Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 1 ORIGINAL PAPER INTRODUCTION Renal cell carcinoma (RCC) with a tumor thrombus (RCC- TT) carries a high morbidity and mortality. Incidence is estimated around 4-10%, and it is well-established that patients with a tumor thrombus tend to have poor prog- nosis (1, 2). Survival of these patients ranges at five years from 18%-57% depending on the study and patient char- acteristics being examined (3). There has recently been an important renewed focus on disparities in health access and survival outcomes in urology. Race has been studied for its association with inequities for RCC. Strong evi- dence exists that black race predisposes patients to worse treatment outcomes, and this research has highlighted the need for more equitable treatment in RCC to ensure the best outcomes for all patients (4, 5). While the impact of race is undoubtedly an area that necessitates further research for RCC, global disparities in presentation, man- agement, and outcomes also exist and have lacked the appropriate attention in the literature currently. It is estimated that there will be nearly 400,000 new cases of RCC worldwide and 175,000 deaths in the year 2024 (6). Current evidence shows that RCC incidence is higher in North America (NA) and Europe relative to other conti- nents, and this has been theorized to be due to greater rates of abdominal imaging in these areas (7, 8). Nevertheless, Purpose: With multi-institutional collabora- tion, the purpose of this study was to analyze geographical differences of renal cell carcinoma with tumor thrombus between patients in North America, Central/South America, and South Korea. Materials and methods: Patients with renal cell carcinoma and a tumor thrombus who underwent nephrectomy plus thrombecto- my were retrospectively analyzed. Patients were from North America, Central/South America, and South Korea. All compar- isons were done based on the region where a patient had their surgery and follow-up. Chi-squared test, analysis of variance, Kaplan-Meier survival with log-rank test, and Cox regression analysis were used. Results: A total of 478 patients were included, 212 from North America, 209 from Central/South America, and 57 from South Korea. Of note, thrombus level was different using the Neves classification system between regions (p < 0.001), with a greater thrombus level in Central/South America. Surgical approach dif- fered, with laparoscopic cases done most often in Central/South America and robotic in North America (p < 0.001). Tumor grade was lowest in South Korea (p < 0.001) and stage (p < 0.001) greatest in Central/South America. Overall survival was greater in South Korea compared to Central/South America (p = 0.026). Cancer-specific survival was greater in South Korea relative to North America and Central/South America (p = 0.026). Conclusions: Patients from North America, Central/South America, and South Korea diagnosed with renal cell carcinoma and tumor thrombus do not present the same and have different outcomes peri-/post-operatively. This includes important vari- ables which have impacts on patient morbidity and mortality. Considering increased efforts on health equity in urology, the causes of these differences call for further investigation. A comparison of renal cell carcinoma with tumor thrombus across North America, Central/South America, and South Korea Maxwell Sandberg 1, Rachel Vancavage 2, Claudia Marie-Costa 3, Emily Ye 3, Mitchell Hayes 4, Justin Miller 5, Reuben Ben David 6, Kartik Patel 7, Kimberly Waggener 1, Brejjette Aljabi 7, SeokSoon Byun 8, Patricio García Marchiñena 9, Thiago Mourao 10, Charles Peyton 7, Reza Mehrazin 6, Philippe Spiess 4, Rafael Zanotti 10, Steven Chang 11, Stenio de Casio Zequi 10, Diego Abreu 12, Alejandro Rodriguez 1 1 Atrium Health Wake Forest Baptist Medical Center, Winston Salem, NC, USA; 2 Albany Medical College, Albany, NY, USA; 3 Wake Forest University School of Medicine, Winston Salem, NC, USA; 4 Moffitt Cancer Institute, Tampa Bay, FL, USA 5 University of South Florida School of Medicine, Tampa Bay, FL, USA; 6 Icahn School of Medicine at Mount Sinai, New York, NY, USA; 7 University of Alabama Birmingham School of Medicine, Birmingham, AL, USA; 8 Seoul Bundang University Hospital, Seoul, South Korea; 9 Hospital Italiano, Buenos Aires, Argentina; 10 AC Camargo Cancer Institute, Sao Paulo, Brazil; 11 Harvard Medical School, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Division of Urology, Boston, USA; 12 Paseur Hospital, Division of Urology, Montevideo, Uruguay. DOI: 10.4081/aiua.2025.13820 Summary KEY WORDS: Renal cell carcinoma; Thrombus; Continental; Equity; Disparities. Submitted 13 March 2025; Accepted 5 April 2025 Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 