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Thulium:yttrium-aluminum–garnet Laser for En Bloc Resection of Bladder Cancer: Clinical and Histopathologic Advantages
Oncology Thulium:yttrium-aluminumegarnet Laser for En Bloc Resection of Bladder Cancer: Clinical and Histopathologic Advantages Giovanni Muto, Devis Collura, Alessandro Giacobbe, Leonardo D’Urso, Gian Luca Muto, Andrea Demarchi, Sergio Coverlizza, and Emanuele Castelli OBJECTIVE MATERIALS AND METHODS
RESULTS
CONCLUSION
To determine whether thulium:yttrium-aluminum-garnet laser resection of bladder tumor (TmLRBT) may offer advantages over classic resection. From April 2011 to September 2012, 55 consecutive patients newly diagnosed with clinical stage T2 bladder cancer were enrolled in a prospective study on TmLRBT. Neoplasm was removed en bloc in all cases. When the tumor size was >3 cm, it was necessary to incise longitudinally and/or across the lesion and the bladder wall at its the base into 2 or more parts. All cases of nonemuscle-invasive bladder cancer underwent second look in 30-90 days. Pathology reported urothelial carcinoma with Ta low grade in 31 patients (56.4%), T1 high grade in 18 (32.7%), and T2 high grade in 6 (10.9%). Histopathologic evaluation showed that the bladder detrusor was provided in all cases. Hemostasis was excellent, and no postoperative hematuria was reported. In a case of T1 G3, endoscopic re-evaluation showed a focal infiltration of the bladder detrusor, so the patient underwent radical cystectomy. To date, with a mean follow-up of 16 months (range, 8-25), the recurrence rate in patients with superficial disease is 14.5%. All recurrences were outside the site of first resection, and there was no progression in tumor grade. TmLRBT is a simple method that seems to overcome the “incise and scatter” problem associated with traditional transurethral resection of bladder tumor. Our initial data on staging accuracy and reduction of the local recurrence rate are encouraging. UROLOGY 83: 851e855, 2014. 2014 Elsevier Inc.
B
ladder carcinoma (BC) is the most common malignancy of the urothelium. Approximately 75%-85% of patients with BC present with disease confined to the mucosa (stage Ta, carcinoma in situ) or submucosa (T1).1 The exact pathologic staging of BC is crucial for determining therapies. Transurethral resection of bladder tumor (TURBT) using a wire loop is still considered the gold standard treatment of nonemuscle-invasive BC (NMIBC) and, at the same time, represents a fundamental step in the diagnosis of muscle-invasive BC. Complete and correct resection is essential to achieve good prognosis in NMIBC.2 The absence of detrusor muscle in the specimen, in fact, is associated with a higher risk of residual disease and early recurrence.3 The main disadvantages of TURBT are thermal damage of the adjacent tissue and fragmentation of the
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, San Giovanni Bosco Hospital, Turin, Italy; the University Campus Biomedico, Rome, Italy; and the Department of Pathological Anatomy, San Giovanni Bosco Hospital, Turin, Italy Reprint requests: Emanuele Castelli, M.D., Department of Urology, San Giovanni Bosco Hospital, Piazza Donatore di Sangue 3, 10154 Turin, Italy. E-mail: castelli2006@ hotmail.it Submitted: August 5, 2013, accepted (with revisions): December 13, 2013
ª 2014 Elsevier Inc. All Rights Reserved
neoplasm, with subsequent risk of recurrence and difficulties in accurate pathologic evaluation.4 To overcome these problems, several en bloc resection techniques have been described over the past 15 years, including the use of modified loops5,6 and laser resection.7,8 The advantages of en bloc laser resection are the absence of obturator reflex, minimum intraoperative and postoperative bleeding, lower risk of intraoperative cancer cell scattering, and easier pathologic evaluation of the specimen. In this work, our initial experience with en bloc resection of superficial BC using a thulium:yttriumaluminum-garnet (Tm:YAG) laser resection of bladder tumor (TmLRBT) has been reported, to evaluate the safety and efficacy of the technique.
MATERIALS AND METHODS From April 2011 to September 2012, 55 patients (49 male and 6 female) newly diagnosed with BC were selected for a prospective study on TmLRBT. Mean patient age was 68 years (range, 28-90). Only naïve patients with clinical stage T2 were included. Exclusion criteria were recurrent BC, locally advanced BC (cT3 or higher), and/or distant metastases. Preoperative evaluation included clinical history, physical examination, chest x-rays, abdominal computed tomographic 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.12.022
851
Figure 1. (A) Circumferential incision of the tumor base. (B) Coagulation of the base of resection. (Color version available online.)
