Risk Factors and Metastasis Prediction in Small (≤4 cm) Clear Cell Renal Cell Carcinoma: A Nested Case-Control Study

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Methods This study retrospectively analyzed the clinical and pathological data, as well as the follow-up data of 1,054 small ccRCC patients undergoing surgery at the Third Hospital of Peking University between 2012 and 2024. Following the identification of 50 small ccRCC patients with metastasis (the case group), a nested case-control study was further carried out with the matching of 281 small ccRCC patients without metastasis during the same period (the control group), according to a ratio of 1:6. Furthermore, risk factors affecting the metastasis of small ccRCC were investigated by using univariate and multivariate logistic regression analyses. Results Of the 1,054 small ccRCC patients, metastasis (synchronous metastasis, 1.8%; and metachronous metastasis, 2.9%) occurred in 4.7% of small ccRCC patients. The 5-year overall survival rates were 99.1% and 75.8% for patients with non-metastatic and metastatic small ccRCC, respectively. Multivariate logistic regression analysis revealed that the presence of clinical symptoms, R.E.N.A.L. score (moderate complexity group and high complexity group), pT3 and pathological grade III and IV were independent risk factors for metastasis in small ccRCC patients. Conclusion Patients with small ccRCC may experience a metastatic rate of 4.7%. Clinical symptoms, higher R.E.N.A.L. score, pT3 stage, and higher pathological grading may be risk factors for metastasis of small ccRCC. Small renal cell carcinoma Metastasis Risk factors Prognosis Figures Figure 1 Figure 2 Figure 3 Introduction Renal carcinoma (RCC), as a malignancy originating from the epithelial cells of the renal tubules, accounts for approximately 2–3% of all adult malignancies, and is the most common type of renal malignancy in adults [ 1 ] . Acting as the most common histological type, clear cell RCC (ccRCC) takes up around 90% for all cases with RCC [ 2 ] . According to the European Association of Urology, RCC with a tumor diameter of ≤ 4 cm is defined as as small RCC [ 3 ] . Most patients with small RCC are clinically staged as stage T1a, which is a limited-stage RCC, which is commonly treated by surgery. Surgical treatment ocan provide favorable oncologic and functional outcomes for patients with small RCC, with a 5-year tumor-specific survival rate of 96–97% for cT1a stage RCC [ 4 ] . Small RCC, even though considered to be at low risk generally, may still develop distant metastasis [ 5 ] . Synchronous and metachronous metastasis has been reported to be 1%-7% in patients with small RCC [ 6 , 7 ] . For example, the synchronous metastasis rate was 7% in patients with small RCC as proposed in a multi-institutional study by Klatte et al. [ 8 ] . Meanwhile, Thompson et al. found that 162 out of 2,691 patients with small RCC (6%) had synchronous metastasis [ 9 ] . In another a systematic review incorporating 18 studies on active surveillance of small RCC by Smaldone et al. [ 10 ] , 880 patients with small RCC were followed up for an average of 40 months, and only 18 patients (2.0%) developed metastases. However and critically, patients may experience significantly worsened prognosis once metastasis occurs in small RCC. Overseas research has documented a 5-year overall survival (OS) rate of only 20% in patients with metastatic small RCC [ 11 ] . Currently, there are few reports on the prognosis of metastatic small RCC in China. Small RCC with synchronous or metachronous metastasis exhibit specific biological characteristics, highlighting the significance of exploring the metastatic potential in small ccRCC for guiding its treatment and follow-up. In this study, we retrospectively examined patients with small RCC who were treated at Peking University Third Hospital between 2012 and 2024. The present study summarized the clinicopathological characteristics of metastatic small RCC patients and explored the risk factors affecting metastasis and prognosis in these patients through a nested case-control study, thereby contributing to clinical treatment decision-making. Materials and methods 1. Study participants This retrospective cohort study included small ccRCC patients who were treated at the Third Hospital of Peking University between 2012 and 2024. 1.1 The inclusion criteria were: 1) renal tumor with a maximum diameter of ≤ 4 cm by complete preoperative abdominal CT or MRI examination; 2) partial nephrectomy (PN) or radical nephrectomy (RN); 3) ccRCC confirmed by postoperative pathology; and 4) complete and accurate clinical follow-up data. For patients with metastasis, there must be clear evidence for the presence of the site of metastasis and the time of onset of progression from imaging or pathological examination of biopsy or surgical tissue. 1.2 The exclusion criteria were: 1) incomplete case data or loss of visit; 2) undergoing puncture, ablation and other treatments only, without surgical excision; and 3) non-ccRCC. Prior to the study, an official ethical approval was acquired from the Ethics Committee of the Third Hospital of Peking University (Ethics No. 2022-147-01). 1.3 Sources of cases and controls: In order to explore the factors influencing metastasis in small ccRCC, patients with metastatic carcinoma were used as the case group. Among patients with non-metastatic small ccRCC, gender, age ,tumor size and tumor location were used for propensity score matching at a ratio of 1:6 on the basis of the utilization of the nearest neighbor matching method, with a caliper value of 0.02. Patients with non-metastatic small ccRCC were matched as the control group. 2. Research Methods 2.1 Clinical data By reviewing the medical record system, this study recorded the clinicopathological characteristics of the enrolled patients, including age, gender, tumor side, body mass index (BMI), clinical symptoms, distant metastases, preoperative R.E.N.A.L. score [ 12 ] , and surgical method. Hematological indices included hemoglobin and serum creatinine values. In addition, pathological data included tumor size, pathological grading, TNM stage and the performance of postoperative adjuvant therapy. In order to obtain prognostic information (e.g., survival status, recurrence and metastasis, adjuvant therapy, etc.), patients were followed up postoperatively through outpatient visits or by telephone. The initial follow-up took place 1 month after surgery, with subsequent follow-ups every 6–12 months. Our inclusion of specific indicators could be explained as follows: 1) A diagnosis of metastasis requires definitive imaging or pathological evidence. The results of pathological examined has been recognized to be the gold standard for patients undergoing resection for metastasis. Among them, synchronous metastasis is defined as distant metastasis present at the time of diagnosis of small ccRCC; while metachronous metastasis refers to distant metastasis occurring after surgery for small ccRCC. 2) Preoperative renal R.E.N.A.L. score: Based on the total scores, patients were categorized into three groups of low complexity (4–6 points), moderate complexity (7–9 points) and high complexity (10–12 points). 3) Pathological grading: The Fuhrman grading system was used prior to 2016 [ 13 ] and the WHO/ISUP nuclear grading system was adopted thereafter [ 14 ] . 4) TNM staging was established by the American Joint Committee on Cancer (AJCC) in 2017 [ 15 ] . 5) Adjuvant therapy includes radiotherapy, chemotherapy, cytokine therapy, targeted therapy and immunotherapy, etc. 6) Survival status: OS is the period between the date of surgery and the date of death from any cause. 2.2 Statistical analysis Statistical analyses in this study were completed in SPSS version 27.0 and R software version 4.5.1. With the performance of normality test, continuous variables following a normal distribution were described using the mean and standard deviation, and compared using independent samples t -tests in the context of equal variance. Categorical variables were expressed as percentages. The chi-squared test, and the non-parametric Mann-Whitney U test were adopted for dichotomous and unordered categorical variables, and ordered categorical variables, respectively. Univariate conditional logistic regression analysis was used to assess risk factors for metastasis in small ccRCC, with the calculation of the odds ratio (OR) and 95% confidence interval (CI) simultaneously. Subsequently, multivariate conditional logistic regression analysis was carried out by considering variables with statistically significant differences in the univariate analysis, as well as clinically recognized factors influencing metastasis. Forward stepwise regression based on maximum likelihood estimation was used for variable selection to validate their independent predictive value. Kaplan-Meier survival analysis and the log-rank test were used to assess risk factors influencing the OS in small ccRCC. For all statistical analyses, a two-sided P < 0.05 was considered statistically significant. Results 1. Clinicopathological characteristics of the enrolled patients A total of 1,054 patients were ultimately included according to the inclusion and exclusion criteria preset in this study (Fig. 1 ). Of these patients, there were 775 (73.5%) male patients, and 279 (26.5%) female patients, with mean age of 56 years, and mean BMI of 25.65 kg/m². Meanwhile, 529 (50.2%) had tumors on the left side and 525 (49.8%) on the right side; moreover, 132 patients (12.5%) presented with clinical symptoms. According to the R.E.N.A.L. score, there were 646 patients (61.5%) in the