Archivio Italiano di Urologia e Andrologia 2016; 88, 286 ORIGINAL PAPER Is a second look necessary in multiple and/or large Ta tumors? Sıtkı Ün 1, Hakan Türk 2, Mustafa Karabıçak 2, Rauf Taner Divrik 3, Ferruh Zorlu 2 1 Katip Çelebi University Atatürk Research and Training Hospital, Department of Urology, Izmir, Turkey; 2 Tepecik Research and Training Hospital, Department of Urology, Turkey; 3 Şifa University Medicine Faculty, Department of Urology, Turkey. Introduction: Most of the bladder cancers are tumors without muscle invasion at the time of diagnosis. Transurethral resection is the standard treatment in bladder tumors without muscle invasion. Proper review of transurethral resection is important for correct risk classification. In this study, our main objective was to show that a “second look” in patients with multiple and/or > 3 cm tumors regardless of T stage during the early term can be helpful in detection of possible residues and determining risk classification. Materials and methods: 156 patients with primary, multiple and/or > 3 cm tumors were included in the study. Patients were divided into 3 groups as Group 1 (Ta), Group 2 (T1 without second TUR) and Group 3 (T1 with second TUR). Macroscopic tumor occurrence rates were compared in their 3rd month control cystoscopy. Results: Macroscopic tumor detection rates in patients’ 3rd month control cystoscopy were 21 (46.7%) in Group 1, 18 (30%) in Group 2 and 4 (7.8%) in Group 3. When compared with Group 3 patients, Group 1 and Group 2 had higher statistically significant macroscopic tumor detection rates (p = 0.001) Conclusion: A second look in patients with multiple and/or > 3 cm tumors during early term will enable the surgeons to detect possible tumors and do a better job in risk classifica- tion. KEY WORDS: Bladder cancer; Multiple; Large; Second look. Submitted 4 October 2015; Accepted 4 December 2015 Summary No conflict of interest declared. MATERIALS AND METHODS Data of 1406 bladder cancer patients who were diag- nosed in our clinic between 2000 and 2014 was retro- spectively reviewed; 156 patients with primary, multiple and/or > 3 cm tumors were included in the study. Patients with secondary tumors, without complete resec- tion, without muscularis propria tissue in pathology samples and microscopic tumors detected in second TUR were excluded. Patients were divided into 3 groups as Group 1 (Ta), Group 2 (T1 without second TUR) and Group 3 (T1 with second TUR). Patients in Group 2 con- sist of T1 patients before second TUR diagnosis. Groups were compared in demographic and clinical parameters. Macroscopic tumor occurrence rates were compared in their 3rd month control cystoscopy. Our main aim was to review the hypothesis “According to TNM staging, patients with Ta (multiple and/or large) tumors warrant a second-look”. In order to retrospectively review this hypothesis, we tried to show the relationship between patients with T1 stage tumors who went under second TUR and patients who did not receive further surgery. Considering that the residual tumor existence can also be seen in patients with Ta-stage tumors, we chose this methodology. Except intracavitary therapy, no additional local adjuvant therapies were used in that patient group. Since the main focus of the study is to prove that a second look is neces- sary following TUR surgery, other patients who received additional local adjuvant therapies were excluded from the study. All patients received a 6-week standard intra- cavitary therapy protocol. The assessments were made on the 3rd month of treatment using cystoscopy findings. Statistical analysis was made using computer software. Chi-square test was used in categorical variables and Student-t test was used in continuous variables. Values under p < 0.05 were considered statistically significant. RESULTS Out of 156 patients, 45 patients were put into Group 1, 60 into Group 2 and 51 into Group 3. Patients were reviewed in terms of sex, age, pathological grade and adjuvant intracavitary treatments (Table 1). Group 1 DOI: 10.4081/aiua.2016.2.86 INTRODUCTION About 80% of bladder cancers are seen without muscle invasion at the time of diagnosis. The “golden standard” in treatment of bladder tumors without muscle invasion is transurethral resection (TUR) (1). Proper review of transurethral resection is important for correct diagnosis and treatment as well as risk classification (2). In this study, our main objective was to show that a “sec- ond look” in patients with multiple and/or > 3 cm tumors regardless of T stage during the early term can be help- ful in detection of possible residues and determining risk classification. Sitki_Stesura Seveso 01/07/16 10:59 Pagina 86 87Archivio Italiano di Urologia e Andrologia 2016; 88, 2 Second look in Ta tumors patients had lower