Upper tract urothelial carcinoma (UTUC) accounts for only 5–10% of all urothelial cancers.¹ Given its uncommon nature, many assumptions regarding the biology of UTUC and the approach to treatment have traditionally been extrapolated from urothelial carcinoma of the bladder (UCB). However, as our molecular understanding of UTUC matures, we are learning that UTUC and UCB may, in fact, reflect distinct biological entities—an epiphany crucial to improving outcomes in patients with UTUC.

The disparate embryologic origins and risk factors underlying the development of each entity provide initial clues into the differences between the two. While UCB develops within endoderm-derived epithelium, given the bladder’s origin from the urogenital sinus, UTUC develops in mesoderm-derived epithelium, as the ureteric bud arises from the mesonephric duct. Lymphatic drainage patterns also vary by the anatomical location of the tumor. Furthermore, while tobacco exposure has been classically associated with the development of most sporadic forms of UCB and UTUC, the latter also has unique associations with Lynch syndrome and aristolochic acid exposure, which are not risk factors identified for UCB.^2,3 Interestingly, aristolochic acid, which is found in some Chinese herbal supplements and serves as the causative agent in Balkan endemic nephropathy, forms nephrotoxic aristolactam-DNA adducts within the renal cortex that generate a unique carcinogenic TP53 mutational spectrum in the urothelium giving rise to UTUC.³ Conceivably, this mechanism of UTUC pathogenesis may even suggest differential biologies or subtypes among UTUC, as evidenced by regional differences in clinicopathological characteristics and patient outcomes in UTUC.⁴ Furthermore, patients with Lynch syndrome have a unique predisposition to develop UTUC by virtue of germline inactivating mutations in mismatch repair genes, which may even hold implications for immunotherapy responsiveness.⁵

Molecular studies characterizing UTUC tumors have emerged over the past few years, providing additional insights into their biology and their clonal relatedness to UCB. In particular, UTUC and UCB have been noted to share substantial overlap in genomic alterations; however, the frequencies of these somatic mutations differ between the two among several genes, including FGFR3, HRAS, and KMT2D (higher in UTUC compared to UCB), along with TP53, RB1, ERBB2, and KDM6A (lower in UTUC compared to UCB), among others.^6,7 That being said, there is genomic evidence supporting a clonal relationship between UTUC and UCB in patients with a history of tumors in both locations.⁶ This observation seems logical based on an antegrade seeding phenomenon that may predispose UTUC patients to developing intravesical recurrence through a continuous urinary medium. This may be further exacerbated by mechanical manipulation (eg ureteroscopy, ureteral stents, surgical manipulation of the upper urinary tract), though a pan-urothelial predisposition to carcinogenesis may also exist. Whether distinct mechanisms of urothelial carcinogenesis are related to the anatomical location of the tumor in the urinary tract remains to be elucidated. Studies of clonal relatedness stratified by the sequence of metachronous recurrence (ie UTUC followed by UCB, versus UCB followed by UTUC) and by the development of bilateral UTUC may help shed further light on differences in field cancerization.

Notoriously, UTUC is fraught with diagnostic and staging challenges. Unlike UCB, which more easily affords tissue yield via transurethral resection to inform management by histological grade and depth of invasion, sampling tissue within the upper urinary tract is subject to technical limitations, with a high rate of pathological grade discordance between biopsies and final pathology.⁸ Urinary cytology is also less sensitive for detecting UTUC compared to UCB. Furthermore, accurately staging UTUC tumors poses additional challenges given the limitations of conventional cross-sectional imaging. By virtue of more aggressive biology and/or lead time bias, UTUC is found more often to be invasive at initial diagnosis compared to UCB (60% versus 15–25%), with poorer prognosis.¹ Identification of diagnostic and predictive urinary biomarkers with improved sensitivity and specificity for UTUC is of paramount contemporary interest to help surmount these challenges noninvasively.

While management of UTUC has traditionally relied on extrapolation from UCB literature, there are inherent challenges with UTUC that limit direct applications of these approaches. In particular, while topical therapies are acceptable standards to manage nonmuscle-invasive UCB via intravesical instillation, they have not been as widely adopted in managing UTUC based on the need for more evidence, challenges in dwell/contact time with the urothelium, and a cumbersome means of administration.⁹ Nevertheless, encouraging data from the OLYMPUS trial has recently led to the U.S. Food and Drug Administration approval of a mitomycin-containing reverse thermal gel for the topical management of selected low-grade UTUC.¹⁰ Furthermore, neoadjuvant chemotherapy followed by radical cystectomy is the gold standard treatment for muscle-invasive UCB based on level 1 evidence.¹¹ For high-risk UTUC in which radical nephroureterectomy serves as the surgical standard of care, however, the use of perioperative systemic platinum-based chemotherapy is complicated by renal functional compromise imposed by surgical removal of a renal unit. Accrual to trials for UTUC is considerably more challenging compared to UCB due to its rarity, but emerging prospective data have supported a growing role for multimodal integration of perioperative systemic treatments in this space.^12-14 Ongoing studies will help inform the role for immune checkpoint inhibitors and other targeted therapies, including FGFR inhibitors, for more precise approaches to treating advanced UTUC.

Indeed, while UTUC and UCB share many overlapping characteristics, they are anatomically, biologically, and practically 2 distinct diseases.⁹ Bearing these differences in mind will be paramount to optimizing outcomes in patients affected by UTUC, while personalizing treatment.