Upper Tract Urothelial Carcinoma: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Panagiotis Vlachostergios.

Upper tract urothelial carcinoma (UTUC) is a rare malignancy, occurring in 5–10% of patients diagnosed with UC, and involves the renal pelvis, calyces, or ureters. UTUC can be sporadic or hereditary as a clinical manifestation of Lynch syndrome. Therapeutic management of these patients is challenging. Following risk stratification of localized disease, patients with low-grade UTUC may undergo kidney-sparing surgery or radical nephroureterectomy (RNU) and/or chemoablation with mitomycin-c instillation to reduce recurrence.

  • upper tract urothelial carcinoma
  • cisplatin-based chemotherapy
  • FGFR3

1. Introduction

Upper tract urothelial carcinoma (UTUC) accounts for approximately 5–10% of cases diagnosed with urothelial carcinoma (UC) [1]. While UTUC presents in pyelocaliceal cavities and ureters, approximately half of UTUC cases will exhibit concurrent UC of the bladder (UCB) [1]. In Western countries, UTUC has an incidence of 1–2 cases per 100,000, diagnosed mainly in older patients; in some Asian countries, UTUC accounts for 25% of all UC cases, presenting with more aggressive features [2,3][2][3]. UTUC and UCB share common risk factors, including cigarette smoking, occupational exposure, and a high dietary intake of aristolochic acid. UTUC may also occur as part of Lynch syndrome, also known as hereditary non-polyposis colorectal cancer syndrome, due to germline mutation in DNA mismatch repair genes [4,5][4][5]. Nevertheless, the majority (80%) of UTUCs are not associated with LS but emerge as a result of sporadic events. UTUC may present with aggressive clinical behavior at diagnosis. More than half of patients are found to have muscle-invasive disease, which is often already metastatic [6]. Moreover, UTUC is also associated with poor clinical outcomes demonstrating a 5-year specific survival of less than 50% and 10% for pT2/T3 and pT4 tumor stages, respectively [7]. Radical nephroureterectomy (RNU) with lymphadenectomy and bladder cuff removal is the standard of care for these patients, while the addition of perioperative platinum-based combination therapy has led to an improvement in prognosis compared to RNU alone and constitutes the gold standard of treatment according to international guidelines [8,9,10][8][9][10]. In the metastatic setting, platinum-based chemotherapy remains the initial treatment of choice in eligible patients. The emergence of immune checkpoint inhibition (ICI), particularly against the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) axis, as a therapeutic strategy for maintenance or beyond progression to platinum-based chemotherapy has offered a significant clinical benefit to UC patients, including those with upper tract disease [8,9,10][8][9][10]. Additionally, recent studies have revealed an important role of FGFR-, nectin-4-, and TROP2-targeting with tyrosine kinase inhibitors and antibody–drug conjugates (ADCs), respectively, in further improving the prognosis of UC patients with platinum- and/or ICI-refractory disease [11,12][11][12].
All of these advances in the therapeutic armamentarium of UTUC would have been impossible without molecular characterization studies in UC. In the era of precision medicine, the entry of novel technologies including next-generation sequencing (NGS) in cancer diagnosis and treatment has transformed our the knowledge in predicting the activity of targeted therapies exploiting the defects or specific oncogene addiction present in various tumor types. In UTUC, an increasing number of studies have focused on the molecular characterization of the disease in an effort to understand the underlying biology of this tumor and identify potential therapeutic targets and corresponding biomarkers or response and resistance. Despite UTUC being poorly represented in the Cancer Genome Atlas (TCGA) data, smaller studies focusing exclusively on UTUC have revealed distinct molecular and genetic features of UTUC compared to UCB [13]. Elucidation of the genomic and immune landscape of UTUC has played an important role in understanding the key pathways involved in its development and progression, resulting in an explosion of novel targeted therapies and combinations [13].

