Composite FOXL2 Mutation-positive Adult Granulosa Cell Tumor and Serous Borderline Tumor of the Ovary

Abstract

We report a case of a cystic ovarian neoplasm in a 76-yr-old female composed of 2 distinct and intimately associated components: a macrocystic adult granulosa cell tumor (AGCT) and a serous borderline tumor. The granulosa cell nature of the tumor was confirmed with positive immunohistochemical staining for inhibin, calretinin, and WT1, while the neoplastic nature of the granulosa cell proliferation was supported by the presence of a point mutation of the FOXL2 gene. A review of 19 previously reported mixed AGCT and epithelial neoplasms of the ovary is included. Of the eight mixed AGCT and epithelial tumors, including our case, that were tested for FOXL2 mutation, 4 of the 5 mutation-positive cases were notable for demonstrating a macroscopically visible nodule or mass of AGCT at the time of gross examination, while 2 of the 3 mutation-negative cases lacked a mass-producing granulosa cell component. This feature by itself may be sufficient to predict the true neoplastic nature of the granulosa cell proliferation. This is the first reported case of a composite neoplastic AGCT and serous borderline tumor. We also discuss the current histogenetic models for these rare mixed AGCT and epithelial tumors.

The impact of the FOXL2 gene on ovarian granulosa cells KGN

“…Previous studies by the applicant have suggested that estrogen regulates FOXL2 to promote apoptosis in human ovarian granulosa cell tumors (Rosario et al 2014, Wu et al 2019a). Mutations in the FOXL2 gene have been found in 95-97% of adult ovarian granulosa cell tumor patients, making FOXL2 gene mutation an important focus of research in ovarian granulosa cell tumors (Guerrieri et al 2023, Singh et al 2014, Yanagida et al 2017). To date, research has mainly focused on FOXL2 as a transcription factor regulating its downstream target genes, while relatively ignoring its own transcription and translation regulation (Caburet et al 2012, Fuller et al 2022, Tucker 2022, which is a limitation in FOXL2 research.…”