2024 Volume 44 Issue 4 Pages 373-378
For upper urinary tract urothelial carcinoma (UTUC), the European Association of Urology and the National Comprehensive Cancer Network guidelines have recommended ureteroscopic surgery (URS) for cases with low-risk tumors (low-grade biopsy and cytology, <1.5–2 cm, unifocal, no invasion on imaging), and cases with bilateral tumors, a solitary kidney, or severe renal dysfunction. However, the 2-year recurrence rate after surgery is remarkably high, leading to the need for salvage radical nephroureterectomy. Furthermore, unlike robotic or laparoscopic surgery, the surgical procedure for URS has not been standardized due to the technical specificity of laser devices and ureteroscopes. Therefore, this procedure is performed only in limited facilities with extensive experience internationally. In this review, we introduce the current issues of URS for UTUC and the use of the photodynamic diagnosis-guided URS procedure, which we are implementing to overcome these challenges.
欧米を中心に尿路内視鏡手術が積極的に選択されつつある．EAUやNCCNガイドラインでは，両側腫瘍を持つ症例や，単腎または高度腎機能低下を来した症例に加え，対側が健腎であってもLow-riskの腫瘍（low grade腫瘍，1.5～2 cm以下，単発など）を持つ症例に対して尿路内視鏡手術を推奨している．しかし，術後の2年再発率は非常に高く，救済腎尿管全摘除術への移行率も高いこと，さらにはロボット手術や腹腔鏡手術と異なりレーザー機器や尿管鏡の技術的な特殊性のため術式が標準化されていないことから，国内外において多数の経験を持つ限定された施設でしか同手術は行われていない．本解説では，尿路内視鏡治療の現状の問題点と，それらを克服するために我々が取り組んでいる光線力学ナビゲーションを用いた尿路内視鏡治療を紹介する．
Upper urinary tract urothelial carcinoma (UTUC) arises in the upper urinary tract (renal pelvis or ureter) urothelium, and is rare compared to bladder cancer originating from the lower urinary tract, accounting for approximately 5% of all urothelial carcinomas1). These tumors are more prevalent in individuals aged 50 to 70 years, with a male predominance of over twice that of females. Based on epidemiological data, the number of deaths caused by renal pelvic tumors increased from 781 in 2002 to 1,558 in 2010, and deaths caused by ureteral tumors increased from 852 in 2002 to 1,593 in 2010, both showing an increasing trend2). The gold standard for the treatment of localized UTUC remains radical nephroureterectomy (RNU), which involves resecting the kidney and ureter with a bladder cuff3,4). However, with the development of devices such as small-diameter ureteroscopes and lasers, ureteroscopic surgery aimed at preserving the kidney is being increasingly performed, particularly for UTUC patients who have a low-risk localized tumor, and solitary kidneys, or severe renal dysfunction3,4). This article describes the conventional diagnostic and surgical methods and their issues, as well as introducing photodynamic diagnosis-guided ureteroscopic surgery as a potential solution for these issues.
The main presenting symptoms of UTUC include hematuria (in over 75% of cases) and flank pain (approximately 30% of cases)3). However, around 15% of patients are asymptomatic and the condition is often incidentally discovered during examinations for other diseases. When UTUC is suspected, imaging studies covering the abdomen to the pelvic region are conducted in parallel with the search for bladder cancer using cystoscopy. Imaging modalities include ultrasonography, retrograde pyelography, CT urography (CT-U), and Magnetic Resonance Imaging (MRI). Particularly, CT-U is the first choice for imaging diagnosis because it can depict the tumor as a defect caused by the contrast agent, with a sensitivity of 93.5–95.8% and a specificity of 94.8–100%5). However, the detection sensitivity of MRI is approximately 80%, which decreases further to 74% for tumors smaller than 2 cm6). Therefore, MRI is only used as an alternative examination for cases where contrast-enhanced CT is a contraindication due to severe renal dysfunction or a history of iodine contrast allergy.
