Advances, recognition, and interpretation of molecular heterogeneity among conventional and subtype histology of urothelial carcinoma (UC): a survey among urologic pathologists and comprehensive review of the literature
Authors: Lobo Anandi , Collins Katrina , Kaushal Seema , Acosta Andres M , Akgul Mahmut , Adhya Amit K , Al‐Ahmadie Hikmat A , Al‐Obaidy Khaleel I , Amin Ali , Amin Mahul B , Aron Manju , Balzer Bonnie L , Biswal Rupanita , Mohanty Subashish , Browning Lisa , Chakrabarti Indranil , Cima Luca , Cimadamore Alessia , Desai Sangeeta , Dhillon Jasreman , Deshwal Akansha , Diego Guillermo G , Diwaker Preeti , Galea Laurence A , Magi‐Galluzzi Cristina , Giannico Giovanna A , Gupta Nilesh S , Haider Aiman , Hirsch Michelle S , Iczkowski Kenneth A , Arora Samriti , Jain Ekta , Jain Deepika , Jha Shilpy , Kandukuri Shivani , Kao Chia‐Sui , Kryvenko Oleksandr N , Kumar Ramani M , Kumari Niraj , Kunju Lakshmi P , Kuthi Levente , Lobo João , Lopez Jose I , Luthringer Daniel J , Maclean Fiona , Manini Claudia , Mannan Rahul , Martos María G , Mehra Rohit , Menon Santosh , Mishra Pritinanda , Moch Holger , Montironi Rodolfo , Baisakh Manas R , Netto George J , Nigam Lovelesh K , Osunkoya Adeboye O , Pagliuca Francesca , Paner Gladell P , Panizo Angel , Parwani Anil V , Picken Maria M , Prendeville Susan , Przybycin Christopher G , Purkait Suvendu , Queipo Francisco J , Rao B Vishal , Rao Priya , Reuter Victor E , Sancheti Sankalp , Sangoi Ankur R , Sardana Rohan , Satturwar Swati , Shah Rajal B , Sharma Shivani , Dixit Mallika , Verma Monica , Sirohi Deepika , Smith Steven C , Soni Shailesh , Sundaram Sandhya , Swain Meenakshi , Tretiakova Maria , Trpkov Kiril , MuñizUnamunzaga Gorka , Zhou Ming , Williamson Sean R , Lopez‐Beltran Antonio , Cheng Liang , Mohanty Sambit K 
Published: July 2024

Aims

Urothelial carcinoma (UC) demonstrates significant molecular and histologic heterogeneity. The WHO 2022 classification has hinted at adding molecular signatures to the morphologic diagnosis. As morphology and associated molecular repertoire may potentially translate to choices of and response to therapy and relapse rate, broader acceptability of recognizing these key features among uropathologists is needed. This prompted an international survey to ascertain the practice patterns in classical/subtype UC among uropathologists across the globe.

Methods and Results

A survey instrument was shared among 98 uropathologists using SurveyMonkey software. Anonymized respondent data were analysed. The response rate was 85%. A majority were in concordance with the profiles of luminal (93%) and basal (82%) types. Opinion on the FGFR3 testing platform was variable. While 95% concurred that TERT promoter mutation is the key driver in UC, 72% had the opinion that APOBEC mutagenesis is the main signature in muscle invasive bladder cancer (MIBC). Uropathologists have divergent opinions on MIBC and ERCC2 mutations. Among the participants, 94% would quantify aggressive micropapillary and sarcomatoid histology, while 88% would reevaluate another transurethral resection of the bladder tumour specimen in nonmuscle invasive tumour with micropapillary, small cell, or sarcomatoid histology. A leading number agreed to specific molecular signatures of micropapillary (93%), plasmacytoid (97%), and small cell (86%) subtypes. Ninety‐six percent of participants agreed that a small‐cell component portends a more aggressive course and should be treated with neoadjuvant chemotherapy and 63% would perform HER2/neu testing only on oncologist's request in advanced tumours. Ninety percent agreed that microsatellite instability testing, although not a standard protocol, should be considered in young patients with upper tract UC. Eighty‐six percent agreed that UC with high tumour mutational burden would be a better candidate for immunotherapy.

Conclusion

In the era of precision medicine, enhanced understanding of molecular heterogeneity of UC will contribute to better therapeutic options, novel biomarker discovery, innovative management protocols, and outcomes. Our survey provides a broad perspective of pathologists' perceptions and experience regarding incorporation of histomolecular approaches to “personalize” therapy. Due to variable clinical adoption, there is a need for additional data using uniform study criteria. This will drive generation of best practice guidelines in this area for widespread and consistent clinical utility.