Transurethral Resection of Bladder Tumors (TURBT)

Transurethral resection of bladder tumor (TURBT), performed endoscopically, is the first-line procedure for diagnosis, staging, and treatment of visible tumors. In select patients, office-based fulguration of small tumors allows control of low-risk bladder lesions without incurring the cost, patient risk, and inefficiencies of the operating room. ^[1]

More than 70% of bladder tumors are non–muscle-invasive bladder cancer (NMIBC), urothelial carcinoma. The prognosis for patients with NMIBC is favorable, with cancer-specific survival in high-grade disease approaching 70-85% at 10 years, and considerably higher in low-grade disease. While NMIBC is a very heterogeneous group of cancers, the variable rates of disease recurrence and progression to muscle-invasive bladder cancer (dependent upon clinical and pathological stage and grade) are important prognostic factors that ultimately drive long-term patient outcomes. ^[2]

TURBT is not effective for carcinoma in situ (CIS) because in such cases the disease is often so diffuse and difficult to visualize that surgical removal is not feasible. Therefore, the role of cystoscopy in these cases is to establish the diagnosis so that therapy can be instituted. Obvious areas of CIS may also be fulgurated, but the benefits of this have not been proven. When a combination of papillary tumor and CIS is present, the papillary tumor is removed before treatment of the CIS is initiated.

Guidelines for the use of TURBT in the diagnosis and management of bladder cancer have been issued by the following organizations:

• American Urological Association/Society of Urological Oncology (AUA/SUO) ^[2]
• European Association of Urology (EAU) ^{[3, 4]}
• National Comprehensive Cancer Network (NCCN) ^[5]

For more information, see Bladder Cancer.

The guidelines (AUA, EAU, ESMO, NCCN) are in agreement that the final diagnosis of bladder cancer is based on cystoscopic examination and bladder tumor histology. The guidelines further agree that all visible lesions should be resected during TURBT with bimanual examination under anesthesia (EUA) and that adequate sampling is required for proper tumor identification and staging. Lastly, imaging of the upper urinary tracts should be evaluated to assess for concomitant disease involvement. ^{[5, 3, 4, 6, 2]}

The AUA/SUO recommendations for repeat TURBT are as follow ^[2] :

• In patients with incomplete initial resection, repeat TURBT if technically feasible.
• For high-risk, high-grade Ta tumors, consider performing repeat TURBT of the primary tumor site within 6 weeks of initial TURBT.
• In T1 disease, repeat TURBT of the primary tumor site, including muscularis propria, within 6 weeks of initial TURBT.

EUA guidelines recommend performing a second TURBT 2-6 weeks after the initial resection in any of the following situations ^{[4, 3]} :

• After incomplete initial TURBT
• If there is no muscle in the specimen after initial resection, with exception of Ta low-grade tumors and, possibly, completely resected primary CIS
• In all T1 tumors
• In all high-grade tumors, except primary CIS; however, it may be beneficial to attempt to resect all CIS lesions at repeat TURBT

The NCCN recommends TURBT as standard treatment for low-grade Ta NMIBC. ^[5]

For high-grade Ta tumors, the NCCN and EAU recommend repeating TURBT if resection is incomplete. If no muscle is present in the specimen, repeat resection should be strongly considered. Repeat TURBT has prognostic, therapeutic, and surveillance indications. Up to 40-70% of patients will have residual bladder cancer at repeat TURBT performed within 4-6 weeks after initial TURBT. ^{[5, 4]}

For treatment of T1 tumors (low- and high-grade) NCCN recommends repeat TURBT. ^[5]

For muscle-invasive disease, NCCN recommends TURBT as the initial diagnostic procedure after CT/MRI imaging of the abdomen and pelvis to help identify the clinical stage of the bladder cancer. Bladder preservation following TURBT with concurrent chemotherapy and radiation is an alternative therapy for patients with multiple medical co-morbidities or who refuse radical cystectomy.

Bladder preservation is generally reserved for patients with the following ^[5] :

• Smaller solitary tumors
• Negative nodes
• No extensive or multifocal CIS
• No tumor-related hydronephrosis
• Good pre-treatment bladder function

Patients will undergo pre-anesthesia testing in order to evaluate physical condition and medical conditions. As antithrombotic therapy has become more prevalent, ^[7]  the decision whether to hold anticoagulants or antiplatelet agents is a commonly discussed topic. While there are no guidelines to follow regarding the perioperative management of these medications, it is an often-debated balance between adverse cardiovascular events and persistent perioperative hematuria. While low-dose aspirin can be continued in most cases, all other antiplatelet agents and anticoagulants are almost always held perioperatively, with the duration and plan for resumption made on a case-by-case basis. 

