- Email: [email protected]
Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study
EUF-885; No. of Pages 9 E U RO P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Kidney Cancer
Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study Angela Pecoraro a,b,*, Carlotta Palumbo a,c, Sophie Knipper a,d, Francesco A. Mistretta a,e, Giuseppe Rosiello a,f, Zhe Tian a, Pierre-Antoine St-Hilaire a,g, Shahrokh F. Shariat h, Fred Saad a,g, Luke Lavalle´e i, Alberto Briganti f, Anil Kapoor j, Cristian Fiori b, Francesco Porpiglia b, Pierre I. Karakiewicz a,g a
Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Quebec, Canada;
b
Department of Urology, San Luigi
Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy; c Urology Unit, ASST Spedali Civili of Brescia. Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Italy; d Martini Klinik, University Medical Center Hamburg-Eppendorf, Hamburg, Germany e Department of Urology, European Institute of Oncology, Milan, Italy; e Department of Urology, European Institute of Oncology, Milan, Italy; f Division of Experimental Oncology/Unit of Urology, Urological Research Institute (URI), IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; g Division of Urology, University of Montreal Hospital Center (CHUM), Montreal, Quebec, Canada; h Department of Urology, Medical University of Vienna, Vienna, Austria; i Division of Urology, The Ottawa Hospital, The University of Ottawa, Ottawa, Ontario, Canada; j Division of Urology, McMaster University, Hamilton, Ontario, Canada
Article info
Abstract
Article history: Accepted February 19, 2020
Background: Synchronous metastasis (SM) rates in T1 renal cell carcinoma (RCC) patients relied on historical cohorts and may not take into account the favorable stage migration toward lower tumor size (TS) that occurred in more recent years. Objective: To investigate SM rates in T1 RCC patients according to histological subtype (HS), tumor grade (TG), and TS. Intervention: Partial nephrectomy, radical nephrectomy, focal ablation, and non-interventional management. Outcome measurements and statistical analysis: Within the Surveillance, Epidemiology, and End Results database (2004–2015), 60 640 stage T1 patients were identified. SM rates were tabulated and tested in multivariable logistic regression models. Results and limitations: According to HS, average SM rates were 0%, 0.5%, 1.1%, 1.4%, 3.7%, 21.5%, and 36.2% for multilocular cystic, chromophobe, papillary, clear cell TG 1–2, clear cell TG 3–4, collecting duct, and sarcomatoid RCC, respectively. In a multivariate logistic regression model, age, TS, HS, and TG were independent predictors of SM. Bone only was the commonest metastatic site (41.0%), followed by lung only (24.5%), liver only (3.6%), and brain only (3.8%). Of all SM patients, 72.8% harbored a single metastatic site. The major limitations of this study are lack of recurrence and metastatic progression data. Conclusions: Within T1 RCC, it was possible to identify five metastatic risk categories according to SM rates: (1) multilocular cystic RCC (0%), (2) chromophobe RCC (0–2.0%), (3) clear cell TG 1–2 and papillary RCC, (4) clear cell TG 3–4 RCC (1.2–8.9%), and (5) sarcomatoid and collecting duct RCC (7.0–49.1%). The most frequent metastatic location is bone only, followed by lung only, and virtually all SMs are solitary. Patient summary: Metastatic rate varies in T1 stage renal cell carcinoma patients according to tumor size, histology, and tumor grade. © 2020 Published by Elsevier B.V. on behalf of European Association of Urology.
Associate Editor: Richard Lee Keywords: Renal cell carcinoma Tumor size Nephrectomy Metastasis Renal mass T1 stage
* Corresponding author. Department of Urology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy. Tel.: +39 347 467 0691; Fax: +39 011 902 6244. E-mail address: [email protected] (A. Pecoraro). https://doi.org/10.1016/j.euf.2020.02.011 2405-4569/© 2020 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 2
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
1.
Introduction[1,2]
Stage T1 renal cell carcinoma (RCC) represents a biologically heterogeneous group of tumors ranging from indolent to aggressive [1,2]. At diagnosis, tumor size (TS), histological subtype (HS), and tumor grade (TG) represent important prognostic factors [3–5]. To date, three studies examined synchronous metastasis (SM) rates in T1 patients [6–8]. However, these reports mostly focused on patients treated well before 2008 and some as early as 1988. In consequence, these findings may not be perfectly applicable to today’s patients. Specifically, these studies may not take into account the favorable stage migration toward lower TS at diagnosis that occurred in RCC patients of T1a and T1b substages [9–11]. Based on these considerations, we reexamined SM rates according to TS intervals of 10 mm in T1 RCC patients in a large contemporary population-based cohort. Moreover, we hypothesized that differences in SM rates may exist according to TG (TG 1–2 vs TG 3–4) and HS. Finally, we tested for specific location and number of SMs in the overall population and according to HS.
2.3.
Statistical analyses
Statistical analyses consisted of three analytical steps. First, we tabulated SM rates according to the year of diagnosis (1995–1999 vs 2000– 2004 vs 2005–2009 vs 2010–2015), as well as according to HS and TG (clear cell TG 1–2 vs clear cell TG 3–4 vs papillary vs chromophobe vs multilocular cystic vs sarcomatoid vs collecting duct RCC). Second, we fitted multivariable logistic regression (MLR) models predicting the presence of SM in the overall population and then in the subgroup of patients harboring clear cell HS. Covariates consisted of age at diagnosis (coded as continuous variable), marital status, ethnicity, TS (coded as continuous variable), and TG (G1, G2, G3, G4, and TG 1–2 and TG 3–4). Third, in the subgroup of patients treated between 2010 and 2015 with available information on the location and number of metastatic sites, additional tabulation of SM rates was performed according to HS. Descriptive statistics included frequencies and proportions for categorical variables. Means, medians, and ranges were reported for continuously coded variables. The chi-square test was used to assess the statistical significance in proportion differences. The t test and Kruskal-Wallis test examined the statistical significance of means and median differences, respectively, and the Cochran-Armitage test focused on statistical significance of trends in proportions. All statistical tests were two sided, with a level of significance set at p
2.
Patients and methods
< 0.05. Analyses were performed using the R software environment for statistical computing and graphics (version 3.4.1; http://www.r-project).
2.1.
Data source and patient selection
3.
Results
3.1.
Patient and tumor characteristics in the overall population
Within the Surveillance, Epidemiology, and End Results (SEER) database [12], we focused on patients diagnosed between 2005 and 2015, aged 18 yr or older with stage T1 RCC (International Classification of Disease for Oncology site codes C64.9), treated with partial nephrectomy ([PN] surgery code 30), radical nephrectomy ([RN] surgery code from 40 to 80), focal ablation ([FA] surgery code 10 and <30), and non-interventional management ([NIM] surgery code 00) as primary treatment. All autopsy or death certificate cases and patients with missing follow-up data, unknown metastatic status, and non–otherwise-specified histol-
The overall study population (Table 1) consisted of 60 640 patients: 25 661 (42.3%), 29 032 (47.9%), 3648 (6.0%), and 2299 (3.8%) patients were treated with PN, RN, FA, and NIM, respectively. Most were males (62.1%), harboring clear cell RCC (73.7%), T1a stage (66.1%), and G2 tumors (50.8%).
ogy (n = 12 573, 17.0%) were excluded. These selection criteria yielded 60 640 patients (Fig. 1A). Moreover, in order to compare contemporary SM
3.2.
rates (2005–2010) with more historical ones (1995–2004), we consid-
population
SM rates according to the year of diagnosis in the overall
ered the historical population of 14 030 T1 RCC patients diagnosed between 1995 and 2004, using the abovementioned selection criteria (Fig. 1B). Finally, two subgroup analyses were performed. The first subgroup consisted of clear cell RCC patients with available TG (n = 39 905). The second subgroup consisted of patients with available number and location of metastases, which became available as of
After stratification according to the year of diagnosis (Fig. 2), SM rates were 9.9%, 7.4%, 2.4%, and 2.3% for 1995–1999, 2000–2004, 2005–2009, and 2010–2015, respectively (trend <0.001).
2010 (n = 753).
3.3. 2.2.
