Original ArticlesCytoplasmic Pattern p53 Immunoexpression in Pelvic and Endometrial Carcinomas With TP53 Mutation Involving Nuclear Localization Domains An Uncommon But Potential Diagnostic Pitfall With Clinical ImplicationsRabban, Joseph T. MD, MPH; Garg, Karuna MD; Ladwig, Nicholas R. MD; Zaloudek, Charles J. MD; Devine, W. Patrick MD, PhDAuthor Information Department of Pathology, University of California San Francisco, San Francisco, CA Conflicts of Interest and Source of Funding: J.T.R. reports that his spouse receives salary and stock options from Merck & Co. For the remaining authors none were declared. Correspondence: Joseph T. Rabban, MD, MPH, Department of Pathology, University of California San Francisco, 1825, 4th Street, M-2359, San Francisco, CA 94158 (e-mail: [email protected]). The American Journal of Surgical Pathology: November 2021 - Volume 45 - Issue 11 - p 1441-1451 doi: 10.1097/PAS.0000000000001713 Buy SDC Metrics Abstract A cytoplasmic pattern of p53 immunohistochemical expression has recently been reported in a rare subset of pelvic and endometrial cancers with a TP53 mutation involving domains affecting nuclear localization. This study reports the clinicopathologic features of 31 cases with a TP53 mutation involving nuclear localization, the largest study to date, emphasizing practical strategies for recognizing this uncommon variant and distinguishing it from the p53 wild-type pattern. The study also evaluates the prognostic significance of TP53 mutation involving nuclear localization in the ovarian high-grade serous carcinoma (HGSC) cohort of The Cancer Genome Atlas database. Most of the 31 tumors were advanced stage pelvic or endometrial HGSC. All TP53 mutations were predicted to result in loss of function. The p53 overexpression pattern was present in 6 tumors; the p53 null pattern in 3 and the p53 cytoplasmic pattern in 22 tumors. The p53 cytoplasmic pattern predominantly consisted of weak to moderate cytoplasmic staining in >95% of tumor cells as well as variable intensity nuclear staining involving a range of just a few cells to just under 80% of tumor cells. The p53 cytoplasmic pattern was observed in 100% of tumors with TP53 mutation in the nuclear localization domain and in 33% to 44% of tumors with a mutation in the adjacent tetramerization domain or nuclear exclusion sequence (P<0.01). p16 immunoexpression was present in 74% of tumors. In The Cancer Genome Atlas ovarian HGSC cohort, 9% of 471 nonredundant TP53-mutant cases had a nuclear localization domain, tetramerization domain, or nuclear exclusion sequence mutation but there was no significant difference in survival when compared to cases with TP53 mutation outside those domains (P>0.05). p53 cytoplasmic staining merits classification as an aberrant result despite coexisting nuclear staining that in some cases may resemble the p53 wild-type pattern. While positive p16 immunostaining may be of value to confirm diagnostically challenging cases of p53 cytoplasmic staining, a negative result is noninformative and molecular testing for TP53 mutation should be considered, if available. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.