Abstract
Isthmin-1 (ISM-1) is a multifunctional secreted protein expressed in various tissues, exhibiting biological activities that overlap with mast cell functions. To date, no study has demonstrated its expression in mast cells. This study presents the first evidence of ISM-1 immunoreactivity in mast cells and investigates its diagnostic relevance in cutaneous mastocytosis. Thirty-nine patients diagnosed with cutaneous mastocytosis from 2 tertiary centers were retrospectively evaluated. Formalin-fixed paraffin-embedded skin biopsy specimens were immunohistochemically stained using antibodies against ISM-1 and CD117. Expression levels were semiquantitatively scored, and associations with clinical, histopathological, and demographic variables were statistically analyzed. All cases exhibited ISM-1 positivity, with 69.2% demonstrating high expression. Notably, ISM-1 remained highly expressed in 2 cases with low CD117 immunoreactivity. While ISM-1 showed diagnostic sensitivity and specificity comparable to CD117, its distinct nuclear localization provided enhanced morphological clarity for mast cell identification. Cases with high ISM-1 expression showed increased eosinophil counts; however, this trend did not reach statistical significance. These findings suggest that ISM-1 may serve as a complementary immunohistochemical marker for mast cell detection, particularly in diagnostically challenging cases. Moreover, its nuclear staining introduces a novel morphological feature that may improve histopathological assessment of mastocytosis and warrants further investigation in mast cell-associated disorders.