Endometrioid Versus Seromucinous Borderline Ovarian Tumors: Divergent Molecular Signatures and a Shared Role as Precursors to Endometrioid Carcinoma

Endometrioid borderline tumors (EBTs) and seromucinous borderline tumors (SMBTs) are rare ovarian neoplasms with distinct histologic features. However, the molecular profiles of EBTs and SMBTs remain incompletely characterized. We performed histologic evaluation and DNA/RNA next-generation sequencing (NGS) using a 1425-gene pan-cancer panel on 11 EBTs and 10 SMBTs to define their mutational landscapes, conduct cross-comparisons between EBTs and SMBTs, and evaluate both against established profiles of endometrioid carcinoma and low-grade serous carcinoma. Histologically, EBTs showed adenofibromatous (64%) or intracystic (36%) growth patterns, with morule formation in 36% of cases. Aberrant nuclear β-catenin expression was observed in 73% of EBTs, significantly higher than in SMBTs (0%, P=0.001). β-catenin abnormalities and morules were absent in SMBTs. 73% EBT and 60% SMBT were associated with endometriosis. Genetically, most EBTs harbored CTNNB1 mutations (73%) with additional alterations in KRAS (36%), ARID1A (27%), ATR (27%), KMT2D (27%), PIK3CA (18%), PIK3R1 (18%), PTEN (18%), AKT1 (18%), TP53 (18%), and several others (≤18%). In contrast, SMBTs lacked CTNNB1 mutations but frequently had KRAS (60%), BRAF (30%), PIK3CA (20%), PIK3R1(20%), PTEN (20%), ATM (20%), ZFHX3 (20%), AUTS2(20%), CIC (20%), FAT1(20%), and PLAT (20%) mutations, with 20% showing concurrent KRAS/PIK3CA mutations. Pathway analysis revealed predominant WNT/β-catenin signaling in EBTs versus RAS-MEK-ERK pathway alterations in SMBTs resembling the seromucinous variant of ovarian endometrioid carcinoma, with additional involvement of PI3K-PTEN-AKT-mTOR and SWI/SNF chromatin remodeling pathways in both. These findings demonstrate that EBTs and SMBTs possess distinct morphologic and molecular profiles, expanding the molecular characterization of early ovarian endometrioid-type neoplasms.