Current opinions regarding the clinical utility of en bloc resection in the treatment of non-muscle invasive bladder cancer—a review of the literature

Abstract

Non-muscle invasive bladder cancer (NMIBC) is currently mainly treated with the approach of transurethral resection of bladder tumor (TURBT) followed by pathology investigation of the obtained specimens. However, this approach—TURBT—has a few drawbacks, owing to the inherent technical defect—“piecemeal” resection. With development of medical science and surgical techniques, a new kind of surgical operation—“en bloc” resection of bladder tumor (ERBT)—emerged, hoping to completely remove bladder tumor with surrounding normal tissue. The detrusor muscle layer beneath the tumor is removed, and the surgical quality of bladder tumor is enhanced, with a better pathological outcome, reduced intraoperative complications and lower recurrence rate eventually. This paper reviews current literature concerning a brief history of ERBT developing, surgical steps, its indications, advantages on surgical margin, recurrence during follow-up, pathological performance—presence of detrusor muscle, residual tumor and upstage, as well as such issue as “is reTURBT necessary after ERBT?” and the guiding significance of ERBT in substaging of T1 bladder cancer.

Background

At present, transurethral resection of bladder tumor (TURBT) remains the gold standard for the treatment of non-muscle invasive bladder cancer (NMIBC) clinically [1]. The main goals of TURBT are to establish the histological diagnosis and clarify the associated prognostic factors, including: complete removal of tumors, provision of tissue biopsies for pathological examination and grading and staging of cancer cells, as well as offering therapeutic protocols and guiding prognosis, among which the precise pathological diagnosis is fundamental [2]. Removal of bladder tumors can be conducted with minimally invasive surgery [3]: TURBT—“piecemeal resection”, or en bloc resection of bladder tumor (ERBT)—“one-piece resection”.

In recent years, however, the approach—TURBT—is receiving more and more questioning, for clinicians found that the recurrence and under-staging rates following TURBT are rather high [4]. Its major drawback is absence of detrusor muscle (DM) in the specimen, as DM is usually considered as the surrogate marker of resection quality [5], with great significance for patient’s treatment and prognosis.

During TURBT, the tumor is cut piece by piece, dispersed, and then extracted out of the bladder. As such, TURBT violates the basic oncological surgical principles of “one-piece” resection and “non-touch” concept [6], carrying potential risks, such as, fragmentation and spread of cell debris, even entering blood circulation through damaged vascular walls with scattering of tumor cells in the irrigation fluid, resulting in a theoretical adverse outcome of tumor cells seeding and/ or metastasis [7]. Moreover, the tumor’s overall structure is destroyed, with the possibilities of DM tissue absence in the specimen, loss of orientation of the specimen, or undefined surgical margins [8]. Subsequently the treatment protocols and prognosis of the patients are influenced negatively.

From a surgical point of view, high quality TURBT cannot always be obtained easily, owing to such factors as the size of tumor, multifocality, incomplete or careless cystoscopic inspection, or insufficient experience of the surgeon [9]. The resection is sometimes incomplete, rendering possible early relapse or progression of bladder cancer (BC).

Anatomically, the bladder wall is not thick, with approximately 1 mm to 15 mm in thickness for adult [10], depending on sex, age, and filling extent. If TURBT resection is too deep, adverse outcomes might occur intraoperatively; for example, perforation, major bleeding, or even conversion to open surgery [11]. Intraoperative bleeding or perforation aggravates the difficulty of operation, so could result in delaying of intravesical instillation. Furthermore, clinical investigations have shown that single TURBT might be insufficient for high grade NMIBC, as DM cannot be ensured to remain in all specimens [12]. As we know, the primary surgical goal of BC is to prevent relapse, and the key point of avoiding relapse is to remove the cancer entirely, particularly including DM. In clinical practice, the question—post—TURBT residual tumor—has not been addressed: about 17–67% of residual rate for pTa tumors and 20–71% for pT1 tumors; and most of them are located within the initial resection area [13]. Actually, TURBT is far more an “easy and safe” operation and could result in potential adverse outcomes. Besides, some of the patients’ compliance is reduced after surgery, unwilling or intolerant to receive regular intravesical instillation and regular cystoscopic examination. Consequently, complete removal of bladder tumor and preventing relapse are of great value for the patients.

TURBT, thus far, is one of the most common operational procedures that has not seen major advancements in urology; and the concerns about the drawbacks of TURBT drive clinicians to seek novel methods or devices to achieve better therapeutic results with fewer complications. With the development of medical theory, technique and equipment, significant breakthrough should be made.

