Characterization ofTP53-wildtype tubo-ovarian high-grade serous carcinomas: rare exceptions to the binary classification of ovarian serous carcinoma

WhileTP53mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rareTP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25TP53-wildtype tubo-ovarian HGSCs, constituting 2.5% of 987 HGSCs profiled by the MSK-IMPACT sequencing platform. Consistent with serous differentiation, positive staining for Pax8 and WT1 was present in virtually allTP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations ofCCNE1andBRCA1/2were identified in these tumors, furthering supporting their classification asbona fideHGSC, despite lackingTP53mutations. Overall, the level of chromosomal instability ofTP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) andTP53-mutated HGSC. Morphologic assessment by observers blinded to mutation status revealed a significant subset of tumors with Grade 2 nuclear atypia (which exceeds the degree of atypia allowed for LGSC, but less than typically encountered for HGSC) combined with micropapillary features (6/19, 32%, chemotherapy-naiveTP53-wildtype HGSCs compared to 0/21, 0%,TP53-mutated HGSCs;p = 0.007). SomeTP53-wildtype HGSCs harbored driver mutations inKRAS(n = 3),BRAF(n = 1) orNRAS(n = 2). Overall, 10 (40%) cases had LGSC-like morphology (i.e., Grade 2 nuclear atypia and micropapillary features) and/orRAS/RAFmutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remainingTP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventionalTP53-mutated HGSC. Despite lacking genetic alterations ofTP53, these usual HGSC-like tumors often showed evidence of p53 dysfunction, including downregulation of expression ('null' or equivocal p53 staining in 9/14, 64%) orMDM2amplification (n = 2). Our results support the existence ofTP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms.

Automated summary

This study retrospectively reviewed 25 TP53-wildtype tubo-ovarian HGSCs and found that they share similar characteristics in morphology, genetic alterations, and pathological features with typical HGSC, despite lacking TP53 mutations.