Tumor Biology

, Volume 35, Issue 9, pp 8743–8747 | Cite as

Expression of MLH1 and MSH2 in urothelial carcinoma of the renal pelvis

  • Laleh Ehsani
  • Adeboye O. Osunkoya
Research Article


In this study, we investigated microsatellite instability in urothelial carcinoma of the renal pelvis by lack of immunohistochemical staining for MLH1 and MSH2. The study included 44 cases of urothelial carcinoma of the renal pelvis obtained from radical nephroureterectomy specimens at our institution. We evaluated the loss of nuclear immunohistochemical staining of MLH1 and MSH2. Eight of 44 (18 %) patients had negative MLH1 expression and 25/44 (57 %) patients had negative MSH2 expression. Six of 8 (75 %) patients with negative MLH1 expression were male and 2/8 (25 %) patients were female. Nineteen of 25 (75 %) patients with negative MSH2 expression were male, and 6/25 (24 %) patients were female. Seven of 8 (88 %) cases with negative MLH1 expression were high-grade urothelial carcinoma, and 21/25 (84 %) cases with negative MSH2 expression were high-grade urothelial carcinoma. Twenty-one of 44 (48 %) cases had an inverted growth pattern, of which 3/21 (14 %) cases had negative MLH1 expression and 14/21 (67 %) cases had negative MSH2 expression. Our study showed that microsatellite instability based on negative expression of MLH1 and MSH2 was more common in male patients with high-grade urothelial carcinoma. There is a strong correlation between inverted growth pattern and negative MSH2 expression. Microsatellite instability testing should be performed in patients with upper urinary tract carcinoma and may have prognostic value.


Microsatellite instability Urothelial carcinoma Renal pelvis 


Conflict of interest



  1. 1.
    Oldbring J, Glifberg I, Mikulowski P, et al. Carcinoma of the renal pelvis and ureter following bladder carcinoma: frequency, risk factors and clinicopathological findings. J Urol. 1989;141:1311–3.PubMedGoogle Scholar
  2. 2.
    Hall MC, Womack S, Sagalowsky AI, et al. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998;52:594–601.CrossRefPubMedGoogle Scholar
  3. 3.
    Loeb LA. A mutator phenotype in cancer. Cancer Res. 2001;61:3230–9.PubMedGoogle Scholar
  4. 4.
    Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919–32.CrossRefPubMedGoogle Scholar
  6. 6.
    van der Post RS, Kiemeney LA, Ligtenberg MJ, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010;47(7):464–70.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 1995;64:430e3.CrossRefGoogle Scholar
  8. 8.
    Vasen HF, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19:4074e80.Google Scholar
  9. 9.
    Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet. 1997;6:105e10.CrossRefGoogle Scholar
  10. 10.
    Hendriks YM, Wagner A, Morreau H, Menko F, Stormorken A, et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology. 2004;127:17e25.CrossRefGoogle Scholar
  11. 11.
    Quehenberger F, Vasen HF, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet. 2005;42:491e6.CrossRefGoogle Scholar
  12. 12.
    Sijmons RH, Kiemeney LA, Witjes JA, Vasen HF. Urinary tract cancer and hereditary nonpolyposis colorectal cancer: risks and screening options. J Urol. 1998;160:466e70.CrossRefGoogle Scholar
  13. 13.
    Lynch HT, Taylor RJ, Lynch JF, et al. Multiple primary cancer, including transitional cell carcinoma of the upper uroepithelial tract in a multigeneration HNPCC family: molecular genetic, diagnostic, and management implications. Am J Gastroenterol. 2003;98:664e70.CrossRefGoogle Scholar
  14. 14.
    Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110:1020e7.CrossRefGoogle Scholar
  15. 15.
    Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993;71:677e85.CrossRefGoogle Scholar
  16. 16.
    Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102:193e201.CrossRefGoogle Scholar
  17. 17.
    Liu B, Nicolaides NC, Markowitz S, et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet. 1995;9:48–55.CrossRefPubMedGoogle Scholar
  18. 18.
    Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.CrossRefPubMedGoogle Scholar
  19. 19.
    Drummond JT, Anthoney A, Brown R, Modrich P. Cisplatin and adriamysin resistance are associated with MutLA and mismatch repair deficiency in an ovarian tumour cell line. J Biol Chem. 1996;271:19645–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Arzimanoglou II, Gilbert F, Barber HR. Microsatellite instability in human solid tumors. Cancer. 1998;82:1808–20.CrossRefPubMedGoogle Scholar
  22. 22.
    Staebler A, Lax SF, Ellenson LH. Altered expression of hMLH1 and hMSH2 protein in endometrial carcinomas with microsatellite instability. Hum Pathol. 2000;31:354–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Cunningham JM, Cunningham JM, Christensen ER, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 1998;58(15):3455–60.PubMedGoogle Scholar
  24. 24.
    Blaszyk H, Wang L, Dietmaier W, et al. Upper tract urothelial carcinoma: a clinicopathologic study including microsatellite instability analysis. Mod Pathol. 2002;15:790–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Hartmann A, Dietmaier W. Hofstädter F, et al Urothelial carcinoma of the upper urinary tract: inverted growth pattern is predictive of microsatellite instability. Hum Pathol. 2003;34(3):222–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Chiura AN, Wirtschafter A, Bagley DH. Upper urinary tract inverted papillomas. Urology. 1998;52:514–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Rey A, Lara PC, Redondo E, et al. Overexpression of p53 in transitional cell carcinoma of the renal pelvis and ureter: relation to tumor proliferation and survival. Cancer. 1997;79:2178–85.CrossRefPubMedGoogle Scholar
  28. 28.
    Bilim VN, Tomita Y, Kawasaki T, et al. Variable Bcl-2 phenotype in benign and malignant lesions of urothelium. Cancer Lett. 1998;128:87–92.CrossRefPubMedGoogle Scholar
  29. 29.
    Hartmann A, Zanardo L, Bocker-Edmonston T, et al. Frequent microsatellite instability in sporadic tumors of the upper urinary tract. Cancer Res. 2002;62(23):6796–802.PubMedGoogle Scholar
  30. 30.
    Rouprêt M, Fromont G, Azzouzi AR, et al. Microsatellite instability as predictor of survival in patients with invasive upper urinary tract transitional cell carcinoma. Urology. 2005;65(6):1233–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Rouprêt M, Azzouzi AR, Cussenot O. Microsatellite instability and transitional cell Carcinoma of the upper urinary tract. BJU Int. 2005;96(4):489–92.CrossRefPubMedGoogle Scholar
  32. 32.
    Ruszkiewicz A, Bennett G, Moore J, et al. Correlation of mismatch repair genes immunohistochemistry and microsatellite instability status in HNPCC-associated tumours. Pathol- ogy. 2002;34:541–7.CrossRefGoogle Scholar
  33. 33.
    Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 2002;20:1043–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Parc Y, Gueroult S, Mourra N, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371–5.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of PathologyEmory University School of MedicineAtlantaUSA
  2. 2.Department of UrologyEmory University School of MedicineAtlantaUSA
  3. 3.Emory Winship Cancer InstituteAtlantaUSA

Personalised recommendations