Oncological Outcomes of Patients with Non-Clear Cell Renal Cell Cancers: Subtypes of Unclassified and Translocation Renal Cell Cancers Fatih Gokalp1, Serdar Celik2, Tevfik Sinan Sozen3, Abdurrahim Haluk Ozen4, Guven Aslan5, Volkan Izol6, Sumer Baltaci7, Talha Muezzinoglu8, Bulent Akdogan4, Evren Suer7, Ilker Tinay9 Purpose: We aimed to compare oncological outcomes in the two rare subtypes, unclassified renal cell cancer (un- RCC) and translocation RCC (tRCC), vs clear cell RCC (ccRCC). Materials and Methods: Between 2004 and 2019, from Turkish Urooncology Society Database, we identified 2324 patients for histological subtypes including 80 unRCC (3.4%), 19 tRCC (0.8%) and 2225 ccRCC (95.8%). Results: The overall (15.8%) and cancer-specific mortalities (11.1%) were found to be higher in tRCC group and the recurrence free mortality (13.8%) was found to be higher in unRCC group. Larger pathological tumor size (p = 0.012) and advanced pathological T stage (p = 0.042) were independent predictive factors on overall mortality in patients with unRCC tumors. Conclusion: The oncological outcomes of the unRCC and tRCC are worse than ccRCC and pathological tumor size and pathological stage are predictive factors for mortality in the unRCC. Keywords: kidney; kidney cancer; oncology; pathology INTRODUCTION The majority of the kidney cancers are diagnosed histologically as renal cell carcinoma (RCC). The most common subtypes are clear cell RCC (ccRCC), chromophobe RCC (chRCC), and papillary RCC (pRCC). Other histopathological subtypes, including unclassified RCC (unRCC) and translocation RCC (tRCC), are rare and their frequencies are below 3% (1,2). With increasing recognition of the morphological over- lap between subtypes, the spectrum of morphological patterns in unclassified RCCs has widened and includes both low-grade and high-grade histological tumors(2). Unclassified RCCs refers to a histologically heteroge- neous tumor spectrum, many of which are high-grade, present with more frequent nodal involvement or dis- tant metastasis, and are reported to have lower survival rates(1,3). tRCC is a group of tumors characterized by recurrent rearrangements at the Xp11 locus or at the 6p21 locus(4). Recently, the diagnosis of tRCC, which is frequently seen in childhood, increases in adults with a more aggressive behavior compared to children(5). 1Department of Urology, Hatay Mustafa Kemal University, School of Medicine, Hatay, Turkey. 2Department of Urology, Bozyaka Training and Research Hospital, Izmir, Turkey. 3Department of Urology, Gazi University, School of Medicine, Ankara, Turkey. 4Department of Urology, Hacettepe University, School of Medicine, Ankara, Turkey. 5Department of Urology, Dokuz Eylul University, School of Medicine, Izmir, Turkey. 6Department of Urology, Cukurova University, School of Medicine, Adana, Turkey. 7Department of Urology, Ankara University, School of Medicine, Ankara, Turkey. 8Department of Urology, Manisa Celal Bayar University, School of Medicine, Manisa, Turkey. 9Department of Urology, Marmara University School of Medicine, Istanbul, Turkey. *Correspondence: Hatay Mustafa Kemal University, Faculty of Medicine Department of Urology, 31060, Antakya, TURKEY Phone : + 90 326 229 1000 . Fax: + 90 326 245 5305. E-mail : fatihgokalp85@gmail.com. Received November 2021 & Accepted June 2022 Treatment strategies for unRCC are depending on tu- mor stage, amenability to resection, and comorbidities, similar to ccRCC. The data of neoadjuvant treatments is still limited and adjuvant treatment for local advanced disease has not showed any benefit for overall surviv- al in patients with unfovarable RCCs(6). The optimal treatment of tRCC remains to be determined and recent data showed that tRCC commonly did