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

Abstract

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.

Striatal Involvement in Neurodegenerative Langerhans Cell Histiocytosis

“…However, he also received multiple lines of chemotherapy and any or a combination of these treatments can for that reason not be excluded as a cause of the increased striatal susceptibility. The treatments for LCH‐ND that this patient received were tested in small research cohorts . Therefore, little is known about their exact effects and side effects.…”

“…The treatments for LCH-ND that this patient received were tested in small research cohorts. 2,6,7 Therefore, little is known about their exact effects and side effects. As far as we know, increased striatal susceptibility has not been described as a side-effect of any of the received treatments, but more research on the treatments for LCH-ND is necessary to validate this.…”

“…Thus far, it is assumed that this neurodegeneration results from paraneoplastic inflammation. However, recent data have shown that LCH‐ND may result from direct brain infiltration by myeloid/monocytic cells, harboring the BRAF mutation, that cause an active demyelinating process . LCH‐ND can clinically express itself in various ways, ranging from movement disorders to cognitive and behavioral problems, depending on the brain structures involved.…”

Langerhans cell histiocytosis: progress and controversies

“…Earlier studies detected CD8 + T cells but not CD207 + histiocytes in biopsied lesions, suggesting an autoimmune phenomenon (Grois et al, 2005). More recently, migration of BRAF V600E-positive myeloid cells to particular regions of the brain via perivascular accumulation and parenchymal infiltration has also been found (McClain et al, 2018). Elucidating the pathogenesis and specific aetiology of LCH-ND will be critical to defining appropriate targets and trial design for experimental interventions.…”

“…Progressive neurodegeneration (LCH‐ND) develops in 5% of patients with LCH (McClain et al , ). Often severe and debilitating, the diagnosis is made by typical signal changes in the brain stem, basal ganglia, and cerebellum on neuroimaging, together with some neurological symptoms, such as ataxia, dysarthria, dysmetria, cognitive problems and behavioural abnormalities.…”