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p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a comparison of antibody clones using patient outcomes and high-risk human papillomavirus RNA status.

口腔鳞状细胞癌p16免疫组化:从患者预后和高危型人乳头瘤病毒RNA来对抗体克隆进行比较分析

Shelton J,Purgina BM,Cipriani NA,Dupont WD,Plummer D,Lewis JS
阅读:1682 Modern PathologySep 2017; 30 (9): 1192 - 1334:1194-1203 

Abstract

High-risk human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas have a more favorable prognosis than HPV-negative ones. p16 immunohistochemistry has been recommended as a prognostic test in clinical practice. Several p16 antibodies are available, and their performance has not been directly compared. We evaluated three commercially available p16 antibody clones (E6H4, JC8 and G175-405) utilizing 199 cases of oropharyngeal squamous cell carcinoma from a tissue microarray, read by three pathologists with three different cutoffs for positivity: any staining, >50% and >75%. Positive predictive values for high-risk HPV status by RNA in situ hybridization for the E6H4, JC8 and G175-405 clones were 98%, 100% and 99% at the 75% cutoff, but negative predictive values were much more variable at 86%, 69% and 56%, respectively. These improved using the 50% cutoff, becoming similar for all three antibodies. Intensity varied substantially, with 85% of E6H4, 72% of JC8 and 67% of G175-405 showing strong (3+) intensity. With Kaplan-Meier survival plots at the 75% cutoff, the E6H4 clone showed the largest differential in disease specific and overall survival between p16-positive and -negative results. Decreasing the cutoff to 50% increased correlation with HPV in situ hybridization and improved the survival differential for the JC8 and G175-405 clones without worsening of performance for the E6H4 clone. Interobserver agreement was also assessed by kappa scores and was highest for the E6H4 clone. Overall, these study results show modest but important performance differences between the three different p16 antibody clones, suggesting that the E6H4 clone performs best because of strongest staining intensity, greatest differential in outcomes between positive and negative results, lowest interobserver variability, and lowest background, nonspecific staining. The results also suggest that a 75% cutoff is very functional but that, in this patient population with high HPV incidence, 50% and any staining cutoffs may be more effective, particularly for the non-E6H4 clones.

摘要

高危型人乳头瘤病毒(HPV)相关口咽鳞癌较HPV阴性者预后好。临床上常用p16蛋白的免疫组化评估预后。目前可用的p16抗体有几种,但几种抗体的效果并没有直接比较。通过199例口咽鳞状细胞癌组织芯片,我们评估了三种市售p16抗体克隆(E6H4,JC8和G175-4056),结果由三名病理医生读取,三个阳性临界(cutoff)值为:有染色、>50%和>75%。E6H4、JC8和G175-4056抗体克隆的高危HPV RNA原位杂交的阳性预测值在临界值75%时分别为98%、100%和99%;但阴性预测值变化较大,分别为86%、69%和56%。使用50%临界值后,三种抗体间的预测值变得相似。而强度差异很大,有85%的E6H4、67%的JC8和72%的G175-4056显示出强阳性(3+)。Kaplan Meier生存曲线的临界值为75%时,p16阳性和阴性结果在疾病特异性生存期和总生存间的差异上,E6H4克隆差异最大。临界值降为50%时,HPV原位杂交相关性提高,JC8和G175-4056克隆的生存差异提高,E6H4克隆的效果没有改变。一致性评价由Kappa评分得出,E6H4克隆一致性最高。总的来说,这些研究结果表明,三种不同的p16抗体克隆之间存在着微小但重要的性能差异,而E6H4克隆效果最好,因为其染色强度最强,阳性和阴性结果间的差异最大,观察者间的变异性最低,背景和非特异性染色最低。研究结果还表明,75%的临界值是非常实用的,但是,在这一HPV高发病率的人群中,50%、或任何染色的临界值可能是更有效的,特别是对非E6H4克隆。

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