Microsatellite instability in diagnostic pathology

Abstract

A defect in the DNA mismatch repair process results in the phenomenon of microsatellite instability (MSI), which is the fundamental genetic alteration in a number of neoplastic conditions. This neoplastic pathway has been most widely studied in the setting of colorectal carcinoma. It is operative in both hereditary [hereditary non-polyposis colorectal carcinoma syndrome, (HNPCC)] and sporadic tumours. In both instances, tumours resulting from this molecular pathway may have important clinical differences in comparison to those resulting from the more common adenoma–carci-noma sequence/suppressor pathway. Patients with these tumours may have a survival advantage, and possibly a different response to commonly used chemotherapeutic agents. In addition, there are histopathological features which may aid in identification of these lesions. However, definite diagnosis requires molecular confirmation of the presence of MSI. Although precise in the diagnosis of MSI tumours, molecular testing requires specialized techniques and cannot be routinely performed in most diagnostic laboratories. Monoclonal antibodies have been recently developed identifying the expression of hMLH1, hMSH2, and other mismatch repair proteins. The expression of these proteins has been shown to correlate well with the existence of MSI in colorectal carcinomas, which allows the identification of MSI-associated tumours in a more rapid and cost-effective manner. This paper reviews the theoretical concept of MSI, and the clinicopathologic features of these tumours. In addition, the use and value of immunohistochemistry in this field is discussed.