ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis

Abstract

Indeterminate cell histiocytosis (ICH) is a rare and controversial disorder first described by Wood et al 1 in 1985. ICH is characterized by a nonepidermotropic histiocytic infiltrate with immunohistochemical features that overlap with Langerhans cells (LCs) and nonLCs 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 molecular finding 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 59-ETV3(x1-4)1 NCOA2(x14-23)-39 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).Patient 2 was a 51-year-old woman who presented with a severalweek history of diffuse nonpruritic papules involving her arms, legs, neck, scalp, face, chest, and back. Histopathologic examination of a skin biopsy demonstrated a dermal infiltrate composed of mononuclear histiocytes with eosinophilic cytoplasm and admixed mature-appearing lymphocytes. The histiocytes were positive for S100, CD68, and CD1a, whereas langerin and BRAF V600E IHC were negative. FISH testing for the ETV3-NCOA2 translocation was positive (Figure 1).Patient 3 was an 81-year-old man who presented with a solitary lesion on the upper arm which had been present for approximately 6 months. Biopsy showed a multinodular dermal infiltrate of large, oval cells with abundant pale eosinophilic cytoplasm and reniform nuclei. The lesional cells were positive for S100, CD68, and CD1a, whereas langerin and BRAF V600E IHC were negative. FISH testing for the ETV3-NCOA2 translo...

Histiocytic neoplasms in the era of personalized genomic medicine

“…However, no gene fusions had been uncovered in the histiocytic neoplasms until 2015 when 2 studies described gene fusions in BRAF V600E-wild type, non-LCH neoplasms [(8)*, (25)**]. The activating or recurrent gene fusions found in the histiocytoses to date are described below.…”

Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes

“…Other kinase fusions detected in adult patients with histiocytosis NOS lesions include TPR-NTRK1, and 1 patient with a ZNF697-NOTCH2 fusion. Two patients in this data set have been previously reported in other publications: the histiocytosis NOS patient with the BRAF-CLIP2 fusion was also described in the study by Diamond et al (11) and one NOS patient bearing an ETV3-NCOA2 fusion was referenced by Brown et al (15). Our data set, however, includes another adult patient with the diagnosis of LCH who also exhibited the ETV3-NCOA2 fusion, suggesting that this is a recurring gene rearrangement and is not restricted to indeterminate histiocytosis.…”

Diagnosis and classification of hematologic malignancies on the basis of genetics

“…In contrast to LCH and ECD, recent work has also identified fusions of ETV3-NCOA2 in nearly all cases with indeterminate cell histiocytosis identifying a unique genetic hallmark for this histologic entity. 173 …”