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, initial maximal tumor diameter (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 four 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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets analysed during the current study are available from the corresponding author on reasonable request.
Code availability
Not applicable.
References
Ben-Skowronek I, Kozaczuk S (2015) Von Hippel-Lindau syndrome. Hormone Res Paediatr 84(3):145–152. https://doi.org/10.1159/000431323
Bihr S, Ohashi R, Moore AL, Rüschoff JH, Beisel C, Hermanns T, Mischo A, Corrò C, Beyer J, Beerenwinkel N, Moch H, Schraml P (2019) Expression and mutation patterns of PBRM1, BAP1 and SETD2 mirror specific evolutionary subtypes in clear cell renal cell carcinoma. Neoplasia 21(2):247–256. https://doi.org/10.1016/j.neo.2018.12.006
Campbell SC, Novick AC, Belldegrun A, Blute ML, Chow GK, Derweesh IH, Faraday MM, Kaouk JH, Leveillee RJ, Matin SF, Russo P, Uzzo RG (2009) Guideline for management of the clinical T1 renal mass. J Urol 182(4):1271–1279. https://doi.org/10.1016/j.juro.2009.07.004
Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DY, Uzzo RG (2006) The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 175(2):425–431. https://doi.org/10.1016/s0022-5347(05)00148-5
Chow WH, Devesa SS (2008) Contemporary epidemiology of renal cell cancer. Cancer J 14(5):288–301. https://doi.org/10.1097/PPO.0b013e3181867628
Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr (1999) Rising incidence of renal cell cancer in the united states. JAMA 281(17):1628–1631. https://doi.org/10.1001/jama.281.17.1628
Cooperberg MR, Mallin K, Ritchey J, Villalta JD, Carroll PR, Kane CJ (2008) Decreasing size at diagnosis of stage 1 renal cell carcinoma: analysis from the national cancer data base, 1993 to 2004. J Urol 179(6):2131–2135. https://doi.org/10.1016/j.juro.2008.01.097
Crispen PL, Boorjian SA, Lohse CM, Sebo TS, Cheville JC, Blute ML, Leibovich BC (2008a) Outcomes following partial nephrectomy by tumor size. J Urol 180(5):1912–1917. https://doi.org/10.1016/j.juro.2008.07.047
Crispen PL, Wong YN, Greenberg RE, Chen DY, Uzzo RG (2008b) Predicting growth of solid renal masses under active surveillance. Urol Oncol 26(5):555–559. https://doi.org/10.1016/j.urolonc.2008.03.010
Crispen PL, Viterbo R, Boorjian SA, Greenberg RE, Chen DY, Uzzo RG (2009) Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance. Cancer 115(13):2844–2852. https://doi.org/10.1002/cncr.24338
Deng FM, Melamed J (2012) Histologic variants of renal cell carcinoma: does tumor type influence outcome? Urol Clin N Am 39(2):119–132. https://doi.org/10.1016/j.ucl.2012.02.001
Edmunds JW, Mahadevan LC, Clayton AL (2008) Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J 27(2):406–420. https://doi.org/10.1038/sj.emboj.7601967
Högner A, Krause H, Jandrig B, Kasim M, Fuller TF, Schostak M, Erbersdobler A, Patzak A, Kilic E (2018) PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient’s overall survival. Urol Oncol 36(3):94.e91-94.e14. https://doi.org/10.1016/j.urolonc.2017.10.027
Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK (2006) Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 98(18):1331–1334. https://doi.org/10.1093/jnci/djj362
Hsieh JJ, Chen D, Wang PI, Marker M, Redzematovic A, Chen YB, Selcuklu SD, Weinhold N, Bouvier N, Huberman KH, Bhanot U, Chevinsky MS, Patel P, Pinciroli P, Won HH, You D, Viale A, Lee W, Hakimi AA, Berger MF, Socci ND, Cheng EH, Knox J, Voss MH, Voi M, Motzer RJ (2017a) Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur Urol 71(3):405–414. https://doi.org/10.1016/j.eururo.2016.10.007
Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, Heng DY, Larkin J, Ficarra V (2017b) Renal cell carcinoma. Nat Rev Dis Primers 3:17009. https://doi.org/10.1038/nrdp.2017.9
