Keratin 17 is a sensitive and specific biomarker of urothelial neoplasia
Keratin 17 is a sensitive and specific biomarker of urothelial neoplasia
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DOI：
10.1038/s41379-018-0177-5
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发表时间：
2019-05-01
期刊：
影响因子：
7.5
通讯作者：
Shroyer, Kenneth R.
中科院分区：
文献类型：
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作者：
Babu, Sruthi;Mockler, Daniel C.;Shroyer, Kenneth R.
临床上需要鉴定新的生物标志物以提高检测尿路上皮肿瘤的诊断准确性。目前的研究旨在评估角蛋白17（K17），一种在多个解剖部位的癌症中驱动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。我们通过免疫组化评估了K17在福尔马林固定的石蜡包埋的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）、低恶性潜能乳头状尿路上皮瘤变（PUNLMP）和正常膀胱粘膜组织标本中的表达。基于显示强染色的细胞比例，确定阈值以将组织标本中的K17状态分为阳性与阴性。此外，对尿细胞学载玻片进行K17免疫细胞化学，根据任何尿路上皮细胞中K17的检测，将阳性检测结果评分为阳性。Mann-Whitney和受试者操作特征分析用于比较组织学诊断类别之间的K17表达。K17阳性肿瘤细胞的中位比例在PUNLMP中为70%（范围20-90%），在PUC-LG中为30%（范围5-100%），在PUC-HG中为20%（范围1-100%），在UC中为35%（范围5-100%），但在正常尿路上皮粘膜中很少检测到染色（范围0-10%）。将在≥ 10%的细胞中检测到K17的病例定义为阳性，活检中K17区分恶性病变（PUC-LG、PUC-HG和UC）与正常尿路上皮粘膜的灵敏度为89%（95% CI：80 - 96%），特异性为88%（95% CI：70-95%）。K17免疫细胞化学对112例尿路上皮癌的敏感性为100%，特异性为96%。因此，K17是组织标本中尿路上皮肿瘤的敏感和特异性生物标志物，应进一步探索作为尿液标本细胞学诊断的新生物标志物。
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.