scan, routine serum chemistry, urine examination, and urine cytology. All patients signed an informed consent. During the surgical procedure, the patient was in the lithotomy position under epidural anesthesia, with normal saline (sodium chloride 0.9%) solution as continuous irrigation. We used an 800-nm laser fiber (RigiFibTM, LISA, Katlenburg, Germany) introduced in the working element of a 26F continuous-flow resectoscope (Karl Storz, GmbH, Tuttlingen, Germany). The fiber was connected to the 2013-nm Tm:YAG laser (RevolixR, LISA, Katlenburg, Germany), which was used in the continuous-wave setting at 30 W. A circumferential incision was performed around the tumor with a safety margin of approximately 2 mm (Fig. 1A). The resection proceeded toward the deeper layers of the bladder wall (down to the deep detrusor muscle), combining the laser vaporesection with the blunt dissection of the resectoscope tip. The resection through the bladder wall proceeded along an oblique plane from the periphery to the center of the tumor base. Consequently, the detrusor resection depth was not the same throughout the specimen, but it was deepest toward the center of the specimen. The tumor, along with its base, was retrieved in 1 piece through the resectoscope sheath using a grasper. When the tumor size was >3 cm, it was necessary to incise longitudinally and/or across the lesion and the bladder wall at the base into 2 or more parts. This operation was performed before completing the resection, with the neoplasm still in situ, to reduce the risk of tumor cell scattering. After resection, the tumor base was coagulated using the Tm:YAG laser in the pulsed-wave setting at 20 W (Fig. 1B). Cold cup biopsies from dyschromic areas and/or normal looking bladder walls (trigone, bladder dome, right, left, anterior, and posterior wall) and from prostatic urethra were performed. The hemostasis after these biopsies was obtained using the Tm:YAG laser in the pulsed-wave setting at 20 W. A 20F Foley catheter was inserted after the procedure. The enucleated specimen and the samples from cold cup biopsies were sent for histopathologic examination. The 2009 TNM classification and the 2004 World Health Organization grading system were used for histopathologic examination.9,10 According to our research protocol, a “second-look” transurethral resection (TUR) was performed within 30-90 days (see “Results”) in patients with NMIBC. The patients with T2 BC, instead, underwent radical cystectomy (RC). All the procedures (TmLRBT and second-look TUR) were performed by the same surgeon (G.M.), and all the pathologic 852
specimens were examined by the same pathologist (A.D.). The pathologist was blinded to the type of endoscopic technique. Statistical analysis was performed using the chi-square test. The P value considered to be statistically significant was <.05.
RESULTS A total of 61 neoplasms were removed from 55 patients. Mean tumor diameter was 2.36 1.47 cm (range, 0.5-4.5). The neoplasms were located on the trigone (7 cases), left lateral wall (20 cases), right lateral wall (14 cases), posterior wall (9 cases), and bladder dome (11 cases). Mean operative time was 33 14 minutes (range, 8-80). No patient experienced obturator nerve reflection intraoperatively. No intraoperative or postoperative complications occurred. Postoperative bladder irrigation was not performed. Mean catheterization time was 34.8 16.1 hours (range, 24-72). Mean hospital stay was 51 20.8 hours (range, 36-96). Pathologic results showed urothelial carcinoma with stage Ta low grade in 31 patients (56.4%), T1 high grade in 18 patients (32.7%), and T2 high grade in 6 patients (10.9%). Histopathologic evaluation demonstrated that the bladder detrusor was provided in all cases. The cold cup biopsies performed during TmLRBT revealed carcinoma in situ in 4 of the 6 patients with T2 high-grade BC. Patients with high-grade T1 (18 cases) and largevolume (2 cm) low-grade Ta (14 cases) BC underwent “second-look” TUR within 30-45 days. Patients with low-volume (<2 cm), low-grade Ta BC underwent second-look TUR at 90 days. In a case of newly diagnosed T1 high-grade, endoscopic reresection showed focal infiltration of the bladder detrusor, so the patient underwent RC. Second-look TUR (in 30-90 days) was negative for BC persistence or recurrence in all other patients newly diagnosed with NMIBC. After a mean follow-up of 16 months (range, 8-25), we found recurrences in 7 of 48 patients (14.5%), without progression in tumor grade. All recurrences were out of the primary resection site. The risk of recurrence was not statistically higher (P ¼ .4) in the group of UROLOGY 83 (4), 2014
patients with multiple primary BC than in those with single primary neoplasm. The 18-month recurrence-free survival was 90% among patients with primary Ta BC and 76% in the group of patients with primary T1 BC. The difference was not statistically significant (Fig. 2). Fourteen patients had bladder neoplasms >3 cm and underwent splitting of their BC during resection. Four of them had T2 high grade BC and, consequently, underwent cystectomy. We had 2 recurrences at follow-up among the remaining 10 patients who needed “splitting” during primary resection (2%) and 5 recurrences among the 33 patients who did not need tumor “splitting” (15%). The difference was not statistically significant (P ¼ .6). Seven patients underwent RC. Histopathologic evaluation of RC specimens revealed BC with stage T2a high grade in 4 cases, T2b high grade in 2 cases, and absence of disease (T0) in 1 case.
