Thulium Laser Treatment of Upper Urinary Tract Carcinoma: A Multi-Institutional Analysis of Surgical and Oncological Outcomes

Abstract

Introduction:

To evaluate the efficacy and safety of ureteroscopic thulium laser (TL) treatment of upper urinary tract carcinoma (UTUC).

Materials and Methods:

Forty-two consecutive patients underwent conservative TL treatment for UTUC at two referral institutions. All patients underwent preliminary biopsy and then laser vaporization. A 272 μm and 365 μm laser fibers were used with a flexible and semirigid scope, respectively. Ablation was carried out with a 10 to 20 W power.

Results:

Mean age at surgery was 68 years (SD 10.7). Mean tumor size was 14.3 mm (range 2–30 mm). Preliminary biopsy revealed the presence of low-grade disease in 29 (69.1%) patients, high-grade disease in 4 (9.5%) and 1 carcinoma in situ 1 (2.4%), whereas it was not conclusive in 8 (19%) cases. Final stage was pTa and pTis in 41 (97.6%) and 1 (2.4%) patients, respectively. Thirty eight percent (16) experienced Clavien–Dindo grade I complication, 47.6% (20) grade II, and 2.4% (1) grade III. Five (12%) patients underwent a second-look procedure due to residual disease. Eight (19%) patients experienced clinical recurrence. The median estimated recurrence-free survival was 44 months (SE 3.68). Four patients (9.5%) underwent a nephroureterectomy. Final pathological stage was pTis, pT3 high grade, pTa low grade, and pT0. Median follow-up was 26.3 months (range 2–54 months), and no progression or upstaging of disease occurred.

Conclusions:

TL management of UTUC is a safe and efficacious conservative treatment. Our experience shows optimal vaporization and hemostatic control in the absence of major complications.

Introduction

Upper tract urinary carcinoma (UTUC) represents 5% to 10% of urothelial lesions.¹ The annual incidence of UTUC increased in western countries during the last decades, up to two new cases per 100,000 people.^2,3

Traditionally, radical nephroureterectomy (RNU) has been the only way of managing UTUC.⁴

Although the oncological outcomes of RNU are well described, this procedure exposes patients to major abdominal surgery morbidity, with an increased risk of post-operative acute or chronic renal failure.⁵

Even though a contralateral upper tract recurrence is rare (5% patients), an a priori radical approach for all patients should be excluded.⁶

The European Association of Urology (EAU) Guidelines include conservative approaches for the treatment of low-risk UTUC and in imperative cases of high-risk cancer.⁷

During the last decade, minimally invasive treatment of UTUC has been described using Holmium laser, diode laser, electrocoagulation, and their combination.⁸

Conversely, only few studies reported the results and follow-up of thulium laser (TL) ablation for pyeloureteral carcinoma.^9

–13 TL is widely used to treat benign prostatic hyperplasia due to its excellent vaporizing and coagulating capabilities combined with a minimal energy tissue penetrance.¹⁴

The aim of this study was to investigate the efficacy and safety of endoscopic treatment of UTUC with TL ablation.

Materials and Methods

From January 2012 to December 2016, 42 patients diagnosed with UTUC underwent conservative TL treatment in two referral Italian centers, European Institute of Oncology (IEO) and IRCCS Policlinico San Donato (PSD). Data were prospectively collected and retrospectively analyzed. Patients were enrolled according to EAU guideline indications for conservative treatment of low-risk lesions,¹ whereas in the case of high-risk tumors, only patients affected by chronic renal failure, solitary kidney, or major comorbidities were enrolled.

The diagnosis of UTUC was made with contrast-enhanced CT scan, urinary cytology, retrograde pyelography, and direct visualization during ureterorenoscopy (URS).

The follow-up flow chart is reported in Figure 1. Recurrences were defined as ipsilateral or contralateral UTUC determined ureteroscopically or radiologically. Disease progression was defined as radiological or pathological upgrading or upstaging.

FIG. 1.

Flowchart of the structured follow-up adopted in the study. URS = ureterorenoscopy.

Surgical technique

Procedures were carried out with Wolf Cobra flexible 6F distal tip ureterorenoscope, or Wolf Fiber ureterorenoscope, flexible 4.5F distal tip ureterorenoscope (Germany). Terumo hydrophilic guidewires were adopted in every procedure.