Patients scheduled for anesthetic cystoscopy with TURBT must have sterile urine documented prior to instrumentation. Sterility is usually presumed on the basis of a microscopic urinalysis showing no bacteria or white blood cells (WBCs). Patients with a positive urine culture are conventionally treated with a course of culture-specific antibiotics to achieve this desired sterility. 

The risk of urinary tract infection with cystoscopic instrumentation is approximately 1%. The flora of concern are primarily gram negative rod species, rarely enterococcus. In the past, a single prophylactic dose of a fluoroquinolone was given to patients undergoing cystoscopy. However, American Urological Association guidelines now recommend single-dose cefazolin or trimethoprim-sulfamethoxazole, in view of the 2016 US Food & Drug Administration (FDA) black box warning on safety issues with fluoroquinolones. ^[8]

In most cases, general or regional anesthesia must be used to establish nerve paralysis, to minimize risk of obturator nerve reflex and subsequently, bladder perforation.

Complete eradication of tumor is the first step in TURBT. Most tumors are papillary and are easily removed by endoscopically transecting (bipolar or monopolar electrocautery) their narrow stalk or base. Following this, biopsy of the base or deeper resection is performed to ensure complete removal and the absence of invasion. The goal is that muscle tissue (or fat) must is present in the base biopsy specimen to ensure accurate staging.

Medium and large tumors are resected in a controlled serial fashion prior to transection of the stalk. This ensures that large segments do not remain that might be too large to evacuate through the resectoscope.

Smaller and more friable tumors may be removed at least partially by knocking off fragments with the cutting loop of the resectoscope without the electricity turned on. This sometimes allows partial removal with less risk of bladder perforation.

Pulling the cutting loop away from the tumor (toward one's self) is generally much safer than pushing it toward the tumor. Lifting the tumor away from the surrounding normal bladder tissue using the cutting loop is also advisable.

Continuous-irrigation during resection is a popular modality as it not only assists in visualization but also lessens the bladder wall movement that occurs during filling and emptying, and thereby may decrease the risk of bladder perforation. Without it, inadvertent overfilling stretches and thins the detrusor, which raises the risk for perforation. 

Transurethral resection (TUR) syndrome, which results from absorption of electrolyte-free irrigating fluid, has become uncommon since the advent of bipolar resectoscopes, which utilize normal saline irrigation. 

Overuse of cautery at the base of the tumor increases cautery artifact, which can complicate pathological determination of muscle invasion status.

Within the first 24 hours, a single intravesical instillation of mitomycin-C (40 mg in 20 mL of normal saline) has been shown to reduce the frequency of tumor recurrence and should be considered the standard of care after TURBT or positive bladder biopsy findings. ^[9]  Gemcitabine (2 g in 100 mL of normal saline) has widely replaced mitomycin-C in this setting, due to its similar efficacy, lower adverse effect profile, ^[10]  and cost. ^[11]  It should be emphasized that while gemcitabine and mitomycin-C have established efficacy, ^{[9, 12]}  there have been no studies comparing them head-to-head in this setting. 

Postoperative intravesical chemotherapy is withheld if there is surgeon concern for bladder perforation; extensive or deep resection; or persistent hematuria, due to the possibility for systemic absorption.

Occasionally, a Foley catheter may need to be left in place for 1-3 days after TURBT. It is usually removed in the urology office.

Postoperatively, symptoms of intermittent dysuria, urinary frequency, urgency, and hematuria are anticipated.

The most common complications after TURBT are as follows ^[13] :

• Persistent hematuria - The estimated incidence rate is 1-4%, higher with antithrombotic agents; significant hematuria (ie, requiring transfusion or reoperation) is often secondary to bladder perforation or resection of a large tumor.
• Bladder perforation - Risk factors include surgeon experience, tumor location, and bladder thickness (lowest in females, patients with lower body mass index). Early recognition vital to minimize the size of the perforation and prevent tumor seeding and extravasation of fluid (retroperitoneal vs intraperitoneal). Mortality rates approach ~20% for unrecognized intraperitoneal perforation.
• Ureteral obstruction - Estimated occurrence rate as high as 13%. Obstruction is typically secondary to ureteral orifice stenosis, which occurs as a result of tumor resection near the ureteral orifice. Risk is highest with cauterization as opposed to resection. It is safe to resect the ureteral orifice if necessary, but placement of a sensor wire for later identification and ureteral stenting is advised by most experts. A postoperative kidney ultrasound is recommended if there is any suspicion of ureteral obstruction, as early intervention can prevent kidney dysfunction.