Jilg CA, Neumann HP, Gläsker S, Schäfer O, Ardelt PU, Schwardt M, Schultze-Seemann W (2012) Growth kinetics in Von Hippel-Lindau-associated renal cell carcinoma. Urol Int 88(1):71–78. https://doi.org/10.1159/000333348
Kümmerlin IP, ten Kate FJ, Wijkstra H, de la Rosette JJ, Laguna MP (2008) Changes in the stage and surgical management of renal tumours during 1995–2005: an analysis of the Dutch national histopathology registry. BJU Int 102(8):946–951. https://doi.org/10.1111/j.1464-410X.2008.07770.x
Lane BR, Abouassaly R, Gao T, Weight CJ, Hernandez AV, Larson BT, Kaouk JH, Gill IS, Campbell SC (2010) Active treatment of localized renal tumors may not impact overall survival in patients aged 75 years or older. Cancer 116(13):3119–3126. https://doi.org/10.1002/cncr.25184
Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, Kuczyk MA, Lam T, Marconi L, Merseburger AS, Mulders P, Powles T, Staehler M, Volpe A, Bex A (2015) EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 67(5):913–924. https://doi.org/10.1016/j.eururo.2015.01.005
Ljungberg B, Albiges L, Abu-Ghanem Y, Bensalah K, Dabestani S, Fernández-Pello S, Giles RH, Hofmann F, Hora M, Kuczyk MA, Kuusk T, Lam TB, Marconi L, Merseburger AS, Powles T, Staehler M, Tahbaz R, Volpe A, Bex A (2019) European association of urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol 75(5):799–810. https://doi.org/10.1016/j.eururo.2019.02.011
Maher ER (2018) Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management. World J Urol 36(12):1891–1898. https://doi.org/10.1007/s00345-018-2288-5
Maher ER, Neumann HP, Richard S (2011) Von Hippel-Lindau disease: a clinical and scientific review. Eur J Human Genet EJHG 19(6):617–623. https://doi.org/10.1038/ejhg.2010.175
Mason RJ, Abdolell M, Trottier G, Pringle C, Lawen JG, Bell DG, Jewett MA, Klotz L, Rendon RA (2011) Growth kinetics of renal masses: analysis of a prospective cohort of patients undergoing active surveillance. Eur Urol 59(5):863–867. https://doi.org/10.1016/j.eururo.2011.02.023
Neumann HP, Bender BU, Berger DP, Laubenberger J, Schultze-Seemann W, Wetterauer U, Ferstl FJ, Herbst EW, Schwarzkopf G, Hes FJ, Lips CJ, Lamiell JM, Masek O, Riegler P, Mueller B, Glavac D, Brauch H (1998) Prevalence, morphology and biology of renal cell carcinoma in Von Hippel-Lindau disease compared to sporadic renal cell carcinoma. J Urol 160(4):1248–1254
Pawłowski R, Mühl SM, Sulser T, Krek W, Moch H, Schraml P (2013) Loss of PBRM1 expression is associated with renal cell carcinoma progression. Int J Cancer 132(2):E11-17. https://doi.org/10.1002/ijc.27822
Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SW, Grishin N, Laurent M, Xie XJ, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J (2012) BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44(7):751–759. https://doi.org/10.1038/ng.2323
Peng X, Chen J, Wang J, Peng S, Liu S, Ma K, Zhou J, Hong B, Zhou B, Zhang J, Cai L, Gong K (2019) Natural history of renal tumours in Von Hippel-Lindau disease: a large retrospective study of Chinese patients. J Med Genet 56(6):380–387. https://doi.org/10.1136/jmedgenet-2018-105567
Schuhmacher P, Kim E, Hahn F, Sekula P, Jilg CA, Leiber C, Neumann HP, Schultze-Seemann W, Walz G, Zschiedrich S (2019) Growth characteristics and therapeutic decision markers in Von Hippel-Lindau disease patients with renal cell carcinoma. Orphanet J Rare Dis 14(1):235. https://doi.org/10.1186/s13023-019-1206-2
Scosyrev E, Messing EM, Sylvester R, Campbell S, Van Poppel H (2014) Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol 65(2):372–377. https://doi.org/10.1016/j.eururo.2013.06.044
Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin 70(1):7–30. https://doi.org/10.3322/caac.21590
