Emma L Kaderly Rasmussen, Susanne K Kjær, Lise G Larsen, Else Mejlgaard, Maria B Franzmann, Alexander K Kjær, Nadia V Salinas, Doris Schledermann, Kirsten Frederiksen, Tatiana Hansen, Birgitte H Winberg, Marianne Waldstrøm, Louise Baandrup
{"title":"Six-pattern p53 interpretation in 1293 vulvar squamous cell carcinomas: inter-pathologist variation and pattern distribution according to p16 status.","authors":"Emma L Kaderly Rasmussen, Susanne K Kjær, Lise G Larsen, Else Mejlgaard, Maria B Franzmann, Alexander K Kjær, Nadia V Salinas, Doris Schledermann, Kirsten Frederiksen, Tatiana Hansen, Birgitte H Winberg, Marianne Waldstrøm, Louise Baandrup","doi":"10.1111/his.15561","DOIUrl":null,"url":null,"abstract":"<p><strong>Aims: </strong>Vulvar squamous cell carcinoma (VSCC) is classified into human papillomavirus (HPV)-associated and HPV-independent types, primarily using p16 immunohistochemistry, with p53 staining playing a complementary role since a subset of HPV-independent VSCC is driven by TP53 mutations. We aimed to assess the robustness of the six-pattern p53 classification by evaluating interobserver agreement and mapping pattern distribution in relation to p16 status.</p><p><strong>Methods: </strong>We performed p53 immunohistochemistry on 1293 VSCC cases, comprising 832 p16-negative and 461 p16-positive cases. Eight pathologists independently evaluated p53, with each case assessed by two pathologists. Expression was classified as wild-type (scattered or mid-epithelial) or mutated (basal overexpression, parabasal/diffuse overexpression, absent or cytoplasmic). Interobserver agreement was measured using kappa statistics.</p><p><strong>Results: </strong>Overall concordance across the six p53 patterns was 66.7%, increasing to 86.9% when dichotomized as wild-type versus mutated. In the p16-negative cases, concordance was 68.8% across all six patterns and 82.6% when dichotomized. Corresponding rates in the p16-positive cases were 62.9% and 94.6%. Kappa values for pairwise assessments ranged from 0.44 to 0.73 (six-pattern) and from 0.60 to 0.88 (dichotomized). After resolving discordant cases, 79.9% of p16-negative cases showed a mutated pattern, and 20.1% were wild type (scattered). Among the p16-positive cases, 93.1% exhibited a wild-type pattern.</p><p><strong>Conclusions: </strong>Findings support the clinical robustness of the six-pattern p53 framework, as interobserver agreement was high and most discrepancies were unlikely to impact tumour classification. While p16 proved helpful in p53 interpretation, certain cases remained challenging due to p53 heterogeneity or ambiguous p16/p53 combinations indicating a need for additional molecular testing in such instances.</p>","PeriodicalId":13219,"journal":{"name":"Histopathology","volume":" ","pages":""},"PeriodicalIF":4.1000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Histopathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/his.15561","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Aims: Vulvar squamous cell carcinoma (VSCC) is classified into human papillomavirus (HPV)-associated and HPV-independent types, primarily using p16 immunohistochemistry, with p53 staining playing a complementary role since a subset of HPV-independent VSCC is driven by TP53 mutations. We aimed to assess the robustness of the six-pattern p53 classification by evaluating interobserver agreement and mapping pattern distribution in relation to p16 status.
Methods: We performed p53 immunohistochemistry on 1293 VSCC cases, comprising 832 p16-negative and 461 p16-positive cases. Eight pathologists independently evaluated p53, with each case assessed by two pathologists. Expression was classified as wild-type (scattered or mid-epithelial) or mutated (basal overexpression, parabasal/diffuse overexpression, absent or cytoplasmic). Interobserver agreement was measured using kappa statistics.
Results: Overall concordance across the six p53 patterns was 66.7%, increasing to 86.9% when dichotomized as wild-type versus mutated. In the p16-negative cases, concordance was 68.8% across all six patterns and 82.6% when dichotomized. Corresponding rates in the p16-positive cases were 62.9% and 94.6%. Kappa values for pairwise assessments ranged from 0.44 to 0.73 (six-pattern) and from 0.60 to 0.88 (dichotomized). After resolving discordant cases, 79.9% of p16-negative cases showed a mutated pattern, and 20.1% were wild type (scattered). Among the p16-positive cases, 93.1% exhibited a wild-type pattern.
Conclusions: Findings support the clinical robustness of the six-pattern p53 framework, as interobserver agreement was high and most discrepancies were unlikely to impact tumour classification. While p16 proved helpful in p53 interpretation, certain cases remained challenging due to p53 heterogeneity or ambiguous p16/p53 combinations indicating a need for additional molecular testing in such instances.
期刊介绍：
Histopathology is an international journal intended to be of practical value to surgical and diagnostic histopathologists, and to investigators of human disease who employ histopathological methods. Our primary purpose is to publish advances in pathology, in particular those applicable to clinical practice and contributing to the better understanding of human disease.
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