Methodology

The research was performed using internet searching engines, and thorough literary and information research was conducted. Articles retrieved after a search conducted in the national and international database were included in our research. The search was carried out using a variety of keywords such as “TURBT”, “en bloc resection”, “bladder cancer”, “bladder carcinoma”, “laser resection”, “types of laser” and so on. A total of 180 articles were found, of which 73 were used for writing this narrative review.

En bloc resection of bladder tumor (ERBT)

During the past few decades, a new kind of surgical approach—ERBT—emerged [4, 14], with the hope of integral resection of bladder tumor in combination with surrounding normal tissues, so as to enhance the surgical quality of BC and lower relapse rate eventually.

The concept of ERBT was first proposed in 1980s [3]. With the gradual improvement of technology, it is generally acknowledged that ERBT has several advantages for the treatment of NMIBC [11, 15]. This technique is in accordance with the principal tenet of oncological surgery [14]: complete removal of tumor with intact specimen; accurate and controlled resection procedure with reduced complications, especially lower rate of bladder perforation [16]; avoiding the “piecemeal” resection of TURBT, minimizing exfoliated tumor cells, and declining the risks for scattering and implantation of tumor cells; comprising DM and assessable safety margin with unambiguous orientation, allowing for precise pathological evaluation [17]. In addition, carcinoma in situ (CIS) accompanied with BC can be easily identified in intact specimen, while such lesion might be omitted in piecemeal specimens. After all, in clinical scenario, the judgment of the integrity of specimen is mainly determined by pathologist, not solely by the subjective decision of surgeons.

ERBT can be accomplished with a variety of medical devices and energy sources [18], including initially used electrical devices [19], loop modification, modified J-shaped electrode needle, later the transurethral mono- or bipolar resection, bipolar button electrode [20], and several types of laser devices [21], water-jet based enucleation, photodynamic diagnosis (PDD)-assisted ERBT [22], and so on.

Although the energy sources vary, the basic principle of the technique is similar, and the surgical procedure is described in more detail in an article by Yuen-Chun Teoh et al. [23]. The brief course of ERBT is as follows: firstly, coagulate the blood vessels that enter the tumor; then, about 0.5–1.0 cm (a safe distance) away from the edge of the tumor, a circular incision is made; the normally-appeared mucosa is cut and the depth is extended to deep DM. With blunt and sharp dissection, the tumor is excised gradually and totally, followed by extraction using grasp or specifically designed device [24]. Cautions must be taken that the dissection depth should be deep enough to excise DM.

The tumors located at the posterior wall are rather difficult for resection: the direction of dissection is lateromedial from both sides gradually to the deep level of DM, then from bottom to top, lifting the tumor from the base to completely remove the tumor.

Contrary to the “piece-by-piece” resection of TURBT, ERBT emphasize more on a delicate en bloc sculpting and tumor excision [3], including complete excision of tumor tissues, surrounding tissues and lymphvessels, so as to maintain the integrity of the tumor specimens. An important purpose of ERBT is to improve the pathohistological evaluation [25], especially the surgical margin and orientation, which is very critical for guiding the treatment of NMIBC.

During conventional TURBT, the resection is done by “top-down” method: i.e., initially resecting from the top of the tumor, then gradually piece-by-piece downward to the base, with fulguration at the base of the tumor; so it is possibly difficult to determine whether the resection is complete, or whether the DM is removed, especially for less experienced surgeons [26]. In addition, diathermy might lead to cautery and crush artifacts, changing the structure of the specimens under microscopy. Thus, the specimen information might be lost or misinterpretated [1]. Moreover, in theory, during “piecemeal” resection of TURBT, the venous vessels are open, so tumor cells might enter the veins when intravesical pressure surpassing the venous pressure. However, during ERBT, the whole tumor is removed and extracted without debris, thus the risk of cancer cells entering blood vessels is decreased greatly [27].

An interesting clinical trial was conducted by Haichao Huang et al. in which they endeavored to verify whether ERBT could decrease the risk of seeding cancer cells into blood circulation during the resection of NMIBC [28]. A total of 21 patients were allocated to receive conventional TURB (9 patients) or ERBT (12 patients). One millilitre of blood samples for circulating tumor cell (CTC) enumeration were drawn from the peripheral vein prior to resection (PV1), immediately after resection of the tumor base (PV2), and at 12 h after resection (PV3). After comparison, they found that for TURB patients, the count of CTCs in PV3 was significantly higher than that in PV1 (p = 0.047). However, no significant difference was found in CTC counts before and after resection for ERBT patients. They concluded that ERBT did not increase the number of tumor cells in the bloodstream.

