Transurethral resection of the bladder (TURBT) is the standard procedure for bladder cancer (BCa) diagnosis and represents, at the same time, the most important therapeutic moment for patients with nonmuscle invasive bladder cancer (NMIBC) . Obtaining a correct staging of the disease is of fundamental importance to select patients for intravesical adjuvant therapies in case of NMIBC or for radical surgery and, eventually, preoperative systemic therapy in case of muscle-invasive disease. However, despite growing attention focused on this procedure over the last years, the accuracy of TURBT in staging and removing all visible tumors remains limited in a nonnegligible percentage of cases, with a detrimental impact on the entire course of the disease, and consequently, on patients’ survival .
With the aim of reducing the likelihood of understaging and the rate of residual disease at first resection, a repeated TURBT (re-TURBT) to be performed within 2–6 weeks from the initial TURBT is recommended in patients harboring tumor invasion into the lamina propria (T1) and in those in whom the resection was deemed incomplete. The importance of re-TURBT lies not only in the inadequacy of the initial resection but also in its ability in providing additional prognostic information essential for risk-stratification refining. However, it should be underlined that re-TURBT is an invasive and morbid procedure that severely affects patients’ quality of life as it has to be performed on a patient that is maybe still suffering from the consequences of the previous surgery. Finally, it an optic of better resource allocation, re-TURBT represents an expensive procedure with negative impacts on health-care costs, and a source of logistic difficulties being one of the reasons for the enlargement of waiting lists.
On the basis of these considerations, one of the main challenges for the upcoming years will be to improve patients’ selection for re-TURBT, thus, limiting this procedure to those patients with a high chance to have residual disease and/or to harbor MIBC. In this review of the literature, the attention will be focused on the evidence supporting re-TURBT and on its future perspectives.
Current recommendations on re-transurethral resection of the bladder tumor across guidelines
The undeniable role of re-TURBT, both for diagnostic and therapeutic reasons, is underlined by all the most followed international guidelines among the urological community [European Association of Urology (EAU), American Urological Association (AUA), National Institute for Health and Care Excellence (NICE), National Comprehensive Cancer Network (NCCN), and Canadian Urological Association (CUA)] (Table 1).
All the guidelines strongly recommend re-TURBT in the case of NMIBC and first incomplete resection, with the aim to remove any residual disease before the initiation of any adjuvant intravesical therapy. Moreover, the importance of the completeness of the resection has also been questioned in case of MIBC. Although it is quite obvious the need for a complete TURBT in case of MIBC patients undergoing trimodal therapy, there is also some evidence that a maximal TURBT could improve oncological outcomes in patients undergoing radical cystectomy . Moreover, all the guidelines recommend re-TURBT in case of T1 tumor, even if the strength of recommendation differs across guidelines. This level of agreement mainly derives from the high risk of understaging the disease in case of T1 tumor that negatively affects the administration of the right treatment. Conversely, guidelines do not completely agree in recommending re-TURBT in case of Ta tumors (except for EAU, all the other guidelines recommend re-TURBT in case of Ta with features of tumor aggressiveness, such as high-risk/high-grade tumors). Finally, most of the guidelines recommend re-TURBT in case of absence of detrusor muscle in resection's specimen and T1 or high-grade tumor. Actually, as discussed below, the presence of detrusor muscle in TURBT specimen could be considered as a marker of the quality of the resection and seems to influence oncological outcomes and decision-making process.
Critical analysis of the reasons for recommending re-transurethral resection of the bladder tumor
Understaging of muscle-invasive bladder cancer
One of the major drawbacks of TURBT is related to its inaccuracy in correctly staging the disease, especially in differentiating between nonmuscle-invasive and muscle-invasive tumors. This could be the consequence of multiple combined factors. First, despite its apparent simplicity, TURBT is a challenging procedure requiring experience, attention to details, and knowledge of BCa biology [4▪]. However, the importance of TURBT has been for too much time underestimated, with a detrimental impact on its quality and, consequently, on pathologic and oncological outcomes. Second, as during TURBT, the tumor is removed in multiple pieces, it is sometimes difficult for the uropathologist to differentiate between muscolaris mucosae and muscolaris propria, thus leading to uncertainty in disease staging. This is even worsened by the use of diathermy during the resection, which may result in cautery and crush artifacts (more commonly occurring with monopolar energy), responsible for tissue modifications leading to possible misinterpretations . Third, to ensure a correct disease staging, TURBT should always involve the muscular layer and detrusor muscle should be available for evaluation in the pathologic specimen. To date, despite technological improvement and even in expert hands, the rate of detrusor muscle in TURBT specimen ranges between 50 and 80%, depending on the series [6,7].