COMMENT TURBT is considered the gold standard treatment of NMIBC and, at the same time, represents a fundamental step in the diagnosis of infiltrating BC.1,11 This technique, however, has many limitations. Intraoperative bleeding and obturator nerve reflex can often make the procedure difficult. Moreover, the use of the “incise and scatter” technique contradicts basic oncologic principles because it causes the fragmentation of the tumor, favoring the implantation of exfoliated cancer cells and making pathologic evaluation more difficult.4,7,12 These limitations of TURBT have led many urologists to recommend an early second-look resection in BC management. In fact, a significant risk of residual tumor after the first TUR has been shown for Ta and T1 BC and understaging of BC.1,2,13 In a meta-analysis of trials by the European Organization for Research and Treatment of Cancer, recurrence rates at 3 months after first TUR range from 3.4% to 20.6% for patients with single Ta-T1 tumors not receiving any intravesical adjuvant treatment and from 0% to 15% in those receiving it. In patients with multiple tumors receiving adjuvant treatment, the recurrence rate at 3 months varied between 7.4% and 45.8%.2 According to the European Association of Urology Association guidelines on BC, a second TUR should be performed 2-6 weeks after the first resection when the latter is incomplete (eg, large and multiple tumors), when no detrusor muscle is found in the specimen, or when high-grade and/or T1 BC is detected.1 To overcome these limitations of TURBT, over the past 15 years, several authors have developed different en bloc resection techniques. Kawada et al5 described a rotational tumor resection using an arched electrode. Ukai et al6 used a J-shaped electrode to retrieve the tumor in one piece. Saito7 reported his experience with en bloc resection using the holmium:yttrium-aluminum-garnet (Ho:YAG) laser fiber (for tumors of the bladder neck) or the knife electrode (for tumors located in the other areas of the bladder). This UROLOGY 83 (4), 2014
Figure 2. Kaplan-Meier curve showing recurrence-free survival (RFS) rates among patients with Ta and T1 primary bladder carcinoma. The numbers near the curves indicate the patients with recurrence in the corresponding period.
series was the first in the literature to describe the use of Ho:YAG laser for en bloc resection of BC. Zhu et al14 compared the Ho:YAG laser resection of bladder tumor (HoLRBT) with standard TURBT in a series of 212 patients with primary NMIBC. They found no difference between the 2 groups in terms of recurrence-free survival, whereas HoLRBT was superior to TURBT in terms of intraoperative complications, postoperative catheterization, and hospitalization time. Moreover, HoLRBT provided sufficient material for pathologic evaluation. Xishuang et al15 compared the safety and efficacy of TURBT, HoLRBT, and plasmakinetic resection of bladder tumor in a series of 173 patients with primary NMIBC. HoLRBT and plasmakinetic resection of bladder tumor proved to be safer than TURBT with regard to complications, catheterization, and hospitalization time, but no advantage was found in terms of tumor recurrence rate. In the literature, there are few articles on Tm:YAG laser for the treatment of BC (Table 1). The use of Tm:YAG laser for BC en bloc resection was first reported in 2008 in a series of 32 patients with recurrent papillary tumors.8 The authors used a flexible cystoscope to deliver laser energy through a 200-mm fiber at 10-15 W. No intraoperative or postoperative complications were observed. Recurrence rates after 1 year were 11% for local relapse and 21% for out-of-field relapse. The accumulated recurrence rates were 9%, 22%, and 28% after 3, 6, and 12 months, respectively. Yang et al16 described a technique of transurethral partial cystectomy based on Tm:YAG laser in 9 patients. No bladder irrigation was required, and the catheter was removed 7-9 days postoperatively. In 1 patient, bladder perforation occurred intraoperatively, and it was treated with abdominal paracentesis drainage. No recurrence at the resection site was reported after a mean follow-up of 7.5 months. Wolters et al12 recently reported their experience with en bloc TmLRBT in a small cohort of 6 patients newly diagnosed with BC. They used the same instrumentation as Yang et al14 but at lower power of laser energy (10-15 W). The incision was extended to the deep muscular layer of 853
Table 1. Thulium:yttrium-aluminum-garnet laser resection of bladder tumor series reported in the literature
Author 7
Gao et al Zhong et al17 Yang et al16 Wolters et al12 Our series
Recurrence Rate (%)
Pts
Operative Time (min)
Complications
Catheterization Time (d)
Follow-up (mo)
Local
Out of Field
All
32 30 9 6 55
25 29.1 8.7 36 33
None None 1 Bladder perforation None None
1 4.47 8 n.r. 1.4
12 24 7.5 2 16
9 n.r. 0 0 2
19 n.r. n.r. n.r. 14.5
28 29.9 n.r. n.r. 16.3
n.r., not reported.
Figure 3. (A) Resected specimen. The muscle layer is present. Reduced from 2.5. (B) The tumor architecture is preserved. (Color version available online.)
