Clinical Trajectories and MRI-Based Triage of Uterine Leiomyoma Molecular Subtypes: A Large-Scale Retrospective Analysis of 720 Genotyped Tumors.

Abstract

Uterine leiomyomas are genetically heterogeneous, yet the clinical and prognostic implications of their primary molecular drivers remain poorly integrated into surgical practice. This study aims to characterize the clinical phenotypes and pharmacogenomic responses of major molecular subtypes and evaluate the predictive value of T2-weighted magnetic resonance imaging (T2WI) for surgical prognosis. We enrolled premenopausal women who underwent myomectomy or hysterectomy at the Department of Gynaecology, the First Affiliated Hospital of Zhengzhou University from January 2019 to June 2025. All leiomyomas were molecularly genotyped as MED12-mutant, HMGA2-overexpressing, FH-deficient, or triple-negative (3X, not belonging to the MED12-mutant, HMGA2-overexpressing, or FH-deficient genotypes). First, clinical and morphological characteristics were compared across the full cohort (n = 720). Second, a pharmacogenomic subset of patients receiving pre-operative gonadotropin-releasing hormone agonist (GnRHa) (n = 84) was analyzed for genotype-specific volume reduction. Third, a subset of 502 patients receiving myomectomy and completing a follow-up of more than 12 months was analyzed for genotype-specific re-intervention risk. Finally, an imaging "gold standard" consisting of 461 patients with pre-operative magnetic resonance imaging (MRI) and long-term follow-up post-myomectomy was used to assess surgical re-intervention rates via Kaplan-Meier estimators. HMGA2 tumors were most likely to be solitary and submucosal (FIGO type 0-2), while FH-deficient cases showed the highest rates of multiple tumors (≥5). MED12-mutant tumors demonstrated significantly lower GnRHa-induced volume reduction compared to 3X variants (P = 0.009). The FH group exhibited the highest surgical re-intervention rate, a trend that was even more pronounced after excluding patients receiving post-operative GnRHa. MRI analyses revealed that low T2WI signal intensity was highly specific for MED12 mutations, whereas a "mixed high" signal was prognostically indicative for FH deficiency and correlated with a higher surgical re-intervention rate. Molecular subtypes of uterine leiomyomas dictate distinct clinical behaviors. MED12 mutations predict hormonal therapy resistance, while FH deficiency signals aggressive recurrence. A T2-weighted MRI-based classification system showed some phenotype-genotype relationships, although these findings require validation in independent cohorts.