Variables of interest
According to the consensus stage assignment, SMs were reported at the time of kidney cancer diagnosis or found during the initial staging workup prior to the first course of treatment. Moreover, SMs were defined as pathological M stage for patients who underwent biopsy of a metastatic
SM rates according to 10-mm TS intervals in the overall
population
According to 10-mm TS intervals (Fig. 3), SM rates ranging from 0.7% for 11–20 mm to 7.4% for 61–70 mm were 0.4%, 0.7%, 2%, and 30.8% in PN, FA, RN, and NIM patients, respectively (trend <0.001).
site at RCC diagnosis, but represented clinical M stage for those who did not undergo biopsy of a metastatic site. Assessment of SM rates was our
3.4.
SM rates according to HS in the overall population
primary endpoint. Risk variables consisted of TS that was stratified according to 10-mm intervals (from 11 to 70 mm) as well as year of diagnosis (1995–1999 vs 2000–2004 vs 2005–2009 vs 2010–2015), HS (clear cell, chromophobe, papillary, multilocular cystic RCC, sarcomatoid RCC, and collecting duct), TG (G1, G2, G3, and G4) for non–clear cell RCC patients, and TG (TG 1–2 vs TG 3–4) for clear cell RCC patients. Covariates consisted of age at diagnosis, gender, ethnicity, and marital status.
According to HS (Fig. 4), average SM rates were 0%, 0.5%, 1.1%, 1.4%, 3.7%, 21.5%, and 36.2% for multilocular cystic, chromophobe, papillary, clear cell TG 1–2, clear cell TG 3–4, collecting duct, and sarcomatoid RCC patients, respectively (trend <0.001).
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
A
3
30 739 renal cell carcinoma T1 stage patients identified with available information regarding type of treatment (partial nephrectomy, radical nephrectomy, focal ablation and non-interventional, management) within the surveillance, epidemiology and end results database (1995–2004)
Excluded (n= 16 709) • n = 120 bilateral renal masses • n = 1065 renal masses from 0 to 10 mm • n = 15 524 non-otherwise-specified renal cell circinoma
14 030 T1 stage patients eligible for the study
B 75,130 renal cell carcinoma T1 stage patients identified with available information regarding type of teratment (partial nephrectomy, radical nephrectomy, focal ablation and non-interventional management) within the surveillance, epidemiology and end results database (2005–2015)
Excluded (n= 14 490) • n = 43 bilateral renal masses • n = 1874 renal masses from 0 to 10 mm • n = 12 573 non-otherwise-specified renal cell circinoma
60 640 T1 stage patients eligible for the study Fig. 1 – (A) Consort diagram depicting the inclusion criteria of the historical population of 14 030 patients diagnosed with T1 renal cell carcinoma and treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management within the Surveillance, Epidemiology, and End Results database (1995–2004). (B) Consort diagram depicting the inclusion criteria for the main population study of 60 640 patients diagnosed with T1 renal cell carcinoma and treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management within the Surveillance, Epidemiology, and End Results database (2005–2015).
3.5.
SM rates according to 10-mm TS intervals, HS, and TG
In 570 multilocular cystic RCC patients, SM rate was zero. In 4206 chromophobe patients, SM rates ranged from 0.1% to 1.9% for TS intervals ranging from 11–20 to 61–70 mm. In 39 905 clear cell RCC patients with available information regarding TG (Fig. 5), SM rates ranged from 0.2% to 3.8% in clear cell TG 1–2 patients versus 1.2% to 8.9% in clear cell TG 3–4 patients, for the same 10-mm TS intervals. In 10 781 papillary RCC patients, SM rates ranged from 0.5% to
4.1% for the same TS intervals. Conversely, in 93 collecting duct RCC patients, SM rates ranged from 7.6% to 36.3% versus 28.5% to 49.1% in 279 sarcomatoid RCC patients, for the same 10-mm TS intervals (Fig. 5). 3.6.
MLR models predicting the presence of SMs in the overall
population and in the subgroup of clear cell RCC patients
Overall (n = 60 640), at the MLR model predicting the presence of SM (Table 2), age (odds ratio [OR]: 1.01), TS
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 4
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
Table 1 – Descriptive characteristics of 60 640 T1 renal cell carcinoma patients with (n = 1425, 2.3%) or without (n = 59 215, 97.7%) synchronous metastases, identified within the Surveillance, Epidemiology and End Results database (2005–2015). Variables
Synchronous metastases, n (%) Age (yr) Tumor size (mm) Gender, n (%) Ethnicity, n (%)
T stage, n (%) Tumor grade, n (%)
Type of treatment, n (%)
Renal cell carcinomahistological subtype, n (%)
Overall (n = 60 640)
Mean (standard error) Median (interquartile range) Mean (standard error) Median (interquartile range) Male Female Caucasian African American Other T1a T1b G1 G2 G3 G4 Unknown Partial nephrectomy Radical nephrectomy Focal ablation Non-interventional management Clear cell Chromophobe Papillary Sarcomatoid Collecting duct Multilocular cyst associated
1425 (2.3) 61 (0.05) 62 (53–70) 36 (0.06) 35 (25–46) 37 629 (62.1) 23 011 (37.9) 49 293 (81.3) 7230 (11.9) 4117 (6.8) 40 086 (66.1) 20 554 (33.9) 8025 (13.2) 30 797 (50.8) 11 980 (19.8) 1215 (2.0) 8623 (14.2) 25 661 (42.3) 29 032 (47.9) 3648 (6.0) 2299 (3.8) 44 711 (73.7) 4206 (6.9) 10 781 (17.8) 279 (0.5) 93 (0.2) 570 (0.9)
Fig. 2 – Rates of synchronous metastases in 74 670 T1 renal cell carcinoma patients treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management, identified within the Surveillance, Epidemiology, and End Results database, according to the year of diagnosis stratification (1995–1999 vs 2000–2004 vs 2005–2009 vs 2010–2015). Rates of synchronous metastases are expressed as a proportion between the number of individuals with synchronous metastases and the total count of individuals within each year of diagnosis stratification. Also shown are 95% confidence intervals around the rate of synchronous metastases within each year of diagnosis stratification.
(OR: 1.04), sarcomatoid (OR: 7.37), collecting duct HS (OR: 6.58), TG 3 (OR: 2.61), and TG 4 (OR: 4.62) were independent predictors of high SM rates (all p < 0.001). In 39 905 clear cell RCC patients, at MLR models predicting the presence of SM (Table 2), age (OR: 1.04), TS (OR: 1.05), as well as TG 3–4 (OR: 2.68) independently predicted higher SM rates (all p < 0.001).
3.7.
Location and number of metastatic sites according to HS
In 732 patients (Table 3) with SM and available site and location information, the site-specific rates were 41.0%, 24.5%, 3.6%, and 3.8% for bone only, lung only, liver only, and brain only, respectively. Virtually, the same rates were recorded in 576 metastatic clear cell RCC patients. Of
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
Fig. 3 – Rates of synchronous metastases in 60 640 T1 renal cell carcinoma patients treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management identified within the Surveillance, Epidemiology, and End Results database (2005–2015), according to tumor size intervals of 10 mm (from 11 to 70 mm). Rates of synchronous metastases are expressed as a proportion between the number of individuals with synchronous metastases and the total count of individuals within each tumor size interval. Also shown are 95% confidence intervals around the rate of synchronous metastases within each year of diagnosis intervals.
