Indeterminate Cell Histiocytosis: a systematic review of the literature with a comprehensive revision of clinical, histopathological, and molecular features.

Abstract

Indeterminate cell histiocytosis (ICH) is a very rare histiocytic disorder, primarily involving the skin. It affects more frequently adults, often presenting with a generalized papular eruption, and needs to be differentiated from other neoplastic, paraneoplastic, and infectious diseases through clinical and histological examination. The knowledge of ICH is limited to case reports and small series. Thus, the lack of larger multicentric studies has prevented recognizing and addressing the specific clinical need of the entity. In this systematic review, we comprehensively analyzed the medical literature describing histologically-confirmed cases of ICH and divided the patients into epidemiologically and clinically different groups. Doing so, we could demonstrate that ICH in adulthood is strongly associated with the development of hematological (and especially myeloid) neoplasms. In this subset of patients, we identify blastic morphology of neoplastic cells as a novel independent prognostic factor and an early histopathological predictor of an associated myeloid neoplasm. Moreover, we highlighted that even though ICH may also present in childhood, these patients often show indolent behavior. Genetically, ICH emerges as a heterogeneous condition. While patients with associated myeloid neoplasms were enriched in pERK pathway gene mutations, in others a specific ETV3::NCOA2 rearrangement has been described. We finally reviewed the nosology of ICH since its first description, its possible cell of origin, and summarized the therapeutic options reported for each different clinical subgroup. With this work, we hope to foster studies on rare cutaneous histiocytosis and their comprehensive multidisciplinary characterization.