At present, globally, transurethral laser therapy is not widespread yet; and it is not commonly used in most Asian countries except in China. The application of laser in the treatment of NMIBC was initially reported in Germany in 1970s [29], when neodymium:YAG lasers was used for vaporization of tissues. Subsequently, laser was applied in many fields of Urology, including urolithiasis, benign prostatic hyperplasia (BPH), stress urinary incontinence and urinary tumors. A plethora of clinical studies have reported the feasibility and safety of laser in Urology, and various laser types have been used to treat bladder tumors. Currently commonly used laser types are holmium (Ho:YAG), thulium (Tm:YAG) and green laser [30].

Different from TURBT during which the obturator nerve might be stimulated by current flow, rendering contraction of the muscles and possible perforation of the bladder; during laser ERBT, no current flow is produced, thus obturator nerve reflex seldom happens and bladder perforation rarely occurs [31]. (Herein, we must acknowledge that obturator nerve reflex is not related to the resection modality but to the energy source used. When removing BC located on the side walls of bladder by use of monopolar or bipolar devices, obturator nerve reflex could be induced, regardless of TURBT or ERBT. Only when using laser ERBT, obturator nerve reflex can be avoided). Other advantages of ERBT technique include: simple and safe, minimal injury, good coagulation effect, clear operation view, as well as accurate and controlled incision [7]. It is suitable for patients with cardiac pacemaker or arrhythmia. Especially, this technique is fit for those patients whose tumor is located at side wall of the bladder, but cannot receive general anesthesia for any reasons. Current clinical evidence demonstrates that ERBT could provide good staging information for tumors, with which pathologists can completely evaluate the specimens, involving local invasion depth/ status and surgical margins [30]. All the information is more helpful for doctors to make more appropriate treatment decisions.

Indications for ERBT

The same as any other surgeries, ERBT has its own unique indications and contraindications. At present, most researchers believe that large or too many tumors are outside the indications of ERBT [32], and these are the reasons that hinder this technique to become the standard procedure. There is no current consensus on its optimal indications, with the size of the tumor being its greatest limitation.

Currently most researchers agree that the maximal tumor suitable for ERBT is set at 3 cm [26], because a whole tumor bigger than that size is very difficult to be extracted. Only a few clinicians conducted a limited number of clinical studies on ERBT bigger than 3 cm [27, 33]. In theory, for tumors over 3 cm in size, most likely it is muscle invasive bladder cancer (MIBC), and ERBT is not considered as a radical therapy under such circumstances. In addition, a modified ERBT was suggested, in which for tumor > 3 cm, the surgeon completely dissected the tumor, and then divided into 2 or 3 pieces, followed by extraction [34]. The biggest tumor that was reported to be removed with en bloc technique was 7 cm; while other authors proposed to deep incision of the tumor to the bladder wall into several parts, immediately followed by complete dissection [35]. However, these perspectives were not accepted by most clinicians, as this is against the fundamental principle of en bloc resection. The advantage of ERBT originates mainly from overall removal of the tumor; after all, if the specimen cannot be extracted in one piece, the advantage is greatly reduced.

Besides its size, the site and the number of tumors are restricted [36]. A lot of researchers excluded the tumors located at the anterior or posterior wall of the bladder, because of the risk for peritoneal injury. Some authors proposed that ERBT should not be used for tumors located at the bladder neck or dome [11]. This issue has not yet been addressed.

However, in a Delphi survey [37], it was agreed that ERBT is feasible for tumors located at the posterior wall, anterior wall, right or left wall, trigone, bladder neck, and the area near the ureteral orifices. Roberto Migliari et al. suggested that [6], for patients with papillary lesion covering the ureteral orifice, after placing a nitinol guide wire into the orifice, the bladder tumor enclosing the orifice could be removed without damaging the orifice. Ureteral stenting was not necessary.

In addition, a consensus has been reached that in case of MIBC or CIS of the bladder, ERBT should not be applied [38]. The reason lies in the fact that the lesion of CIS is flat without protrusion of the urothelium, and some even show normal appearance or velvet-like erythema or granules, so it is difficult to distinguish from inflammatory lesions; moreover, the area of the lesion is difficult to determine. A cold biopsy is to be preferred under such circumstances.

