Solid tumors, mostly breast cancer, lung cancer and melanoma, can result in leptomeningeal metastasis (LM) in 5 to 19% of patients . The incidence of central nervous system (CNS) metastasis and LM may increase in the coming years because of a prolonged control of extra-cerebral disease and because of the use of antineoplastic agents with a poor diffusion into the CNS .
The median survival of untreated patients with LM is 4–6 weeks. Breast cancers LM have the best prognosis, and median overall survival may reach 3 to 5 months with a combined treatment in recent studies [3–8]. The aim of treatment is to improve or stabilize neurological functions, maintain quality of life and prolong survival .
Prognostic factors have been identified: age, performance status, neurological status, LM characteristics, cerebrospinal fluid (CSF) block, LM related encephalopathy, extension of systemic disease and its treatment options, interval between diagnosis of primary tumour and LM and type of primary tumour [1, 9]. These factors remain heterogeneous among studies and are not very well validated. LM should be diagnosed in the early stages of the disease to prevent the progression of disabling neurological deficits. The diagnosis is assessed by CSF cytomorphological analysis or by concomitant typical CNS involvement symptoms and gadolinium enhanced magnetic resonance imaging (MRI) signs. CNS signs and symptoms, indicative of LM in more than 90% of patients, may be pleomorphic and are often subtle and difficult to distinguish from other cancer or antineoplastic treatment complications . The specificity of gadolinium-enhanced MRI signs is up to 100% in solid tumors, balanced by a risk of false negative as high as 65% and false positive approaching 10% . Evidence of malignant cells in the CSF is diagnostic of LM. However, in patients ultimately positive for CSF cytology, up to 45% are cytologically negative on initial examination. The sensitivity reaches 80% with a second CSF analysis, but little benefit is obtained from more than two repeated lumbar punctures . Insufficient CSF sampling, collecting CSF at distant site of symptoms and delayed processing have been reported to be sources of error [10–13]. Various biomarkers, such as tumour antigens, molecules involved in extravasation, migration or angiogenesis as well as chemokines [14–18] are under evaluation for their performance in detecting LM. Flow cytometry has been proposed as well as cytomics approaches, especially for CNS haematological involvement [17, 19].
CSF cytomorphology thus remains the gold standard for LM detection, but readout is only qualitative and not quantitative. Besides microscopic enumeration and morphological examination, cellular biomarkers appear promising.
The Veridex CellSearch® technology has been designed for the detection of circulating tumour cells (CTC) in blood from cancer patients and validated for the follow-up and prognosis of breast, prostate, colorectal, and lung cancer [20–22]. We adapted the technique and applied it to detect malignant cells in the CSF of 8 patients with breast cancer LM.