Archivio Italiano di Urologia e Andrologia 2018; 90, 3172 ORIGINAL PAPER Effect of variant histology presence and squamous differentiation on oncological results and patient’s survival after radical cystectomy Ertugrul Sefik, Serdar Celik, Ismail Basmaci, Serkan Yarımoglu, Ibrahim Halil Bozkurt, Tarık Yonguc, Bulent Gunlusoy Bozyaka Training and Research Hospital, Department of Urology, Izmir, Turkey. Objective: To evaluate the effect of variant histology on pathological and survival find- ings in patients undergoing radical cystectomy due to muscle invasive bladder cancer. Materials and methods: Data from 146 patients with radical cystectomy performed due to muscle-invasive urothelial carci- noma between January 2006 to November 2016 at our clinic were investigated. The preoperative and postoperative data of patients with variant histology were compared with nonvariant urothelial carcinoma patients. Then of patients with variant histology only those with squamous differentiation (SqD) were compared with nonvariant urothelial carcinoma patients in terms of preoperative, postoperative and survival data. Results: Of the 146 patients, 23 had carcinoma with variant histology. Of these, 17 had SqD, 4 had glandular differentia- tion, 1 patient had plasmocytoid variant and 1 patient had sar- comatoid variant. In patients with variant histology, postopera- tive T stage and upstaging was higher, with no difference observed in terms of overall and cancer-specific survival com- pared with nonvariant urothelial cancer patients. SqD patients were observed to have higher postoperative T stage compared to nonvariant urothelial cancer patients, with no significant dif- ference observed in terms of survival. Conclusions: In cystectomy pathologies, patients with variant histology (especially SqD patients) were observed to have pro- portionally higher T stage compared to nonvariant urothelial carcinoma; however there were no significant differences for overall survival and cancer-specific survival. KEY WORDS: Bladder cancer; Radical cystectomy; Squamous differentiation; Variant histology; Survival. Submitted 26 March 2018; Accepted 7 May 2018 Summary No conflict of interest declared. of urothelial carcinoma is squamous differentiation (SqD), though other non-SqD variants may be observed (5). There are studies reporting that the survival for non-SqD histologic variants is lower (6). In our study in patients with radical cystectomy per- formed due to muscle-invasive bladder cancer, firstly we aimed to assess the effect of the presence of variant his- tology on oncologic results and survival results, and sec- ondly we aimed to compare oncologic data and survival data between the most commonly observed histologic variant of SqD with nonvariant urothelial carcinoma. MATERIALS AND METHODS The data belonging to 178 patients with radical cystec- tomy performed for bladder tumors from January 2006 to November 2016 at our clinic were retrospectively investigated. Patients who undergone radical cystectomy due to high risk non-muscle-invasive bladder, patients with non-urothelial carcinoma pathology and patients who had missed data were excluded from the study. Finally the study included 146 patients who undergone radical cystectomy operation due to muscle-invasive urothelial bladder carcinoma. Pathologic staging of patients was performed according to the 2002 Union for International Cancer Control (UICC) TNM staging system. All patients provided informed consent before the pro- cedure. Before radical cystectomy, patients had preoper- ative clinical staging with examination, transurethral resection (TUR) and computed tomography. The age, gender, preoperative data (presence of hydronephrosis, clinical stage and tumor grade and pres- ence of carcinoma in situ (CIS) in TUR pathology data, postoperative data (postoperative T stage, tumor grade, surgical margin positivity, lymph node metastasis, pres- ence of prostate and urethra invasion and lymphovascu- lar invasion), upstaging and overall and cancer-specific survival data were assessed. Additionally patients with variant histology on radical cystectomy pathology and the histologic type of this vari- ant were