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 26^th, 2022 to July 29^th, 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