2. Diagnosis and Staging of UTUC

The diagnosis and staging of UTUC involves a combination of urine cytology, imaging studies, and endoscopy in order to stratify patients into risk groups for tailoring treatment selection. Computed tomographic (CT) urography is an integral part of the diagnosis and staging of these patients, with a sensitivity and specificity of 92% and 95%, respectively [14]. However, radiation exposure, nephrotoxicity, and allergic reactions after iodine contrast administration must be taken under consideration. When CT urography is contraindicated, magnetic resonance urography represents an alternative imaging study. However, it lacks sensitivity (around 75%), compared to CT urography, in diagnosing tumors < 2 cm [15]. In the metastatic setting, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can be performed for the detection of nodal metastases, demonstrating a sensitivity and specificity of 82 and 84%, respectively [16]. Patients with suspicious lymph nodes on FDG-PET/CT experience a worse recurrence-free survival [16]. Endoscopy with ureteroscopy (URS) and cystoscopy remains the cornerstone in the diagnosis of patients with UTUC. Direct visualization of a suspected lesion in the ureter or the pyelocaliceal system using a flexible or rigid ureteroscope is used to confirm the diagnosis and assess its main features, including appearance, multifocality, and size, stratifying patients into low- and high-risk groups [1]. Selective ureteral sampling for cytology in situ can also be obtained [17[17][18],18], while performing a biopsy of the suspected lesion is questionable due to the observed under-staging occurring with URS as compared to RNU [19,20][19][20]. Additionally, in a meta-analysis comparing the use of URS prior to RNU, 8 out of 12 studies found that there was a higher risk of intravesical recurrence if URS was performed before RNU compared to conducting RNU without prior URS [21]. Conducting a biopsy during URS was also identified as a factor increasing the risk of intravesical recurrence [21]. Another systematic review of 16 studies indicated that URS alone did not have a significant association with intravesical recurrence; in contrast, URS combined with a biopsy significantly increased the risk of subsequent intravesical recurrence, although it did not have an independent effect on long-term survival outcomes [22]. Further to diagnostic URS, urethrocystoscopy is also important in the diagnostic workup of UTUC due to the presence of concomitant UCB in around 50% of patients [1]. Urinary cytology can also be used in the diagnosis and staging of UTUC patients. Abnormal cytology indicates high-grade disease when cystoscopy is normal, and there is no evidence of carcinoma in situ in the bladder and prostatic urethra [23]. However, cytology is less sensitive in the diagnosis of UTUC compared to UCB and should be performed selectively from the affected upper tract [24].

3. Clinical Phenotype and Management of Localized UTUC

According to the European Association of Urology (EAU), UTUC can be stratified into low-risk and high-risk disease based on clinical, endoscopic, radiographic, and histopathologic factors [1,25][1][25]. Low-risk localized disease is unifocal—with a tumor size < 2 cm, low-grade cytology, and/or URS biopsy—and noninvasive on imaging. In contrast, high-risk disease is characterized by hydronephrosis, multifocal tumors > 2 cm, high-grade cytology and/or URS biopsy, invasive disease on imaging, and a history of prior UCB treated with radical cystectomy [1,25][1][25]. Patients presenting with low-risk localized disease can be treated with kidney-sparing surgical approaches including segmental ureterectomy, ureteroscopy, percutaneous tumor resection, or radical nephroureterectomy (RNU). Kidney-sparing approaches reduce the morbidity associated with radical surgery and are well-suited for patients possessing a solitary kidney or compromised renal function [1,25][1][25]. However, offering kidney-sparing surgery must be accompanied by meticulous and strict follow-up with repeat cystoscopy, ureteroscopy, upper urinary tract imaging, and urine cytology to avoid compromising oncological outcomes [26]. In order to reduce recurrence rates in patients undergoing kidney-sparing surgeries, several studies have examined the use of intraluminal therapies with Bacillus Calmette–Guérin (BCG) or mitomycin-c (MMC) in low-risk localized UTUC. Instillation of these agents in the renal pelvis or the ureter can be performed with a percutaneous approach through a nephrostomy catheter or retrograde through a single J open-end ureteric stent, while the use of a double J stent is not recommended because the reflux may be inadequate to transfer the drug to the renal pelvis [27]. However, both percutaneous and retrograde administration of these drugs may be complicated by ureteric obstruction and pyelovenous influx. Several studies have evaluated recurrence rates after administration of BCG in the adjuvant setting of low-risk localized UTUC [27,28,29][27][28][29] or as a primary therapy for carcinoma in situ [27,28,30,31][27][28][30][31]. These studies have reported a recurrence rate of 13–59% after adjuvant therapy with BCG. However, administration of adjuvant BCG after endoscopic tumor resection did not result in significantly lower recurrence rates (26% for endoscopic management alone and 33% for those receiving adjuvant BCG) [29]. Similar results were reported in a meta-analysis by Foerster et al. [32]. An insufficient concentration of the drug for an adequate time period, due to urine excretion, seems to be the main reason why BCG instillation has been an inadequate measure for preventing recurrences. Mitomycin-c is another drug that has been studied for intraluminal treatment of low-grade UTUC. Recently, UGN-101 (JELMYTO), a mitomycin-containing reverse thermal gel (4 mg MMC/mL) was evaluated in the OLYMPUS study, a phase-III trial, showing promising results after kidney-sparing surgery [33]. UGN-101 exhibits a liquid form in a cold environment. Upon instillation, it becomes a semisolid gel at body temperature that dissolves during urine production over 4–6 h, allowing mitomycin to act at the tumor site. A total of 74 patients were enrolled in the OLYMPUS trial, with 71/74 receiving at least one dose of UGN-101, while 61 completed the 6-weekly instillation protocol. Of the 71 patients who received induction therapy, 42 achieved a complete response, and 41/42 initiated follow-up. Of these 41 patients, 56% remained in complete response after one year with or without maintenance treatment. The most common adverse event related to UGN-101 instillation was ureteric stenosis, while urinary tract infection, hematuria, and flank pain were also related to drug administration and/or the procedure. However, there was no statistically significant difference in the mean eGFR change before, during, or after treatment. Therefore, instillation of UGN-101 appears to be effective in the treatment of low-risk localized UTUC, with a low rate of adverse events [33].

