Urinary bladder cancer (BCa) is the most common malignancy of the urinary system with an estimated 81,180 new cases in the United States in 2022 (61,700 cases in men and 19,480 cases in women) [1]. It is the fourth most commonly diagnosed cancer in men in the US accounting for approximately 6 % of all new cancer cases among this patient population [1]. Tumor pathologic grade is an important factor in predicting the outcome of urothelial carcinoma [2].

Different grading systems have been used during the past decades to classify urothelial carcinomas, the latest being the World Health Organization/International Society of Urological Pathology (WHO/ISUP) consensus classification system which emerged in 2004 and had an updated revision in 2016 [3]. Previous classification systems were once limited in their utility due to issues with inter-observer reproducibility and misclassifications [4]. The ISUP classification system of flat and papillary lesions of the urothelium – which has been endorsed by the WHO – places papillary urothelial neoplasms into 4 categories: papilloma; papillary urothelial neoplasm of low malignant potential (PUNLMP); low-grade papillary urothelial carcinoma (LGPUC); and high-grade papillary urothelial carcinoma (HGPUC) [5]. Specifically, LGPUC is characterized by an overall orderly appearance with minimal variability in architecture and absence of significant cytologic atypia and mitotic activity [4]. Patients with LGPUC usually have a lower risk for tumor recurrence following transurethral resection of bladder tumor (TURBT) than patients with HGPUC, with a subset of patients developing grade and/or stage progression [4], [6]. Several clinicopathological and molecular/genetic factors contribute to this progression.

In a study by Miamoto et al., the authors showed that recurrence of LGPUC of the urinary bladder occurs in 53.8 %, including 35.6 % without upgrading and 18.3 % with upgrading to HGPUC [4]. The only factor shown to be significantly correlated to higher risk of recurrence was the presence of multiple tumors at initial diagnosis [4]. Another study by Dutta et al. revealed that none of the clinicopathological variables studied were significantly associated with grade or stage progression [6]. Nevertheless, patients with larger initial tumor sizes or multiple lesions at initial diagnosis had an increased recurrence rate [6].

The finding of upgraded recurrences reinforced the hypothesis of tumor heterogeneity and proved that different uroprogenitor cells potentially exist within LGPUC tumors and in the tumor microenvironment (TME) surrounding the lesion [7]. Those uroprogenitor cells harbor various intrinsic genetic signatures and molecular aberrations prompting differential tumor behaviors between patients [8]. This concept has been recently studied by Guo et al. in 2019 wherein the authors demonstrated the presence of distinct alterations of DNA and RNA in urinary BCa that may underlie its diverse clinicopathologic features, leading to a proposed novel molecular classification [8]. Accordingly, patients with LGPUC might also have different genomic signatures based on the presence of distinct uroprogenitor cells that could explain the differential tumor behavior and outcomes [9]. Studying the clinicopathological variables of those patients and histopathological features along with the genetic signatures of their tumors and correlating them with the tumor behavior can provide novel insights into deciphering the biological nature underlying this complex disease, which may lead to more effective patient-oriented personalized treatments.

In this study, we aimed to identify the incidence of tumor recurrence of LGPUC on initial biopsies, upgrading to HGPUC, or lack of recurrence utilizing the WHO/ISUP grading system. The efforts of this study can be applied to patient care as well as urological oncology guidelines and care planning.