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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., (© 2024 John Wiley & Sons Ltd.)

A handful of therapeutic procedures are used to treat malignancies of the urinary tract, most frequently intravesical immunotherapy or chemotherapy, but also neoadjuvant systemic chemotherapy. These treatment modalities produce morphological changes in the urothelium that can be mistaken for carcinoma; in particular, these therapies frequently mimic urothelial carcinoma in situ (CIS) urothelial dysplasia or true invasive neoplasia. Drugs such as mitomycin C used after transurethral resection of bladder tumour to reduce recurrences, bacillus Calmette-Guérin (BCG) intravesical immunotherapy to treat high-risk non-muscle-invasive bladder cancer and urothelial CIS and platin-based systemic chemotherapy to improve postcystectomy disease-specific survival are examples of therapy-related atypia seen in the urinary tract. To complicate the pathologist's life, a number of systemic drugs in use to treat other diseases, such cyclophosphamide, used to treat some autoimmune disorders or certain haematological malignancies or, in the case of anaesthetics, ketamine, used increasingly as an illegal recreational drug, may produce similarly relevant atypical changes in the urothelium, and therefore need to be differentiated from intraepithelial neoplasia. Other less frequent procedures, such as photodynamic and laser therapy or the newer gene therapy to treat urothelial neoplasia, remain experimental. An immunohistochemical approach to reactive urothelium versus carcinoma in situ using p53, cytokeratin 20 and CD44 is also valid in the post-therapy setting. The pathologist should be aware of these novelties, as he or she plays a crucial role in evaluating treatment efficacy, but at the same time needs to avoid misdiagnosing secondary atypia as intraepithelial neoplasia., (© 2016 John Wiley & Sons Ltd.)

Aims: We performed a head-to-head comparison of an antibody against uroplakin III (UP3) and a new uroplakin II (UP2) antibody that remains untested in diagnostically challenging settings., Methods and Results: We immunostained high-grade bladder neck carcinomas (n = 35), high-grade upper tract urothelial carcinomas (UC) and renal carcinomas (n = 85), metastases of UC (n = 30) and a multicancer tissue microarray (n = 88) for UP3 and UP2, and scored staining intensity and proportion. UP3 showed membranous plaque-like expression, while UP2 staining showed both membranous and cytoplasmic positivity. Significantly greater intensity (P = 0.003) and proportion (P = 0.03) of staining was noted for UP2 among bladder neck lesions, with UP2 staining showing greater sensitivity (63% versus 19%) and similar specificity (95% versus 100%) for UC over prostate carcinoma (P = 0.02). Among upper tract lesions, UP2 staining showed greater intensity and proportion than UP3 (both P < 0.001), including improved sensitivity (68% versus 23%) and equal specificity (both 100%) for UC (P = 0.006). Among UC metastases, UP2 staining showed greater intensity and proportion (both P < 0.001) with higher sensitivity (73% versus 37%, respectively, P = 0.001). Of 88 additional cases tested, no non-urothelial cases stained for either UP., Conclusions: The UP2 antibody outperforms the UP3 antibody, including in diagnostically challenging settings, and is a useful addition to the armamentarium of biomarkers for UC., (© 2014 John Wiley & Sons Ltd.)

Non-epithelial prostatic neoplasms are infrequent and cover a broad array of entities that include both benign and highly aggressive tumours. Because they are very infrequent, there is often limited understanding of them, and the recognition of these entities, when encountered, may pose a diagnostic challenge, owing to histological overlap between them or their rarity. Most lesions in this category are mesenchymal in origin, such as prostatic stromal tumours arising from specialized prostatic stroma, smooth muscle tumours, both benign and malignant, and solitary fibrous tumours. Less commonly occurring tumours include neural, germ cell and melanocytic tumours that may be derived from cells not normally present in the prostate. Some tumours have well-established extraprostatic counterparts and, when encountered, are more commonly extraprostatic/secondary in origin; these include gastrointestinal stromal tumours and most haematopoietic tumours. The majority of tumours are characterized by a spindle cell pattern with significant overlap in morphological features. In this setting, appropriate use of immunohistochemistry and molecular studies are often necessary for accurate diagnosis, prognosis, or prediction for therapy. This review addresses and updates the clinicopathological features of the entire spectrum of non-epithelial tumours with an approach to the histological diagnosis., (© 2011 Blackwell Publishing Limited.)