References

  1. Rouprêt, M.; Seisen, T.; Birtle, A.J.; Capoun, O.; Compérat, E.M.; Dominguez-Escrig, J.L.; Gürses Andersson, I.; Liedberg, F.; Mariappan, P.; Hugh Mostafid, A.; et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. Eur. Urol. 2023, 84, 49–64.
  2. Soria, F.; Shariat, S.F.; Lerner, S.P.; Fritsche, H.-M.; Rink, M.; Kassouf, W.; Spiess, P.E.; Lotan, Y.; Ye, D.; Fernández, M.I.; et al. Epidemiology, Diagnosis, Preoperative Evaluation and Prognostic Assessment of Upper-Tract Urothelial Carcinoma (UTUC). World J. Urol. 2017, 35, 379–387.
  3. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2020. CA Cancer J. Clin. 2020, 70, 7–30.
  4. Colin, P.; Koenig, P.; Ouzzane, A.; Berthon, N.; Villers, A.; Biserte, J.; Rouprêt, M. Environmental Factors Involved in Carcinogenesis of Urothelial Cell Carcinomas of the Upper Urinary Tract. BJU Int. 2009, 104, 1436–1440.
  5. Rouprêt, M.; Yates, D.R.; Comperat, E.; Cussenot, O. Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum. Eur. Urol. 2008, 54, 1226–1236.
  6. Collà Ruvolo, C.; Nocera, L.; Stolzenbach, L.F.; Wenzel, M.; Cucchiara, V.; Tian, Z.; Shariat, S.F.; Saad, F.; Longo, N.; Montorsi, F.; et al. Incidence and Survival Rates of Contemporary Patients with Invasive Upper Tract Urothelial Carcinoma. Eur. Urol. Oncol. 2021, 4, 792–801.
  7. Ruvolo, C.C.; Nocera, L.; Stolzenbach, L.F.; Wenzel, M.; Califano, G.; Tian, Z.; Verze, P.; Shariat, S.F.; Saad, F.; Briganti, A.; et al. Tumor Size Predicts Muscle-Invasive and Non–Organ-Confined Disease in Upper Tract Urothelial Carcinoma at Radical Nephroureterectomy. Eur. Urol. Focus 2022, 8, 498–505.
  8. Califano, G.; Xylinas, E. Re: Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma. Eur. Urol. 2020, 78, 113–114.
  9. Pradère, B.; Califano, G.; Xylinas, E. Perioperative Chemotherapy for Upper Tract Urothelial Carcinoma: Show Me the Evidence. Curr. Opin. Urol. 2021, 31, 66–67.
  10. Leow, J.J.; Chong, Y.L.; Chang, S.L.; Valderrama, B.P.; Powles, T.; Bellmunt, J. Neoadjuvant and Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A 2020 Systematic Review and Meta-Analysis, and Future Perspectives on Systemic Therapy. Eur. Urol. 2021, 79, 635–654.
  11. Witjes, J.A.; Bruins, H.M.; Cathomas, R.; Compérat, E.M.; Cowan, N.C.; Gakis, G.; Hernández, V.; Linares Espinós, E.; Lorch, A.; Neuzillet, Y.; et al. European Association of Urology Guidelines on Muscle-Invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur. Urol. 2021, 79, 82–104.
  12. Califano, G.; Ouzaid, I.; Verze, P.; Hermieu, J.-F.; Mirone, V.; Xylinas, E. Immune Checkpoint Inhibition in Upper Tract Urothelial Carcinoma. World J. Urol. 2021, 39, 1357–1367.
  13. Hassler, M.R.; Bray, F.; Catto, J.W.F.; Grollman, A.P.; Hartmann, A.; Margulis, V.; Matin, S.F.; Roupret, M.; Sfakianos, J.P.; Shariat, S.F.; et al. Molecular Characterization of Upper Tract Urothelial Carcinoma in the Era of Next-Generation Sequencing: A Systematic Review of the Current Literature. Eur. Urol. 2020, 78, 209–220.
