Probleme der HNPCC-Diagnostik am Beispiel der molekularen Analyse von kolorektalen Adenomen - Ergebnisse einer Follow-up Studie Pitfalls in HNPCC-screening using molecular analysis of colorectal adenomas - Results of a follow-up study

Adenomas are well established as precursors of colorectal cancer. In most cases the progression to malignancy is not a rapid process. However, in Hereditary Non-Polyposis Colorectal Carcinoma (HNPCC) an earlier onset of adenomas and a faster progression to cancer is well known. 122 known HNPCC patients were followed for five years to detect colorectal adenomas. The goal of the study was to determine whether microsatellite instability (MSI) can be identified at the premalignant stage. 36 patients were identified who had developed a total of 71 adenomas. The adenomas were analyzed for MSI and loss of mismatch repair (MMR) protein expression by immunohistochemistry. In most cases, results of MSI analysis and immunohistochemistry of adenomas were identical to the corresponding carcinomas, demonstrating that MMR deficiency occurs very early in the neoplastic process. In addition, three adenomas that were MSS, demonstrated immunohistochemical loss of expression of the same MMR proteins as the corresponding carcinomas. However, immunohistochemical staining alone would have missed four adenomas with high MSI, which underlines the importance of using both screening methods. Interestingly, seven adenomas out of 31 that were located more than 5 cm away from the carcinoma may have followed a MMR proficient pathway. These adenomas revealed an MSS (n = 6) or low MSI (n = 1) status and expressed all MMR proteins. 6 of these 7 adenomas occurred in patients who had other adenomas with the same molecular profile as the corresponding carcinomas. These findings indicate that these adenomas might indeed be sporadic adenomas or that very early stages of MMR deficient lesions may not yet display MSI-H and loss of MMR protein expression, the hallmarks of MMR deficiency. These results support the decision to exclude MSI testing of adenomas for HNPCC screening from the revised Bethesda guidelines.