% of cases.[23–28,30] Headache, nausea, and vomiting due to raised intracranial pressure are frequent. Seizures are uncommon and occur in fewer than 10% of patients.[30]

Clinical manifestations may overlap with those of concomitant brain metastasis, treatment-related toxicity, metabolic disturbances, other causes of chronic meningitis (tuberculosis, fungal infections, sarcoidosis), or — rarely — paraneoplastic syndromes.[1,7,8]

However, the presentation differs from that of infectious or hemorrhagic meningitis, because fever, meningismus, and photophobia are rare in this patient population.[4,7] Concomitant primary or secondary brain cancer may amplify the neurological manifestations of neoplastic meningitis.

Imaging Assessment

MRI with contrast of the brain and spinal cord is the imaging modality of choice for the radiographical evaluation of neoplastic meningitis.[4,6,7] Contrast-enhanced, T1-weighted imaging and sequences of fluid attenuation inversion recovery are the most sensitive for detecting neoplastic meningitis.[4,7] At diagnosis, brain involvement can be observed in 40% to 75% of patients and spinal involvement can be seen in 15% to 25%.[7] Findings on MRI can include focal or diffuse pial enhancement; ependymal, sulcal, folia, or cranial nerve enhancement; and subarachnoid, ventricular, or parenchymal-enhancing nodules. Hydrocephalus, which is a secondary consequence of neoplastic meningitis, may also be observed. Characteristic findings on MRI are illustrated in Figure 1 and Figure 2.[7]

Figure 1.

Leptomeningeal sulcal enhancement at the cranial level on axial T1-weighted, gadolinium-enhanced magnetic resonance imaging of the brain.

Figure 2.

Leptomeningeal perimedullary enhancement on sagittal T1-weighted, gadolinium-enhanced magnetic resonance imaging of the spinal column.

In a cohort of 125 patients who had non–brain solid tumors, neoplastic meningitis, and positive findings on CSF cytology, as well as 40 patients with clinical neoplastic meningitis and negative findings on CSF cytology, MRI findings were abnormal in 40% of study patients with positive CSF cytology and 100% of study patients with MRI-defined neoplastic meningitis and negative CSF cytology.[29] The sensitivity of neuraxis MRI in detecting neoplastic meningitis varies between 40% and 86%.[29,31–37] Normal findings on MRI do not exclude the diagnosis of neoplastic meningitis.[1] Co-existent brain metastases have been reported in 21% to 83% of patients with neoplastic meningitis.[13,29,31–34,38,39] The value of computed tomography (CT) with contrast of the cranium is limited in neoplastic meningitis (sensitivity rate, 23%–38%), and use of CT is restricted to the detection of hydrocephalus or if obtaining MRI is contraindicated.[4,7,35,40]

Radionuclide studies using indium, diethylene, and triamine penta-acetic or Tc macro-aggregated albumin permits the detection of CSF flow blocks present in 30% to 70% of patients with neoplastic meningitis.[19] In a cohort of 165 patients with neoplastic meningitis and solid tumors, the results of radioisotope CSF flow studies were abnormal in 25% of those with positive cytology results and in 28% of those whose disease was defined by MRI.[29] CSF blocks generally occur at the skull base, within the spinal subarachnoid space, and across the cerebral convexities.[4,7,41] Compared with patients without a disruption of CSF dynamics, patients with interruptions in CSF flow have a shorter survival.[42] Furthermore, a block of the CSF flow reduces the efficacy of the intra-CSF administration of treatment by limiting the distribution of the drug in the CNS and increasing treatmentrelated toxicity.[4] Nonetheless, radioisotope CSF flow dynamics is infrequently utilized. Determination of CSF flow interruption is relevant with respect to intra-CSF drug delivery, and, if documented, re-establishing normal CSF flow by treating the affected area with radiotherapy re-establishes CSF flow in 30% of intraspinal blocks and 50% of intracranial blocks.[41]

Normalizing CSF dynamics results in survival rates similar to that of patients initially without CSF flow interruption.[41]

Analysis of the Cerebrospinal Fluid

Most patients (> 90%) with neoplastic meningitis manifest nonspecific CSF abnormalities, such as raised CSF opening pressure (46%), elevated protein levels (76%), decreased glucose levels (54%), or increased white blood cell counts (57%).[4,7] The finding of CTCs in the CSF can be used to establish the definitive diagnosis of neoplastic meningitis.[1] The specificity rate of CSF cytology is high (80%–95%), but the sensitivity rate of initial lumbar puncture is estimated to be below 50%.[1,4] Using measures such as sampling a large volume of CSF (> 10 mL), avoiding a hemorrhagic CSF specimen, and prompt processing can improve the sensitivity of CSF cytology. Not obtaining a CSF sample from a clinically or radiologically symptomatic site may increase the rate of false-negative results on CSF cytology. Repeat lumbar puncture increases the likelihood of identifying CTCs to 80%.[1,43] Little benefit is obtained from obtaining a third CSF cytology sample.[1,4,7,43] In contemporary series of breast cancer–related neoplastic meningitis, the sensitivity rate of CSF cytology was reported to be 67% to 83%.[31–37]

Many CSF biomarkers have been examined for their use in neoplastic meningitis. Biomarkers may be nonspecific (eg, α-glucuronidase, lactate dehydrogenase, β-2-microglobulin, carcinoembryonic antigen) or organ specific (eg, cancer antigen [CA] 15–3, CA 125, CA 19–9, CA 724, α-fetoprotein, neuron-specific enolase, cytokeratin 19 fragment). However, no clear relationship exists between these various biomarkers and treatment response.[7] Proangiogenic molecules, such as vascular endothelial growth factor, urokinase plasminogen activator, and tissue plasminogen activator, have been evaluated with varying rates of sensitivities and specificities that do not appear to improve the performance of CSF cytology.[7,44,45] CSF metabolomics, protein profiling, micro-RNA studies, and genomic analysis may represent another method to aid in the diagnosis and treatment of neoplastic meningitis.[46–49] Identification of cell-surface, tumor-associated proteins in CSF is another method under investigation.[50–53] Due to lack of agreement on cutoff levels to standardize CSF sampling and processing with respect to the above-mentioned biomarkers, CSF cytology remains the gold standard for the detection of CTCs in the CSF.[1,6,7]

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