low complexity group, 379 patients (35.1%) in the moderate complexity group, and 25 patients (2.4%) in the high complexity group. Furthermore, the surgical approach was PN in 868 cases (82.4%) and RN in 186 cases (17.6%). Tumor size was ≤ 2 cm in 194 cases (18.4%), 2.1-3 cm in 424 cases (40.2%), 3.1-4 cm in 436 cases (41.1%), and > 4 cm in 25 cases (2.4%). In addition, pathological grading was highly differentiated (grades I-II) in 911 cases (86.5%), moderately differentiated (grade III) in 127 cases (12.0%), and poorly differentiated or undifferentiated (grade IV) in 16 cases (1.5%). The clinicopathological characteristics of all patients are shown in Table 1. Critically, 50 (4.7%) had distant metastases, including 19 (1.7%) with synchronous metastases and 31 (2.7%) with metachronous metastases (Table 2 ). Furthermore, a nested case-control study was designed to investigate the risk factors influencing metastasis in small ccRCC. The case group comprised 50 patients with metastatic small ccRCC, and the control group comprised 281 patients with non-metastatic small ccRCC. As presented in Table 3 regarding the clinical and pathological characteristics, there were statistically significant differences between groups in clinical symptoms, R.E.N.A.L. score, hemoglobin, surgical approach, pT3 stage, pathological grade, microvascular invasion, perirenal fat invasion and renal pelvis and calyx invasion (all P < 0.05). Univariate logistic regression analysis revealed statistically significant differences in clinical symptoms, R.E.N.A.L. score, surgical approach, pT3 stage, pathological grading, and invasion of perirenal fat related to the occurrence of metastasis in small ccRCC patients (all P < 0.05). On these basis, subsequent multivariate logistic regression analysis showed that clinical symptoms (OR = 6.03, 95% CI 1.74–20.93, P = 0.005), R.E.N.A.L. score [moderate complexity group (OR = 3.46, 95% CI 1.01–11.84, P = 0.048), and high complexity group (OR = 6.52, 95% CI 1.09–39.10, P = 0.004) ], pT3 (OR = 3.17, 95% CI 1.06–9.49, P = 0.04), pathological grade III (OR = 5.19, 95% CI 1.60-16.75, P = 0.006), and pathological grade IV (OR = 4.44, 95% CI 0.99–19.92, P = 0.05) were independent risk factors for metastasis in small ccRCC patients (Table 4 ). All these six variables screened were selected to establish a nomogram for small ccRCC (Fig. 2 a). The C-index (0.813) and the area under the receiver operating characteristic curve (> 0.7) indicated satisfactory discriminative ability of the nomogram (Fig. 2 b/c). 2. Prognostic analysis for small ccRCC patients All patients were followed up with a median follow-up period of 38 months (from 2 to 133 months). Among the cohort, 12 patients (1.04%) died. Tumor-specific death occurred in 10 patients (0.87%). According to the Kaplan-Meier survival curves, the 5-year OS rate of was 98.3%, 99.1%, and 75.8% for patients with small ccRCC, non-metastatic small ccRCC, and metastatic small ccRCC, respectively, showing significantly different difference ( P < 0.001) (Fig. 3 a). Further survival analysis stratified by metastatic status demonstrated significant prognostic differences (P = 0.051), with synchronous metastatic patients exhibiting the poorest survival outcomes compared to metachronous metastatic groups, as evidenced by Kaplan-Meier analysis (Fig. 3 b). Discussion It has currently been well-established with respect to the epidemiology, clinicopathological characteristics, metastatic risk factors and prognosis of RCC. Moreover, great concern has been attached to 'large RCC (> 4 cm in diameter)', with relatively little controversy over its treatment and follow-up. However, for patients with metastatic small RCC, it is still poorly understood owing to the lack of certain standards with regard to corresponding clinicopathological characteristics, metastasis and prognostic factors. Current studies on small RCC exhibit disadvantages of small sample sizes, and the inclusion of European and American populations merely, with fewer reports on Asian populations. Significantly, this study was designed a large-sample, long-term retrospective research among the Chinese population, with the summary of the clinicopathological characteristics of metastatic small ccRCC. Moreover, a nested case-control study was carried out to explore the risk factors affecting the metastasis and prognosis of small ccRCC, which may provide valuable insights for clinicians in China to make treatment decisions. Of the 1,054 small ccRCC patients who underwent surgery, 50 patients (4.7%) had distant metastases, including 19 patients (1.7%) with synchronous metastases and 31 patients (2.7%) with metachronous metastases, consistent with domestic and international studies [ 6 , 16 ] . There were 22 cases of lung metastasis, 21 cases of bone metastasis, 4 cases of liver metastasis, 7 cases of adrenal metastasis, 4 cases of brain metastasis and 8 cases of metastasis to other sites. Further statistical analysis revealed more prevalent multiple metastases in the synchronous metastasis group than in the metachronous metastasis group with the most common distant metastatic site confirmed to be bones. Similarly, a multi-center retrospective study [ 17 ] found that the most common site of concomitant metastasis was the skeleton (65.4%) in patients with small ccRCC. Clinically, RCC patients may usually present with systemic symptoms (e.g., ever, malaise, weight loss and cachexia) and local symptoms (e.g., low back pain, a palpable abdominal mass and hematuria). Due to the increased availability of physical examinations and routine screening, the traditionally believed 'triad of RCC' (i.e., low back pain, hematuria and a palpable abdominal mass) is becoming increasingly rare among patients with small RCC. However and noticeably, the disease can be determined to be progressed, once these symptoms appear, and should be taken seriously in clinical practice. Tan et al. reported the presence of clinical symptoms in 155 (27.4%) cases among 565 patients with small RCC [ 18 ] . The most common symptoms are hematuria, muscle pain and bone pain. Further multivariate logistic regression analysis revealed that synchronous metastases in small RCC could be independently predicted by the presence of clinical symptoms and an age of over 65 years. Kume et al. retrospectively analyzed 165 cases of surgically treated small RCC (≤ 3 cm), and revealed that advanced age and clinical symptoms were significant risk factors for metastasis through multivariate logistic regression analysis [ 19 ] . Consistently, our study identified the presence of clinical symptoms as an independent predictor of metastasis in small ccRCC. Therefore, patients presenting with clinical symptoms at initial diagnosis of small RCC are at higher risk of developing metastasis, requiring more comprehensive evaluation and rigorous postoperative follow-up. The R.E.N.A.L. scoring system, proposed by Kutikov for the first time in 2009, was developed based on five oncological characteristics, namely the size of the renal tumor; the degree of convexity; the distance from the collecting system; the ventral or dorsal location; and the relationship to the upper and lower poles of the kidney [ 12 ] . It can facilitate clinical assessment of the anatomical characteristics of renal tumors more accurately, and the development of appropriate surgical approaches. In the study of 830 patients who underwent PN for limited-stage RCC, Mouracade et al. found that pT stage, pathological grade, and R.E.N.A.L. score were independent predictors of disease-free survival [ 20 ] . In our study, the R.E.N.A.L. score was an independent risk factor for metastasis in patients with small RCC, suggesting its value in both assessing the complexity and surgical risk of renal tumor surgery, and also in predicting metastasis in small RCC patients. Furthermore, Fuhrman grading system, enabling the reflection of the tumor’s cellular heterogeneity and biological behavior, is an important indicator for identifying the degree of malignancy of RCC [ 13 ] . Fuhrman grades I and II tumors are highly differentiated; grade III tumors are moderately differentiated; while Grade IV tumors are poorly differentiated or undifferentiated. Subjects with higher Fuhrman grade would have less differentiated nucleus and worse prognosis. In an investigation on 2,033 cases of stage T1 RCC, patients with Fuhrman grade III or IV were four times more likely to experience metastasis than those with grade I or II [ 21 ] . Moreover, higher Fuhrman grade is usually associated with greater aggressiveness and poorer prognosis. For example, Kato et al. retrospectively analyzed 198 patients with small RCC from fifteen centers, and found obviously higher Fuhrman grade III or IV and more significant tumor invasive growth in patients with metastatic small RCC than in those without [ 17 ] . As in previous national and international studies, a high pathological grade of small RCC suggests a higher risk of metastasis, as well as poorer survival. In our study, pathological grade (grade III and grade IV) was an independent risk factor for metastasis in small ccRCC patients. In the context of current advancement in targeted therapy, we know little about the specific role of cytoreductive nephrectomy for patients with metastatic RCC [ 22 – 24 ] . Surgical treatment, despite controversy over its therapeutic effect on metastatic renal cell carcinoma, can still improve patients' OS and cancer-specific survival [ 25 ] . Previous retrospective evidence also supports the idea that complete tumor reduction resulted in favorable OS and progression-free survival when treating concurrent metastatic