Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair

Abstract

Background-Despite intensive research into the molecular abnormalities associated with colorectal cancer (CRC), no diagnostic tests have emerged which usefully complement standard histopathological assessments. Aims-To assess the feasibility of using immunohistochemistry to detect replication error (RER) positive CRCs and determine the incidence of RER positivity within distinct patient subgroups. Methods-502 CRCs were analysed for RER positivity (at least two markers aVected) and/or expression of hMSH2 and hMLH1. Results-There were 15/30 (50%) patients with metachronous CRCs, 16/51 (31%) with synchronous CRCs, 14/45 (31%) with a proximal colon carcinoma, and 4/23 (17%) who developed a CRC under the age of 50 showed RER positivity. However, 0/54 patients who developed a solitary carcinoma of the rectum/left colon over the age of 50 showed RER positivity. Immunohistochemical analysis revealed that 66/66 (100%) RER positive carcinomas were associated with complete lack of expression of either hMSH2 or hMLH1. This correlation was confirmed using a further 101 proximal colon carcinomas. Patients with a mismatch repair defective carcinoma showed improved survival but a 5.54 times relative risk of developing a metachronous CRC. A prospective immunohistochemical study revealed 13/117 (11%) patients had a mismatch repair defective carcinoma. A fivefold excess of hMLH1 defective cases was noted. Conclusions-All RER positive carcinomas were identified by the immunohistochemical test. This is the first simple laboratory test which can be performed routinely on all CRCs. It will provide a method for selecting patients who should be investigated for HNPCC, oVered long term follow up, and who may not respond to standard chemotherapy regimens. (Gut 1999;45:409-415)

Microsatellite instability and intratumoural heterogeneity in 100 right-sided sporadic colon carcinomas

“…This study indicates that IHC detection of the MMR proteins may be as efficient as a PCR based assay for screening MMR deficiency in certain conditions. Analysing a total of 100 carcinomas, we have confirmed the association between MSI positivity and the loss of protein expression reported in other studies (Thibodeau et al, 1996;Cawkwell et al, 1999). After the first analysis, immunochemistry of hMLH1, hMSH2 and hMSH6 proteins identified 39 MSI carcinomas.…”

“…After the first analysis, immunochemistry of hMLH1, hMSH2 and hMSH6 proteins identified 39 MSI carcinomas. This percentage (39%) is slightly higher than those previously reported in proximal sporadic colon carcinomas which varied between 23.1 and 33% (Kim et al, 1994;Cawkwell et al, 1999;Chao et al, 2000;Hemminki et al, 2000). These studies were only performed with hMLH1 and hMSH2 whereas in the present series, the use of the hMSH6 antibody enabled us to identify 10.3% of the MSI cases (i.e.…”

“…As recently reported , we also noted a preponderance of hMLH1 abnormalities over hMSH2 defects (overall 5 : 1) and over hMSH6 deficiency (overall 3 : 1). As the loss of hMLH1 expression correlates with hypermethylation of its promoter (Kane et al, 1997;Herman et al, 1998), we hypothesised that an excess of hMLH1 abnormalities could be produced since the hMSH2 promoter is less likely to be inactivated via this mechanism (Cawkwell et al, 1999). One patient had a lack of expression of hMLH1 and hMSH2, suggesting somatic mutations of both of these genes during tumour progression, or an inherited defect in one gene and a somatic alteration of the other.…”

Signet ring cell carcinoma of the colorectum: correlations between microsatellite instability, clinicopathologic features and survival

“…MSI-H is an independent predictor of relatively favorable outcome [10][11][12][13][14][15][16] and decreased likelihood of metastasis 13 in sporadic colorectal carcinoma. In most of these reports, histologic subtypes are not discussed.…”

“…[4][5][6][7][8][9] Colon cancer with MSI-H has a better prognosis than other colon cancers; the difference is partly dependent on stage (microsatellite instability-high tumors tend not to produce metastatic disease), but has been found to be independent of stage in some studies. [10][11][12][13][14][15][16] Signet ring cell carcinoma is a rare subtype of colorectal cancer, accounting for 0.1-2.4% of all colorectal malignancy. [17][18][19][20] By definition, more than 50% of tumor cells must have signet ring cell morphology.…”