not respond to immunotherapy and chemotherapy when compared to ccRCC(7). In this study, we aimed to compare onco- logical outcomes in the two rare subtypes, unRCC and tRCC, vs ccRCC. MATERIALS AND METHODS Between 2007-2019, total of 2324 patients who had un- dergone radical or partial nephrectomy from 15 center due to renal cell carcinoma (RCC) were evaluated ret- rospectively. Study data were collected and managed using REDCap (Research Electronic Data Capture) tools hosted at the Urologic Cancer Database - Testis, UROLOGICAL ONCOLOGY Urology Journal/Vol 20 No. 1/ January-February 2023/ pp. 29-33. [DOI:10.22037/uj.v19i.7091] Turkish Urooncology Association (UroCaD-T). Pa- tients with a solitary kidney, other urological diseases, and other malignancies were excluded from the study. Patients were divided into three groups as ccRCC, un- RCC, and tRCC according to RCC histopathological classification. The pathological specimens were evalu- ated using the 2016 World Health Organization classifi- cation system. Demographic data including age, gender, BMI, tumor size, recurrence, and mortality status of the groups were collected from Redcap Database and com- pared. The recurrence-free survival (RFS), overall sur- vival (OS) and cancer-specific survival (CSS) data were investigated. The Shapiro Wilk test was used for de- termining the normality. The continuous variables were shown as mean and standard derivation. The categoric variables were shown as count and frequency. The Chi- square test was used for comparison. The Kruskal-Wal- lis test was used for comparison and Mann Whitney U test was used for Post hoc test. Survival was analyzed using Kaplan-Meier estimate for histological subtypes between 2007-2019 and mean follow up for ccRCC is 24.6 ± 30.2 months. Uni- and multivariable Cox regres- sion was used to analyze prognostic factors for overall survival (OS), recurrence-free survival (RFS) and can- cer-specific survival (CSS). The variables entered the model as Age, Gender, BMI, Pathological tumor size, Pathological stage, Radiological T3-4 stage, Fuhrman 3-4. The p value of the model was meaningful for each group in first step. RESULTS We identified 2324 patients with RCC. The propor- tion of unRCC, tRCC and ccRCC in the 2324 patients were 80 (3.4%), 19 (0.8%) and 2225 (95.8%), respec- tively. Patient demographics are presented in Table 1. The mean age was lower, and the female ratio was higher in the tRCC group. Radiological local invasion rate, tumor diameter and pT3a/b ratio were higher in unRCC (12.5%, 6.7 ± 4.5 cm and 25% respectively). Fuhrman grade 3-4 ratio was also mostly observed in unRCC (79.7%). On the other hand, the pathological T4 stage rate was highest in the tRCC group (21.1%). Recurrences were found to be higher in unRCC group and no recurrence was observed in tRCC possibly due to relatively short follow-up periods in this group com- pared to the other groups (Table 1). The overall and cancer-specific mortalities were found to be higher in tRCC group (Figure 1 and 2 and Table 1). The predictive factors affecting recurrence and overall mortality in unRCC and tRCC groups are given in Ta- ble 2. The recurrence rate was 13.8% in unRCC group (Table 1) and none of the clinical and pathological factors were found to be statistically significant for re- currence in this group (Table 2). Overall mortality was 10% in unRCC group (Table 1) and larger pathological tumor size (HR:1.203. 95%CI:1.042-1.388. p = 0.012) and advanced pathological T stage (HR:1.517. 