Specimen extraction is one of the trickiest issues in ERBT and has been extensively studied. The primary restriction is the size of the specimen and its consistency. No clear cutoff size recommendation is established currently. For overall extraction of specimens less than 3 cm, it is relatively easy and various extracting methods have been proposed, including tumor flowing out with water through the inner sheath, or standard Ellik evacuator through the resectoscope sheath, or a grasper inserted into the working channel to grasp the base, or from the outer channel of the resectoscope that was used like a trocar. Extracting larger specimens (more than 3 cm) is the challenging problem, and many authors have proposed a variety of approaches. In an article, it was suggested to use a nephroscope sheath by applying laparoscopic forceps or an endo bag (retrieval bag or prototype nylon bag) to maintain its integrity while avoiding tumor spillage during extraction [31]. On the other hand, some authors proposed to extract in a divisional manner, by cutting into 2 or 4 pieces. While this method was criticized for theoretically losing one of the main advantages of ERBT, namely specimen integrity. And it has to be noted that the need for larger tumor extraction could be offset by additional equipment costs and potential long-term complications, such as urethral strictures. However, refinements in endoscopic technology have been introduced into clinical practice. In a clinical study [24], the author employed a two-step technique. The first step was resection of the larger exophytic tumor with the base being intact. After morcellation, the first part was extracted for determining tumor morphology and grading. The second step included overall resection of the tumor base, then it was removed through the resectoscope. They believed this technique follows the main principles of ERBT, minimizing contact of the removed tumor with the intact bladder wall. Anyway, during extraction, it had better avoid to be squeezed or torn.

Given the technical restrictions of ERBT, we need to be clear that ERBT is not a rather excellent method presently, and not suitable for all T1 bladder tumors. Its indications and contraindications are still developing and under clinical investigation.

Surgical margin of the specimen

During ERBT, the tumor base is excised circumferentially with a combination of blunt and sharp dissection, thus the dissection depth could be controlled exactly [27]. The resection includes the whole tumor, and the surrounding normally-appeared urothelium, so the DM is included in the specimen. The presence of DM may be the marker of complete resection of NMIBC [39]. Therefore, the diagnosis is more accurate. The procedures for thulium ERBT are illustrated in Figs. 1, 2 and 3.

Fig. 1.

Illustrating the procedures for thulium laser ERBT: 5–10 mm circumferential incision of the tumor base

Fig. 2.

Illustrating the procedures for thulium laser ERBT: the resection proceeding to the deep muscle layer

Fig. 3.

Illustrating the procedures for thulium laser ERBT: the en bloc resection being almost finished

ERBT offers the intrinsic advantage of complete removal of NMIBC [40], with sufficient sampling of muscularis propria (MP) and muscularis mucosae (MM), as well as orientation and precise identification of the surgical margins, allowing for horizontal and vertical evaluation of the pathological specimens [41]. Pathologically, the horizontal surgical margin refers to the presence or absence of cancer at the edge of the continuous mucosa; and vertical surgical margin refers to the presence or absence of cancer at the edge of the continuous MP.

In Takafumi Yanagisawa’s study [41], a total of 106 patients were treated with ERBT. They found horizontal surgical margins of 89 specimens were detectable, with 51 negative and 38 positive. The reasons for unable to detect horizontal margins included injury of mucosal edges, exfoliation or fragmentation. As to the rate of concomitant CIS with initial cancer, the patients with positive horizontal margin was significantly higher than the negative patients (61% vs. 24%, P < 0.001). During follow up, they found among patients with negative margin, 14 patients had relapse (28%), and the relapse occurred outside the initial resection area. Among the patients with positive surgical margin, 18 patients presented with relapse (47%); and in 7 patients, the relapse occurred within the former resection area. Cox proportional hazard analysis showed that positive vertical margin was an independent prognostic factor of worse progression free survival (PFS). After reresection, 6 cases of pTa/is residual tumors were identified in patients with positive horizontal margins, and 3 pT1 residual tumors were identified in a patient with positive vertical margin. In one meta-analysis [42], it was reported that the pooled rate of surgical margin diagnosis was 85% (191/224) in ERBT specimens; while in TURBT specimens, that rate was 8.7% (13/150); moreover, the detectable rate of vertical margin was higher than horizontal margin. In one observational report on 140 NMIBC patients treated with ERBT, the result demonstrated that the detectable horizontal margin and vertical margin rates were 63% and 99%, respectively [43].

Follow-up: recurrence

With the accumulation of clinical data, much more articles regarding follow-up of patients treated with ERBT were published, including observational, comparative, historically controlled, etc. Among them, the topics—postoperative recurrence—are the main focus. Furthermore, questions remain whether it offers advantages concerning recurrence-free survival (RFS), PFS, and cancer specific survival (CSS).