noted. Patients with variant histology observed were called Group 1, with patients with nonvariant his- tology called Group 2. Patients in Group 1 with SqD were separately assessed. DOI: 10.4081/aiua.2018.3.172 INTRODUCTION The most common histologic type observed in bladder cancers is urothelial carcinoma. Urothelial carcinoma is known to sometimes display extraordinary characteris- tics (variants) differentiated from normal morphology (1). The histologic variant differentiation rate for bladder urothelial carcinoma is reported as 7-81% in radical cys- tectomy series (2). There are some studies stating that oncologic results and especially survival results are worse for bladder cancers with variant histology (3, 4). The most commonly observed among histologic variants Sefik2_Stesura Seveso 03/10/18 09:40 Pagina 172 173Archivio Italiano di Urologia e Andrologia 2018; 90, 3 Variant histology and survival after radical cystectomy Statistical analysis Patient data was first compared between Group 1 and Group 2 and then between patients with SqD and Group 2 using the Mann-Whitney U test and the Pearson X2 test. The cancer-specific survival and overall survival times in the groups were assessed with the Kaplan-Maier survival analysis. Statistical analysis was completed using the Statistical Package for the Social Sciences (SPSS) Version 20.0 (SPSS, Chicago, Illinois, USA). Data are pre- sented as mean and standard deviation, with statistical analysis calculated on the median values. The analysis results with p value < 0.05 were accepted as significant. RESULTS There were 13 females and 133 males with radical cys- tectomy performed due to muscle-invasive bladder can- cer. The mean age of all patients was 64.4 ± 9 years. The mean follow-up time was 31.7 ± 31.8 months. A total of 23 patients had variant histology; 17 had SqD, 4 had glandular differentiation, 1 patient had plasmocy- toid variant and 1 patient had sarcomatoid variant. The preoperative, postoperative and survival data and comparison between Group 1 (n = 23) and Group 2 (n = 123) are given in Table 1. When the comparison results are investigated, in the preoperative data, age, gender and clinical T stage and TUR pathology tumor grade and CIS presence were similar in Group 1 and Group 2. In the postoperative data, tumor grade, surgical margin positivity, prostate invasion, urethral invasion and pres- ence of lymphovascular invasion were similar in both groups. However, the postoperative pathologic T stage and pathologic upstaging were significantly higher in Group 1. There were no significant differences observed between the groups in terms of overall and cancer-spe- cific survival. Data for patients with urothelial carcinoma with the most commonly observed variant histology of SqD along with Group 2 patient data were com- pared and results are given in Table 2. Patients with SqD had significantly higher rates of preoperative tumor grade (p = 0.020) and postoperative pathologic T stage (p = 0.040) com- pared with Group 2. When survival data were examined, though patients with SqD had lower overall survival (52.3 ± 4.7 and 49.6 ± 10.4 months, respectively) and cancer-specific sur- vival times (64.7 ± 5.3 and 58.4 ± 10.7 months, respectively) compared to Group 2, no statistically significant dif- ference was found between the two groups. DISCUSSION In our study, the rate of patients with variant histology on radical cystectomy pathology was 16%, while the SqD rate was 12%. In the literature, different studies show different rates for variant histology, with these rates reported between 7 and 81% (2). This large difference in variant histology rates may be explained by not using defined criteria for evaluation. SqD is reported to be most common among observed histologic variants, in fact in our study the rate of SqD among all his- tologic variants is 74% (17/23). Though SqD is characterized by histologic inter- cellular bridges and keratinization, the World Health Organization (WHO) defines it is a urothelial carcinoma vari- ant (7). Among non-urothelial bladder cancers, squamous cell carcinoma and adenocarcinoma are known for their aggressive nature and low survival rates (8). However there is no consensus on the prognostic importance of histologic Table 1. Preoperative and postoperative patient characteristics and survival results for Group 1 and Group 2. Variant Variant P* histology (+) histology (-) n: 23 n: 123 Age 63.7 ± 10.4 64.5 ± 8.7 0.119 Gender Female 4 9 0.136 Male 19 114 Preoperative hydronephrosis Positive 11 40 0.158 Negative 12 83 Preoperative T stage T2 23 118 0.325 T3 0 5 Preoperative tumor grade Grade 1 1 0 0.065 Grade 2 1 4 Grade 3 21 119 CIS Positive 5 37 0.380 Negative 18 83 Postoperative T stage ≤ T1 0 19 0.035 T2 10 61 T3 10 17 T4 3 26 Postoperative tumor grade 1 1 4 0.967 2 1 4 3 21 104 Surgical margin Positive 3 25 0.416 Negative 20 98 Lymph node metastasis Positive 7 23 0.160 Negative 16 93 Invasion of prostate Positive 2 15 0.606 Negative 20 100 Invasion of urethra Positive 2 8 0.760 Negative 21 108 Lymphovasculer invasion Positive 7 18 0.081 Negative 16 100 Perineural invasion Positive 3 17 0.864 Negative 17 101 Upstaging Positive 14 45 0.029 Negative 9 78 Overall survival 47.1 ± 8.6 52.3 ± 4.70 0.816 Cancer spesific survival 52.8 ± 4.8 64.8 ± 5.3 0.824 *Mann-Whitney U test CIS:carcinoma in situ. Sefik2_Stesura Seveso 03/10/18 09:40 Pagina 173 Archivio Italiano di Urologia e Andrologia 2018; 90, 3 E. Sefik, S. Celik, I. Basmaci, S. Yarımoglu, I. Halil Bozkurt, T. Yonguc, B. Gunlusoy 174 variants of urothelial carcinoma. Studies of variant his- tologies and their clinical importance are examined, have generally heterogeneous populations and small scale. A study by Monn et al. observed that generally patients with variant histology have high pathologic T stage. When subtypes are investigated, while plasmocytoid and micropapillary variants have high mortality, SqD and sar- comatoid variants were identified to have similar survival to nonvariant urothelial carcinoma (9). In our study, patients with variant histology had higher postoperative pathologic T stage and upstaging rate com- pared to nonvariant urothelial carcinoma patients, while survival rates were similar in accordance with the litera- ture. There are studies showing that bladder cancers with vari- ant histology forms are aggressive tumors with high tumor stage and high lymph node metastasis rates (10-12). Xylinas et al. reported that patients with variant histology on radical cystectomy pathology were correlated with high tumor stage, high lymph node metastasis, lymphovascular invasion (LVI) presence, high recurrence risk and increased cancer-specific mortality. Furthermore, they stated the patients with non-squamous differentiation were the worst prognostic group. In spite of this, they reported that variant histology was not an independent risk factor in terms of prognosis (13). In the present study, though the pre- operative tumor grade and postopera- tive tumor stage were high among patients with SqD, the overall survival and cancer-specific survival were simi- lar to nonvariant urothelial carcinoma. Our findings support the report of Moschini et al. who assessed 1067 radi- cal cystectomy cases, observing SqD in 10.2% of patients with no effect of SqD on survival (14). Our study has some limitations. The most important of these are that it is a retrospective study and the low number of patients. CONCLUSIONS Patients with variant histology on cys- tectomy pathology were observed to have high T stage compared to those with nonvariant urothelial cancer; however there were no significant dif- ferences in overall survival and cancer- specific survival. When the most commonly observed histologic variant of SqD is investigat- ed, though there was higher stage dis- ease compared to nonvariant urothelial cancers, there was no effect shown on overall survival and cancer-specific survival. REFERENCES 1. Shah RB, Montgomery JS, Montie JE, Kunju LP. 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Correspondence Ertugrul Sefik, MD (Corresponding Author) sefikanamur@yahoo.com Serdar Celik, MD Ismail Basmaci, MD Serkan Yarımoglu, MD Ibrahim Halil Bozkurt, MD Tarık Yonguc, MD Bulent Gunlusoy, MD Bozyaka Training and Research Hospital, Department of Urology, Izmir, Turkey Sefik2_Stesura Seveso 03/10/18 09:40 Pagina 175