Concurrent with imaging studies, urine cytology (using selected urine from the renal pelvis and ureter, or voided urine) is performed3). Urine cytology involves centrifuging urine and observing the cells under a microscope to determine the presence of malignant cells. Generally, if UTUC is strongly suspected based on imaging and the urine cytology is positive, a definitive diagnosis of UTUC can be made. However, urine cytology has a sensitivity of only around 30%, often resulting in false-negative cases even where the presence of a tumor is confirmed7). Additionally, there are cases where urine cytology is positive but no UTUC is detected on imaging, such as flat lesions or microlesions. Therefore, a ureteroscopy with biopsy is further recommended for a definitive diagnosis.
The diagnostic accuracy of ureteroscopic biopsy ranges from 78% to 92%8). The examination is performed using a small-diameter rigid or flexible ureteroscope under white light, and biopsies are obtained from suspected tumor sites for pathological diagnosis. However, there are some issues. Approximately 25% of cases undergoing ureteroscopy have missed tumors, with around half of them with flat lesions, such as carcinoma in situ, not being distinguishable from normal mucosa8). Furthermore, because the biopsy samples obtained through ureteroscopy are only a few millimeters in size, a definitive diagnosis of benign or malignant status is challenging for 25% of cases, and decisions are made based on a comprehensive assessment, taking into account clinical features9). Therefore, accurately identifying the lesion tissue and ensuring reliable sample collection are clinical unmet needs because these have a significant impact on the diagnostic accuracy and subsequent treatment selection for UTUC.
Two optical endoscopic techniques have been used to identify tumors that are difficult to distinguish under white light in bladder cancer. One of these techniques is narrow-band imaging technology (NBI), which illuminates the mucosa with two narrow-bandwidth lights (wavelengths: blue: 390–445 nm/green: 530–550 nm) that are readily absorbed by hemoglobin in the blood, enhancing the contrast of mucosal microvessels and other fine structures10).
Photodynamic diagnosis (PDD), which utilizes intravesical hexaminolevulinate or oral 5-aminolevulinic acid hydrochloride (5-ALA), is a photosensitizer technique that excites protoporphyrin IX accumulated in the tumor by irradiating it with blue light (wavelength: 380–440 nm), using a cut filter allowing wavelengths above 440 nm to pass. The use of oral 5-ALA in bladder cancer has already been approved for insurance coverage and is routinely used in clinical practice in Japan only.
Reports on these imaging diagnostic modalities in UTUC are limited compared to bladder cancer. For example, there have been only two prospective studies on NBI, both of which involved a small number of cases11). However, regarding PDD using oral 5-ALA, there have been reports from a single facility in the UK, although recent reports have emerged from several facilities in Japan, including our institution12,13). In this study, we present some of our data.
Our study included 20 patients suspected of UTUC who required ureteroscopy13). They were orally administered 5-ALA (20 mg/kg) 3 hours before the ureteroscopy. The procedure involved observation under white light followed by observation under PDD. Biopsies were performed on each abnormal or normal site, and the correlation between ureteroscopic findings and pathological diagnosis was evaluated. A total of 63 biopsy specimens were examined, and the overall sensitivity of PDD was significantly higher than that of white light (93.8% vs. 62.5%, p = 0.0025). Although there was no significant difference in specificity, the diagnostic accuracy of PDD was better than that of white light (86% vs. 75%, p = 0.0297) (Fig.1). PDD was particularly effective for cases with tumors that were not apparently visible under white light (such as flat lesions), showing a significantly higher sensitivity (83.3% vs. 0.0%, p < 0.001). Adverse events related to oral 5-ALA administration were observed in eight cases (40%), but none experienced Grade 3 or higher adverse events according to the Common Terminology Criteria for Adverse Events version 4.013).
Comparing area under receiver operating characteristic curves (AUC) for detecting upper urinary tract carcinoma between white light and photodynamic diagnosis (PDD). The Delong test was used for statistics.
Based on the above, we confirmed that PDD-guided ureteroscopy improved the detection ability for UTUC compared to white light alone. Although it is not covered by insurance and can only be used within specific clinical studies worldwide, we considered conducting a clinical trial to investigate whether PDD is useful for detecting residual tumors or surgical margins accurately during endoscopic surgery for UTUC.
