Clinical and molecular risk factors for repeat interventions due to symptomatic uterine leiomyomas

• Published in: American journal of obstetrics and gynecology 2025-01, Vol.232 (1), p.110.e1-110.e23
• Main Authors: Khamaiseh, Sara, Äyräväinen, Anna, Arffman, Maare, Reinikka, Siiri, Mehine, Miika, Härkki, Päivi, Bützow, Ralf, Pasanen, Annukka, Vahteristo, Pia
• Format: Article
• Language: English
• Subjects: Adult; Cohort Studies; Female; Fumarate Hydratase - genetics; HLRCC; HMGA2; Humans; Kaplan-Meier Estimate; Laparoscopy; Leiomyoma - genetics; Leiomyoma - surgery; MED12; Mediator Complex - genetics; Middle Aged; Mutation; myomectomy; Proportional Hazards Models; Reoperation; Retrospective Studies; Risk Factors; Uterine Myomectomy; Uterine Neoplasms - genetics; Uterine Neoplasms - surgery; YEATS4
• ISSN: 0002-9378; 1097-6868; 1097-6868
• DOI: 10.1016/j.ajog.2024.06.051

Repeat leiomyoma occurrence or even reintervention is common after myomectomy. Little is known about the factors related to repeat interventions. This study aimed to determine the frequency of leiomyoma-related reintervention after an initial laparoscopic or abdominal myomectomy and to analyze both clinical and molecular risk factors for reinterventions. Another objective was to define the frequency of clonally related tumors from repeat operations. This retrospective cohort study included 234 women who had undergone laparoscopic or abdominal myomectomy in 2009 to 2014. Information on repeat leiomyoma-related interventions as well as on other clinical factors was collected from medical records after a median follow-up time of 11.4 years (range 7.9–13.8 years) after the index procedure. The effect of clinical risk factors on the risk of reintervention was analyzed by the Kaplan-Meier estimator and the Cox proportional hazards model. For molecular analyses, we examined the mutation profiles of 133 formalin-fixed paraffin-embedded leiomyoma samples from 33 patients with repeat operations. We screened the tumors for the 3 primary leiomyoma driver alterations—mediator complex subunit 12 mutations, high mobility group AT-hook 2 overexpression, and fumarate hydratase-deficiency—utilizing Sanger sequencing and immunohistochemistry. To further assess the clonal relationship of the tumors, we executed whole-exome sequencing for 52 leiomyomas from 21 patients who exhibited the same driver alteration in tumors obtained from multiple procedures. Reintervention rate at 11.4 years after myomectomy was 20% (46/234). Number of leiomyomas removed at the index myomectomy was a risk factor (hazard ratio 1.21; 95% confidence interval 1.09–1.34). Age at index myomectomy (hazard ratio 0.94; 95% confidence interval 0.89–0.99) and postoperative parity (hazard ratio 0.23; 95% confidence interval 0.09–0.60) were protective factors. Molecular characterization of tumors from index and nonindex operations confirmed a clonal relationship of the tumors in 3/33 (9%) patients. None of the leiomyomas harboring a mediator complex subunit 12 mutation—the most common leiomyoma driver—were confirmed clonally related. Fumarate hydratase-deficiency was detected in repeat leiomyomas from 3/33 (9%) patients. All these patients harbored a germline fumarate hydratase mutation, which is distinctive for the hereditary leiomyomatosis and renal cell cancer syndrome. Finally, we identified 3 (3/33; 9%) pa