Prognostic outcomes of surgical modalities and predictive factors for distant metastases in T1a renal cell carcinoma: a SEER database analysis
Highlight box
Key findings
• Distant metastases occur in 2.67% of pathologic T1a renal cell carcinoma (RCC) patients, leading to significantly worse overall survival (OS) (P<0.001).
• No significant OS difference exists between cytoreductive partial nephrectomy (cPN) and cytoreductive radical nephrectomy (cRN) (P=0.11).
• A predictive model incorporating age, gender, histologic differentiation, sarcomatoid features, capsular invasion, and lymph node metastasis achieved an area under the curve of 0.789 for metastasis risk stratification.
What is known and what is new?
• T1a RCC (tumor ≤4 cm confined to the kidney) is typically low-risk, but distant metastases can still occur. There is no conclusive evidence to determine whether cPN or cRN is superior in managing primary renal lesions.
• This study demonstrates comparable survival outcomes between cPN and cRN in metastatic T1a RCC. Novel risk factors (e.g., sarcomatoid features, capsular invasion) were identified, enhancing metastasis prediction accuracy.
What is the implication, and what should change now?
• cPN may be a feasible, nephron-sparing alternative to cRN in metastatic T1a RCC, preserving renal function without compromising survival. The validated risk model aids in stratifying high-risk T1a patients for intensified surveillance or adjuvant therapy.
• cPN should be considered as a viable option for selected metastatic T1a RCC patients. Prospective studies are warranted to validate the risk model and refine personalized management strategies.
Introduction
Renal cell carcinoma (RCC) has an incidence rate of about 5% in men and 3% in women, making up roughly 90% of all malignant kidney tumors (1). The prevalence of RCC is notably higher in Western countries (1). According to the 2017 tumor-node-metastasis (TNM) staging system, T1a renal cancer is defined as a tumor measuring 4 cm or less in diameter, commonly referred to as small renal masses (SRM). For these patients, the European Association of Urology (EAU) Guidelines recommend partial nephrectomy as the preferred surgical method (2). Active surveillance is also recognized as a viable option for managing SRM (3). However, distant metastases can still occur, with a study indicating a distant metastatic rate of 1.1% to 6% for T1a renal cancer (4). Cytoreductive nephrectomy (CN) is an optional modality for metastatic RCC to deal with primary lesions (2). Currently, there is no conclusive evidence to determine whether cytoreductive partial nephrectomy (cPN) or cytoreductive radical nephrectomy (cRN) is superior in managing primary renal lesions. There is also a lack of comprehensive research to identify which patients are at a higher risk for developing distant metastases. To address these, the SEER database was used to analyze prognostic outcomes and risk factors associated with distant metastases in T1a RCC and developed a nomogram based on these factors. We present this article in accordance with the TRIPOD reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2024-637/rc).
Methods
Patient and data selection
This study utilized data from the Surveillance, Epidemiology, and End Results (SEER) database (https://seer.cancer.gov/), established in 1973 by the Department of Cancer Control and Population Sciences of the National Cancer Institute (NCI). The database compiles comprehensive information on cancer patients from 18 regions across the United States (U.S.), including details on clinicopathology, tumor characteristics, and treatment details. Our research employed the “Incidence-SEER Research Plus Data” (17 registries, November 2021 submission), which covers the years from 2000 to 2019. This dataset, representing approximately 26.5% of the U.S. population according to the 2010 census, contains records for 8,721,474 individual tumors. Inclusion criteria included the following: (I) histologically diagnosed RCC between 2004 and 2015; (II) patients with pathologic T1a stage. The exclusion criteria were as follows: (I) incomplete demographic or clinicopathology information; (II) missing survival status or follow-up information; (III) diagnostic information from only autopsy or death certificate records. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
SEER*Stat Software (version 8.4.3; seer.cancer.gov) was used to extract data from the SEER database. A total of 19,175 patients with complete clinical data who met the inclusion and exclusion criteria were enrolled in the study.
Statistical analysis
Group comparisons were conducted using the t-test, Mann-Whitney U test, chi-square test, and Fisher’s exact test. Propensity score matching (PSM) was applied to balance baseline characteristics. The effect of metastasis on patients’ prognosis and the outcomes of different surgical methods were evaluated using Kaplan-Meier analysis. Univariate and multivariate logistic regression analyses identified risk factors, and the results informed the development of a nomogram. The model’s discrimination and accuracy were internally evaluated using receiver operating characteristic (ROC) curves. Statistical analyses were performed with R software (version 4.4.1) and SPSS software (version 26.0), considering a two-sided P value of less than 0.05 as statistically significant.
