Natural History of Von Hippel-Lindau Disease-associated and Sporadic Clear Cell Renal Cell Carcinoma: a Comparative Study
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Abstract Purpose: To compare the tumor growth kinetics between sporadic clear cell renal cell carcinoma (ccRCC) and Von Hippel-Lindau disease-associated renal cell carcinoma (VHL-associated RCC). To analyze predictive markers for the growth rate of these two types of RCC.Methods: The clinical data of patients with renal tumors who received active surveillance were collected retrospectively. Immunohistochemical staining was utilized to analyze the expression levels of VHL, PBRM1, H3K36me3, and BAP1 in the postoperative specimens.Results: The age of the VHL group was significantly younger than that of the sporadic group (P<0.0001). The mean linear growth rate (LGR) was significantly faster in the sporadic group (P=0.0004). The tumors of those in the sporadic group tended to have a higher histologic grade (P=0.0011). In the sporadic group, tumor histologic grade was an independent predictor for rapid mean LGR (P=0.0022). In the VHL group, tumor initial MTD was the only independent predictor for rapid mean LGR (P＜0.0001). Tumors with low VHL expression and negative PBRM1 expression showed a faster growth rate in the sporadic group (P=0.001 and P=0.008, respectively). The expression levels of the 4 biomarkers showed no impact on the tumor growth rate in the VHL group.Conclusion: Sporadic ccRCC grew faster than VHL-associated RCC. High histologic grade, low VHL expression and negative PBRM1 expression were predictors of faster growth in sporadic ccRCC. A large initial MTD was a predictor of faster growth for VHL-associated RCC.
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Natural History of Von Hippel-Lindau Disease-associated and Sporadic Clear Cell Renal Cell Carcinoma: a Comparative Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Natural History of Von Hippel-Lindau Disease-associated and Sporadic Clear Cell Renal Cell Carcinoma: a Comparative Study Jie Wang, Lei Zhang, Jianhui Qiu, Ziao Li, Yucai Wu, Cuijian Zhang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-675576/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Purpose: To compare the tumor growth kinetics between sporadic clear cell renal cell carcinoma (ccRCC) and Von Hippel-Lindau disease-associated renal cell carcinoma (VHL-associated RCC). To analyze predictive markers for the growth rate of these two types of RCC. Methods: The clinical data of patients with renal tumors who received active surveillance were collected retrospectively. Immunohistochemical staining was utilized to analyze the expression levels of VHL, PBRM1, H3K36me3, and BAP1 in the postoperative specimens. Results: The age of the VHL group was significantly younger than that of the sporadic group (P<0.0001). The mean linear growth rate (LGR) was significantly faster in the sporadic group (P=0.0004). The tumors of those in the sporadic group tended to have a higher histologic grade (P=0.0011). In the sporadic group, tumor histologic grade was an independent predictor for rapid mean LGR (P=0.0022). In the VHL group, tumor initial MTD was the only independent predictor for rapid mean LGR (P＜0.0001). Tumors with low VHL expression and negative PBRM1 expression showed a faster growth rate in the sporadic group (P=0.001 and P=0.008, respectively). The expression levels of the 4 biomarkers showed no impact on the tumor growth rate in the VHL group. Conclusion: Sporadic ccRCC grew faster than VHL-associated RCC. High histologic grade, low VHL expression and negative PBRM1 expression were predictors of faster growth in sporadic ccRCC. A large initial MTD was a predictor of faster growth for VHL-associated RCC. Cancer Biology Oncology Clear cell renal cell carcinoma VHL-associated RCC Natural history Active surveillance Growth rate Figures Figure 1 Figure 2 Figure 3 Introduction Renal cell carcinomas (RCCs) represent approximately 3% of all cancers, of which clear cell renal cell carcinoma (ccRCC) is the most common histotype, representing 70–80% of cases(Deng and Melamed, 2012 ; Ljungberg et al., 2019 ). Although the vast majority of RCCs are sporadic, approximately 3% of RCCs are hereditary, and Von Hippel-Lindau disease-associated renal cell carcinoma (VHL-associated RCC) is a common hereditary RCC(Maher, 2018 ). The detection of renal masses (RMs) has increased worldwide over the past several decades due to the widespread use of advanced imaging examinations(Chow et al., 1999 ; Kümmerlin et al., 2008 ; Wagstaff et al., 2014 ). Of all the newly discovered RMs, the proportion of renal masses ≤ 4.0 cm (small RMs) is increasing(Chow and Devesa, 2008 ; Cooperberg et al., 2008 ; Hsieh et al., 2017 ). However, the mortality rate of RMs has not decreased as the operation rate of small RMs has increased, and the specific mortality rate of small RMs has even increased gradually(Hollingsworth et al., 2006 ; Van Poppel et al., 2007 ; Campbell et al., 2009 ; Sun et al., 2011 ; Scosyrev et al., 2014 ; Ljungberg et al., 2019 ). A number of studies have demonstrated that 20–30% of small RMs are confirmed to be benign tumors after surgery(Vasudevan et al., 2006 ; Crispen et al., 2008 ). In addition, Campbell et al. reported that in patients aged 75 years or older with small RMs, only patient age and comorbidities were independent predictors of overall survival outcomes, and surgical intervention did not provide significant survival benefits(Lane et al., 2010 ). Based on the above factors, urologists have paid increasing attention to researching the therapeutic effect of active surveillance (AS) of small RMs. To date, several researchers have assessed the natural history of sporadic ccRCC and VHL-associated RCC, but no consensus has been reached on the tumor growth rate and its predictive markers(Crispen et al., 2009 ; Zhang et al., 2009 ; Staehler et al., 2010 ; Mason et al., 2011 ; Zhang et al., 2012 ; Zhang et al., 2015 ; Peng et al., 2019 ; Schuhmacher et al., 2019 ). Few studies have explored the difference in natural history between the two types of RCC. In this study, sporadic ccRCC and VHL-associated RCC were analyzed together to compare the differences in growth rate between the two tumors. In addition, RCC is a highly heterogeneous tumor(2013; Hsieh et al., 2017 ). The TRACERx renal study showed, for the first time, that ccRCC can be divided into several evolutionary subtypes, and the main basis for typing is mutations in the VHL, PBRM1, SETD2 and BAP1 genes(Edmunds et al., 2008 ; Turajlic et al., 2018 ). Schraml et al. verified that the four subtypes of ccRCC have differences in tumor stage and nuclear grade(Bihr et al., 2019 ). Therefore, we believe that it may be possible to predict the growth rate of ccRCC by determining whether there are mutations in these four genes. In the present study, the differences in the expression levels of VHL, PBRM1, H3K36me3 and BAP1 between the two groups were measured by immunohistochemical staining, and their relationship with the tumor growth rate was analyzed. Materials And Methods Patient selection We searched the databases of renal tumors at the Institute of Urology, Peking University to identify patients who had renal tumors and received AS from January 1990 to December 2019. A total of 87 patients with 137 tumors were diagnosed with VHL-associated RCC; the mean age of all patients was 33 (range, 18–69) years, and more than half of the patients were men (50/87, 57.3%). The mean period of AS was 19.2 (range, 3-211.4) months. A total of 60 patients had 61 tumors that were considered sporadic ccRCC, and patients with pathologically confirmed non-ccRCC were excluded. The mean age was 55 (range, 26–81) years, and the majority of patients were men (47/60, 78.3%). The mean period of AS was 27 (range, 2-155) months. Delayed intervention, including radical nephrectomy and nephron-sparing surgery, was performed for all sporadic ccRCCs and 28 tumors the VHL-associated RCC group. Methods Patient characteristics, clinicopathological features, VHL disease information and natural tumor history were recorded. The linear growth rate (LGR) and volumetric growth rate (VGR) were used to evaluate the growth rate of tumors. The former refers to the growth rate of tumors on a certain diameter line, often expressed by the growth rate (cm/year) of the maximal tumor diameter (MTD) measured on the tumor cross section. The latter can also be described as the volume doubling time (VDT). Immunohistochemical staining was utilized to analyze the expression levels of VHL, PBRM1, H3K36me3, and BAP1 in the postoperative specimens. All results were evaluated with the assistance of urological pathologists blinded to the patients’ clinical data. According to the comparison with normal renal tissue staining, the VHL, H3K36me3 and BAP1 staining results were used to divide the tumors into low expression and high expression groups, and PBRM1 staining results were used to divide the tumors into negative and positive groups. Statistical analysis The Wilcoxon rank-sum test was used to compare the two groups. Fisher’s exact test was used to compare the expression levels of VHL, PBRM1, H3K36me3, and BAP1 between the two groups. Logistic regression and a general linear model were used to analyze the growth rate predictors. All data were recorded using Microsoft Office Excel and processed using SPSS V.22.0 statistical software. A P value < 0.05 was considered statistically significant. Result Patient characteristics and tumor features The patient characteristics, clinicopathologic features and tumor growth rates of the two groups are summarized in Table 1 . The VHL disease information of the VHL group is summarized in Table 2 . Although male patients were predominant in both of the groups, there was a statistically significant difference in the sex ratio between the two groups, which means that there were more male patients in the sporadic group (P = 0.0087). The median age of tumor onset in patients in the sporadic group was 55 (range, 26–81) years, while that of the patients in the VHL group was lower, at 33 (range, 18–69) years, and the difference between the two groups was statistically significant (P < 0.0001). Only one patient in the sporadic group had bilateral disease. The number of patients with bilateral disease in the VHL group was significantly higher than that in the sporadic group (P < 0.0001), with a total of 60 bilateral cases (69%). Regardless of whether the initial tumor size was measured by MTD or volume, there was no statistically significant difference between the two groups. The median AS times of the two groups were 27 (range, 2-155) months in the sporadic group and 19.2 (range, 3-221.4) months in the VHL group. The AS time of the sporadic group was significantly longer than that of the VHL group (P = 0.001). Regardless of whether tumor size was measured by MTD or tumor volume, the final average size of the tumor in the sporadic group was significantly larger than that in the VHL group (MTD, P < 0.0001; volume, P < 0.0001). It is worth mentioning that not all VHL-associated RCCs were resected during the study. We found that the AS time in the sporadic group was still longer than that in the VHL group when we included only patients with VHL-associated RCCs who underwent surgery; however, there was no significant difference in the final average tumor size between the sporadic group and the VHL group. Table 1 Patient characteristics and tumor features Variables Over all Sporadic group VHL group P Sex 0.0087 Male (%) 97 (66.0) 47 (78.3) 50 (57.5) Female (%) 50 (34.0) 13 (21.7) 37 (42.5) Age, yr Median (range) 40 (18–81) 55 (26–81) 33 (18–69) <0.0001 Side <0.0001 Unilateral (%) 86 (58.5) 59 (98.3) 27 (31.0) Bilateral (%) 61 (41.5) 1 (1.7) 60 (69.0) Initial tumor size Median (range) MTD, cm 2.0 (0.3–7.8) 1.9 (0.3–6.7) 2.1 (0.4–7.8) 0.8739 Volume, cm 3 4.9 (0.03–252.7) 5.5 (0.58–135.8) 4.9 (0.03–252.7) 0.4715 Duration of AS, mo Median (range) 22.8 (2-221.4) 27(2-155) 19.2(3-221.4) 0.001 Final tumor size Median (range) MTD, cm 3.0 (0.5–14.1) 4.0 (1.4–11.8) 2.6 (0.5–14.1) <0.0001 Volume, cm 3 17.4 (0.07–1493.0) 42.9 (1.6-895.4) 9.4 (0.07–1493.0) <0.0001 LGR, cm/yr 0.0004 Mean ± SD 0.62 ± 0.92 0.91 ± 1.0 0.49 ± 0.84 Median (range) 0.38 (-2.5-4.7) 0.61 (0-4.7) 0.30 (-2.5-4.7) VGR, cm 3 /yr <0.0001 Mean ± SD 28.0 ± 68.0 37.2 ± 66.2 23.9 ± 68.6 Median (range) 3.5 (-149.3-464.0) 9.3 (0.64–303.3) 2.0 (-149.3-464.0) VDT, days 0.1176 Mean ± SD 542.0 ± 943.7 673.9 ± 625.9 480.2 ± 1057 Median (range) 443.2 (-2255.7-7115.7) 560.6 (32.5-3214.3) 425.6 (-2255.7-7115.7) Surgery <0.0001 NSS (%) 41 (46.1) 19 (31.2) 22 (78.6) RN (%) 48 (53.9) 42 (68.8) 6 (21.4) Pathological stage 0.7913 T1 (%) 74 (83.2) 51 (83.6) 23 (82.1) T2 (%) 6 (6.7) 5 (8.2) 1 (3.6) T3 (%) 9 (10.1) 5 (8.2) 4 (14.3) Histological grade 0.0011 G1 (%) 40 (44.9) 20 (32.8) 20 (71.4) G2 (%) 43 (48.3) 36 (59.0) 7 (25.0) G3 (%) 6 (6.7) 5 (18.2) 1 (3.6) MTD, maximal tumor diameter; LGR, linear growth rate; VGR, volumetric growth rate; VDT, volume doubling time. Table 2 VHL disease information of VHL group Variables Amount, n (%) VHL subtypes Subtype I 64(73.6) Subtype II 23(26.4) Mutations Missense mutation 40(46.0) Truncating mutation 47(54.0) mutation sites Exon 1 34(39.1) Exon 2 20(23.0) Exon 3 27(31.0) Others 6(6.9) Combined tumors Central nervous system hemangioblastoma (CHB) 41(47.1) Retinal hemangioblastoma (RHB) 13(14.9) CHB + RHB 13(14.9) None 20(23.0) Family history Yes 20(23.0) No 59(67.8) Not clear 8(9.2) Table 3 Expression of VHL, PBRM1, H3K36me3, and BAP1 in the two groups Biomarkers Over all (n = 73) Sporadic group (n = 56) VHL group (n = 17) P VHL 0.7829 Low expression (%) 38 (52.1) 30 (53.6) 8 (47.1) High expression (%) 35 (47.9) 26 (46.4) 9 (52.9) PBRM1 0.4100 Negative (%) 28 (38.4) 20 (35.7) 8 (47.1) Positive (%) 45 (61.6) 36 (64.3) 9 (52.9) H3K36me3 1.0000 Low expression (%) 15 (20.6) 12 (21.4) 3 (17.6) High expression (%) 58 (79.4) 44 (78.6) 14 (82.4) BAP1 0.0574 Low expression (%) 17 (23.3) 10 (17.9) 7 (41.2) High expression (%) 56 (76.7) 46 (82.1) 10 (58.8) For patients who ultimately received surgical treatment, the proportion of nephron-sparing surgery was 31.2% in the sporadic group and 78.6% in the VHL group, and the difference was statistically significant (P < 0.0001). There was no difference in the tumor stage of all tumors that were finally removed between the two groups (P = 0.7913). The vast majority of tumors in the two groups were T1 stage (sporadic group, 83.6%; VHL group, 82.1%). The most common histological grade of the sporadic group was G2 (59.0%), and that of the VHL group was G1 (71.4%). There was a statistically significant difference in tumor histological grade between the two groups (P = 0.0011). Comparison of tumor growth rate in the two groups The tumor growth kinetics of the sporadic group and VHL group are presented in Table 1 . The growth rate of tumors in the sporadic group was significantly faster than that of the VHL group (LGR, P = 0.0004; VGR, P < 0.0001). However, there was no significant difference in VDT between the two groups (P = 0.1176). The distribution of LGR, VGR and VDT in the two groups is presented in Fig. 1 . The distribution of these three growth rate indicators in the sporadic group presented a “right-side tailing”. In contrast, the three indicators in the VHL group had an obvious central tendency. Immunohistochemical analysis The immunohistochemical staining results of the analyzed 4 biomarkers are shown in Fig. 2 . The results of VHL, H3K36me3, and BAP1 staining were distinguished by low and high expression because all of the tumors expressed these markers, while PBRM1 staining was distinguished by negative and positive. The comparison of the expression levels of these 4 biomarkers in the two groups is presented in Table 2 . Obviously, the expression levels of these 4 biomarkers were not significantly different between the two groups. A further log-linear model analysis showed that there was no correlation between any two of the four biomarkers between the two groups. Influencing factors of tumor growth rate In the sporadic group, age, sex, and tumor initial MTD were not correlated with the tumor growth rate, and only tumor histological grade was correlated with the LGR (P = 0.0022) and VGR (P = 0.0043), which means that the higher the tumor grade was, the faster the tumor growth rate was. However, initial MTD was correlated with VDT (P = 0.0012). In the VHL group, age, sex, histological grade, VHL subtypes, mutation types, combined tumors and family history were not associated with the tumor growth rate. However, initial MTD significantly affected the LGR (P < 0.0001) and VGR (P < 0.0001). In addition, only the combination of central nervous system hemangioblastoma or retinal hemangioblastoma was correlated with VDT (P = 0.0407). The effects of the expression of VHL, PBRM1, H3K36me3, and BAP1 on tumor LGR, VGR and VDT are presented in Table 4 . In the VHL group, the expression levels of the 4 biomarkers were not correlated with the tumor growth rate. In the sporadic group, the expression levels of H3K36me3 and BAP1 were not correlated with the tumor growth rate. However, the expression of VHL was correlated with the tumor LGR (P = 0.001), VGR (P = 0.021) and VDT (P = 0.002), and low expression of VHL promoted the tumor growth rate. The expression of PBRM1 was correlated with the tumor LGR (P = 0.008) and VDT (P = 0.047) and had a weak correlation with VGR (P = 0.051). Tumors with negative expression of PBRM1 grew faster. We further performed a subgroup analysis, which classified low VHL expression with negative PBRM1 as group 1, low VHL expression with positive PBRM1 and high VHL expression with negative PBRM1 as group 2, and high VHL expression with positive PBRM1 as group 3. The tumor growth rates of the three groups are shown in Fig. 3 . Obviously, for LGR and VGR, the relationship between the three groups was group 1 > group 2 > group 3. For VDT, the relationship between the three groups was group 3 > group 2 > group 1. There was a statistically significant difference between group 1 and group 3 (LGR, P = 0.000; VGR, P = 0.012; VDT, P = 0.003). There was a significant difference between group 2 and group 3 (LGR, P = 0.004; VDT, P = 0.014;but VGR, P = 0.058;). However, there was no significant difference between group 1 and group 2. In summary, we conclude that both low expression of VHL and negative PBRM1 expression are predictors of the rapid growth of sporadic ccRCC. Table 4 The effect of four biomarkers expression on tumor growth rate. VHL PBRM1 H3K36me3 BAP1 low high negative positive low high low high Sporadic group (n = 56) LGR (cm/yr) median (range) 0.74 (0.12–4.74) 0.37 (0-1.53) 0.77 (0.22–3.60) 0.42 (0-4.74) 0.62 (0.20–2.80) 0.58 (0-4.74) 0.58 (0.17–4.74) 0.61 (0-3.80) P 0.001 0.008 0.348 0.381 VGR (cm 3 /yr) median (range) 61.3 (0.73–303.3) 6.43 (0.65–42.9) 26.8 (0.79–303.3) 7.74 (0.65–245.8) 14.5 (0.75–303.3) 9.96 (0.65–274.0) 5.02 (0.79–205.8) 17.5 (0.65–303.3) P 0.021 0.051 0.466 0.295 VDT (days) median (range) 322.9 (32.5-2633.4) 658.0 (157.7-1948.1) 377.6 (69.0-1518.9) 587.7 (32.5-2633.4) 378.3 (117.6-1518.9) 573.9 (32.5-2633.4) 362.5 (32.5-1581.3) 573.3 (69.0-2633.4) P 0.002 0.047 0.358 0.285 VHL group (n = 17) LGR (cm/yr) median (range) 0.42 (-0.41-1.89) 0.72 (0.21–2.07) 0.50 (-0.41-1.89) 0.64 (0.21–2.07) 0.29 (-0.41-0.36) 0.95 (-0.25-2.07) 0.29 (-0.41-2.07) 0.68 (0.24–1.89) P 0.423 0.481 0.068 0.270 VGR (cm 3 /yr) median (range) 8.11 -9.42-159.6) 10.4 (2.39–87.6) 5.32 (-9.42-159.6) 10.4 (2.39–87.6) 6.22 (-9.42-10.0) 21.5 (-3.41-159.6) 6.22 (-9.42-72.6) 10.2 (3.35–159.6) P 0.963 0.321 0.300 0.364 VDT (day) median (range) 289.0 (-1015.5-1053.2) 284.0 (165.4-1197.6) 240.8 (-1015.5-1197.6) 424.6 (173.7-1047.9) 851.3 (-785.6-1053.2) 280.7 -1015.5-1197.6) 233.9 -1015.5- 1053.3) 366.4 (165.4-1197.6) P 0.815 0.423 0.591 0.364 LGR, linear growth rate; VGR, volumetric growth rate; VDT, volume doubling time. Discussion The gold standard for RM treatment is surgical resection(Campbell et al., 2009 ; Ljungberg et al., 2015 ). However, with the advancement of modern medicine, the increase in the detection rate and operation rate of small RMs has not reduced the mortality rate(Hollingsworth et al., 2006 ; Sun et al., 2011 ). Therefore, AS was recommended as a strategy for managing small RMs(Campbell et al., 2009 ; Ljungberg et al., 2015 ). However, there have been few studies on the natural history of sporadic ccRCC and VHL-associated RCC reported in the global literature. The present study aimed to compare the natural history of sporadic ccRCC and VHL-associated RCC combined with immunohistochemical analysis. Compared to sporadic ccRCC, we found that patients with VHL-associated RCC were younger, more likely to develop bilateral tumors, and had a lower histological grade at onset, which was consistent with the conclusions of previous studies(Maher et al., 2011 ; Ben-Skowronek and Kozaczuk, 2015 ). In addition, our study revealed that the sex ratio in patients with VHL-associated RCC was more equal, while the proportion of males in the sporadic group was higher, which was closer to the sex ratio of sporadic ccRCC shown in a previous large-scale epidemiological study(Siegel et al., 2020 ). There was no significant difference in the initial tumor size between the two groups, regardless of whether the tumor size was measured by MTD or volume. The sporadic group received AS for a longer period than the VHL group. We believe that this might be due to selection bias, as most sporadic ccRCC patients receiving AS had surgical contraindications. This conjecture is supported by the fact that the final average tumor size of the sporadic group at the last follow-up was larger than that of tumors in the VHL group. A previous meta-analysis showed that the mean LGR of sporadic small RMs was 0.28 cm/yr, and the growth rate of RCC diagnosed pathologically was approximately 0.4 cm/yr(Chawla et al., 2006 ). Our study only included patients diagnosed with ccRCC through pathology; the mean LGR was 0.91 cm/yr, and the median was 0.61 cm/yr. This result more accurately reflects the growth rate of ccRCC. In the VHL group in our study, the mean LGR was 0.49 cm/yr, and the median was 0.30 cm/yr, which was similar to that described in previous reports(Jilg et al., 2012 ; Zhang et al., 2012 ). We further compared the tumor growth rate of the two groups and found that the mean LGR and mean VGR of the sporadic group were significantly faster than those of the VHL group, which was consistent with previous findings that VHL-associated RCC is more indolent(Neumann et al., 1998 ; Zhang et al., 2012 ). We also found that VHL-associated RCC had zero or even negative growth, which was not observed for sporadic ccRCCs. Compared with sporadic ccRCC, the LGR distribution of VHL-associated RCC was more concentrated, which indirectly indicates that the heterogeneity of sporadic ccRCC was greater than that of VHL-associated RCC. Mutations in VHL, PBRM1, SETD2, and BAP1 cause loss of function of the encoded proteins in ccRCC. A study based on whole-genome sequencing found that PBRM1 and BAP1 mutations are largely mutually exclusive in ccRCC(Peña-Llopis et al., 2012 ). Schraml et al. reported that there was a significant correlation between the expression levels of PBRM1, H3K36me3 and BAP1 based on the tissue chip technique(Bihr et al., 2019 ). However, our study used immunohistochemical staining to analyze the expression levels of VHL, PBRM1, H3K36me3, and BAP1 in all tumors of the two groups and revealed that there was no correlation between any of them. We hypothesize that the reason for the different results in our study is that immunohistochemistry cannot accurately reflect gene mutations, and the results of immunohistochemical staining were also affected by the time of tissue fixation and conditions of wax block storage. Which factors are predictors of the tumor growth rate have always been the focus of research on the natural history of renal tumors, but there are still no widely accepted conclusions. This study revealed that in the sporadic ccRCC group, the patient’s age, sex, and initial size of the tumor had no effect on the tumor growth rate, which was consistent with the results of most other studies, including our previous studies(Chawla et al., 2006 ; Crispen et al., 2008 ; Zhang et al., 2015 ). However, histological grade was correlated with the tumor growth rate, and the higher the grade was, the faster the growth rate was. In the VHL group, the initial size of the tumor was an influencing factor for the growth rate, and other VHL disease-related factors, such as subtypes and mutation types, were not correlated with the tumor growth rate. We believe that these differences further prove that VHL-associated RCC and sporadic ccRCC are two different tumors, even though they are both classed as ccRCCs by histology. Loss of VHL protein is known to contribute to the initiation and progression of VHL disease-associated tumors as well as certain sporadic tumors, including ccRCC. Schraml et al. reported that PBRM1 