Is it really relevant?
On the basis of data from historical series, disease understaging at TURBT is a relevant problem that makes re-TURBT essential in the high-risk population. Fritsche et al., by analyzing the largest cohort (1136 patients) of clinical T1G3 NMIBC who underwent RC without neoadjuvant chemotherapy. At final pathology, half of the patients were upstaged to MIBC and one out of three patients was found to harbor nonorgan-confined disease, thus supporting the inadequacy of clinical decision-making based on the results of TURBT and preoperative staging tools.
Can we make it irrelevant with a good first transurethral resection of bladder tumor?
Several factors play an undeniable role in determining disease upstaging at RC. Among these, we have to acknowledge those factors that represent characteristics of tumor aggressiveness, such as the presence of lymphovascular invasion (LVI) and variant histology at first TURBT as well as the molecular subtype of the tumor. In a recently published systematic review and meta-analysis of the literature, Mari et al. confirmed the association between the presence of LVI and upstaging to nonorgan-confined disease at RC in patients with cT1-T2 BCa (pooled hazard ratio 3.08). Moreover, it is well known that some histological variants are expression of particularly aggressive tumors and patients harboring these variants are, therefore, at higher risk to be upstaged at surgery: this is the case for micropapillary, plasmacytoid, sarcomatoid, or nested variants [10▪▪].
Recently, the impact of BCa molecular classification on upstaging to nonorgan-confined disease at RC has been evaluated in a retrospective cohort of 206 patients with clinical T1 (42%) or T2 (58%) [11▪▪]. A whole-transcriptome assay was used to generate a genomic subtyping classifier score, and tumors were classified in luminal, basal, infiltrated luminal, and claudin-low subtypes; luminal tumors showed a significantly lower rate of upstaging compared with nonluminal tumors.
In patients presenting these characteristics, a good first TURBT does not probably change the risk of upstaging at RC and patients should, therefore, be counseled either for immediate surgery or re-TURBT. Conversely, for patients without features of tumor aggressiveness, a good first TURBT can play a role in diminishing the risk of upstaging. This consideration is based on data coming from historical retrospective series where the association between the presence of detrusor muscle at initial TURBT and the final pathology at RC was analyzed. In patients with cT1 NMIBC treated with RC, upstaging to T2 was found in 49% of patients without detrusor muscle in TURBT specimen compared with 14% when detrusor muscle was present . Dutta et al. confirmed these initial findings by reporting a significant difference in the risk of upstaging at RC based on the absence or presence of detrusor muscle at the time of TURBT (62% vs. 30%).
Therefore, the presence of detrusor muscle in surgical specimen has been considered as a proxy of the quality of the resection and several attempts have been made aiming to increase the probability of including the muscular layer in the resection field. Among these, the development and the adoption of a surgical checklist for TURBT are of undeniable importance. Mariappan et al. firstly developed the concept of good-quality TURBT, defined as complete resection with detrusor muscle presence carried out by experienced surgeons. Successively, the introduction of a surgical checklist in order to standardize the procedure, enhance its performance, and improve oncological outcomes was proposed and externally validated [13,14]. Suarez-Ibarrola et al.[4▪] tested the impact of an eight-item surgical checklist (tumor status, preresection bimanual palpation, macroscopic appearance of the tumor, focality, size and location, completeness of the resection, and postresection bimanual palpation) on oncological outcomes. The implementation of this surgical checklist in clinical practice increased the quality of operative reports and improved recurrence-free survival.
Pathology of residual nonmuscle invasive disease at re-transurethral resection of the bladder tumor: does it influence treatment choice (conservative vs. cystectomy)?
The presence of residual disease at the time of re-TURBT is, unfortunately, a quite common event. In a recently published systematic review and meta-analysis on the role of re-TURBT, Cumberbatch et al.  reported a residual disease rate of 55% (range 17--67%) and 51% (range 20--71%) for Ta and T1 tumors, respectively. Additionally, it has to be underlined that upstaging to MIBC has been reported to be quite negligible for Ta tumors (0.4%), but not for patients with T1 disease (8%, range 0–32%). Previously, Naselli et al. reported a residual disease rate for T1 patients of 61%, with an upstage to muscle-invasive disease of 15%. If it is quite clear that the upstaging at re-TURBT influences treatment choice in favor of radical therapies (either RC, eventually preceded by neoadjuvant chemotherapy or trimodal therapy), the impact of nonmuscle invasive residual disease (pTa, pTis, pT1) at re-TURBT remains questionable.
