Garczyk Stefan, Bischoff Felix, Schneider Ursula, Golz Reinhard, von Rundstedt Friedrich-Carl, Knüchel Ruth, Degener Stephan
Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074, Aachen, Germany.
Institute of Pathology, Helios University Hospital Wuppertal, Wuppertal, Germany.
Virchows Arch. 2021 Aug;479(2):325-335. doi: 10.1007/s00428-021-03054-0. Epub 2021 Mar 1.
Reliable factors predicting the disease course of non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) are unavailable. Molecular subtypes have potential for prognostic stratification of muscle-invasive bladder cancer, while their value for CIS patients is unknown. Here, the prognostic impact of both clinico-pathological parameters, including CIS focality, and immunohistochemistry-based surrogate subtypes was analyzed in a cohort of high-risk NMIBC patients with CIS. In 128 high-risk NMIBC patients with CIS, luminal (KRT20, GATA3, ERBB2) and basal (KRT5/6, KRT14) surrogate markers as well as p53 were analyzed in 213-231 biopsies. To study inter-lesional heterogeneity of CIS, marker expression in independent CIS biopsies from different bladder localizations was analyzed. Clinico-pathological parameters and surrogate subtypes were correlated with recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Forty-six and 30% of CIS patients exhibited a luminal-like (KRT20-positive, KRT5/6-negative) and a null phenotype (KRT20-negative, KRT5/6-negative), respectively. A basal-like subtype (KRT20-negative, KRT5/6-positive) was not observed. A significant degree of inter-lesional CIS heterogeneity was noted, reflected by 23% of patients showing a mixed subtype. Neither CIS surrogate subtype nor CIS focality was associated with patient outcome. Patient age and smoking status were the only potentially independent prognostic factors predicting RFS, PFS, OS, and PFS, respectively. In conclusion, further clarification of heterogeneity of surrogate subtypes in HR NMIBC and their prognostic value is of importance with regard to potential implementation of molecular subtyping into clinical routine. The potential prognostic usefulness of patient age and smoking status for high-risk NMIBC patients with CIS needs further validation.
目前尚无可靠的因素能够预测伴有原位癌（CIS）的非肌层浸润性膀胱癌（NMIBC）的疾病进程。分子亚型对肌层浸润性膀胱癌具有预后分层的潜力，但其对CIS患者的价值尚不清楚。在此，我们分析了临床病理参数（包括CIS灶性）和基于免疫组化的替代亚型对一组高危NMIBC合并CIS患者的预后影响。在128例高危NMIBC合并CIS患者中，对213 - 231份活检样本分析了腔面（KRT20、GATA3、ERBB2）和基底（KRT5/6、KRT14）替代标志物以及p53。为研究CIS的病灶间异质性，分析了来自不同膀胱部位的独立CIS活检样本中的标志物表达。临床病理参数和替代亚型与无复发生存期（RFS）、无进展生存期（PFS）、癌症特异性生存期（CSS）和总生存期（OS）相关。分别有46%和30%的CIS患者表现出腔面样（KRT20阳性、KRT5/6阴性）和无表型（KRT20阴性、KRT5/6阴性）。未观察到基底样亚型（KRT20阴性、KRT5/6阳性）。观察到显著程度的病灶间CIS异质性，23%的患者表现为混合亚型。CIS替代亚型和CIS灶性均与患者预后无关。患者年龄和吸烟状态分别是预测RFS、PFS、OS和PFS的唯一潜在独立预后因素。总之，进一步阐明HR NMIBC中替代亚型的异质性及其预后价值对于将分子亚型分类潜在应用于临床常规非常重要。患者年龄和吸烟状态对高危NMIBC合并CIS患者的潜在预后有用性需要进一步验证。
