Bründl Johannes, Neppl Christina, Hommer Thomas, Otto Wolfgang, Breyer Johannes, Brookman-May Sabine, Weber Florian, Burger Maximilian, May Matthias, Eichelberg Christian
Urologische Klinik des Caritas-Krankenhauses St. Josef, Universität Regensburg, Regensburg.
Universität Regensburg, Institut für Pathologie, Regensburg.
Aktuelle Urol. 2019 Sep;50(5):491-501. doi: 10.1055/a-0664-0316. Epub 2018 Sep 18.
Human papillomavirus (HPV) infection plays an important role in the pathogenesis of penile squamous cell carcinoma (PSCC) in about one third of the affected patients. Initial data indicate that HPV status could facilitate optimised risk stratification and individualised targeted therapy. The polymerase chain reaction (PCR) assay is the reference method for detection of HPV DNA. It is unclear if alternatives such as in situ hybridisation (ISH) or various surrogate markers (defined as immunohistochemical detection of p16INK4a, histological subtype, tumour invasion front, koilocytosis) are sufficient to determine HPV status METHODS: In this single centre study on 34 patients with PSCC, multiplex nested PCR and ISH were conducted for HPV detection and identification of HPV DNA genotypes. Various histological criteria and p16INK4a were determined by central review. The influence of different criteria on cancer-specific mortality (CSM) was investigated with the Cox proportional hazards models (FU: 92 mo.). Furthermore, the discriminative qualities of various tumour invasion patterns (i. e., pT-classification 7th vs. 8th ed.) for CSM prediction were compared.
Pursuant to PCR assay, HPV DNA was detected in 26 % of patients (n = 9). ISH and the examined histological criteria were of inadequate quality in the prediction of HPV status (p > ;0.3). Test parameters of p16INK4a were calculated as follows: sensitivity 66.7 %, specificity 84 %, positive predictive value 60 %, negative predictive value 87.5 %, overall agreement 79.4 % (Area-Under-Curve: 0.753, p = 0.026). None of the examined HPV criteria significantly influenced CSM. In comparison to the 7th pT-edition, the 8th version was superior in CSM prediction (c-indices 70.2 % vs. 72.9 %). In addition to penile corpora invasion, infiltration of the urethra had no independent predictive value. Regrouping of the corpora invasion patterns, as proposed by us, resulted in an increase in discriminative quality (c-index 77.9 %).
In contrast to ISH and the examined histological criteria, p16INK4a allows a reasonable prediction of HPV status. Neither HPV DNA nor its surrogate markers independently impacted CSM. As urethral tumour invasion does not independently influence CSM, the recent pT classification can be considered useful for prognosis.
人乳头瘤病毒（HPV）感染在约三分之一的阴茎鳞状细胞癌（PSCC）患者的发病机制中起重要作用。初步数据表明，HPV状态有助于优化风险分层和个体化靶向治疗。聚合酶链反应（PCR）检测是检测HPV DNA的参考方法。尚不清楚诸如原位杂交（ISH）或各种替代标志物（定义为p16INK4a的免疫组织化学检测、组织学亚型、肿瘤浸润前沿、挖空细胞）等替代方法是否足以确定HPV状态。
在这项针对34例PSCC患者的单中心研究中，采用多重巢式PCR和ISH进行HPV检测及HPV DNA基因型鉴定。通过集中审查确定各种组织学标准和p16INK4a。采用Cox比例风险模型（随访时间：92个月）研究不同标准对癌症特异性死亡率（CSM）的影响。此外，比较了各种肿瘤浸润模式（即第7版与第8版pT分类）对CSM预测的判别质量。
根据PCR检测，26%的患者（n = 9）检测到HPV DNA。ISH和所检查的组织学标准在预测HPV状态方面质量不足（p > 0.3）。p16INK4a的检测参数计算如下：敏感性66.7%，特异性84%，阳性预测值60%，阴性预测值87.5%，总体一致性79.4%（曲线下面积：0.753，p = 0.026）。所检查的HPV标准均未对CSM产生显著影响。与第7版pT分类相比，第8版在CSM预测方面更优（c指数分别为70.2%和72.9%）。除阴茎海绵体浸润外，尿道浸润无独立预测价值。按照我们提出的方法对海绵体浸润模式进行重新分组，判别质量有所提高（c指数为77.9%）。
与ISH和所检查的组织学标准不同，p16INK4a能够合理预测HPV状态。HPV DNA及其替代标志物均未独立影响CSM。由于尿道肿瘤浸润不独立影响CSM，因此最近的pT分类可认为对预后有用。
