Upper tract urothelial carcinoma (UTUC) is rare and accounts for 5-10% of all urothelial carcinomas with an estimated five-year recurrence-free survival and cancer-specific survival of 73% and 78%, respectively. To date, much of decision-making in UTUC comes from knowledge acquired in UCB due to its relative rarity, although a large body of evidence has proven that UTUC and UCB differ in a significant degree.
Continued research has led to the discovery of new risk factors, enhancing our understanding of this disease and potentially improving the prevention and early detection of UTUC. The sensitivity and specificity of CT urography to detect UTUC are continuously improving and are estimated to be in the range of 67-100% and 93-99%, respectively. Positive urinary cytology is crucial in the diagnosis of UTUC and it is recommended to perform it in situ before the contrast injection in case of retrograde uretero-pyelography. Routine flexible ureteroscopy (URS) associated with biopsy has been estimated to reduce misdiagnoses from 15.5% to 2%. In addition to diagnosis, URS allows also therapy in those patients benefitting from conservative therapy. Not only tumor stage and grade, but also tumor multifocality, lymphovascular invasion, extensive tumor necrosis, tumor size ≥ 3cm, sessile tumor architecture and hydronephrosis negatively influence UTUC prognosis. Genetic and epigenetic biomarkers, based on tissue, urine and blood, have achieved good sensitivities and specificities for diagnosis and prognosis in pilot studies but none has so far been validated.
Regarding the different surgcal options, the gold standard treatment for localized high-risk UTUC is a radical nephroureterectomy (RNU), which consists of en block removal of the kidney, renal pelvis, extra-mural and intra-mural ureter, ureteral orifice, and a cuff of bladder around the ureteral orifice. The available data suggest comparable oncologic outcomes following either open or minimally invasive RNU. From an oncologic standpoint, it is imperative to (1) avoid entry into the urinary tract to prevent tumor spillage or seeding; and (2) completely excise of the ureter distal to the tumor and bladder cuff because of a high risk of recurrence. Lymph node dissection (LND) allows for optimal staging of disease and numerous retrospective studies have found a survival benefit in patients with ≥pT2 disease. Therefore although randomized trials are not available to clarify its role on overall survival, LND is recommended when technically feasible. Although no randomized trials comparing conservative treatment with RNU are available nowadays, the nephron-sparing approach may be a valid alternative especially in case of renal insufficiency, solitary functional kidney, bilateral disease or low-risk tumors. However, despite a better protection of kidney function, endoscopic treatment of UTUC have a rate of local and bladder recurrence of approximately 25% and 15%. Complete distal ureterectomy and neocystostomy is another valid and oncologic safe alternative for large volume non-invasive low-grade UTUC located in the distal ureter, which are not possible to manage endoscopically. The percutaneous approach could be considered for low-grade tumors in the lower caliceal system, even though only small case series have been reported and technical improvements in new flexible ureteroscopes are replacing this procedure.
Compared to urothelial carcinoma of the bladder, there has been less robust evidence in terms of randomized clinical trials to clarify the role of perioperative chemotherapy in UTUC. Neoadjuvant chemotherapy is a promising and emerging approach for UTUC patients, particularly those with good renal function and histologic evidence of high-grade muscle-invasive disease. The latest meta-analysis investigating the role of adjuvant chemotherapy (AC) found a 57% benefit in OS among those patients treated with AC compared to those who received surgery alone.
Information on the role of surgery among patients with metastatic UTUC is lacking and so far there is no clear survival benefit of a RNU in patients with metastatic disease. Instead, metastatic UTUC is typically managed with systemic chemotherapy.
In conclusion, while RNU remains the gold standard treatment for localized invasive UTUC, the use of nephron-sparing options for select patients as well as minimally invasive RNU has decreased morbidity and will likely play an increasing important role in the care of patients with UTUC. There has been little improvement in the prognosis of this disease over the past two decades, highlighting the necessity for better multimodality therapeutic options incorporating the latest advances in chemotherapy and radiotherapy to achieve improved outcomes for our patients with UTUC.
Ilaria Lucca, MD, Jeffrey J Leow, MD, Shahrokh F Shariat, MD, Steven L Chang, MD MS
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, Vienna A-1090, Austria; Department of Urology, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, Lausanne 1011, Switzerland; Department of Urology, Bladder Cancer Center, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, 450 Brookline Ave, Boston, MA 02215, USA; Division of Urology, Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; Department of Urology, University of Texas Southwestern Medical Center, 1801 Inwood Rd, Dallas, TX 75235, USA; Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, Cornell University, 1300 York Avenue, New York, NY 10065, USA.