With recent advancements in laser systems and endourological surgical instruments, ureteroscopic surgery (URS) is increasingly being considered as an option for kidney-sparing surgery. According to the European Association of Urology (EAU) guidelines, URS is the first choice for non-invasive tumors measuring less than 2 cm of low grade without evidence of infiltration on imaging4). The Japanese Urological Association guidelines (2014 edition) state that URS can be considered for tumors of less than 1 cm, unifocal, low grade without apparent imaging evidence of infiltration, in experienced institutions3). In addition, URS has also become an option for cases such with a single kidney or severe renal dysfunction where radical nephroureterectomy would lead to the necessity of dialysis3,4). However, due to its high recurrence rate and other issues mentioned later, URS is not commonly performed at present worldwide. Moreover, in clinical practice, it remains a challenge to determine the appropriate use of URS for patients who are elderly, or who have a poor physical condition, severe comorbidities, or other progressive tumors that make radical nephroureterectomy difficult.
4.2 Conventional surgical techniquesBagley et al. from Thomas Jefferson University reported on the general technique of URS14). Under saline irrigation, the ureteroscope is advanced to the tumor site, and for small-sized tumors, resection is performed using a Holmium Yttrium Aluminum Garnet laser (Ho:YAG) with a shallow depth of penetration (0.4 mm). In cases of larger tumors, Ho:YAG alone may have difficulty in achieving adequate hemostasis with pulse wave modulation, thus, requiring the combination of a Neodymium YAG laser (Nd:YAG) with high coagulation capabilities. Typically, the tumor is coagulated using Nd:YAG and then resected using Ho:YAG or other lasers. However, Nd:YAG, due to its greater depth of penetration (4–6 mm), poses a higher risk of postoperative stricture in thin-walled tissues and is not recommended for use within the ureter. Therefore, for larger ureteral tumors, Ho:YAG alone is necessary but it may present challenges in achieving hemostasis. Surgery is usually considered complete if no visible tumor residue is observed under white light.
4.3 Issues with the conventional URS procedureUsing URS to treat larger tumors using a ureteroscope with approximately 3 mm diameter and laser fibers with a diameter of 200–365 μm within a few operative hours is challenging. Tumors in the upper tract are prone to bleeding, and performing surgery while maintaining a bloodless field is crucial. However, the combination of Nd:YAG, which has excellent hemostatic properties, is not easily applicable to ureteral tumors due to their deeper penetration, necessitating a novel laser with a shallower depth and superior hemostatic capabilities. Furthermore, in the second-look URS conducted 6–8 weeks after initial URS, residual tumors were detected in 51.2% of cases, with 85.7% of those being at the same site as the initial treatment, indicating incomplete tumor resection had occurred after the initial URS15). Therefore, it is important to accurately assess residual tumors and achieve complete resection during URS.
Additionally, the prognosis of this procedure is far from satisfactory. Long-term follow-up (median observation period of 54 months) after URS in low-risk patients revealed a recurrence rate of 68%, with 19% of cases eventually requiring radical nephroureterectomy16). In further studies including high-risk cases, the disease-free progression survival rate for low-grade tumors was 75%, whereas, 52% of cases with high-grade tumors required radical nephroureterectomy17). These findings suggest that even in low-risk patients, there is a considerable risk of local recurrence and the need for radical nephroureterectomy increases significantly in cases with a high grade tumor.
Based on the aforementioned issues, we have made improvements to establish a more effective URS procedure.
5.1 Thulium YAG Laser AblationWe focused on the use of a Thulium YAG laser (Tm:YAG) for ablation. Tm:YAG has a wavelength of 1.75–2.22 μm, which has high absorption in water molecules (soft tissues), and its penetration depth into the tissue is shallow, approximately 0.2 mm. This laser demonstrates excellent coagulation properties, making hemostasis easier while minimizing damage to surrounding tissues. Unlike the pulsed-wave Ho:YAG laser, Tm:YAG operates in continuous-wave mode, thus not promoting bleeding from the tumor. Although Tm:YAG is mainly used for enucleation in the field of urology for treating benign prostatic hyperplasia, we were the first to attempt its introduction for UTUC in Japan18). However, the shallow penetration depth of Tm:YAG is a disadvantage, because it is difficult to address bleeding from deeper tissue layers. Therefore, it is necessary to position the fiber tip as close as possible to the target, such as by puncturing the tumor. Additionally, the usable fiber diameter for insertion through the ureteroscope is approximately 272 μm, allowing for power settings up to 30 W or lower. The lower power limits the ability to achieve strong ablation, resulting in lower resection efficiency. To overcome these limitations, we utilize Tm:YAG for tumor coagulation and subsequent tumor resection using Ho:YAG, thereby complementing each laser’s weaknesses.
