Penn State College of Medicine, Departments of Pathology and Urology, Hershey, PA.
Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, NY.
Am J Surg Pathol. 2024 Jan 1;48(1):e32-e42. doi: 10.1097/PAS.0000000000002053. Epub 2023 May 18.
Molecular subtyping has been a major focus of bladder cancer research over the past decade. Despite many promising associations with clinical outcomes and treatment response, its clinical impact has yet to be defined. As part of the 2022 International Society of Urological Pathology Conference on Bladder Cancer, we reviewed the current state of the science for bladder cancer molecular subtyping. Our review included several different subtyping systems. We derived the following 7 principles, which summarize progress and challenges of molecular subtyping: (1) bladder cancer has 3 major molecular subtypes: luminal, basal-squamous, and neuroendocrine; (2) signatures of the tumor microenvironment differ greatly among bladder cancers, particularly among luminal tumors; (3) luminal bladder cancers are biologically diverse, and much of this diversity results from differences in features unrelated to the tumor microenvironment, such as FGFR3 signaling and RB1 inactivation; (4) molecular subtype of bladder cancer associates with tumor stage and histomorphology; (5) many subtyping systems include idiosyncrasies, such as subtypes recognized by no other system; (6) there are broad fuzzy borders between molecular subtypes, and cases that fall on these fuzzy borders are often classified differently by different subtyping systems; and (7) when there are histomorphologically distinct regions within a single tumor, the molecular subtypes of these regions are often discordant. We reviewed several use cases for molecular subtyping, highlighting their promise as clinical biomarkers. Finally, we conclude that data are currently insufficient to support the routine use of molecular subtyping to guide bladder cancer management, an opinion shared with the majority of conference attendees. We also conclude that molecular subtype should not be considered an "intrinsic" property of a tumor but should instead be considered the result of a specific laboratory test, performed using a specific testing platform and classification algorithm, validated for a specific clinical application.
在过去的十年中，分子亚型已成为膀胱癌研究的重点。尽管与临床结果和治疗反应有许多有希望的关联，但它的临床影响尚未确定。作为 2022 年国际泌尿病理学会膀胱癌会议的一部分，我们回顾了膀胱癌分子亚型的当前科学状况。我们的综述包括几种不同的亚型系统。我们得出了以下 7 条原则，总结了分子亚型的进展和挑战：(1)膀胱癌有 3 种主要的分子亚型：腔型、基底-鳞状和神经内分泌型；(2)膀胱癌肿瘤微环境的特征差异很大，尤其是腔型肿瘤；(3)腔型膀胱癌具有很强的生物学异质性，其中许多异质性是由于与肿瘤微环境无关的特征差异造成的，如 FGFR3 信号和 RB1 失活；(4)膀胱癌的分子亚型与肿瘤分期和组织形态学有关；(5)许多亚型系统都存在特殊性，如其他系统无法识别的亚型；(6)分子亚型之间存在广泛的模糊边界，落在这些模糊边界上的病例往往被不同的亚型系统分类不同；(7)当单个肿瘤内存在组织形态学上明显不同的区域时，这些区域的分子亚型通常是不一致的。我们综述了分子亚型的几个应用案例，突出了它们作为临床生物标志物的潜力。最后，我们得出的结论是，目前的数据不足以支持常规使用分子亚型来指导膀胱癌的管理，这一观点与会议的大多数与会者一致。我们还得出结论，分子亚型不应被视为肿瘤的“固有”特性，而应被视为使用特定的检测平台和分类算法进行的特定实验室检测的结果，该检测经过了特定的临床应用验证。