M. Sandberg, R. Vancavage, C. Marie-Costa, et al. 2 regions like Latin America and Asia, who historically have had a lower incidence of RCC, are expected to mirror that of NA and Europe in the coming years (9). Though there are few studies, survival from RCC has been examined across the world with results tending to point towards equivalent overall survival (OS) with worse cancer-specific survival (CSS), access to clinical trials, and/or guideline- based care in lower-income countries and regions of the world (6, 9). Perhaps most importantly, despite strong evi- dence that RCC is a cause for significant inequitable out- comes globally and is estimated to be responsible for approximately 2.5% of all cancer-related deaths across the world yearly, there is a paucity of research examining RCC- TT worldwide as most publications lack analysis on this important patient population (6, 7, 9, 10). Over the last two years, a joint collaborative project was started to address global disparities in RCC-TT between institutions in NA, Central/South America (CSA) (via the Latin American Renal Cell Group), and South Korea known as the Intercontinental Collaboration on Renal Cell Carcinoma (ICORCC). The purpose of this study was to compare pre-, peri-, and post-operative management along with survival of patients with RCC-TT between NA, CSA, and South Korea using the ICORCC database. We hypoth- esized that no difference in presentation, operative man- agement, or survival outcomes would exist by geography. MATERIALS AND METHODS This was a multi-institutional study conducted under insti- tutional review board number IRB00096722 across NA, CSA, and South Korea. Data was retrospectively collected from 1999-present and stored on a master database as part of the ICORCC project. Participating institutions were from the United States of America, Mexico, Peru, Uruguay, Bolivia, Chile, Argentina, Brazil, and South Korea. All patients required both a diagnosis of RCC-TT on computer- ized tomography (CT) and/or magnetic resonance imaging (MRI) and had to have undergone radical nephrectomy with tumor thrombectomy for inclusion. A variety of pre- operative variables were collected including patient age, gender, race, diabetes mellitus (DM), chronic kidney disease (CKD), symptoms at presentation (local and metastatic), Karnofsky performance status, Charlson Comorbidity Index (CCI), preoperative CT chest scan, preoperative tumor size, and presence of preoperative metastasis. Perioperative vari- ables were surgical approach, operative time, tumor grade, tumor stage, tumor pathologic characteristics (necrosis, sar- comatoid, rhabdoid), lymph node (LN) dissection, and soft tissue margin positivity. Postoperative variables were metas- tasis after surgery, metastasis-free survival (MFS), follow-up time, OS, and CSS. Local symptoms were defined as flank pain and/or palpa- ble abdominal or flank mass. Metastatic symptoms were shortness of breath, chest pain, hemoptysis, bone pain/swelling, jaundice, seizures, fever, weight loss, or dizziness. For patients with preoperative metastatic loca- tion information available, locations were defined as the lungs, bone, liver, brain, retroperitoneum, regional lymph nodes, adrenal gland, and “other regions”. Thrombus level was classified according to the Neves classification system (11). Preoperative tumor size was taken as the greatest dimension of tumor size on CT or MRI imaging as closest to the date of surgery. Systemic therapy was defined as any use/combination of chemotherapy (chemo), immunother- apy (immuno), or targeted therapy (targeted) for treating RCC-TT either before or after surgery. A minority of patients did not have complete data on the specific sys- temic therapeutic used and were defined as “unknown”. Surgical approach was classified as either open, laparo- scopic (pure or hand-assist), or robotic. Tumors were staged according to the TNM classification system and graded according to the International Society of Urological Pathology grading system (12, 13). Patients were classified according to geographic location where they underwent primary surgery for their RCC-TT and received most of their postoperative care (NA, CSA, or South Korea). Analysis of variance (ANOVA) was run to compare continuous variables by geographic location. Chi-squared test was used to compare categorical vari- ables by geographic location. Kaplan-Meier survival curves with log-rank test were used to compare OS, MFS, and CSS by geographic location. Additionally, a cox- regression analysis model for OS and CSS was also per- formed using variables with p < 0.05 and/or clinical rele- vance. Patients with missing values for a particular vari- able were excluded from that analysis. Significance was set to p < 0.05 and conducted using SPSS Statistics Version 