Intrathecal synthesis of tumor markers is a highly sensitive test in the diagnosis of leptomeningeal metastasis from solid cancers

Abstract

Background: Identification of neoplastic cells in cerebrospinal fluid (CSF) by cytological analysis is the key diagnostic feature of leptomeningeal metastasis (LM). Because of the lack of sensitivity of this test, considerable efforts have been made to identify alternative diagnostic markers. Data from the literature suggest that measurement of tumor markers (TM) in CSF may be helpful for improving the diagnosis. Methods: We analyzed the concentrations of the TM carcinoembryonic antigen (CEA), CA15.3, CA125 and CA19.9 in both CSF and serum from 18 patients with neoplastic meningitis diagnosed by CSF cytology. We also performed these same measurements in 50 patients affected by other neurological diseases (OND) in order to evaluate putative intrathecal synthesis. In addition, CSF and serum concentrations of the proangiogenic factor VEGF (vascular endothelial growth factor) were evaluated. Results: All LM patients showed intrathecal synthesis for at least one TM. In one patient, a negative CSF cytology after treatment paralleled normalization of tumor marker synthesis. None of the OND patients displayed intrathecal TM synthesis. The VEGF Index (CSF/serum VEGF relative to CSF/serum albumin ratios) was significantly higher in LM patients compared with the control group. However, significant overlap between LM patients and values seen in those with OND was observed. Conclusions: Evaluation of intrathecal TM synthesis is a specific, sensitive, reliable, and reproducible diagnostic tool, and is useful to support diagnosis of carcinomatous meningitis. Clin Chem Lab Med 2009;47:874-9.

Cerebrospinal fluid approach on neuro-oncology

“…These biomarkers may be nonspecific, such as β-glucuronidase, lactate dehydrogenase, beta2-microglobulin, carcinoembryonic antigen or alternatively. CSF release of tumor biomarkers markers has been demonstrated in many patients with LM, however, there was no clear correlation with the type of carcinoma or response to treatment observed 12,13,14 . Particular organ-specific tumor markers such as CA 15-3, CA 125, CA 19-9, CA724, AFP, NSE, Cyfra 21-1, EGFR, a-fetoprotein, b-human chorionic gonadotropin can be relatively specific for LM when elevated in CSF in the absence of markedly elevated serum levels 6,[11][12][13][14] .…”

“…CSF release of tumor biomarkers markers has been demonstrated in many patients with LM, however, there was no clear correlation with the type of carcinoma or response to treatment observed 12,13,14 . Particular organ-specific tumor markers such as CA 15-3, CA 125, CA 19-9, CA724, AFP, NSE, Cyfra 21-1, EGFR, a-fetoprotein, b-human chorionic gonadotropin can be relatively specific for LM when elevated in CSF in the absence of markedly elevated serum levels 6,[11][12][13][14] . Nonspecific tumor markers such as molecules involved in CNS penetration (eg, matrix metalloproteinases and cathepsins), tumor cell tropism (eg, chemokines CXCL8 and CCL18) and vascular endothelial growth factor can be strong indirect indicators of LM but none are sensitive enough to improve the cytological diagnosis 3,6,11,17 .…”

“…Biochemical markers, immunohistochemistry and molecular biology techniques applied to CSF have been explored in an attempt to find a reliable biological marker of disease 3,6,11 . Numerous biochemical markers have been evaluated, for early diagnosis and to effectiveness of treatment evaluation [12][13][14] . In general, their use has been limited by poor sensitivity and specificity.…”

Clinical Presentation, Diagnosis, and Radiological Findings of Neoplastic Meningitis

“…However, if their levels are elevated when neoplastic meningitis is diagnosed, then a return to normal levels of both markers signifies successful treatment. 85,86 CSF β-glucuronidase values are frequently elevated, but wide fluctuations make it unreliable as a marker, and elevations can also occur with bacterial, viral, fungal, or tubercular meningitis. However, in association with an elevated LDH level, high CSF β-glucuronidase levels can indicate neoplastic meningitis from a breast primary tumor with high sensitivity and specificity rates.…”

Tumor biomarkers: PSA and beyond

“…However, other sample matrices, including cerebrospinal fl uid (24,25) , urine (26 -28) , stool (29) , secretions (30) or breath (31 -33) have been explored in patients with benign or malignant conditions and, in cancer patients, may offer an advantage in certain situations over peripheral blood or tumor tissue. Malignant effusions, e.g., ascites (34 -36) or pleural effusion (37) , represent other interesting sample matrices that may allow a direct study of the changes associated with proliferation of cancer cells and host response against neoplasia in the tumor microenvironment.…”