RCC [ 26 ] . Dutcher et al. studied patients with metastatic small RCC who underwent PN [ 27 ] , and found that adjuvant targeted drug therapy such as sunitinib and sorafenib could significantly improve the prognosis of patients with metastatic RCC. Abel et al. reviewed patients with small RCC who underwent surgery with PN [ 28 ] . Of some of these patients who did not receive adjuvant molecular targeted drug therapy after surgery, 20/774 (2.6%) with pT1 stage RCC developed metastasis. The researchers concluded that, adjuvant targeted drug therapy should be routinely recommended after PN for some high-risk patients with small RCC to reduce the risk of postoperative recurrence and metastasis. In our study, all patients with small RCC underwent surgical treatment of the primary site, with the majority opting for PN. For patients with metastatic small RCC, cytoreductive nephrectomy and combined adjuvant therapy may be effective to improve their prognosis. This study still has certain limitations. Firstly, patients with small ccRCC usually have a favorable prognosis and low malignancy, as a result, the incidence of outcomes such as metastasis or death remained low despite the inclusion of 1,054 patients between 2012 and 2024 in our study. While the nested case-control study enhanced the credibility of the results, longer-term follow-up and larger multi-center studies are still needed for thorough validation and to establish predictive models with clinical application value. Secondly, due to the diversity of treatment regimens, the study did not include specific postoperative adjuvant therapies for patients with metastatic small ccRCC. Furthermore, all patients with metastatic small ccRCC underwent debulking surgery, with the exclusion of patients who received only targeted or immunotherapy. Therefore, this study failed to assess the independent impact of these treatments on the prognosis of patients with metastatic small ccRCC. In the future, there may be more therapeutic options to consider with the publication of more clinical trials and approval of new drugs. Selecting an appropriate treatment regimen is critical in improving the prognosis of patients with metastatic small RCC. Conclusion In conclusion, this study summarizes the clinical and pathological characteristics as well as prognosis of patients with metastatic small ccRCC. Univariate and multivariate logistic regression analyses revealed that clinical symptoms, clinical symptoms, higher R.E.N.A.L. score, pT3 stage, and higher pathological grading may be risk factors for metastasis of small ccRCC. Declarations Author ’ s contributions This is the first submission of this manuscript and no parts of this manuscript are being considered for publication elsewhere. All authors have approved this manuscript. No author has financial or other contractual agreements that might cause conflicts of interest. Conception and design: MQ. Acquisition of data: ZW, DP, JJ. Analysis and interpretation of data: ZW. Drafting of the manuscript: ZW, DP. Critical revision of the manuscript for important intellectual content: MQ. Administrative, technical, or material support: XT, HZ, LM, SZ. Supervision: LM, MQ. Funding None. Data availability All data generated for this analysis were from the Renal cancer database of Department of Urology, Peking University Third Hospital database. The de-identified patient data supporting the findings of this study have been deposited in Science Data Bank (ScienceDB) and are publicly available under the accession code doi: 10.57760/sciencedb.28616 . Researchers may access these data in accordance with ScienceDB's terms of use and data protection policies. Conflict of interest Zhiying Wu 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. Ethics statement All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by Peking University Third Hospital Medical Science Research Ethics Committee (Ethics No. 2022-147-01). Informed consent was obtained from all individual participants included in the study. Authors and Affiliations Zhiying Wu • Dameng Pan • Jinghui Ji • Xiaojun Tian • Hongxian Zhang • Min Qiu • Lulin Ma • Shudong Zhang Corresponding author: Lulin Ma [email protected] ; Min Qiu [email protected] Department of Urology, Peking University Third Hospital, Beijing 100083, China References BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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Tables Table 1 The clinical and pathological characteristics of patients diagnosed with small clear cell renal cell carcinoma (≤4cm) Variable Description Age 55.83±11.80 BMI 25.65±3.32 Hgb 145.14±13.78 Plt 242.78±42.06 Scr 81 (37, 1220) Gender Male 775 (73.5%) Female 279 (26.5%) Symptoms 132 (12.5%) Surgery PN 868 (82.4%) RN 186 (17.6%) Lateral Left 529 (50.2%) Right 525 (49.8%) R.E.N.A.L score low 646 (61.5%) moderate 379 (35.1%) high 25 (2.4%) Tumor diameter (cm) ≤2 194 (18.4%) 2.1-3 424 (40.2%) 3.1-4 436 (41.4%) pT3 70 (6.6%) N1 3 (0.3%) M1 50 (4.7%) pathological grade I 200 (19.0%) II 711 (67.5%) III 127 (12%) IV 16 (1.5%) Vessel 16 (1.5%） Perirenal fat 18 (1.7%) Renal cavity 48 (4.6%) ASA 1 195 (18.5%) 2 809 (76.8%) 3 48 (4.6%) 4 2 (0.2%) BMI body mass index, Hgb hemoglobin, Plt platelet count, Scr serum creatinine, R.E.N.A.L. score groups low (4-6), moderate (7-9), high (10-12) complexity, Vessel vascular invasion, Perirenal fat perirenal fat invasion, Renal cavity renal sinus/pelvis invasion, ASA American society of anesthesiologists. Table 2. Distribution of metastatic sites in patients with small renal cell carcinoma (≤4 cm) Distant metastasis sites Metastasis 50 Synchronous 19 metachronous 31 P value Number of metastatic lesions 0.027 * Single lesion 39 12 27 Multiple lesions 11 7 4 Lung, n 22 7 15 0.42 Bone, n 21 13 8 0.002 * Liver, n 4 2 2 0.58 Adrenal, n 7 3 4 0.69 Brain, n 4 2 2 0.58 Other, n 8 1 7 0.25 Table 3 Comparison of clinicopathological characteristics between metastatic (case group) and non-metastatic (control group) small renal cell carcinoma patients Variable Non-metastasis Metastasis P value Age 60.54±9.99 60.85±8.86 0.833 BMI 25.35±3.09 25.12±3.74 0.640 Hg 145.46±12.90 133.39±17.61 <0.001 * Scr 92.83 76.89 83.04 19.36 0.405 Gender 0.918 M 223 40 F 58 10 Side 0.448 L 141 28 R 140 22 Symptom 31 16 <0.001 * R.E.N.A.L. score <0.001 * low 181 17 moderate 97 27 high 7 6 Surgery <0.001 * PN 217 23 RN 64 27 Tumor diameter 0.253 1 9 3 2 80 10 3 192 37 pT3 18 12 <0.001 * N1 1 1 0.280 pathological grade <0.001 * I 46 5 II 200 24 III 28 16 IV 4 5 Vessel 3 3 0.047 * Perirenal Fat 4 4 0.020 * Renal Cavity 25 6 0.046* Table 4 Univariate and multivariate logistic regression analysis of factors influencing metastasis in small renal cell carcinoma (≤4cm). Variable Univariable logistic Multivariable logistic OR (95% CI) P OR (95% CI) P R.E.N.A.L. score low Ref moderate 2.28 (1.15-4.52) 0.019 * 3.46 (1.01–11.84) 0.048 * high 7.19 (2.08-24.88) 0.002 ** 6.52 (1.09–39.10) 0.004 ** Gender (M vs. F) 0.80(0.33-1.92) 0.611 Symptom 4.58 (2.08-10.05) <0.001* * 6.03(1.74-20.93) 0.005 ** Surgery (PN vs RN) 6.25（3.03-12.89） <0.001 ** 1.37(0.44-4.32) 0.587 pT3 5.39（2.26-12.84） 0.001 ** 3.17 (1.06-9.49) 0.04 * Pathological grade I Ref II 0.44 (0.22-0.88) 0.021 * 0.89(0.40-1.95) 0.762 III 4.48 (1.95-10.28) <0.001 ** 5.19 (1.60–16.75) 0.006 ** IV 10.62（2.43-46.38） 0.002 ** 4.44 (0.99-19.92) 0.05 * Perirenal Fat 5.57 (1.09-28.45) 0.04 * 0.48(0.04-6.16) 0.569 *, a significance level of p<0.05; **, a significance level of p<0.01 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 21 Oct, 2025 Read the published version in World Journal of Urology → Version 1 posted Editorial decision: Revision requested 21 Aug, 2025 Reviews received at journal 20 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviews received at journal 18 Aug, 2025 Reviewers agreed at journal 17 Aug, 2025 Reviewers agreed at journal 16 Aug, 2025 Reviews received at journal 15 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers invited by journal 15 Aug, 2025 Editor assigned by journal 30 Jul, 2025 Submission checks completed at journal 30 Jul, 2025 First submitted to journal 29 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7244316","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":503630294,"identity":"0ff71fbc-f70a-470e-9cbb-2d5f58a70dd0","order_by":0,"name":"Zhiying Wu","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhiying","middleName":"","lastName":"Wu","suffix":""},{"id":503630295,"identity":"39fea006-045a-4ee6-b781-43367ecb47c6","order_by":1,"name":"Dameng Pan","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dameng","middleName":"","lastName":"Pan","suffix":""},{"id":503630298,"identity":"664515eb-ebc3-46cb-89fc-c73805c77e54","order_by":2,"name":"Jinghui Ji","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinghui","middleName":"","lastName":"Ji","suffix":""},{"id":503630299,"identity":"b771c656-d434-4ad0-b619-207e463fb7c3","order_by":3,"name":"Xiaojun Tian","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaojun","middleName":"","lastName":"Tian","suffix":""},{"id":503630300,"identity":"a501b795-b957-4ed3-b7ff-d0b466edd935","order_by":4,"name":"Hongxian Zhang","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongxian","middleName":"","lastName":"Zhang","suffix":""},{"id":503630301,"identity":"3bb0ced7-5da0-458c-9af3-83fa32338d23","order_by":5,"name":"Min Qiu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYDACZiBOYLBJYGwA8diI15JGihYIOJwAoYnRwnecx3TDwx3n85innTFg+FB2mIF/dgN+LZKHecxuJJ65Xcw4O8eAcca5wwwSdw7g12IA1tJ2O7ERqIWZt+0wg4FEAlFazkG0/CVBywGIFkZitEgeZisDakkG+iWt4GDPuXQeiRsEtPCdP7zt5s82uzzD2ckbH/wos5bjn0FAC8MBKG3YAGHzEFCPpEWesNJRMApGwSgYqQAAY5NHI03Cqy4AAAAASUVORK5CYII=","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":true,"prefix":"","firstName":"Min","middleName":"","lastName":"Qiu","suffix":""},{"id":503630302,"identity":"95c9aac0-716f-4ded-8188-4292b09d2679","order_by":6,"name":"Lulin Ma","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lulin","middleName":"","lastName":"Ma","suffix":""},{"id":503630303,"identity":"4c2bf785-e313-4d56-83b1-70594259dd48","order_by":7,"name":"Zhiying Zhang","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhiying","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-07-29 14:23:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7244316/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7244316/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00345-025-05967-w","type":"published","date":"2025-10-21T16:16:22+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89673093,"identity":"07d02804-fd63-44d4-96b5-66244306d480","added_by":"auto","created_at":"2025-08-22 13:11:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":100830,"visible":true,"origin":"","legend":"\u003cp\u003ePatient enrollment flowchart of small renal cell carcinoma (≤4 cm) surgical cases.