BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+CD33+CD163+P2RY12-) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20.
Bibliographical noteFunding Information:
The TXCH Histiocytosis Program is supported by a research grant from the HistioCure Foundation. Additional support was received from National Institutes of Health (NIH) grants R01 CA154489 (to M.M. and C.E.A.), CA154947 (to M.M. and C.E.A.), and UL1TR001857 (to J.P.); NIH SPORE in Lymphoma (grant P50CA126752 to C.E.A.); the NIH Alex’s Lemonade Stand Foundation Young Investigator Grant (to R.C.); the American Society of Hematology Scholar Award (to R.C.); and the Stand Up to Cancer–St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) (to N.A. and D.W.P.). This article was a collaborative project with support from St. Baldrick’s Foundation, which sponsors the North American Consortium for Histiocytosis Research (K.L.M., A.K., C.R.-G., P.C., D.W.P., M.M., C.E.A.).
- CNS neoplasms
- Langerhans cell histiocytosis