Miyake et al. compared the results of photodynamic diagnosis (PDD)-assisted resections using a rectangular cutting loop [44]. Out of 40 patients, 12 underwent PDD-ERBT and 28 underwent PDD-assisted conventional TURBT (cTURBT), then they performed pathologic assessment of horizontal and vertical margins in specimens from PDD-ERBT. As a result, they found all specimens had MP and the rate of ERBT was 100%. After a median follow-up of 11 months, no recurrence occurred in PDD-ERBT group and 2 cases had Ta low-grade recurrence in PDD-cTURBT group. Similarly, in a prospective clinical study, Dmitry Enikeeva et al. [24] compared 58 cases of conventional TURBT and 71 cases of Tm-fiber ERBT. Their finding showed that 3- and 6-month RFS were 84.5% and 67.2% for TURBT, 97.2% and 91.5% for ERBT, respectively (p = 0.011 and < 0.001), with the result in favor of ERBT.

In addition, comparisons between different ERBT methods were also conducted. In a multi-center clinical study in Europe, the difference between monopolar/bipolar electrical ERBT and holmium/thulium ERBT was observed, and the result showed that the average size of tumors was 2.1 cm, with the maximal size of 5 cm [33]. Most of conversion to conventional TURBT occurred in the “electrical” group. After a follow-up of 12 months, 33 cases (22.3%) of recurrence were identified. There was no difference between the two ERBT methods. Overall, 63.6% of recurrence were outside of the initial ERBT area.

During laser operation, beneath the vaporization tissue formed a “coagulation layer”, thus seeding opportunity of cancer cells is reduced and the risk of recurrence is minimized. This is attributable to the characteristic of lasers.

Li et al. [45] conducted an umbrella review and meta-analysis, comparing the clinical outcomes between ERBT and cTURBT for NMIBC patients within 1-year follow up. They found that patients undergoing ERBT were significantly associated with a lower rate of bladder perforation and obturator nerve reflex, while both methods took similar operation time. Meanwhile, ERBT exhibited a higher 3-month RFS rate (p < 0.05). In subgroup analysis, laser ERBT group revealed a significant improvement in 12-month RFS as compared to cTURBT group (p < 0.05). Their results were similar to that of Yuen-Chun Teoh J, et al. [23].

In a clinical study by Muto et al., they took cold cup biopsies during thulium laser ERBT [46]. After an average follow-up of 16 months, relapses were found in 7 of 48 patients (14.5%), without progression in tumor grade. All relapses were also distant from the former resection site. They concluded that the it seemed to have a good power of local tumor eradication.

Similarly, in a meta-analysis including 9 trials, Yang et al. [47] stated that regarding 24-month relapse rate, ERBT was much better than TURBT (p = 0.008). They concluded that ERBT could improve the quality of tumor specimens and decrease the need for re-TURBT.

Apart from lasers, various alternative types of ERBT were also reported concerning the follow-up. Hurle et al. applied electrical ERBT in 87 patients [48]. After 2-year follow up, an RFS of 85.59% was found. Multivariate analysis showed that only male sex and presence of CIS were the independent predictive factors of recurrence. The major shortcoming of that clinical study was short follow-up period and lack of control group. In another observational study [49], the authors reported that 4 out of 74 patients relapsed on the first cystoscopic follow up (5.4%). After 5 years, 57 patients did not relapse (77%). None progressed to MIBC, with a perfect PFS of 100%.

It is known that pT1 BC has a very heterogeneous nature and the treatment outcomes may be highly variable and unpredictable. ERBT might lead to fine long-term oncological outcomes with respect to both the recurrence and the progression rates for well-selected patients.

However, some researchers held conflicting opinions on this issue. In Sari et al.’s article [26], they compared the risk of recurrence for patients treated with three types of ERBT, including hybridknife, laser, and bipolar electrosurgery. The authors found that hybridknife (RR: 1.68, 95% CrI: 0.35–7.92), laser (RR: 0.62, 95% CrI: 0.24–1.21) and bipolar (RR: 0.74, 95% CrI: 0.14–3.78) ERBT were not related to a significantly reduced probability of the 12-month recurrence risk, in comparison with cTURBT. However, they also found that laser ERBT appeared as the top approach, and hybridknife was inferior to cTURBT.

The abovementioned clinical studies were compared among different modalities and time points. Nonetheless, most of the relevant literature have shown that ERBT is superior to conventional TURBT in terms of recurrence of bladder cancer in patients with an indication. Furthermore, the discrepancy implies that the biological behavior of BC is complex and variable, requiring further more in-depth research to elucidate the clinical effect of ERBT.