\u003c/p\u003e","description":"","filename":"Picture1.png","url":"https://assets-eu.researchsquare.com/files/rs-7244316/v1/ec51d7a7108187288d6587f1.png"},{"id":89673551,"identity":"1be4370b-fc6d-4dce-b42f-74ed06d21cea","added_by":"auto","created_at":"2025-08-22 13:19:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32708,"visible":true,"origin":"","legend":"\u003cp\u003ePredictive model for small ccRCC metastasis. (a) Nomogram, (b) ROC curve, (c) Calibration plot. (a) Nomogram incorporating independent risk factors (points assigned for each variable, total points map to metastasis probability). (b) ROC curve showing model discrimination (AUC 0.813 [95% CI 0.742–0.883]). (c) Calibration plot of the training set with bootstrap-corrected estimates (dotted 45° line = ideal fit; solid line = observed vs predicted risk).\u003c/p\u003e","description":"","filename":"Picture2.png","url":"https://assets-eu.researchsquare.com/files/rs-7244316/v1/9feb19961cbf1cefb6201ff9.png"},{"id":89673094,"identity":"25d5abec-b0c7-44fa-a346-f740d47cf371","added_by":"auto","created_at":"2025-08-22 13:11:59","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":91311,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival analysis of small renal cell carcinoma (≤4 cm) patients. (a) Metastatic vs non-metastatic groups, (b) Subgroup analysis of metastatic cases (non-metastatic \u0026nbsp;vs synchronous vs metachronous). (a) Comparison of overall survival between metastatic (n=50) and non-metastatic groups (n=1004). The 5-year survival rate was 75.8% vs 99.1% (log-rank P\u0026lt;0.0001). (b) Survival stratification within metastatic cases: synchronous (n=19, 3-year OS 71.2%) vs metachronous metastasis (n=31, 3-year OS 85.3%; log-rank P=0.051).\u003c/p\u003e","description":"","filename":"Picture3.png","url":"https://assets-eu.researchsquare.com/files/rs-7244316/v1/08ab24986fe9d1f154921db9.png"},{"id":94490568,"identity":"e78a6d8d-b6b7-406d-a2c0-273945545fe6","added_by":"auto","created_at":"2025-10-27 17:12:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":955304,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7244316/v1/a442a177-7f09-4b89-b080-4f5e0264776a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk Factors and Metastasis Prediction in Small (≤4 cm) Clear Cell Renal Cell Carcinoma: A Nested Case-Control Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRenal carcinoma (RCC), as a malignancy originating from the epithelial cells of the renal tubules, accounts for approximately 2\u0026ndash;3% of all adult malignancies, and is the most common type of renal malignancy in adults\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Acting as the most common histological type, clear cell RCC (ccRCC) takes up around 90% for all cases with RCC\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. According to the European Association of Urology, RCC with a tumor diameter of \u0026le;\u0026thinsp;4 cm is defined as as small RCC\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Most patients with small RCC are clinically staged as stage T1a, which is a limited-stage RCC, which is commonly treated by surgery. Surgical treatment ocan provide favorable oncologic and functional outcomes for patients with small RCC, with a 5-year tumor-specific survival rate of 96\u0026ndash;97% for cT1a stage RCC\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSmall RCC, even though considered to be at low risk generally, may still develop distant metastasis\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Synchronous and metachronous metastasis has been reported to be 1%-7% in patients with small RCC\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. For example, the synchronous metastasis rate was 7% in patients with small RCC as proposed in a multi-institutional study by Klatte et al.\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Meanwhile, Thompson et al. found that 162 out of 2,691 patients with small RCC (6%) had synchronous metastasis\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. In another a systematic review incorporating 18 studies on active surveillance of small RCC by Smaldone et al.\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, 880 patients with small RCC were followed up for an average of 40 months, and only 18 patients (2.0%) developed metastases. However and critically, patients may experience significantly worsened prognosis once metastasis occurs in small RCC. Overseas research has documented a 5-year overall survival (OS) rate of only 20% in patients with metastatic small RCC\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Currently, there are few reports on the prognosis of metastatic small RCC in China. Small RCC with synchronous or metachronous metastasis exhibit specific biological characteristics, highlighting the significance of exploring the metastatic potential in small ccRCC for guiding its treatment and follow-up. In this study, we retrospectively examined patients with small RCC who were treated at Peking University Third Hospital between 2012 and 2024. The present study summarized the clinicopathological characteristics of metastatic small RCC patients and explored the risk factors affecting metastasis and prognosis in these patients through a nested case-control study, thereby contributing to clinical treatment decision-making.\u003c/p\u003e"},{"header":"Materials and methods","content":"\n\u003ch3\u003e1. Study participants\u003c/h3\u003e\n\u003cp\u003eThis retrospective cohort study included small ccRCC patients who were treated at the Third Hospital of Peking University between 2012 and 2024.\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e1.1 The inclusion criteria were: 1) renal tumor with a maximum diameter of \u0026le;\u0026thinsp;4 cm by complete preoperative abdominal CT or MRI examination; 2) partial nephrectomy (PN) or radical nephrectomy (RN); 3) ccRCC confirmed by postoperative pathology; and 4) complete and accurate clinical follow-up data. For patients with metastasis, there must be clear evidence for the presence of the site of metastasis and the time of onset of progression from imaging or pathological examination of biopsy or surgical tissue.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e1.2 The exclusion criteria were: 1) incomplete case data or loss of visit; 2) undergoing puncture, ablation and other treatments only, without surgical excision; and 3) non-ccRCC. Prior to the study, an official ethical approval was acquired from the Ethics Committee of the Third Hospital of Peking University (Ethics No. 2022-147-01).\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e1.3 Sources of cases and controls: In order to explore the factors influencing metastasis in small ccRCC, patients with metastatic carcinoma were used as the case group. Among patients with non-metastatic small ccRCC, gender, age ,tumor size and tumor location were used for propensity score matching at a ratio of 1:6 on the basis of the utilization of the nearest neighbor matching method, with a caliper value of 0.02. Patients with non-metastatic small ccRCC were matched as the control group.\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ch3\u003e2. Research Methods\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Clinical data\u003c/h2\u003e\u003cp\u003eBy reviewing the medical record system, this study recorded the clinicopathological characteristics of the enrolled patients, including age, gender, tumor side, body mass index (BMI), clinical symptoms, distant metastases, preoperative R.E.N.A.L. score\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, and surgical method. Hematological indices included hemoglobin and serum creatinine values. In addition, pathological data included tumor size, pathological grading, TNM stage and the performance of postoperative adjuvant therapy.\u003c/p\u003e\u003cp\u003eIn order to obtain prognostic information (e.g., survival status, recurrence and metastasis, adjuvant therapy, etc.), patients were followed up postoperatively through outpatient visits or by telephone. The initial follow-up took place 1 month after surgery, with subsequent follow-ups every 6\u0026ndash;12 months.\u003c/p\u003e\u003cp\u003eOur inclusion of specific indicators could be explained as follows: 1) A diagnosis of metastasis requires definitive imaging or pathological evidence. The results of pathological examined has been recognized to be the gold standard for patients undergoing resection for metastasis. Among them, synchronous metastasis is defined as distant metastasis present at the time of diagnosis of small ccRCC; while metachronous metastasis refers to distant metastasis occurring after surgery for small ccRCC. 