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

Kenneth L. McClain, Jennifer Picarsic, Rikhia Chakraborty, Daniel Zinn, Howard Lin, Harshal Abhyankar, Brooks Scull, Albert Shih, Karen Phaik Har Lim, Olive Eckstein, Joseph Lubega, Tricia L. Peters, Walter Olea, Thomas Burke, Nabil Ahmed, M. John Hicks, Brandon Tran, Jeremy Jones, Robert Dauser, Michael JengRobert Baiocchi, Deborah Schiff, Stanton Goldman, Kenneth M. Heym, Harry Wilson, Benjamin Carcamo, Ashish Kumar, Carlos Rodriguez-Galindo, Nicholas S. Whipple, Patrick Campbell, Geoffrey Murdoch, Julia Kofler, Simon Heales, Marian Malone, Randy Woltjer, Joseph F. Quinn, Paul Orchard, Michael C. Kruer, Ronald Jaffe, Markus G. Manz, Sergio A. Lira, D. Williams Parsons, Miriam Merad, Tsz Kwong Man, Carl E. Allen

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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.

Original languageEnglish
Pages (from-to)2607-2620
Number of pages14
Issue number12
StatePublished - 15 Jun 2018


  • BRAF-V600E
  • CNS neoplasms
  • Langerhans cell histiocytosis
  • neurodegeneration
  • osteopontin


Dive into the research topics of 'CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions'. Together they form a unique fingerprint.

Cite this