Jung Minsun, Kim Bohyun, Lee Jae Seok, Kim Jun Yong, Han Dohyun, Kim Kwangsoo, Yang Sunah, Kim Eun Na, Kim Hyeyooon, Nikas Ilias P, Yang Sohyeon, Moon Kyung Chul, Lee Hyebin, Ryu Han Suk
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea.
Pathobiology. 2025;92(1):28-39. doi: 10.1159/000540926. Epub 2024 Aug 27.
Although urothelial papilloma (UP) is an indolent papillary neoplasm that can mimic the morphology of low-grade papillary urothelial carcinoma (PUC), there is no immunomarker to differentiate reliably these two entities. In addition, the molecular characteristics of UP are not fully understood.
We conducted an in-depth proteomic analysis of papillary urothelial lesions (n = 31), including UP and PUC along with normal urothelium. Protein markers distinguishing UP and PUC were selected with machine learning analysis, followed by internal and external validation using immunohistochemistry.
In the proteomic analysis, UP and PUC showed overlapping proteomic profiles. We identified EHD4 and KRT18 as candidate diagnostic biomarkers of UP. Through immunohistochemical validation in two independent cohorts (n = 120), KRT18 was suggested as a novel UP diagnostic marker, able to differentiate UP from low-grade PUC. We also found that 3.5% of patients with UP developed urothelial carcinoma in subsequent resections, supporting the malignant potential of UP. KRT18 downregulation was significantly associated with UPs subsequently progressing to urothelial carcinoma, following their initial diagnosis.
This is the first study that successfully revealed UPs comprehensive proteomic landscape, while it also identified KRT18 as a potential diagnostic biomarker of UP.
尽管尿路上皮乳头状瘤（UP）是一种惰性乳头状肿瘤，可模仿低级别乳头状尿路上皮癌（PUC）的形态，但尚无免疫标志物能可靠地区分这两种实体。此外，UP的分子特征尚未完全明确。
我们对包括UP、PUC以及正常尿路上皮在内的乳头状尿路上皮病变（n = 31）进行了深入的蛋白质组学分析。通过机器学习分析选择区分UP和PUC的蛋白质标志物，随后使用免疫组织化学进行内部和外部验证。
在蛋白质组学分析中，UP和PUC显示出重叠的蛋白质组谱。我们将EHD4和KRT18鉴定为UP的候选诊断生物标志物。通过在两个独立队列（n = 120）中进行免疫组织化学验证，KRT18被认为是一种新型的UP诊断标志物，能够将UP与低级别PUC区分开来。我们还发现，3.5%的UP患者在后续切除术中发生了尿路上皮癌，这支持了UP的恶性潜能。KRT18下调与初次诊断后进展为尿路上皮癌的UP显著相关。
这是第一项成功揭示UP全面蛋白质组图谱的研究，并将KRT18鉴定为UP的潜在诊断生物标志物。