28 (Armonk, NY). RESULTS A total of 478 patients were included in the study, 212 from NA, 209 from CSA, and 57 from South Korea (Table 1; Table 1. Geographical comparisons for Renal Cell Carcinoma with Tumor Thrombus. The following table compares pre-, peri-, and postoperative outcomes between each geographical region in the study. Continuous variables are reported as means with standard deviations in parentheses aside from Variable NA CSA South Korea P-value N 212 209 57 - Age (years) 63.1 (10.9) 61.3 (12.4) 61.1 (10.9) 0.282 BMI 29.3 (6.6) 27.3 (4.7) 23.4 (3.4) < 0.001 Female 64 (30.2) 52 (24.9) 12 (21.1) 0.273 Race Caucasian 163/208 (78.4) 70/169 (41.4) 0 < 0.001 Black 24/208 (11.5) 7/169 (4.1) 0 Hispanic 0 84/169 (49.7) 0 Asian 12/208 (5.8) 8/169 (4.7) 57 (100) Other 9/208 (4.3) 0 0 Active smoker 32 (15.1) 24 (11.5) 6 (10.5) 0.612 Former smoker 97/205 (47.3) 75 /172 (43.6) 12 (21.1) 0.002 Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 3 Renal cell carcinoma with tumor thrombus Karnofsky performance status, Charlson Comorbidity Index, and the number of positive and negative lymph nodes which are medians with interquartile ranges in parentheses. Categorical variables are reported as total numbers with percentage of the cohort in parentheses. Associated p-values for each comparison are also provided. DM 65 (30.7) 39 (18.7) 15 (26.3) 0.021 Hypertension 153 (72.2) 82 (39.2) 33 (57.9) < 0.001 CKD 39 (18.4) 13 (6.2) 3 (5.3) < 0.001 Karnofsky 90 (80-90) 90 (80-97.5) 90 (90-90) 0.692 CCI 6 (4-8) 5 (3-6) 1 (0-6) < 0.001 Local symptoms at diagnosis 147 (69.3) 98 (46.9) 30 (52.6) 0.020 Metastatic symptoms at diagnosis 19 (9) 25 (12) 0 0.007 Preoperative chest CT 167 (78.8) 81 (38.8) 34 (59.6) < 0.001 Preoperative tumor size (cm) 9.1 (3.3) 9.8 (3.6) 8.4 (3) 0.021 Thrombus level I 109/204 (53.4) 29/93 (31.2) 32 (56.1) < 0.001 II 45/204 (22.1) 25/93 (26.9) 7 (12.3) III 24/204 (11.8) 26/93 (28) 16 (28.1) IV 26/204 (12.7) 13/93 (14) 2 (3.5) Metastatic before surgery 80/122 (65.6) 36/94 (38.3) 20/39 (51.3) 0.002 Multiple metastatic sites at presentation 27/80 (33.4) 24/36 (66.7) 8/20 (40) 0.128 Preoperative metastatic locale Lung 15 13 0 - Bone 10 5 1 Liver 8 12 0 Brain 3 0 0 Retroperitoneum 16 16 3 Nodal 1 5 4 Adrenal 9 3 2 Other 10 1 7 Approach Open 107/211 (50.7) 107/185 (57.8) 50 (87.7) < 0.001 Laparoscopic 13/211 (6.2) 65/185 (35.1) 5 (8.8) Robotic 91/211 (43.1) 13/185 (7) 2 (3.5) Operative time (minutes) 290.8 (122.7) 285.6 (138.3) 265 (121.1) 0.422 Length of stay (days) 6.6 (6) 15.5 (76.3) 12.3 (7.1) 0.199 Stage T3a 63/182 (34.6) 40/153 (26.1) 0 < 0.001 T3b 80/182 (44) 74/153 (48.4) 49 (86) T3c 25/182 (13.7) 23/153 (15) 8 (14) T4 14/182 (7.7) 16/153 (10.5) 0 Grade 1 7/202 (3.5) 2/155 (1.3) 0 < 0.001 2 36/202 (17.8) 17/155 (11) 2 (3.5) 3 101/202 (50) 54/155 (34.8) 33 (57.9) 4 58/202 (28.7) 82/155 (53) 22 (38.6) Sarcomatoid 28 (13.9) 82 (39.2) 9 (15.8) < 0.001 Rhabdoid 24 (11.3) 9 (4.3) 0 0.371 Necrosis 119/201 (59.2) 112/166 (67.5) 43 (75.4) 0.048 Subtype Clear cell 162/205 (79) 166/188 (88.3) 50 (87.7) 0.071 Papillary 17/205 (8.3) 12/188 (6.4) 4 (7) Other 26/205 (12.7) 10/188 (5.3) 3 (5.3) Lymph node dissection 100 (47.2) 67 (32.1) 25 (43.9) 0.004 Lymph nodes positive 0 (0-1) 0 (0-1) 0 (0-1) 0.123 Lymph nodes negative 2 (0-4) 2 (0-5) 5 (2-14.5) 0.003 Soft tissue margin positive 58 (27.4) 34 (16.3) 1 (1.8) < 0.001 Systemic therapy 92 (43.3) 56 (26.8) 30 (52.6) < 0.001 Systemic therapy type Chemo 6 7 0 - Immuno 16 10 0 Targeted 26 34 12 Chemo and immuno 6 1 2 Chemo and targeted 3 0 0 Immuno and targeted 21 4 0 Chemo, immuno, targeted 1 0 3 Unknown 13 0 13 Postoperative tumor size (cm) 9.6 (3.7) 9.7 (3.5) 9.3 (3.2) 0.768 Metastatic after surgery 42/122 (34.4) 58/94 (61.7) 19/39 (48.7) < 0.001 Metastatic ever 122/211 (57.8) 94/181 (51.9) 39 (68.4) 0.075 Initial number of metastatic sites 1.5 (1.1) 2.2 (1.2) 1.1 (0.6) < 0.001 Metastasis-free survival (months) 15.5 (25.8) 15.4 (21.9) 17.8 (23.7) 0.938 Overall survival (years) 1.9 (2.1) 1.3 (2) 3 (2.9) 0.012 Cancer-specific survival (years) 1.5 (1.5) 1.5 (1.3) 2.9 (2.9) 0.014 Dead 70 (33) 67 (32.1) 26 (45.6) 0.207 Cancer-specific death 46/53 (86.8) 28/54 (51.9) 21/26 (80.8) < 0.001 Follow-up (years) 3.9 (6.4) 2.7 (3.5) 3.4 (5.4) 0.023 Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 M. Sandberg, R. Vancavage, C. Marie-Costa, et al. 4 Figure 1). Mean age at surgery, gender, active smoking sta- tus, and Karnofsky performance status were not signifi- cantly different between the geographical regions (p > 0.05). CCI was greatest in NA patients (median-6) com- pared to both CSA (median-5) and South Korea (median-1; p < 0.001). BMI was significantly greater in NA patients compared to CSA and South Korean patients (29.3 versus 27.3 versus 23.4; p < 0.001). Race of the patients from each