ALK-Positive Histiocytosis and its Distinctive Manifestation in the Breast

Abstract Introduction/Objective ALK-positive histiocytosis (APH) is a rare histiocytic proliferation disease that harbors ALK rearrangements, often involving fusion with KIF5B. Primary cases in the unilateral breast are exceptionally uncommon, with only a few reported cases globally, characterizing it as a unique histiocytic proliferation disorder. Methods/Case Report In our study, we report a case of unilateral multifocal breast involvement of ALK-positive histiocytosis following bilateral breast core biopsies in a 56-year-old Hispanic woman who presented with bilateral breast masses. Right breast imaging demonstrated multiple nodular densities, further characterized on ultrasound as a hypoechoic region of 8 cm with increased vascularity. On right breast biopsy, prominent proliferation of histiocytes (lacking high-grade cytologic atypia) with chronic inflammation, few giant cells, and focal cholesterol clefts were identified. On immunohistochemical studies, the lesional cells were variably positive for histiocytic markers CD68, CD163, and PU.1 and were negative for S100 and pancytokeratin. ALK1 showed multifocal staining in the lesional cells as confirmed on repeat study; however, ALK (D5F3), GMS and acid fast studies were negative. The presence of focal cholesterol clefts, scattered giant cells, and chronic inflammation lead us to consider aberrant ALK expression in a reactive process. However, APH was definitively diagnosed through confirmation of clonal histiocyte proliferation, observed findings on morphology, immunophenotyping, and the presence of KIF5B-ALK gene fusion as detected by comprehensive solid tumor fusion panel testing. Results (if a Case Study enter NA) NA Conclusion It is noteworthy that ALK-positive histiocytosis can occasionally present alongside features of a reactive process in the breast. Therefore, considering any history of prior surgery or trauma at the lesion site is crucial. However, we recommend a comprehensive approach in most cases, which includes morphological, immunohistochemical, and molecular analysis on all suspected histiocytosis cases. This approach aims to increase awareness and detection of this rarely described entity and to precisely distinguish it from other diseases for prognostic and therapeutic purposes.