Endoscopic Management of Upper Tract Urothelial Carcinoma (UTUC)

Anup Patel, BSc(1st Class), MBBS, MS, FRCS, FRCS(Urol)
Consultant Urological Surgeon, London, UK

Introduction

Radical nephro-ureterectomy (RNU) has been held as the gold standard treatment of all UTUC for over a century. During the initial development of Endourology as a specialist area of Urology at the end of the last millennium, the primary focus was to develop techniques and technology for stone management. These were later subsumed to manage other upper tract conditions such as UTUC by select pioneers in USA centers of excellence and training. Demetrius Bagley (east) and Gerhard Fuchs (west) championed natural orifice endoscopic management bi-coastally, while Arthur Smith championed percutaneous UTUC treatment in New York.

Rationale 

UTUC is a largely a disease of the elderly mostly male patient with a long-lifelong smoking history. As such, these patients are often frail, have multiple co-morbidities with limited renal reserve and in many cases, will have had a history of bladder UC. Even with the advent of minimally invasive excisional surgery, RNU, it’s potential complications, and the potential for dialysis after loss of vital functioning nephrons, may each take a significant toll on an elderly patient population from the triple perspectives of quality of life, morbidity and mortality. Moreover, analysis of large datasets in different continents has shown that about 1 in 3 patients uniformly subjected to RNU may have been over-treated for the long term threat posed by the disease present on final specimen pathology, while in reality, the true quality of the RNU gold standard falls well short of common belief. Together, these compelling facts set the scene for a concerted effort by a growing number of endourologists to embark on a renal preservation strategy, which after many decades, has belatedly been incorporated into contemporary International Guidelines.

Eligibility and Characterization

This depends on multiple factors relating to the patient (vide supra, imperative factors mandating renal functional preservation and patient choice), low risk disease biology (low grade + size<2cm), extent (focality), and timely referral to regional-national referral centers adequately resourced (equipment and expertise), where case volumes can be built up sufficiently over time to improve both performance and outcomes indicators, as with all complex specialist urological surgery. Use of an adequately sized ureteral access sheath placed only after optical inspection dilation of the entire ureter with a small tipped semi-rigid ureteroscope is mandatory. This provides twin benefits of low-pressure with small calibre flexible re-usable endoscopes, plus reduced downstream seeding risk.

Accurate characterization of “risk” is vital before embarking on a renal-urothelial preservation strategy to prevent both under and overtreatment. So as to leave no stone unturned, a combination of voided urine cytology, contrast based imaging (CTU-MRU-Retrograde Pyelogram) and direct endoscopic inspection are mandatory. Risk is based on a combination of multiple factors. Grade is invariably used as a surrogate for stage as deep biopsies from the tumor base risk perforating the thin upper tract collecting system integrity. High Grade tumor carries the highest risk tumor cell spread beyond the confines of the kidney and percutaneous resection should be avoided wherever possible in it’s presence. Adequate suspect lesion(s) should be mapped, and sized in comparison to a 1cm wide Nitinol basket. Tumor material sent to a specialist pathologist should include a combination of cup biopsies (as many as safely possible from both lesion [minimum 3 – ideally 6] and it’s base) and exophytic papillary lesions avulsed-debulked by the nitinol basket, plus wash cytology is obtained at regular intervals throughout the procedure to maximize exfoliated cell yield. 

Ablation

In the beginning, only a 3Fr monopolar electrode was available for ablation, which limited the amount of tumor that could be ablated in a single session before the electrode function was impaired by adherent char. With the availability of the short penetration Holmium:YAG pulsed stone laser in the mid 1990’s, more tumor could be ablated in a single sitting with relatively low energy (10-15 watts) using larger spot size for coagulation effects to control bleeding and maintain safe vision. It could also be used to slice off exophytic portions of tumor in stages with removal for pathology. However, the pulsed nature of the energy from the fiber tip created tip vibration and provided less control of precision at the lesion base. In the last decade, this has been overcome by the combination use of the Holmium-Thulium:YAG Duo laser. The benefits of additional Thulium:YAG incorporation come from its continuous wavelength and smaller thermo acoustic bubble size, providing superior coagulative precision ablation in contact mode (akin to bipolar electrocoagulation) with greater fiber tip stability. This makes it ideal for ablating the tumor base at the end of the procedure. The disadvantage is adherent tumor tissue to the fiber tip, which can be removed using the Holmium:YAG pulsed mode as described. Our international collaborative group has championed the use of this combination laser and recently reported 10-year outcomes, as the new gold standard UTUC ablative device. Lesions that are low risk but large in size should be ablated in stages with re-inspection at 3-week intervals to provide sufficient time for sloughing of treated tumor.  The procedure is completed by DJ stent placement and 24 hours Foley catheter bladder drainage to maintain low upper tract pressure and facilitate loose cell washout.

