Medicine, Health & Food

Medicine, Health & Food

The Correlation of Fibrosis with Tumor Size and International Society of Urological Pathology (ISUP) Grading of Clear Cell Renal Cell Carcinoma

Pages: 8  ,  Volume: 45  ,  Issue: 1 , January   2020
Received: 24 Jan 2020  ,  Published: 27 January 2020
Views: 124  ,  Download: 55


# Author Name
1 Dina Kharismawaty
2 Delyuzar
3 Lidya Imelda Laksmi


Background: Clear cell renal cell carcinoma (ccRCC) is one of the most aggressive sub-types of renal carcinoma causing most deaths from all urogenital cancers. Handling of ccRCC has been hampered due to the radio resistance and chemo resistance. This is thought to be due to the increasing involvement of the extracellular matrix produced by Cancer Associated Fibroblasts (CAF) and cancer cells. Fibrosis is an extracellular matrix accumulation process that can increase the tumor progression and metastasis.

Materials and methods: This study was a cross sectional study conducted on 21 patients with ccRCC that taken from their formalin-fixed paraffin embedded tissue blocks, each stained with hematoxylin and eosin to assess ISUP grading and Masson trichrome to assess fibrosis. Spearman correlation test (p <0.005) was performed to asses the correlation of fibrosis with tumor size and grading ISUP.

Results: Among 21 specimens of ccRCC patients, the most cases were 8 (38.1%) severe fibrosis found in tumors> 7 cm 5 (62.5%) and at grade IV 6 (75%). It was found that no significant result between fibrosis with tumor size (p = 0.135) and ISUP grading (p = 0.285) according to spearman correlation test


Although no significant correlation was found from the statistical analysis, there appeared to be the increasing impression of fibrosis which was also followed by the increasing of tumor size and ISUP grading.

Keywords: Clear cell renal cell carcinoma, fibrosis, tumor size, ISUP grading


  • clear cell renal cell carcinoma
  • fibrosis
  • tumor size
  • References


    1.           Cairns P. Renal cell carcinoma. Cancer Biomark. 2011;9(1):461–73.

    2.           Torre LA, Bray F, Siegel RL, Ferlay J. Global Cancer Statistics , 2012. Ca Cancer J Clin. 2015;65(2):87–108.

    3.           Leibovich BC, Lohse CM, Crispen PL, Boorjian SA, Thompson RH, Blute ML, et al. Oncology?: adrenal / renal / upper tract / bladder histological subtype is an independent predictor of outcome for patients with renal cell carcinoma. J Urol. 2010;183(4):1309–16.


    4.           Dagher J, Delahunt B, Rioux-leclercq N, Egevad L, Srigley JR, Coughlin G, et al. Clear cell renal cell carcinoma: Validation of WHO/ISUP grading. Histophatology. 2017;71(6):918–25.

    5.           Hanahan D, Coussens LM. Accessories to the Crime?: Functions of Cells Recruited to the Tumor Microenvironment. Cancer Cell. 2012;21(3):309–22.

    6.           Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol. 2014;4:1–8.

    7.           Gascard P, Tlsty TD. Carcinoma-associated fibroblasts?: orchestrating the composition of malignancy. 2016;1002–19.

    8.           Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment ?. Adv Drug Deliv Rev. 2016;99:186–96. Available from:

    9.           Kalluri R. The biology and function of fibroblasts in cancer. Nat Publ Gr. 2016;16(9):582–98.

    10.         Yue B. Biology of the Extracellular Matrix: An Overview. J Glaucoma. 2014;1–8.

    11.         Cox TR, Erler JT. Molecular pathways: Connecting fibrosis and solid tumor metastasis. Clin Cancer Res. 2014;20(14):3637–43.

    12.         Liu F, Mih JD, Shea BS, Kho AT, Sharif AS, Tager AM, et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol. 2010;190(4):693–706.

    13.         Barcellos-hoff MH, Lyden D, Wang TC. The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer [Internet]. 2013;1–8. Available from:

    14.         Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: Implications for fibrotic diseases and cancer. Dis Model Mech. 2011;4(2):165–78.

    15.         Won J, Hoon J, Oh K, Jae S, Young L, Kim A. Significance of intratumoral fibrosis in clear cell renal cell carcinoma. J Pathol Tradit Med. 2018;323–30.

    16.         Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-galluzzi C, Mckenney J, et al. The International Society of Urological Pathology ( ISUP ) Grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013;37(10):1490–504.

    17.         Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary System and male genital Organs — part A?: renal , penile , and testicular tumours. J Urol. 2016;70(1):93–105. Available from:

    18.         Kenney JM. Kidney?: tumors and tumorlike condition. In: Rosai Acherman Surgical Pathology. 11st ed. Philadelphia; 2018. p. 1025–39.