geographical region also was significantly different (p < 0.001). A greater percentage of patients were former smok- ers in NA (47.3%) and CSA (43.6%) in comparison to South Korea (21.1%; p = 0.002). DM was less prevalent in CSA patients (18.7%) relative to NA (30.7%) and South Korea (26.3%; p = 0.021). Hypertension was more preva- lent in NA patients (72.2%) compared to CSA and South Korea (p < 0.001). CKD was also more likely in NA patients (18.4%) compared to CSA and South Korea (p < 0.001). At diagnosis local symptoms were more likely in NA (69.3%) in comparison to CSA (46.9%) and South Korea (52.6%; p = 0.020). Metastatic symptoms were more common in NA (9%) and CSA (12%) relative to South Korea (0%; p = 0.007). Patients from NA (78.8%) and South Korea (59.6%) were more likely to undergo a pre- operative chest CT scan compared to CSA (38.8%; p < 0.001). Preoperative tumor size was significantly smaller in South Korea (8.4 cm) relative to NA (9.1 cm) and CSA (9.8 cm; p = 0.021). Thrombus level also differed by region, with a greater average thrombus level in CSA (p < 0.001). NA had the greatest percentage of patients metastatic at diagnosis (65.6%; p = 0.002). The most common location of metastases seen preoperatively was the retroperitoneum for NA (N = 16) and CSA (N = 16), and “other regions” for South Korea (N = 7). No differ- ence existed in the number of patients with multiple metastatic sites at presentation (p > 0.05). Operative approach also differed, with a significantly greater pro- portion of robotic cases in NA (43.1%) and a greater pro- portion of laparoscopic cases in CSA (35.1%) (Figure 2; Figure 1. Geographical Differences. The following figure shows each geographical region in the study: North America, Central/South America, and South Korea. Patients from the United States of America were labeled as “North America” in red, patients from South Korea were labeled as “South Korea” in blue, and all other regions were labeled as “Central/South America” in green. Relevant demographic, peri-, and post-operative differences are shown. The most common thrombus level, tumor stage, and tumor grade are provided for each region. The total number of metastatic patients pre- and post-operatively are also shown. Means for overall survival and cancer specific survival are represented with standard deviation in parentheses. Figure 2. Operative Approach by Geographical Region. The following figure shows all operations performed in each of the three geographical regions: North America, Central/South America, and South Korea. Each bar represents a specific operative approach, which was either open, laparoscopic, or robotic. Number of operations is on the y-axis and geographical region is on the x-axis. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 5 Renal cell carcinoma with tumor thrombus p < 0.001). Operative time and length of stay were simi- lar (p > 0.05). Tumor stage was different by geographic region, with a greater percentage of T3b patients (86%) in South Korea (p < 0.001). Tumor grade was also different by region, with a greater proportion of grade 4 RCC in CSA (p < 0.001). On pathology, sarcomatoid variants were significantly more prevalent in CSA (39.2%), com- pared to NA and South Korea (p < 0.001). Tumor necro- sis was most prevalent in NA patients (59.2%; p = 0.048). Tumor subtype was not different (p > 0.05). CSA had the lowest percentage of LN dissections performed (23.1%; p = 0.004). The median number of LNs positive for can- cer were similar (p > 0.05), and the median number of negative LNs was greatest in South Korea (median-5; p = 0.003). Soft tissue margin positivity was least likely in South Korean patients (1.8%; p < 0.001). CSA patients were significantly less likely to receive sys- temic therapy (26.8%) in comparison to NA (43.3%) and South Korean patients (52.6%; p < 0.001). The most common regimen was targeted therapy in NA (N = 24), CSA (N = 34), and South Korea (N = 12). Postoperative tumor size on gross specimen was similar by geographi- cal region (p > 0.05). The percentage of patients metasta- tic at any time in the study window and MFS was not dif- ferent (p > 0.05). The percentage of patients who went on to develop metastasis after surgery was highest in CSA (61.7%; p < 0.001). CSA patients had a greater number of initial metastatic sites (2.1) compared to the NA (1.5) and South Korea (1.1; p < 0.001). OS favored South Korean patients (3 years) in comparison to CSA (1.9 years) and on log-rank test this was significantly different (Figure 3; p = 0.026). No OS survival difference existed between South Korea and NA, nor NA and CSA (p > 0.05). CSS favored South Korean patients (2.9 years) compared to both NA (1.5 years) and CSA (1.5 years) and on log-rank test this was significantly different (Figure 3; p = 0.026). On Cox regression analysis for OS no significant differences were seen (Table 2 and Figure 4; p > 0.05) and for CSS, CSA patients had a significantly greater hazard (HR) of cancer- specific death (Table 3 and Figure 4; HR = 0.44; p = 0.015). Figure 3. Kaplan-Meier Survival Analysis by Geographical Region. The following figure represents a Kaplan-Meier survival analysis comparison between North American patients, Central/South American patients, and South Korean patients in the study for (A) - overall survival and (B) - cancer-specific survival, and (C) - metastasis-free survival. The proportion of patients surviving at each time interval is shown on the y-axis and time is represented on the x-axis in years or months. Log-rank significance p-values are shown below the figure legends. Number at risk tables of all patients experiencing the event of interest during the study are also provided below the graphs with censored patients in parentheses. Table 2. Cox Regression Analysis for Overall Survival. The following table is a cox regression analysis with death as the outcome of interest. S.E. is standard error, B represents the predicted hazard of the terminal event (death) and Exp(B) is the hazard ratio for each variable in the model. For geographical region, South Korea is the reference category and for approach, robotic surgery is the reference category. Associated p-values for each variable are also provided. Variable B S.E P-value Exp(B) Confidence interval Upper Lower Geographical region 0.14 North America 0.16 0.42 0.7 1.2 0.52 2.64 Central/South America -0.45 0.27 0.1 0.64 0.38 1.1 Thrombus level 0.29 0.11 0.008 1.3 1.08 1.67 Approach 0.83 Open 0.08 0.42 0.85 1.1 0.48 2.44 Laparoscopic 0.18 0.3 0.55 1.2 0.67 2.17 Tumor stage -0.01 0.16 0.95 1 0.73 1.34 Tumor grade 0.22 0.19 0.25 1.2 0.86 1.8 Sarcomatoid pathology 0.37 0.32 0.26 1.4 0.77 2.71 Metastatic anytime 0.37 0.31 0.23 1.4 0.79 2.66 Systemic therapy -0.8 0.27 0.003 0.45 0.27 0.77 Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 M. Sandberg, R. Vancavage, C. Marie-Costa, et al. 6 DISCUSSION Several important differences were identified in how patients presented prior to surgery with RCC-TT. BMI was greater in the NA cohort, which has been linked to an increased likelihood of RCC, but results are mixed with respect to survival, as some studies show a protective effect (14). Unsurprisingly, race differed by geographical region, and as stated it is also known to impact patient outcomes for RCC and RCC-TT (4, 15). Patients from NA and CSA were more likely to be former smokers, which is a well-established factor predisposing to poor survival in RCC (16). Despite a variety of comorbidities differing by region, Karnofsky performance status was equivalent, and is known to correlate with poor outcomes for RCC-TT (17). Interestingly, CSA patients had the lowest preva- lence of local symptoms at diagnosis but the highest rate of metastatic symptoms. This may indicate that these patients are more likely to present later in their disease course and fits with some publications showing a high rate of metastatic presentation for RCC in CSA countries (18). Nevertheless, NA patients had the highest percent- age of metastasis at presentation. CSA patients had a sig- nificantly lower likelihood of undergoing a chest CT pre- operatively, which should be done prior to surgery and is well-supported in the literature (19). This is of concern and the disparity is difficult to ascertain by current access to care alone. CT chest omission could be due in part to the large time span of the study including cases from 1999 onward where CT scan access and care guidelines were not as ubiquitous. Additionally, patients without a CT chest did have a chest x-ray in most instances. Nevertheless, this is one of the most significant discrep- ancies we identify in our study and requires additional investigation as to its causes. While the prognostic signif- icance of thrombus level remains controversial, NA and South Korea had the most patients with a level I throm- bus, and it has been shown that rates of abdominal imag- ing differ worldwide, potentially catching the thrombus before further spread to a higher level (7, 8). Peri-operative management/outcomes also differed by region. NA had the greatest percentage of robotic surgery and CSA had the greatest percentage of laparoscopic. While the open approach has traditionally been employed for RCC-TT, a robotic approach has been described with equivalent to superior postoperative out- comes (20). With the ubiquitous use of robotic access across academic centers in NA, it is unsurprising this region had the greatest rate of robotic surgery. Pure/hand- assist laparoscopy has also been reported on for RCC-TT, but its use may be greater and