was the second most frequently mutated gene in RCC after VHL, and loss of PBRM1 was correlated with advanced tumor stage, low differentiation grade and worse patient outcome(Pawłowski et al., 2013 ). However, Kilic et al. reported that weak PBRM1 and VHL expression was significantly associated with higher Fuhrman grade, but only weak VHL expression was associated with a higher pT stage and with decreased patient overall survival times, but PBRM1 expression did not affect the overall survival outcome(Högner et al., 2018 ). Our study revealed that the expression of VHL and PBRM1 was correlated with tumor histological grade; lower VHL expression was associated with higher tumor histological grade, but this trend was not observed for PBRM1. Moreover, we found that low VHL expression and negative PBRM1 were both correlated with the tumor growth rate and may have had additive effects in sporadic ccRCC. It is possible that VHL and PBRM1 will become sensitive predictors of the growth rate of sporadic ccRCC. Due to the limitations of retrospective design and sample size, prospective studies with a larger sample size are required to verify these results. Moreover, this study only qualitatively measured the protein expression level through immunohistochemistry; thus, the results remain to be further verified at the quantitative level. Conclusions Sporadic ccRCC grew faster than VHL-associated RCC and showed more variation in growth rate. The expression levels of VHL, PBRM1, H3K36me3, and BAP1 were not different between sporadic ccRCC and VHL-associated RCC. High histologic grade, low VHL expression and negative PBRM1 expression were predictors of faster growth in sporadic ccRCC. A large initial MTD was a predictor of faster growth for VHL-associated RCC. Declarations Acknowledgments: None. Funding: There was no funding for this study. Conflict of interest: The authors declare that they have no conflict of interest. Availability of data and material: The datasets analysed during the current study are available from the corresponding author on reasonable request. Code availability: Not applicable. Author contributions: Xuesong Li and Kan Gong contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jie Wang, Lei Zhang, Jianhui Qiu and Ziao Li. The first draft of the manuscript was written by Jie Wang and Lei Zhang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics approval: The ethics approval was obtained from the Ethics Committee of Peking University First Hospital. Consent to participate: Not applicable. Consent for publication: Not applicable. References 2013. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 499(7456): 43-49. DOI 10.1038/nature12222. Ben-Skowronek, I. and S. Kozaczuk, 2015. Von hippel-lindau syndrome. Hormone research in paediatrics, 84(3): 145-152. DOI 10.1159/000431323. Bihr, S., R. Ohashi, A.L. Moore, J.H. Rüschoff, C. Beisel, T. Hermanns, A. Mischo, C. Corrò, J. Beyer, N. Beerenwinkel, H. Moch and P. Schraml, 2019. Expression and mutation patterns of pbrm1, bap1 and setd2 mirror specific evolutionary subtypes in clear cell renal cell carcinoma. Neoplasia (New York, N.Y.), 21(2): 247-256. DOI 10.1016/j.neo.2018.12.006. Campbell, S.C., A.C. Novick, A. Belldegrun, M.L. Blute, G.K. Chow, I.H. Derweesh, M.M. Faraday, J.H. Kaouk, R.J. Leveillee, S.F. Matin, P. Russo and R.G. Uzzo, 2009. Guideline for management of the clinical t1 renal mass. The Journal of urology, 182(4): 1271-1279. DOI 10.1016/j.juro.2009.07.004. Chawla, S.N., P.L. Crispen, A.L. Hanlon, R.E. Greenberg, D.Y. Chen and R.G. Uzzo, 2006. The natural history of observed enhancing renal masses: Meta-analysis and review of the world literature. The Journal of urology, 175(2): 425-431. DOI 10.1016/s0022-5347(05)00148-5. Chow, W.H. and S.S. Devesa, 2008. Contemporary epidemiology of renal cell cancer. Cancer journal (Sudbury, Mass.), 14(5): 288-301. DOI 10.1097/PPO.0b013e3181867628. Chow, W.H., S.S. Devesa, J.L. Warren and J.F. Fraumeni, Jr., 1999. Rising incidence of renal cell cancer in the united states. Jama, 281(17): 1628-1631. DOI 10.1001/jama.281.17.1628. Cooperberg, M.R., K. Mallin, J. Ritchey, J.D. Villalta, P.R. Carroll and C.J. Kane, 2008. Decreasing size at diagnosis of stage 1 renal cell carcinoma: Analysis from the national cancer data base, 1993 to 2004. The Journal of urology, 179(6): 2131-2135. DOI 10.1016/j.juro.2008.01.097. Crispen, P.L., S.A. Boorjian, C.M. Lohse, T.S. Sebo, J.C. Cheville, M.L. Blute and B.C. Leibovich, 2008. Outcomes following partial nephrectomy by tumor size. The Journal of urology, 180(5): 1912-1917. DOI 10.1016/j.juro.2008.07.047. Crispen, P.L., R. Viterbo, S.A. Boorjian, R.E. Greenberg, D.Y. Chen and R.G. Uzzo, 2009. Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance. Cancer, 115(13): 2844-2852. DOI 10.1002/cncr.24338. Crispen, P.L., Y.N. Wong, R.E. Greenberg, D.Y. Chen and R.G. Uzzo, 2008. Predicting growth of solid renal masses under active surveillance. Urologic oncology, 26(5): 555-559. DOI 10.1016/j.urolonc.2008.03.010. Deng, F.M. and J. Melamed, 2012. Histologic variants of renal cell carcinoma: Does tumor type influence outcome? The Urologic clinics of North America, 39(2): 119-132, v. DOI 10.1016/j.ucl.2012.02.001. Edmunds, J.W., L.C. Mahadevan and A.L. Clayton, 2008. Dynamic histone h3 methylation during gene induction: Hypb/setd2 mediates all h3k36 trimethylation. The EMBO journal, 27(2): 406-420. DOI 10.1038/sj.emboj.7601967. Högner, A., H. Krause, B. Jandrig, M. Kasim, T.F. Fuller, M. Schostak, A. Erbersdobler, A. Patzak and E. Kilic, 2018. Pbrm1 and vhl expression correlate in human clear cell renal cell carcinoma with differential association with patient's overall survival. Urologic oncology, 36(3): 94.e91-94.e14. DOI 10.1016/j.urolonc.2017.10.027. Hollingsworth, J.M., D.C. Miller, S. Daignault and B.K. Hollenbeck, 2006. Rising incidence of small renal masses: A need to reassess treatment effect. Journal of the National Cancer Institute, 98(18): 1331-1334. DOI 10.1093/jnci/djj362. Hsieh, J.J., D. Chen, P.I. Wang, M. Marker, A. Redzematovic, Y.B. Chen, S.D. Selcuklu, N. Weinhold, N. Bouvier, K.H. Huberman, U. Bhanot, M.S. Chevinsky, P. Patel, P. Pinciroli, H.H. Won, D. You, A. Viale, W. Lee, A.A. Hakimi, M.F. Berger, N.D. Socci, E.H. Cheng, J. Knox, M.H. Voss, M. Voi and R.J. Motzer, 2017. Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. European urology, 71(3): 405-414. DOI 10.1016/j.eururo.2016.10.007. Hsieh, J.J., M.P. Purdue, S. Signoretti, C. Swanton, L. Albiges, M. Schmidinger, D.Y. Heng, J. Larkin and V. Ficarra, 2017. Renal cell carcinoma. Nature reviews. Disease primers, 3: 17009. DOI 10.1038/nrdp.2017.9. Jilg, C.A., H.P. Neumann, S. Gläsker, O. Schäfer, P.U. Ardelt, M. Schwardt and W. Schultze-Seemann, 2012. Growth kinetics in von hippel-lindau-associated renal cell carcinoma. Urologia internationalis, 88(1): 71-78. DOI 10.1159/000333348. Kümmerlin, I.P., F.J. ten Kate, H. Wijkstra, J.J. de la Rosette and M.P. Laguna, 2008. Changes in the stage and surgical management of renal tumours during 1995-2005: An analysis of the dutch national histopathology registry. BJU international, 102(8): 946-951. DOI 10.1111/j.1464-410X.2008.07770.x. Lane, B.R., R. Abouassaly, T. Gao, C.J. Weight, A.V. Hernandez, B.T. Larson, J.H. Kaouk, I.S. Gill and S.C. Campbell, 2010. Active treatment of localized renal tumors may not impact overall survival in patients aged 75 years or older. Cancer, 116(13): 3119-3126. DOI 10.1002/cncr.25184. Ljungberg, B., L. Albiges, Y. Abu-Ghanem, K. Bensalah, S. Dabestani, S. Fernández-Pello, R.H. Giles, F. Hofmann, M. Hora, M.A. Kuczyk, T. Kuusk, T.B. Lam, L. Marconi, A.S. Merseburger, T. Powles, M. Staehler, R. Tahbaz, A. Volpe and A. Bex, 2019. European association of urology guidelines on renal cell carcinoma: The 2019 update. European urology, 75(5): 799-810. DOI 10.1016/j.eururo.2019.02.011. Ljungberg, B., K. Bensalah, S. Canfield, S. Dabestani, F. Hofmann, M. Hora, M.A. Kuczyk, T. Lam, L. Marconi, A.S. Merseburger, P. Mulders, T. Powles, M. Staehler, A. Volpe and A. Bex, 2015. Eau guidelines on renal cell carcinoma: 2014 update. European urology, 67(5): 913-924. DOI 10.1016/j.eururo.2015.01.005. Maher, E.R., 2018. Hereditary renal cell carcinoma syndromes: Diagnosis, surveillance and management. World journal of urology, 36(12): 1891-1898. DOI 10.1007/s00345-018-2288-5. Maher, E.R., H.P. Neumann and S. Richard, 2011. Von hippel-lindau disease: A clinical and scientific review. European journal of human genetics : EJHG, 19(6): 617-623. DOI 10.1038/ejhg.2010.175. Mason, R.J., M. Abdolell, G. Trottier, C. Pringle, J.G. Lawen, D.G. Bell, M.A. Jewett, L. Klotz and R.A. Rendon, 2011. Growth kinetics of renal masses: Analysis of a prospective cohort of patients undergoing active surveillance. European urology, 59(5): 863-867. DOI 10.1016/j.eururo.2011.02.023. Neumann, H.P., B.U. Bender, D.P. Berger, J. Laubenberger, W. Schultze-Seemann, U. Wetterauer, F.J. Ferstl, E.W. Herbst, G. Schwarzkopf, F.J. Hes, C.J. Lips, J.M. Lamiell, O. Masek, P. Riegler, B. Mueller, D. Glavac and H. Brauch, 1998. Prevalence, morphology and biology of renal cell carcinoma in von hippel-lindau disease compared to sporadic renal cell carcinoma. The Journal of urology, 160(4): 1248-1254. Pawłowski, R., S.M. Mühl, T. Sulser, W. Krek, H. Moch and P. Schraml, 2013. Loss of pbrm1 expression is associated with renal cell carcinoma progression. International journal of cancer, 132(2): E11-17. DOI 10.1002/ijc.27822. Peña-Llopis, S., S. Vega-Rubín-de-Celis, A. Liao, N. Leng, A. Pavía-Jiménez, S. Wang, T. Yamasaki, L. Zhrebker, S. Sivanand, P. Spence, L. Kinch, T. Hambuch, S. Jain, Y. Lotan, V. Margulis, A.I. Sagalowsky, P.B. Summerour, W. Kabbani, S.W. Wong, N. Grishin, M. Laurent, X.J. Xie, C.D. Haudenschild, M.T. Ross, D.R. Bentley, P. Kapur and J. Brugarolas, 2012. Bap1 loss defines a new class of renal cell carcinoma. Nature genetics, 44(7): 751-759. DOI 10.1038/ng.2323. Peng, X., J. Chen, J. Wang, S. Peng, S. Liu, K. Ma, J. Zhou, B. Hong, B. Zhou, J. Zhang, L. Cai and K. Gong, 2019. Natural history of renal tumours in von hippel-lindau disease: A large retrospective study of chinese patients. Journal of medical genetics, 56(6): 380-387. DOI 10.1136/jmedgenet-2018-105567. Schuhmacher, P., E. Kim, F. Hahn, P. Sekula, C.A. Jilg, C. Leiber, H.P. Neumann, W. Schultze-Seemann, G. Walz and S. Zschiedrich, 2019. Growth characteristics and therapeutic decision markers in von hippel-lindau disease patients with renal cell carcinoma. Orphanet journal of rare diseases, 14(1): 235. DOI 10.1186/s13023-019-1206-2. Scosyrev, E., E.M. Messing, R. Sylvester, S. Campbell and H. Van Poppel, 2014. Renal function after nephron-sparing surgery versus radical nephrectomy: Results from eortc randomized trial 30904. European urology, 65(2): 372-377. DOI 10.1016/j.eururo.2013.06.044. Siegel, R.L., K.D. Miller and A. Jemal, 2020. Cancer statistics, 2020. CA: a cancer journal for clinicians, 70(1): 7-30. DOI 10.3322/caac.21590. Staehler, M., N. Haseke, T. Stadler, E. Zilinberg, C. Nordhaus, P. Nuhn, W.Y. Khoder, A. Karl and C.G. Stief, 2010. The growth rate of large renal masses opposes active surveillance. BJU international, 105(7): 928-931. DOI 10.1111/j.1464-410X.2009.08840.x. Sun, M., R. Thuret, F. Abdollah, G. Lughezzani, J. Schmitges, Z. Tian, S.F. Shariat, F. Montorsi, J.J. Patard, P. Perrotte and P.I. Karakiewicz, 2011. Age-adjusted incidence, mortality, and survival rates of stage-specific renal cell carcinoma in north america: A trend analysis. European urology, 59(1): 135-141. DOI 10.1016/j.eururo.2010.10.029. Turajlic, S., H. Xu, K. Litchfield, A. Rowan, S. Horswell, T. Chambers, T. O'Brien, J.I. Lopez, T.B.K. Watkins, D. Nicol, M. Stares, B. Challacombe, S. Hazell, A. Chandra, T.J. Mitchell, L. Au, C. Eichler-Jonsson, F. Jabbar, A. Soultati, S. Chowdhury, S. Rudman, J. Lynch, A. Fernando, G. Stamp, E. Nye, A. Stewart, W. Xing, J.C. Smith, M. Escudero, A. Huffman, N. Matthews, G. Elgar, B. Phillimore, M. Costa, S. Begum, S. Ward, M. Salm, S. Boeing, R. Fisher, L. Spain, C. Navas, E. Grönroos, S. Hobor, S. Sharma, I. Aurangzeb, S. Lall, A. Polson, M. Varia, C. Horsfield, N. Fotiadis, L. Pickering, R.F. Schwarz, B. Silva, J. Herrero, N.M. Luscombe, M. Jamal-Hanjani, R. Rosenthal, N.J. Birkbak, G.A. Wilson, O. Pipek, D. Ribli, M. Krzystanek, I. Csabai, Z. Szallasi, M. Gore, N. McGranahan, P. Van Loo, P. Campbell, J. Larkin and C. Swanton, 2018. Deterministic evolutionary trajectories influence primary tumor growth: Tracerx renal. Cell, 173(3): 595-610.e511. DOI 10.1016/j.cell.2018.03.043. Van Poppel, H., L. Da Pozzo, W. Albrecht, V. Matveev, A. Bono, A. Borkowski, J.M. Marechal, L. Klotz, E. Skinner, T. Keane, I. Claessens and R. Sylvester, 2007. A prospective randomized eortc intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. European urology, 51(6): 1606-1615. DOI 10.1016/j.eururo.2006.11.013. Vasudevan, A., R.J. Davies, B.A. Shannon and R.J. Cohen, 2006. Incidental renal tumours: The frequency of benign lesions and the role of preoperative core biopsy. BJU international, 97(5): 946-949. DOI 10.1111/j.1464-410X.2006.06126.x. Wagstaff, P.G., P.J. Zondervan, J.J. de la Rosette and M.P. Laguna, 2014. The role of imaging in the active surveillance of small renal masses. Current urology reports, 15(3): 386. DOI 10.1007/s11934-013-0386-x. Zhang, J., S.K. Kang, L. Wang, A. Touijer and H. Hricak, 2009. Distribution of renal tumor growth rates determined by using serial volumetric ct measurements. Radiology, 250(1): 137-144. DOI 10.1148/radiol.2501071712. Zhang, J., J.H. Pan, B.J. Dong, W. Xue, D.M. Liu and Y.R. Huang, 2012. Active surveillance of renal masses in von hippel-lindau disease: Growth rates and clinical outcome over a median follow-up period of 56 months. Familial cancer, 11(2): 209-214. DOI 10.1007/s10689-011-9503-5. Zhang, L., W. Yin, L. Yao, X. Li, D. Fang, D. Ren, Z. Zhang, Y. Fan, Q. He, W. Ci, Z. He and L. Zhou, 2015. Growth pattern of clear cell renal cell carcinoma in patients with delayed surgical intervention: Fast growth rate correlates with high grade and may result in poor prognosis. BioMed research international, 2015: 598134. DOI 10.1155/2015/598134. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 28 Jul, 2021 Reviewers invited by journal 04 Jul, 2021 Editor assigned by journal 30 Jun, 2021 First submitted to journal 30 Jun, 2021 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-675576","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":37314034,"identity":"dad706f3-d328-4b5d-b9e6-e15fdaad0e8b","order_by":0,"name":"Jie Wang","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Wang","suffix":""},{"id":37314035,"identity":"f9aa309a-15c9-4ef1-b11f-3579431fb444","order_by":1,"name":"Lei Zhang","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Zhang","suffix":""},{"id":37314036,"identity":"65f4702e-62d5-4956-8520-7a02edb99074","order_by":2,"name":"Jianhui Qiu","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jianhui","middleName":"","lastName":"Qiu","suffix":""},{"id":37314037,"identity":"bf637d84-83bd-41bc-a68f-e58c439a3420","order_by":3,"name":"Ziao Li","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ziao","middleName":"","lastName":"Li","suffix":""},{"id":37314038,"identity":"5990121f-0294-4cb5-a6ff-10b71fadea3b","order_by":4,"name":"Yucai Wu","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yucai","middleName":"","lastName":"Wu","suffix":""},{"id":37314039,"identity":"18aaee8c-bb7e-4740-9ba2-1cd6e6a493b8","order_by":5,"name":"Cuijian Zhang","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cuijian","middleName":"","lastName":"Zhang","suffix":""},{"id":37314040,"identity":"bcdf1938-5e0a-4902-94c9-93c67c3fa164","order_by":6,"name":"Lin Yao","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Yao","suffix":""},{"id":37314041,"identity":"08ffddba-335c-4df9-aee8-95b488257121","order_by":7,"name":"Kan Gong","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kan","middleName":"","lastName":"Gong","suffix":""},{"id":37314042,"identity":"aa3ed06e-a754-4e6f-9843-fa24c136637f","order_by":8,"name":"Xuesong Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYDACZgjF2MfAfIAhgSQtbQxsCURqYYBr4TEgTqk5O+/BxwUVNrJt7D2fPzzcYcfA396N3zLLZr5k4xln0ozbeM5uk0g8k8wgcebsBrxaDA7zmEnzth1ObJPI3caQ2MbMYCCRS1CL+W/ef/8T2+TfPP6Q2FZPlBYzZt6GA0BbeBgkEtsOE9Zi2cxjLM1zLBnolzQzoJbjPAT9Ys5/xvAzT42dbD/74ccff7ZVy/G39xJwGLoAD17lWLWMglEwCkbBKMAAAGaQQd0AJxPrAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7030-0856","institution":"Department of Urology, Peking University First Hospital. Institute of Urology, Peking University. National Urological Cancer Center, Beijing, China.","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xuesong","middleName":"","lastName":"Li","suffix":""},{"id":37314043,"identity":"09ffd475-2b67-4f9c-9b36-db19afcfb946","order_by":9,"name":"Liqun Zhou","email":"","orcid":"","institution":"Peking University First Hospital Department of Urology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liqun","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2021-07-01 04:00:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-675576/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-675576/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":11250798,"identity":"3c6c9895-342c-492a-bbae-23e7b757e815","added_by":"auto","created_at":"2021-07-08 12:15:08","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":434024,"visible":true,"origin":"","legend":"The distribution of tumor growth rate in the two groups: (A) and (B) are the distribution histograms of LGR in the sporadic group and VHL group, respectively; (C) and (D) are distribution histograms of the VGR in the sporadic group and VHL group, respectively; (E) and (F) are the distribution histograms of VDT in the sporadic group and VHL group, respectively.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-675576/v1/c7da982c6e62623c0ec8a17b.jpg"},{"id":11251064,"identity":"70a0dafb-0dac-4c08-ad18-2491c77541b2","added_by":"auto","created_at":"2021-07-08 12:18:08","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":267368,"visible":true,"origin":"","legend":"Schematic diagram of the results of VHL, PBRM1, H3K36 me3, and BAP1 staining. (A) The low expression of VHL. (B) The high expression of VHL. (C) The negative of PBRM1. (D) The positive of PBRM1. (E) The low expression of H3K36 me3. (F) The high expression of H3K36 me3. (G) The low expression and of BAP1.\n(H) The high expression of BAP1.","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-675576/v1/b74e0806d73f405f07b5e661.jpg"},{"id":11250797,"identity":"51ab8a92-7b6f-4e19-97fe-4cdfb509218c","added_by":"auto","created_at":"2021-07-08 12:15:08","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":138578,"visible":true,"origin":"","legend":"Comparison of the sporadic ccRCC growth rate in the three groups. Group 1 included patients who had low VHL expression and were negative for PBRM1. Group 2 included patients who had low VHL expression with positive PBRM1 and high VHL expression with negative PBRM1. Group 3 included patients who had high VHL expression and were positive for PBRM1. (A) The comparison of the median LGR between the three groups was group 1\u003egroup 2\u003egroup 3. (B) The comparison of median VGR between the three groups was group 1\u003egroup 2\u003egroup 3. (C) The comparison of median VDT between the three groups was group 3\u003egroup 2\u003egroup 1.","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-675576/v1/5762a410c5ddcdac6059175f.jpg"},{"id":13702926,"identity":"57a1136b-7a26-427c-8a38-fdfbef2989ee","added_by":"auto","created_at":"2021-09-17 13:38:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":764488,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-675576/v1/851998fa-5899-41c8-adbd-35cd8ad3b527.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eNatural History of Von Hippel-Lindau Disease-associated and Sporadic Clear Cell Renal Cell Carcinoma: a Comparative Study\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cp\u003eRenal cell carcinomas (RCCs) represent approximately 3% of all cancers, of which clear cell renal cell carcinoma (ccRCC) is the most common histotype, representing 70\u0026ndash;80% of cases(Deng and Melamed, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Ljungberg et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Although the vast majority of RCCs are sporadic, approximately 3% of RCCs are hereditary, and Von Hippel-Lindau disease-associated renal cell carcinoma (VHL-associated RCC) is a common hereditary RCC(Maher, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). The detection of renal masses (RMs) has increased worldwide over the past several decades due to the widespread use of advanced imaging examinations(Chow et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; K\u0026uuml;mmerlin et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Wagstaff et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Of all the newly discovered RMs, the proportion of renal masses\u0026thinsp;\u0026le;\u0026thinsp;4.0 cm (small RMs) is increasing(Chow and Devesa, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Cooperberg et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Hsieh et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). However, the mortality rate of RMs has not decreased as the operation rate of small RMs has increased, and the specific mortality rate of small RMs has even increased gradually(Hollingsworth et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Van Poppel et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Campbell et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Sun et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Scosyrev et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Ljungberg et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). A number of studies have demonstrated that 20\u0026ndash;30% of small RMs are confirmed to be benign tumors after surgery(Vasudevan et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Crispen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). In addition, Campbell et al. reported that in patients aged 75 years or older with small RMs, only patient age and comorbidities were independent predictors of overall survival outcomes, and surgical intervention did not provide significant survival benefits(Lane et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Based on the above factors, urologists have paid increasing attention to researching the therapeutic effect of active surveillance (AS) of small RMs. To date, several researchers have assessed the natural history of sporadic ccRCC and VHL-associated RCC, but no consensus has been reached on the tumor growth rate and its predictive markers(Crispen et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Staehler et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Mason et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Peng et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Schuhmacher et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Few studies have explored the difference in natural history between the two types of RCC. In this study, sporadic ccRCC and VHL-associated RCC were analyzed together to compare the differences in growth rate between the two tumors. In addition, RCC is a highly heterogeneous tumor(2013; Hsieh et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). The TRACERx renal study showed, for the first time, that ccRCC can be divided into several evolutionary subtypes, and the main basis for typing is mutations in the VHL, PBRM1, SETD2 and BAP1 genes(Edmunds et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Turajlic et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Schraml et al. verified that the four subtypes of ccRCC have differences in tumor stage and nuclear grade(Bihr et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Therefore, we believe that it may be possible to predict the growth rate of ccRCC by determining whether there are mutations in these four genes. In the present study, the differences in the expression levels of VHL, PBRM1, H3K36me3 and BAP1 between the two groups were measured by immunohistochemical staining, and their relationship with the tumor growth rate was analyzed.