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

Abstract

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 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 >5 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.

Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer

“…All adenomas showing loss of mismatch repair protein immunostaining showed a concomitant loss of either MLH1/PMS2 or of MSH2/ MSH6 (Table 1) and the analysis of microsatellite instability performed did in all cases correlate with the mismatch repair protein staining ( Table 1). The overall rate of loss of immunostaining in our study, 0.66, is similar to that found by Rijcken et al, 3 who demonstrated loss of immunostaining for mismatch repair proteins in 15/25 (0.6) HNPCC-associated microsatellite instability-high adenomas. We found the highest rates of loss of immunostaining in large (45 mm) and proximal adenomas, in which the fractions of immunohistochemical loss of staining for the mismatch repair proteins were 0.88 and 0.87.…”

“…3,18 In our series, all 13 adenomas with retained expression in our study showed low-grade dysplasia, and the four adenomas with high-grade dysplasia showed loss of staining (Table 1). In the series by Rijcken et al, 3 the 10 HNPCC-adenomas with retained expression were small and had low-grade dysplasia.…”

“…The adenomas also occur at younger age, have a predilection for the proximal colon, are larger and do more often display high-grade dysplasia and villous components. [1][2][3] The hallmark of HNPCCassociated tumors-defective mismatch repair-is in the tumor tissue reflected as microsatellite instability and loss of immunostaining for the mismatch repair protein affected. 4,5 Mismatch repair defects are found in about 15% of sporadic colorectal cancer and in 490% of HNPCC-associated cancers.…”

“…7,12 Data on the frequency of microsatellite instability in HNPCC-associated adenomas are still quite scarce, but indicate that defective mismatch repair can be found in 24-93% of the adenomas. 3,[13][14][15][16][17][18][19] Detection of defective mismatch repair through analysis of microsatellite instability and/or loss of mismatch repair protein immunostaining in colorectal carcinomas predicts HNPCC with high sensitivity and specificity. 4,5,20 Clinically, analysis of defective mismatch repair in an HNPCC-associated adenoma is sometimes requested since this may be the only tumor tissue available and to pinpoint the gene that mutation analysis should focus on.…”

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

“…Particularly important is full colonoscopy (due to the syndrome's predilection toward proximal CRC), 62 initiated at the age of 25 years (due to early onset of CRC), 3 with good cleanout for visualization to the cecum, and repeated annually (due to accelerated carcinogenesis). 4,63 For women, endometrial aspiration coupled with transvaginal ultrasound is advised for screening, beginning at the age of 30 -35 years. We recommend semiannual CA 125 testing, beginning at the same age, for ovarian cancer.…”