Proximal adenomas in hereditary non-polyposis colorectal cancer are prone to rapid malignant transformation

Background: Hereditary non-polyposis colorectal cancer (HNPCC) is thought to arise from adenomas. HNPCC mostly occurs in the proximal colon. We investigated whether this proximal preponderance is due to a proximal preponderance of adenomas or (also) differences in transformation rates from adenomas to cancer between the distal and proximal colon. Methods: A total of 100 HNPCC adenomas were evaluated and compared with 152 sporadic authors' affiliations adenomas for location, size, and dysplasia. Twenty five adenomas from patients with a known mismatch repair (MMR) gene mutation were stained for expression of MLH1 and MSH2. Results: HNPCC adenomas were more often located proximally (50% v 26%; p=0.018) and were smaller in comparison with sporadic adenomas. They were similarly dysplastic. However, all proximal HNPCC adenomas greater than or equal to5 mm were highly dysplastic compared with 17% of the larger proximal sporadic polyps (p<0.001). They were also more often highly dysplastic than larger distal HNPCC adenomas (p<0.001). Small HNPCC adenomas were, except for their location, not different from sporadic adenomas. Fifteen of the 25 "known mutation" adenomas showed loss of expression of either MLH1 or MSH2. The 10 adenomas with expression were all small with low grade dysplasia. Conclusion: HNPCC adenomas are located mainly in the proximal colon. The progression to high grade dysplasia is more common in proximal than distal HNPCC adenomas, indicating a faster transformation rate from early adenoma to cancer in the proximal colon. MMR gene malfunction probably does not initiate adenoma development but is present at a very early stage of tumorigenesis and heralds the development of high grade dysplasia.