An Anaplastic Lymphoma Kinase (ALK) Immunohistochemical Pitfall: ALK-positive Histiocytosis versus Angiomatoid Fibrous Histiocytoma

Abstract Introduction/Objective The 5th Edition WHO classification expanded the histiocytic/dendritic cell neoplasms to include ALK-positive histiocytosis, which can present as multisystem or single-site disease, affecting various age groups. These tumors lack high-grade cytologic features but express ALK by immunohistochemistry, typically indicating ALK locus rearrangements. In this case study, a cutaneous mass initially suspected as ALK-positive histiocytosis was found to be angiomatoid fibrous histiocytoma (AFH) with ALK expression, highlighting the potential diagnostic pitfall due to overlapping histomorphology and ALK expression. Methods/Case Report A previously healthy twelve-year-old boy sought evaluation for a growing and ulcerating mass on his left arm, which developed gradually over a year post-injury. Laboratory tests showed elevated inflammatory markers and mild anemia. A biopsy of the ulcer revealed Staphylococcus aureus infection. Initial histological examination revealed mixed inflammatory infiltrates with focal necrosis, prominent histiocytes, and giant cells. Despite favoring an infectious cause, immunostains were performed. AE1/AE3, ERG, CD34, CD30, S100, SOX10, SMA, and MyoD1 were negative, while INI1 was retained. However, ALK was strongly positive in some histiocytoid cells, suggesting ALK-positive histiocytosis. Surgical resection was subsequently performed to manage the abscess and characterize the lesion. Histologic examination revealed a solid nodule containing spindled and epithelioid cells with a bland histiocytoid appearance, arranged in a compact syncytial growth pattern within the dermis and subcutis. Surrounding the tumor, there was a distinct cuffing of fibrosis with organized lymphoplasmacytic cells. Break apart fluorescence in situ hybridization studies showed rearrangement of EWSR1 but not ALK. The diagnosis of angiomatoid fibrous histiocytoma was rendered. Results (if a Case Study enter NA) NA Conclusion This case highlights the importance of understanding immunohistochemical features, especially those that are unusual and unexpected in rare diseases. With the growing use of minimally invasive sampling techniques, this case study underscores the significance of integrating molecular diagnostics with clinical, histological, and immunophenotypic evaluations to achieve an accurate diagnosis in surgical pathology.