Uterine cellular leiomyoma with a novel HMGA2::PLCZ1 fusion and aberrant cyclin D1 expression: expanding the molecular spectrum and highlighting a diagnostic pitfall

We describe the case of a 41-year-old woman undergoing hysteroscopic resection of a submucosal uterine mass, histologically consistent with a cellular leiomyoma. Immunohistochemistry showed diffuse cyclin D1 expression, an unexpected finding in leiomyomas and typically seen in high-grade endometrial stromal sarcomas. Targeted RNA sequencing revealed a novel HMGA2::PLCZ1 fusion transcript, not previously described in leiomyomas or other tumors. Given the known role of HMGA2 in regulating cyclin D1 transcription, this mechanism may plausibly account for the aberrant immunoprofile, although cyclin D1 expression has not been systematically evaluated in cellular leiomyomas. This case brings forward two key considerations: (i) cyclin D1 expression may, in rare cases, reflect HMGA2 rearrangements in leiomyomas; (ii) cyclin D1 positivity alone should not prompt misdiagnosis of high-grade endometrial stromal sarcoma, particularly in fragmented hysteroscopic specimens. To our knowledge, this is the first report of an HMGA2::PLCZ1 rearrangement, expanding the molecular spectrum of uterine smooth muscle tumors. This case also emphasizes the biological link between HMGA2 activation and cyclin D1 overexpression, providing new insights into the molecular mechanisms underlying uterine smooth muscle tumorigenesis.