Clinical phenotype of endometrial carcinoma in Lynch Syndrome: MSH2 mutation carriers

Nichols, Adam Harry Gerald (2020) Clinical phenotype of endometrial carcinoma in Lynch Syndrome: MSH2 mutation carriers. Masters thesis, Memorial University of Newfoundland.

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Abstract

Objective The purpose of this study is to compare histological and clinical variables of individuals with Lynch Syndrome associated Endometrial Carcinoma with a cohort with sporadic Endometrial Carcinomas derived from the general population with sporadic Endometrial Carcinomas. The patients in the Lynch Syndrome cohort were genetically confirmed carriers of MSH2 mismatch repair gene mutations all with previously diagnosed Endometrial Carcinoma. Methods Clinical data was abstracted retrospectively from the medical charts of 46 women with endometrial caner who had a known MSH2 mismatch repair mutation confirmed through genetic sequencing. Clinical variables abstracted from the medical files of these patients included (1) Age at diagnosis (2) International Federation of Gynecology and Obstetrics (FIGO) Stage (3) International Federation of Gynecology and Obstetrics Grade and (4) Cell type of endometrial carcinoma. The characteristics of the MSH2 carriers were subsequently compared to the clinically relevant variables of sporadic endometrial cancers that were retrieved from the Newfoundland and Labrador Cancer Care Registry (NLCCR) diagnosed between 2000 and 2010. The Newfoundland and Labrador Cancer Care Registry is a provincial cancer care program and database operated by Eastern Health that combines 5 core cancer programs and registries. The NLCCR includes the provinces Colon, Breast and Cervical screening programs and the provincial tumour and systemic therapy surveillance programs. Results The mean age at diagnosis of Endometrial Cancer (EC) in the MSH2 Lynch syndrome mutation carriers was 46.3 years vs. 60.9 years in the sporadic cohort (p=<0.001). The Lynch Syndrome ECs were diagnosed more frequently prior to 55 years of age (p=<0.001). Comparing local and advanced stages of disease, the Lynch Syndrome cohort had more advanced disease at diagnosis (p=0.047). The prevalence of papillary serous cell type carcinomas in the Lynch Syndrome (23.7%) cohort was statistically more frequent than in the sporadic cohort (3.6%) (p=< 0.001). Clear cell carcinomas were observed more frequently in Lynch Syndrome related EC (7.9%) compared to the sporadic cohort (0.8%) (p=<0.001). The prevalence of grade 3 tumours in the Lynch Syndrome related EC cohort was higher compared to the sporadic cohort; 32.4% and 11.9% respectively (p=0.001). Merger of low-grade (1/2) tumours compared to high grade (3) tumours observed the Lynch Syndrome cohort to present with higher-grade tumours. In the Lynch Syndrome cohort 69.6% had endometrial carcinoma as a sentinel cancer. Survival after diagnosis of EC was similar in each cohort (p=0.068). Logistic regression models indicated that a diagnosis of EC prior to age 55 and a histological diagnosis of papillary serous/clear cell carcinoma to were independently associated with LS (p=<0.001 and p=<0.001 respectively). Multivariate analysis demonstrated that grade, stage of disease, age and cell type were independently associated with a diagnosis of LS. Conclusion This is a preliminary study focusing on the clinical features present in Lynch Syndrome related endometrial carcinomas in women carrying MSH2 mismatch repair mutations. This study serves as a pilot study for a larger, population-based study of the genetics and epidemiology of endometrial carcinomas in Newfoundland and Labrador. We have concluded that Lynch Syndrome associated endometrial cancers are diagnosed at a younger age than the endometrial cancers in the general population, and that prevalence of cell types with unfavorable prognosis was higher in Lynch Syndrome related endometrial carcinomas. The stage of cancer in the Lynch syndrome related endometrial carcinoma cohort at diagnosis was more advanced, and was associated with a higher histological grade. Multivariate analysis found these characteristics to be predictive of LS. Lynch Syndrome related EC patients demonstrated no difference in survival (p=0.068) when compared to the sporadic cohort via Kaplan-Meier survival analysis.

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