2) Preoperative renal R.E.N.A.L. score: Based on the total scores, patients were categorized into three groups of low complexity (4\u0026ndash;6 points), moderate complexity (7\u0026ndash;9 points) and high complexity (10\u0026ndash;12 points). 3) Pathological grading: The Fuhrman grading system was used prior to 2016\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e and the WHO/ISUP nuclear grading system was adopted thereafter\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. 4) TNM staging was established by the American Joint Committee on Cancer (AJCC) in 2017\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. 5) Adjuvant therapy includes radiotherapy, chemotherapy, cytokine therapy, targeted therapy and immunotherapy, etc. 6) Survival status: OS is the period between the date of surgery and the date of death from any cause.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Statistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses in this study were completed in SPSS version 27.0 and R software version 4.5.1. With the performance of normality test, continuous variables following a normal distribution were described using the mean and standard deviation, and compared using independent samples \u003cem\u003et\u003c/em\u003e-tests in the context of equal variance. Categorical variables were expressed as percentages. The chi-squared test, and the non-parametric Mann-Whitney U test were adopted for dichotomous and unordered categorical variables, and ordered categorical variables, respectively. Univariate conditional logistic regression analysis was used to assess risk factors for metastasis in small ccRCC, with the calculation of the odds ratio (OR) and 95% confidence interval (CI) simultaneously. Subsequently, multivariate conditional logistic regression analysis was carried out by considering variables with statistically significant differences in the univariate analysis, as well as clinically recognized factors influencing metastasis. Forward stepwise regression based on maximum likelihood estimation was used for variable selection to validate their independent predictive value. Kaplan-Meier survival analysis and the log-rank test were used to assess risk factors influencing the OS in small ccRCC. For all statistical analyses, a two-sided \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003ch3\u003e1. Clinicopathological characteristics of the enrolled patients\u003c/h3\u003e\n\u003cp\u003eA total of 1,054 patients were ultimately included according to the inclusion and exclusion criteria preset in this study (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Of these patients, there were 775 (73.5%) male patients, and 279 (26.5%) female patients, with mean age of 56 years, and mean BMI of 25.65 kg/m\u0026sup2;. Meanwhile, 529 (50.2%) had tumors on the left side and 525 (49.8%) on the right side; moreover, 132 patients (12.5%) presented with clinical symptoms. According to the R.E.N.A.L. score, there were 646 patients (61.5%) in the low complexity group, 379 patients (35.1%) in the moderate complexity group, and 25 patients (2.4%) in the high complexity group. Furthermore, the surgical approach was PN in 868 cases (82.4%) and RN in 186 cases (17.6%). Tumor size was \u0026le;\u0026thinsp;2 cm in 194 cases (18.4%), 2.1-3 cm in 424 cases (40.2%), 3.1-4 cm in 436 cases (41.1%), and \u0026gt;\u0026thinsp;4 cm in 25 cases (2.4%). In addition, pathological grading was highly differentiated (grades I-II) in 911 cases (86.5%), moderately differentiated (grade III) in 127 cases (12.0%), and poorly differentiated or undifferentiated (grade IV) in 16 cases (1.5%). The clinicopathological characteristics of all patients are shown in Table 1. Critically, 50 (4.7%) had distant metastases, including 19 (1.7%) with synchronous metastases and 31 (2.7%) with metachronous metastases (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eFurthermore, a nested case-control study was designed to investigate the risk factors influencing metastasis in small ccRCC. The case group comprised 50 patients with metastatic small ccRCC, and the control group comprised 281 patients with non-metastatic small ccRCC. As presented in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e regarding the clinical and pathological characteristics, there were statistically significant differences between groups in clinical symptoms, R.E.N.A.L. score, hemoglobin, surgical approach, pT3 stage, pathological grade, microvascular invasion, perirenal fat invasion and renal pelvis and calyx invasion (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cp\u003eUnivariate logistic regression analysis revealed statistically significant differences in clinical symptoms, R.E.N.A.L. score, surgical approach, pT3 stage, pathological grading, and invasion of perirenal fat related to the occurrence of metastasis in small ccRCC patients (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). On these basis, subsequent multivariate logistic regression analysis showed that clinical symptoms (OR\u0026thinsp;=\u0026thinsp;6.03, 95% CI 1.74\u0026ndash;20.93, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), R.E.N.A.L. score [moderate complexity group (OR\u0026thinsp;=\u0026thinsp;3.46, 95% CI 1.01\u0026ndash;11.84, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048), and high complexity group (OR\u0026thinsp;=\u0026thinsp;6.52, 95% CI 1.09\u0026ndash;39.10, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) ], pT3 (OR\u0026thinsp;=\u0026thinsp;3.17, 95% CI 1.06\u0026ndash;9.49, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04), pathological grade III (OR\u0026thinsp;=\u0026thinsp;5.19, 95% CI 1.60-16.75, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006), and pathological grade IV (OR\u0026thinsp;=\u0026thinsp;4.44, 95% CI 0.99\u0026ndash;19.92, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05) were independent risk factors for metastasis in small ccRCC patients (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). All these six variables screened were selected to establish a nomogram for small ccRCC (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). The C-index (0.813) and the area under the receiver operating characteristic curve (\u0026gt;\u0026thinsp;0.7) indicated satisfactory discriminative ability of the nomogram (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb/c).\u003c/p\u003e\n\u003ch3\u003e2. Prognostic analysis for small ccRCC patients\u003c/h3\u003e\n\u003cp\u003eAll patients were followed up with a median follow-up period of 38 months (from 2 to 133 months). Among the cohort, 12 patients (1.04%) died. Tumor-specific death occurred in 10 patients (0.87%). According to the Kaplan-Meier survival curves, the 5-year OS rate of was 98.3%, 99.1%, and 75.8% for patients with small ccRCC, non-metastatic small ccRCC, and metastatic small ccRCC, respectively, showing significantly different difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea). Further survival analysis stratified by metastatic status demonstrated significant prognostic differences (P\u0026thinsp;=\u0026thinsp;0.051), with synchronous metastatic patients exhibiting the poorest survival outcomes compared to metachronous metastatic groups, as evidenced by Kaplan-Meier analysis (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIt has currently been well-established with respect to the epidemiology, clinicopathological characteristics, metastatic risk factors and prognosis of RCC. Moreover, great concern has been attached to 'large RCC (\u0026gt;\u0026thinsp;4 cm in diameter)', with relatively little controversy over its treatment and follow-up. However, for patients with metastatic small RCC, it is still poorly understood owing to the lack of certain standards with regard to corresponding clinicopathological characteristics, metastasis and prognostic factors. Current studies on small RCC exhibit disadvantages of small sample sizes, and the inclusion of European and American populations merely, with fewer reports on Asian populations. Significantly, this study was designed a large-sample, long-term retrospective research among the Chinese population, with the summary of the clinicopathological characteristics of metastatic small ccRCC. Moreover, a nested case-control study was carried out to explore the risk factors affecting the metastasis and prognosis of small ccRCC, which may provide valuable insights for clinicians in China to make treatment decisions.\u003c/p\u003e\u003cp\u003eOf the 1,054 small ccRCC patients who underwent surgery, 50 patients (4.7%) had distant metastases, including 19 patients (1.7%) with synchronous metastases and 31 patients (2.7%) with metachronous metastases, consistent with domestic and international studies\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. There were 22 cases of lung metastasis, 21 cases of bone metastasis, 4 cases of liver metastasis, 7 cases of adrenal metastasis, 4 cases of brain metastasis and 8 cases of metastasis to other sites. Further statistical analysis revealed more prevalent multiple metastases in the synchronous metastasis group than in the metachronous metastasis group with the most common distant metastatic site confirmed to be bones. Similarly, a multi-center retrospective study \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e found that the most common site of concomitant metastasis was the skeleton (65.4%) in patients with small ccRCC.