Fig. 4 – Rates of synchronous metastases in 60 640 T1 renal cell carcinoma patients treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management identified within the Surveillance, Epidemiology, and End Results database (2005–2015), according to histological subtypes such as chromophobe (n = 4206, 6.9%), clear cell TG 1–2 (n = 30 509, 76.4%), papillary (n = 10 781, 17.8%), clear cell TG 3–4 (n = 9396, 23.0%), collecting duct (n = 93, 0.2%), and sarcomatoid (n = 279, 0.5%) renal cell carcinoma. Rates of synchronous metastases are expressed as a proportion between the number of individuals with synchronous metastases and the total count of individuals within each histological subtype category. Also shown are 95% confidence intervals around the rate of synchronous metastases within each histological subtype category. TG = tumor grade.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
5
EUF-885; No. of Pages 9 6
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
Fig. 5 – Rates of synchronous metastases in 60 640 T1 renal cell carcinoma patients treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management identified within the Surveillance, Epidemiology, and End Results database (2005–2015), according to histological subtypes such as chromophobe (n = 4206, 6.9%), clear cell TG 1–2 (n = 30 509, 76.4%), papillary (n = 10 781, 17.8%), clear cell TG 3–4 (n = 9396, 23.0%), collecting duct (n = 93, 0.2%), and sarcomatoid (n = 279, 0.5%) renal cell carcinoma. Within each histological subtype, further stratification was made according to 10-mm tumor size intervals. Rates of synchronous metastases are expressed as a proportion between the number of individuals with synchronous metastases and the total count of individuals within each 10-mm tumor size interval for each histological subtype category. Also shown are 95% confidence intervals around the rate of synchronous metastases within each 10-mm tumor size interval for each histological subtype category. TG = tumor grade.
Table 2 – Multivariable logistic regression models predicting the presence of synchronous metastases in 60 640 T1 clear cell carcinoma patients treated with partial nephrectomy or radical nephrectomy or focal ablation or non-interventional management, and in 39 905 T1 clear cell renal cell carcinoma patients treated with partial nephrectomy or radical nephrectomy or focal ablation or non-interventional management identified within the Surveillance, Epidemiology, and End Results database between 2004 and 2015.a Variables
OR
CI (2.5–97.5 %)
Multivariable logistic regression models predicting synchronous metastases in overall population Age 1.01 1.00–1.02 1.04 1.03–1.05 Tumor size Tumor grade G1 1 (Ref.) – G2 1.11 0.85–1.46 2.61 2.00–3.44 G3 G4 4.62 3.30–6.50 Renal cell carcinoma histological subtype Clear cell 1 (Ref.) – 0.23 0.12–0.38 Chromophobe Papillary 0.56 0.44–0.70 Collecting duct 6.58 3.29–12.12 7.37 5.12–10.42 Sarcomatoid Multivariable logistic regression models predicting synchronous metastases in T1 clear cell renal cell carcinoma patients Age 1.04 1.00–1.05 1.05 1.04–1.06 Tumor size TG 1–2 1 (Ref.) – Tumor grade TG 3–4 3.10 2.63–3.65
p value
<0.001 <0.001 – 0.44 <0.001 <0.001 – <0.001
<0.001 <0.001 – <0.001
CI = confidence interval; OR = odds ratio; Ref. = reference; TG = tumor grade. Adjusted for: marital status, gender, and ethnicity.
a
10 metastatic chromophobe RCC patients, eight had one site involved and the sites were distributed as follows: bone only (five), lung only (one), liver only (one), and brain only (one). Of 72 metastatic papillary RCC patients, 56 had one metastatic site involved. Lung only (36.1%) represented the most frequent metastatic site, followed by bone only (27.8%), liver only (9.7%), and brain only (4.2%). Of 63 metastatic sarcomatoid RCC patients, 36 had one metastatic site involved. Bone only (34.9%) represented the most frequent metastatic site, followed by lung only (15.9%), liver only (3.2%), and brain only (3.2%). Finally, of 11 collecting duct patients, seven had two metastatic sites involved. A combination of lung and bone (54.5%) represented the most
frequent site, followed by a combination of bone with brain or liver (9.1%).
4.
Discussion
We re-examined SM rates according to TS intervals of 10 mm in T1 RCC patients in a large contemporary populationbased cohort. Moreover, we hypothesized that differences in SM rates may exist according to TS, TG (TG 1–2 vs TG 3–4), and HS. Finally, we tested for specific location and number of SMs in the overall population and according to HS. Our study resulted in several noteworthy findings.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 7
E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
Table 3 – Descriptive characteristics of 732 T1 renal cell carcinoma patients treated with partial nephrectomy or radical nephrectomy or focal ablation or non-interventional management, and with known number and location of metastasis sites according to histological subtype, identified within the Surveillance, Epidemiology, and End Results database (2010–2015). Renal cell carcinoma histological subtype
No. of metastatic sites, n (%) 1 site 2 sites 3 sites 4 sites Location of metastatic sites, n (%) Bone only Lung only Liver only Brain only Lung and bone Lung and brain or liver Bone and brain or liver Lung, bone, and liver or brain
Overall (n = 732)
Clear cell (n = 576)
Chromophobe (n = 10)
Papillary (n = 72)
Sarcomatoid (n = 63)
Collecting duct (n = 11)
533 (72.8) 152 (20.8) 42 (5.7) 5 (0.7)
430 (74.7) 112 (19.4) 30 (5.2) 4 (0.7)
8 2 0 0
(80.0) (20.0) (0) (0)
56 (77.8) 11 (15.3) 5 (6.9) 0 (0)
36 (57.1) 20 (31.7) 6 (9.5) 1 (1.6)
3 7 1 0
(27.3) (63.6) (9.1) (0)
300 (41.0) 179 (24.5) 26 (3.6) 28 (3.8) 85 (11.6) 30 (4.1) 37 (5.1) 47 (6.4)
252 (43.8) 140 (24.3) 16 (2.8) 22 (3.8) 67 (11.6) 26 (4.5) 19 (3.3) 34 (5.9)
5 1 1 1 1 0 1 0
(50.0) (10.0) (10.0) (10.0) (10.0) (0) (10.0) (0)
20 (27.8) 26 (36.1) 7 (9.7) 3 (4.2) 3 (4.2) 0 (0) 8 (11.1) 5 (6.9)
22 (34.9) 10 (15.9) 2 (3.2) 2 (3.2) 8 (12.7) 4 (6.3) 8 (12.7) 7 (11.1)
1 2 0 0 6 0 1 1
(9.1) (18.2) (0) (0) (54.5) (0) (9.1) (9.1)
First, the overall SM rate in T1 RCC population was 2.3% (Table 1). Conversely, according to more historical year of diagnosis (Fig. 2), we observed an almost fourfold increase in SM rates (9.9% for 1995–1999 and 7.4% for 2000–2004). Our findings are in agreement with more historical T1 RCC cohorts (from 1988 to 2008) that presented SM rates ranging from about 4.3% to 7.0% [6–8]. Our results confirmed our hypothesis that contemporary SM rates not only differ from the more historical cohort, but also are lower. Second, SM rates varied significantly according to HS and ranged from 0% (confidence interval: 0.00–0.05) for multilocular cystic RCC to 36.2% for sarcomatoid RCC. Similarly, in clear cell RCC, SM rates also varied according to TG (from 0.2% to 3.8% for TG 1–2 vs from 1.2% to 8.9% for TG 3–4). Finally, SMs also increased in proportion to TS. For example, in collecting duct RCC patients, SM rates increased from 7.8% for 11–20-mm TS interval up to 36.3% for 61–70-mm TS interval. Thanks to our findings, it was possible to identify four metastatic risk categories according to SM rates. The first SM risk category was represented by multilocular cystic RCC with zero SM rate. The second SM risk category accounted for chromophobe RCC alone, with SM rates ranging from 0.1% to 1.9%. The third SM risk category included both clear cell TG 1–2 and papillary RCC, with SM rates ranging from 0.2% to approximately 4.1%. The fourth SM risk category accounted for clear cell TG 3–4, with SM rates ranging from 1.2% to 8.9%. Finally, the fifth SM risk category recorded the highest SM rates: from 7.6% in collecting duct RCC patients up to 49.1% in sarcomatoid RCC patients. These observations support HS-specific stratification of SM rates. According to such a scheme, a different SM risk profile should be attributed to HS and associated TS within each HS category. A renal mass biopsy could allow such stratification if clinically indicated. These findings were also validated in the main population study (n = 60 640), as well as in the clear cell RCC subgroup (n = 39 905), with our MLR model that demonstrated independent predictor status of HS, TG, and TS.
