Indeterminate cell histiocytosis (ICH) is a rare and controversial disorder first described by Wood et al1 in 1985. ICH is characterized by a nonepidermotropic histiocytic infiltrate with immunohistochemical features that overlap with Langerhans cells (LCs) and non-LCs of monocyte-macrophage-dendritic cell lineage. 1 It is unclear whether ICH is distinct from Langerhans cell histiocytosis (LCH) or instead represents a variant form of LCH. The gold standard for distinguishing ICH from LCH is demonstration of the absence of Birbeck granules by electron microscopy or, more practically, through use of langerin (CD207) immunohistochemistry (IHC), which is positive in LCH and non-reactive in ICH. 2 Although LCH is understood to be a clonal proliferation, there has not been sufficient support for a common molecular pathway in ICH in the literature to date, leading some authors to consider ICH a reactive condition. Herein, we present 3 cases of ICH with a recurrent ETV3-NCOA2 translocation. This molecularfinding provides evidence that ICH is a true clonal entity deserving of separate classification.

Patient 1 was a 62-year-old woman who presented with a 30-year history of innumerable dome-shaped smooth red and brown papules and nodules scattered diffusely over her face, chest, back, and extremities. Skin biopsy demonstrated a dermal infiltrate of mononuclear histiocytes highlighted by CD1a and CD68 without langerin reactivity. Scattered mature lymphocytes and rare eosinophils were intermixed. S100 was positive in 5% of the histiocytic infiltrate. Electron microscopy confirmed the absence of Birbeck granules. Targeted next-generation sequencing was performed by Foundation Medicine (Cambridge, MA) using the previously described FoundationOne assay, 3 and it revealed an ETV3-NCOA2 gene fusion characterized as 5!-ETV3 (x1-4) 1 NCOA2 (x14-23)-3! resulting in an aberrant NCOA2. Other aberrant mutations, including those involving the RAS-RAF-MEK pathway, were not found. BRAF V600E IHC was negative. Fluorescence in situ hybridization (FISH) for the ETV3-NCOA2 translocation was positive (Figure 1, inset).