A second TURBT should be performed 2-6 weeks after initial TURBT for several patient populations. Indications include the following:

• Incomplete initial resection
• Absence of muscularis propria in the specimen
• T1 tumor
• High-grade tumor

A second TURBT can be omitted for patients with primary carcinoma in situ or for solitary low-grade Ta tumors. The rationale for second TURBT is the risk of understaging and subsequently, undertreating, as well as the significant risk of residual tumor after initial TURBT.

Bipolar TURBT

Traditionally, TURBT was performed using monopolar electrocautery to provide the necessary energy for resecting the tumor and cauterizing blood vessels. More recently, as bipolar technology has emerged and improved, its application has extended to TURBT. It has the potential benefit of decreased risk of bladder perforation via obturator reflex and decreased risk of TUR syndrome. With bipolar technology, the active and return electrodes are located in proximation within the resection loop so that the patient does not have to be grounded via an external pad, as is the case with monopolar cautery. This also allows for the use of nonconductive isotonic irrigation fluid (eg, normal saline), mitigating the risk of TUR syndrome. ^[14]

Wang et al were the first to report on bipolar TURBT in 2004 and compared the pathologic specimens from 11 patients who underwent bipolar TURBT with a matched historic cohort of 11 patients who underwent standard monopolar TURBT. No differences in the degree of cautery artifact were noted between the 2 groups, and a full and proper diagnosis was achieved in all cases when assessed by a single pathologist who was blinded to the form of electrocautery used. ^[15]

Yang and associates retrospectively compared clinical and pathologic results in 115 patients who underwent bipolar (n=64) versus monopolar (n=51) TURBT. ^[16] Postoperative change in hemoglobin (-0.58±0.91 g/dL vs -0.95±1.28 g/dL, P = 0.038) and mean duration of catheterization (2.20±0.96 d vs 2.65±1.45 d, P = 0.026) favored the bipolar TURBT group. A randomized controlled trial comparing monopolar vs bipolar TURBT (31 vs 36 patients) found that bipolar was not significantly superior with respect to obturator reflex, transfusion requirement, bladder perforation, hyponatremia, hospital stay, or pathologic quality of tumor specimen. However, the postoperative hemoglobin and resection time were significantly less. ^[17]  Furthermore, reducing the power settings to 50-W cutting and 40-W coagulation may reduce the incidence of obturator nerve reflex and bladder perforation to close to zero while still maintaining diagnostic and therapeutic efficacy. ^[18]  

Blue Light Cystoscopy

Blue light (BL) cystoscopy has emerged as a viable adjunct to conventional, white-light (WL) cystoscopy to assist in the performance of a complete TURBT. ^[19]  Lesions can be missed using WL cystoscopy, and BL cystoscopy has been developed to assist in the detection of these lesions, improve the completeness of resection, and reduce the rate of recurrence. BL cystoscopy exploits the photodynamic properties of several compounds, including hexaminolevulinate (HAL) (Hexvix, Cysview, Photocure; Oslo, Norway) and 5-aminolevulinic acid (5-ALA).

For BL cystoscopy, approximately 1 hour prior to planned TURBT, 50 mL of reconstituted solution of HAL (100 mg dissolved in phosphate-buffered normal saline) is instilled into the emptied bladder via an intravesical catheter. Following instillation, protoporphyrin IX preferentially accumulates in metabolically active tissue (eg, neoplastic tissue), producing a clearly demarcated red fluorescence under illumination with blue-violet light (380-440 nm). Cysview (HAL hydrochloride) was approved by the US Food and Drug Administration in 2010 for use with the Karl Storz D-Light C system with the BL setting as an adjunct to the WL setting in the detection of non–muscle invasive papillary cancer of the bladder in patients suspected or known to have lesions on the basis of a prior cystoscopy. ^[20]

Currently, the American Urologic Association/Society of Urologic Oncology (AUA/SUO) recommends that BL cystoscopy should be offered at the time of TURBT to enhance disease detection and to decrease recurrence. Furthermore, a patient with a history of non–muscle invasive bladder cancer (NMIBC) who has positive cytology yet a normal WL cystoscopy should be offered prostatic urethral biopsies, BL cystoscopy, upper urinary tract imaging, ureteroscopy, or random bladder biopsies. ^[2]

A multicenter phase III study evaluated the efficacy of WL vs BL cystoscopy in the setting of bladder cancer surveillance. ^[21]  Of the 103 patients included, 63 had confirmed malignancy (26/63 (41%) being carcinoma in-situ, CIS), with 13/63 (20.6%) patients' recurrence seen only via BL flexible cystoscopy (P < 0.0001). Operative cystoscopy confirmed CIS in 26/63 (41%), which was detected only via blue light cystoscopy in 9/26 (34.6%; P < 0.0001). The false-positive rate was 9.1% for both WL and BL cystoscopy. Jocham and colleagues noted a similar result in a phase III prospective study, with improved disease detection and improved treatment in a significant number of patients (P < 0.0001). ^[22]