Third, we identified a previously unreported pattern of distribution regarding the number and location of metastatic sites. Of 576 clear cell RCC patients, 74.7% harbored a solitary metastatic site and the most frequent metastatic site was bone only (43.8%), followed by lung only (24.3%), brain only (3.8%), and liver only (2.8%). Conversely, of 72 papillary RCC patients who accounted for the second highest absolute number of SM patients, 77.8% harbored a solitary metastatic site and lung only was the commonest metastatic site (36.1%), followed by bone only (27.8%), liver only (9.7%), and brain only (4.2%). Moreover, of 63 sarcomatoid RCC patients, 57.1% harbored a solitary metastatic site and the most frequent metastatic site was bone only (34.9%), followed by lung only (15.9%), liver only (3.2%), and brain only (3.2%). Finally, in chromophobe and collecting duct RCC, the number of low SM patients (10 and 11) precluded any generalizations. To the best of our knowledge, only two studies [13,14] reported the number and location of metastases, without specifically focusing on patients with T1 RCC. Our observations regarding the differences between clear cell RCC and papillary RCC metastatic distribution are novel, and have not been reported previously in T1 RCC patients. Taken together, this is the first study that reports SM rates in stage T1 RCC patients according to TS, HS, and TG. We proposed HS- and TS-specific stratification of SMs. Moreover, for clear cell RCC, we provided further stratification according to TG (TG 1–2 vs TG 3–4). Our stratification illustrates SM rates that range from 0.2% to 8.9%. Moreover, we show that in clear cell stage T1 RCC patients, bone only represents the commonest metastatic site versus lung only in papillary stage T1 RCC patients. Clinical implications of our findings are twofold. First, renal mass biopsy can provide HS information accurately [15–17]. Grade information can also be provided with virtually equal accuracy [15,16,17][15,16,117]. Therefore, systematic use of renal mass biopsy could risk stratify patients regarding the likelihood of SM, prior to any kind of treatment (PN vs RN vs FA vs NIM). Second, our findings also
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 8
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
allow most detailed risk stratification predicting the likelihood of SM after surgical or ablation treatment and could help with risk-based follow-up of patients according to HS, TG, and TS. Unfortunately, the specific elements of such workup cannot be defined or even recommended from the current study due to limited data on the location and number of SMs. Additionally, our findings may direct clinicians after nephrectomy or focal treatment to improve the accuracy of staging, especially for high-risk SM patients, such as those with T1 sarcomatoid RCC or T1 collecting duct. Despite its novelty, our study also has limitations. First, this study represents a retrospective analysis with high potential for selection biases, is unable to assess whether NIM patients were observed with an active surveillance protocol versus watchful waiting without intent for cure, lacks standardized specimen handling as well as a central review regarding HS, and has no information regarding nucleolar grade. Second, the SEER database does not give information regarding the type of surgical approach (laparoscopic vs robot assisted). In consequence, data could not have been stratified according to this characteristic. Third, the relationship of TS with benign disease could not be evaluated because the SEER database does not provide data regarding benign histology as well as data regarding subclassification of papillary HS (type 1 vs type 2). Fourth, the nature of the SEER database that relies on consensus stage assignment does not allow discrimination between clinical and pathological metastatic stage. Moreover, the type of metastatic workup aimed at identified SMs is unknown and may have varied according to clinicians. Additionally, the SEER data are unable to capture patient-reported symptoms. It is possible that symptom-based screening may capture some brain or bone metastases. However, those may predominantly reflect the prevalence of symptomatic metastases, without representing true rates of metastases. Fifth, no data regarding the exact tumor burden as the number and/or size of metastases for each metastatic site are available within the SEER database. Finally, SEER database reports sarcomatoid RCC as a separate RCC entity. Moreover, the percentage of the sarcomatoid component or the subtype of the epithelioid component (clear cell vs non–clear cell) was not available in the database, and this might limit the generability of our results regarding this specific HS.
Study concept and design: Pecoraro, Palumbo, Mistretta, Knipper, Rosiello, St-Hilaire, Karakiewicz. Acquisition of data: Pecoraro, Tian. Analysis and interpretation of data: Pecoraro, Palumbo, Mistretta, Knipper, Rosiello, St-Hilaire, Karakiewicz. Drafting of the manuscript: Pecoraro, Karakiewicz. Critical revision of the manuscript for important intellectual content: Shariat, Saad, Briganti, Lavallée, Kapoor, Fiori, Porpiglia, Karakiewicz. Statistical analysis: Pecoraro, Tian. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Karakiewicz. Other: None. Financial disclosures: Angela Pecoraro certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
References [1] Kutikov A, Fossett LK, Ramchandani P, et al. Incidence of benign pathologic findings at partial nephrectomy for solitary renal mass presumed to be renal cell carcinoma on preoperative imaging. Urology 2006;68:737–40. [2] Thompson RH, Hill JR, Babayev Y, et al. Metastatic renal cell carcinoma risk according to tumor size. J Urol 2009;182:41–5. [3] Kim SP, Campbell SC, Gill I, et al. Collaborative review of risk benefit trade-offs between partial and radical nephrectomy in the management of anatomically complex renal masses. Eur Urol 2017;72:64–75. [4] Gershman B, Thompson RH, Boorjian SA, et al. Radical versus partial nephrectomy for cT1 renal cell carcinoma. Eur Urol 2018;74:825–32. [5] Lane BR, Golan S, Eggener S, et al. Differential use of partial nephrectomy for intermediate and high complexity tumors may explain variability in reported utilization rates. J Urol 2013;189: 2047–53. [6] Klatte T, Patard J-J, de Martino M, et al. Tumor size does not predict risk of metastatic disease or prognosis of small renal cell carcinomas. J Urol 2008;179:1719–26. [7] Guðmundsson E, Hellborg H, Lundstam S, et al. Metastatic potential in renal cell carcinomas 7cm: Swedish Kidney Cancer Quality Register data. Eur Urol 2011;60:975–82. [8] Lughezzani G, Jeldres C, Isbarn H, et al. Tumor size is a determinant of the rate of stage T1 renal cell cancer synchronous metastasis. J Urol 2009;182:1287–93.
5.
Conclusions
Within T1 RCC, it was possible to identify five metastatic risk categories according to SM rates: (1) multilocular cystic RCC (0%), (2) chromophobe RCC (0–2.0%), (3) clear cell TG 1– 2 and papillary RCC, (4) clear cell TG 3–4 RCC (1.2–8.9%), and (5) sarcomatoid and collecting duct RCC (7.0–49.1%). The most frequent metastatic location is bone only, followed by lung only, and virtually all SMs are solitary.
[9] Patel HD, Gupta M, Joice GA, et al. Clinical stage migration and survival for renal cell carcinoma in the United States. Eur Urol Oncol 2019;2:343–8. [10] Gandaglia G, Ravi P, Abdollah F, et al. Contemporary incidence and mortality rates of kidney cancer in the United States. J Can Urol Assoc 2014;8:247–52. [11] Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer 2008;113:78–83. [12] National Cancer Institute. Overview of the SEER program. National Cancer Institute Web site. https://seer.cancer.gov/about/overview. html.
Author contributions: Angela Pecoraro had full access to all the data in
[13] Bianchi M, Sun M, Jeldres C, et al. Distribution of metastatic sites in
the study and takes responsibility for the integrity of the data and the
renal cell carcinoma: a population-based analysis. Ann Oncol
accuracy of the data analysis.