\u003c/p\u003e\u003cp\u003eClinically, RCC patients may usually present with systemic symptoms (e.g., ever, malaise, weight loss and cachexia) and local symptoms (e.g., low back pain, a palpable abdominal mass and hematuria). Due to the increased availability of physical examinations and routine screening, the traditionally believed 'triad of RCC' (i.e., low back pain, hematuria and a palpable abdominal mass) is becoming increasingly rare among patients with small RCC. However and noticeably, the disease can be determined to be progressed, once these symptoms appear, and should be taken seriously in clinical practice. Tan et al. reported the presence of clinical symptoms in 155 (27.4%) cases among 565 patients with small RCC\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. The most common symptoms are hematuria, muscle pain and bone pain. Further multivariate logistic regression analysis revealed that synchronous metastases in small RCC could be independently predicted by the presence of clinical symptoms and an age of over 65 years. Kume et al. retrospectively analyzed 165 cases of surgically treated small RCC (\u0026le;\u0026thinsp;3 cm), and revealed that advanced age and clinical symptoms were significant risk factors for metastasis through multivariate logistic regression analysis\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Consistently, our study identified the presence of clinical symptoms as an independent predictor of metastasis in small ccRCC. Therefore, patients presenting with clinical symptoms at initial diagnosis of small RCC are at higher risk of developing metastasis, requiring more comprehensive evaluation and rigorous postoperative follow-up.\u003c/p\u003e\u003cp\u003eThe R.E.N.A.L. scoring system, proposed by Kutikov for the first time in 2009, was developed based on five oncological characteristics, namely the size of the renal tumor; the degree of convexity; the distance from the collecting system; the ventral or dorsal location; and the relationship to the upper and lower poles of the kidney\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. It can facilitate clinical assessment of the anatomical characteristics of renal tumors more accurately, and the development of appropriate surgical approaches. In the study of 830 patients who underwent PN for limited-stage RCC, Mouracade et al. found that pT stage, pathological grade, and R.E.N.A.L. score were independent predictors of disease-free survival \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. In our study, the R.E.N.A.L. score was an independent risk factor for metastasis in patients with small RCC, suggesting its value in both assessing the complexity and surgical risk of renal tumor surgery, and also in predicting metastasis in small RCC patients.\u003c/p\u003e\u003cp\u003eFurthermore, Fuhrman grading system, enabling the reflection of the tumor\u0026rsquo;s cellular heterogeneity and biological behavior, is an important indicator for identifying the degree of malignancy of RCC\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Fuhrman grades I and II tumors are highly differentiated; grade III tumors are moderately differentiated; while Grade IV tumors are poorly differentiated or undifferentiated. Subjects with higher Fuhrman grade would have less differentiated nucleus and worse prognosis. In an investigation on 2,033 cases of stage T1 RCC, patients with Fuhrman grade III or IV were four times more likely to experience metastasis than those with grade I or II\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Moreover, higher Fuhrman grade is usually associated with greater aggressiveness and poorer prognosis. For example, Kato et al. retrospectively analyzed 198 patients with small RCC from fifteen centers, and found obviously higher Fuhrman grade III or IV and more significant tumor invasive growth in patients with metastatic small RCC than in those without\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. As in previous national and international studies, a high pathological grade of small RCC suggests a higher risk of metastasis, as well as poorer survival. In our study, pathological grade (grade III and grade IV) was an independent risk factor for metastasis in small ccRCC patients.\u003c/p\u003e\u003cp\u003eIn the context of current advancement in targeted therapy, we know little about the specific role of cytoreductive nephrectomy for patients with metastatic RCC\u003csup\u003e[\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Surgical treatment, despite controversy over its therapeutic effect on metastatic renal cell carcinoma, can still improve patients' OS and cancer-specific survival\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Previous retrospective evidence also supports the idea that complete tumor reduction resulted in favorable OS and progression-free survival when treating concurrent metastatic RCC\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Dutcher et al. studied patients with metastatic small RCC who underwent PN\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e, and found that adjuvant targeted drug therapy such as sunitinib and sorafenib could significantly improve the prognosis of patients with metastatic RCC. Abel et al. reviewed patients with small RCC who underwent surgery with PN\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Of some of these patients who did not receive adjuvant molecular targeted drug therapy after surgery, 20/774 (2.6%) with pT1 stage RCC developed metastasis. The researchers concluded that, adjuvant targeted drug therapy should be routinely recommended after PN for some high-risk patients with small RCC to reduce the risk of postoperative recurrence and metastasis. In our study, all patients with small RCC underwent surgical treatment of the primary site, with the majority opting for PN. For patients with metastatic small RCC, cytoreductive nephrectomy and combined adjuvant therapy may be effective to improve their prognosis.\u003c/p\u003e\u003cp\u003eThis study still has certain limitations. Firstly, patients with small ccRCC usually have a favorable prognosis and low malignancy, as a result, the incidence of outcomes such as metastasis or death remained low despite the inclusion of 1,054 patients between 2012 and 2024 in our study. While the nested case-control study enhanced the credibility of the results, longer-term follow-up and larger multi-center studies are still needed for thorough validation and to establish predictive models with clinical application value. Secondly, due to the diversity of treatment regimens, the study did not include specific postoperative adjuvant therapies for patients with metastatic small ccRCC. Furthermore, all patients with metastatic small ccRCC underwent debulking surgery, with the exclusion of patients who received only targeted or immunotherapy. Therefore, this study failed to assess the independent impact of these treatments on the prognosis of patients with metastatic small ccRCC. In the future, there may be more therapeutic options to consider with the publication of more clinical trials and approval of new drugs. Selecting an appropriate treatment regimen is critical in improving the prognosis of patients with metastatic small RCC.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this study summarizes the clinical and pathological characteristics as well as prognosis of patients with metastatic small ccRCC. Univariate and multivariate logistic regression analyses revealed that clinical symptoms, clinical symptoms, higher R.E.N.A.L. score, pT3 stage, and higher pathological grading may be risk factors for metastasis of small ccRCC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003es contributions\u003c/strong\u003e This is the first submission of this manuscript and no parts of this manuscript are being considered for publication elsewhere. All authors have approved this manuscript. No author has financial or other contractual agreements that might cause conflicts of interest. Conception and design: MQ. Acquisition of data: ZW, DP, JJ. Analysis and interpretation of data: ZW. Drafting of the manuscript: ZW, DP. Critical revision of the manuscript for important intellectual content: MQ. Administrative, technical, or material support: XT, HZ, LM, SZ. Supervision: LM, MQ.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e All data generated for this analysis were from the Renal cancer database of Department of Urology, Peking University Third Hospital database. The de-identified patient data supporting the findings of this study have been deposited in Science Data Bank (ScienceDB) and are publicly available under the accession code \u003cem\u003edoi: 10.57760/sciencedb.28616\u003c/em\u003e. Researchers may access these data in accordance with ScienceDB\u0026apos;s terms of use and data protection policies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e Zhiying Wu 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by Peking University Third Hospital Medical Science Research Ethics Committee (Ethics No. 2022-147-01). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhiying Wu \u0026bull; Dameng Pan \u0026bull; Jinghui Ji \u0026bull; Xiaojun Tian \u0026bull; Hongxian Zhang \u0026bull; Min Qiu \u0026bull; Lulin Ma \u0026bull; Shudong Zhang\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCorresponding author: Lulin Ma [email protected]; Min Qiu [email protected]\u003c/p\u003e\n\u003cp\u003eDepartment of Urology, Peking University Third Hospital, Beijing 100083, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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Urologia, 2022, 89(2): 307-10. http://doi: 10.1177/03915603211007059.