statistically significant high-grade tumor rates compared to other groups. There were no statistically significant differences between the groups when other parameters were reviewed. Since all patients included in the study required intracavitary therapy, all patients received this treatment. No statistically signifi- cant differences were seen between the groups in terms of intracavitary therapy during statistical analysis. Macroscopic tumor detection rates at 3rd month control cystoscopy were 21 (46.7%) in Group 1, 18 (30%) in Group 2 and 4 (7.8%) in Group 3. Nineteen patients in Group 3 were diagnosed with macroscopic tumors dur- ing their second TUR. When compared with Group 3 patients, Group 1 and Group 2 had higher statistically significant macroscopic tumor detection rates (p = 0.001) (Table 2A). When macroscopic tumor detection during re-TUR rates in Group 3 patients were compared to control cystoscopy results of the other 2 groups, there was a correlation (Table 2B). DISCUSSION TUR is accepted as the basic surgical procedure in diag- nosis and treatment of bladder cancers without muscle invasion. However, many studies suggest a second TUR after the initial TUR for resection of residual tumors (3, 4). Tumors detected during initial control cystoscopy on 3rd month of surgery in multiple and/or > 3 cm tumors were known to be mainly residual tumors (5). A residual tumor from a previously incomplete TUR detected in first control cystoscopy on 3rd month will be labeled as early recurrence which will change the patient’s risk classification. Residual tumors are impor- tant in the treatment of multiple and/or tumors larger than 3 cm. Literature reports residual tumor rates as 33- 78% (6). Divrik et al. prospective and randomized study reports this rate as 33.8% in T1 patients. In Grimm et al. prospective study, the authors suggested a second TUR to patients that received the initial TUR in their clinic and reported a residual tumor detection rate of 33.7% (8). Similarly in our study, 19 (37.2%) out of 51 T1 stage patients who underwent re-TUR were diagnosed with residual tumors. Herr et al. performed a secondary TUR in 150 patients who underwent the initial TUR in differ- ent clinics and reported 70.4% residual tumor rate (2). The initial TUR quality of those patients is unknown as well as the presence of muscle tissue in pathological sam- ples and if the tumor was completely finished or not. In the other 2 studies mentioned above and our study, the initial TUR was done in their respective clinics, complete removal of tumor was reported by the surgeon and mus- cle tissue was found in pathological samples. Even after a proper and complete TUR, 1 out of 3 patients is diag- nosed with residual tumors. This rate is deemed as sig- nificant. A significant drop in recurrence and progression rates in high-risk Ta/T1 patients was reported with secondary TUR (7-9). Yet in most of the studies, second TUR is only recommended to T1 patients (10-12) There are also studies that recommend second TUR in high grade Ta patients (13, 14). In a study done by Lazica et al., high- risk Ta patients who underwent a second TUR were reviewed and 41.4% of those patients were diagnosed with residual tumors (14). In this study, there was a sig- nificantly higher rate of tumors in multifocal tumor cases diagnosed in second TUR. There was a similar increase in tumor detection rates in patients with tumors > 3 cm, but this was not deemed as statistically significant (14). Residual tumor presence following TUR is connected with the stage, degree, size and number of the initial tumor (7). Multiple tumors increase recurrence risk (15- 18). In addition, tumor size is also found to be in con- nection with recurrence risk (16, 19). These results were compatible with the meta-analysis reports done by EORTC (20). In our study, 19 (37.3%) patients were diagnosed with macroscopic tumors during re-TUR and only 4 (7.8%) patients were diagnosed with macroscopic tumors dur- ing 3rd month control cystoscopy. It was seen that most of the macroscopic tumors detected during re-TUR were residual tumors which were missed during initial TUR. 21 (46.7%) patients in Group 1 and 18 (30%) patients in Group 2 were diagnosed with macroscopic tumors in their 3rd month control cystoscopy. Those rates were consistent with macroscopic tumors diagnosed during re-TUR rates seen in Group 3 patients. We think that a second look done in 4-6 weeks after the initial TUR in Group 1 patients will decrease those rates similar to Group 1 Group 2 Group 3 p N Y Z W Age (mean ± SD) 66.7 ± 10.9 64.1 ± 12.2 68.0 ± 9.1 0.158 Sex Male 40 (88.8%) 57 (95%) 48 (94.1%) 0.444 Female 5 (11.2%) 3 (5%) 3 (5.9%) Grade Low 34 (75.5%) 41 (68.3%) 28 (54.9%) 0.009 High 11 (14.5%) 19 (31.7%) 23 (45.1%) Adjuvant therapy IC