When the lesion became visible during endoscopy, selective urinary sample was taken and sent for cytological examination; then a biopsy was performed with a Piranha pinch (Boston Scientific), Zero Tip Basket (Boston Scientific), Olympus FB-56D-1 forceps, or PFM medical Multi-Snare^® Retrieval Snare, and sent for the definitive histological analysis.

Particularly, Multi-Snare Retrieval Snare was introduced due to the rate of inconclusive biopsy. Contrary to biopsy pinches, it allows a retrieval of a bigger sample, improving the quality of the tissue to analyze. Differently to endoscopic baskets, the two-plane shaped loop (with adjustable diameter) enables the retrieval of different kinds of samples.

The lesions were vaporized with TL: a Revolix TM 200 W or Quanta System Cyber TM 150 W. The power setting was 10 to 20 W, to obtain optimal vapo-coagulation effect with minimal tissue injuries; 272 μm fibers were adopted for flexible ureterorenoscope and, in case of ureteral lesions, 365 μm for semirigid ureterorenoscope. Moreover, lowering power emission to 5 W or distancing the laser tip from the site of interest (using 10–20 W) allowed having similar good results in terms of coagulative effect (Figs. 2, 3).

FIG. 2.

Preoperative and postoperative imaging of pyeloureteral lesion treated with TL vaporization. Contrast-enhanced CT imaging of pyeloureteral lesion treated with TL vaporization in (A) axial plane and (B) coronal plane. (C) Preoperative imaging of the lesion acquired during URS. (D) Picture acquired after the complete TL vaporization of the lesion. (E) Bioptical specimen of the lesion obtained by PFM medical Multi-Snare^®Retrieval Snare before laser vaporization. TL, thulium laser.

FIG. 3.

Preoperative and postoperative imaging of pyeloureteral lesion treated with TL vaporization. Contrast-enhanced CT imaging of pyeloureteral lesion treated with TL vaporization in (A) axial plane and (B) coronal plane. (C) Postoperative imaging of the treated urothelial upper tract acquired during URS at 3 months after laser ablation. (D) Pyelographic study acquired at 3 months after laser ablation. Contrast-enhanced CT imaging acquired at 6 months after laser ablation, in (E) axial plane and (F) coronal plane.

To optimize visibility, vaporization began from the most cranial portion of the lesion, toward the caudal part. At the procedure end, a Double-J ureteral stent was positioned (Boston Scientific or Porges). If vaporization was considered not radical second-look procedure was performed within 4 to 6 weeks.

No postprocedural topical chemotherapy was used.

Complications were evaluated according to Clavien–Dindo scale.¹⁵

Statistical analysis

Data are reported as mean, median, range, and standard deviation. Relapse-free survival (RFS) was assessed using Kaplan–Meier method.

Statistical analysis was performed using SPSS, version 20 (IBM, New York, NY).

p < 0.05 was considered statistically significant.

Results

A total of 42 consecutive patients (12 women and 30 men) were enrolled in the current study. Mean age at surgery was 68 years (SD 10.7 years).

Patients' indication for conservative treatment was stratified into three classes: imperative 19% (solitary kidney patients or advanced chronic kidney disease), relative 59.3% (advanced medical comorbidity), and elective 21.7% (low-risk tumor).

Most patients had a positive history of previous or concomitant transitional cell carcinoma (TCC). In particular, 7 (16.6%) patients had a previous contralateral UTUC, whereas 30 (71.4%) had bladder TCC diagnosis.

Table 1 summarizes the lesions' cytopathological characteristics according to WHO classifications of tumors 2004 (18) and TNM staging (19).

Table 1.

Cytopathological Characteristics of the Lesions Treated with Thulium Laser Ablation

Tumor size (mm)
Mean	14.3
Median	14 (range 2–30)
Tumor location
Renal pelvis	13 (31%)
Upper urinary tract	4 (9.5%)
Middle urinary tract	5 (12%)
Lower urinary tract	15 (35.5%)
Multifocal	5 (12%)
Cytology
Positive	4 (9.5%)
Negative	27 (64.2%)
Atypical	11 (26.3%)
Biopsy–tumor grade
Low grade	29 (69.1%)
High grade	4 (9.5%)
Tis	1 (2.4%)
Inconclusive	8 (19%)
Tumor stage
Ta	41 (97.6%)
Tis	1 (2.4%)

Table summarizes the cytopathological characteristics of the lesions treated according to WHO classifications of tumors 2004 and TNM staging.