2012;23:973–80.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
9
[14] Chandrasekar T, Klaassen Z, Goldberg H, Kulkarni GS, Hamilton RJ,
[16] Richard PO, Jewett MAS, Tanguay S, et al. Safety, reliability and
Fleshner NE. Metastatic renal cell carcinoma: Patterns and predic-
accuracy of small renal tumour biopsies: results from a multi-
tors of metastases—a contemporary population-based series. Urol Oncol Semin Orig Investig 2017;35, 661. e7–14.. [15] Millet I, Curros F, Serre I, Taourel P, Thuret R. Can renal biopsy accurately predict histological subtype and Fuhrman grade of renal
institution registry. BJU Int 2017;119:543–9. [17] Richard PO, Jewett MAS, Bhatt JR, et al. Renal tumor biopsy for small renal masses: a single-center 13-year experience. Eur Urol 2015;68:1007–13.
cell carcinoma? J Urol 2012;188:1690–4.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Kidney Cancer
Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study Angela Pecoraro a,b,*, Carlotta Palumbo a,c, Sophie Knipper a,d, Francesco A. Mistretta a,e, Giuseppe Rosiello a,f, Zhe Tian a, Pierre-Antoine St-Hilaire a,g, Shahrokh F. Shariat h, Fred Saad a,g, Luke Lavalle´e i, Alberto Briganti f, Anil Kapoor j, Cristian Fiori b, Francesco Porpiglia b, Pierre I. Karakiewicz a,g a
Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Quebec, Canada;
b
Department of Urology, San Luigi
Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy; c Urology Unit, ASST Spedali Civili of Brescia. Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Italy; d Martini Klinik, University Medical Center Hamburg-Eppendorf, Hamburg, Germany e Department of Urology, European Institute of Oncology, Milan, Italy; e Department of Urology, European Institute of Oncology, Milan, Italy; f Division of Experimental Oncology/Unit of Urology, Urological Research Institute (URI), IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; g Division of Urology, University of Montreal Hospital Center (CHUM), Montreal, Quebec, Canada; h Department of Urology, Medical University of Vienna, Vienna, Austria; i Division of Urology, The Ottawa Hospital, The University of Ottawa, Ottawa, Ontario, Canada; j Division of Urology, McMaster University, Hamilton, Ontario, Canada
Article info
Abstract
Article history: Accepted February 19, 2020
Background: Synchronous metastasis (SM) rates in T1 renal cell carcinoma (RCC) patients relied on historical cohorts and may not take into account the favorable stage migration toward lower tumor size (TS) that occurred in more recent years. Objective: To investigate SM rates in T1 RCC patients according to histological subtype (HS), tumor grade (TG), and TS. Intervention: Partial nephrectomy, radical nephrectomy, focal ablation, and non-interventional management. Outcome measurements and statistical analysis: Within the Surveillance, Epidemiology, and End Results database (2004–2015), 60 640 stage T1 patients were identified. SM rates were tabulated and tested in multivariable logistic regression models. Results and limitations: According to HS, average SM rates were 0%, 0.5%, 1.1%, 1.4%, 3.7%, 21.5%, and 36.2% for multilocular cystic, chromophobe, papillary, clear cell TG 1–2, clear cell TG 3–4, collecting duct, and sarcomatoid RCC, respectively. In a multivariate logistic regression model, age, TS, HS, and TG were independent predictors of SM. Bone only was the commonest metastatic site (41.0%), followed by lung only (24.5%), liver only (3.6%), and brain only (3.8%). Of all SM patients, 72.8% harbored a single metastatic site. The major limitations of this study are lack of recurrence and metastatic progression data. Conclusions: Within T1 RCC, it was possible to identify five metastatic risk categories according to SM rates: (1) multilocular cystic RCC (0%), (2) chromophobe RCC (0–2.0%), (3) clear cell TG 1–2 and papillary RCC, (4) clear cell TG 3–4 RCC (1.2–8.9%), and (5) sarcomatoid and collecting duct RCC (7.0–49.1%). The most frequent metastatic location is bone only, followed by lung only, and virtually all SMs are solitary. Patient summary: Metastatic rate varies in T1 stage renal cell carcinoma patients according to tumor size, histology, and tumor grade. © 2020 Published by Elsevier B.V. on behalf of European Association of Urology.
Associate Editor: Richard Lee Keywords: Renal cell carcinoma Tumor size Nephrectomy Metastasis Renal mass T1 stage
* Corresponding author. Department of Urology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy. Tel.: +39 347 467 0691; Fax: +39 011 902 6244. E-mail address: [email protected] (A. Pecoraro). https://doi.org/10.1016/j.euf.2020.02.011 2405-4569/© 2020 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 2
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
1.
Introduction[1,2]
Stage T1 renal cell carcinoma (RCC) represents a biologically heterogeneous group of tumors ranging from indolent to aggressive [1,2]. At diagnosis, tumor size (TS), histological subtype (HS), and tumor grade (TG) represent important prognostic factors [3–5]. To date, three studies examined synchronous metastasis (SM) rates in T1 patients [6–8]. However, these reports mostly focused on patients treated well before 2008 and some as early as 1988. In consequence, these findings may not be perfectly applicable to today’s patients. Specifically, these studies may not take into account the favorable stage migration toward lower TS at diagnosis that occurred in RCC patients of T1a and T1b substages [9–11]. Based on these considerations, we reexamined SM rates according to TS intervals of 10 mm in T1 RCC patients in a large contemporary population-based cohort. Moreover, we hypothesized that differences in SM rates may exist according to TG (TG 1–2 vs TG 3–4) and HS. Finally, we tested for specific location and number of SMs in the overall population and according to HS.
2.3.
Statistical analyses
Statistical analyses consisted of three analytical steps. First, we tabulated SM rates according to the year of diagnosis (1995–1999 vs 2000– 2004 vs 2005–2009 vs 2010–2015), as well as according to HS and TG (clear cell TG 1–2 vs clear cell TG 3–4 vs papillary vs chromophobe vs multilocular cystic vs sarcomatoid vs collecting duct RCC). Second, we fitted multivariable logistic regression (MLR) models predicting the presence of SM in the overall population and then in the subgroup of patients harboring clear cell HS. Covariates consisted of age at diagnosis (coded as continuous variable), marital status, ethnicity, TS (coded as continuous variable), and TG (G1, G2, G3, G4, and TG 1–2 and TG 3–4). Third, in the subgroup of patients treated between 2010 and 2015 with available information on the location and number of metastatic sites, additional tabulation of SM rates was performed according to HS. Descriptive statistics included frequencies and proportions for categorical variables. Means, medians, and ranges were reported for continuously coded variables. The chi-square test was used to assess the statistical significance in proportion differences. The t test and Kruskal-Wallis test examined the statistical significance of means and median differences, respectively, and the Cochran-Armitage test focused on statistical significance of trends in proportions. All statistical tests were two sided, with a level of significance set at p
2.
Patients and methods
< 0.05. Analyses were performed using the R software environment for statistical computing and graphics (version 3.4.1; http://www.r-project).
2.1.
Data source and patient selection
3.
Results
3.1.
Patient and tumor characteristics in the overall population
Within the Surveillance, Epidemiology, and End Results (SEER) database [12], we focused on patients diagnosed between 2005 and 2015, aged 18 yr or older with stage T1 RCC (International Classification of Disease for Oncology site codes C64.9), treated with partial nephrectomy ([PN] surgery code 30), radical nephrectomy ([RN] surgery code from 40 to 80), focal ablation ([FA] surgery code 10 and <30), and non-interventional management ([NIM] surgery code 00) as primary treatment. All autopsy or death certificate cases and patients with missing follow-up data, unknown metastatic status, and non–otherwise-specified histol-
The overall study population (Table 1) consisted of 60 640 patients: 25 661 (42.3%), 29 032 (47.9%), 3648 (6.0%), and 2299 (3.8%) patients were treated with PN, RN, FA, and NIM, respectively. Most were males (62.1%), harboring clear cell RCC (73.7%), T1a stage (66.1%), and G2 tumors (50.8%).
ogy (n = 12 573, 17.0%) were excluded. These selection criteria yielded 60 640 patients (Fig. 1A). Moreover, in order to compare contemporary SM
3.2.
rates (2005–2010) with more historical ones (1995–2004), we consid-
population
SM rates according to the year of diagnosis in the overall
ered the historical population of 14 030 T1 RCC patients diagnosed between 1995 and 2004, using the abovementioned selection criteria (Fig. 1B). Finally, two subgroup analyses were performed. The first subgroup consisted of clear cell RCC patients with available TG (n = 39 905). The second subgroup consisted of patients with available number and location of metastases, which became available as of
After stratification according to the year of diagnosis (Fig. 2), SM rates were 9.9%, 7.4%, 2.4%, and 2.3% for 1995–1999, 2000–2004, 2005–2009, and 2010–2015, respectively (trend <0.001).
2010 (n = 753).
3.3. 2.2.
