中国Peutz-Jeghers综合征女性患者妇科疾病诊治现状调查

石月, 陈奕清, 丁景新, 宁燕, 汪清, 马凤华, 谭灏文, 康玉

  1. 1.复旦大学附属妇产科医院妇科肿瘤科,上海 200090
    2.复旦大学上海医学院临床医学院,上海 200032
    3.江西合因教育科技有限公司,江西 赣州 342604
  • 收稿日期:2022-10-12 修回日期:2022-11-16 出版日期:2022-11-30 发布日期:2022-12-14
  • 通信作者: 康玉
  • 作者简介:石月(ORCID: 0000-0003-3213-3863),博士,主治医师;
    陈奕清(ORCID: 0000-0003-0374-4059),博士。
    康玉,医学博士,主任医师,博士研究生导师,复旦大学附属妇产科医院临床研究中心办公室主任,复旦大学附属妇产科医院Ⅰ期临床试验病房负责人,遗传性妇科肿瘤诊疗和预防团队首席专家。获教育部科技发明二等奖、教育部科技进步二等奖、中华医学奖三等奖,以及上海医学科技奖三等奖3次。获“上海市科技启明星”称号,上海市卫生系统第十四届“银蛇奖”,第十七届“明治生命科学奖”,上海卫生系统优秀学科带头人,Gynecologic Oncology杂志编委。
    第一联系人:

    石月和陈奕清为共同第一作者。

  • 基金资助:
    上海申康医院发展中心临床科技创新项目(SHDC12020108);上海市老龄化和妇儿健康研究专项(2020YJZX0202)

摘要/Abstract

摘要:

背景与目的:Peutz-Jeghers综合征(Peutz-Jeghers syndrome,PJS)相关的妇科疾病包括小叶状子宫颈内膜腺体增生(lobular endocervical glandular hyperplasia,LEGH)、子宫颈胃型腺癌(gastric type adenocarcinoma of the uterine cervix,GAS)和卵巢环状小管性索肿瘤(sex cord tumor with annular tubules,SCTAT)等。特别是LEGH发病早,疾病进展为GAS快,早诊困难,预后不佳,为患者诊治带来了巨大挑战。目前相关研究数据,尤其是在中国进行的临床研究有限。本研究旨在调查中国PJS患者妇科相关疾病的临床表现、患病情况、健康筛查及诊治现状,以期帮助指导早筛早诊,为PJS女性妇科疾病,特别是为恶性肿瘤的诊治和预后预测提供可靠的临床依据。方法:基于目前妇科临床PJS患者诊疗现状、患者反馈,结合文献阅读设计针对性调查问卷,并于2022年3月26日—2022年7月29日发放,以有效填写的患者为调查对象,统计患者的一般情况、既往史、家族史、妇科临床表现和诊疗情况。对各项目进行分层分析以找出相关高危因素保护因素及诊疗欠缺之处。结果:本调查共回收有效问卷154份,根据入组和排除标准剔除5份,149例患者中114例(76.51%)具有妇科临床症状,主诉多为异常子宫出血(55.70%),近一半(41.61%)患者诉阴道排液。不到一半(47.65%)的患者接受过子宫颈筛查,人乳头状瘤病毒(human papilloma virus,HPV)阳性率低(7.04%)。约1/3(36.91%)的患者接受过基因检测,52例(94.5%)的患者存在STK11突变,其中64.52%系蛋白截断突变,但在癌症和癌前病变发病率及发病年龄上差异无统计学意义。胚系突变遍布整个基因,但未发现位于非编码的9号外显子(E9)上的突变,突变发生率最高为E7(25.81%)。本研究中,无亲缘关系的患者携带相同突变,其发病年龄和疾病谱完全不同。因妇科肿瘤接受手术的患者中,1/3出现了女性生殖道多部位同步胃型黏液性病变(synchronous mucinous metaplasia and neoplasia of the female genital tract,SMMN-FGT)。GAS患者中不到一半的患者得到了及时干预和规范化手术治疗,73.33%的患者接受了术后辅助治疗。40%的患者术前完成生育,0例接受植入前遗传学检测(preimplantation genetic testing,PGT)。结论:本研究聚焦中国PJS女性妇科临床表现及相关诊治现状,发现子宫异常出血、阴道排液作为主要临床症状存在于一半的PJS女性中,发生年龄显著左移。蛋白截断突变作为队列中主要突变类型,与临床表型无相关性,并不影响其癌症风险及发病年龄。携带相同突变的无亲缘关系女性疾病发生情况完全不同,证明环境因素极大地影响PJS患者的疾病外显率。中国PJS女性群体未建立起遗传咨询和妇科健康筛查意识,基因检测普及度低,不到一半罹患妇科肿瘤的患者接受标准手术和辅助治疗。罹患妇科肿瘤的PJS患者普遍生育率低,极少接受PGT。这主要由于临床对于PJS的认知度局限,遗传咨询普及度低,干预不及时,使得PJS患者,尤其罹患妇科肿瘤的PJS女性患者失去了优生优育的机会。