\u003c/p\u003e "},{"header":"Materials And Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eWe searched the databases of renal tumors at the Institute of Urology, Peking University to identify patients who had renal tumors and received AS from January 1990 to December 2019. A total of 87 patients with 137 tumors were diagnosed with VHL-associated RCC; the mean age of all patients was 33 (range, 18\u0026ndash;69) years, and more than half of the patients were men (50/87, 57.3%). The mean period of AS was 19.2 (range, 3-211.4) months. A total of 60 patients had 61 tumors that were considered sporadic ccRCC, and patients with pathologically confirmed non-ccRCC were excluded. The mean age was 55 (range, 26\u0026ndash;81) years, and the majority of patients were men (47/60, 78.3%). The mean period of AS was 27 (range, 2-155) months. Delayed intervention, including radical nephrectomy and nephron-sparing surgery, was performed for all sporadic ccRCCs and 28 tumors the VHL-associated RCC group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatient characteristics, clinicopathological features, VHL disease information and natural tumor history were recorded. The linear growth rate (LGR) and volumetric growth rate (VGR) were used to evaluate the growth rate of tumors. The former refers to the growth rate of tumors on a certain diameter line, often expressed by the growth rate (cm/year) of the maximal tumor diameter (MTD) measured on the tumor cross section. The latter can also be described as the volume doubling time (VDT). Immunohistochemical staining was utilized to analyze the expression levels of VHL, PBRM1, H3K36me3, and BAP1 in the postoperative specimens. All results were evaluated with the assistance of urological pathologists blinded to the patients\u0026rsquo; clinical data. According to the comparison with normal renal tissue staining, the VHL, H3K36me3 and BAP1 staining results were used to divide the tumors into low expression and high expression groups, and PBRM1 staining results were used to divide the tumors into negative and positive groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe Wilcoxon rank-sum test was used to compare the two groups. Fisher\u0026rsquo;s exact test was used to compare the expression levels of VHL, PBRM1, H3K36me3, and BAP1 between the two groups. Logistic regression and a general linear model were used to analyze the growth rate predictors. All data were recorded using Microsoft Office Excel and processed using SPSS V.22.0 statistical software. A P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e "},{"header":"Result","content":"\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003ePatient characteristics and tumor features\u003c/h2\u003e\n \u003cp\u003eThe patient characteristics, clinicopathologic features and tumor growth rates of the two groups are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The VHL disease information of the VHL group is summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Although male patients were predominant in both of the groups, there was a statistically significant difference in the sex ratio between the two groups, which means that there were more male patients in the sporadic group (P\u0026thinsp;=\u0026thinsp;0.0087). The median age of tumor onset in patients in the sporadic group was 55 (range, 26\u0026ndash;81) years, while that of the patients in the VHL group was lower, at 33 (range, 18\u0026ndash;69) years, and the difference between the two groups was statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Only one patient in the sporadic group had bilateral disease. The number of patients with bilateral disease in the VHL group was significantly higher than that in the sporadic group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), with a total of 60 bilateral cases (69%). Regardless of whether the initial tumor size was measured by MTD or volume, there was no statistically significant difference between the two groups. The median AS times of the two groups were 27 (range, 2-155) months in the sporadic group and 19.2 (range, 3-221.4) months in the VHL group. The AS time of the sporadic group was significantly longer than that of the VHL group (P\u0026thinsp;=\u0026thinsp;0.001). Regardless of whether tumor size was measured by MTD or tumor volume, the final average size of the tumor in the sporadic group was significantly larger than that in the VHL group (MTD, P \u0026lt; 0.0001; volume, P \u0026lt; 0.0001). It is worth mentioning that not all VHL-associated RCCs were resected during the study. We found that the AS time in the sporadic group was still longer than that in the VHL group when we included only patients with VHL-associated RCCs who underwent surgery; however, there was no significant difference in the final average tumor size between the sporadic group and the VHL group.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient characteristics and tumor features\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOver all\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSporadic group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVHL group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0087\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 (78.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 (57.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 (34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (42.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge, yr Median (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (18\u0026ndash;81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (26\u0026ndash;81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (18\u0026ndash;69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnilateral (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86 (58.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (98.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBilateral (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (41.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (69.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eInitial tumor size\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMTD, cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0 (0.3\u0026ndash;7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9 (0.3\u0026ndash;6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1 (0.4\u0026ndash;7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.8739\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVolume, cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.9 (0.03\u0026ndash;252.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.5 (0.58\u0026ndash;135.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.9 (0.03\u0026ndash;252.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.4715\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration of AS, mo Median (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.8 (2-221.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27(2-155)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.2(3-221.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFinal tumor size\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMTD, cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.0 (0.5\u0026ndash;14.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.0 (1.4\u0026ndash;11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.6 (0.5\u0026ndash;14.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVolume, cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.4 (0.07\u0026ndash;1493.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42.9 (1.6-895.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.4 (0.07\u0026ndash;1493.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLGR, cm/yr\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.91\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.38 (-2.5-4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.61 (0-4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.30 (-2.5-4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVGR, cm\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e/yr\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.0\u0026thinsp;\u0026plusmn;\u0026thinsp;68.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.2\u0026thinsp;\u0026plusmn;\u0026thinsp;66.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.9\u0026thinsp;\u0026plusmn;\u0026thinsp;68.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5 (-149.3-464.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.3 (0.64\u0026ndash;303.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0 (-149.3-464.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVDT, days\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e542.0\u0026thinsp;\u0026plusmn;\u0026thinsp;943.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e673.9\u0026thinsp;\u0026plusmn;\u0026thinsp;625.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e480.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e443.2\u003c/p\u003e\n \u003cp\u003e(-2255.7-7115.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e560.6\u003c/p\u003e\n \u003cp\u003e(32.5-3214.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e425.6\u003c/p\u003e\n \u003cp\u003e(-2255.7-7115.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNSS (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (46.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (53.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathological stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.7913\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT1 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74 (83.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (83.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (82.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT3 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistological grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0011\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG1 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (32.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG2 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (48.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (59.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG3 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eMTD, maximal tumor diameter; LGR, linear growth rate; VGR, volumetric growth rate; VDT, volume doubling time.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eVHL disease information of VHL group\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAmount, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVHL subtypes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubtype I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e64(73.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubtype II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23(26.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMutations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMissense mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40(46.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTruncating mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47(54.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003emutation sites\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExon 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34(39.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExon 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20(23.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExon 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27(31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6(6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCombined tumors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCentral nervous system hemangioblastoma (CHB)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41(47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRetinal hemangioblastoma (RHB)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13(14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCHB\u0026thinsp;+\u0026thinsp;RHB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13(14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20(23.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFamily history\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20(23.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59(67.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot clear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8(9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eExpression of VHL, PBRM1, H3K36me3, and BAP1 in the two groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBiomarkers\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOver all (n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSporadic group (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVHL group (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVHL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.7829\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow expression (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38 (52.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh expression (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35 (47.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26 (46.