Photodynamic Diagnosis-Assisted En Bloc Transurethral Resection of Bladder Tumor for Nonmuscle Invasive Bladder Cancer: Short-Term Oncologic and Functional Outcomes

Introduction

Transurethral resection of bladder tumor (TURBT) is the mainstay of treatment, diagnosis, and staging in bladder cancer, especially in nonmuscle invasive bladder cancer (NMIBC). ¹ Pathologic examination on fragmented and heat-denatured specimens obtained by conventional TURBT (cTURBT) can be inaccurate and difficult, resulting in understaging and interobserver variability, largely due to poor anatomic orientation and indistinguishable muscularis propria from muscularis mucosae. ² This drawback inherent in cTURBT could be overcome by tumor resection in one piece with intact surrounding normal tissues. Since the first report by Kawada and colleagues in 1997, the usefulness and safety of en bloc TURBT (herein referred to as “EBTUR,” also known as “TURBT in one piece, TURBO” ³ ) have been reported by several publications. ^{3 –9}

The main purpose of developing the EBTUR technique is to not only conduct accurate pathologic assessment but also improve oncologic outcome without compromising safety. It is considered that intravesical recurrence (IVR) after surgery is largely attributed to dissemination of cancer cells and consequent seeding to the bladder mucosa. ¹⁰ This phenomenon is inevitable in cTURBT during resection and fragmentation of the tumor, while it could be minimized in EBTUR. Among several prospective and retrospective studies, only one prospective randomized controlled trial (RCT) was reported so far. This RCT failed to show any significant clinical advantage of EBTUR. ⁶ Two prospective studies ^7,8 reported by an Indian group focused on yield of detrusor muscle on EBTUR and IVR after TURBT as the primary end point, respectively. The latter confirmed a significantly longer IVR-free survival, not progression-free survival, in the EBTUR group compared to that in the cTURBT group (45.1 vs 28.5 months, p = 0.018). ⁸ The clinical evidence regarding oncologic outcomes is still limited in this field.

One of the unsolved problems underlying EBTUR is the variation in technique, procedure, resection device, and extraction method of dissected specimens. Particularly, circumferent demarcation around the bladder tumor depends on the surgeon's preference and has not been established. Recently, the clear benefit of photodynamic diagnosis (PDD)-assisted TURBT using 5-aminolevulinic acid (5-ALA) has been confirmed by RCTs and meta-analyses. ¹¹ Based on favorable evidence, oral 5-ALA was approved as an intraoperative diagnostic drug in Japan during December 2017. ¹²

In this study, we reported that PDD guidance could be useful and helpful for the decision of intraoperative circumferent demarcation around the bladder tumor. Furthermore, we hypothesized that PDD-EBTUR could suppress dissemination of cancer cells to bladder cavity compared to cTURBT. This study described a novel technique, PDD-assisted EBTUR (PDD-EBTUR) with a rectangular cutting loop, and evaluated the short-term IVR rate, complication, and postoperative health-related quality of life (QoL) compared with PDD-assisted cTURBT (PDD-cTURBT) in NMIBC.

Methods

Surgical procedure and device for PDD-EBTUR

Surgical procedures of PDD-EBTUR were performed by a single surgeon (M.M.). Approximately 3 hours (range, 2–4 hours) before surgery, patients orally received a water-dissolved 5-ALA solution at a dose of 20 mg/kg (ALAGLIO^®; Chugai Pharmaceutical Co., Ltd., and SBI Pharmaceuticals Co., Ltd.). EBTUR was performed using a bipolar 26F resectoscope (KARL STORZ Endoscopy Japan) with a rectangular cutting loop (Fig. 1a). The Storz Professional Image Enhancement System (IMAGE1 S^™) was utilized for the visualization of tumors during surgery. This system provides a white light, blue light (fluorescence cystoscopy), and imaging enhancement modes, such as spectra A, spectra B, chroma, and clara. ¹¹

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FIG. 1.

Procedure of PDD-EBTUR. (a) A rectangular cutting loop from KARL STORZ Endoscopy Japan (code: K27040 JBE130). (b) A lobulated papillary T_a low-grade tumor is examined by both WL and PDD. A small and short lesion spreads in the skirt of tumor, which is clearly identified by PDD. (c) The tumor is demarcated circumferentially in the normal urothelium with PDD guidance using a pointed cutting electrode. Yellow dashed lines indicate the border of the tumor and normal urothelium. (d) After the point marking is connected, en bloc resection is initiated through the superficial muscularis propria under the circumferential incision. (e) Dual imaging in a side-by-side view using chroma (left) and spectra A (right) modes is utilized during dissection of the tumor stalk. Chroma enhances the sharpness of the displayed image. Spectra A is based on color tone shift algorithms to increase the contrast of blood vessels and submucosal architecture. Yellow arrowheads indicate the dissection point of the tumor stalk. (f) After tumor resection, we confirmed no residual tumor in the resected margin with PDD guidance. The yellow dashed line indicates the border of the scar and normal mucosa. PDD, photodynamic diagnosis; PDD-EBTUR, photodynamic diagnosis-assisted en bloc transurethral resection of bladder tumor; WL, white-light source.

Under general or spinal anesthesia, careful examination of the entire bladder mucosa with white and blue light modes was conducted (Fig. 1b) according to the previous phase III trial. ¹² The effect setting was set to 3 for cutting and 4 for coagulation in the bipolar cautery system (AUTOCON^® III 400; KARL STORZ Endoscopy Japan). Physiologic saline was used as an irrigant during surgery. First, the tumor was demarcated circumferentially in the normal urothelium with PDD guidance, and the point markings were connected using a pointed cutting electrode (Fig. 1c and Supplementary Movie S1) or rectangular cutting loop (Supplementary Movies S2 and S3). Bladder cancer is characterized by growth with a skirt of tumor and small daughter tumors. When setting margins of resection, these occult tumors are often missed under the white light mode but captured under the blue light mode. Superficial blood vessels feeding the tumor were coagulated first. En bloc tumor resection was initiated through the superficial muscularis propria under circumferential incision (Fig. 1d). The tumor base was lifted off using the beak of rectangular cutting loop (Fig. 1e). After the tumor was dissected with the surrounding normal tissues and muscularis propria, we confirmed no residual tumor in the resected margin with PDD guidance (Fig. 1f).

The dissected specimens were extracted using grasping forceps through the lumen of the 26F resectoscope sheath and subjected to pathologic processing. If specimens were too large to be extracted through the resectoscope, the papillary-growing portion was superficially cut by TUR to avoid disrupting the tumor base architecture.

Results

Surgical movies of three representative cases are uploaded in Supplementary Movies S1 to S3. The circumferent demarcation was made with PDD guidance using a pointed cutting electrode (case 1) or rectangular cutting loop (cases 2 and 3). The tumor was located on the left wall close to the left ureteral orifice in cases 2 and 3. The EBTUR technique seems to prevent damage of the ureteral orifice and intramural ureter due to minimized tissue coagulation. Active urine efflux could be confirmed after intravenous injection of indigo carmine.

From October 2018 to September 2019, 69 consecutive patients found to have NMIBC underwent PDD-assisted TURBT in our hospital. Of 69 patients, 12 (17%) and 57 (83%) underwent PDD-EBTUR and PDD-cTURBT, respectively. None of the 12 patients undergoing PDD-EBTUR received intravesical BCG treatment postoperatively. To minimize the difference in the patient background, we excluded 29 (51%) patients receiving intravesical BCG treatment due to the presence of CIS lesion from 57 patients undergoing PDD-cTURBT, leaving 28 patients (Fig. 2). The clinicopathologic background between PDD-EBTUR (n = 12) and PDD-cTURBT (n = 28) is compared and presented in Table 1. None of the variables, including histology, tumor size, and risk stratification, showed significant difference between the two groups. One female patient in the PDD-EBTUR group had grade II bladder perforation requiring prolonged catheterization (for 7 days). The other 39 patients did not have any complications of grade II or higher.

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FIG. 2.

Flowchart of the patient's cohort dataset. ALA, aminolevulinic acid; CIS, carcinoma in situ; cTURBT, conventional TURBT; EBTUR, en bloc TURBT; FACT-BL, Functional Assessment of Cancer Therapy-Bladder; IPSS, International Prostate Symptom Score; OABSS, overactive bladder symptom score; QoL, quality of life; TURBT, transurethral resection of bladder tumor.

Representative data of tissue processing are shown in Figure 3. Well-oriented histologic sections were obtained by EBTUR (Fig. 3a, b), while cTURBT yielded fragmented tumor specimens with poor anatomic orientation (Fig. 3c). This drawback is associated with interobserver variability and understaging in pathologic diagnosis. EBTUR successfully diagnosed a T₁ high-grade tumor that invaded the deep area of the lamina propria but not the muscularis propria (Fig. 3d). Pathologic assessment of the horizontal and vertical margins in resected specimens by PDD-EBTUR revealed that all specimens had muscularis propria, and the rate of en bloc resection was 100%. Accurate T category can be diagnosed only when resected specimens include appropriate muscularis propria with negative vertical margin.

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FIG. 3.

Tissue processing and pathologic diagnosis in EBTUR. (a) A tumor specimen was stretched with 27G needles before formalin fixation. Normal-looking urothelial mucosa surrounds the papillary tumor. Microscopic examination of sections cut along the lines revealed T_a low-grade urothelial carcinoma containing peripheral dysplasia mucosa, which was negative for horizontal margin. (b) Another representative case with a T_a low-grade tumor was negative for horizontal and vertical margin. (c) HE sections of fragmented tumor specimens in a representative case undergoing PDD-assisted cTURBT. (d) A nodular tumor diagnosed as T₁ high-grade urothelial carcinoma by PDD-EBTUR. The tumor invasion front (dashed white lines) approaching the muscularis propria (dashed yellow lines) but did not reach it. HE, hematoxylin and eosin.

The median follow-up period was 11 and 8 months in the PDD-EBTUR and PDD-cTURBT groups, respectively. No patient had IVR in the PDD-EBTUR group, while two patients had T_a low-grade recurrent tumors at 10 and 16 months after initial TURBT in the PDD-cTURBT group (Fig. 4a). Progression to muscle invasive disease was not noted in any patient.

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FIG. 4.

Comparison of intravesical recurrence rate and QoL assessment between the PDD-EBTUR and PDD-cTURBT groups. Intravesical recurrence-free survival after TURBT was compared between the two surgical techniques. (b) Baseline scores (blue-line polygon) and postoperative scores (red-line polygon) from the SF-8^™ survey and FACT-BL were shown separately for the PDD-EBTUR and PDD-cTURBT groups. Data are expressed by means ± standard deviations and compared between “Before” and “After” (approximately 1 month) with Wilcoxon signed-rank test. A high score indicates a high level of QoL or function. Asterisks (*) indicate p < 0.05. BP, bodily pain; EWB, emotional well-being; FWB, functional well-being; GH, general health perception; MCS, mental component summary; MH, mental health; PCS, physical component summary; PF, physical function; PWB, physical well-being; RE, role limitation because of emotional problems; RP, role limitation because of physical problems; SF, social function; SF-8 survey, 8-item Short Form survey; SWB, social/family well-being; VT, vitality.

The postoperative changes in the seven IPSS parameters, voiding and storage subscores, and total IPSS are summarized in Table 2. Elevated scores of frequency (question 2) and nocturia (question 7) were observed in the PDD-EBTUR group, whereas only the nocturia score was increased in the PDD-cTURBT group. Assessment of FACT-BL revealed that most domains did not change postoperatively; however, a significant decrease in the bladder-specific subscale was observed in the PDD-EBTUR group (Fig. 4b, upper panels, and Supplementary Table S2). Changes in the eight domains and two summary scores from the SF-8 survey are summarized in Supplementary Table S2. While all domains and scores showed a decrease to some degree postoperatively (Supplementary Table S3), there was a significant change noted in the two scores (role limitation because of emotional problems and mental component summary) in the PDD-EBTUR group and one score (role limitation because of physical problems) in the PDD-cTURBT group (Fig. 4b, lower panels).

Discussion

We described the surgical technique of PDD-EBTUR using a rectangular cutting loop with its oncologic and functional outcomes. Various types of electrocautery such as standard loop, 45° to 90° bended loop, J-shaped electrode, Collins loop, and snare were utilized for EBTUR so far. ² To the best of our knowledge, this was the first study to address the utility and safety of the rectangular cutting loop. Surgical procedures of PDD-EBTUR were performed by a single surgeon in this study. The surgeon would say that this endoscopic method would be easy and reproducible in any of the urologists. Previous studies have reported the advantages of EBTUR, including accurate pathologic assessment and decreased risk of IVR through suppressed dissemination of cancer cells to bladder cavity. ^2,3,8 Bladder cancer is characterized by an ambiguous border between the tumor and normal urothelium and white light-undetectable daughter lesions scattered around the main tumor. Therefore, PDD guidance provided substantial help for circumferent demarcation around the bladder tumor, which precedes tumor dissection. In this study, all dissected tumors by PDD-EBTUR were negative for horizontal and vertical margin, indicating that the rate of both en bloc resection and incidence of the muscularis propria in the specimens was 100%.

The systematic review of 544 patients with NMIBC treated with EBTUR demonstrated that the IVR rate was 23% (range, 6%–55%) in 20 months of mean weighted follow-up duration. To date, two RCTs compared IVR after TUR between EBTUR and cTURBT. ^6,8 Chen and coworkers evaluated the practicability of 2 μm continuous-wave laser in EBTUR. Notably, obturator jerk occurred in 18 (25%) of 71 patients undergoing cTURBT, whereas none was noted in patients undergoing EBTUR with laser resection. However, EBTUR did not decrease the IVR rate. Another RCT demonstrated that EBTUR with 45° to 90° bended loop decreased the IVR rate compared to the cTURBT. Although our study did not show a significant difference in the IVR rate between the two groups, we cannot draw a conclusion because the sample size was extremely small in our cohort. The clinical evidence regarding oncologic outcomes is still limited in this field.

Maximal effort should be made to ameliorate postoperative urinary symptoms and deterioration of QoL even though they are transient. Tan and colleagues reported that patients found to have NMIBC are most psychologically affected during the period between initial diagnosis by cystoscopy and TURBT. ¹⁷ The functional patient-reported outcomes after TURBT, especially in EBTUR, have been rarely investigated. We focused on the difference in worsening of urinary symptoms and deterioration of health-related QoL between the EBTUR and cTURBT groups. Although an increase in the nocturia score (IPSS 7) was common in the two groups, the score of daytime frequency (IPSS 2) increased only in the EBTUR group. We speculated that resection of the deeper layer of the bladder wall, wider range of the bladder mucosa, and longer operative time in EBTUR compared with those in cTURBT might be associated with difference in worsening of urinary symptoms. Besides, a unique finding was noted in QoL assessment. A decrease in emotional and mental scores was noted in the EBTUR group but not in the cTURBT group. One of the possible interpretations would be that postoperative urinary problems, including frequent urination, nocturia, and bladder irritability, affect mental health. Further study with a larger sample size may elucidate the importance of QoL assessment in patients undergoing EBTUR.

The present study has several limitations. There is a potential selection bias because the decision between the EBTUR and cTURBT groups was made based on the physician's preference rather than randomization. Second, the sample size is small, only 12 patients in the EBTUR group, with a short follow-up duration. Finally, follow-up assessment and recovery regarding patient-reported outcome was not monitored.

Conclusion

Effective management of NMIBC depends on complete resection and accurate pathologic diagnosis. Based on the initial experience on 12 patients, we considered that PDD-EBTUR is a simple, easy, safe, and acceptable surgical method. Further experience and research are mandatory to determine whether this technique yields better outcomes and has true clinical value.