Pathological performance: presence of DM, residual tumor and upstage

Clinical evidence has demonstrated that the presence of DM is an important landmark displaying the quality of resection, representing a good effect of cancer control, and is also necessary for sufficient and accurate staging of BC [50]. At present, despite the advancements in resection techniques and visualization of optical instrument, the presence of DM in TURBT specimens is still unsatisfactory—remaining around 70%, even if for skilled surgeons [51, 52].

In Gontero’s article [52], they reported that in patients with re-TURBT, DM was present in only 69.3% of the initial specimens. Further, they found DM in the initial TURBT specimen was associated with a lower rate of residual disease at re-TURBT as compared to absence of DM (65.1% vs 85.9%), and the patients undergoing re-TURBT had a higher proportion of “upstaged” T1G3 disease in comparison with the patients without re-TURBT.

Theoretically, during ERBT, the DM layer should be exposed and dissected, thus the DM tissue is composed in all the specimens. In clinical practice, it has been found that the ERBT increases the presence rate of DM in specimens, irrespective of the type of ERBT.

Hashem et al. evaluated the rate of residual tumor and RFS at reTURBT 4 weeks after the initial resection, and compared the results of reresection between holmium laser TURBT and cTURBT [40]. Their results showed that presence rates of DM in specimen were 98% and 62%, respectively (p < 0.001). Residual tumors were seen in 7% of ERBT specimens and 27.7% of cTURBT specimens, respectively (p = 0.01). Their result was similar with Wang et al. [1], who found that ERBT had a much higher rate of DM (p = 0.003) and a significant lower rate of residual tumor (p < 0.001), comparing to TURBT. In Liu’s clinical study [53], they compared the difference between thulium laser ERBT and TURBT, and found the presence of DM in TmLRBT group was much higher than that of TURBT group (97.4 vs 87.6%, p = 0.001). In another multicenter clinical study by Hurle et al. [54], they applied various types of ERBT-including J-electrode Collins loop, Collins loop bipolar, Thulium laser, Storz bladder round loop and bladder rectangular loop; and performed re-ERBT for patients who had undergone ERBT about 40 days before. Their result revealed all specimens had DM, and only 1 patient had positive surgical margin.

In clinical context, residual tumor is also one of the main points of concern due to its well-known hazards. The predictive factors of residual tumor following TURBT was explored in one study [51]. Residual tumor might be located in the initial resection area or other areas, attributing to such reasons as imperfect technique, omission of lesions, as well as invasion of cancer. Furthermore, in 188 patients receiving reTURBT, 48 patients were found to have new tumor within the former resection area (25.5%), and 34 outside of the former area (18%). Both univariate and multivariate analyses had shown that after reTURBT, there was a significant correlation between the primary multifocal tumors and residual tumors. The authors concluded that multifocal tumors were an important factor resulting in residual tumors.

When ERBT was introduced into clinical application, the outcomes turn out differently. An interesting propensity score-matched analysis was conducted [55]. After matching, 202 patients (cTURBT: n = 101, ERBT: n = 101) were enrolled, with a bipolar TURis needle system as ERBT source. The result showed: the rate of residual tumor on reTUR was significantly lower in the ERBT group (ERBT: 15% vs cTURBT: 36%; p = 0.029).

Migliari et al. [6] evaluated 58 patients treated with thulium laser ERBT followed by reresection and cold biopsy, and found no residual tumor at the tumor base. Also, in Soria’s study, they observed that residual tumor rate at second look TURB was close to 0% after EBRT [56]. Although probably there existed a temporal difference in terms of the rate of residual tumor after TURBT, which was thought to be related to the accumulation of surgeons’ experience and clinical proficiency, ERBT has no such concern. And this also highlights its advantages in another way.

In addition, research on the issue of “upstaging” in pathological examination were conducted recently. In one meta-analysis, the authors investigated the upstaging rate in patients undergoing re-TURBT after ERBT, and concluded that when DM was present in the specimen of initial ERBT, the risk for pathological upstaging declined greatly [57]. Their result was similar with that of Yanagisawa et al. in whose study [58], 44 patients receiving cTURBT were compared with 46 patients receiving ERBT. After reTURBT, 2 patients were upstaged to pT2 among cTURBT group; but no case upstaged among ERBT group. Technically, upstaging to T2 reflects lower quality of resection and/ or specimen of initial resection.

