eMedicine Specialties > Neurology > Neuro-oncology

Leptomeningeal Carcinomatosis: Differential Diagnoses & Workup

Author: R Andrew Sewell, MD, Clinical Instructor in Psychiatry and Mental Illness Research, Education, and Clinical Center (MIRECC) Fellow, Veterans Affairs Connecticut Health Care System, Yale University School of Medicine
Coauthor(s): Lawrence D Recht, MD, Professor of Neurology and Neurosurgery, Department of Neurology and Clinical Neurosciences, Stanford University Medical School
Contributor Information and Disclosures

Updated: Nov 23, 2009

Differential Diagnoses

Other Problems to Be Considered

New signs or symptoms may represent leptomeningeal carcinomatosis (LC) progression, but must be distinguished from parenchymal disease, because 30-40% of those with LC also have brain metastases also, paraneoplastic syndromes, or the adverse effects of chemotherapy or radiation. Multifocal neurologic signs can also be characteristic signs of multiple brain or epidural metastases, and signs of meningeal irritation can also be caused by infection.

LC can be difficult to distinguish from subacute or chronic meningoencephalitis caused by tuberculosis or fungus, as CSF findings in both show moderate mononuclear pleocytosis and decreased glucose. However, patients with LC usually are afebrile, and their neurologic symptoms appear early in the course with a preserved level of consciousness, rather than late with depressed mental status as in tubercular or fungal meningoencephalitis.

Workup

Laboratory Studies

• The diagnosis is made with positive CSF cytologic results (the most useful test), subarachnoid metastases identified on radiologic studies, or a history and physical examination suggestive of LC along with abnormal CSF findings. Order a workup for LC in patients presenting with the following:
  • Neurologic signs and symptoms at more than 1 level of the neuraxis (present in 75% of patients with LC).
  • Neurologic signs and symptoms consistent with a single lesion but with no mass evident on imaging.
  • Neurologic signs and symptoms consistent with inflammatory meningitis but without fever.
  • Imaging showing leptomeningeal enhancement or CSF-flow obstruction.
  • Elevated CSF protein level in a patient with cancer but without known cerebral metastases.
• The first step in the diagnostic workup should be gadolinium-enhanced MRI of the area of maximal symptomatology, followed by a lumbar puncture (LP) if the patient has no evidence of increased ICP, repeated as many as 3 times or until findings are positive.

Imaging Studies

• In general, imaging findings are consistent with or suggestive rather than diagnostic of LC, and they are most useful in detecting secondary complications of LC, such as hydrocephalus, periventricular edema, and gyral effacement.
  • About 50% of patients with LC have abnormal imaging findings, most commonly contrast enhancement of the basilar cisterns, cortical convexities, cauda equina, or hydrocephalus without a mass legion. However, this enhancement usually follows positive cytologic findings by 6 months.
  • MRI of the spinal cord involvement can show nerve-root thickening, cord enlargement, intraparenchymal and subarachnoid nodules, or epidural compression.
  • Meningeal enhancement, which reflects either a blood supply outside the blood-brain barrier or a disturbed blood-brain barrier, is also seen in infections, inflammatory diseases, trauma, or subdural hematomas; after craniotomy; and sometimes after LP. Nevertheless, delineation of the extent of leptomeningeal disease through imaging is important because radiotherapy then can be effectively targeted to these regions rather than to the entire neuraxis.
• Perform contrast-enhanced brain CT or gadolinium-enhanced MRI in patients with cancer and neurologic symptoms to look for metastases and to determine the risk of herniation from LP. However, these tests are relatively insensitive for LC itself. As many as 60% of CT scans appear normal; MRI is more sensitive.
• CT results will most likely be normal. Scans may reveal unexplained communicating hydrocephalus or abnormal enhancement of the tentorium, sylvian fissures and basal cisterns, cortical subarachnoid space, and ventricular walls.
• MRI with gadolinium enhancement is the imaging study of choice and slightly more sensitive than CT (66%) because of the use of paramagnetic contrast agents. Imaging of the entire CNS is required. A false-negative rate of 60% means that a negative MRI does not exclude LC, but an abnormal MRI with a typical clinical presentation is adequate to establish the diagnosis.
• Although seldom indicated, myelography may show nodularities or thickening of the nerve roots in approximately 25% of patients with LC, with similar findings apparent on MRI. Myelography can show intra-arachnoid nodular filling defects, longitudinal striations, prominent and crowded nerve roots of the cauda equina, or scalloping of the subarachnoid space.

Other Tests

• Radionuclide studies using either¹¹¹ indium-diethylenetriamine penta-acetic acid or⁹⁹ Tc macroaggregated albumin can be used to assess CSF flow, which is abnormal in 30-40% of patients with LC. Abnormal CSF flow must be addressed prior to the administration of intrathecal chemotherapy, as it can prevent homogenous delivery.
• Myelography, cerebral arteriography, and other tests, such as EEG, seldom are indicated.
• Electromyography (EMG) can assist with diagnosis, but it is rarely necessary.
• Monoclonal antibodies can be useful in diagnosing CSF lymphoma, particularly if cytologic examination cannot distinguish between reactive lymphocytes and malignant lymphocytes.

Procedures

Lumbar puncture is the most useful test.