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePBRM1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.4100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNegative (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28 (38.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45 (61.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eH3K36me3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow expression (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh expression (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58 (79.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (82.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBAP1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.0574\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow expression (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17 (23.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh expression (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56 (76.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46 (82.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFor patients who ultimately received surgical treatment, the proportion of nephron-sparing surgery was 31.2% in the sporadic group and 78.6% in the VHL group, and the difference was statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). There was no difference in the tumor stage of all tumors that were finally removed between the two groups (P\u0026thinsp;=\u0026thinsp;0.7913). The vast majority of tumors in the two groups were T1 stage (sporadic group, 83.6%; VHL group, 82.1%). The most common histological grade of the sporadic group was G2 (59.0%), and that of the VHL group was G1 (71.4%). There was a statistically significant difference in tumor histological grade between the two groups (P\u0026thinsp;=\u0026thinsp;0.0011).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eComparison of tumor growth rate in the two groups\u003c/h2\u003e\n \u003cp\u003eThe tumor growth kinetics of the sporadic group and VHL group are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The growth rate of tumors in the sporadic group was significantly faster than that of the VHL group (LGR, P\u0026thinsp;=\u0026thinsp;0.0004; VGR, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). However, there was no significant difference in VDT between the two groups (P\u0026thinsp;=\u0026thinsp;0.1176). The distribution of LGR, VGR and VDT in the two groups is presented in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The distribution of these three growth rate indicators in the sporadic group presented a \u0026ldquo;right-side tailing\u0026rdquo;. In contrast, the three indicators in the VHL group had an obvious central tendency.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec9\"\u003e\n \u003ch2\u003eImmunohistochemical analysis\u003c/h2\u003e\n \u003cp\u003eThe immunohistochemical staining results of the analyzed 4 biomarkers are shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The results of VHL, H3K36me3, and BAP1 staining were distinguished by low and high expression because all of the tumors expressed these markers, while PBRM1 staining was distinguished by negative and positive. The comparison of the expression levels of these 4 biomarkers in the two groups is presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Obviously, the expression levels of these 4 biomarkers were not significantly different between the two groups. A further log-linear model analysis showed that there was no correlation between any two of the four biomarkers between the two groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003eInfluencing factors of tumor growth rate\u003c/h2\u003e\n \u003cp\u003eIn the sporadic group, age, sex, and tumor initial MTD were not correlated with the tumor growth rate, and only tumor histological grade was correlated with the LGR (P\u0026thinsp;=\u0026thinsp;0.0022) and VGR (P\u0026thinsp;=\u0026thinsp;0.0043), which means that the higher the tumor grade was, the faster the tumor growth rate was. However, initial MTD was correlated with VDT (P\u0026thinsp;=\u0026thinsp;0.0012). In the VHL group, age, sex, histological grade, VHL subtypes, mutation types, combined tumors and family history were not associated with the tumor growth rate. However, initial MTD significantly affected the LGR (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and VGR (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). In addition, only the combination of central nervous system hemangioblastoma or retinal hemangioblastoma was correlated with VDT (P\u0026thinsp;=\u0026thinsp;0.0407).\u003c/p\u003e\n \u003cp\u003eThe effects of the expression of VHL, PBRM1, H3K36me3, and BAP1 on tumor LGR, VGR and VDT are presented in Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. In the VHL group, the expression levels of the 4 biomarkers were not correlated with the tumor growth rate. In the sporadic group, the expression levels of H3K36me3 and BAP1 were not correlated with the tumor growth rate. However, the expression of VHL was correlated with the tumor LGR (P\u0026thinsp;=\u0026thinsp;0.001), VGR (P\u0026thinsp;=\u0026thinsp;0.021) and VDT (P\u0026thinsp;=\u0026thinsp;0.002), and low expression of VHL promoted the tumor growth rate. The expression of PBRM1 was correlated with the tumor LGR (P\u0026thinsp;=\u0026thinsp;0.008) and VDT (P\u0026thinsp;=\u0026thinsp;0.047) and had a weak correlation with VGR (P\u0026thinsp;=\u0026thinsp;0.051). Tumors with negative expression of PBRM1 grew faster. We further performed a subgroup analysis, which classified low VHL expression with negative PBRM1 as group 1, low VHL expression with positive PBRM1 and high VHL expression with negative PBRM1 as group 2, and high VHL expression with positive PBRM1 as group 3. The tumor growth rates of the three groups are shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. Obviously, for LGR and VGR, the relationship between the three groups was group 1\u0026thinsp;\u0026gt;\u0026thinsp;group 2\u0026thinsp;\u0026gt;\u0026thinsp;group 3. For VDT, the relationship between the three groups was group 3\u0026thinsp;\u0026gt;\u0026thinsp;group 2\u0026thinsp;\u0026gt;\u0026thinsp;group 1. There was a statistically significant difference between group 1 and group 3 (LGR, P\u0026thinsp;=\u0026thinsp;0.000; VGR, P\u0026thinsp;=\u0026thinsp;0.012; VDT, P\u0026thinsp;=\u0026thinsp;0.003). There was a significant difference between group 2 and group 3 (LGR, P\u0026thinsp;=\u0026thinsp;0.004; VDT, P\u0026thinsp;=\u0026thinsp;0.014;but VGR, P\u0026thinsp;=\u0026thinsp;0.058;). However, there was no significant difference between group 1 and group 2. In summary, we conclude that both low expression of VHL and negative PBRM1 expression are predictors of the rapid growth of sporadic ccRCC.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe effect of four biomarkers expression on tumor growth rate.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eVHL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ePBRM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eH3K36me3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBAP1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehigh\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eSporadic\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003egroup\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLGR (cm/yr)\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003cp\u003e(0.12\u0026ndash;4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003cp\u003e(0-1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003cp\u003e(0.22\u0026ndash;3.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003cp\u003e(0-4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003cp\u003e(0.20\u0026ndash;2.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003cp\u003e(0-4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003cp\u003e(0.17\u0026ndash;4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003cp\u003e(0-3.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.381\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVGR (cm\u003csup\u003e3\u003c/sup\u003e/yr)\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.3\u003c/p\u003e\n \u003cp\u003e(0.73\u0026ndash;303.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.43\u003c/p\u003e\n \u003cp\u003e(0.65\u0026ndash;42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.8\u003c/p\u003e\n \u003cp\u003e(0.79\u0026ndash;303.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.74\u003c/p\u003e\n \u003cp\u003e(0.65\u0026ndash;245.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.5\u003c/p\u003e\n \u003cp\u003e(0.75\u0026ndash;303.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.96\u003c/p\u003e\n \u003cp\u003e(0.65\u0026ndash;274.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.02\u003c/p\u003e\n \u003cp\u003e(0.79\u0026ndash;205.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.5\u003c/p\u003e\n \u003cp\u003e(0.65\u0026ndash;303.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.021\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.466\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.295\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVDT (days)\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e322.9\u003c/p\u003e\n \u003cp\u003e(32.5-2633.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e658.0\u003c/p\u003e\n \u003cp\u003e(157.7-1948.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e377.6\u003c/p\u003e\n \u003cp\u003e(69.0-1518.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e587.7\u003c/p\u003e\n \u003cp\u003e(32.5-2633.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e378.3\u003c/p\u003e\n \u003cp\u003e(117.6-1518.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e573.9\u003c/p\u003e\n \u003cp\u003e(32.5-2633.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e362.5\u003c/p\u003e\n \u003cp\u003e(32.5-1581.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e573.3\u003c/p\u003e\n \u003cp\u003e(69.0-2633.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.047\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.358\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.285\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eVHL\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003egroup\u003c/strong\u003e (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLGR (cm/yr)\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003cp\u003e(-0.41-1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003cp\u003e(0.21\u0026ndash;2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003cp\u003e(-0.41-1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003cp\u003e(0.21\u0026ndash;2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003cp\u003e(-0.41-0.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003cp\u003e(-0.25-2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003cp\u003e(-0.41-2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003cp\u003e(0.24\u0026ndash;1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.423\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.481\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.270\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVGR (cm\u003csup\u003e3\u003c/sup\u003e/yr)\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.11\u003c/p\u003e\n \u003cp\u003e-9.42-159.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003cp\u003e(2.39\u0026ndash;87.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.32\u003c/p\u003e\n \u003cp\u003e(-9.42-159.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003cp\u003e(2.39\u0026ndash;87.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.22\u003c/p\u003e\n \u003cp\u003e(-9.42-10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.5\u003c/p\u003e\n \u003cp\u003e(-3.41-159.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.22\u003c/p\u003e\n \u003cp\u003e(-9.42-72.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.2\u003c/p\u003e\n \u003cp\u003e(3.35\u0026ndash;159.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.963\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.364\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVDT (day)\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e289.0\u003c/p\u003e\n \u003cp\u003e(-1015.5-1053.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e284.0\u003c/p\u003e\n \u003cp\u003e(165.4-1197.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e240.8\u003c/p\u003e\n \u003cp\u003e(-1015.5-1197.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e424.6\u003c/p\u003e\n \u003cp\u003e(173.7-1047.