Variables of interest
According to the consensus stage assignment, SMs were reported at the time of kidney cancer diagnosis or found during the initial staging workup prior to the first course of treatment. Moreover, SMs were defined as pathological M stage for patients who underwent biopsy of a metastatic
SM rates according to 10-mm TS intervals in the overall
population
According to 10-mm TS intervals (Fig. 3), SM rates ranging from 0.7% for 11–20 mm to 7.4% for 61–70 mm were 0.4%, 0.7%, 2%, and 30.8% in PN, FA, RN, and NIM patients, respectively (trend <0.001).
site at RCC diagnosis, but represented clinical M stage for those who did not undergo biopsy of a metastatic site. Assessment of SM rates was our
3.4.
SM rates according to HS in the overall population
primary endpoint. Risk variables consisted of TS that was stratified according to 10-mm intervals (from 11 to 70 mm) as well as year of diagnosis (1995–1999 vs 2000–2004 vs 2005–2009 vs 2010–2015), HS (clear cell, chromophobe, papillary, multilocular cystic RCC, sarcomatoid RCC, and collecting duct), TG (G1, G2, G3, and G4) for non–clear cell RCC patients, and TG (TG 1–2 vs TG 3–4) for clear cell RCC patients. Covariates consisted of age at diagnosis, gender, ethnicity, and marital status.
According to HS (Fig. 4), average SM rates were 0%, 0.5%, 1.1%, 1.4%, 3.7%, 21.5%, and 36.2% for multilocular cystic, chromophobe, papillary, clear cell TG 1–2, clear cell TG 3–4, collecting duct, and sarcomatoid RCC patients, respectively (trend <0.001).
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
A
3
30 739 renal cell carcinoma T1 stage patients identified with available information regarding type of treatment (partial nephrectomy, radical nephrectomy, focal ablation and non-interventional, management) within the surveillance, epidemiology and end results database (1995–2004)
Excluded (n= 16 709) • n = 120 bilateral renal masses • n = 1065 renal masses from 0 to 10 mm • n = 15 524 non-otherwise-specified renal cell circinoma
14 030 T1 stage patients eligible for the study
B 75,130 renal cell carcinoma T1 stage patients identified with available information regarding type of teratment (partial nephrectomy, radical nephrectomy, focal ablation and non-interventional management) within the surveillance, epidemiology and end results database (2005–2015)
Excluded (n= 14 490) • n = 43 bilateral renal masses • n = 1874 renal masses from 0 to 10 mm • n = 12 573 non-otherwise-specified renal cell circinoma
60 640 T1 stage patients eligible for the study Fig. 1 – (A) Consort diagram depicting the inclusion criteria of the historical population of 14 030 patients diagnosed with T1 renal cell carcinoma and treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management within the Surveillance, Epidemiology, and End Results database (1995–2004). (B) Consort diagram depicting the inclusion criteria for the main population study of 60 640 patients diagnosed with T1 renal cell carcinoma and treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management within the Surveillance, Epidemiology, and End Results database (2005–2015).
3.5.
SM rates according to 10-mm TS intervals, HS, and TG
In 570 multilocular cystic RCC patients, SM rate was zero. In 4206 chromophobe patients, SM rates ranged from 0.1% to 1.9% for TS intervals ranging from 11–20 to 61–70 mm. In 39 905 clear cell RCC patients with available information regarding TG (Fig. 5), SM rates ranged from 0.2% to 3.8% in clear cell TG 1–2 patients versus 1.2% to 8.9% in clear cell TG 3–4 patients, for the same 10-mm TS intervals. In 10 781 papillary RCC patients, SM rates ranged from 0.5% to
4.1% for the same TS intervals. Conversely, in 93 collecting duct RCC patients, SM rates ranged from 7.6% to 36.3% versus 28.5% to 49.1% in 279 sarcomatoid RCC patients, for the same 10-mm TS intervals (Fig. 5). 3.6.
MLR models predicting the presence of SMs in the overall
population and in the subgroup of clear cell RCC patients
Overall (n = 60 640), at the MLR model predicting the presence of SM (Table 2), age (odds ratio [OR]: 1.01), TS
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 4
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
Table 1 – Descriptive characteristics of 60 640 T1 renal cell carcinoma patients with (n = 1425, 2.3%) or without (n = 59 215, 97.7%) synchronous metastases, identified within the Surveillance, Epidemiology and End Results database (2005–2015). Variables
Synchronous metastases, n (%) Age (yr) Tumor size (mm) Gender, n (%) Ethnicity, n (%)
T stage, n (%) Tumor grade, n (%)
Type of treatment, n (%)
Renal cell carcinomahistological subtype, n (%)
Overall (n = 60 640)
Mean (standard error) Median (interquartile range) Mean (standard error) Median (interquartile range) Male Female Caucasian African American Other T1a T1b G1 G2 G3 G4 Unknown Partial nephrectomy Radical nephrectomy Focal ablation Non-interventional management Clear cell Chromophobe Papillary Sarcomatoid Collecting duct Multilocular cyst associated
1425 (2.3) 61 (0.05) 62 (53–70) 36 (0.06) 35 (25–46) 37 629 (62.1) 23 011 (37.9) 49 293 (81.3) 7230 (11.9) 4117 (6.8) 40 086 (66.1) 20 554 (33.9) 8025 (13.2) 30 797 (50.8) 11 980 (19.8) 1215 (2.0) 8623 (14.2) 25 661 (42.3) 29 032 (47.9) 3648 (6.0) 2299 (3.8) 44 711 (73.7) 4206 (6.9) 10 781 (17.8) 279 (0.5) 93 (0.2) 570 (0.9)
Fig. 2 – Rates of synchronous metastases in 74 670 T1 renal cell carcinoma patients treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management, identified within the Surveillance, Epidemiology, and End Results database, according to the year of diagnosis stratification (1995–1999 vs 2000–2004 vs 2005–2009 vs 2010–2015). Rates of synchronous metastases are expressed as a proportion between the number of individuals with synchronous metastases and the total count of individuals within each year of diagnosis stratification. Also shown are 95% confidence intervals around the rate of synchronous metastases within each year of diagnosis stratification.
(OR: 1.04), sarcomatoid (OR: 7.37), collecting duct HS (OR: 6.58), TG 3 (OR: 2.61), and TG 4 (OR: 4.62) were independent predictors of high SM rates (all p < 0.001). In 39 905 clear cell RCC patients, at MLR models predicting the presence of SM (Table 2), age (OR: 1.04), TS (OR: 1.05), as well as TG 3–4 (OR: 2.68) independently predicted higher SM rates (all p < 0.001).
3.7.
Location and number of metastatic sites according to HS
In 732 patients (Table 3) with SM and available site and location information, the site-specific rates were 41.0%, 24.5%, 3.6%, and 3.8% for bone only, lung only, liver only, and brain only, respectively. Virtually, the same rates were recorded in 576 metastatic clear cell RCC patients. Of
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
Fig. 3 – Rates of synchronous metastases in 60 640 T1 renal cell carcinoma patients treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management identified within the Surveillance, Epidemiology, and End Results database (2005–2015), according to tumor size intervals of 10 mm (from 11 to 70 mm). Rates of synchronous metastases are expressed as a proportion between the number of individuals with synchronous metastases and the total count of individuals within each tumor size interval. Also shown are 95% confidence intervals around the rate of synchronous metastases within each year of diagnosis intervals.
Fig. 4 – Rates of synchronous metastases in 60 640 T1 renal cell carcinoma patients treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management identified within the Surveillance, Epidemiology, and End Results database (2005–2015), according to histological subtypes such as chromophobe (n = 4206, 6.9%), clear cell TG 1–2 (n = 30 509, 76.4%), papillary (n = 10 781, 17.8%), clear cell TG 3–4 (n = 9396, 23.0%), collecting duct (n = 93, 0.2%), and sarcomatoid (n = 279, 0.5%) renal cell carcinoma. Rates of synchronous metastases are expressed as a proportion between the number of individuals with synchronous metastases and the total count of individuals within each histological subtype category. Also shown are 95% confidence intervals around the rate of synchronous metastases within each histological subtype category. TG = tumor grade.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
5
EUF-885; No. of Pages 9 6
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
Fig. 5 – Rates of synchronous metastases in 60 640 T1 renal cell carcinoma patients treated with partial nephrectomy, radical nephrectomy, focal ablation, or non-interventional management identified within the Surveillance, Epidemiology, and End Results database (2005–2015), according to histological subtypes such as chromophobe (n = 4206, 6.9%), clear cell TG 1–2 (n = 30 509, 76.4%), papillary (n = 10 781, 17.8%), clear cell TG 3–4 (n = 9396, 23.0%), collecting duct (n = 93, 0.2%), and sarcomatoid (n = 279, 0.5%) renal cell carcinoma. Within each histological subtype, further stratification was made according to 10-mm tumor size intervals. Rates of synchronous metastases are expressed as a proportion between the number of individuals with synchronous metastases and the total count of individuals within each 10-mm tumor size interval for each histological subtype category. Also shown are 95% confidence intervals around the rate of synchronous metastases within each 10-mm tumor size interval for each histological subtype category. TG = tumor grade.