Results
Patient baseline characteristics and survival analyses
The study included 64,338 RCC patients with stage T1a, of which 55,957 were with complete survival data and confirmed through pathological diagnosis. A total of 1,496 RCC patients were metastatic renal cell carcinoma (mRCC). After excluding patients with incomplete demographic or clinicopathological data such as tumor grade, stage, sarcomatoid differentiation, tumor capsule invasion, surgical approach, 19,175 were included in the nomogram, of which 125 had distant metastases at the time of surgery. The screening process is detailed in Figure 1. The Clinicopathological characteristics is described in Table 1. RCC patients with distant metastases were more likely to be older (P<0.001), male (P<0.001), and were more likely to exhibit poor differentiation (P<0.001), sarcomatoid changes (P<0.001) and capsular invasion (P<0.001). More patients underwent radical nephrectomy and regional lymph node dissection, alongside systemic chemotherapy and radiation therapy (P<0.001). The comparison of overall survival (OS) indicated a significant decline in prognosis following metastasis, as detailed in Figure 2.
Table 1
| Characteristics | NDMs (N=54,461) | DMs (N=1,496) | Overall (N=55,957) | P |
|---|---|---|---|---|
| Age (years) | 60.9±12.8 | 66.0±12.6 | 61.0±12.8 | <0.001 |
| Sex | <0.001 | |||
| Female | 20,972 (38.51) | 461 (30.82) | 21,433 (38.30) | |
| Male | 33,489 (61.49) | 1,035 (69.18) | 34,524 (61.70) | |
| Race | 0.38 | |||
| White | 44,581 (81.86) | 1,242 (83.02) | 45,823 (81.89) | |
| Black | 6,375 (11.71) | 170 (11.36) | 6,545 (11.70) | |
| Other | 3,505 (6.44) | 84 (5.61) | 3,589 (6.41) | |
| Marital status | <0.001 | |||
| Married | 17,708 (32.52) | 563 (37.63) | 18,271 (32.65) | |
| Unmarried | 34,231 (62.85) | 885 (59.16) | 35,116 (62.76) | |
| Unknown | 2,522 (4.63) | 48 (3.21) | 2,570 (4.59) | |
| Histology | <0.001 | |||
| Clear cell adenocarcinoma | 31,321 (57.51) | 572 (38.24) | 31,893 (57.00) | |
| Papillary carcinoma | 8,351 (15.33) | 92 (6.15) | 8,443 (15.09) | |
| Chromophobe type | 2,913 (5.35) | 14 (0.94) | 2,927 (5.23) | |
| Other | 11,876 (21.81) | 818 (54.68) | 12,694 (22.69) | |
| Grade | <0.001 | |||
| Well differentiated | 8,393 (15.41) | 56 (3.74) | 8,449 (15.10) | |
| Moderately differentiated | 26,899 (49.39) | 197 (13.17) | 27,096 (48.42) | |
| Poorly differentiated | 8,965 (16.46) | 304 (20.32) | 9,269 (16.56) | |
| Undifferentiated | 876 (1.61) | 111 (7.42) | 987 (1.76) | |
| Unknown | 9,328 (17.13) | 828 (55.35) | 10,156 (18.15) | |
| Stage N | <0.001 | |||
| N0 | 53,626 (98.47) | 936 (62.57) | 54,562 (97.51) | |
| N1 | 171 (0.31) | 225 (15.04) | 396 (0.71) | |
| N2 | 77 (0.14) | 134 (8.96) | 211 (0.38) | |
| Nx | 587 (1.08) | 201 (13.44) | 788 (1.41) | |
| Tumor size (mm) | 26.5±8.68 | 28.8±9.35 | 26.5±8.71 | <0.001 |
| Sarcomatoid features | <0.001 | |||
| No | 28,139 (51.67) | 308 (20.59) | 28,447 (50.84) | |
| Yes | 201 (0.37) | 59 (3.94) | 260 (0.46) | |
| Unknown | 26,121 (47.96) | 1,129 (75.47) | 27,250 (48.70) | |
| Invasion beyond capsule | <0.001 | |||
| No | 26,227 (48.16) | 195 (13.03) | 26,422 (47.22) | |
| Yes | 1,179 (2.16) | 66 (4.41) | 1245 (2.22) | |
| Unknown | 27,055 (49.68) | 1,235 (82.55) | 28,290 (50.56) | |
| Surgery | <0.001 | |||
| cPN | 26,609 (48.86) | 90 (6.02) | 26,699 (47.71) | |
| cRN | 17,320 (31.80) | 368 (24.60) | 17,688 (31.61) | |
| Other/unknown | 10,532 (19.34) | 1,038 (69.38) | 11,570 (20.68) | |
