BRAFV600E -mutated ovarian serous borderline tumors are at relatively low risk for progression to serous carcinoma.

// M. Herman Chui 1 , Susanne K. Kjaer 3 , 4 , Kirsten Frederiksen 3 , Charlotte G. Hannibal 3 , Tian-Li Wang 1 , Russell Vang 1 , 2 , * and Ie-Ming Shih 1 , 2 , * 1 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of Obstetrics & Gynecology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark 4 Gynecologic Clinic, Juliane Marie Centre, Copenhagen University Hospital, Copenhagen, Denmark * These authors contributed equally to this work Correspondence to: Russell Vang, email: rvang1@jhmi.edu Keywords: ovarian serous borderline tumor; mutation; genotyping; risk prediction; serous carcinoma Abbreviations: SBT: serous borderline tumor; ddPCR: digital droplet polymerase chain reaction Received: July 29, 2019     Accepted: October 19, 2019     Published: December 03, 2019 ABSTRACT Ovarian serous borderline tumor (SBT) is a known precursor of low-grade serous carcinoma. While most SBTs are cured surgically, some progress to carcinoma and a risk predictor for malignant relapse is needed to ensure vigilant follow-up and additional treatment. Activating mutations in KRAS or BRAF are present in around 60% of SBTs, but their relative impact on progression is unclear. We performed mutational analysis of KRAS and BRAF on 201 SBTs identified from a longitudinal cohort of SBTs after centralized pathology review. Compared to wildtype and KRAS -mutated SBTs, BRAF -mutated group of SBTs were less likely to exhibit micropapillary variant histology (p < 0.0001), were more frequently Stage I (p = 0.0023) and had a lower prevalence of associated endosalpingiosis (p = 0.0069). The histologic feature of diffuse presence of tumor cells with dense eosinophilic cytoplasm, while significantly associated with the BRAF V600E mutation (p < 0.0001), is 62% sensitive and 93% specific in identifying tumors with this mutation. After adjusting for age and stage, the risk of subsequent serous carcinoma was lower for SBTs harboring BRAF (HR 0.27, 95% CI 0.08–0.93), but not KRAS (HR 1.00, 95% CI 0.45–2.23) mutations, in comparison to wildtype SBTs. This study establishes the potential utility of mutation testing for guiding clinical management of ovarian SBT and underscores the importance of accurate morphologic distinction of micropapillary SBT from SBT with eosinophilic tumor cells, given their disparate prognostic implications.