A meta-analysis by Burger and colleagues reviewed the raw data from prospective studies on 1345 patients with known or suspected NMIBC on whom BL was used an adjunct to WL cystoscopy. ^[23]  BL cystoscopy detected significantly more Ta tumors (14.7%; P < .001) and CIS lesions (40.8%; P < .001) than WL cystoscopy. Furthermore, recurrence rates up to 12 months were significantly lower overall with BL versus WL cystoscopy (34.5% vs 45.4%; P = 0.006).

The management of NMIBC is expensive, stemming from high recurrence rates necessitating repeat TURBT and frequent surveillance cystoscopies. As HAL and 5-ALA have been shown to help increase the detection and reduce the recurrence of NMIBC, this technology may reduce the cost of bladder cancer management. Garfield et al assessed the cost effectiveness of BL cystoscopy as an adjunct to WL cystoscopy versus WL cystoscopy, alone at the time of initial TURBT and noted a cost savings of nearly $5,000 in the BL group in their model over a 5-year projected period. ^{[24, 25]}

Narrowband imaging

Narrowband imaging (NBI) technology takes advantage of the hypervascular nature of bladder cancer to aid in differentiation from normal urothelium. WL is filtered into 2 bandwidths of 415 and 540 nm, which is preferentially absorbed by hemoglobin in hypervascular neoplastic tissues. A meta-analysis of the diagnostic accuracy of NBI-assisted cystoscopy compared with WL cystoscopy for NMIBC determined that NBI detected tumors in an additional 17% of patients and found an additional 24% of tumors compared with WL cystoscopy. No difference in the rate of false-positive tumor detection was noted between NBI and WL cystoscopy. ^[26]  

A systematic review and meta-analysis of randomized controlled trials that evaluated the efficacy of NBI-TURBT for NMIBC compared with WL imaging–assisted (WLI) TURBT found that NBI-TUR was associated with improvements in the 3-mo recurrence risk (RR: 0.39; 95% CI, 0.26-0.60; P < 0.0001), 1-yr recurrence risk (RR: 0.52; 95% CI, 0.40-0.67; P < 0.00001) and 2-yr recurrence risk (RR: 0.60; 95% CI, 0.42-0.85; P = 0.004) compared with WLI-TUR. ^[27]

At present, the AUA/SUO recommends considering NBI cystoscopy in patients with a history of NMIBC, to increase disease detection and decrease recurrence. ^[2]

En Bloc Transurethral Resection of Bladder Tumors

En bloc transurethral resection of bladder tumors (ETURBT) is newer technique in which the tumor and the surrounding normal urothelium are removed as a single unit. ^[28]  A meta-analysis of seven trials found that ETURBT was associated with shorter hospital stays and catheterization time,fewer complications, and a lower recurrence-free rate than conventional TURBT. ^[29]  In a separate systematic review of 17 studies, the results were comparable to conventional TURBT. ^[30] Both papers cited the ability to provide high-qualityspecimens for histological assessment as a significant advantage of ETURBT over TURBT. ^{[29, 30]}  

A prospective, non-randomized interventional study was performed to compare ETURBT to TURBT in the setting of NMBIC, in terms of progression and recurrence. ^[31]  Cohort groups were comparable (location of tumor, stage, grade) with 21 patients undergoing ETURBT vs 24 TURBT, with results being notable for significantly decreased recurrence rate (28.6% vs. 62.5%, P=0.03) and recurrence-free survival (45.1 vs. 28.5 months, P=0.018) while progression rate (19% vs. 33.3%, P=0.32) and progression-free survival rate (48.3 vs. 44 months, P = 0.46) were not significantly different. 

Interesting, Uphadhyay et al. found that with non-pedunculated bladder tumors 2-4 cm in size that were resected via ETURBT vs TURBT, a greater yield of detrusor muscle was found in histopathological examination of specimens obtained with ETURBT (20/21, 94% vs 15/25, 60%; P = 0.001). 

While these results are attractive, there are several limitations of ETURBT to consider ^[32] :

• TURBT is a more technically convenient approach.
• Tumor characteristics (eg, location, size) significantly influence the feasibility of ETURBT.
• ETURBT has a learning curve; early on, there is the possiblity for prolonging procedures and making mistakes.
• Tumor removal may present difficulties.