背景:子宫肌瘤切除术后重复发生或甚至再次干预是常见的。对与重复干预有关的因素知之甚少。
目的:本研究旨在确定初次腹腔镜或开腹子宫肌瘤切除术后平滑肌瘤相关再干预的频率,并分析再干预的临床和分子风险因素。另一个目的是确定来自重复手术的克隆相关肿瘤的频率。
方法:这项回顾性队列研究包括2009-2014年接受腹腔镜或开腹子宫肌瘤切除术的234名妇女。在索引程序后的中位随访时间为11,4年(范围为7,9-13,8年)后,从病历中收集了与平滑肌瘤相关的重复干预措施以及其他临床因素的信息。通过Kaplan-Meier估计器和Cox比例风险模型分析临床危险因素对再干预风险的影响。对于分子分析,我们检测了33例重复手术患者的133例福尔马林固定石蜡包埋的平滑肌瘤样本的突变谱.我们筛选了三种原发性平滑肌瘤驱动改变-MED12突变的肿瘤,HMGA2过表达,和FH缺乏利用Sanger测序和免疫组织化学。为了进一步评估肿瘤的克隆关系,我们对来自21例患者的52例平滑肌瘤进行了全外显子组测序,这些患者在多次手术获得的肿瘤中表现出相同的驱动改变.
结果:子宫肌瘤切除术后11、4年的再干预率为20%(46/234)。在索引子宫肌瘤切除术中切除的平滑肌瘤数量是一个危险因素(风险比1.21;95%置信区间1.09-1.34)。子宫肌瘤切除术的年龄(风险比0.94;95%置信区间0.89-0.99)和术后均等(风险比0.23;95%置信区间0.09-0.60)是保护因素。来自索引和非索引手术的肿瘤的分子表征证实了3/33(9%)患者中肿瘤的克隆关系。没有一个带有MED12突变的平滑肌瘤-最常见的平滑肌瘤驱动者-被证实是克隆相关的。在3/33(9%)患者的重复平滑肌瘤中检测到FH缺乏。所有这些患者都有生殖系FH突变,这是独特的遗传性平滑肌瘤和肾细胞癌(HLRCC)综合征。最后,我们确定了三名(3/33;9%)患有两种肿瘤的患者,每种肿瘤在最近发现的新型平滑肌瘤驱动基因中显示体细胞突变,YEATS4.所有YEATS4突变是不同的,因此肿瘤不是克隆相关的。
结论:我们的研究表明,手术子宫肌瘤切除术后再干预是常见的。子宫平滑肌瘤通常独立发展,但有些人有克隆起源.重复平滑肌瘤的发生可能是由于遗传易感性,例如种系FH突变。在同一患者的多发性平滑肌瘤中发现的不同体细胞YEATS4突变表明YEATS4在重复平滑肌瘤中可能发挥作用。
BACKGROUND: Repeat leiomyoma occurrence or even reintervention is common after
myomectomy. Little is known about the factors related to repeat interventions.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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%) patients with 2 tumors each displaying somatic mutations in a recently identified novel leiomyoma driver gene, YEATS domain-containing protein 4. All YEATS domain-containing protein 4 mutations were different and thus the tumors were not clonally related.
CONCLUSIONS: Our study shows that reintervention is common after surgical
myomectomy. Uterine leiomyomas typically develop independently, but some share a clonal origin. Repeat leiomyoma occurrence may be due to genetic predisposition, such as a germline fumarate hydratase mutation. Distinct somatic YEATS domain-containing protein 4 mutations identified in multiple leiomyomas from the same patient indicate a possible role for YEATS domain-containing protein 4 in repeat leiomyomas.