  14. Janisch, F.; Shariat, S.F.; Baltzer, P.; Fajkovic, H.; Kimura, S.; Iwata, T.; Korn, P.; Yang, L.; Glybochko, P.V.; Rink, M.; et al. Diagnostic Performance of Multidetector Computed Tomographic (MDCTU) in Upper Tract Urothelial Carcinoma (UTUC): A Systematic Review and Meta-Analysis. World J. Urol. 2020, 38, 1165–1175.
  15. Takahashi, N.; Glockner, J.F.; Hartman, R.P.; King, B.F.; Leibovich, B.C.; Stanley, D.W.; Fitz-Gibbon, P.D.; Kawashima, A. Gadolinium Enhanced Magnetic Resonance Urography for Upper Urinary Tract Malignancy. J. Urol. 2010, 183, 1330–1365.
  16. Voskuilen, C.S.; Schweitzer, D.; Jensen, J.B.; Nielsen, A.M.; Joniau, S.; Muilwijk, T.; Necchi, A.; Azizi, M.; Spiess, P.E.; Briganti, A.; et al. Diagnostic Value of 18F-Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography for Lymph Node Staging in Patients with Upper Tract Urothelial Carcinoma. Eur. Urol. Oncol. 2020, 3, 73–79.
  17. Clements, T.; Messer, J.C.; Terrell, J.D.; Herman, M.P.; Ng, C.K.; Scherr, D.S.; Scoll, B.; Boorjian, S.A.; Uzzo, R.G.; Wille, M.; et al. High-Grade Ureteroscopic Biopsy Is Associated with Advanced Pathology of Upper-Tract Urothelial Carcinoma Tumors at Definitive Surgical Resection. J. Endourol. 2012, 26, 398–402.
  18. Ishikawa, S.; Abe, T.; Shinohara, N.; Harabayashi, T.; Sazawa, A.; Maruyama, S.; Kubota, K.; Matsuno, Y.; Osawa, T.; Shinno, Y.; et al. Impact of Diagnostic Ureteroscopy on Intravesical Recurrence and Survival in Patients with Urothelial Carcinoma of the Upper Urinary Tract. J. Urol. 2010, 184, 883–887.
  19. Mori, K.; Katayama, S.; Laukhtina, E.; Schuettfort, V.M.; Pradere, B.; Quhal, F.; Sari Motlagh, R.; Mostafaei, H.; Grossmann, N.C.; Rajwa, P.; et al. Discordance Between Clinical and Pathological Staging and Grading in Upper Tract Urothelial Carcinoma. Clin. Genitourin Cancer 2022, 20, 95.e1–95.e6.
  20. Smith, A.K.; Stephenson, A.J.; Lane, B.R.; Larson, B.T.; Thomas, A.A.; Gong, M.C.; Jones, J.S.; Campbell, S.C.; Hansel, D.E. Inadequacy of Biopsy for Diagnosis of Upper Tract Urothelial Carcinoma: Implications for Conservative Management. Urology 2011, 78, 82–86.
  21. Sharma, V.; Miest, T.S.; Juvet, T.S.; Toussi, A.; Packiam, V.; Chamie, K.; Matin, S.F.; Boorjian, S.A.; Thompson, R.H.; Frank, I.; et al. The Impact of Upper Tract Urothelial Carcinoma Diagnostic Modality on Intravesical Recurrence after Radical Nephroureterectomy: A Single Institution Series and Updated Meta-Analysis. J. Urol. 2021, 206, 558–567.
  22. Nowak, Ł.; Krajewski, W.; Chorbińska, J.; Kiełb, P.; Sut, M.; Moschini, M.; Teoh, J.Y.-C.; Mori, K.; Del Giudice, F.; Laukhtina, E.; et al. The Impact of Diagnostic Ureteroscopy Prior to Radical Nephroureterectomy on Oncological Outcomes in Patients with Upper Tract Urothelial Carcinoma: A Comprehensive Systematic Review and Meta-Analysis. J. Clin. Med. 2021, 10, 4197.
