Optimization of CSF biological investigations for CNS lymphoma diagnosis

Abstract

Diagnosis of lymphoma leptomeningeal dissemination is challenging and relies on a wide array of methods. So far, no consensus biological guidelines are available. This increases the chance of intra-and interpractice variations, despite the shared concern to perform the minimum amount of tests while preserving clinically relevant results. We evaluated a training cohort of 371 cerebrospinal fluid (CSF) samples from patients with putative lymphomatous central nervous system (CNS) localization using conventional cytology (CC), flow cytometry (FCM), molecular clonality assesment by PCR and cytokine quantification (CQ). This led us to propose a biological algorithm, which was then verified on a validation cohort of 197 samples. The samples were classified according to the clinical context and the results of each technique were compared. Using all four techniques was not useful for exclusion diagnosis of CNS lymphoma (CNSL), but they proved complementary for cases with suspected CNSL.This was particularly true for CQ in primary CNSL. Overall, diagnosis can be obtained with a two-step approach. The first step comprises CC and FCM, as results are available quickly and FCM is a sensitive method. Both PCR and CQ can be postponed and performed in a second step, depending on the results from the first step and the clinical context.The proposed algorithm missed none of the CNSL samples of the validation cohort. Moreover, applying this algorithm would have spared 30% of PCR tests and 20% of CQ over a one-year period, without compromising clinical management.

Value of cerebrospinal fluid white cell count and protein level in predicting leptomeningeal involvement by systemic aggressive B‐cell lymphoma

“…Given the prognostic impact, 1,2,7 and availability of MFC analysis for diagnosis of secondary leptomeningeal disease, one would expect MFC to remain the central diagnostic technique for some time. There are, however, emerging data for future directions, including regarding the possible integration of CSF biomarkers, and more recently detection of tumoral DNA by molecular techniques including clonotypic NGS‐MRD into current approaches 23,24 …”

“…There are, however, emerging data for future directions, including regarding the possible integration of CSF biomarkers, and more recently detection of tumoral DNA by molecular techniques including clonotypic NGS-MRD into current approaches. 23,24…”

Detection of clonotypic DNA in the cerebrospinal fluid as a marker of central nervous system invasion in lymphoma

“… 2,3,6,8 , 9,34 Performance of PCR-based IGH clonality assays has been inconsistent, and they have not been adopted to guide clinical decisions. 35-37 The accuracy of other proposed CSF biomarkers such as soluble CD19 or cytokines including the C-X-C motif chemokine ligand 13 (CXCL13) in the absence of gross disease is uncertain. 14,38 Relying on the CNS-IPI for delivery of CNS prophylaxis leads to both undertreatment (with half of relapses occurring among untreated patients with low or intermediate risk) and overtreatment, as >90% of high-risk patients did not experience a CNS relapse in a large clinical trial and in a retrospective cohort of >1000 individuals with DLBCL selected for CNS-directed therapy.…”

Combining MYD88 L265P mutation detection and clonality determination on CSF cellular and cell‐free DNA improves diagnosis of primary CNS lymphoma

“…They were part of the French oculo‐cerebral lymphoma (LOC) registry 32,33 . Most of them were part of a larger cohort previously published 18 . The study was approved by the local ethics review committee, and informed consent was obtained from the patients.…”

“…The benefit of these molecular assays is somehow hampered by the small quantity or the absence of tumour cells present in the CSF. Indeed, the tumour cells in PCNSL are often in small quantity or absent thus leading to frequent negative results 18 . Quantification of cytokines such as interleukin‐10 (IL‐10) and IL‐6 has been shown to provide useful complementary biomarkers: an increased IL‐10 CSF level and IL‐10 /IL‐6 ratio allow to discriminate PCNSL from other neurologic diseases, 19,20 independent or not of the presence of tumour cells.…”