| Radiation | <0.001 | |||
| No/unknown | 54,319 (99.74) | 941 (62.90) | 55,260 (98.75) | |
| Yes | 142 (0.26) | 555 (37.10) | 697 (1.25) | |
| Chemotherapy | <0.001 | |||
| No/unknown | 54,135 (99.40) | 850 (56.82) | 54,985 (98.26) | |
| Yes | 326 (0.60) | 646 (43.18) | 972 (1.74) | |
| Surgery of LNs | <0.001 | |||
| No | 52,099 (95.66) | 1,297 (86.70) | 53,396 (95.42) | |
| 1 to 3 regional LNs removed | 1,442 (2.65) | 85 (5.68) | 1,527 (2.73) | |
| 4 or more regional LNs removed | 632 (1.16) | 64 (4.28) | 696 (1.24) | |
| Unknown | 288 (0.53) | 50 (3.34) | 338 (0.60) |
Data are presented as mean ± SD or n (%). P<0.05 indicating statistical significance. cPN, cytoreductive partial nephrectomy; cRN, cytoreductive radical nephrectomy; DMs, distant metastases; LN, lymph node; NDMs, no distant metastases; SD, standard deviation.
A total of 1,496 RCC patients with stage T1a developed distant metastases.458 patients received CN. Ninety patients were treated with cPN and 368 underwent cRN. After propensity-score matching, Kaplan-Meier analysis showed that the OS did not significantly differ between the two surgical methods. As shown in Figure 3.
Univariate and multivariate analyses
The univariate logistic regression analysis encompassed the following variables: age, gender, race, tumor size, marital status, grade, sarcomatoid features, capsular invasion, lymph node metastasis. Variables with a P value <0.05, such as age, gender, tumor size, grade, sarcomatoid features, capsular invasion, and lymph node metastasis, were selected for multivariate analysis. The multivariate logistic regression confirmed that age, gender, grade, sarcomatoid features, capsular invasion, and lymph node metastasis were independent risk factors for distant metastases in RCC patients with stage T1a. Details of both the univariate and multivariate logistic analyses are presented in Table 2.
Table 2
| Characteristics | Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|---|
| OR | 95% CI | P value | OR | 95% CI | P value | ||
| Age | 1.033 | 1.017–1.049 | <0.001* | <0.001* | |||
| Sex | |||||||
| Female | Ref | ||||||
| Male | 1.928 | 1.299–2.941 | 0.002* | 1.548 | 1.027–2.392 | 0.042* | |
| Race | |||||||
| White | Ref | ||||||
| Black | 0.729 | 0.369–1.296 | 0.32 | ||||
| Other | 0.604 | 0.236–1.261 | 0.23 | ||||
| Marital status | |||||||
| Married | Ref | ||||||
| Unmarried | 1.019 | 0.700–1.507 | 0.92 | ||||
| Unknown | 1.203 | 0.492–2.527 | 0.65 | ||||
| Tumor size | 1.028 | 1.006–1.050 | 0.011* | 1.012 | 0.991–1.039 | 0.28 | |
| Sarcomatoid features | |||||||
| No | Ref | ||||||
| Yes | 23.578 | 11.183–44.867 | <0.001* | 5.742 | 2.243–13.410 | <0.001* | |
| Invasion beyond capsule | |||||||
| No | Ref | ||||||
| Yes | 6.699 | 4.324–10.071 | <0.001* | 2.840 | 1.709–4.551 | <0.001* | |
| Histology | |||||||
| Clear cell adenocarcinoma | Ref | ||||||
| Papillary carcinoma | 0.813 | 0.489–1.283 | 0.40 | ||||
| Chromophobe type | – | – | 0.97 | ||||
| Grade | |||||||
| Grade I | Ref | ||||||
| Grade II | 4.035 | 1.483–16.595 | 0.01* | 3.456 | 1.265–1.424 | 0.03* | |
| Grade III | 12.374 | 4.558–50.844 | <0.001* | 7.956 | 2.888–32.922 | <0.001* | |
| Grade IV | 60.762 | 20.560–259.691 | <0.001* | 19.528 | 5.990–87.736 | <0.001* | |
| N stage | |||||||
| N0 | Ref | ||||||
| N+ | 83.104 | 45.825–146.073 | <0.001* | 34.936 | 17.862–65.965 | <0.001* | |
*, P<0.05 indicating statistical significance. CI, confidence interval; OR, odds ratio.