\u003c/li\u003e\n\u003cli\u003eSCHIEDA N, KRISHNA S, PEDROSA I, et al. Active Surveillance of Renal Masses: The Role of Radiology [J]. Radiology, 2022, 302(1): 11-24. http://doi.org/10.1148/radiol.2021204227.\u003c/li\u003e\n\u003cli\u003eTHOMPSON R H, HILL J R, BABAYEV Y, et al. Metastatic renal cell carcinoma risk according to tumor size. J Urol, 2009, 182(1): 41-5. http://doi.org/10.1016/j.juro.2009.02.128.\u003c/li\u003e\n\u003cli\u003eKLATTE 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(5): 1719-26. http://doi.org/10.1016/j.juro.2008.01.018.\u003c/li\u003e\n\u003cli\u003eUmbreit EC, Shimko MS, Childs MA, et al. Metastatic potential of a renal mass according to original tumour size at presentation. 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T1a Renal Cell Carcinoma With Metastasis: Japanese Society of Renal Cancer Retrospective Multi-institute Results. Anticancer Research, 2023, 43(9):4061-5. http://doi.org/10.21873/anticanres.16595.\u003c/li\u003e\n\u003cli\u003eTAN Y G, KHALID M F B, VILLANUEVA A, et al. Are small renal masses all the same? Int J Urol, 2020, 27(5): 439-47. http://doi.org/10.1111/iju.14219.\u003c/li\u003e\n\u003cli\u003eKUME H, SUZUKI M, FUJIMURA T, et al. Distant metastasis of renal cell carcinoma with a diameter of 3 cm or less-which is aggressive cancer? J Urol, 2010, 184(1): 64-8. http://doi.org/10.1016/j.juro.2010.03.019.\u003c/li\u003e\n\u003cli\u003eMOURACADE P, KARA O, MAURICE M J, et al. Patterns and Predictors of Recurrence after Partial Nephrectomy for Kidney Tumors. J Urol, 2017, 197(6): 1403-9. http://doi.org/10.1016/j.juro.2016.12.046.\u003c/li\u003e\n\u003cli\u003eGU\u0026eth;MUNDSSON E, HELLBORG H, LUNDSTAM S, et al. Metastatic potential in renal cell carcinomas \u0026le;7 cm: Swedish Kidney Cancer Quality Register data. Eur Urol, 2011, 60(5): 975-82. http://doi.org/10.1016/j.eururo.2011.06.029.\u003c/li\u003e\n\u003cli\u003eDahm P, Ergun O, Uhlig A, Bellut L, et al. Cytoreductive nephrectomy in metastatic renal cell carcinoma. Cochrane Database Syst Rev. 2024 Jun 7;6(6):CD013773. http://doi.org/10.1002/14651858.CD013773.pub2.\u003c/li\u003e\n\u003cli\u003ePindoria N, Raison N, Blecher G, et al. Cytoreductive nephrectomy in the era of targeted therapies: a review. BJU Int. 2017 Sep;120(3):320-328. http://doi.org/10.1111/bju.13860.\u003c/li\u003e\n\u003cli\u003eBex A, Mulders P, Jewett M, et al. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol. 2019 Feb 1;5(2):164-170. http://doi.org/10.1001/jamaoncol.2019.0117.\u003c/li\u003e\n\u003cli\u003eDABESTANI S, MARCONI L, BEX A. Metastasis therapies for renal cancer. Curr Opin Urol, 2016, 26(6): 566-72. http://doi.org/10.1097/MOU.0000000000000330.\u003c/li\u003e\n\u003cli\u003eBARBASTEFANO J, GARCIA J A, ELSON P, et al. Association of percentage of tumour burden removed with debulking nephrectomy and progression-free survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. BJU Int, 2010, 106(9):1266-9. http://doi.org/10.1111/j.1464-410X.2010.09323.x.\u003c/li\u003e\n\u003cli\u003eDUTCHER J P. Recent developments in the treatment of renal cell carcinoma . Ther Adv Urol, 2013, 5(6): 338-53. http://doi.org/10.1177/1756287213505672.\u003c/li\u003e\n\u003cli\u003eABEL E J, CULP S H, MEISSNER M, et al. Identifying the risk of disease progression after surgery for localized renal cell carcinoma . BJU Int, 2010, 106(9): 1277-83. http://doi.org/10.1111/j.1464-410X.2010.09337.x.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eTable 1 The clinical and pathological characteristics of patients diagnosed with small clear cell renal cell carcinoma (\u0026le;4cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eDescription\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e55.83\u0026plusmn;11.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e25.65\u0026plusmn;3.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eHgb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e145.14\u0026plusmn;13.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003ePlt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e242.78\u0026plusmn;42.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eScr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e81 (37, 1220)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e775 (73.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e279 (26.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e132 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003ePN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e868 (82.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eRN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e186 (17.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eLateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e529 (50.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e525 (49.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eR.E.N.A.L score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003elow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e646 (61.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003emoderate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e379 (35.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003ehigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e25 (2.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eTumor diameter (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026le;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e194 (18.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e2.1-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e424 (40.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e3.1-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e436 (41.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003epT3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e70 (6.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eN1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e3 (0.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e50 (4.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003epathological grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e200 (19.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e711 (67.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e127 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e16 (1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eVessel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e16 (1.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003ePerirenal fat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e18 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eRenal cavity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e48 (4.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eASA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e195 (18.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e809 (76.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e48 (4.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e2 (0.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cem\u003eBMI\u003c/em\u003e body mass index, \u003cem\u003eHgb\u0026nbsp;\u003c/em\u003ehemoglobin,\u003cem\u003e\u0026nbsp;Plt\u0026nbsp;\u003c/em\u003eplatelet count,\u003cem\u003e\u0026nbsp;\u003c/em\u003eScr serum creatinine,\u003cem\u003e\u0026nbsp;R.E.N.A.L. \u0026nbsp;score groups\u0026nbsp;\u003c/em\u003elow (4-6), moderate (7-9), high (10-12) complexity,\u003cem\u003e\u0026nbsp;Vessel\u0026nbsp;\u003c/em\u003evascular invasion,\u003cem\u003e\u0026nbsp;Perirenal fat\u0026nbsp;\u003c/em\u003eperirenal fat invasion, \u003cem\u003eRenal cavity\u003c/em\u003e renal sinus/pelvis invasion,\u003cem\u003e\u0026nbsp; ASA\u003c/em\u003e American society of anesthesiologists.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eTable 2. Distribution of metastatic sites in patients with small renal cell carcinoma (\u0026le;4 cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eDistant metastasis sites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003eMetastasis\u003c/p\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003eSynchronous\u003c/p\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003emetachronous\u003c/p\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eNumber of metastatic lesions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e0.027\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eSingle lesion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eMultiple lesions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eLung, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eBone, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eLiver, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eAdrenal, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eBrain, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eOther, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 528px;\"\u003e\n \u003cp\u003eTable 3\u0026nbsp;Comparison of clinicopathological characteristics between metastatic (case group) and non-metastatic (control group) small renal cell carcinoma patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eNon-metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eMetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e60.54\u0026plusmn;9.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e60.85\u0026plusmn;8.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.833\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e25.35\u0026plusmn;3.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e25.12\u0026plusmn;3.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.640\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e145.46\u0026plusmn;12.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e133.39\u0026plusmn;17.