the bladder wall. No complications were observed, but bladder irrigation was necessary in 50% of cases. Five of the 6 patients underwent a second-look resection 6 weeks after the initial treatment, and all were negative for residual tumor. Zhong et al17 compared TmLRBT with HoLRBT and standard TURBT in a retrospective series of 97 patients. TmLRBT was associated with less hemoglobin decrease than TURBT (P <.05), whereas no statistical difference was noted for bladder irrigation, postoperative catheterization, and hospitalization. No intraoperative or postoperative complications were reported. The recurrence rates of the 3 groups during 24-month follow-up showed no statistical difference. Our results confirm the data previously reported in the literature on smaller series of patients (Table 1). No intraoperative or postoperative complications were observed. Bladder irrigation was not necessary. Detrusor muscle was present in all pathologic specimens (Fig. 3A). This represents an advantage of en bloc resection vs traditional TURBT because it gives the pathologist the opportunity for correct staging. TURBT causes fragmentation of BC, whereas TmLRBT guarantees preservation of the tumor architecture, which is very important for the classification of papillary tumors (Fig. 3B). The risk of residual tumor after TUR of Ta-T1 lesions ranges from 4% to 53%.1,2 In our series, the persistence of residual tumor after primary TmLRBT involved 1 of 49 patients (2%) with Ta-T1 BC. BC is often understaged at initial resection. The likelihood that a T1 tumor has been understaged and that a muscle-invasive BC will be 854
discovered at a second resection ranges from 4% to 25%.1 In our experience, 1 of 18 patients (5.5%) newly diagnosed with T1 high-grade BC showed focal infiltration of detrusor muscle at second-look TUR. The recurrence rate after a mean follow-up of 16 months was 14.5%; interestingly, all the recurrences were out of the field of primary resection. This result seems to confirm that the TmLRBT has a good power of local tumor eradication. These data, if confirmed by further prospective studies, may reduce the need for second-look TUR after TmLRBT in patients with NMIBC. The Ho:YAG laser and the Tm:YAG laser have very close wavelengths (2100 and 2013 nm, respectively) and use the same chromophore (water). Both these lasers have rapid and high-power tissue vaporization and reach excellent hemostasis.18-20 The Tm:YAG laser, however, produces a smoother cutting line and thus a more accurate incision than the Ho:YAG laser.21
CONCLUSION TmLRBT appears to be a simple and reliable method that offers many advantages over traditional TURBT: It reduces intraoperative and postoperative complications, such as obturator nerve reflex and bleeding. It overcomes the incise and scatter problem associated with the traditional technique of resection. It allows the preservation of tumor architecture and guarantees optimal staging accuracy. It allows an accurate ablation on the basis of the tumor and seems to reduce the risk of local persistence and/or UROLOGY 83 (4), 2014
relapse. This may reduce the need for second look TUR after TmLRBT in patients with NMIBC. References 1. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU Guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 2011;59:997-1008. 2. Brausi M, Collette L, Kurth K, et al. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined study of seven EORTC studies. Eur Urol. 2002;41:523-531. 3. Mariappan P, Zachou A, Grigor KM. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol. 2010;57:843-849. 4. Wilby D, Kay T, Ray E, et al. Bladder cancer: new TUR techniques. World J Urol. 2009;27:309-312. 5. Kawada T, Ebihara K, Suzuki T, et al. A new technique for transurethral resection of bladder tumors: rotational tumor resection using a new arched electrode. J Urol. 1997;157:2225-2226. 6. Ukai R, Kawashita E, Ikeda H. A new technique for transurethral resection of superficial bladder tumour in 1 piece. J Urol. 2000;163: 878-879. 7. Saito S. Transurethral en bloc resection of bladder tumours. J Urol. 2001;166:2148-2150. 8. Gao X, Ren S, Xu C, et al. Thulium laser resection via a flexible cystoscope for recurrent non-muscle invasive bladder cancer: initial clinical experience. BJU Int. 2008;102:1115-1118. 9. Sobin LH, Gospodarowicz MK, Wittekind C, et al. TNM Classification of Malignant Tumors (UICC International Union Against Cancer). 7th ed. New York, NY: Wiley-Blackwell; 2009: 262-265.
UROLOGY 83 (4), 2014
10. Sauter G, Algaba F, Amin M, et al. Tumours of the urinary system: non-invasive urothelial neoplasias. In: Eble JN, Sauter G, Epstein JI, et al., eds. WHO classification of tumours of the urinary system and male genital organs. Lyon, France: IARCC Press; 2004. 11. Stenzl A, Cowan NC, De Santis M, et al. Treatment of muscleinvasive and metastatic bladder cancer. Update of the EAU Guidelines. Eur Urol. 2011;59:1009-1018. 12. Wolters M, Kramer MW, Becker JU, et al. Tm:YAG laser en bloc mucosectomy for accurate staging of primary bladder cancer: early experience. World J Urol. 2011;29:429-432. 13. Jakse G, Algaba F, Malmstr€om P-U, et al. A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol. 2004;45:539-546. 14. Zhu Y, Jiang X, Zhang J, et al. Safety and efficacy of holmium laser resection for primary nonmuscle-invasive bladder cancer versus transurethral electroresection: single-center experience. Urology. 2008;72:608-612. 15. Xishuang S, Deyong Y, Xiangyu C, et al. Comparing the safety and efficiency of conventional monopolar, plasmakinetic, and holmium laser transurethral resection of primary non-muscle invasive bladder cancer. J Endourol. 2012;24:69-73. 16. Yang Y, Wei ZT, Zhang X, et al. Transurethral partial cystectomy with continuous wave laser for bladder carcinoma. J Urol. 2009;182: 66-69. 17. Zhong C, Guo S, Tang Y, et al. Clinical observation on 2 micron laser for non-muscle-invasive bladder tumor treatment: single center experience. World J Urol. 2010;28:157-161. 18. Johnson DE, Cromeens DM, Price RE. Use of the holmium:YAG laser in urology. Lasers Surg Med. 1992;12:353-363. 19. Fried NM, Murray KE. High-power thulium fiber laser ablation of urinary tissues at 1,94 mm. J Endourol. 2005;19:25-31. 20. Teichmann HO, Herrmann TR, Bach T. Technical aspects of laser in urology. World J Urol. 2007;25:221-225. 21. Kranmer MW, Bach T, Wolters M, et al. Current evidence for transurethral laser therapy of non-muscle invasive bladder cancer. World J Urol. 2011;29:433-442.