Perioperative complications were recorded according to the Clavien–Dindo classification. No grade IV or V complications were observed, whereas 38% (16), 47.6% (20), and 2.4% (1) patients experienced grade I, II, and III complications, respectively. In five (12%) patients a second-look procedure was carried out due to the presence of residual disease after first ablation. In all these patients, the lesions were larger than 15 mm. Furthermore, one or more subsequent TL vaporizations were mandatory in eight (19%) patients affected by clinical recurrence.

According to the Kaplan–Meier method, the median estimated RFS was 44 months (SE 3.68).

Overall, four patients (9.5%) underwent RNU and bladder cuff resection: one patient due to carcinoma in situ (CIS) presence at biopsy after the first laser treatment; the second one due to high-grade neoplasia at rebiopsy during the second minimally invasive treatment; the third one due to impossibility to achieve complete laser vaporization after several procedures; and the last patient refused to continue the conservative protocol. For each patient, the pathological outcomes after RNUs were pTis, pT3 high grade, pTa low grade, and pT0, respectively.

The median follow-up time was 26.3 months (range 2–54 months). No spread of disease to lymph nodes or distant organs was observed. Only one patient had a disease upgrading at a subsequent biopsy.

Discussion

Since 2013, EAU guidelines included minimally invasive and conservative surgical approach for low-grade UTUC as a valid alternative for RNU, without providing any detail about the treatment modality.⁷

Different studies demonstrated how the conservative approach in patients with low-grade lesions has a cancer-specific mortality comparable to radical management.^5,16

Several studies reported the use of Holmium and diode lasers for conservative treatment of ureteral lesions,⁸ whereas data on endoscopic TL treatment of UTUC are still very limited. Mostly in the upper urinary tract, thulium use was reported anecdotally for urothelial carcinoma resection located in the distal ureter and bladder cuff during nephroureterectomy¹² and in the coagulative ablation of renal calix bleeding small papillary lesions.¹⁷

Defidio et al.¹¹ first described TL as a valid alternative to Holmium for the UTUC ablation showing similar RFS rate, reduction in bleeding and mucosal perforation, and better median parameter performance scores in fiber-tip stability and precision.

Most recently, Kallidonis and colleagues^9,10 described in vitro and in animal experimental settings the TL safety for UTUC treatment.

The current study represents one of the largest series regarding TL treatment for pyeloureteral neoplasia, in which prospective enrolment, retrospective analysis of outcomes and structured follow-up were conducted.

One of the most significant findings of our study is the absence of major complications in short- and medium-term follow-up, such as impairment of pelvic contractility, ureteral perforations or stenosis, and lesions of adjacent organs. We reported grade I Clavien–Dindo complications in 16 (38%) patients due to analgesics intake. Fifteen (35.7%) patients required administration of antibiotics due to hyperpyrexia persistence after the first postoperative day. One (2.4%) patient experienced grade III Clavien–Dindo complication due to macrohematuria caused by a concomitant URS contralateral to laser ablation site (Table 2 describes the complications occurred).

Table 2.

Descriptive Table of Occurred Complications Stratified According to Clavien–Dindo Classification

Clavien–Dindo classification	No. of patients (%)	Description
Grade I	16 (38%)	Analgesic administration
Grade II	15 (35.7%)	Antibiotic administration
Grade III	1 (2.4%)	Hemostatic endoscopic procedure required by macrohematuria caused by concomitant URS contralateral to laser ablation site
Grade IV	None
Grade V	none

See Ref.¹⁵

URS = ureterorenoscopy.

Cutress and coworkers¹⁸, in 73 patients treated with Holmium and/or diode lasers, found ureteral stenosis in 16% patients, bleeding requiring salvage nephrectomy in 1%, whereas a damage to the small bowel in another 1% of cases. These findings do not conflict with ours since these were obtained from a larger population with longer follow-up. However, a lower rate of surgical complications could be explained by the intrinsic characteristics of TL approach, such as high vaporization and coagulation power, associated with reduced tissue damage (0.2 mm).