success better than what is Figure 4. Cox Regression Analysis for Overall Survival and Cancer-Specific Survival. The following figure represents the survival curve from the cox regression model for (A) - overall survival and (B) - cancer-specific survival. The proportion of patients surviving at each time interval based on the mean of covariates in the model is shown on the y-axis and time is represented on the x-axis in years. Table 2. Cox Regression Analysis for Cancer-specific Survival. The following table is a cox regression analysis with cancer-specific death as the outcome of interest. B represents the predicted hazard of the terminal event (death) and Exp(B) is the adjusted hazard ratio for each variable in the model. For geographical region, South Korea is the reference category and for approach, robotic surgery is the reference group. Associated p-values for each variable are also provided. Variable B S.E P-value Exp(B) Confidence interval Upper Lower Geographical region 0.053 North America -0.29 0.47 0.54 0.75 0.3 1.9 Central/South America -0.82 0.34 0.015 0.44 0.23 0.86 Thrombus level 0.003 0.13 0.98 1 0.77 1.3 Approach 0.98 Open -0.08 0.49 0.86 0.92 0.35 2.4 Laparoscopic 0.01 0.36 0.98 1 0.5 2.03 Tumor stage 0.19 0.18 0.3 1.2 0.84 1.73 Tumor grade 0.38 0.23 0.1 1.5 0.92 2.23 Sarcomatoid pathology -0.01 0.39 0.97 0.99 0.46 2.13 Metastatic anytime -0.81 0.42 0.06 0.45 0.2 1.02 Systemic therapy -0.95 0.31 0.002 0.39 0.21 0.71 Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 7 Renal cell carcinoma with tumor thrombus currently accepted, especially in CSA countries (21). A lower tumor stage was more prevalent in South Korea rel- ative to both NA and CSA. It is worth noting that CSS was greatest in South Korean patients and tumor stage is asso- ciated with poor survival for RCC and RCC-TT (22). Tumor grade was highest in CSA, a poor prognostic fac- tor for RCC-TT (23). Similarly, sarcomatoid variants were most common in CSA, which is linked to poor outcomes in patients treated surgically for RCC-TT (24). Rates of LN dissection were lowest in CSA, but the number of pos- itive nodes on pathology was similar by region. This is relevant as research shows the number of positive LNs after radical nephrectomy and tumor thrombectomy is independently associated with worse CSS (25). Multiple postoperative and survival outcomes differed by geography. The overall number of patients metastatic in the study window was similar, but there was a greater number of patients metastatic at presentation in NA and a greater number of metastatic sites at presentation in CSA. Further, CSA had the highest proportion of patients who developed metastasis after surgery. Despite these dif- ferences, MFS was similar amongst each region. This is particularly relevant as MFS has been shown to predict OS for RCC (26). In our population though, OS was not equivalent on primary analysis, and patients from South Korea had a significantly greater OS relative to CSA. CSS was also greatest in South Korean patients but whereas OS was greater only compared to CSA, CSS was greater than both CSA and NA. Tian et al. published on prognos- tic indicators for OS and CSS in RCC-TT patients, noting that lower tumor grade, lower tumor stage, lower throm- bus level, and the use of systemic therapy predicted bet- ter outcomes (23). South Korean patients had lower tumor stages in the study, and CSA patients had greater tumor grades and thrombus level, which appears to fall in line with Tian et al.’s findings. Moreover, systemic therapy utilization was not equivalent across each region, with CSA patients having the lowest usage. Importantly, access to systemic therapy clinical trials in RCC differs across the world, and patients with higher risk RCC are not as well represented in these trials in CSA (6, 9, 10). On Cox regression analysis, when controlling for variables like tumor stage, grade, and metastasis, most survival differ- ences disappeared, unsurprisingly showing that survival is multifactorial and additional factors besides geography are clearly at play. However, CSS was still worse in CSA, which is concerning and calls for further investigation. Several limitations are worth acknowledging in our analy- sis. While the multi-continental and diverse nature of our cohort is a strength, we rely on the fact that the medical records at each participating institution are correct and up to date with patient information. Further, our findings are subject to the inherent biases of any retrospective review, and every patient in the study did not necessarily have a complete set of data to include in statistical analy- sis. While the Cox regression attempted to control for confounding variables, we cannot fully control for the fact that each geographical regions’ demographic