Department of Pathology, UMass Memorial Health Care, University of Massachusetts, Worcester, MA, USA.
Department of Mathematical Sciences, Worcester Polytechnic Institute, Worcester, MA, USA.
Mod Pathol. 2021 May;34(5):1017-1030. doi: 10.1038/s41379-020-00729-y. Epub 2021 Jan 22.
Squamous cell carcinoma (SqCC) is the most common malignancy of the anal canal, where it is strongly associated with HPV infection. Characteristic genomic alterations have been identified in anal SqCC, but their clinical significance and correlation with HPV status, pathologic features, and immunohistochemical markers are not well established. We examined the molecular and clinicopathologic features of 96 HPV-positive and 20 HPV-negative anal SqCC. HPV types included 89 with HPV16, 2 combined HPV16/HPV18, and 5 HPV33. HPV-positive cases demonstrated frequent mutations or amplifications in PIK3CA (30%; p = 0.027) or FBXW7 mutations (10%). HPV-negativity was associated with frequent TP53 (53%; p = 0.00001) and CDKN2A (21%; p = 0.0045) mutations. P16 immunohistochemistry was positive in all HPV-positive cases and 3/20 HPV-negative cases (p < 0.0001; sensitivity: 100%; specificity: 85%) and was associated with basaloid morphology (p = 0.0031). Aberrant p53 immunohistochemical staining was 100% sensitive and specific for TP53 mutation (p < 0.0001). By the Kaplan-Meier method, HPV-negativity, aberrant p53 staining, and TP53 mutation were associated with inferior overall survival (OS) (p < 0.0001, p = 0.0103, p = 0.0103, respectively) and inferior recurrence-free survival (p = 0.133, p = 0.0064, and p = 0.0064, respectively). TP53/p53 status stratified survival probability by HPV status (p = 0.013), with HPV-negative/aberrant p53 staining associated with the worst OS, HPV-positive/wild-type p53 with best OS, and HPV-positive/aberrant p53 or HPV-negative/wild-type p53 with intermediate OS. On multivariate analysis HPV status (p = 0.0063), patient age (p = 0.0054), T stage (p = 0.039), and lymph node involvement (p = 0.044) were independently associated with OS. PD-L1 expression (CPS ≥ 1) was seen in 30% of HPV-positive and 40% of HPV-negative cases, and PD-L1 positivity was associated with a trend toward inferior OS within the HPV-negative group (p = 0.064). Our findings suggest that anal SqCC can be subclassified into clinically, pathologically, and molecularly distinct groups based on HPV and TP53 mutation status, and p16 and p53 immunohistochemistry represent a clinically useful method of predicting these prognostic groups.
鳞状细胞癌（SqCC）是肛管最常见的恶性肿瘤，与 HPV 感染密切相关。 在分析肛管 SqCC 时发现了一些特征性的基因组改变，但是这些改变与 HPV 状态、病理特征和免疫组织化学标志物的相关性以及它们的临床意义尚未得到充分的确定。本研究对 96 例 HPV 阳性和 20 例 HPV 阴性肛管 SqCC 的分子和临床病理特征进行了检测。所检测的 HPV 类型包括 89 例 HPV16、2 例 HPV16/HPV18 混合感染和 5 例 HPV33。HPV 阳性病例常出现 PIK3CA 基因突变或扩增（30%；p=0.027）或 FBXW7 突变（10%）。HPV 阴性病例则常出现 TP53（53%；p=0.00001）和 CDKN2A（21%；p=0.0045）基因突变。所有 HPV 阳性病例的 P16 免疫组化均为阳性，而 20 例 HPV 阴性病例中有 3 例（p<0.0001；敏感性：100%；特异性：85%）为阳性，并且与基底样形态学（p=0.0031）相关。异常的 p53 免疫组化染色对 TP53 突变的敏感性和特异性均为 100%（p<0.0001）。Kaplan-Meier 方法显示 HPV 阴性、异常的 p53 染色和 TP53 突变与较差的总生存率（OS）（p<0.0001、p=0.0103 和 p=0.0103）和无复发生存率（p=0.133、p=0.0064 和 p=0.0064）相关。TP53/p53 状态根据 HPV 状态分层生存概率（p=0.013），HPV 阴性/异常 p53 染色与最差的 OS 相关，HPV 阳性/野生型 p53 与最佳 OS 相关，HPV 阳性/异常 p53 或 HPV 阴性/野生型 p53 与中间 OS 相关。多因素分析显示 HPV 状态（p=0.0063）、患者年龄（p=0.0054）、T 分期（p=0.039）和淋巴结受累（p=0.044）与 OS 独立相关。在 HPV 阳性病例中，有 30%存在 PD-L1 表达（CPS≥1），在 HPV 阴性病例中，有 40%存在 PD-L1 表达，并且 HPV 阴性病例中 PD-L1 阳性与 OS 较差相关（p=0.064）。本研究结果表明，肛管 SqCC 可根据 HPV 和 TP53 突变状态以及 p16 和 p53 免疫组化进行临床、病理和分子上的亚分类，代表了一种预测这些预后组的临床有用方法。