Is reTURBT necessary after ERBT?

reTURBT

Due to the inherent defects of TURBT, reTURBT is strongly recommended in many guidelines, for better staging the patients and guiding treatment [59, 60]. In the case that DM is lack in the initial specimen, reTURBT could improve the prognosis. For T1G3 tumors, cancer cells might spread and metastasize through lymphvessels; by means of reTURBT, residual tumors could be identified and removed earlier [3, 51]. Basically, reTURBT is a better modality to overcome the defects of TURBT. However, some adverse effects might be resulted from reTURBT [57]; for example, patients may feel anxiety or horror, thus reducing the compliance. ReTURBT also bears similar drawbacks to TURBT: deep resection is very important and crucial for reTURBT, so potential risks—such as bleeding and bladder perforation—should be considered. Additionally, the marked influence of reTURBT on economic cost was also reported by Contier et al. [61]. They estimated the average cost of reTURBT at 1854€ per patient, while that of conservative approach (only outpatient cystoscopy) was at 95€ per patient; so the estimated saving for each avoided reTURBT was 1759€. They concluded that if reTURBT was not performed in selected T1 patients, the estimated saving was about 855.6€ for one patient.

Hence, unnecessary reTURBT might be avoided with the development of medical technology and theories, without compromising its positive effects and long-term outcomes.

Comparison of reTURBT after ERBT or TURBT

The outcomes of reTURBT after ERBT have been investigated in clinical studies, and some were compared with that after TURBT.

In a clinical study [62], 28 patients in ERBT group and 32 patients in TURBT group received reTURBT. The authors found the proportion of residual tumor at the initial resection area in TURBT group was higher than that in the ERBT group (OR: 0.32, 95% CI 0.17–0.60, p < 0.001); so, they concluded that for initial TURBT patients, the predictors of residual tumor on reTURBT was: concomitant with CIS, multifocality, no DM and inexperienced surgeons. While there was no correlation between ERBT and residual tumor. It is speculated that the technique of TURBT bears the risks of understaging due to lack of DM in the specimen, as well as inhomogeneous specimen quality, thus making up the great difference with ERBT.

Generally, the common parameters that clinicians focus most in oncology include: RFS and PFS, as well as CSS and overall survival (OS). Zhou et al. [63] reported that in a propensity score analysis, according to 1:1 proportion, 30 pairs of high risk NMIBC patients were enrolled who had undergone reTURBT or no-reTURBT after ERBT. As a result, DM tissues were present in 99.6% of the patients and no patient was found to be upstaging in reTURBT group. During the follow-up, 5 patients (16.7%) in the reTURBT group and 7 (23.3%) in the no-reTURBT group relapsed. One patient in each group presented with progression (3.3%). The 1-year relapse-free rate was similar between the two groups (86.7% vs 83.3%, p = 0.86). Therefore, they concluded that reTURBT after ERBT seemed unable to improve the accuracy of staging, relapse or progression.

The predictors of avoiding unnecessary reTURBT were explored in many studies. Soria et al. [64] underwent reTURBT within 2–6 weeks after the initial resection, and evaluated the predictive factors of pT0 at reTURBT with logistic-regression model. They found presence of DM, without concomitant CIS, and procedure of ERBT were the independent factors of pT0 at reTURBT, with a conclusion that ERBT is associated with negative histology at reTURBT, meaning that reTURBT was unnecessary after ERBT. Mariappan et al. [65] suggested that high quality TURBT, ERBT, and experienced surgeon, seemed to be the predictors to avoid unnecessary reTURBT.

In short, the disease of BC features particular cancer aggressiveness, including presence of variant histology, lymphovascular invasion (LVI) and concomitant CIS. The presence of residual tumor at reTURB represents a strong predictor of unfavorable outcomes. If complete resection is done with ERBT, then the risk of relapse is reduced greatly. Consequently, in some well-selected patients, reTURBT could be avoided after ERBT. However, we should keep in mind that the abovementioned clinical studies were performed with relatively strict restrictions, not in the popularized clinical settings. And the purpose of this review is to explore the beneficial effects of ERBT, not meant to replace, or even oppose the need of reTURBT in clinical practice.

Guiding significance in T1 substaging

Current investigations have shown that in T1 BC patients, the highest risk factor for relapse and progression is the depth of invasion to MM—which is beneath the basement membrane [57, 66]. Therefore, the concept of T1 substaging was proposed since the 2016 WHO classification—stratification by the depth of invasion based on the level of the MM [67].

At present, two substaging systems are commonly used: two tiers (T1a: MM uninvolved; T1b: MM invaded), or three tiers (TT1a: invasion up to the MM; T1b: invasion into the MM; and T1c: invasion beyond the MM), both with MM as the landmark [68].