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e851.3\u003c/p\u003e\n \u003cp\u003e(-785.6-1053.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e280.7\u003c/p\u003e\n \u003cp\u003e-1015.5-1197.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e233.9\u003c/p\u003e\n \u003cp\u003e-1015.5-\u003c/p\u003e\n \u003cp\u003e1053.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e366.4\u003c/p\u003e\n \u003cp\u003e(165.4-1197.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.423\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.591\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.364\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\"\u003eLGR, linear growth rate; VGR, volumetric growth rate; VDT, volume doubling time.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eThe gold standard for RM treatment is surgical resection(Campbell et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Ljungberg et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). However, with the advancement of modern medicine, the increase in the detection rate and operation rate of small RMs has not reduced the mortality rate(Hollingsworth et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Sun et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Therefore, AS was recommended as a strategy for managing small RMs(Campbell et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Ljungberg et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). However, there have been few studies on the natural history of sporadic ccRCC and VHL-associated RCC reported in the global literature. The present study aimed to compare the natural history of sporadic ccRCC and VHL-associated RCC combined with immunohistochemical analysis. Compared to sporadic ccRCC, we found that patients with VHL-associated RCC were younger, more likely to develop bilateral tumors, and had a lower histological grade at onset, which was consistent with the conclusions of previous studies(Maher et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Ben-Skowronek and Kozaczuk, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). In addition, our study revealed that the sex ratio in patients with VHL-associated RCC was more equal, while the proportion of males in the sporadic group was higher, which was closer to the sex ratio of sporadic ccRCC shown in a previous large-scale epidemiological study(Siegel et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). There was no significant difference in the initial tumor size between the two groups, regardless of whether the tumor size was measured by MTD or volume. The sporadic group received AS for a longer period than the VHL group. We believe that this might be due to selection bias, as most sporadic ccRCC patients receiving AS had surgical contraindications. This conjecture is supported by the fact that the final average tumor size of the sporadic group at the last follow-up was larger than that of tumors in the VHL group.\u003c/p\u003e \u003cp\u003eA previous meta-analysis showed that the mean LGR of sporadic small RMs was 0.28 cm/yr, and the growth rate of RCC diagnosed pathologically was approximately 0.4 cm/yr(Chawla et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Our study only included patients diagnosed with ccRCC through pathology; the mean LGR was 0.91 cm/yr, and the median was 0.61 cm/yr. This result more accurately reflects the growth rate of ccRCC. In the VHL group in our study, the mean LGR was 0.49 cm/yr, and the median was 0.30 cm/yr, which was similar to that described in previous reports(Jilg et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). We further compared the tumor growth rate of the two groups and found that the mean LGR and mean VGR of the sporadic group were significantly faster than those of the VHL group, which was consistent with previous findings that VHL-associated RCC is more indolent(Neumann et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). We also found that VHL-associated RCC had zero or even negative growth, which was not observed for sporadic ccRCCs. Compared with sporadic ccRCC, the LGR distribution of VHL-associated RCC was more concentrated, which indirectly indicates that the heterogeneity of sporadic ccRCC was greater than that of VHL-associated RCC.\u003c/p\u003e \u003cp\u003eMutations in VHL, PBRM1, SETD2, and BAP1 cause loss of function of the encoded proteins in ccRCC. A study based on whole-genome sequencing found that PBRM1 and BAP1 mutations are largely mutually exclusive in ccRCC(Pe\u0026ntilde;a-Llopis et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Schraml et al. reported that there was a significant correlation between the expression levels of PBRM1, H3K36me3 and BAP1 based on the tissue chip technique(Bihr et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). However, our study used immunohistochemical staining to analyze the expression levels of VHL, PBRM1, H3K36me3, and BAP1 in all tumors of the two groups and revealed that there was no correlation between any of them. We hypothesize that the reason for the different results in our study is that immunohistochemistry cannot accurately reflect gene mutations, and the results of immunohistochemical staining were also affected by the time of tissue fixation and conditions of wax block storage.\u003c/p\u003e \u003cp\u003eWhich factors are predictors of the tumor growth rate have always been the focus of research on the natural history of renal tumors, but there are still no widely accepted conclusions. This study revealed that in the sporadic ccRCC group, the patient\u0026rsquo;s age, sex, and initial size of the tumor had no effect on the tumor growth rate, which was consistent with the results of most other studies, including our previous studies(Chawla et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Crispen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). However, histological grade was correlated with the tumor growth rate, and the higher the grade was, the faster the growth rate was. In the VHL group, the initial size of the tumor was an influencing factor for the growth rate, and other VHL disease-related factors, such as subtypes and mutation types, were not correlated with the tumor growth rate. We believe that these differences further prove that VHL-associated RCC and sporadic ccRCC are two different tumors, even though they are both classed as ccRCCs by histology. Loss of VHL protein is known to contribute to the initiation and progression of VHL disease-associated tumors as well as certain sporadic tumors, including ccRCC. Schraml et al. reported that PBRM1 was the second most frequently mutated gene in RCC after VHL, and loss of PBRM1 was correlated with advanced tumor stage, low differentiation grade and worse patient outcome(Pawłowski et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). However, Kilic et al. reported that weak PBRM1 and VHL expression was significantly associated with higher Fuhrman grade, but only weak VHL expression was associated with a higher pT stage and with decreased patient overall survival times, but PBRM1 expression did not affect the overall survival outcome(H\u0026ouml;gner et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Our study revealed that the expression of VHL and PBRM1 was correlated with tumor histological grade; lower VHL expression was associated with higher tumor histological grade, but this trend was not observed for PBRM1. Moreover, we found that low VHL expression and negative PBRM1 were both correlated with the tumor growth rate and may have had additive effects in sporadic ccRCC. It is possible that VHL and PBRM1 will become sensitive predictors of the growth rate of sporadic ccRCC.\u003c/p\u003e \u003cp\u003eDue to the limitations of retrospective design and sample size, prospective studies with a larger sample size are required to verify these results. Moreover, this study only qualitatively measured the protein expression level through immunohistochemistry; thus, the results remain to be further verified at the quantitative level.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eSporadic ccRCC grew faster than VHL-associated RCC and showed more variation in growth rate. The expression levels of VHL, PBRM1, H3K36me3, and BAP1 were not different between sporadic ccRCC and VHL-associated RCC. High histologic grade, low VHL expression and negative PBRM1 expression were predictors of faster growth in sporadic ccRCC. A large initial MTD was a predictor of faster growth for VHL-associated RCC.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no funding for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXuesong Li and Kan Gong contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jie Wang, Lei Zhang, Jianhui Qiu and Ziao Li. The first draft of the manuscript was written by Jie Wang and Lei Zhang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethics approval was obtained from the Ethics Committee of Peking University First Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e2013. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 499(7456): 43-49. DOI 10.1038/nature12222.\u003c/li\u003e\n \u003cli\u003eBen-Skowronek, I. and S. Kozaczuk, 2015. Von hippel-lindau syndrome. Hormone research in paediatrics, 84(3): 145-152. DOI 10.1159/000431323.\u003c/li\u003e\n \u003cli\u003eBihr, S., R. Ohashi, A.L. Moore, J.H. R\u0026uuml;schoff, C. Beisel, T. Hermanns, A. Mischo, C. Corr\u0026ograve;, J. Beyer, N. Beerenwinkel, H. Moch and P. Schraml, 2019. Expression and mutation patterns of pbrm1, bap1 and setd2 mirror specific evolutionary subtypes in clear cell renal cell carcinoma. Neoplasia (New York, N.Y.), 21(2): 247-256. DOI 10.1016/j.neo.2018.12.006.\u003c/li\u003e\n \u003cli\u003eCampbell, S.C., A.C. Novick, A. Belldegrun, M.L. Blute, G.K. Chow, I.H. Derweesh, M.M. Faraday, J.H. Kaouk, R.J. Leveillee, S.F. Matin, P. Russo and R.G. Uzzo, 2009. Guideline for management of the clinical t1 renal mass. The Journal of urology, 182(4): 1271-1279. DOI 10.1016/j.juro.2009.07.004.\u003c/li\u003e\n \u003cli\u003eChawla, S.N., P.L. Crispen, A.L. Hanlon, R.E. Greenberg, D.Y. Chen and R.G. Uzzo, 2006. The natural history of observed enhancing renal masses: Meta-analysis and review of the world literature. The Journal of urology, 175(2): 425-431. DOI 10.1016/s0022-5347(05)00148-5.\u003c/li\u003e\n \u003cli\u003eChow, W.H. and S.S. Devesa, 2008. Contemporary epidemiology of renal cell cancer. Cancer journal (Sudbury, Mass.), 14(5): 288-301. DOI 10.1097/PPO.0b013e3181867628.\u003c/li\u003e\n \u003cli\u003eChow, W.H., S.S. Devesa, J.L. Warren and J.F. Fraumeni, Jr., 1999. Rising incidence of renal cell cancer in the united states. Jama, 281(17): 1628-1631. DOI 10.1001/jama.281.17.1628.\u003c/li\u003e\n \u003cli\u003eCooperberg, M.R., K. Mallin, J. Ritchey, J.D. Villalta, P.R. Carroll and C.J. Kane, 2008. Decreasing size at diagnosis of stage 1 renal cell carcinoma: Analysis from the national cancer data base, 1993 to 2004. The Journal of urology, 179(6): 2131-2135. DOI 10.1016/j.juro.2008.01.097.\u003c/li\u003e\n \u003cli\u003eCrispen, P.L., S.A. Boorjian, C.M. Lohse, T.S. Sebo, J.C. Cheville, M.L. Blute and B.C. Leibovich, 2008. Outcomes following partial nephrectomy by tumor size. The Journal of urology, 180(5): 1912-1917. DOI 10.1016/j.juro.2008.07.047.\u003c/li\u003e\n \u003cli\u003eCrispen, P.L., R. Viterbo, S.A. Boorjian, R.E. Greenberg, D.Y. Chen and R.G. Uzzo, 2009. Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance. Cancer, 115(13): 2844-2852. DOI 10.1002/cncr.24338.\u003c/li\u003e\n \u003cli\u003eCrispen, P.L., Y.N. Wong, R.E. Greenberg, D.Y. Chen and R.G. Uzzo, 2008. Predicting growth of solid renal masses under active surveillance. Urologic oncology, 26(5): 555-559. DOI 10.1016/j.urolonc.2008.03.010.\u003c/li\u003e\n \u003cli\u003eDeng, F.M. and J. Melamed, 2012. Histologic variants of renal cell carcinoma: Does tumor type influence outcome? The Urologic clinics of North America, 39(2): 119-132, v. DOI 10.1016/j.ucl.2012.02.001.\u003c/li\u003e\n \u003cli\u003eEdmunds, J.W., L.C. Mahadevan and A.L. Clayton, 2008. Dynamic histone h3 methylation during gene induction: Hypb/setd2 mediates all h3k36 trimethylation. The EMBO journal, 27(2): 406-420. DOI 10.1038/sj.emboj.7601967.\u003c/li\u003e\n \u003cli\u003eH\u0026ouml;gner, A., H. Krause, B. Jandrig, M. Kasim, T.F. Fuller, M. Schostak, A. Erbersdobler, A. Patzak and E. Kilic, 2018. Pbrm1 and vhl expression correlate in human clear cell renal cell carcinoma with differential association with patient\u0026apos;s overall survival. Urologic oncology, 36(3): 94.e91-94.e14. DOI 10.1016/j.urolonc.2017.10.027.