855
RESULTS
CONCLUSION
To determine whether thulium:yttrium-aluminum-garnet laser resection of bladder tumor (TmLRBT) may offer advantages over classic resection. From April 2011 to September 2012, 55 consecutive patients newly diagnosed with clinical stage T2 bladder cancer were enrolled in a prospective study on TmLRBT. Neoplasm was removed en bloc in all cases. When the tumor size was >3 cm, it was necessary to incise longitudinally and/or across the lesion and the bladder wall at its the base into 2 or more parts. All cases of nonemuscle-invasive bladder cancer underwent second look in 30-90 days. Pathology reported urothelial carcinoma with Ta low grade in 31 patients (56.4%), T1 high grade in 18 (32.7%), and T2 high grade in 6 (10.9%). Histopathologic evaluation showed that the bladder detrusor was provided in all cases. Hemostasis was excellent, and no postoperative hematuria was reported. In a case of T1 G3, endoscopic re-evaluation showed a focal infiltration of the bladder detrusor, so the patient underwent radical cystectomy. To date, with a mean follow-up of 16 months (range, 8-25), the recurrence rate in patients with superficial disease is 14.5%. All recurrences were outside the site of first resection, and there was no progression in tumor grade. TmLRBT is a simple method that seems to overcome the “incise and scatter” problem associated with traditional transurethral resection of bladder tumor. Our initial data on staging accuracy and reduction of the local recurrence rate are encouraging. UROLOGY 83: 851e855, 2014. 2014 Elsevier Inc.
B
ladder carcinoma (BC) is the most common malignancy of the urothelium. Approximately 75%-85% of patients with BC present with disease confined to the mucosa (stage Ta, carcinoma in situ) or submucosa (T1).1 The exact pathologic staging of BC is crucial for determining therapies. Transurethral resection of bladder tumor (TURBT) using a wire loop is still considered the gold standard treatment of nonemuscle-invasive BC (NMIBC) and, at the same time, represents a fundamental step in the diagnosis of muscle-invasive BC. Complete and correct resection is essential to achieve good prognosis in NMIBC.2 The absence of detrusor muscle in the specimen, in fact, is associated with a higher risk of residual disease and early recurrence.3 The main disadvantages of TURBT are thermal damage of the adjacent tissue and fragmentation of the
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, San Giovanni Bosco Hospital, Turin, Italy; the University Campus Biomedico, Rome, Italy; and the Department of Pathological Anatomy, San Giovanni Bosco Hospital, Turin, Italy Reprint requests: Emanuele Castelli, M.D., Department of Urology, San Giovanni Bosco Hospital, Piazza Donatore di Sangue 3, 10154 Turin, Italy. E-mail: castelli2006@ hotmail.it Submitted: August 5, 2013, accepted (with revisions): December 13, 2013
ª 2014 Elsevier Inc. All Rights Reserved
neoplasm, with subsequent risk of recurrence and difficulties in accurate pathologic evaluation.4 To overcome these problems, several en bloc resection techniques have been described over the past 15 years, including the use of modified loops5,6 and laser resection.7,8 The advantages of en bloc laser resection are the absence of obturator reflex, minimum intraoperative and postoperative bleeding, lower risk of intraoperative cancer cell scattering, and easier pathologic evaluation of the specimen. In this work, our initial experience with en bloc resection of superficial BC using a thulium:yttriumaluminum-garnet (Tm:YAG) laser resection of bladder tumor (TmLRBT) has been reported, to evaluate the safety and efficacy of the technique.
MATERIALS AND METHODS From April 2011 to September 2012, 55 patients (49 male and 6 female) newly diagnosed with BC were selected for a prospective study on TmLRBT. Mean patient age was 68 years (range, 28-90). Only naïve patients with clinical stage T2 were included. Exclusion criteria were recurrent BC, locally advanced BC (cT3 or higher), and/or distant metastases. Preoperative evaluation included clinical history, physical examination, chest x-rays, abdominal computed tomographic 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.12.022
851
Figure 1. (A) Circumferential incision of the tumor base. (B) Coagulation of the base of resection. (Color version available online.)
