Synchronous endometrial/cervical and ovarian/fallopian tube carcinoma: a genome‐wide mutation analysis

In this study, we explored the genomic underpinnings of synchronous endometrial and ovarian/fallopian tube carcinoma (SEOC) and synchronous cervical and ovarian/fallopian tube carcinoma (SCOC), focusing on their clonal relationships to discern whether these malignancies represent dual primary tumors (DPTs) or have metastatic origins. We established a cohort comprising 54 SEOC patients and 7 SCOC patients. After selection, 17 patients (12 SEOC and 5 SCOC) underwent comprehensive analysis via whole-exome sequencing. The study encompassed a diverse array of histological subtypes, including high-grade serous carcinoma (HGSC) or uterine serous carcinoma (USC), endometrioid carcinoma exhibiting papillary/mucinous features, dedifferentiated carcinoma (DC), clear cell carcinoma (CCC), HPV-associated cervical squamous cell carcinoma, and HPV-independent cervical adenocarcinoma. Analysis revealed that 58.3% (7 of 12) of SEOC cases and all SCOC cases demonstrated shared mutations. This suggests a clonal relationship and supports a metastatic origin for these tumors. Notably, metastatic SEOC instances included co-occurrences of USC and HGSC in both the endometrium and the ovaries/fallopian tubes, endometrial and ovarian CCC, concurrent endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) with mucinous metaplasia, as well as cases of endometrial DC with ovarian CCC, and both EEC and ovarian DC. Among the SEOC cases classified as metastatic, patients with high-grade tumors and advanced ovarian stage succumbed to their disease, whereas the remainder survived without relapse. In the SCOC cohort, one patient died from the disease. The favorable survival outcomes across varied histotypes suggest that a stage upgrade may not be warranted. Given the favorable clinical outcomes observed, the term 'trans-tubal spread' may be more appropriate than 'metastasis' in this context to prevent potential overtreatment. Directionality analysis revealed a bidirectional pattern of trans-tubal spread between the uterus/cervix and ovary/fallopian tubes. The presence of dedifferentiated carcinoma confirms the manifestation of dedifferentiation during spread. These findings lend support to the trans-tubal implantation hypothesis and contribute novel insights into the molecular mechanisms underlying tumor dissemination in SEOC and SCOC.