\u003c/li\u003e\n \u003cli\u003eHollingsworth, J.M., D.C. Miller, S. Daignault and B.K. Hollenbeck, 2006. Rising incidence of small renal masses: A need to reassess treatment effect. Journal of the National Cancer Institute, 98(18): 1331-1334. DOI 10.1093/jnci/djj362.\u003c/li\u003e\n \u003cli\u003eHsieh, J.J., D. Chen, P.I. Wang, M. Marker, A. Redzematovic, Y.B. Chen, S.D. Selcuklu, N. Weinhold, N. Bouvier, K.H. Huberman, U. Bhanot, M.S. Chevinsky, P. Patel, P. Pinciroli, H.H. Won, D. You, A. Viale, W. Lee, A.A. Hakimi, M.F. Berger, N.D. Socci, E.H. Cheng, J. Knox, M.H. Voss, M. Voi and R.J. Motzer, 2017. Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. European urology, 71(3): 405-414. DOI 10.1016/j.eururo.2016.10.007.\u003c/li\u003e\n \u003cli\u003eHsieh, J.J., M.P. Purdue, S. Signoretti, C. Swanton, L. Albiges, M. Schmidinger, D.Y. Heng, J. Larkin and V. Ficarra, 2017. Renal cell carcinoma. Nature reviews. Disease primers, 3: 17009. DOI 10.1038/nrdp.2017.9.\u003c/li\u003e\n \u003cli\u003eJilg, C.A., H.P. Neumann, S. Gl\u0026auml;sker, O. Sch\u0026auml;fer, P.U. Ardelt, M. Schwardt and W. Schultze-Seemann, 2012. Growth kinetics in von hippel-lindau-associated renal cell carcinoma. Urologia internationalis, 88(1): 71-78. DOI 10.1159/000333348.\u003c/li\u003e\n \u003cli\u003eK\u0026uuml;mmerlin, I.P., F.J. ten Kate, H. Wijkstra, J.J. de la Rosette and M.P. Laguna, 2008. Changes in the stage and surgical management of renal tumours during 1995-2005: An analysis of the dutch national histopathology registry. BJU international, 102(8): 946-951. DOI 10.1111/j.1464-410X.2008.07770.x.\u003c/li\u003e\n \u003cli\u003eLane, B.R., R. Abouassaly, T. Gao, C.J. Weight, A.V. Hernandez, B.T. Larson, J.H. Kaouk, I.S. Gill and S.C. Campbell, 2010. Active treatment of localized renal tumors may not impact overall survival in patients aged 75 years or older. Cancer, 116(13): 3119-3126. DOI 10.1002/cncr.25184.\u003c/li\u003e\n \u003cli\u003eLjungberg, B., L. Albiges, Y. Abu-Ghanem, K. Bensalah, S. Dabestani, S. Fern\u0026aacute;ndez-Pello, R.H. Giles, F. Hofmann, M. Hora, M.A. Kuczyk, T. Kuusk, T.B. Lam, L. Marconi, A.S. Merseburger, T. Powles, M. Staehler, R. Tahbaz, A. Volpe and A. Bex, 2019. European association of urology guidelines on renal cell carcinoma: The 2019 update. European urology, 75(5): 799-810. DOI 10.1016/j.eururo.2019.02.011.\u003c/li\u003e\n \u003cli\u003eLjungberg, B., K. Bensalah, S. Canfield, S. Dabestani, F. Hofmann, M. Hora, M.A. Kuczyk, T. Lam, L. Marconi, A.S. Merseburger, P. Mulders, T. Powles, M. Staehler, A. Volpe and A. Bex, 2015. Eau guidelines on renal cell carcinoma: 2014 update. European urology, 67(5): 913-924. DOI 10.1016/j.eururo.2015.01.005.\u003c/li\u003e\n \u003cli\u003eMaher, E.R., 2018. Hereditary renal cell carcinoma syndromes: Diagnosis, surveillance and management. World journal of urology, 36(12): 1891-1898. DOI 10.1007/s00345-018-2288-5.\u003c/li\u003e\n \u003cli\u003eMaher, E.R., H.P. Neumann and S. Richard, 2011. Von hippel-lindau disease: A clinical and scientific review. European journal of human genetics : EJHG, 19(6): 617-623. DOI 10.1038/ejhg.2010.175.\u003c/li\u003e\n \u003cli\u003eMason, R.J., M. Abdolell, G. Trottier, C. Pringle, J.G. Lawen, D.G. Bell, M.A. Jewett, L. Klotz and R.A. Rendon, 2011. Growth kinetics of renal masses: Analysis of a prospective cohort of patients undergoing active surveillance. European urology, 59(5): 863-867. DOI 10.1016/j.eururo.2011.02.023.\u003c/li\u003e\n \u003cli\u003eNeumann, H.P., B.U. Bender, D.P. Berger, J. Laubenberger, W. Schultze-Seemann, U. Wetterauer, F.J. Ferstl, E.W. Herbst, G. Schwarzkopf, F.J. Hes, C.J. Lips, J.M. Lamiell, O. Masek, P. Riegler, B. Mueller, D. Glavac and H. Brauch, 1998. Prevalence, morphology and biology of renal cell carcinoma in von hippel-lindau disease compared to sporadic renal cell carcinoma. The Journal of urology, 160(4): 1248-1254.\u003c/li\u003e\n \u003cli\u003ePawłowski, R., S.M. M\u0026uuml;hl, T. Sulser, W. Krek, H. Moch and P. Schraml, 2013. Loss of pbrm1 expression is associated with renal cell carcinoma progression. International journal of cancer, 132(2): E11-17. DOI 10.1002/ijc.27822.\u003c/li\u003e\n \u003cli\u003ePe\u0026ntilde;a-Llopis, S., S. Vega-Rub\u0026iacute;n-de-Celis, A. Liao, N. Leng, A. Pav\u0026iacute;a-Jim\u0026eacute;nez, S. Wang, T. Yamasaki, L. Zhrebker, S. Sivanand, P. Spence, L. Kinch, T. Hambuch, S. Jain, Y. Lotan, V. Margulis, A.I. Sagalowsky, P.B. Summerour, W. Kabbani, S.W. Wong, N. Grishin, M. Laurent, X.J. Xie, C.D. Haudenschild, M.T. Ross, D.R. Bentley, P. Kapur and J. Brugarolas, 2012. Bap1 loss defines a new class of renal cell carcinoma. Nature genetics, 44(7): 751-759. DOI 10.1038/ng.2323.\u003c/li\u003e\n \u003cli\u003ePeng, X., J. Chen, J. Wang, S. Peng, S. Liu, K. Ma, J. Zhou, B. Hong, B. Zhou, J. Zhang, L. Cai and K. Gong, 2019. Natural history of renal tumours in von hippel-lindau disease: A large retrospective study of chinese patients. Journal of medical genetics, 56(6): 380-387. DOI 10.1136/jmedgenet-2018-105567.\u003c/li\u003e\n \u003cli\u003eSchuhmacher, P., E. Kim, F. Hahn, P. Sekula, C.A. Jilg, C. Leiber, H.P. Neumann, W. Schultze-Seemann, G. Walz and S. Zschiedrich, 2019. Growth characteristics and therapeutic decision markers in von hippel-lindau disease patients with renal cell carcinoma. Orphanet journal of rare diseases, 14(1): 235. DOI 10.1186/s13023-019-1206-2.\u003c/li\u003e\n \u003cli\u003eScosyrev, E., E.M. Messing, R. Sylvester, S. Campbell and H. Van Poppel, 2014. Renal function after nephron-sparing surgery versus radical nephrectomy: Results from eortc randomized trial 30904. European urology, 65(2): 372-377. DOI 10.1016/j.eururo.2013.06.044.\u003c/li\u003e\n \u003cli\u003eSiegel, R.L., K.D. Miller and A. Jemal, 2020. Cancer statistics, 2020. CA: a cancer journal for clinicians, 70(1): 7-30. DOI 10.3322/caac.21590.\u003c/li\u003e\n \u003cli\u003eStaehler, M., N. Haseke, T. Stadler, E. Zilinberg, C. Nordhaus, P. Nuhn, W.Y. Khoder, A. Karl and C.G. Stief, 2010. The growth rate of large renal masses opposes active surveillance. BJU international, 105(7): 928-931. DOI 10.1111/j.1464-410X.2009.08840.x.\u003c/li\u003e\n \u003cli\u003eSun, M., R. Thuret, F. Abdollah, G. Lughezzani, J. Schmitges, Z. Tian, S.F. Shariat, F. Montorsi, J.J. Patard, P. Perrotte and P.I. Karakiewicz, 2011. Age-adjusted incidence, mortality, and survival rates of stage-specific renal cell carcinoma in north america: A trend analysis. European urology, 59(1): 135-141. DOI 10.1016/j.eururo.2010.10.029.\u003c/li\u003e\n \u003cli\u003eTurajlic, S., H. Xu, K. Litchfield, A. Rowan, S. Horswell, T. Chambers, T. O\u0026apos;Brien, J.I. Lopez, T.B.K. Watkins, D. Nicol, M. Stares, B. Challacombe, S. Hazell, A. Chandra, T.J. Mitchell, L. Au, C. Eichler-Jonsson, F. Jabbar, A. Soultati, S. Chowdhury, S. Rudman, J. Lynch, A. Fernando, G. Stamp, E. Nye, A. Stewart, W. Xing, J.C. Smith, M. Escudero, A. Huffman, N. Matthews, G. Elgar, B. Phillimore, M. Costa, S. Begum, S. Ward, M. Salm, S. Boeing, R. Fisher, L. Spain, C. Navas, E. Gr\u0026ouml;nroos, S. Hobor, S. Sharma, I. Aurangzeb, S. Lall, A. Polson, M. Varia, C. Horsfield, N. Fotiadis, L. Pickering, R.F. Schwarz, B. Silva, J. Herrero, N.M. Luscombe, M. Jamal-Hanjani, R. Rosenthal, N.J. Birkbak, G.A. Wilson, O. Pipek, D. Ribli, M. Krzystanek, I. Csabai, Z. Szallasi, M. Gore, N. McGranahan, P. Van Loo, P. Campbell, J. Larkin and C. Swanton, 2018. Deterministic evolutionary trajectories influence primary tumor growth: Tracerx renal. Cell, 173(3): 595-610.e511. DOI 10.1016/j.cell.2018.03.043.\u003c/li\u003e\n \u003cli\u003eVan Poppel, H., L. Da Pozzo, W. Albrecht, V. Matveev, A. Bono, A. Borkowski, J.M. Marechal, L. Klotz, E. Skinner, T. Keane, I. Claessens and R. Sylvester, 2007. A prospective randomized eortc intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. European urology, 51(6): 1606-1615. DOI 10.1016/j.eururo.2006.11.013.\u003c/li\u003e\n \u003cli\u003eVasudevan, A., R.J. Davies, B.A. Shannon and R.J. Cohen, 2006. Incidental renal tumours: The frequency of benign lesions and the role of preoperative core biopsy. BJU international, 97(5): 946-949. DOI 10.1111/j.1464-410X.2006.06126.x.\u003c/li\u003e\n \u003cli\u003eWagstaff, P.G., P.J. Zondervan, J.J. de la Rosette and M.P. Laguna, 2014. The role of imaging in the active surveillance of small renal masses. Current urology reports, 15(3): 386. DOI 10.1007/s11934-013-0386-x.\u003c/li\u003e\n \u003cli\u003eZhang, J., S.K. Kang, L. Wang, A. Touijer and H. Hricak, 2009. Distribution of renal tumor growth rates determined by using serial volumetric ct measurements. Radiology, 250(1): 137-144. DOI 10.1148/radiol.2501071712.\u003c/li\u003e\n \u003cli\u003eZhang, J., J.H. Pan, B.J. Dong, W. Xue, D.M. Liu and Y.R. Huang, 2012. Active surveillance of renal masses in von hippel-lindau disease: Growth rates and clinical outcome over a median follow-up period of 56 months. Familial cancer, 11(2): 209-214. DOI 10.1007/s10689-011-9503-5.\u003c/li\u003e\n \u003cli\u003eZhang, L., W. Yin, L. Yao, X. Li, D. Fang, D. Ren, Z. Zhang, Y. Fan, Q. He, W. Ci, Z. He and L. Zhou, 2015. Growth pattern of clear cell renal cell carcinoma in patients with delayed surgical intervention: Fast growth rate correlates with high grade and may result in poor prognosis. BioMed research international, 2015: 598134. DOI 10.1155/2015/598134.\u003c/li\u003e\n\u003c/ol\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Clear cell renal cell carcinoma, VHL-associated RCC, Natural history, Active surveillance, Growth rate","lastPublishedDoi":"10.21203/rs.3.rs-675576/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-675576/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTo compare the tumor growth kinetics between sporadic clear cell renal cell carcinoma (ccRCC) and Von Hippel-Lindau disease-associated renal cell carcinoma (VHL-associated RCC). To analyze predictive markers for the growth rate of these two types of RCC.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe clinical data of patients with renal tumors who received active surveillance were collected retrospectively. Immunohistochemical staining was utilized to analyze the expression levels of VHL, PBRM1, H3K36me3, and BAP1 in the postoperative specimens.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe age of the VHL group was significantly younger than that of the sporadic group (P\u0026lt;0.0001). The mean linear growth rate (LGR) was significantly faster in the sporadic group (P=0.0004). The tumors of those in the sporadic group tended to have a higher histologic grade (P=0.0011). In the sporadic group, tumor histologic grade was an independent predictor for rapid mean LGR (P=0.0022). In the VHL group, tumor initial MTD was the only independent predictor for rapid mean LGR (P＜0.0001). Tumors with low VHL expression and negative PBRM1 expression showed a faster growth rate in the sporadic group (P=0.001 and P=0.008, respectively). The expression levels of the 4 biomarkers showed no impact on the tumor growth rate in the VHL group.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eSporadic ccRCC grew faster than VHL-associated RCC. High histologic grade, low VHL expression and negative PBRM1 expression were predictors of faster growth in sporadic ccRCC. A large initial MTD was a predictor of faster growth for VHL-associated RCC.\u003c/p\u003e","manuscriptTitle":"Natural History of Von Hippel-Lindau Disease-associated and Sporadic Clear Cell Renal Cell Carcinoma: a Comparative Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-07-08 12:15:06","doi":"10.21203/rs.3.rs-675576/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-07-28T11:28:33+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-07-05T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-07-01T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cancer Research and Clinical Oncology","date":"2021-06-30T12:21:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dd38cece-ad72-49eb-8148-53b6ced6e65e","owner":[],"postedDate":"July 8th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":5509437,"name":"Cancer Biology"},{"id":5509438,"name":"Oncology"}],"tags":[],"updatedAt":"2021-09-16T13:05:17+00:00","versionOfRecord":[],"versionCreatedAt":"2021-07-08 12:15:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-675576","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-675576","identity":"rs-675576","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}
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