scan, routine serum chemistry, urine examination, and urine cytology. All patients signed an informed consent. During the surgical procedure, the patient was in the lithotomy position under epidural anesthesia, with normal saline (sodium chloride 0.9%) solution as continuous irrigation. We used an 800-nm laser fiber (RigiFibTM, LISA, Katlenburg, Germany) introduced in the working element of a 26F continuous-flow resectoscope (Karl Storz, GmbH, Tuttlingen, Germany). The fiber was connected to the 2013-nm Tm:YAG laser (RevolixR, LISA, Katlenburg, Germany), which was used in the continuous-wave setting at 30 W. A circumferential incision was performed around the tumor with a safety margin of approximately 2 mm (Fig. 1A). The resection proceeded toward the deeper layers of the bladder wall (down to the deep detrusor muscle), combining the laser vaporesection with the blunt dissection of the resectoscope tip. The resection through the bladder wall proceeded along an oblique plane from the periphery to the center of the tumor base. Consequently, the detrusor resection depth was not the same throughout the specimen, but it was deepest toward the center of the specimen. The tumor, along with its base, was retrieved in 1 piece through the resectoscope sheath using a grasper. When the tumor size was >3 cm, it was necessary to incise longitudinally and/or across the lesion and the bladder wall at the base into 2 or more parts. This operation was performed before completing the resection, with the neoplasm still in situ, to reduce the risk of tumor cell scattering. After resection, the tumor base was coagulated using the Tm:YAG laser in the pulsed-wave setting at 20 W (Fig. 1B). Cold cup biopsies from dyschromic areas and/or normal looking bladder walls (trigone, bladder dome, right, left, anterior, and posterior wall) and from prostatic urethra were performed. The hemostasis after these biopsies was obtained using the Tm:YAG laser in the pulsed-wave setting at 20 W. A 20F Foley catheter was inserted after the procedure. The enucleated specimen and the samples from cold cup biopsies were sent for histopathologic examination. The 2009 TNM classification and the 2004 World Health Organization grading system were used for histopathologic examination.9,10 According to our research protocol, a “second-look” transurethral resection (TUR) was performed within 30-90 days (see “Results”) in patients with NMIBC. The patients with T2 BC, instead, underwent radical cystectomy (RC). All the procedures (TmLRBT and second-look TUR) were performed by the same surgeon (G.M.), and all the pathologic 852
specimens were examined by the same pathologist (A.D.). The pathologist was blinded to the type of endoscopic technique. Statistical analysis was performed using the chi-square test. The P value considered to be statistically significant was <.05.
RESULTS A total of 61 neoplasms were removed from 55 patients. Mean tumor diameter was 2.36 1.47 cm (range, 0.5-4.5). The neoplasms were located on the trigone (7 cases), left lateral wall (20 cases), right lateral wall (14 cases), posterior wall (9 cases), and bladder dome (11 cases). Mean operative time was 33 14 minutes (range, 8-80). No patient experienced obturator nerve reflection intraoperatively. No intraoperative or postoperative complications occurred. Postoperative bladder irrigation was not performed. Mean catheterization time was 34.8 16.1 hours (range, 24-72). Mean hospital stay was 51 20.8 hours (range, 36-96). Pathologic results showed urothelial carcinoma with stage Ta low grade in 31 patients (56.4%), T1 high grade in 18 patients (32.7%), and T2 high grade in 6 patients (10.9%). Histopathologic evaluation demonstrated that the bladder detrusor was provided in all cases. The cold cup biopsies performed during TmLRBT revealed carcinoma in situ in 4 of the 6 patients with T2 high-grade BC. Patients with high-grade T1 (18 cases) and largevolume (2 cm) low-grade Ta (14 cases) BC underwent “second-look” TUR within 30-45 days. Patients with low-volume (<2 cm), low-grade Ta BC underwent second-look TUR at 90 days. In a case of newly diagnosed T1 high-grade, endoscopic reresection showed focal infiltration of the bladder detrusor, so the patient underwent RC. Second-look TUR (in 30-90 days) was negative for BC persistence or recurrence in all other patients newly diagnosed with NMIBC. After a mean follow-up of 16 months (range, 8-25), we found recurrences in 7 of 48 patients (14.5%), without progression in tumor grade. All recurrences were out of the primary resection site. The risk of recurrence was not statistically higher (P ¼ .4) in the group of UROLOGY 83 (4), 2014
patients with multiple primary BC than in those with single primary neoplasm. The 18-month recurrence-free survival was 90% among patients with primary Ta BC and 76% in the group of patients with primary T1 BC. The difference was not statistically significant (Fig. 2). Fourteen patients had bladder neoplasms >3 cm and underwent splitting of their BC during resection. Four of them had T2 high grade BC and, consequently, underwent cystectomy. We had 2 recurrences at follow-up among the remaining 10 patients who needed “splitting” during primary resection (2%) and 5 recurrences among the 33 patients who did not need tumor “splitting” (15%). The difference was not statistically significant (P ¼ .6). Seven patients underwent RC. Histopathologic evaluation of RC specimens revealed BC with stage T2a high grade in 4 cases, T2b high grade in 2 cases, and absence of disease (T0) in 1 case.
