CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions

Identification: Eckstein, Olive


CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions
Olive S. Eckstein1, Kenneth L. McClain1, Jennifer Picarsic2, Rikhia Chakraborty1 PhD, Carl E. Allen1* - Additional authors/affiliations omitted here due to limits on length of submission
1Texas Children's Cancer and Hematology Centers, Department of Pediatrics Baylor College of Medicine, Houston, TX; 2Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
*Corresponding Author: Carl E. Allen, MD, PhD
Introduction: Langerhans cell histiocytosis brain involvement (CNS LCH) may include mass lesions and/or a neurodegenerative syndrome (LCH-ND) of unknown etiology. This study aimed to define mechanisms of pathogenesis that drive CNS LCH. Methods: Cerebral spinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS LCH lesions compared to patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMC) as well as brain biopsies from LCH-ND patients, and 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 to 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+ PBMC were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCHND. 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 four patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. Conclusions: In LCH-ND patients, BRAFV600E+ cells in PBMC 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.


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