  23. VandenBussche, C.J.; Hang, J.-F.; McIntire, P.J.; Miki, Y.; Peyton, S.; Vohra, P.; Zhang, M.L. Cytopathology of the Upper Urinary Tract. In The Paris System for Reporting Urinary Cytology; Wojcik, E.M., Kurtycz, D.F.I., Rosenthal, D.L., Eds.; Springer International Publishing: Cham, Switzerland, 2022; pp. 115–141. ISBN 978-3-030-88686-8.
  24. Messer, J.; Shariat, S.F.; Brien, J.C.; Herman, M.P.; Ng, C.K.; Scherr, D.S.; Scoll, B.; Uzzo, R.G.; Wille, M.; Eggener, S.E.; et al. Urinary Cytology Has a Poor Performance for Predicting Invasive or High-Grade Upper-Tract Urothelial Carcinoma. BJU Int. 2011, 108, 701–705.
  25. Coleman, J.A.; Clark, P.E.; Bixler, B.R.; Buckley, D.I.; Chang, S.S.; Chou, R.; Hoffman-Censits, J.; Kulkarni, G.S.; Matin, S.F.; Pierorazio, P.M.; et al. Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline. J. Urol. 2023, 209, 1071–1081.
  26. Seisen, T.; Peyronnet, B.; Dominguez-Escrig, J.L.; Bruins, H.M.; Yuan, C.Y.; Babjuk, M.; Böhle, A.; Burger, M.; Compérat, E.M.; Cowan, N.C.; et al. Oncologic Outcomes of Kidney-Sparing Surgery Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the EAU Non-Muscle Invasive Bladder Cancer Guidelines Panel. Eur. Urol. 2016, 70, 1052–1068.
  27. Giannarini, G.; Kessler, T.M.; Birkhäuser, F.D.; Thalmann, G.N.; Studer, U.E. Antegrade Perfusion with Bacillus Calmette-Guérin in Patients with Non–Muscle-Invasive Urothelial Carcinoma of the Upper Urinary Tract: Who May Benefit? Eur. Urol. 2011, 60, 955–960.
  28. Katz, M.H.; Lee, M.W.; Gupta, M. Setting a New Standard for Topical Therapy of Upper-Tract Transitional-Cell Carcinoma: BCG and Interferon-Alpha2B. J. Endourol. 2007, 21, 374–377.
  29. Rastinehad, A.R.; Ost, M.C.; Vanderbrink, B.A.; Greenberg, K.L.; El-Hakim, A.; Marcovich, R.; Badlani, G.H.; Smith, A.D. A 20-Year Experience with Percutaneous Resection of Upper Tract Transitional Carcinoma: Is There an Oncologic Benefit with Adjuvant Bacillus Calmette Guérin Therapy? Urology 2009, 73, 27–31.
  30. Kojima, Y.; Tozawa, K.; Kawai, N.; Sasaki, S.; Hayashi, Y.; Kohri, K. Long-Term Outcome of Upper Urinary Tract Carcinoma in Situ: Effectiveness of Nephroureterectomy versus Bacillus Calmette-Guérin Therapy. Int. J. Urol. 2006, 13, 340–344.
  31. Shapiro, E.Y.; Lipsky, M.J.; Cha, D.Y.; McKiernan, J.M.; Benson, M.C.; Gupta, M. Outcomes of Intrarenal Bacillus Calmette-Guérin/Interferon-A2B for Biopsy-Proven Upper-Tract Carcinoma in Situ. J. Endourol. 2012, 26, 1645–1650.
  32. Foerster, B.; D’Andrea, D.; Abufaraj, M.; Broenimann, S.; Karakiewicz, P.I.; Rouprêt, M.; Gontero, P.; Lerner, S.P.; Shariat, S.F.; Soria, F. Endocavitary Treatment for Upper Tract Urothelial Carcinoma: A Meta-Analysis of the Current Literature. Urol. Oncol. Semin. Orig. Investig. 2019, 37, 430–436.
  33. Matin, S.F.; Pierorazio, P.M.; Kleinmann, N.; Gore, J.L.; Shabsigh, A.; Hu, B.; Chamie, K.; Godoy, G.; Hubosky, S.G.; Rivera, M.; et al. Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report. J. Urol. 2022, 207, 779–788.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback