Recent advances in transurethral resection of bladder tumors

Introduction

Current EAU guidelines state that transurethral resection of a bladder tumor (TURBT) is an essential procedure in bladder cancer management. This operation was designed to achieve the following goals: first, excising the tumor so that a precise pathology assessment can be performed and second, eliminating tumor sites to reach a sufficient relapse-free survival rate. The main indicator of a properly performed resection is the presence of detrusor muscle in a specimen which allows one to define the tumor invasion into the muscle layer. These factors determine the kind of treatment to follow [1]. Muscle layer presence also enables one to understand how deep the tissue is excised and helps us to predict a relapse. Recurrence rate after TURBT may reach 81.3% when detrusor muscle is absent and 34.9% if it is present (OR: 8.1; 95%CI: 1.7 – 42.9; p = 0.002) [2]. However, it can be a complicated procedure to collect muscle layer and remove all lesions during conventional TURBT. Therefore, several options have been proposed to increase the quality of resection. This article aims to discuss them in detail and describe their effectiveness and determine what kind of place they should have in daily clinical practice.

Tools for tumor visualization

There is an opinion in the literature that a relapse occurs because initially we failed to identify the whole tumor(s) or their margins [3]. White-light cystoscopy (WLC) is a standard visualization method during TURBT [4]. WLC allows the surgeon to detect papillary tumors for the resection. However, flat tumors (particularly carcinoma in situ (CIS)), dysplasia and microscopic lesions are not always detected and sometimes inadequately resected [5]. It has been determined for instance that WLС missed 24.9% of Ta and T1 tumors and 26.7% of CIS tumors [5]. To improve visualization, a few techniques including photodynamic diagnostic (PDD) and narrow-band imaging (NBI) have been proposed.

PDD is based on the intravesical instillation of 5-aminolevulinic acid or its hexyl ester. It metabolizes into protoporphyrin IX which accumulates preferentially in cancer cells. The use of a blue light highlights those malignant lesions with red fluorescence [6]. A study by Mowatt et al. showed that this technique was 92% effective in detecting lesions compared to 71% for WLC, but the specificity of PDD vs WLC was 57% vs 72% respectively [7]. Therefore, one might infer that PDD should be used in combination with WLC to enhance the detection of bladder cancer during TURBT [8].

NBI was introduced into the medical field to improve cancer detection in endoscopy (urology, general surgery). It works by separating the white light into two narrow bands (green - 415 nm and blue - 540 nm), both of which are highly absorbed by hemoglobin. This enables us to precisely see the blood vessels through a thin mucosal layer. Although most tumors are hypervascularized due to neoangiogenesis, NBI in addition to WLC is capable of improving the bladder cancer detection rate [9]. The sensitivity of NBI is as high as 95.8% compared to 81.6% for WLC, but the specificity of NBI is inferior to WLC - 73.6% and 79.2%, respectively [10]. Cumulative data on the efficacy of the techniques allow us to recommend its use whenever possible to improve the detection rate of bladder cancer [11].

One should note that in general PDD and NBI can be interchangeable for the visualization of CIS and flat dysplasia. This was approved in the study of Drejer et al. in 2017: both methods have comparable specificity (NBI: 52.0%, PDD: 48.0%) and sensitivity (NBI: 95.7%, PDD: 95.7%) [12]. Also, the positive predictive values are not significantly different (NBI: 23.7%, PDD: 22.2%). Both techniques are recommended in the current EAU guidelines [13].

Techniques of bladder tumor resection

Conventional TURBT (TURBT) is a separate resection of the exophytic part of the tumor, the underlying bladder wall, and the edges of the resection area.

It is still believed that TURBT is a rather simple surgery. For example, the TURBT is one of the most commonly performed operations among Italian residents [14]. However, we believe TURBT remains a challenging procedure which requires experience. Mariappan et al. (2010) found that specimens resected by senior surgeons (5-year-training or higher) were more likely to contain muscular layer comparing to specimens obtained by junior colleagues (less than 5-year-experience) [2]. Poletajew et al. (2020) concluded that the rate of muscle layer excised by junior urologist specimens increased with experience of surgeons, as did the 3-month recurrence-free survival of patients [15]. Significant improvement in outcomes was reached after 101 procedures and the best result was obtained after 170 performed operations in this trial. These data show that surgical experience determines the quality of the resection. TURBT outcomes depend on surgical skill as well as adherence to the algorithm of resection and attention to details.

In order to help surgeons carry out complete resection, special check-lists were proposed [16][17]. These provide recommendations on how to perform TURBT step by step in a standardized way and so avoid mistakes during the procedure. Surgery checklists were shown to improve oncological outcomes among patients with NMIBC. Suarez-Ibarrola et al. (2018) presented an 8-item surgical checklist and after its implementation in clinical practice compared two groups: the first group was operated using an 8-item surgical checklist while the other one was operated without it [16]. Surgical checklist use allowed us to reduce the recurrence rate (HR 0.57, 95% CI 0.35 -0.92, p=0.02). Nevertheless, it was found that the check-list implementation was not associated with the presence of detrusor muscle in the specimens (p>0,05).

In recent decades, the TURBT modification - ERBT has gained in popularity as the new standard for bladder tumor resection. En bloc resection aimed to complete the removal of a tumor in one piece, allowing better spatial orientation of the specimen by the pathologist. Introduced in 1997 by Kawada et al., this technique proved to be an effective tool in ensuring the detection of the muscle layer in the specimen in the majority of cases [18]. Current EAU guidelines recommend the en bloc resection for NMIBC diagnosis and treatment in line with conventional TURBT [13].

EBRT consists of a few conventional steps. During the first step, a circular incision around the tumor at approximately 5 mm from its visible margin is performed. The incision is made in macroscopically ‘normal’ mucosa surrounding the lesion, and then is extended through the subepithelial connective tissue, the muscularis mucosae, and the muscularis propria layers [19]. After that, a deeper incision is made in the muscular layer. Having identified it, the surgeon resects the base of the tumor with the muscular layer using traction and incisions of the muscle fibers. Subsequently, the tumor is dissected from the bottom respecting the incision line. The presence of detrusor muscle is crucial for adequate resection. The tumor might then be evacuated through the resectoscope channel.

ERBT can increase the detection rate of the muscle layer compared to TURBT. In some studies, this rate reached 100% [20][21]. Several studies suggest that ERBT can reduce the frequency of recurrence [22] and the need for additional procedures because it allows better tumor excision [6]. One of the last meta-analyses published in 2020 demonstrates that 24-month recurrence rate after ERBT was comparable with TURBT [23]. Also, no significant difference was found between TURBT and ERBT groups regarding the rate of detrusor muscle detection (OR: 3.59; 95% Cl: 0.6 – 21.63; p = 0,16) [23].

The implementation of ERBT might be limited by hard-to-reach localization of the lesion and may be less effective in multiple tumors. However, the results of the Delphi consensus published by Teoh et al. demonstrated that most surgeons consider EBRT to be a feasible option for large or multiple tumors with different localizations [24].

To overcome all the difficulties during ERBT of large tumors (>3 cm), different approaches have been proposed. To extract the tumor after the ERBT nephroscopy sheet, laparoscopic grasp and extraction bags (endobags) are used [19][25]. One rarely used option for the large tumors is plasma vaporization of the exophytic tumor part, leaving only a small portion of it for resection, and this part might be extracted through the resectoscope [26]. Enikeev et al. presented the two-step technique of ERBT for tumors larger than 3 cm [27]. Its first step includes resection of the larger exophytic area while the base of the lesion is left intact. The exophytic part is removed using a morcellator. This part of the specimen is used to determine the morphology and grading of the tumor. The second step is en bloc resection of the tumor base which is typically removed subsequently in one piece through the resectoscope [27]. It enables the surgeon to obtain muscle layer for the pathological examination.

Energy sources

Conventional energy sources for bladder tumor resection are either monopolar or bipolar electrosurgery. In meta-analysis published by the Zhao et al. (2016) it was shown that bipolar TURBT use is characterized with shorter operative time (p = 0.002), less blood loss (p < 0.001), a lower frequency rate of obturator nerve reflex (p < 0.001) and bladder perforation (p = 0.003) and lower 2-year postoperative recurrence rate (p = 0.04) [28]. However, the use of electrosurgery for bladder tumor resection could cause thermal cautery artefacts in the specimen, leading to poor quality histological examination [29]. The presence of severe artefacts occurs more rarely when bipolar energy is used for TURBT (p = 0,03) compared to monopolar. [28].

The introduction of lasers (Ho:YAG, Tm:YAG) for the resection of the bladder tumor made it possible to improve the quality of the specimens and partially reduce complications. In addition, laser energy allows for more precise cutting, making the ERBT procedure more convenient. According to Teoh et al., the usage of holmium and thulium laser for ERBT can help to decrease the risk of obturator nerve reflex during the procedure [24]. Holmium laser en bloc resection of bladder tumors (HolERBT) was shown to be safer than conventional TURBT with a higher rate of presence of the detrusor muscle compared to TURBT (98% vs 62%, p< 0.001) [30]. This might be due to easier incision depth control: Ho:YAG laser in ex vivo conditions has shown no carbonization and deep narrow incisions, but also a tissue rupturing with vapor bubble [35]. The rate of residual tumors was also lower in HolERBT group than that of TURBT, 7.0% vs 27.7% respectively (p = 0.01) [30].