95% CI:1.015-2.268. p = 0.042) were found to be independ- ent predictive factors for overall mortality in patients with unRCC tumors (Table 2). Overall mortality was 15.8% in tRCC group (Table 1). Although, larger pathological tumor size was found to be a significant factor for overall mortality on univari- ate analysis (5.9 ± 2.4 vs 9.5 ± 3.1. p = 0.035), this fac- tor was not found to be an independent factor for over- all mortality after the multivariate analysis (HR:1.673 95%CI:0.958-2.920. p = 0.070). DISCUSSION The behavior and prognosis of non-clearcell RCC is varies. unRCC molecular characterization is particular- ly different from ccRCC, such as frequently seen mu- Oncological Outcomes of Non-Clear Cell Renal Cell Cancers-Gokalp et al. ccRCC (n=2225) (93%) unRCC (n=80) (3.3%) tRCC (n=19) (0.8%) p Age (years) a 57.2 ± 11.8 59.6 ± 10.8 34.5 ± 10* < 0.001 Gender b Female 788 (35.6) 28 (35.4) 12 (63.2)* 0.045 Male 1425 (64.4) 51 (64.6) 7 (36.8)* BMI (kg/m2) a 28.1 ± 5 29 ± 7.4 25.5 ± 2.6 0.231 Radiological tumor size (cm) a 5.5 ± 3.3 6.7 ± 4.5* 6.2 ± 2.3 0.003 Tumor diameter b < 4cm 874 (39.4) 21 (26.3) 3 (15.8) 0.026 4-7cm 795 (35.8) 31 (38.8) 12 (63.2)* 7-10cm 378 (17) 18 (22.5)* 2 (10.5) >10cm 171 (7.7) 10 (12.5)* 2 (10.5) Tumor involvement b Locally 1984 (89.2) 70 (87.5) 17 (89.5) 0.894 Locally invasive 241 (10.8) 10 (12.5) 2 (10.5) Patological tumor size (cm) a 5.7 ± 3.3 7.6 ± 4.6* 6.5 ± 2.7 < 0.001 Pathological stage b T1a 825 (37.1) 13 (16.3) 3 (15.8) < 0.001 T1b 632 (28.4) 16 (20) 10 (52.6)* T2a 242 (10.9) 13 (16.3) 2 (10.5) T2b 91 (4.1) 6 (7.5) 0 (0) T3a 290 (13) 18 (22.5)* 0 (0) T3b 19 (0.9) 2 (2.5)* 0 (0) T4 126 (5.7) 12 (15) 4 (21.1)* Fuhrman grade b 1-2 1118 (61.7) 12 (20.3) 3 (42.9) < 0.001 3-4 693 (38.3) 47 (79.7) 4 (57.1)* Upstaging to T3-4 b 314 (14.1) 28 (35)* 2 (10.5) < 0.001 Recurrence b 149 (6.7) 11 (13.8)* 0 (0) 0.025 Overall mortality b 73 (3.3) 8 (10) 3 (15.8)* < 0.001 Cancer-specific mortality b 25 (1.1) 4 (5.3) 2 (11.1)* < 0.001 Mean follow-up (month) a 24.6 ± 30.2 27.6 ± 31.6 16.1 ± 14 0.530 Table 1. Clinical, pathological and oncological data of patients with ccRCC, unRCC and tRCC. *The values showed statistically significance a Data was expressed as mean and standard derivation b Data was expressed as count and frequency Urological Oncology 30 tations such as TP53, NF2, SETD2, and BAP1, while there are distinct differences such as lack of VHL alter- ations with unRCC(8,9). But it is difficult to determine the histopathological type correctly and it can be determined by histomorpholo- gy, immunohistochemical and molecular genetic tests in selected cases. The literature makes comparisons of histopathological one subtype with ccRCC. Our study is an addition to literature because of compares sub- types within their self. In our study, the worst prognosis was seen in tRCC, when compared with unRCC and ccRCC. Karakiewicz et al. reported that Fuhrman grade III-IV and metastatic disease were higher in unRCC compared to ccRCC (80% vs. 37.8% and 54.1% vs. 16.8%, re- spectively) and mortality rate was 1.6 times higher in patients with unRCC compared to ccRCC(2). Addition- ally, a novel study which assessed 136 unRCC and di- vided four patterns included: predominantly oncocyto- ma/chromophobe RCC-like phenotype, predominantly papillary RCC-like phenotype, predominantly clear cell RCC- like phenotype, predominantly collecting duct-like phenotype, and pure sarcomatoid phenotype showed that he majority of the oncocytoma/chromo- Histological subtype Recurrence Overall Mortality Univariate p value Multivariate HR (CI) Univariate p value Multivariate HR (CI) unRCC • Age (year) 0.548 - 0.304 - • Gender 0.597 - 0.590 - • BMI (kg/m2) 0.338 - 0.841 - • Pathological tumor size 0.070 - 0.043 1.203 (1.042-1.388) • Pathological stage 0.216 - 0.031 1.517 (1.015-2.268) • Radiological T3-4 stage 0.136 - 0.057 - • Fuhrman 3-4 0.482 - 0.647 - tRCC • Age (year) - - 0.177 - • Gender - - 0.296 - • BMI (kg/m2) - - 0.460 - • Pathological tumor size - - 0.035 1.673 (0.958-2.920) • Pathological stage - - 0.419 - • Radiological T3-4 stage - - 0.702 - • Fuhrman 3-4 - - 0.571 - Table 2. Predictive factors affecting recurrence and overall mortality in unRCC and tRCC groups. Figure 1. Cancer specific survival plots of ccRCC. unRCC and tRCC. Oncological Outcomes of Non-Clear Cell Renal Cell Cancers-Gokalp et al. Vol 20 No 1 January-February 2023 31 phobe and clear cell RCC-like phenotypes were low stage (pT1 or pT2). The papillary RCC-like, collecting duct-like, and pure sarcomatoid phenotypes were most- ly high stage (pT3 or pT4)(10). Controversially, Crispen et al. also reported that the Fuhrman grade III-IV was higher in unRCC group (p < 0.001) however, they found no difference in metastatic disease rate and over- all survival rate between unRCC and ccRCC patients (p = 0.239, and p = 0.345, respectively)(11). Additional- ly, a novel. study which assessed patients with unRCC showed that 58.8% of patients were in advanced stage and 76.5% had high Fuhrman grade(12). In our study, like Karakiewicz et al, we found that unRCC had higher upstaging and local recurrence rates and worse cancer specific survival compared to ccRCC. tRCC also had heterogeneity in oncological outcomes due to genetic heterogeneity. tRCC is a rare pathology and case series seen in childhood RCC and rarely adult age with an average age of onset of 50 years. The tRCC in childhood is generally considered mild prognosis(13). The published studies pointed that the tRCC in adults had worse prognosis than papillary RCC and may be comparable or worse than clear cell RCC(14). Campa- ro et al. reported that the rate of pT3-4 and metastatic disease were 30% and 42% in patients with tRCC. The recurrence rate was 32% and 16% of patients were died at a mean follow-up period of 29.5 months(15). Simi- larly, our study showed that pT4 disease was higher in tRCC group and pathological tumor size was found to be a predictive factor for overall mortality both in tRCC and unRCC patients. Limitations of the study: First, the lack of lymphad- enectomy data and demographic data including co- morbidities or smoking status is an important limita- tion. The literature demonstrated that the lymphnode dissection serves an important staging role by provid- ing pathologic lymphnodestage, which has been inde- pendently associated with survival in nonmetastatic and metastatic renal cell carcinoma. However, literature also pointed that lymphnode dissection does not seem to provide a survival benefit for nonmetastatic or meta- static renal cell carcinoma, even in patients at increased risk for lymph node metastases. Second, our study is a multicenter study which represents the data of major urooncology institutions nationwide. Third, the absence of adjuvant treatment data is an important limitation regarding disease recurrence or progression, however due to the limited adjuvant treatment options in these rare histological subgroups, we believe this limitation should be accepted as a minor limitation. CONCLUSIONS Oncological outcomes of the tRCC and unRCC are worse than ccRCC. Pathological tumor size and patho- logical stage are predictive factors for mortality in the unRCC group. Pathological tumor size is also a predic- tive factor for overall mortality for tRCC. SUMMARY The rare histopathological subtypes, including unclassi- fied RCC (unRCC) and translocation RCC (tRCC) have worse outcomes. Large pathological tumor size is found to be independent predictive factors for overall mortali- ty in patients with unRCC tumors and tRCC. Addition- Figure 4. Overall survival plots of ccRCC, unRCC and tRCC Oncological Outcomes of Non-Clear Cell Renal Cell Cancers-Gokalp et al. 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