5.2 Detection of residual tumors using PDDTo address the issue of detecting residual tumors and assessing resection margins, we use intraoperative navigation with 5-ALA-induced PDD. The advantage of PDD is that once 5-ALA is taken up by tumor cells, they emit red fluorescence upon exposure to blue light, allowing the identification of residual tumors, as well as post-resection tumor fragments and floating cancer cells. Therefore, we consider PDD superior to NBI in situations where assessing vascular structures in disrupted tissue becomes challenging due to laser ablation.
5.3 PDD-Guided Dual Laser Ablation TechniqueWe established the PDD-guided dual laser ablation technique by integrating Tm:YAG, Ho:YAG, and PDD. We perform URS for UTUC using this approach19). The outline of the procedure is described as follows:
1. Preoperative preparation and equipment
Oral administration of 20 mg/kg 5-ALA 1 hour before the operation. Laser devices used: Revolix120® (settings: 5 W or 15 W) for Tm:YAG and Lumenis®PulseTM 120 H (settings: 0.8–1 J/10 Hz short pulse) for Ho:YAG. Laser fibers with a diameter of Φ272 μm are used. D-LightC® system for PDD and a protoporphyrin IX excitation eyepiece lens filter for detecting red fluorescence. URF®-P6/P7 (7.95-Fr) and Ultrathin® (6-Fr) ureteroscopes are used, and N-Circle® is used for the tumor retrieval basket.
2. Surgical procedure (Fig.2)
Endoscopic appearances during the photodynamic diagnosis-guided dual laser ablation (PDD-DLA) technique for upper urinary tract carcinoma.
The patient is placed in a lithotomy position under general or spinal anesthesia. A rigid or flexible ureteroscope is used to reach the tumor site. The laser fiber is inserted into the tumor and ablated using 15 W Tm:YAG to diminsh blood flow at the center of the tumor. If the target tumor is close to normal tissues, such as the ureteral wall, a 5 W laser setting is used. These steps are repeated until the tumor becomes ischemic. Then, these tissues are resected or fragmented using Ho:YAG, and the fragments are removed extracorporeally using basket forceps. PDD is performed to confirm the presence of residual tumors and assess the resection margins, followed by complete resection using the two lasers for positive lesions. The surgery is concluded when the positive sites disappear upon confirmation using PDD. A second-look URS is conducted 6–8 weeks later to confirm complete resection.
3. Surgical outcomes (Fig.3)
Kaplan-Meier curves stratified by the use of laser ablation modalities showing oncological outcomes, including disease progression (defined as tumor relapse that could not be continued with endoscopic management), local recurrence (defined as primary tumor relapse in the ipsilateral upper urinary tract after surgery), and intravesical recurrence (defined as primary tumor relapse in the bladder after surgery), and median survival duration. The log-rank test was used for statistics.
With Institutional Review Board approval (IRB no. 2018036), we performed an extended 3-year follow-up analysis of our previous study19), finding that patients treated with PDD-guided dual laser ablation (n = 10) had significantly lower rates of disease progression (defined as tumor relapse that could not be continued with URS, requiring radical nephroureterectomy) and intravesical recurrence, compared to those who underwent Ho:YAG ablation alone (n = 16) (p = 0.0253, and p = 0.0292, respectively).
URS for UTUC is expected to be in high demand as a minimally invasive treatment in an aging society. However, it is not yet widely adopted, and concerns regarding prognosis and unstandardized procedures remain. Although further evaluation of this technique in the long-term period is required, we believe that the PDD-guided dual laser ablation technique may be a highly useful procedure that addresses the issues of other techniques.
The authors declare that they have no conflict of interest.