Preliminary data demonstrated that Tm:YAG is a safe and effective tool for bladder tumor resection [31]. Tm:YAG is a continuous mode laser with low penetration depth that allows precise cutting with smoother and deeper incisions compared to Ho:YAG [32]. Chen et al. in their randomized trial compared Tm:YAG en bloc resection of bladder tumor and TURBT and found no differences in terms of hemoglobin drop (p = 0.63), catheterization stay (p = 0.115) and recurrence-rate at 18 months (p = 0.383) [33].

In terms of laser technology, the thulium fiber laser proved itself to be a game changer in the field of urology (e.g. in benign prostate hyperplasia and urolithiasis treatment) [34]. With a wavelength of 1940 nm, its theoretical penetration depth does not exceed 0.15 mm, which should result in precise and effective cutting. Thulium fiber laser in contrast to Tm:YAG, is a pulsed laser which aims to decrease carbonization [35]. It creates clear-сut incision margins with no rupture, non-extensive carbonization with low mechanical impact to the tissue compared to the Ho:YAG [35][39]. Enikeev et al. presented their initial experience using thulium fiber laser for en bloc resection of bladder cancer [27]. The authors reported a recurrence-free survival at 6 months of follow-up of 67.2% for conventional TURBT vs. 91.5% for thulium fiber ERBT (p <  0.001, respectively). Pathological examination showed a significantly higher rate of detrusor muscle presence compared to TURBT (91.5% vs. 58.6%, respectively) [27]. Moreover, the likelihood of intraoperative (such as obturator nerve reflex) and postoperative complications were less frequent in the Tm-fiber ERBT group. However, further prospective trials and evaluation of the technique are needed.

Despite all of this, there is still no consensus on which energy source is preferable. Kramer et al. in their article compared two lasers (Ho:YAG and Tm:YAG) with electrocautery (mono- or bipolar) for ERBT [36]. The authors found no significant differences in terms of detrusor muscle presence (p = 0.18), the duration of surgical procedure (p = 0.16), catheter stay (p = 0.16), overall complication rate between laser and eERBT (p = 0.49) [36]. However, conversion to TURBT was significantly more frequent in the eERBT group (26,3 vs 1,5%, p< 0,001) [36]. The authors concluded that ERBT regardless of the energy source is a safe and effective method of NMIBC treatment with sufficient oncological outcomes, so the technique itself might be more crucial than the energy source.

Experimental techniques

Although bladder tumor resection has already established itself as a safe and effective treatment, urologists are still trying to develop more effective approaches. Among them are methods such as HybridKnife® and combined method of endoscopic mucosal resection and en bloc resection of bladder cancer.

Mundhenk et al. described an alternative technique for bladder cancer treatment using HybridKnife® [37]. The HybridKnife® is a multifunctional probe that combines water-jet and electrosurgical technology. The technique was described as a focused waterjet that penetrates the bladder mucosa and forms a spacer in the subepithelial layer. Furthermore, the incision of mucosa was made, and the tumor was excised. The authors presented their initial results using HybridKnife® in 16 patients. No major complications (Clavien III) were observed during the procedure. Cheng et al. compared the novel technique with TURBT. The authors observed a significant difference in terms of lower complication rates and relapse-free survival between the two groups (95% for HybridKnife® vs. 79% for TURBT, p = 0.028) [22]. Nagele et al. presented their experience of using waterjet hydrodissection which resulted in an adequate histological examination of whole samples and with a negative surgical margin [38]. However, the body of evidence on this technique is still too limited.

Hayashida et al. were the first to describe a method of combined endoscopic mucosal resection and en bloc resection of bladder cancer. Endoscopic muscular resection was used to remove the tumor mass that protruded from the mucosa using a polypectomy snare and electrocautery-guided en bloc resection was performed for the residual lesion [20]. Compared to TURBT, the combined technique resulted in a similar operating time, catheterization duration, safety profile, and recurrence rate. Furthermore, all samples were included in tumor muscle in the combined technique [20]. However, further large-scale evaluation of the technique is needed in prospective randomized trials.

Conclusion

Resection of the bladder tumor is the main part of the diagnosis and treatment of NMIBC. Additional imaging techniques (PDD, NBI) should be used to achieve the best treatment results. The use of novel (e.g. laser) energy for tumor resection could be useful to enhance the quality of the specimens and reduce complications. However, its superiority over electrosurgery still needs solid confirmation. En bloc technique has proven to increase the detrusor muscle presence in the specimen which allows for better grading of bladder tumor and reduces recurrence rate.