Characterization of TP53-wildtype tubo-ovarian high-grade serous carcinomas: Rare exceptions to the binary classification of ovarian serous carcinoma Journal Article
| Authors: | Chui, M. H.; Momeni Boroujeni, A.; Mandelker, D.; Ladanyi, M.; Soslow, R. A. |
| Article Title: | Characterization of TP53-wildtype tubo-ovarian high-grade serous carcinomas: Rare exceptions to the binary classification of ovarian serous carcinoma |
| Abstract: | While TP53 mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rare TP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25 TP53-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 all TP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations of CCNE1 and BRCA1/2 were identified in these tumors, furthering supporting their classification as bona fide HGSC, despite lacking TP53 mutations. Overall, the level of chromosomal instability of TP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) and TP53-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-naive TP53-wildtype HGSCs compared to 0/21, 0%, TP53-mutated HGSCs; p = 0.007). Some TP53-wildtype HGSCs harbored driver mutations in KRAS (n = 3), BRAF (n = 1) or NRAS (n = 2). Overall, 10 (40%) cases had “LGSC-like” morphology (i.e., Grade 2 nuclear atypia and micropapillary features) and/or RAS/RAF mutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remaining TP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventional TP53-mutated HGSC. Despite lacking genetic alterations of TP53, these “usual HGSC-like” tumors often showed evidence of p53 dysfunction, including downregulation of expression (‘null’ or equivocal p53 staining in 9/14, 64%) or MDM2 amplification (n = 2). Our results support the existence of TP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms. © 2020, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology. |
| Journal Title: | Modern Pathology |
| Volume: | 34 |
| Issue: | 2 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2021-02-01 |
| Start Page: | 490 |
| End Page: | 501 |
| Language: | English |
| DOI: | 10.1038/s41379-020-00648-y |
| PUBMED: | 32801341 |
| PROVIDER: | scopus |
| PMCID: | PMC8409220 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2021 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work