Résumé
Background: Bing-Neel syndrome (BNS) is a rare complication of Waldenström Macroglobulinemia (WM) defined as the direct involvement of central nervous system (CNS) by neoplastic cells. Because of its rarity, few data are currently available in the literature, which is mostly based on case-reports descriptions. The management of these patients is challenging with no consensus about the best treatment strategies to use.
Patients and Methods: We retrospectively analyzed 37 patients out of 15 French centers databases, treated for a BNS between 1995 and 2014.
Results: At the time of BNS diagnosis, the median age was 64 years. In 13 cases (35%), BNS was the first manifestation of WM. In others cases, median time between WM diagnosis and BNS was 96 months (range 2-300).BNS occurrence was correlated with a systemic progression of WM in 30% of cases. For the others patients with no systemic progression of WM, median time between the end of the last treatment of WM and BNS diagnosis was 30 months (range 10-72). The median IgM level was 11.25 g/L (range 0.35-60.8) at the time of BNS onset.
Clinical manifestations: the most frequent symptoms at the time of BNS diagnosis were cognitive impairment (32%), motor or sensory deficits (30% and 16% respectively), pain (16%), cranial nerves involvement (30%), headache (21%), poor performance status (32%) and cauda equina syndrome (18%). The median interval between appearance of neurological symptoms and diagnosis of BNS was 4 months.
Cerebrospinal fluid (CSF) analysis showed a lymphocytic meningitis in 81% of cases with a median of 33 cells/mm3 (range 7-3900), all with monoclonal B-cell population when phenotyping was available (except one case). Protein level was elevated in 94% (1,77 g/L in median, range 0,52-7,23).
Magnetic resonance imaging (MRI) showed abnormalities in 83% (n=29/35) of cases. Meningeal enhancement was present in 52% of cases with conus medullaris infiltration in half of these patients. Cerebral enhancement was present in 45 % of cases and a normal pressure hydrocephalus in 3 cases. In 17% of cases, MRI was normal.
Based on MRI results and CSF analysis, the majority of patients (81%, n=30/37) had an infiltrative form with only 7 patients presenting with a pseudotumoral involvement of brain parenchyma. The diagnosis was made on CSF analysis in the majority of cases (82%, n= 28/34). In four cases the diagnosis required a brain biopsy.
First-line treatment comprised systemic chemotherapy in 89% (n=33/37) of cases. Treatment of CNS involvement was based on high-dose chemotherapy in 17 cases (methotrexate and/or aracytine). Intra-thecal chemotherapy was used in 70% of cases, and rituximab in 58% of cases. Autologous stem-cell transplantation (ASCT) in first-line was performed in 4 cases. 4 patients were treated up-front by whole-brain radiotherapy (in combination with systemic chemotherapy by fludarabine, cyclophosphamide and rituximab in 1 case).
Outcome: 31 patients were assessable for first-line treatment response: overall response rate (ORR) was 68% (n=21/31) including 7 complete remissions; 7 patients had a progressive disease. 9 patients died. Median follow-up of alive patients was 23 months. At 5 years after BNS diagnosis, 79% of the patients were alive.
Conclusion: Up to now, this is the most important retrospective cohort of patients presenting with Bing-Neel syndrome. In more than one third of the cases, BNS was the first manifestation of WM disease. Noteworthy is the late occurrence of some cases, up to 25 years. No correlation was observed between systemic progression of WM and BNS occurrence. BNS should be considered even in the context of a stable WM disease. In order to define the best treatment strategies, collection of additional cases is currently ongoing, and data will be up-dated at time of the meeting.