Chemotherapy 40 (88.9%) 50 (83.4%) 40 (78.5%) 0.390 IC Immunotherapy 5 (11.1%) 10 (16.6%) 11 (21.5%) Table 1. Comparison of groups in terms of age, sex, grade and adjuvant therapy. Macroscopic tumor Group 1 Group 2 Group 3 p Yes 21 (46.7%) 18 (30%) 4 (7.8%) 0.001 No 24 (53.3%) 42 (70%) 47 (92.7%) Table 2A. Group comparison of macroscopic tumor presence detected on 3rd month control cystoscopy. Macroscopic tumor Group 1 Group 2 Group 3 p Yes 21 (46.7%) 18 (30%) 19 (37.3%) 0.216 No 24 (53.3%) 42 (70%) 32 (62.7%) Table 2B. Comparison of macroscopic tumors detected on second TUR in Group 3 patients with Group 1 and Group 2. Sitki_Stesura Seveso 01/07/16 10:59 Pagina 87 Archivio Italiano di Urologia e Andrologia 2016; 88, 2 S. Ün, H. Türk, M. Karabıçak, R. Taner Divrik, F. Zorlu 88 Group 3 patients. As a result, risk classification and treat- ment strategies of the patients will be more realistic. The main limitation in our study was the small number of patients. More widespread and prospective studies are necessary on this subject. REFERENCES 1. Babjuk M, Oosterlinck W, Sylvester R, et al. European Association of Urology (EAU). EAU guidelines on non-muscle-invasive urothe- lial carcinoma of the bladder. Eur Urol. 2008; 54:303-14. 2. Mariappan P, Zachou A, Grigor KM; Edinburgh Uro-Oncology Group. 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; 57:843-9. 3. Herr HW. The value of a second transurethral resection in evalu- ating patients with bladder tumors. J Urol. 1999; 162:74-6. 4. Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? J Urol. 2001; 165:808-10. 5. Schulze M, Stotz N, Rassweiler J. Retrospective analysis of transurethral resection, second-look resection, and long-term chemo-metaphylaxis for superficial bladder cancer: indications and efficacy of a differentiated approach. J Endourol. 2007; 21:1533-41. 6. Miladi M, Peyromaure M, Zerbib M, et al. The value of a second transurethral resection in evaluating patients with bladder tumours. Eur Urol. 2003; 43:241-5. 7. Divrik RT, Sahin AF, Yildirim U, et al. Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 urothelial carcinoma with respect to recur- rence, progression rate, and disease-specific survival: a prospective randomised clinical trial. Eur Urol. 2010; 58:185-90. 8. Grimm MO, Steinhoff C, Simon X, et al. Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J Urol. 2003; 170:433-7. 9. Babjuk M. Transurethral resection of nonmuscle-invasive bladder cancer. Eur Urol Suppl. 2009; 8:542-8. 10. Dalbagni G, Herr HW, Reuter VE. Impact of a second transurethral resection on the staging of T1 bladder cancer. Urology. 2002; 60:822-4. 11. Kulkarni GS, Hakenberg OW, Gschwend JE, et al. An updated crit- ical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer. Eur Urol. 2010; 57:60-70. 12. Yucel M, Hatipoglu NK, Atakanli C, et al. Is repeat transurethral resection effective and necessary in patients with T1 bladder carci- noma? Urol Int. 2010; 85:276-80. 13. Herr HW. Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3) bladder tumors: 15-year out- come. J Urol. 2000; 163:60-61. 14. Lazica DA, Roth S, Brandt AS, et al. Second transurethral resec- tion after Ta high-grade bladder tumor: a 4.5-year period at a sin- gle university center. Urol Int. 2014; 92:131-5. 15. Parmar MK, Freedman LS, Hargreave TB, Tolley DA. Prognostic factors for recurrence and followup policies in the treat- ment of superficial bladder cancer: report from the British Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party). J Urol. 1989; 142:284-8. 16. Millán-Rodríguez F, Chéchile-Toniolo G, Salvador-Bayarri J, et al. Multivariate analysis of the prognostic factors of primary super- ficial bladder cancer. J Urol. 2000; 163:73-8. 17. Shinka T, Hirano A, Uekado Y, Ohkawa T. Clinical study of prognostic factors of superficial bladder cancer treated with intrav- esical bacillus Calmette-Guerin.Br J Urol. 1990; 66:35-9. 18. Kiemeney LA, Witjes JA, Heijbroek RP, et al. Dysplasia in normal- looking urothelium increases the risk of tumour progression in primary superficial bladder cancer. Eur J Cancer. 1994; 30A:1621-5. 19. Kurth KH, Denis L, Bouffioux C, et al. Factors affecting recur- rence and progression in superficial bladder tumours. Eur J Cancer. 1995; 31A:1840-6. 20. Oosterlinck W, Kurth KH, Schröder F, et al. A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol. 1993; 149:749-52. Correspondence Sıtkı Ün, MD (Corresponding Author) sitki@doctor.com Katip Çelebi University Atatürk Research and Training Hospital, Department of Urology Basın Sitesi, Izmir, Turkey Hakan Türk, MD Mustafa Karabıçak, MD Ferruh Zorlu, MD Tepecik Research and Training Hospital, Department of Urology Rauf Taner Divrik, MD Şifa University Medicine Faculty, Department of Urology Sitki_Stesura Seveso 01/07/16 10:59 Pagina 88