ALK1-Negative Epithelioid Histiocytoma: Lessons From a Rare Case

Abstract: Epithelioid cell histiocytoma (ECH) has been previously classified as a rare variant of fibrous histiocytoma (FH). The epithelioid nature of this lesion imitates the appearance of neoplastic lesions such as melanocytic, dermatofibroma/histiocytoma, non-Langerhans histiocytosis such as reticulohistiocytoma, atypical fibroxanthoma, and rhabdomyosarcoma. Most ECH cases are characterized by Anaplastic lymphoma kinase (ALK) protein rearrangement and overexpression. ALK has several fusion partners, the most common being Sequestosome 1 (SQSTM1) which produces proteins involved in signal transduction and autophagy. A recent detection of ALK protein expression and/or ALK gene rearrangement in ECH suggests that it may be biologically different from conventional FH. The epithelioid nature of the lesion in this case imitates the appearance of neoplastic lesions such as melanocytic, dermatofibroma/histiocytoma, non-Langerhans histiocytosis such as reticulohistiocytoma, atypical fibroxanthoma, and rhabdomyosarcoma. Owing to the unusual morphology and aberrant immunohistochemical staining pattern, the sample was analyzed through next-generation sequencing (NGS), which showed the presence of a fusion of genes Sequestosome 1 (SQSTM1) and Anaplastic lymphoma kinase (ALK). SQSTM1 gene produces proteins involved in signal transduction pathways and autophagy, whereas ALK mainly serves the role of cellular communication and development. The most well-known ALK fusion partners include SQSTM and Vinculin (VCL). The spectrum of neoplasms produced through these fusions is wide as seen in lung adenocarcinoma and renal cell carcinoma (EML4-ALK), epithelioid histiocytoma (SQSTM1::ALK and VCL-ALK), and pediatric renal cell carcinoma (VCL-ALK) among others. We hope this case is a helpful addition to the literature to further aid diagnoses of future ALK fusion cases.