Most of the published literature agree in indicating the presence of nonmuscle invasive residual disease at re-TURBT as prognostic factor of worse oncological outcomes. Initially, Herr et al. reported the oncological outcomes of 710 NMIBC patients treated with TURBT and re-TURBT. Despite the heterogeneity of the population, which included also 136 patients with Ta low-grade disease, only 278 (39%) patients had no residual tumor at re-TURBT and upstaging to invasive cancer was found in 9% of Ta high-grade and in 23% of T1G3 patients. Moreover, the authors found a significant association between the pathology of residual disease and the recurrence and progression rates: patients with pT0, pTa, and pT1 tumors experienced disease recurrence and progression in 53, 83–86, 90%, and 9, 9–16 76%, respectively. These findings were successively externally validated in a small retrospective cohort of 72 patients who underwent re-TURBT; on multivariable analyses, tumor stage at re-TURBT was an independent predictor of recurrence-free and progression-free survival . These dramatic data indicated the need for more aggressive management in case of persistent disease at re-TURBT, especially in case of persistent T1 high-grade tumors.
However, recently, the impact of residual disease was confirmed but mitigated by a large retrospective multicenter trial on 2451 T1G3 patients, 934 (38%) of whom underwent re-TURBT . Of these, the majority was found to have residual disease (Ta in 40% and T1 in 31% of the cases). Pathology at re-TURBT was directly correlated with oncological outcomes: within a median follow up of 5.2 years, persistent T1 disease was an independent predictor of disease recurrence and disease progression occurred in 25.3, 14.6, and 14.2% of patients with T1, Ta, and T0. This translated into higher cancer-specific mortality for patients with residual disease, especially for those with persistent T1 tumors. Despite confirming the increased risk of progression in T1 patients, this risk was not as high as previously thought, leaving the opportunity for conservative management with close follow up.
In conclusion, the pathology of re-TURBT alone is not sufficient to select patients for early radical treatment but it should be taken into consideration in the decision-making process together with other established risk factors, such as the presence of LVI, variant histology, associated carcinoma in situ, and hydronephrosis.
Identification of clinicopathologic prognostic factors: can we predict the pathology of re-transurethral resection of the bladder tumor?
In recent years, several attempts have been made to identify clinicopathologic factors able to predict final pathology at re-TURBT. Initially, in a hypothesis-generating study on 52 consecutive patients with biopsy-proven NMIBC on initial TURBT, tumor grade, tumor stage, and macroscopic appearance (solid vs. papillary) were significantly associated with both residual disease and upstaging at re-TURBT, whereas the presence of concomitant carcinoma in situ (CIS) and the absence of muscle in pathologic specimen only predicted residual disease and upstaging to MIBC, respectively . More recently, our group developed a nomogram to predict negative histology (pT0) at re-TURBT, with the aim to select those patients in whom, in the next future, this procedure may be safely avoided . In this retrospective study of 321 patients harboring T1HG NMIBC, the presence of detrusor muscle in TURBT specimen, the absence of concomitant CIS and the en bloc resection were found to be independent predictors of negative re-TURBT. For example, based on this model, a patient with T1HG without concomitant CIS, with detrusor muscle in resection's specimen and who received an en bloc resection under photodynamic diagnosis-guidance has a probability higher of 95% to be found with pT0 at re-TURBT.
The en bloc resection technique, by removing the tumor in one piece, has been developed with the aim to improve the quality of the resection compared with the conventional TURBT and to provide better surgical specimens for pathologic evaluation. Consequently, it is assumed that better resection may decrease the need for re-TURBT. The presence of detrusor muscle in surgical specimen has been considered a proxy of the quality of the resection [4▪], and higher rates of residual disease at re-TURBT in patients without detrusor muscle in TURBT specimen compared with those with detrusor muscle have been reported . Finally, the presence of detrusor muscle allows correct identification of the muscular layer, thus diminishing the probability of understaging the disease. On the basis of a recently published systematic review of the literature, detrusor muscle was shown to be 100% present in four out of seven studies on en bloc resection, and more than 95.6% in the other three reports . These data are significantly higher compared with those obtained with conventional TURBT, where the presence of detrusor muscle in resection specimens is reported to range between 55 and 85%, even in expert hands . Beyond allowing a more complete resection and an easier and more accurate pathologic evaluation, the en bloc resection technique seems to impact on the presence of residual disease at re-TURBT performed within 2–6 weeks from the initial TURBT. Hurle et al. performed an international, multicenter, retrospective analysis of patients undergoing re-TURBT because of the high-risk NMIBC, who were previously treated with en bloc resection. Overall, 78 patients were enrolled in the study, and residual disease at re-TURBT performed within 40 days from the first procedure was found in only five patients (one patient had a pTaHG whereas four had a pTis). The extremely low rate of residual disease in this cohort compared with that reported in the literature for conventional TURBT (between 25 and 50%, depending on the series), raises the question of the utility of re-TURBT after en bloc resection.