COMMENT TURBT is considered the gold standard treatment of NMIBC and, at the same time, represents a fundamental step in the diagnosis of infiltrating BC.1,11 This technique, however, has many limitations. Intraoperative bleeding and obturator nerve reflex can often make the procedure difficult. Moreover, the use of the “incise and scatter” technique contradicts basic oncologic principles because it causes the fragmentation of the tumor, favoring the implantation of exfoliated cancer cells and making pathologic evaluation more difficult.4,7,12 These limitations of TURBT have led many urologists to recommend an early second-look resection in BC management. In fact, a significant risk of residual tumor after the first TUR has been shown for Ta and T1 BC and understaging of BC.1,2,13 In a meta-analysis of trials by the European Organization for Research and Treatment of Cancer, recurrence rates at 3 months after first TUR range from 3.4% to 20.6% for patients with single Ta-T1 tumors not receiving any intravesical adjuvant treatment and from 0% to 15% in those receiving it. In patients with multiple tumors receiving adjuvant treatment, the recurrence rate at 3 months varied between 7.4% and 45.8%.2 According to the European Association of Urology Association guidelines on BC, a second TUR should be performed 2-6 weeks after the first resection when the latter is incomplete (eg, large and multiple tumors), when no detrusor muscle is found in the specimen, or when high-grade and/or T1 BC is detected.1 To overcome these limitations of TURBT, over the past 15 years, several authors have developed different en bloc resection techniques. Kawada et al5 described a rotational tumor resection using an arched electrode. Ukai et al6 used a J-shaped electrode to retrieve the tumor in one piece. Saito7 reported his experience with en bloc resection using the holmium:yttrium-aluminum-garnet (Ho:YAG) laser fiber (for tumors of the bladder neck) or the knife electrode (for tumors located in the other areas of the bladder). This UROLOGY 83 (4), 2014
Figure 2. Kaplan-Meier curve showing recurrence-free survival (RFS) rates among patients with Ta and T1 primary bladder carcinoma. The numbers near the curves indicate the patients with recurrence in the corresponding period.
series was the first in the literature to describe the use of Ho:YAG laser for en bloc resection of BC. Zhu et al14 compared the Ho:YAG laser resection of bladder tumor (HoLRBT) with standard TURBT in a series of 212 patients with primary NMIBC. They found no difference between the 2 groups in terms of recurrence-free survival, whereas HoLRBT was superior to TURBT in terms of intraoperative complications, postoperative catheterization, and hospitalization time. Moreover, HoLRBT provided sufficient material for pathologic evaluation. Xishuang et al15 compared the safety and efficacy of TURBT, HoLRBT, and plasmakinetic resection of bladder tumor in a series of 173 patients with primary NMIBC. HoLRBT and plasmakinetic resection of bladder tumor proved to be safer than TURBT with regard to complications, catheterization, and hospitalization time, but no advantage was found in terms of tumor recurrence rate. In the literature, there are few articles on Tm:YAG laser for the treatment of BC (Table 1). The use of Tm:YAG laser for BC en bloc resection was first reported in 2008 in a series of 32 patients with recurrent papillary tumors.8 The authors used a flexible cystoscope to deliver laser energy through a 200-mm fiber at 10-15 W. No intraoperative or postoperative complications were observed. Recurrence rates after 1 year were 11% for local relapse and 21% for out-of-field relapse. The accumulated recurrence rates were 9%, 22%, and 28% after 3, 6, and 12 months, respectively. Yang et al16 described a technique of transurethral partial cystectomy based on Tm:YAG laser in 9 patients. No bladder irrigation was required, and the catheter was removed 7-9 days postoperatively. In 1 patient, bladder perforation occurred intraoperatively, and it was treated with abdominal paracentesis drainage. No recurrence at the resection site was reported after a mean follow-up of 7.5 months. Wolters et al12 recently reported their experience with en bloc TmLRBT in a small cohort of 6 patients newly diagnosed with BC. They used the same instrumentation as Yang et al14 but at lower power of laser energy (10-15 W). The incision was extended to the deep muscular layer of 853
Table 1. Thulium:yttrium-aluminum-garnet laser resection of bladder tumor series reported in the literature
Author 7
Gao et al Zhong et al17 Yang et al16 Wolters et al12 Our series
Recurrence Rate (%)
Pts
Operative Time (min)
Complications
Catheterization Time (d)
Follow-up (mo)
Local
Out of Field
All
32 30 9 6 55
25 29.1 8.7 36 33
None None 1 Bladder perforation None None
1 4.47 8 n.r. 1.4
12 24 7.5 2 16
9 n.r. 0 0 2
19 n.r. n.r. n.r. 14.5
28 29.9 n.r. n.r. 16.3
n.r., not reported.
Figure 3. (A) Resected specimen. The muscle layer is present. Reduced from 2.5. (B) The tumor architecture is preserved. (Color version available online.)
