Department of Obstetrics and Gynaecology, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Department of Histopathology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Int J Cancer. 2019 Feb 1;144(3):641-650. doi: 10.1002/ijc.31913. Epub 2018 Nov 20.
Obesity is the strongest risk factor for endometrial cancer (EC). To inform targeted screening and prevention strategies, we assessed the impact of obesity and subsequent bariatric surgery-induced weight loss on endometrial morphology and molecular pathways implicated in endometrial carcinogenesis. Blood and endometrial tissue were obtained from women with class III-IV obesity (body mass index ≥40 and ≥50 kg/m , respectively) immediately prior to gastric bypass or sleeve gastrectomy, and at two and 12 months' follow up. The endometrium underwent pathological examination and immunohistochemistry was used to quantify proliferation (Ki-67), oncogenic signaling (PTEN, pAKT, pERK) and hormone receptor (ER, PR) expression status. Circulating biomarkers of insulin resistance, reproductive function and inflammation were also measured at each time point. Seventy-two women underwent bariatric surgery. At 12 months, the mean change in total and excess body weight was -32.7 and -62.8%, respectively. Baseline endometrial biopsies revealed neoplastic change in 10 women (14%): four had EC, six had atypical hyperplasia (AH). After bariatric surgery, most cases of AH resolved (5/6) without intervention (3/6) or with intrauterine progestin (2/6). Biomarkers of endometrial proliferation (Ki-67), oncogenic signaling (pAKT) and hormone receptor status (ER, PR) were significantly reduced, with restoration of glandular PTEN expression, at 2 and 12 months. There were reductions in circulating biomarkers of insulin resistance (HbA1c, HOMA-IR) and inflammation (hsCRP, IL-6), and increases in reproductive biomarkers (LH, FSH, SHBG). We found an unexpectedly high prevalence of occult neoplastic changes in the endometrium of women undergoing bariatric surgery. Their spontaneous reversal and accompanying down-regulation of PI3K-AKT-mTOR signaling with weight loss may have implications for screening, prevention and treatment of this disease.
肥胖是子宫内膜癌（EC）最强的风险因素。为了提供靶向筛查和预防策略，我们评估了肥胖及其随后的减重手术诱导的体重减轻对子宫内膜形态和涉及子宫内膜癌变的分子途径的影响。在胃旁路或袖状胃切除术前，以及术后 2 个月和 12 个月时，从患有 III-IV 类肥胖（体重指数分别≥40 和≥50kg/m ）的女性中获得血液和子宫内膜组织。对子宫内膜进行病理检查，并使用免疫组织化学定量增殖（Ki-67）、致癌信号（PTEN、pAKT、pERK）和激素受体（ER、PR）表达状态。还在每个时间点测量了胰岛素抵抗、生殖功能和炎症的循环生物标志物。72 名女性接受了减重手术。在 12 个月时，总体重和超重体重的平均变化分别为-32.7%和-62.8%。基线子宫内膜活检显示 10 名女性（14%）发生了肿瘤性变化：4 名患有 EC，6 名患有不典型增生（AH）。减重手术后，大多数 AH 病例（6 例中的 5 例）无需干预（3 例）或宫内孕激素（2 例）即可解决。子宫内膜增殖（Ki-67）、致癌信号（pAKT）和激素受体状态（ER、PR）的生物标志物显著降低，2 个月和 12 个月时，PTEN 表达的腺表达得到恢复。胰岛素抵抗（HbA1c、HOMA-IR）和炎症（hsCRP、IL-6）的循环生物标志物减少，生殖生物标志物（LH、FSH、SHBG）增加。我们发现接受减重手术的女性子宫内膜中存在意外高发的隐匿性肿瘤性变化。它们自发逆转以及随着体重减轻而随之下调的 PI3K-AKT-mTOR 信号可能对这种疾病的筛查、预防和治疗具有重要意义。
