Colorectal carcinomas with high microsatellite instability: Defining a distinct immunologic and molecular entity with respect to prognostic markers

Tina Bocker Edmonston, Kimberly H. Cuesta, Susan Burkholder, Alan Barusevicius, Deborah Rose, Albert J. Kovatich, Bruce Boman, Robert Fry, Richard Fishel, Juan P. Palazzo

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bc1-2, cell cycle proteins p21WAF1/CIP1, and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bc1-2 and absence of p53. p21WAF1/CIP1 is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bc1-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRC's irrespective of the microsatellite status, MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21WAF1/CIP1. MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bc1-2 expression; p21WAF1/CIP1 expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis.

Original languageEnglish
Pages (from-to)1506-1514
Number of pages9
JournalHuman Pathology
Issue number12
StatePublished - 2000
Externally publishedYes


  • Cell cycle proteins
  • Colorectal cancer
  • Microsatellite instability
  • Prognosis


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