the bladder wall. No complications were observed, but bladder irrigation was necessary in 50% of cases. Five of the 6 patients underwent a second-look resection 6 weeks after the initial treatment, and all were negative for residual tumor. Zhong et al17 compared TmLRBT with HoLRBT and standard TURBT in a retrospective series of 97 patients. TmLRBT was associated with less hemoglobin decrease than TURBT (P <.05), whereas no statistical difference was noted for bladder irrigation, postoperative catheterization, and hospitalization. No intraoperative or postoperative complications were reported. The recurrence rates of the 3 groups during 24-month follow-up showed no statistical difference. Our results confirm the data previously reported in the literature on smaller series of patients (Table 1). No intraoperative or postoperative complications were observed. Bladder irrigation was not necessary. Detrusor muscle was present in all pathologic specimens (Fig. 3A). This represents an advantage of en bloc resection vs traditional TURBT because it gives the pathologist the opportunity for correct staging. TURBT causes fragmentation of BC, whereas TmLRBT guarantees preservation of the tumor architecture, which is very important for the classification of papillary tumors (Fig. 3B). The risk of residual tumor after TUR of Ta-T1 lesions ranges from 4% to 53%.1,2 In our series, the persistence of residual tumor after primary TmLRBT involved 1 of 49 patients (2%) with Ta-T1 BC. BC is often understaged at initial resection. The likelihood that a T1 tumor has been understaged and that a muscle-invasive BC will be 854
discovered at a second resection ranges from 4% to 25%.1 In our experience, 1 of 18 patients (5.5%) newly diagnosed with T1 high-grade BC showed focal infiltration of detrusor muscle at second-look TUR. The recurrence rate after a mean follow-up of 16 months was 14.5%; interestingly, all the recurrences were out of the field of primary resection. This result seems to confirm that the TmLRBT has a good power of local tumor eradication. These data, if confirmed by further prospective studies, may reduce the need for second-look TUR after TmLRBT in patients with NMIBC. The Ho:YAG laser and the Tm:YAG laser have very close wavelengths (2100 and 2013 nm, respectively) and use the same chromophore (water). Both these lasers have rapid and high-power tissue vaporization and reach excellent hemostasis.18-20 The Tm:YAG laser, however, produces a smoother cutting line and thus a more accurate incision than the Ho:YAG laser.21
CONCLUSION TmLRBT appears to be a simple and reliable method that offers many advantages over traditional TURBT: It reduces intraoperative and postoperative complications, such as obturator nerve reflex and bleeding. It overcomes the incise and scatter problem associated with the traditional technique of resection. It allows the preservation of tumor architecture and guarantees optimal staging accuracy. It allows an accurate ablation on the basis of the tumor and seems to reduce the risk of local persistence and/or UROLOGY 83 (4), 2014
relapse. This may reduce the need for second look TUR after TmLRBT in patients with NMIBC. References 1. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU Guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 2011;59:997-1008. 2. Brausi M, Collette L, Kurth K, et al. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined study of seven EORTC studies. Eur Urol. 2002;41:523-531. 3. Mariappan P, Zachou A, Grigor KM. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol. 2010;57:843-849. 4. Wilby D, Kay T, Ray E, et al. Bladder cancer: new TUR techniques. World J Urol. 2009;27:309-312. 5. Kawada T, Ebihara K, Suzuki T, et al. A new technique for transurethral resection of bladder tumors: rotational tumor resection using a new arched electrode. J Urol. 1997;157:2225-2226. 6. Ukai R, Kawashita E, Ikeda H. A new technique for transurethral resection of superficial bladder tumour in 1 piece. J Urol. 2000;163: 878-879. 7. Saito S. Transurethral en bloc resection of bladder tumours. J Urol. 2001;166:2148-2150. 8. Gao X, Ren S, Xu C, et al. Thulium laser resection via a flexible cystoscope for recurrent non-muscle invasive bladder cancer: initial clinical experience. BJU Int. 2008;102:1115-1118. 9. Sobin LH, Gospodarowicz MK, Wittekind C, et al. TNM Classification of Malignant Tumors (UICC International Union Against Cancer). 7th ed. New York, NY: Wiley-Blackwell; 2009: 262-265.
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10. Sauter G, Algaba F, Amin M, et al. Tumours of the urinary system: non-invasive urothelial neoplasias. In: Eble JN, Sauter G, Epstein JI, et al., eds. WHO classification of tumours of the urinary system and male genital organs. Lyon, France: IARCC Press; 2004. 11. Stenzl A, Cowan NC, De Santis M, et al. Treatment of muscleinvasive and metastatic bladder cancer. Update of the EAU Guidelines. Eur Urol. 2011;59:1009-1018. 12. Wolters M, Kramer MW, Becker JU, et al. Tm:YAG laser en bloc mucosectomy for accurate staging of primary bladder cancer: early experience. World J Urol. 2011;29:429-432. 13. Jakse G, Algaba F, Malmstr€om P-U, et al. A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol. 2004;45:539-546. 14. Zhu Y, Jiang X, Zhang J, et al. Safety and efficacy of holmium laser resection for primary nonmuscle-invasive bladder cancer versus transurethral electroresection: single-center experience. Urology. 2008;72:608-612. 15. Xishuang S, Deyong Y, Xiangyu C, et al. Comparing the safety and efficiency of conventional monopolar, plasmakinetic, and holmium laser transurethral resection of primary non-muscle invasive bladder cancer. J Endourol. 2012;24:69-73. 16. Yang Y, Wei ZT, Zhang X, et al. Transurethral partial cystectomy with continuous wave laser for bladder carcinoma. J Urol. 2009;182: 66-69. 17. Zhong C, Guo S, Tang Y, et al. Clinical observation on 2 micron laser for non-muscle-invasive bladder tumor treatment: single center experience. World J Urol. 2010;28:157-161. 18. Johnson DE, Cromeens DM, Price RE. Use of the holmium:YAG laser in urology. Lasers Surg Med. 1992;12:353-363. 19. Fried NM, Murray KE. High-power thulium fiber laser ablation of urinary tissues at 1,94 mm. J Endourol. 2005;19:25-31. 20. Teichmann HO, Herrmann TR, Bach T. Technical aspects of laser in urology. World J Urol. 2007;25:221-225. 21. Kranmer MW, Bach T, Wolters M, et al. Current evidence for transurethral laser therapy of non-muscle invasive bladder cancer. World J Urol. 2011;29:433-442.
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