Nomogram construction and validation
A nomogram model was constructed based on these six independent risk factors, as depicted in Figure 4. A ROC curve was plotted for the model, see Figure 5. The area under the curve of the model was 0.789. The calibration curve is presented in Figure 6, while the decision curve analysis (DCA) is illustrated in Figure 7.
Discussion
Renal carcinoma, a prevalent malignancy of the kidney, includes stage T1a, defined by tumor diameters of 4 cm or less. However, the risk of metastasis for these patients should not be overlooked. A previous study reported that overall rate of metastasis was 3.1% (4). We leveraged the SEER database to identify 125 RCC patients with stage T1a, distant metastases, and complete records. Our research yielded two significant insights: (I) the presence of distant metastases markedly reduced OS; (II) among those with metastases, OS did not differ significantly between patients undergoing cPN and those receiving cRN. There is no recommended approach for managing the primary lesion in metastatic T1a RCC. The role of CN in patients with mRCC is still unclear, the selection of appropriate patients is crucial, as many factors influence its effectiveness such as the patient’s clinical and symptom presentation (5). Clinically, the options include cPN and cRN, but there is no consensus on which is superior. In elderly patients with mRCC who exhibit specific clinical features such as a tumor size ≤7 cm, N0 stage, or isolated metastasis, performing cPN appears to improve survival outcomes (6). We selected mRCC patients with stage T1a and conducted survival analyses utilizing the SEER database. Our findings indicated no difference in OS between cPN and cRN. cPN better preserves renal function post-operatively, potentially reducing the risk of cardiovascular diseases (7,8). Additionally, maintaining kidney function supports the implementation of subsequent systemic therapies. It is important to note that, in clinical practice, ablation therapies are considered a potential alternative for the localized treatment of SRM (9,10). The treatment approach should be selected based on the specific circumstances of each case.
Although a study has investigated risk factors for distant metastases in renal cancer (11), focused research on T1a mRCC is sparse. Poor histological differentiation, capsular invasion, sarcomatoid features, and lymph node metastasis were independent risk factors for distant metastases. The renal capsule, which encases the kidney, is encircled by perirenal adipose tissue. Invasion of the capsule by a tumor marks an early phase of metastasis and signifies the aggressiveness of the tumor. Other traits also suggest increased tumor aggressiveness, thereby heightening the risk of distant metastases such as sarcomatoid features. Sarcomatoid RCC typically results in a dire prognosis and is prone to early metastatic spread (12). Existing literature posited that larger tumor size and a history of diabetes could elevate the risk of metastasis in T1a RCC (4). Yet, our multivariate analysis does not support tumor size as an independent risk factor. The 125 metastatic cases included in our study may not comprehensively represent the general T1a mRCC demographic, suggesting that these findings necessitate further corroboration.
Advanced age and male gender were also independent risk factors for distant metastases in RCC patients with stage T1a. Previous research indicated that 65% of patients with mRCC were male (13). That may be linked to unhealthy lifestyle habits, such as smoking. The poor immunity in elderly patients may increase the incidence rate of distant metastases.
Our study faced several limitations. Firstly, the SEER database has several limitations that should be acknowledged: (I) the retrospective nature of the research inherently introduced selection bias; (II) potential coding inaccuracies and misclassifications may affect data reliability, requiring cautious interpretation of our findings. Future prospective studies are needed to validate the true incidence and prognostic; (III) the absence of data on comorbidities and performance status limits the ability to account for patient-specific factors that influence survival and treatment selection. Secondly, the predictive accuracy of our nomograms requires external validation through larger cohort studies.
Conclusions
T1a RCC patients with distant metastases had worse OS, there were no significant differences in OS between cPN and cRN. Advanced age, male gender, poor histological differentiation, capsular invasion, sarcomatoid changes, and lymph node metastasis were independent risk factors for distant metastases in RCC patients with stage T1a.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2024-637/rc
Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2024-637/prf
Funding: This study was supported by
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2024-637/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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