characteris- tics were not equivalent at baseline. In addition, NA, CSA, and South Korea are not homogeneous regions and there is variability in patient management within regions which we did not assess in this study. Despite using the same staging and grading systems for RCC, pathologist evalua- tion could have varied by both institution and geograph- ical region and may account for some of the differences seen in sarcomatoid, rhabdoid, and necrotic tumor fea- tures. We also recognize that the external validity of our results is limited by the institutions that submitted data to participate in this study, all of which are tertiary academ- ic centers. Nevertheless, we feel most cases of RCC-TT end up being referred to high-volume academic centers for definitive management and thus still see utility in our results. CONCLUSIONS This is one of the largest series of patients with RCC-TT in the literature, and one of the only publications to focus on geographical differences in presentation, man- agement, and outcomes using collaboration via the ICORCC database. Given the need for stronger emphasis on health equity worldwide, our findings are particular- ly timely. While multiple studies have examined demo- graphics such as race, gender, and functional status in RCC-TT, few have recognized how patient geography plays into this. A multifaceted approach should be taken to address the disparities we identify. There is no single fix to this complex patient population. However, what we do feel is that a global health emphasis on funding and investment in CSA is required to improve access to optimal patient care like systemic therapy, surgical robots, and the like. Moreover, new clinical trials need to be better about inclusion of patients and healthcare cen- ters around the globe, rather than just the United States. We hope this study sheds light on important regional dif- ferences in the interest of narrowing worldwide gaps in healthcare and achieving more equitable outcomes in RCC-TT for all. DECLARATIONS Ethical approval: The following study was approved by an insti- tutional review board on 5/16/2023 under IRB00096722. Availability of data and material: The data sets generated during and/or analyzed during the current study are not pub- licly available due patient privacy, but are available from the corresponding author on reasonable request. Competing interests: None. Funding: None. Authors' contributions: Project design: MS, RV, CMC, EY, MH, JM, RBD, KP, KW, BA, SB, PM, TM, CP, RM, PS, RZ, SC, SZ, DA, AR. Data collection: MS, RV, CMC, EY, MH, JM, RBD, KP, KW, BA, SB, PM, TM, RM, RZ, SC. Visualization: MS, RV, CMC, EY, MH, SB, PM, TM, CP, RM, PS, RZ, SC, SZ, DA, AR. Statistical analysis: MS, RV, CP, PS, RZ, SC, SZ, DA, AR. Validation: MS, CP, PS, SC, AR. Drafting manuscript original draft: MS, RV, CMC, EY, CP, PS, SZ, AR. Drafting manuscript editing draft: MS, RV, CMC, EY, MH, JM, RBD, KP, KW, BA, SB, PM, TM, CP, RM, PS, RZ, SC, SZ, DA, AR. Acknowledgments: None. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 M. Sandberg, R. Vancavage, C. Marie-Costa, et al. 8 REFERENCES 1. Almatari AL, Sathe A, Wideman L, et al. Renal cell carcinoma with tumor thrombus: A review of relevant anatomy and surgical techniques for the general urologist. Urol Oncol 2023; 41:153-165. 2. Tilki D, Hu B, Nguyen HG, et al. Impact of synchronous metasta- sis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy. J Urol. 2015; 193:436-42. 3. Tang Q, Song Y, Li X, et al. Prognostic outcomes and risk factors for patients with renal cell carcinoma and venous tumor thrombus after radical nephrectomy and thrombectomy: The prognostic significance of venous tumor thrombus level. Biomed Res Int. 2015; 2015:163423. 4. Anastos H, Martini A, Waingankar N, et al. Black race may be associated with worse overall survival in renal cell carcinoma patients. Urol. Oncol. 2020; 38:938.e9-938.e17. 5. Gupta A, Roy AM. Racial and Ethnic Disparities in Survival Outcomes of Metastatic Renal Cell Carcinoma Patients Receiving Immunotherapy. Clin Genitourin Cancer. 2024; 22:102104. 6. Cirillo L, Innocenti S, Becherucci F. Global epidemiology of kidney cancer. Nephrol Dial Transplant. 2024; 39:920-928. 7. Bukavina L, Bensalah K, Bray F, et al. Epidemiology of Renal Cell Carcinoma: 2022 Update. Eur Urol. 2022; 82:529-542. 8. Capitanio U, Bensalah K, Bex A, et al. Epidemiology of Renal Cell Carcinoma. Eur Urol. 2019; 75:74-84. 9. Padala SA, Barsouk A, Thandra KC, et al. Epidemiology of renal cell carcinoma. World J Oncol. 2020; 11:79-87. 10. Fay AP, McKay RR, Lin X, et al. Impact of geographic regions on overall survival in patients with metastatic renal cell carcinoma: Results from an international clinical trials database. J Glob Oncol. 2018; 2018:1-14. 