T1 substaging is reported to present several advantages: improving the stratification accuracy of patients with high-risk NMIBC for PFS [69]; correlation with BCG failure, as well as a higher prognostic value for disease-specific survival [70]. In addition, accurate T1 substaging can lead to more reliable prediction for relapse and progression, and may be helpful for guiding decisions about adjuvant therapies and follow-up strategies.

However, pathologically accurate diagnosis of the MM invasion level is difficult with the technique of TURBT, because the specimens are piecemeal without orientation, possibly leading to underestimation of the invasion depth and inaccurate evaluation of surgical margins. Furthermore, the MM layers might be interrupted, incontinuous, or even lost. Thus, substaging is often unavailable in many instances at TURBT [71]. While the specimens obtained with ERBT has good orientation—including the mucosa, lamina propria, submucosa and DM layers—so it is available to conduct a thorough pathological evaluation.

In a meta-analysis, the detection rates of MM for pT1 cancers between ERBT and TURBT were compared [42]. The resultant forest plot of RCTs revealed the detection rate of ERBT was much higher than that of TURBT (RR: 2.69, 95% CI 1.81–3.97, z = 4.94). Observational studies also showed that ERBT was associated with a higher rate of detectable MM (RR: 2.02, 95% CI 1.09–3.75, z = 2.22).

In a single center study [72], Gallioli et al. found that all 40 pT1 cases could be substaged in the ERBT group; but in the TURBT group, the result was 34 in all 37 cases (100% vs 80%; p = 0.02). Thus they concluded that T1 substaging feasibility was significantly superior for ERBT. Moreover, their findings had been confirmed in per-lesion analysis, which showed a statistically significant difference in T1 substaging feasibility in favor of ERBT (100% vs 84%; p = 0.03). Similarly, Yanagisawa et al. [58] compared the pathological results of ERBT and TURBT in the treatment of T1HG bladder cancers. In ERBT specimens, the presence rate of DM and pT1a/b substaging diagnosis rate were much higher than that in TURBT specimens, with multivariate analysis showing that pT1a/b substaging was the predictor of disease progression.

Hashem et al. observed that among patients with NMIBC, lamina propria invasion substaging was feasible in only 18.4% of the TURBT patients and 68.2% of the Hol-ERBT patients (p < 0.001) [40]. Further, in Gallioli et al.’s article [72], they even stated that T1 substaging was possible in all ERBT cases.

Really, although substaging systems are promising prognosticators for T1 BC, real-world problems preclude their widespread use in TURBT, including bad orientation, lack of criteria for assessing invasion depth, specimen fragmentation, and issues with measurement reproducibility. However, many of these shortcomings can be overcome by means of ERBT. In particular, T1 substaging has not yet been recommended in clinical guidelines; but we believe that with gradually extensive application of ERBT in clinical practice and advancements of pathologcial examination, T1 substaging will be further explored and can provide better prediction of prognosis.

Conclusion

TURBT is still the gold standard for treatment of NMIBC; however, this technique is inherent with several disadvantages. Nowadays, with the advancement of medical science and technology, ERBT is growing a widely-applied and promising approach, and providing many advantages: complete resection of the tumor; accurate and controlled resection depth; avoiding the “piecemeal” resection of TURBT and minimizing exfoliated tumor cells, reducing the risks of spreading of tumor cells; including DM tissue and assessable safety margin, as well as good orientation, rendering precise pathological evaluation; lowering complications, such as massive bleeding or bladder perforation. These seem to overcome the inherent limitations of TURBT. Moreover, T1 substaging can be well conducted with a thorough pathological evaluation after ERBT and guiding treatment of BC patients. But the technique of ERBT is not perfect and it is a difficult method to apply in multiple, broad-based and solid tumors. Therefore, we can see its advantage in certain cases. However, it is reasonable to believe that with the gradual and widespread application of this technique, greater clinical value and effects will be achieved.

Abbreviations

NMIBC

Non-muscle invasive bladder cancer

TURBT

Transurethral resection of bladder tumor

ERBT

En bloc resection of bladder tumor

DM

Detrusor muscle

BC

Bladder cancer

CIS

Carcinoma in situ

CTC

Circulating tumor cell

BPH

Benign prostatic hyperplasia

MP

Muscularis propria

MM

Muscularis mucosae

PFS

Progression free survival

RFS

Recurrence-free survival

CSS

Cancer specific survival

PDD

Photodynamic diagnosis

Author contributions

Conceptualization, data collection, writing and editing—Wenbo Gao.

Funding

This work was supported by Yinzhou District Science and Technology Bureau (No. 2023AS027).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.