In the rare instances where a percutaneous approach is needed (large lower calcyceal inaccessible tumor after deployment of laser fiber), puncture and collection system entry with a sheath is safest, and should be from a clean opposite polar calyx from which a combination of rigid and flexible nephroscopes can be deployed with appropriate energy sources.

Endo-surveillance

Due to the poly-chrono-tropic nature of UTUC, all patients embarking on a renal preservation strategy require lifelong direct endoscopic surveillance (as with the lower tract) and a regimen advocated by the recent EAU guidelines is usually followed based on initial disease risk. “Recurrence” is dichotomised and either represents inadequate initial ablation leaving residual disease at the same site or true recurrence with new tumor formation at the same or new site.  Definitive evidence of the value of improved endoscopic tumor-abnormal urothelium visualization techniques such as PDD, NBI and SPIES in reducing recurrence is lacking at this time.

New Frontiers

There have been no reliable objective predictive or prognostic predictors of recurrence and disease progression. Since the link between advanced cancer and inflammation has been recognized for years, as proof of concept, our collaborative team has studied the role of inflammatory cells in a UTUC patient cohort selected for renal preservation. A retrospective large series analysis of baseline Neutrophil-Lymphycyte Ratio (NLR) has shown it’s predictive risk performance with a cut-off >3, in multivariate analysis for the first time. If the prospective study currently under way validates these findings, then future higher risk patients (beyond grade and tumor size-stage) could avoid under-treatment early on and others could benefit from risk adjusted individualized endo-surveillance regimens. Additional studies of other inflammatory markers are currently under way.

Take Home Messages

If Radical Cystectomy is not the panacea for all Bladder UC, then why is Radical Nephro-ureterectomy still the panacea for all UTUC irrespective of risk? In contemporary urological practice, urologists should assess risk carefully and select the optimal treatment option to get the best outcomes, taking into account the needs of the patient and the threat posed by tumor biology, rather than the preference(s) of an individual surgeon-center. Endoscopic renal preserving management options for UTUC should be developed in Regional- National Centers of Referral and Excellence.

Relevant References – Additional Reading

1. Long Term Outcome after Percutaneous Treatment of Transitional Cell Carcinoma of the Renal Pelvis. A.Patel, P.Soonawalla, S.Shepherd, D.Dearnaley, M.Kellett and C.R.J.Woodhouse. Journal of Urology, 1996, 155, 3, 868-873.

2. Laparoscopic Approaches to Transitional Cell Carcinoma of the Upper Urinary Tract. A.Patel and G.J.Fuchs Seminars in Surgical Oncology 996, 12, 1-8.

3. New Techniques for the Administration of Topical Adjuvant Therapy After Endoscopic Ablation of Upper Urinary Tract Transitional Cell Carcinoma. A.Patel and G.J.Fuchs. Journal of Urology 1998, 159, 1, 71-75.

4. The Role of Endoscopy in the Management of Patients with Upper Urinary Tract Transitional Cell Carcinomas I.M.Mills, M.Laniado and A.Patel European Urology Update Series: B.J.U.International 2001, 87, 150-162.

5. Thulium-Holmium:YAG Duo Laser in Conservative Upper Tract Urothelial Cancer Treatment: 13 Years Experience from a Tertiary National Referral Center. J Endourol. 2019 11; 33(11):902-908. Defidio L, Antonucci M, De Dominicis M, Fuchs G, Patel A. PMID: 31422699.

6. Combination of holmium and thulium laser ablation in upper tract urothelial carcinoma. World J Urol (2020). https://doi.org/10.1007/s00345-020-03124 z. World J Urol (2020). https://doi.org/10.1007/s00345-020-03279-9

7. Utility of preoperative Neutrophil / Lymphocyte ratio (NLR) as a new prognostic tool in renal conservation endoscopic management of upper tract urothelial carcinoma (UTUC). A retrospective evaluation. Antonucci M, Defidio L, De Dominicis M, Russo N, Nacchia A, Lombardo R, Patel A. J.Endourol. 2020 Sep;34(9):993-1000. doi: 10.1089/end.2020.0283. Epub 2020 Jul 31.

8. Troubling Outcomes From Population-level Analysis of Surgery for Upper Tract Urothelial Carcinoma. Abouassaly R. Alibhai SMH, Shah N, Timilshina N, Fleshner N, Finelli A. Urology 2010, 76, 4, 895-901.

Acknowledgements

This article is a summary of personal experience gained by the author over a professional lifetime in Endo-oncology, and I am most grateful in particular for mentorship, collaboration and friendship over many decades, to my senior colleagues Gerhard J Fuchs (my endourology teacher), Demetrius Bagley and Lorenzo Defidio.

Endoscopic Management of Upper Tract Urothelial Carcinoma (UTUC)
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