关键词: 黑斑息肉综合征, STK11基因, 妇科肿瘤, 小叶状子宫颈内膜腺体增生, 子宫颈胃型腺癌, 蛋白截断突变

Abstract:

Background and purpose: Peutz-Jeghers syndrome (PJS)-related diseases in female reproductive system include lobular endocervical glandular hyperplasia (LEGH), gastric type adenocarcinoma of the uterine cervix (GAS) and sex cord tumor with annular tubules (SCTAT), etc. In particularly, PJS-related LEGH has an early age-onset, and the disease could progress rapidly to GAS. Early diagnosis is difficult, and the prognosis has been proved poor, which brings great challenges to the diagnosis and treatment of patients. Research data are limited, especially in China. The purpose of this study was to investigate the clinical manifestations, disease pattern, related risk factors, and the status of disease screening, management of gynecological diseases in Chinese PJS patients, providing more clinical evidence and helping with the early screening and early diagnosis of gynecological diseases, especially malignant diseases in female PJS patients. Methods: Based on the status of management of gynecological diseases in female patients with PJS and patients’ feedback, our questionnaire was designed and launched from March 26th, 2022 to July 29th, 2022. The general condition, past family history, past medical history, gynecological clinical manifestations and management of the patients were investigated. A stratified analysis of each item was conducted to find out the high-risk factors and protective factors associated. Results: A total of 154 valid questionnaires were recruited in our study, and 5 patients were excluded according to the inclusion/exclusion criteria. 114/149 patients (76.51%) had gynecological symptoms, and the main complaint was abnormal uterine bleeding (83 patients, 55.70%), nearly half of them had vaginal watery discharge (62 patients, 41.61%), 47.65% (71/149) had received cervical screening tests, and the human papilloma virus (HPV) positive rate was only 7.04%. Only one-third of the patients (55/149, 36.91%) had received genetic testing, and 52 patients had STK11 mutations (94.5%). 64.52% were truncating mutations, but with no significant differences in the incidence and oneset age of gynecological disease compared with non-truncating mutations in our cohort. STK11 germline mutations were found all over the whole gene, while no mutation found in non-coding exon 9. Exon7 was found with the highest mutation rate (25.81%). Unrelated patients with the same STK11 mutation had completely different disease spectrum and onset age of gynecological diseases. Among the patients with gynecological cancer treated with surgery, 1/3 were found with synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT) on pathology. Less than half received standardized intervention and prompt surgery, and only 73.33% of them received adjuvant therapy. Only 40% of the patients completed fertility before surgery, and none received PGT. Conclusion: This study first put the focus on the gynecological symptoms, diagnosis and management of Chinese women with PJS. We found that abnormal uterine bleeding and vaginal watery discharge were the main symptoms in half of the women with PJS, and the age of onset was significantly shifted to the younger population. Truncating mutations, as the main mutation type in Chinese women with PJS, has no significant association with clinical phenotype, for which the mutation type does not affect their risk of cancer or age onset. Environmental factors may play an important role in disease development and progression of PJS patients as the age onset and disease spectrum of unrelated females carrying the same STK11 mutation were completely different. At the same time, the awareness of genetic counseling and gynecological disease screening system have not been established in the PJS female population, as the genetic test coverage is low (1/3), and only less than half of the patients with gynecological cancer received standard surgery and adjuvant therapy. PJS patients with gynecological cancer generally have low fertility rate, and only one case received PGT in our cohort, which is mainly due to the low cognition and understanding of PJS in our society. The low coverage of genetic counseling, and the delay of intervention made PJS patients, especially females with gynecological diseases lose their fertility opportunity.

Key words: Peutz-Jeghers syndrome, STK11 gene, Gynecological cancer, Lobular endocervical glandular hyperplasia, Gastric type adenocarcinoma of the uterine cervix, Protein truncation mutation

中图分类号: 

相关文章

[1] 王 利,任玉兰,王华英 . 宫颈癌根治术后肺栓塞1例报道[J]. 中国癌症杂志, 2019, 29(8): 599-601.
[2] 胡宏峰,卢仁泉,胡 娟,等. 卵巢癌患者血清唾液酸含量检测的价值[J]. 中国癌症杂志, 2017, 27(7): 588-592.