Fisch AS, Laklouk I, Nakaguro M, et al. - Given a heterogeneous group of molecular changes driving neoplasia has been revealed in early studies of intraductal carcinoma (IC), and recent investigations have characterized three primary morphological/immunohistochemical variants, subsequently connecting these morphologic variants with defined molecular signatures, researchers herein applied a novel strategy, focusing mainly on six cases of IC with NCOA4-RET gene rearrangement as ascertained via next-generation sequencing, and reporting the range of clinicopathologic findings within that molecularly-defined group, among them a unique link between the NCOA4-RET fusion and hybrid variant IC and the first case of IC originating in association with a pleomorphic adenoma. Histological and immunohistochemical overlap of RET-rearranged IC with the more broadly known secretory carcinoma was evident, including low-grade morphology, a lumen-forming or microcystic growth pattern, and co-expression of S100, SOX10, and mammaglobin, findings undoubtedly resulting in misdiagnosis. Overall, experts suggest a diagnostic algorithm that combines histological elements, including atypia and invasiveness, and the possibility of specific molecular changes to enhance diagnostic precision in what can be a very subtle diagnosis with crucial clinical implications.