Trial Information

Determining the Sensitivity and Specificity of Circulating Tumor Cells and Cytology in Cerebrospinal Fluid of Patients Clinically Suspected for Leptomeningeal Metastases

Leptomeningeal metastases (LM), is a diffuse dissemination of tumor cells into the
cerebrospinal fluid (CSF) and leptomeninges.[1] Up to 8% of all patients with cancer develop
LM. Gadolinium enhanced MRI of the symptomatic location of the nervous system is the
radiological method of choice when LM is clinically suspected. In patients with a
metastasized tumor, based on clinical signs of LM and contrast enhancement of either the
leptomeninges, pia mater/cortex or cranial or spinal nerves on MRI, the diagnosis LM can be
made. The sensitivity of MRI with gadolineum for LM is 75% and the specificity 77%. If MRI
does not show equivocal abnormalities, CSF cytology needs to be performed. In 55% of
patients with LM from solid tumors, malignant cells are found during the first CSF
examination. The sensitivity raises to 80-90% after the second CSF sampling, as determined
in the pre-MRI era. The volume of sampled CSF determines partly the sensitivity of CSF
cytology. If possible, 10 ml CSF needs to be taken and the material must be processed as
quickly as possible.

Recently, Patel et al (2011) described the detection of breast cancer cells in the CSF using
the Cell Search System (Veridex). [6] Using this method, the CSF is enriched
immuno-magnetically for the epithelial cell adhesion molecule (EpCAM). Next nuclear staining
with 4 ',6-diamidino-2-phenylindole (DAPI) and immunofluorescent detection with cytokeratin
and CD45 is performed in 5 patients with leptomeningeal metastases from breast cancer and
approximately 104 circulating tumor cells (CTCs)in 7,5 ml CSF were found, using this method.
There seemed to be an association between the number of CTCs and response to intrathecal
administered chemotherapy in this small group of patients.

In the future, the determination of CTCs in the CSF could be a new quantitative method for
the anti-tumor response assessment of systemic or intrathecal therapy (as opposed to CSF
cytology, which is subjective and not a quantitative method). If the method shows greater
sensitivity than CSF cytology and can reliably measure single tumor cells, the sensitivity
of CSF examination in patients with a clinical suspicion of LM will increase. Possibly, this
method can also be used to detect micrometastases in the CSF in patients without
neurological symptoms, but with a high risk of CNS metastases.