Thulium laser consists of a diode-pumped laser, which provides a continuous wave allowing defined incisions and excellent coagulation, avoiding temperature rising, dangerous for tissues.^9,10 The continuous wave mode creates smaller pressure micro-bubbles causing less fiber-tip vibration when compared with other lasers, leading to greater precision and effectiveness.

On the contrary, Holmium lasers, although demonstrated similar to the former in terms of efficacy, cause discontinuous “tear-like” damage to tissues and ureteral transluminal micro- or macroperforations. These observations agree with Defidio et al's. outcomes showing the TL superiority in terms of effectiveness and precision compared with Holmium.¹¹

Noteworthy, the aforementioned characteristic allowed higher power setting (10–20 W) if compared with other laser approaches, without an increase of tissue damage. This allowed a faster vaporization of the lesions, maintaining optimal coagulation results, which reduced the time of the procedures. The latter aspect is usually aimed to avoid renal injuries, particularly in case of impaired renal function or solitary kidney patients.

Upper tract recurrence is common and strict URS surveillance is mandatory. Cutress and associates¹⁸, in one of the largest series of low-grade UTUC treated conservatively, showed RFU at 5 years of 53.4%, with an overall percentage of recurrences of 68.5%.

Our results show 19% of UTUC recurrences (eight patients: three with imperative indication, two relative, and three elective). Of these, only three experienced another recurrence after second laser ablation, and two needed multiple successive conservative treatments due to disease persistence.

Instead, in five patients (12%), close second-look endoscopic control was performed due to inadequate vaporization of low-grade lesions larger than 15 mm. Persistency was described in two of them from the first treatment and multiple ablations were necessary; conversely, RNU was required in other two patients.

Our data agree with previous conservative series describing 20% to 25% of UTUC recurrence rate,^19

–22 but differ with other series with longer follow-up, where recurrence rate rises from 55% to 90%.^18,23
–25

These data could be explained by an increase of recurrence rate with follow-up extension. In our opinion, follow-up plays a pivotal role in these patients, in which a tailored treatment process is often structured upon each patient and each lesion characteristics.

Although recurrence in the contralateral ureter is rare, it is a possibility in patients with history of ureteral or urinary bladder TCC, making renal functional units preservation precious.²⁶

Our results confirm this data; we described 16.6% of previous history of contralateral UTUC. All these patients were enrolled as “imperative indication” due to previous RNU or concomitant advanced stage of chronic kidney disease.

In the current study, four patients (9.5%) enrolled underwent RNU, slightly lower than rates (11%–33%) previously described.^{18,20

–25} Noteworthy, in our series only two (4.75%) of the RNUs executed could be attributed to conservative approach failure.

In these two patients, radical approach was performed due to disease progression to high-grade neoplasia or malignancy persistence with the impracticality to complete eradication.

Data of this study are encouraging about TL efficacy to manage low-grade UTUC and its recurrences, maintaining in the largest part of patients optimal renal units' survival, avoiding unnecessary RNU.

However, obtaining a larger population with a longer follow-up to better assess the strength of our results is necessary. Particularly, the increasing trend of recurrence described in literature cannot be confirmed or denied by our follow-up time. Moreover, even if our safety and efficacy of TL treatment results for low-grade UTUC are promising, prospective and randomized multicenter studies should be conducted to determine long-term efficacy of this approach compared with nephroureterectomy.

Conclusions

Thulium laser ablation is a safe and effective technique for UTUC treatment. Optimal lesion vaporization and a fine hemostatic control were obtained without any major complication. Although a longer follow-up and a larger cohort are needed to confirm these results, our outcomes encourage the use of TL ablation as an alternative for upper urinary tract neoplasms' treatment.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Authors' Contributions

G.M.: project development and article writing; F.A.M.: project development, article writing, analysis, and interpretation of the data; C.M.: project development and article writing; A.R.: analysis and interpretation of the data; M.C.: data collection; S.N.: data collection; M.F.: project development and article editing; A.C.: data collection; S.L.: data collection; D.V.M.: intellectual content; L.C.: intellectual content and article editing; O.D.C.: intellectual content and article editing.

Footnotes

Author Disclosure Statement

Prof. Luca Carmignani has a scientific contract with Quanta System. The other authors declare no conflicts of interest, including specific financial interests or relationships or affiliations relevant to the subject matter or materials discussed in the article.

Abbreviations Used

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