    19.         Patel C, Ahmed A, Ellsworth P. Renal cell carcinoma?: A reappraisal. Urol Nurs. 2012;32(4):182–90.

    20.         Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, et al. The International Society of Urological Pathology ( ISUP ) Vancouver Classification of enal eoplasia. Am J Surg Pathol. 2013;37(10):1469–89.

    21.         Moch H, B AM, P A, J C, B D, G M, et al. Clear cell renal cell carcinoma. In: Moch H, Humphrey PA, Ulbright TM, Reuter VE, editors. World Health Organization Classification of Tumours WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed. Lyon, France: International Agency for Research on Cancer; 2016. p. 18–21.

    22.         Rini BI, Campbell SC, Escudier B, Roussy IG. Renal cell carcinoma. Lancet [Internet]. 2009;373(9669):1119–32.

    23.         Singam P, Ho C, Hong GE, Mohd A, Cheok LB, Zainuddin Z. Clinical characteristics of renal cancer in malaysia?: A ten year review. Asian Pasific J Cancer Prev. 2010;11:503–6.

    24.         López JI, Errarte P, Erramuzpe A, Guarch R, Irazusta J, Llarena R, et al. Fibroblast activation protein predicts prognosis in clear cell renal cell carcinoma ?. Hum Pathol [Internet]. 2016;54:100–5.

    25.         Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol  Off J Eur Soc Med Oncol. 2019;30(5):706–20.

    26.         Pavlovich CP, Schmidt LS. Searching for the hereditary causes of renal cell carcinoma. Nat Rev. 2004;4:381–93.

    27.         Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Schmidinger M, Heng DY, et al. Renal cell carcinoma. Nat Rev Dis. 2018;1–42.

    28.         W. Marston Linehan, Srinivasan R, Schmidt LS. The genetic basis and kidney cancer: a metabolic disease. Natl Rev Urol. 2010;7(5):277–85.

    29.         Maher ER. Hereditary renal cell carcinoma syndromes?: diagnosis , surveillance and management. World J Urol. 2018;36(12):1891–8.

    30.         Mukhopadhyay SG, Mukherjee K, Manna AK. Renal tumours in adults with correlation between fuhrman grading and proliferative marker. Iran J Pathol. 2015;10(4):281–9.

    31.         Samaratunga H, Gianduzzo T, Delahunt B. The ISUP system of staging , grading and classification of renal cell neoplasia. J Kidney Cancer VHL. 2014;1(3):26–39.

    32.         Rybinski B, Franco-barraza J, Cukierman E, Rybinski B, Franco-barraza J, Cukierman E. The wound healing , chronic fibrosis , and cancer progression triad. Physiol Genomics. 2014;111(46):223–44.

    33.         Takai H, Kanematsu M, Yano K, Tsuda E, Higashio K, Ikeda K, et al. Transforming growth factor- ? stimulates the production of osteoprotegerin / osteoclastogenesis inhibitory factor by bone marrow Stromal Cells *. J Biol Chem. 1998;273(42):27091–6.

    34.         Penn MS. Preservation and repair. Nat Rev. 2010;177(5):2166–8.

    35.         Xu S, Cao X. Interleukin-17 and its expanding biological functions. Cell Mol Immunol. 2010;7(3):164–74.

    36.         Khan Z, Khan N, P. Tiwari R, K. Sah N, Prasad G, S. Bisen P. Biology of Cox-2: An Application in Cancer Therapeutics. Curr Drug Targets. 2011;12(7):1082–93.

    37.         Choy E, Rose-John S. Interleukin-6 as a multifunctional regulator: inflammation, immune response, and fibrosis. J Scleroderma Relat Disord. 2017;2:1–5.

    38.         Németh Á, Mózes MM, Calvier L, Hansmann G, Kökény G. The PPAR γ agonist pioglitazone prevents TGF- β induced renal fibrosis by repressing EGR-1 and STAT3. BMC Nephrol. 2019;245(20):1–9.

    39.         Cernaro V, Lacquaniti A, Donato V, Fazio MR, Buemi A, Buemi M. Fibrosis , regeneration and cancer?: what is the link?? Nephrol Dial Transplant. 2012;27(1):21–7.

    40.         Bondon FB, Huong T, Ho N, Elena M, Sanchez F, Farge E. Mechanotransduction in tumor progression?: The dark side of the force. J Cell Biol. 2018;217(5):1571–87.

    41.         Farris AB, Adams CD, Brousaides N, Della Pelle PA, Collins AB, Moradi E, et al. Morphometric and visual evaluation of fibrosis in renal biopsies. J Am Soc Nephrol. 2011;22(1):176–86.