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.
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