Overall Outcomes of Bing-Neel Syndrome after Treatment - a Review of 40 Cases

Background: Bing-Neel syndrome (BNS) or central nervous system (CNS) involvement in Waldenströms macroglobulinemia (WM) is rare and typically results from the infiltration of CNS by neoplastic lympho-plasmacytoid cells. The aim of this study is to present a review of the clinical characteristics, practices for treatment and overall prognosis of BNS. We present the largest systematic review to date of BNS cases reported in the literature.

Material and Methods: A systematic review of PUBMED (http://www.pubmed.gov) was conducted to search for primary articles and case reports under keywords "Bing-Neel syndrome" and "Waldenströms macroglobulinemia", "leptomeningeal", "central nervous system", and "lympho-plasmacytoid cells". The search was extensive, ranging from 1955 to 2014. All adult cases written in English language were included. The search yielded 35 results and was individually examined by two authors. All studies that described hyperviscosity due to WM aside from BNS were excluded. The effect of regimens with high CSF penetration or intrathecal chemotherapy (IT) on overall survival (OS) was analyzed using Kaplan-Meier curves and Wilcoxon test.

Results: This review summarizes the clinical characteristics and treatment modalities for 40 patients with BNS reported in the literature. The mean age at diagnosis was 62 years (range 36-82 years); 37.5% were females and 62.5% were males. Mean time from diagnosis of WM to BNS was 4.8 years, however about 10% (n=4) had neurologic symptoms due to BNS at the time of diagnosis of WM. The longest time from diagnosis of WM to BNS was 17 years. Patients presented with a wide spectrum of neurological symptoms and signs. Most common clinical manifestation was a progressive cognitive decline, seen in 43% (n=17) of patients. Other common presenting symptoms were acute or insidious neurologic deficits, memory impairment, persistent headaches and ataxic gait. Ninety percent of patients (n=36) had an elevated serum IgM (average 7.8 g/L), of which 97% (n=35) had IgM kappa, compared to 3% (n=1) with IgM lambda paraproteinemia. CSF lymphoplasmacytic pleocytosis was present in 89% (n=25/28) of patients, with a mean CSF WBC count of 76/µL at diagnosis. Most commonly these clonal B cells had an immune phenotype profile characterized by CD5+/-, CD10-, CD19+, CD20+, CD79b+, sIgM with light chain restriction (κ/λ). Tissue histology was performed in 55% (n=22/40) of cases and revealed either a diffuse perivascular or tumor like infiltration by small mature lymphocytes or lymphoplasmacytoid cells, immunohistochemically positive for CD20, surface IgM and light chain restriction.

Radiographically, BNS presents either as a pseudo-tumoral form (mass lesions) or diffuse form (infiltration into cerebral parenchyma, cranial/spinal nerves or leptomeninges). Two-thirds (n= 30/40) of all cases presented with a diffuse pattern of CNS involvement, 15% (n=6/40) with pseudo-tumoral form, and 5% (n=2/40) had a combined diffuse and tumoral pattern. Magnetic resonance imaging (MRI) is the most sensitive imaging modality, used for diagnosis in 90% of patients (n=35/40). Characteristic findings on MRI are hyperintensities on T2 weighted imaging (diffuse or localized), increased signal intensity on FLAIR and diffusion weighted imaging with low ADC values.

Mean time from diagnosis to death, reported in 15 publications, was 7 months (range: death during work up-2 years). Twenty patients were alive at last follow-up, with a mean time from diagnosis to last follow-up of 33.2 months (range 3 months - 14 years). Patients treated with multi-agent chemotherapy (R-DHAC, R-DT-PACE, FR,BR) along with IT chemotherapy (MTX or AraC) or CNS penetrating systemic therapy (HD MTX, RHyperCVAD), with or without RT or ASCT (3 patients only) had improved outcomes, with 71% (n=15/21) of such patients reported alive at last follow up (mean follow of 25 months). Median OS in this group was 19.6 months compared to 3.3 months (p=0.045) in patients receiving older systemic chemotherapy alone (cyclophosphamide, 2Cda, chlorambucil etc.), suggesting that CNS penetrating regimens may improve outcomes.

Conclusion: BNS is a rare and aggressive complication of WM. Newer multi-agent chemotherapy combined with CNS penetrating systemic therapy or intra-thecal chemotherapy may improve outcomes. This study highlights an unmet need in this subset of patients with WM.