Table 2 – Multivariable logistic regression models predicting the presence of synchronous metastases in 60 640 T1 clear cell carcinoma patients treated with partial nephrectomy or radical nephrectomy or focal ablation or non-interventional management, and in 39 905 T1 clear cell renal cell carcinoma patients treated with partial nephrectomy or radical nephrectomy or focal ablation or non-interventional management identified within the Surveillance, Epidemiology, and End Results database between 2004 and 2015.a Variables
OR
CI (2.5–97.5 %)
Multivariable logistic regression models predicting synchronous metastases in overall population Age 1.01 1.00–1.02 1.04 1.03–1.05 Tumor size Tumor grade G1 1 (Ref.) – G2 1.11 0.85–1.46 2.61 2.00–3.44 G3 G4 4.62 3.30–6.50 Renal cell carcinoma histological subtype Clear cell 1 (Ref.) – 0.23 0.12–0.38 Chromophobe Papillary 0.56 0.44–0.70 Collecting duct 6.58 3.29–12.12 7.37 5.12–10.42 Sarcomatoid Multivariable logistic regression models predicting synchronous metastases in T1 clear cell renal cell carcinoma patients Age 1.04 1.00–1.05 1.05 1.04–1.06 Tumor size TG 1–2 1 (Ref.) – Tumor grade TG 3–4 3.10 2.63–3.65
p value
<0.001 <0.001 – 0.44 <0.001 <0.001 – <0.001
<0.001 <0.001 – <0.001
CI = confidence interval; OR = odds ratio; Ref. = reference; TG = tumor grade. Adjusted for: marital status, gender, and ethnicity.
a
10 metastatic chromophobe RCC patients, eight had one site involved and the sites were distributed as follows: bone only (five), lung only (one), liver only (one), and brain only (one). Of 72 metastatic papillary RCC patients, 56 had one metastatic site involved. Lung only (36.1%) represented the most frequent metastatic site, followed by bone only (27.8%), liver only (9.7%), and brain only (4.2%). Of 63 metastatic sarcomatoid RCC patients, 36 had one metastatic site involved. Bone only (34.9%) represented the most frequent metastatic site, followed by lung only (15.9%), liver only (3.2%), and brain only (3.2%). Finally, of 11 collecting duct patients, seven had two metastatic sites involved. A combination of lung and bone (54.5%) represented the most
frequent site, followed by a combination of bone with brain or liver (9.1%).
4.
Discussion
We re-examined SM rates according to TS intervals of 10 mm in T1 RCC patients in a large contemporary populationbased cohort. Moreover, we hypothesized that differences in SM rates may exist according to TS, TG (TG 1–2 vs TG 3–4), and HS. Finally, we tested for specific location and number of SMs in the overall population and according to HS. Our study resulted in several noteworthy findings.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 7
E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
Table 3 – Descriptive characteristics of 732 T1 renal cell carcinoma patients treated with partial nephrectomy or radical nephrectomy or focal ablation or non-interventional management, and with known number and location of metastasis sites according to histological subtype, identified within the Surveillance, Epidemiology, and End Results database (2010–2015). Renal cell carcinoma histological subtype
No. of metastatic sites, n (%) 1 site 2 sites 3 sites 4 sites Location of metastatic sites, n (%) Bone only Lung only Liver only Brain only Lung and bone Lung and brain or liver Bone and brain or liver Lung, bone, and liver or brain
Overall (n = 732)
Clear cell (n = 576)
Chromophobe (n = 10)
Papillary (n = 72)
Sarcomatoid (n = 63)
Collecting duct (n = 11)
533 (72.8) 152 (20.8) 42 (5.7) 5 (0.7)
430 (74.7) 112 (19.4) 30 (5.2) 4 (0.7)
8 2 0 0
(80.0) (20.0) (0) (0)
56 (77.8) 11 (15.3) 5 (6.9) 0 (0)
36 (57.1) 20 (31.7) 6 (9.5) 1 (1.6)
3 7 1 0
(27.3) (63.6) (9.1) (0)
300 (41.0) 179 (24.5) 26 (3.6) 28 (3.8) 85 (11.6) 30 (4.1) 37 (5.1) 47 (6.4)
252 (43.8) 140 (24.3) 16 (2.8) 22 (3.8) 67 (11.6) 26 (4.5) 19 (3.3) 34 (5.9)
5 1 1 1 1 0 1 0
(50.0) (10.0) (10.0) (10.0) (10.0) (0) (10.0) (0)
20 (27.8) 26 (36.1) 7 (9.7) 3 (4.2) 3 (4.2) 0 (0) 8 (11.1) 5 (6.9)
22 (34.9) 10 (15.9) 2 (3.2) 2 (3.2) 8 (12.7) 4 (6.3) 8 (12.7) 7 (11.1)
1 2 0 0 6 0 1 1
(9.1) (18.2) (0) (0) (54.5) (0) (9.1) (9.1)
First, the overall SM rate in T1 RCC population was 2.3% (Table 1). Conversely, according to more historical year of diagnosis (Fig. 2), we observed an almost fourfold increase in SM rates (9.9% for 1995–1999 and 7.4% for 2000–2004). Our findings are in agreement with more historical T1 RCC cohorts (from 1988 to 2008) that presented SM rates ranging from about 4.3% to 7.0% [6–8]. Our results confirmed our hypothesis that contemporary SM rates not only differ from the more historical cohort, but also are lower. Second, SM rates varied significantly according to HS and ranged from 0% (confidence interval: 0.00–0.05) for multilocular cystic RCC to 36.2% for sarcomatoid RCC. Similarly, in clear cell RCC, SM rates also varied according to TG (from 0.2% to 3.8% for TG 1–2 vs from 1.2% to 8.9% for TG 3–4). Finally, SMs also increased in proportion to TS. For example, in collecting duct RCC patients, SM rates increased from 7.8% for 11–20-mm TS interval up to 36.3% for 61–70-mm TS interval. Thanks to our findings, it was possible to identify four metastatic risk categories according to SM rates. The first SM risk category was represented by multilocular cystic RCC with zero SM rate. The second SM risk category accounted for chromophobe RCC alone, with SM rates ranging from 0.1% to 1.9%. The third SM risk category included both clear cell TG 1–2 and papillary RCC, with SM rates ranging from 0.2% to approximately 4.1%. The fourth SM risk category accounted for clear cell TG 3–4, with SM rates ranging from 1.2% to 8.9%. Finally, the fifth SM risk category recorded the highest SM rates: from 7.6% in collecting duct RCC patients up to 49.1% in sarcomatoid RCC patients. These observations support HS-specific stratification of SM rates. According to such a scheme, a different SM risk profile should be attributed to HS and associated TS within each HS category. A renal mass biopsy could allow such stratification if clinically indicated. These findings were also validated in the main population study (n = 60 640), as well as in the clear cell RCC subgroup (n = 39 905), with our MLR model that demonstrated independent predictor status of HS, TG, and TS.