11. Neves RJ, Zincke H. Surgical Treatment of Renal Cancer with Vena Cava Extension. Br J Urol. 1987; 59:390-5. 12. Brierley J.D., Gospodarowicz M.K., Wittekind C. TNM Classification of Malignant Tumours, 8th edition. Union for International Cancer Control. Published online 2017. https://www. uicc.org/resources/tnm-classification-malignant-tumours-8th-edition. 13. Delahunt B, Cheville JC, Martignoni G, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013; 37:1490-504. 14. Goebell PJ, Müller L, Hübner A, et al. Body mass index as inde- pendent predictor of overall survival in patients with advanced renal cell carcinoma at start of systemic treatment—Analyses from the German clinical RCC-Registry. Urol Oncol 2018; 36:433-472. 15. Dursun F, Patel R, Hui D, et al. The Latinx Disparity in Surgery for Kidney Cancer: Data from The South Texas Region. Kidney Cancer J. 2022; 20:6-13. 16. Xu Y, Qi Y, Zhang J, et al. The impact of smoking on survival in renal cell carcinoma: A systematic review and meta-analysis. Tumor Biol. 2014; 35:6633-40. 17. Kaptein FHJ, van der Hulle T, Braken SJE, et al. Prevalence, Treatment, and Prognosis of Tumor Thrombi in Renal Cell Carcinoma. JACC CardioOncol. 2022; 4:522-531. 18. Soares A, Monteiro FSM, da Trindade KM, et al. Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update. J Cancer Res Clin Oncol. 2024; 150:183. 19. Woodruff DY, Van Veldhuizen P, Muehlebach G, et al. The peri- operative management of an inferior vena caval tumor thrombus in patients with renal cell carcinoma. Urol. Oncol. 2013; 31:517-21. 20. Garg H, Psutka SP, Hakimi AA, et al. A Decade of Robotic-Assisted Radical Nephrectomy with Inferior Vena Cava Thrombectomy: A Systematic Review and Meta-Analysis of Perioperative Outcomes. J Urol. 2022; 208:542-560. 21. Sun Y, De Castro Abreu AL, Gill IS. Robotic inferior vena cava thrombus surgery: Novel strategies. Curr Opin Urol. 2014; 24:140-7. 22. Pandey J, Syed W. Renal Cancer. Treasure Island, FL:StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK558975/. Accessed September 14, 2024 23. Tian J, Zeng X, Guan W, et al. Prognostic indicators for survival in renal cell carcinoma with venous thrombus and development of predictive nomograms. Transl Androl Urol. 2022; 11:1374-1388. 24. Yang B, Xia H, Xu C, et al. Impact of sarcomatoid differentiation and rhabdoid differentiation on prognosis for renal cell carcinoma with vena caval tumour thrombus treated surgically. BMC Urol. 2020; 20:14. 25. Tilki D, Chandrasekar T, Capitanio U, et al. Impact of lymph node dissection at the time of radical nephrectomy with tumor thrombecto- my on oncological outcomes: Results from the International Renal Cell Carcinoma-Venous Thrombus Consortium (IRCC-VTC). Urol Oncol. 2018; 36:79.e11-79.e17. 26. Smith MR, Mehra M, Nair S, et al. Relationship Between Metastasis-free Survival and Overall Survival in Patients With Nonmetastatic Castration-resistant Prostate Cancer. Clin Genitourin Cancer. 2020; 18:e180-e189. Correspondence Maxwell Sandberg (Corresponding Author) maxwellsandberg@msn.com 950 N Trade Street, Winston Salem, NC, 27101, USA Rachel Vancavage vancavr@amc.edu Albany Medical College, Albany, NY, USA Claudia Marie-Costa cmcosta@wakehealth.edu Emily Ye ewye@wakehealth.edu Alejandro Rodriguez alrrodri@wakehealth.edu Wake Forest Baptist Medical Center, Winston Salem, NC, USA, 27157 Mitchell Hayes Mitchell.Hayes@moffitt.org Moffitt Cancer Institute, Tampa Bay, FL, USA Justin Miller justinmiller1@usf.edu University of South Florida School of Medicine, Tampa Bay, FL, USA Reuben Ben David Reuben.BenDavis@mountsinai.org Reza Mehrazin reza.mehrazin@mountsinai.org Icahn School of Medicine at Mount Sinai, New York, NY, USA Kartik Patel kartikp@uab.edu Brejjette Aljabi bnaljabi@uab.edu Archivio Italiano di Urologia e Andrologia 2025; 97(2):13820 9 Renal cell carcinoma with tumor thrombus Charles Peyton cpeyton@uabmc.edu University of Alabama Birmingham School of Medicine, Birmingham, AL, USA Kimberly Waggener kwaggene@wakehealth.edu Atrium Health Wake Forest Baptist Medical Center, Winston Salem, NC, USA, 27157 SeokSoon Byun seoksoo.byeon@gmail.com Seoul Bundang University Hospital, Seoul, South Korea Patricio García Marchiñena patricio.garcia@hospitalitaliano.org.ar Hospital Italiano, Buenos Aires, Argentina Thiago Mourao thiago.mourao@accamargo.org.br Rafael Zanotti rafael.zannotti@accamargo.org.br Stenio de Casio Zequi stenio.zequi@accamargo.org.br AC Camargo Cancer Institute, Sao Paulo, Brazil Philippe Spiess Philippe.Spiess@moffitt.org Moffitt Cancer Institute, Tampa Bay, FL, USA Steven Chang slchang@bwh.harvard.edu Harvard Medical School, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Division of Urology, 45 Francis Street, Boston, MA 02115, USA. Diego Abreu die.abreu@gmail.com Paseur Hospital, Division of Urology, Montevideo, Uruguay