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Reliable detection of leptomeningeal disease has the potential of facilitating the diagnosis of central nervous system (CNS) lymphoma and is important for therapeutic considerations. Currently, the standard diagnostic procedure for the detection of lymphoma in the cerebrospinal fluid is cytopathology. To improve the limited specificity and sensitivity of cytopathology, flow cytometry has been suggested as an alternative. Here, we evaluated multi-parameter flow cytometry in combination with conventional cytopathology in cerebrospinal fluid (CSF) samples from 30 patients with primary CNS lymphoma and seven patients with secondary CNS lymphoma. Overall, in 11 of 37 (29.7%) patients with CNS lymphoma, lymphoma cells were detected in CSF by flow cytometry, while cytopathology was less sensitive displaying unequivocally malignant CSF cells in only seven of all 37 (18.9%) patients. Six (16.2%) patients showed cytopathological results suspicious of lymphoma; however, in only one of these patients, the diagnosis of CSF lymphoma cells could be confirmed by flow cytometry. In primary CNS lymphomas (PCNSL), seven of 30 (23.3%) patients were positive for CSF lymphoma cells in flow cytometry, in contrast to four (13.3%) patients with PCNSL with definitely positive cytopathology. In summary, our results suggest that multi-parameter flow cytometry increases the sensitivity and specificity of leptomeningeal disease detection in CNS lymphomas. Both methods should be applied concurrently for complementary diagnostic assessment in patients with CNS lymphoma. [ABSTRACT FROM AUTHOR]

Diagnosis of central nervous system (CNS) lymphoma depends on histopathology of brain biopsies, because no reliable disease marker in the cerebrospinal fluid (CSF) has been identified yet. B-cell lymphomas such as CNS lymphomas are clonally restricted and express either kappa or lambda immunoglobulin light chains. The aim of this study was to find out a potential diagnostic value of free immunoglobulin light chains released into the CSF of CNS lymphoma patients. Kappa (κ) and lambda (λ) free immunoglobulin light chains (FLC) were measured in CSF and serum samples collected from 21 patients with primary and secondary CNS lymphomas and 14 control patients with different neurologic disorders. FLC concentrations and ratios were compared between patient groups and were further analyzed in correlation with clinical, cytopathological, and radiological findings. FLC concentrations for all patients were lower in CSF when compared to serum. In patients with CNS lymphoma, the FLC ratios in CSF were higher (range 392–0.3) compared to control patients (range 3.0–0.3). Irrespective of cytopathological proven lymphomatous meningitis, in 11/21 lymphoma CSF samples the FLC ratios were markedly above 3.0 indicating a clonally restricted B-cell population. Increased FLC ratios in CSF were found in those patients showing subependymal lymphoma contact as detected in magnetic resonance imaging. In summary, this is the first report demonstrating that a significant proportion of patients with CNS lymphomas display a markedly increased FLC ratio in the CSF. [ABSTRACT FROM AUTHOR]

Simple Summary: Primary central nervous system lymphoma (PCNSL) is an uncommon disease accounting for around 3% of primary CNS tumors. PCNSL exhibits aggressive clinical behavior and has an overall poor prognosis. The clinical presentation is variable, and there are no specific symptoms. Despite progress in radiographic neuroimaging, stereotactic brain biopsy remains obligatory for definitive diagnosis. Advanced standard diagnostics, including CSF cytology and flow cytometry, have limited sensitivity. Accordingly, there is an urgent need to improve the diagnostic tools for PCNSL, including novel non-invasive procedures. The aim of this review is to present and discuss modern methods that have the potential to contribute standard clinical diagnostics within the next few years. Primary central nervous system lymphoma is a rare but highly aggressive form of non-Hodgkin lymphoma that remains confined to the CNS neuroaxis. The diagnosis of PCNSL requires a high level of suspicion as clinical presentation varies depending on the involved CNS areas. Neurological symptoms and MRI findings may mimic gliomas, demyelinating lesions, or infectious and granulomatous diseases. Almost all PCNSL patients undergo invasive surgical procedures for definite diagnosis. Stereotactic biopsy is still the gold standard in achieving a diagnostic accuracy of 73–97%. Both the potential procedural morbidity and mortality, as well as the time to definite histopathologic diagnosis resulting in delays of treatment initiation, have to be considered. On the contrary, minimally invasive procedures, such as MRI, CSF cytology, and flow cytometry, still have limited value due to inferior specificity and sensitivity. Hence, novel diagnostic approaches, including mutation analyses (MYD88) in circulating tumor DNA (ctDNA) and the determination of microRNAs (miR-21, miR-19b, and miR-92) as well as cytokine levels (IL10 and IL6) in blood, cerebrospinal fluid (CSF), and vitreous fluid (VRF), move into the focus of investigation to facilitate the diagnosis of PCNSL. In this review, we outline the most promising approaches that are currently under clinical consideration. [ABSTRACT FROM AUTHOR]