Following the tremendous impact achieved for prostate cancer diagnosis and management, multiparametric MRI (mpMRI) has been recently tested in BCa as an imaging tool to predict the invasion of the muscolaris propria, thus aiming to improve the diagnostic accuracy of TURBT. As for prostate cancer, Panebianco et al.[26▪▪] developed a five-point VI-RADS (Vesical Imaging-Reporting and Data System) derived using T2-weighted MRI, diffusion-weighted imaging, and dynamic contrast enhancement, which suggests the risks of muscle invasion. A first validation study of 75 patients undergoing mpMRI before TURBT reported accuracy of mpMRI in discriminating between NMIBC and muscle-invasive disease ranging between 87 and 93% . These first findings have been successively externally validated, with consistently reported results: a recently published meta-analysis on the topic reported a mpMRI sensitivity and specificity of 0.84 and 0.91, respectively . Del Giudice et al. tried to evaluate the accuracy of VI-RADS for identifying high-risk NMIBC patients who could avoid re-TURBT and detecting those at higher risk to have been understaged at the first resection and to, consequently, harbor residual disease. A total of 231 patients were enrolled in the study; the mpMRI showed an accuracy of 94% in predicting muscle-invasive disease at first resection and an accuracy of 97% in predicting muscle invasion at re-TURBT among the 114 high-risk patients who underwent the procedure. These promising exploratory results lay the foundation for future prospective trials aiming to evaluate the role of mpMRI in selecting high-risk patients who could safely avoid re-TURBT.
When could re-transurethral resection of the bladder tumor be safely avoided (in spite of current guidelines recommendations): the two extremes
Despite guidelines recommendations, based on the previously discussed evidence, there are cases in which re-TURBT could be safely avoided, either in favor of immediate radical treatment or of immediate conservative treatment with intravesical immunotherapy. Here, two practical clinical cases will be discussed as examples of the extremes of a bell curve.
The case for immediate conservative treatment
A male patient, 82 years old with cardiovascular comorbidity under anticoagulant therapy, underwent a complete en bloc resection of a primary 1 cm BCa of the left lateral wall. The histology revealed a pure urothelial T1HG tumor, without LVI and carcinoma in situ. Detrusor muscle was present in the resection's specimen. At the staging abdominal CT scan, no hydronephrosis was detected. In this case, considering the absence of features of tumor aggressiveness, the presence of detrusor muscle in the specimen and the technique of the resection, the estimated probability of tumor understaging, and/or residual disease is very low. Moreover, it should be underlined that a new endoscopic procedure within 2–6 weeks in a comorbid elderly patient may severely affect his quality of life and performance status. Therefore, based on these considerations and after a proper patient counseling, re-TURBT could be in this case safely avoided in favor of an immediate induction cycle of intravesical Bacillus Calmette-Guerin (BCG).
The case for immediate radical cystectomy
A female patient of 62 years old in good general conditions underwent TURBT for a primary 3.5 cm tumor of the trigonum; in the operative report, the macroscopic appearance of the tumor was described as solid. Histology revealed a T1HG tumor with micropapillary differentiation and LVI. Detrusor muscle was absent in surgical specimen and staging CT scan showed the presence of left hydronephrosis. In this case, the absence of detrusor muscle in surgical specimen may indicate the need for re-TURBT. However, the presence of LVI and hydronephrosis suggest a high probability of understaging and the presence of an aggressive histological variant drives the decision regarding treatment. Actually, even in case of a confirmed T1 tumor at re-TURBT, the correct management of a micropapillary tumor is represented by RC. Moreover, even in case of muscle-invasive disease, neoadjuvant chemotherapy would be not indicated because of the low chance of response of this tumor to cisplatin-based systemic therapy. Therefore, in this clinical scenario, the performance of re-TURBT would not change the indication to RC and may lead to unnecessary delays that could potentially negatively impact on the oncological outcomes.
To date, re-TURBT represents a cornerstone for the treatment of NMIBC because of its ability in removing residual disease after TURBT, diminishing the risk of understaging and providing information useful in their decision-making process regarding treatment and follow-up. However, there is evidence that re-TURBT could be safely spared in some cases in favor of immediate conservative or radical treatments. Actually, we are moving from the era of ‘one fits all’ to that of precision medicine, where treatments are personalized based on patients’ and tumors’ characteristics. Future studies should focus on patients’ selection, thus paving the way forward to a randomized controlled trial aiming to evaluate the need of re-TURBT in selected category of patients.
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Conflicts of interest
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