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eScr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e92.83 76.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e83.04 19.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.405\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.918\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e223\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eSide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.448\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eSymptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eR.E.N.A.L. score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003elow\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e181\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003emoderate\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003ehigh\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003ePN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e217\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eRN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eTumor diameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.253\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003epT3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eN1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.280\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003epathological grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eVessel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.047\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003ePerirenal Fat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.020\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 162px;\"\u003e\n \u003cp\u003eRenal Cavity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.046*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 62.4509%;\"\u003e\n \u003cp\u003eTable 4 Univariate and multivariate logistic regression analysis of factors influencing metastasis in small renal cell carcinoma (\u0026le;4cm).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 26.5511%;\"\u003e\n \u003cp\u003eUnivariable logistic\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 23.174%;\"\u003e\n \u003cp\u003eMultivariable logistic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eR.E.N.A.L. score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003elow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003emoderate\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e2.28 (1.15-4.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e0.019\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e3.46 (1.01\u0026ndash;11.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.048\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003ehigh\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e7.19 (2.08-24.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e0.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e6.52\u0026nbsp;(1.09\u0026ndash;39.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.004\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eGender (M vs. F)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e0.80(0.33-1.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e0.611\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eSymptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e4.58 (2.08-10.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e\u0026lt;0.001*\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e6.03(1.74-20.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.005\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eSurgery (PN vs RN)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e6.25（3.03-12.89）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e1.37(0.44-4.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.587\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003epT3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e5.39（2.26-12.84）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e3.17 (1.06-9.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.04\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003ePathological grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e0.44 (0.22-0.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e0.021\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e0.89(0.40-1.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.762\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e4.48 (1.95-10.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e5.19\u0026nbsp;(1.60\u0026ndash;16.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.006\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e10.62（2.43-46.38）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e0.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e4.44\u0026nbsp;(0.99-19.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.05\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17.2349%;\"\u003e\n \u003cp\u003ePerirenal Fat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.1185%;\"\u003e\n \u003cp\u003e5.57 (1.09-28.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.4326%;\"\u003e\n \u003cp\u003e0.04\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3717%;\"\u003e\n \u003cp\u003e0.48(0.04-6.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7.8023%;\"\u003e\n \u003cp\u003e0.569\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 67.8916%;\"\u003e\n \u003cp\u003e*, a significance level of p\u0026lt;0.05; **, a significance level of p\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Small renal cell carcinoma, Metastasis, Risk factors, Prognosis","lastPublishedDoi":"10.21203/rs.3.rs-7244316/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7244316/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTo investigate the clinicopathological factors affecting the metastasis and prognosis in small clear cell renal carcinoma (ccRCC) (\u0026le;\u0026thinsp;4 cm), so as to guide clinical management and follow-up.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis study retrospectively analyzed the clinical and pathological data, as well as the follow-up data of 1,054 small ccRCC patients undergoing surgery at the Third Hospital of Peking University between 2012 and 2024. Following the identification of 50 small ccRCC patients with metastasis (the case group), a nested case-control study was further carried out with the matching of 281 small ccRCC patients without metastasis during the same period (the control group), according to a ratio of 1:6. Furthermore, risk factors affecting the metastasis of small ccRCC were investigated by using univariate and multivariate logistic regression analyses.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOf the 1,054 small ccRCC patients, metastasis (synchronous metastasis, 1.8%; and metachronous metastasis, 2.9%) occurred in 4.7% of small ccRCC patients. The 5-year overall survival rates were 99.1% and 75.8% for patients with non-metastatic and metastatic small ccRCC, respectively. Multivariate logistic regression analysis revealed that the presence of clinical symptoms, R.E.N.A.L. score (moderate complexity group and high complexity group), pT3 and pathological grade III and IV were independent risk factors for metastasis in small ccRCC patients.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePatients with small ccRCC may experience a metastatic rate of 4.7%. Clinical symptoms, higher R.E.N.A.L. score, pT3 stage, and higher pathological grading may be risk factors for metastasis of small ccRCC.\u003c/p\u003e","manuscriptTitle":"Risk Factors and Metastasis Prediction in Small (≤4 cm) Clear Cell Renal Cell Carcinoma: A Nested Case-Control Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 13:11:54","doi":"10.21203/rs.3.rs-7244316/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-21T11:07:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-20T22:05:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"231720683086502763071880934866226989178","date":"2025-08-20T21:32:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-19T03:29:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"282738110196308690914330248798488819139","date":"2025-08-17T20:43:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242720836565711183765756164459694153646","date":"2025-08-16T16:16:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-15T23:01:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9843389773727084978207774524076534020","date":"2025-08-15T12:13:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237983122728336908787239009822062726118","date":"2025-08-15T10:26:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-15T07:26:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-30T17:03:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-30T15:27:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Urology","date":"2025-07-29T14:19:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"85d1558b-c3c5-42eb-91ba-bdbeb0a34115","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T16:33:36+00:00","versionOfRecord":{"articleIdentity":"rs-7244316","link":"https://doi.org/10.1007/s00345-025-05967-w","journal":{"identity":"world-journal-of-urology","isVorOnly":false,"title":"World Journal of Urology"},"publishedOn":"2025-10-21 16:16:22","publishedOnDateReadable":"October 21st, 2025"},"versionCreatedAt":"2025-08-22 13:11:54","video":"","vorDoi":"10.1007/s00345-025-05967-w","vorDoiUrl":"https://doi.org/10.1007/s00345-025-05967-w","workflowStages":[]},"version":"v1","identity":"rs-7244316","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7244316","identity":"rs-7244316","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}