Staehler M, Haseke N, Stadler T, Zilinberg E, Nordhaus C, Nuhn P, Khoder WY, Karl A, Stief CG (2010) The growth rate of large renal masses opposes active surveillance. BJU Int 105(7):928–931. https://doi.org/10.1111/j.1464-410X.2009.08840.x
Sun M, Thuret R, Abdollah F, Lughezzani G, Schmitges J, Tian Z, Shariat SF, Montorsi F, Patard JJ, Perrotte P, Karakiewicz PI (2011) Age-adjusted incidence, mortality, and survival rates of stage-specific renal cell carcinoma in North America: a trend analysis. Eur Urol 59(1):135–141. https://doi.org/10.1016/j.eururo.2010.10.029
The Cancer Genome Atlas Research Network (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499(7456):43–49. https://doi.org/10.1038/nature12222
Turajlic S, Xu H, Litchfield K, Rowan A, Horswell S, Chambers T, O’Brien T, Lopez JI, Watkins TBK, Nicol D, Stares M, Challacombe B, Hazell S, Chandra A, Mitchell TJ, Au L, Eichler-Jonsson C, Jabbar F, Soultati A, Chowdhury S, Rudman S, Lynch J, Fernando A, Stamp G, Nye E, Stewart A, Xing W, Smith JC, Escudero M, Huffman A, Matthews N, Elgar G, Phillimore B, Costa M, Begum S, Ward S, Salm M, Boeing S, Fisher R, Spain L, Navas C, Grönroos E, Hobor S, Sharma S, Aurangzeb I, Lall S, Polson A, Varia M, Horsfield C, Fotiadis N, Pickering L, Schwarz RF, Silva B, Herrero J, Luscombe NM, Jamal-Hanjani M, Rosenthal R, Birkbak NJ, Wilson GA, Pipek O, Ribli D, Krzystanek M, Csabai I, Szallasi Z, Gore M, McGranahan N, Van Loo P, Campbell P, Larkin J, Swanton C (2018) Deterministic evolutionary trajectories influence primary tumor growth: TRACERx renal. Cell 173(3):595-610.e511. https://doi.org/10.1016/j.cell.2018.03.043
Van Poppel H, Da Pozzo L, Albrecht W, Matveev V, Bono A, Borkowski A, Marechal JM, Klotz L, Skinner E, Keane T, Claessens I, Sylvester R (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. Eur Urol 51(6):1606–1615. https://doi.org/10.1016/j.eururo.2006.11.013
Vasudevan A, Davies RJ, Shannon BA, Cohen RJ (2006) Incidental renal tumours: the frequency of benign lesions and the role of preoperative core biopsy. BJU Int 97(5):946–949. https://doi.org/10.1111/j.1464-410X.2006.06126.x
Wagstaff PG, Zondervan PJ, de la Rosette JJ, Laguna MP (2014) The role of imaging in the active surveillance of small renal masses. Curr Urol Rep 15(3):386. https://doi.org/10.1007/s11934-013-0386-x
Zhang J, Kang SK, Wang L, Touijer A, Hricak H (2009) Distribution of renal tumor growth rates determined by using serial volumetric CT measurements. Radiology 250(1):137–144. https://doi.org/10.1148/radiol.2501071712
Zhang J, Pan JH, Dong BJ, Xue W, Liu DM, Huang YR (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. Fam Cancer 11(2):209–214. https://doi.org/10.1007/s10689-011-9503-5
Zhang L, Yin W, Yao L, Li X, Fang D, Ren D, Zhang Z, Fan Y, He Q, Ci W, He Z, Zhou L (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 Res Int 2015:598134. https://doi.org/10.1155/2015/598134
Acknowledgements
None.
Funding
There was no funding for this study.
Author information
Authors and Affiliations
Contributions
XL and KG contributed to the study conception and design. Material preparation, data collection and analysis were performed by JW, LZ, JQ and ZL. The first draft of the manuscript was written by JW and LZ and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical 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.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Wang, J., Zhang, L., Qiu, J. et al. Natural history of Von Hippel–Lindau disease-associated and sporadic clear cell renal cell carcinoma: a comparative study. J Cancer Res Clin Oncol 148, 2631–2641 (2022). https://doi.org/10.1007/s00432-021-03806-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-021-03806-0