Departments of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Departments of Pathology, Barts Health NHS Trust, London, UK.
Mod Pathol. 2022 Oct;35(10):1475-1483. doi: 10.1038/s41379-022-01102-x. Epub 2022 Jun 25.
Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumor material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumor showed a mutant expression pattern (including subclonal): overexpression, null or cytoplasmic. The presence of pathogenic mutations was determined by next generation sequencing (NGS). Abnormal p53 expression was observed in 131/408 (32%) tumors. The most common abnormal p53 IHC pattern was overexpression (n = 89, 68%), followed by null (n = 12, 9%) and cytoplasmic (n = 3, 2%). Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLE mutations and/or MMRd (n = 22/27; p < 0.001). Agreement between p53 IHC and TP53 NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Excluding POLEmut and MMRd EC, as per the WHO-endorsed algorithm, increased the accuracy to 94.5% with sensitivity and specificity of 95.0% and 94.1%, respectively. Our data shows that awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC. No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns. Our data support use of the WHO-endorsed algorithm and combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC).
子宫内膜癌（EC）的标准分子分类现已得到世界卫生组织（WHO）的认可，其中 p53 异常（p53abn）EC 被认为是预后最差、最有可能从辅助化疗（放疗）中获益的亚组。p53abn EC 为 POLE 野生型，错配修复功能正常，且 p53 的免疫组化（IHC）染色异常。因此，正确解读常规进行的 p53 IHC 变得至关重要。我们旨在全面研究异常 p53 IHC 模式及其与临床病理和分子特征的关系。从 PORTEC-3 临床试验中同意参与的患者的分子分类高危 EC 肿瘤标本中收集了 411 例。对 408 例 EC 进行了 p53 IHC 检测，当肿瘤显示突变表达模式（包括亚克隆）时，肿瘤被认为是异常的：过表达、缺失或细胞质。通过下一代测序（NGS）确定是否存在致病性突变。在 408 例肿瘤中观察到 131 例（32%）存在异常 p53 表达。最常见的异常 p53 IHC 模式是过表达（n=89，68%），其次是缺失（n=12，9%）和细胞质（n=3，2%）。27 例（21%）观察到亚克隆异常 p53 染色，其与 POLE 突变和/或 MMRd 密切相关（n=22/27；p<0.001）。p53 IHC 与 TP53 NGS 的一致性为 90.7%，灵敏度和特异性分别为 83.6%和 94.3%。排除 POLEmut 和 MMRd EC 后，根据 WHO 认可的算法，准确性提高至 94.5%，灵敏度和特异性分别为 95.0%和 94.1%。我们的数据表明，了解异常 p53 IHC 模式是正确进行 EC 分子分类的前提。亚克隆异常 p53 表达是 POLEmut 和/或 MMRd EC 的强烈指标。异常 p53 IHC 模式之间的临床结局无显著差异。我们的数据支持使用 WHO 认可的算法，并将不同的异常 p53 IHC 模式组合成一个诊断实体（p53abn EC）。
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