Indeterminate DC histiocytosis is distinct from LCH and often associated with other hematopoietic neoplasms

Indeterminate dendritic cell histiocytosis (IDCH) is a rare and poorly understood entity characterized by accumulation of CD1a+/S100+ histiocytes (as Langerhans cell histiocytosis [LCH]) but with reduced-absent expression of Langerin/CD207. We assembled 43 cases of IDCH (defined by CD1a+/CD207<20% immunophenotypic profile) examining the clinical, pathologic, and molecular landscape. Median age at presentation was 70 years (interquartile range, 44-80) with cutaneous (31/43; 72%) and nodal (11/43; 26%) involvement predominating. Eighteen (42%) individuals had an associated nonhistiocytic hematopoietic neoplasm ("secondary" IDCH) whereas 7 of 43 (16%) had a concurrent non-IDCH histiocytosis ("mixed" histiocytosis). Most cases exhibited morphology indistinguishable from LCH but with a CD1c+/CSF1R(CD115)- phenotype, mirroring the signature of normal indeterminate cells and conventional DC type 2. Mutational analysis revealed frequent KRAS (13/32; 41%) and BRAF p.V600E (11/36, 31%) mutations that were nearly mutually exclusive. RNA-sequencing analysis uncovered ETV3::NCOA2 fusion in 6 other patients presenting as a sole genetic alteration without any other concurrent histiocytic or hematopoietic neoplasm. BRAF and MAP2K1 alterations were significantly associated with partial/retained (1%-20%) Langerin expression (P = .005) and mixed histiocytosis (P = .002). Remarkably, myeloid alterations (DNMT3A, TET2, and SRSF2) co-occurred in IDCH tissues of several individuals. Paired sequencing of IDCH and concurrent non-IDCH hematopoietic neoplasm in 4 individuals revealed shared mutations. Age at diagnosis and any nodal involvement at diagnosis predicted inferior overall survival, but BRAF/RAS pathway alterations did not affect outcome. These data have implications for the diagnostic evaluation, classification, and therapeutic management of IDCH.