MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome

Abstract

SummaryBing-Neel syndrome (BNS), a rare neurological syndrome associated with Waldenstr€ om macroglobulinaemia (WM), is a direct involvement of the central nervous system by lymphoplasmacytoid cells characterized with an adverse prognostic. The MYD88 L265P mutation has been identified in the vast majority of patients with WM. The diagnosis of BNS is often challenging because of the variety of clinical presentations associated with difficult histological techniques. We hypothesized that identification of MYD88 L265P mutation in the cerebrospinal fluid (CSF) would contribute to the diagnosis of BNS in addition to imaging, flow cytometry and cytology. We identified MYD88 L265P mutation in the CSF and the bone marrow of all cases of BNS using quantitative polymerase chain reaction qPCR and Sanger sequencing. Copy neutral loss of heterozygosity including MYD88 was observed in one case. No mutation of CXCR4, CD79A and CD79B was observed in parallel. We further showed that monitoring the quantitative expression of MYD88 L265P mutation might be a useful molecular tool to monitor response to chemotherapy using qPCR. In conclusion, identification of MYD88 L265P mutation might be a new molecular-based biomarker tool to add to the diagnostic and monitoring armamentarium for BNS.

Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome

“…Using a highly sensitive real time quantitative PCR (qPCR) technique, it has been demonstrated that MYD88 L265P can be detected in the CSF of BNS patients, and the mutation was also present in the CNS biopsy in one patient. 4,18,26 Moreover, disappearance of the MYD88 L265P by AS-PCR correlated with clinical and MRI response. Since the qPCR is a very sensitive technique, caution must be taken to avoid blood contamination of the CSF since MYD88 L265P can also be detected in peripheral blood.…”

“…15,16 MFC analysis demonstrating B-cell or plasma-cell markers with light chain restriction is essential for establishing tumor clonality. 17,18 MFC should be performed as soon as possible because of the potential for rapid decay of viable cells in native CSF. A cell-stabilizing agent, such as TransFix, may enhance the detection of B-cell clones in the CSF by preventing cellular decay.…”

“…18,20,21 If there is no blood-brain barrier disruption, the presence of an IgM M-protein in the CSF with the same light chain restriction as the LPC in the BM and correlation with the serum M-protein may be indicative of the presence of LPC in the leptomeninges. 22 However, in the case of increased permeability of the blood-brain barrier, IgM proteins may diffuse from the blood into the CSF and do not reflect the presence of LPC in the CNS.…”

“…35 Sanger sequencing of cells obtained from CSF and BM of 3 BNS patients did not identify CXCR4 mutations, though detection of these mutations by Sanger may have been outside the limits of detection. 18 Further studies, including the use of the more sensitive AS-PCR to detect nonsense mutations or high depth targeted re-sequencing may help identify CXCR4 mutations in LPC from CSF in WM patients with BNS.…”

“…Serial quantitative measurement of the CSF cellular compartment for MYD88 L265P mutation by qPCR has not been examined, but may represent a promising technology given its ability to detect changes in systemic WM disease. 18,48 The task force therefore proposes the following response criteria:…”