Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.
Program of Public Health and Department of Preventative Medicine, Stony Brook Medicine, Stony Brook, NY, USA.
Mod Pathol. 2019 May;32(5):717-724. doi: 10.1038/s41379-018-0177-5. Epub 2018 Nov 15.
There is a clinical need to identify novel biomarkers to improve diagnostic accuracy for the detection of urothelial tumors. The current study aimed to evaluate keratin 17 (K17), an oncoprotein that drives cell cycle progression in cancers of multiple anatomic sites, as a diagnostic biomarker of urothelial neoplasia in bladder biopsies and in urine cytology specimens. We evaluated K17 expression by immunohistochemistry in formalin-fixed, paraffin embedded tissue specimens of non-papillary invasive urothelial carcinoma (UC) (classical histological cases), high grade papillary UC (PUC-LG), low grade papillary UC (PUC-HG), papillary urothelial neoplasia of low malignant potential (PUNLMP), and normal bladder mucosa. A threshold was established to dichotomize K17 status in tissue specimens as positive vs. negative, based on the proportion of cells that showed strong staining. In addition, K17 immunocytochemistry was performed on urine cytology slides, scoring positive test results based on the detection of K17 in any urothelial cells. Mann-Whitney and receiver operating characteristic analyses were used to compare K17 expression between histologic diagnostic categories. The median proportion of K17 positive tumor cells was 70% (range 20-90%) in PUNLMP, 30% (range 5-100%) in PUC-LG, 20% (range 1-100%), in PUC-HG, 35% (range 5-100%) in UC but staining was rarely detected (range 0-10%) in normal urothelial mucosa. Defining cases in which K17 was detected in ≥10% of cells were considered positive, the sensitivity of K17 in biopsies was 89% (95% CI: 80-96%) and the specificity was 88% (95% CI: 70-95%) to distinguish malignant lesions (PUC-LG, PUC-HG, and UC) from normal urothelial mucosa. Furthermore, K17 immunocytochemistry had a sensitivity of 100% and a specificity of 96% for urothelial carcinoma in 112 selected urine specimens. Thus, K17 is a sensitive and specific biomarker of urothelial neoplasia in tissue specimens and should be further explored as a novel biomarker for the cytologic diagnosis of urine specimens.
目前需要鉴定新的生物标志物，以提高对尿路上皮肿瘤检测的诊断准确性。本研究旨在评估角蛋白 17（K17），一种驱动多个解剖部位癌症细胞周期进展的癌蛋白，作为膀胱活检和尿细胞学标本中尿路上皮肿瘤的诊断生物标志物。我们通过免疫组织化学方法评估了 K17 在非乳头状浸润性尿路上皮癌（UC）（经典组织学病例）、高级别乳头状 UC（PUC-LG）、低级别乳头状 UC（PUC-HG）、低级别尿路上皮肿瘤低恶性潜能（PUNLMP）和正常膀胱黏膜的福尔马林固定石蜡包埋组织标本中的表达。根据显示强染色的细胞比例，建立了一个阈值来将组织标本中的 K17 状态分为阳性与阴性。此外，还对尿细胞学涂片进行了 K17 免疫细胞化学检测，根据任何尿路上皮细胞中 K17 的检测结果对阳性检测结果进行评分。采用 Mann-Whitney 和受试者工作特征分析比较组织学诊断类别之间的 K17 表达。PUNLMP 中 K17 阳性肿瘤细胞的中位数比例为 70%（范围 20-90%），PUC-LG 为 30%（范围 5-100%），PUC-HG 为 20%（范围 1-100%），UC 为 35%（范围 5-100%），但在正常尿路上皮黏膜中很少检测到（范围 0-10%）。将 K17 检测到≥10%细胞的病例定义为阳性，K17 在活检中的灵敏度为 89%（95%CI：80-96%），特异性为 88%（95%CI：70-95%），可区分恶性病变（PUC-LG、PUC-HG 和 UC）与正常尿路上皮黏膜。此外，K17 免疫细胞化学在 112 例选定尿标本中对尿路上皮癌的灵敏度为 100%，特异性为 96%。因此，K17 是组织标本中尿路上皮肿瘤的一种敏感且特异的生物标志物，应进一步探索作为尿标本细胞学诊断的新型生物标志物。