Third, we identified a previously unreported pattern of distribution regarding the number and location of metastatic sites. Of 576 clear cell RCC patients, 74.7% harbored a solitary metastatic site and the most frequent metastatic site was bone only (43.8%), followed by lung only (24.3%), brain only (3.8%), and liver only (2.8%). Conversely, of 72 papillary RCC patients who accounted for the second highest absolute number of SM patients, 77.8% harbored a solitary metastatic site and lung only was the commonest metastatic site (36.1%), followed by bone only (27.8%), liver only (9.7%), and brain only (4.2%). Moreover, of 63 sarcomatoid RCC patients, 57.1% harbored a solitary metastatic site and the most frequent metastatic site was bone only (34.9%), followed by lung only (15.9%), liver only (3.2%), and brain only (3.2%). Finally, in chromophobe and collecting duct RCC, the number of low SM patients (10 and 11) precluded any generalizations. To the best of our knowledge, only two studies [13,14] reported the number and location of metastases, without specifically focusing on patients with T1 RCC. Our observations regarding the differences between clear cell RCC and papillary RCC metastatic distribution are novel, and have not been reported previously in T1 RCC patients. Taken together, this is the first study that reports SM rates in stage T1 RCC patients according to TS, HS, and TG. We proposed HS- and TS-specific stratification of SMs. Moreover, for clear cell RCC, we provided further stratification according to TG (TG 1–2 vs TG 3–4). Our stratification illustrates SM rates that range from 0.2% to 8.9%. Moreover, we show that in clear cell stage T1 RCC patients, bone only represents the commonest metastatic site versus lung only in papillary stage T1 RCC patients. Clinical implications of our findings are twofold. First, renal mass biopsy can provide HS information accurately [15–17]. Grade information can also be provided with virtually equal accuracy [15,16,17][15,16,117]. Therefore, systematic use of renal mass biopsy could risk stratify patients regarding the likelihood of SM, prior to any kind of treatment (PN vs RN vs FA vs NIM). Second, our findings also
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 8
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
allow most detailed risk stratification predicting the likelihood of SM after surgical or ablation treatment and could help with risk-based follow-up of patients according to HS, TG, and TS. Unfortunately, the specific elements of such workup cannot be defined or even recommended from the current study due to limited data on the location and number of SMs. Additionally, our findings may direct clinicians after nephrectomy or focal treatment to improve the accuracy of staging, especially for high-risk SM patients, such as those with T1 sarcomatoid RCC or T1 collecting duct. Despite its novelty, our study also has limitations. First, this study represents a retrospective analysis with high potential for selection biases, is unable to assess whether NIM patients were observed with an active surveillance protocol versus watchful waiting without intent for cure, lacks standardized specimen handling as well as a central review regarding HS, and has no information regarding nucleolar grade. Second, the SEER database does not give information regarding the type of surgical approach (laparoscopic vs robot assisted). In consequence, data could not have been stratified according to this characteristic. Third, the relationship of TS with benign disease could not be evaluated because the SEER database does not provide data regarding benign histology as well as data regarding subclassification of papillary HS (type 1 vs type 2). Fourth, the nature of the SEER database that relies on consensus stage assignment does not allow discrimination between clinical and pathological metastatic stage. Moreover, the type of metastatic workup aimed at identified SMs is unknown and may have varied according to clinicians. Additionally, the SEER data are unable to capture patient-reported symptoms. It is possible that symptom-based screening may capture some brain or bone metastases. However, those may predominantly reflect the prevalence of symptomatic metastases, without representing true rates of metastases. Fifth, no data regarding the exact tumor burden as the number and/or size of metastases for each metastatic site are available within the SEER database. Finally, SEER database reports sarcomatoid RCC as a separate RCC entity. Moreover, the percentage of the sarcomatoid component or the subtype of the epithelioid component (clear cell vs non–clear cell) was not available in the database, and this might limit the generability of our results regarding this specific HS.
Study concept and design: Pecoraro, Palumbo, Mistretta, Knipper, Rosiello, St-Hilaire, Karakiewicz. Acquisition of data: Pecoraro, Tian. Analysis and interpretation of data: Pecoraro, Palumbo, Mistretta, Knipper, Rosiello, St-Hilaire, Karakiewicz. Drafting of the manuscript: Pecoraro, Karakiewicz. Critical revision of the manuscript for important intellectual content: Shariat, Saad, Briganti, Lavallée, Kapoor, Fiori, Porpiglia, Karakiewicz. Statistical analysis: Pecoraro, Tian. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Karakiewicz. Other: None. Financial disclosures: Angela Pecoraro certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
References [1] Kutikov A, Fossett LK, Ramchandani P, et al. Incidence of benign pathologic findings at partial nephrectomy for solitary renal mass presumed to be renal cell carcinoma on preoperative imaging. Urology 2006;68:737–40. [2] Thompson RH, Hill JR, Babayev Y, et al. Metastatic renal cell carcinoma risk according to tumor size. J Urol 2009;182:41–5. [3] Kim SP, Campbell SC, Gill I, et al. Collaborative review of risk benefit trade-offs between partial and radical nephrectomy in the management of anatomically complex renal masses. Eur Urol 2017;72:64–75. [4] Gershman B, Thompson RH, Boorjian SA, et al. Radical versus partial nephrectomy for cT1 renal cell carcinoma. Eur Urol 2018;74:825–32. [5] Lane BR, Golan S, Eggener S, et al. Differential use of partial nephrectomy for intermediate and high complexity tumors may explain variability in reported utilization rates. J Urol 2013;189: 2047–53. [6] Klatte T, Patard J-J, de Martino M, et al. Tumor size does not predict risk of metastatic disease or prognosis of small renal cell carcinomas. J Urol 2008;179:1719–26. [7] Guðmundsson E, Hellborg H, Lundstam S, et al. Metastatic potential in renal cell carcinomas 7cm: Swedish Kidney Cancer Quality Register data. Eur Urol 2011;60:975–82. [8] Lughezzani G, Jeldres C, Isbarn H, et al. Tumor size is a determinant of the rate of stage T1 renal cell cancer synchronous metastasis. J Urol 2009;182:1287–93.
5.
Conclusions
Within T1 RCC, it was possible to identify five metastatic risk categories according to SM rates: (1) multilocular cystic RCC (0%), (2) chromophobe RCC (0–2.0%), (3) clear cell TG 1– 2 and papillary RCC, (4) clear cell TG 3–4 RCC (1.2–8.9%), and (5) sarcomatoid and collecting duct RCC (7.0–49.1%). The most frequent metastatic location is bone only, followed by lung only, and virtually all SMs are solitary.
[9] Patel HD, Gupta M, Joice GA, et al. Clinical stage migration and survival for renal cell carcinoma in the United States. Eur Urol Oncol 2019;2:343–8. [10] Gandaglia G, Ravi P, Abdollah F, et al. Contemporary incidence and mortality rates of kidney cancer in the United States. J Can Urol Assoc 2014;8:247–52. [11] Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer 2008;113:78–83. [12] National Cancer Institute. Overview of the SEER program. National Cancer Institute Web site. https://seer.cancer.gov/about/overview. html.
Author contributions: Angela Pecoraro had full access to all the data in
[13] Bianchi M, Sun M, Jeldres C, et al. Distribution of metastatic sites in
the study and takes responsibility for the integrity of the data and the
renal cell carcinoma: a population-based analysis. Ann Oncol
accuracy of the data analysis.
2012;23:973–80.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011
EUF-885; No. of Pages 9 E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
9
[14] Chandrasekar T, Klaassen Z, Goldberg H, Kulkarni GS, Hamilton RJ,
[16] Richard PO, Jewett MAS, Tanguay S, et al. Safety, reliability and
Fleshner NE. Metastatic renal cell carcinoma: Patterns and predic-
accuracy of small renal tumour biopsies: results from a multi-
tors of metastases—a contemporary population-based series. Urol Oncol Semin Orig Investig 2017;35, 661. e7–14.. [15] Millet I, Curros F, Serre I, Taourel P, Thuret R. Can renal biopsy accurately predict histological subtype and Fuhrman grade of renal
institution registry. BJU Int 2017;119:543–9. [17] Richard PO, Jewett MAS, Bhatt JR, et al. Renal tumor biopsy for small renal masses: a single-center 13-year experience. Eur Urol 2015;68:1007–13.
cell carcinoma? J Urol 2012;188:1690–4.
Please cite this article in press as: Pecoraro A, et al. Synchronous Metastasis Rates in T1 Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results Database–based Study. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.02.011