• Analysis of CSF obtained is more accurate than that obtained by using a ventricular catheter, as ventricular fluid usually has higher glucose and lower protein levels and is less likely to yield positive cytologic findings. For this reason, periodic LP is recommended, even in patients with catheters.
• Measure the opening pressure (elevated in 50% of patients) and send the CSF for an analysis of cytology, cell counts, and protein and glucose levels.
• Carcinoma cells in the CSF are diagnostic, with the exception of a few false-positive results in patients who have reactive lymphocytes (which are difficult to distinguish from malignant lymphomatous cells) because of an infectious or inflammatory process in the CSF. However, negative cytologic findings do not rule out the diagnosis, as 50% of patients with LC have a negative cytologic result on the first LP. This percentage drops to 20% after 2 high-volume LPs and 15% after 3.
• Cytologic findings are more likely to be positive in patients with extensive leptomeningeal involvement than in patients with focal involvement because CSF obtained from a site distant to the pathology is more likely to yield negative pathology.
• Other causes of false negatives can include not obtaining CSF from a site of symptomatic or radiographically demonstrated disease, withdrawing <10.5 mL CSF, delayed processing of samples, and obtaining only 1 sample.
• CSF pleocytosis and modest protein elevations are consistent with but not indicative of the diagnosis, but reduced glucose levels usually are seen only with LC (ie, abnormal glucose transport) or infection (ie, increased glucose utilization).
• The lymphocyte count is elevated in more than 50% of patients with LC, and the presence of eosinophils should raise the suspicion of lymphomatous infiltration (except patients who are given ibuprofen).
• Xanthochromia can occur from leptomeningeal bleeding, which is most likely in LC from a melanoma.
• Most biochemical markers in CSF have poor sensitivity and specificity, but when present, levels decline with successful therapy. Their reelevation can thus signal a relapse before any other findings become apparent. Useful markers include carcinoembryonic antigen (CEA) from adenocarcinomas, alpha-fetoprotein and beta-human chorionic gonadotropin from testicular cancers, 5-hydroxyindoleacetic acid (5-HIAA) from carcinoid tumors, and immunoglobulins from multiple myeloma; their presence in CSF is virtually diagnostic. Nonspecific markers such as endothelial growth factor can be strong indirect indicators of LC, but none are sensitive enough to improve th e cytological diagnosis.
  • Epithelial-associated glycoprotein (HMFGI antigen) is present in 90% of LCs.
  • Cytokeratins measured by tissue polypeptide antigen (TPA) and tissue polypeptide-specific antigen (TPS) have 80% sensitivity to LC from breast cancer.
  • Neither CEA nor beta-glucuronidase is helpful in detecting solid tumors or metastases, nor are they useful in detecting leptomeningeal lymphomatosis. However, if their levels are elevated, a return to normal levels of both markers signifies successful treatment.
  • Elevated CSF CEA is specific, unless serum levels are unusually high (ie, >100 ng/mL).
  • CSF beta-glucuronidase values are frequently elevated, but wide fluctuations make it unreliable as a marker, and elevations also occur with bacterial, viral, fungal, or tubercular meningitis. In association with elevated lactate dehydrogenase (LDH), however, high CSF beta-glucuronidase levels can indicate LC from a breast primary tumor with a high sensitivity and specificity.
  • CSF fibronectin values are elevated in LC but also in bacterial meningitis and tick-borne encephalitis.
  • Myelin basic protein can indicate disease activity, particularly if values are measured longitudinally.
  • CSF vascular growth factor has recently been suggested as a useful biomarker.¹
  • Antithrombin III has been suggested as a useful biomarker in patients with primary CNS lymphoma but has not been evaluated in patients with LC.
• For lymphoma and leukemia, the weight of the evidence (as well as recent National Comprehensive Cancer Network guidelines) suggests that flow cytometry is more sensitive than cytology and should be used instead.²
• Monoclonal antibodies are not more sensitive than cytology but can be used to distinguish between reactive and neoplastic lymphocytes in the case of LC from lymphoma.
• Creatine-kinase BB isoenzyme (CK-BB), tissue polypeptide antigen (TPA), b_2- microglobulin, β -glucuronidase, LDH isoenzyme-5, and vascular endothelial growth factor (VEGF) are strong indirect indicators of LC, but are not sensitive enough to improve on cytology.
• LDH concentrations are elevated in cases of stroke, bacterial meningitis, CSF pleocytosis, head injury, primary CNS tumors, and some metastases. Levels are also elevated in 80% of LCs; therefore, they can be useful in confirming the diagnosis. LDH isoenzyme-5 levels are elevated in LCs from breast or lung primary tumors and melanoma, as well as bacterial meningitis, but they are sometimes normal even when cytologic findings are positive
• Levels of CSF β ₂ -microglobulin may be useful in detecting LC caused by hematologic spread but not in LC from solid tumors. levels may be elevated after treatment with intrathecal methotrexate (MTX).
• Ferritin levels are sensitive to inflammatory changes in the CSF, but they are nonspecific for early LC.
• CSF alkaline phosphatase levels may be elevated in an LC from a lung primary tumor.
• CSF prostate-specific antigen (PSA) may be elevated in an LC from a prostate primary tumor.
• PCR is not useful as the precise genetic alteration of the neoplasia is usually not known.

Histologic Findings

Leptomeningeal biopsy may be necessary if the patient has no evidence of a primary tumor. The findings can be diagnostic if results of all other tests are negative, especially if taken from an enhancing region identified on MRI. Macroscopic pathology shows diffuse fibrotic thickening of the brain and spinal cord, as well as layering of the nerve roots with tumor tissue. Microscopic examination shows local fibrosis with tumor cells covering the blood vessels and nerves, either as a single layer or as aggregates.

Staging

Staging varies by primary cancer, but metastatic disease is stage IV by definition.

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