Non-langerhans cell histiocytosis: A growing category of emerging entities

Histiocytoses are uncommon and comprise a diverse group of disorders of myeloid-derived cells with a macrophage or dendritic cell phenotype. They encompass a large number of subtypes, including Langerhans cell histiocytosis (LCH) and non-LCH. LCH is most common and perhaps best understood. The non-LCH in the current World Health Organization Classification of Hematolymphoid Tumors (WHO-HAEM5) includes Erdheim-Chester disease, juvenile xanthogranuloma, Rosai-Dorfman disease, ALK⁺ histiocytosis, and histiocytic sarcoma. Due to the rarity of non-LCH, there is a lack of awareness, knowledge and experience among general pathologists in the diagnosis of these entities, often resulting in significant delays or even misinterpretation. These histiocytic neoplasms also exhibit clinical, pathological and molecular heterogeneity. Given that these neoplasms all resemble histiocytes to some degree, there is substantial morphologic overlap between these entities, reactive histiocytes, and some non-histiocytic neoplasms. The diagnostic process can be further complicated by unusual morphologic features, such as epithelioid and spindle cell cytology, a marked inflammatory reaction, and prominent fibrosis. Beginning in 2010 with the discovery of BRAF mutations in LCH, our biologic understanding of histiocytic neoplasms greatly expanded with recognition of the importance of the mitogen activated protein kinase (MAPK) pathway in pathogenesis. The biologic spectrum of histiocytic neoplasms continues to expand, in large part driven by discovery of novel molecular genetic aberrations, suggesting that additional non-LCH or modifications to the classification of these entities may be included to future editions of the WHO classification. In this article, we systemically review the clinicopathologic and molecular genetic features of each type of non-LCH. We also provide differential diagnoses and diagnostic algorithms to assist pathologists in establishing the diagnosis of these entities.