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We read with a great interest the study by Sawyer et al (Gut 2002;51:200–6). This well performed study of numerous genetic and immunohistochemical features of serrated adenomas (SAs) of the colorectum furnishes very important findings that may help to clarify the confusing field of colorectal tumorigenesis. Using both molecular and immunohistochemical techniques, Sawyer et al found in a series of 39 SAs a relatively low frequency of most abnormalities described in classical adenomas and adenocarcinomas of the colorectum. Comparative genomic hybridisation, performed in four cases, was always normal. These differences from classical adenomas may be due either to a distinct mechanism of tumorigenesis or to the presence of a large number of SAs showing only mild (64%) or moderate (28%) dysplasia. An interesting result obtained by Sawyer et al is the absence of high level microsatellite instability (MSI-H) in SAs, and the rarity of low level microsatellite instability (MSI-L) (two of 39 cases). Again, there is a debate in the literature concerning the frequency of MSI in SAs.1–3 Sawyer et al also studied the expression of two mismatch repair proteins (MMR), hMLH1 and hMSH2, and they found no loss of cellular expression of these two proteins in SAs. This result confirms the MSI analysis, as many studies have now demonstrated that only MSI-H tumours lose expression of MMR proteins while microsatellite stable and MSI-L tumours have normal expression.4
In their study, Sawyer et al did not describe precisely the pattern of expression of hMLH1 and hMSH2 proteins. We recently performed an immunohistochemical study of MMR proteins in a series of 30 colorectal SAs (19 low grade and 11 high grade), 10 hyperplastic polyps (HP), and 20 classical adenomas (10 high grade and 10 low grade) of the colorectum. Two SAs came from patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome, one from a patient with familial adenomatous polyposis, and one from a patient with a juvenile polyposis. All classical adenomas were sporadic. Immunohistochemistry was performed on formalin fixed deparaffinised sections with the following antibodies: anti-hMLH1 (Pharmingen, clone G168- 728, 1:70), anti-hMSH2 (Calbiochem, clone FE11, 1:100), and anti-hMSH6 (Transduction laboratories, clone 44, 1/100).
Loss of expression of hMLH1 protein was only observed in one high grade SA, developed in a patient with HNPCC syndrome due to a mutation of the hMLH1 gene. In the second SA (of low grade) occurring in a patient with HNPCC syndrome due to mutation of the hMSH2 gene, there was no loss of expression in the SA, while the synchronous colon adenocarcinoma in the same patient showed loss of hMSH2 and hMSH6. All other SAs expressed the three MMR proteins. This expression was also present in all HP and classical adenomas. These results confirm that MSI is highly uncommon in all types of adenomas of the colon, both in SAs and in classical adenomas.5 Interestingly, we observed two distinct patterns of expression in the three types of polyps studied. One pattern was similar to that observed in the normal mucosa of the colon, with a moderate nuclear expression limited to the lower part of the crypts, and with a negative upper part of the crypts and surface epithelium. The other “dysplastic” pattern was characterised by strong nuclear expression of the surface epithelium and upper part of the lesion, with the lower part showing moderate positivity. This pattern was identical for the three antibodies. The normal pattern was always preserved in HP and low grade SAs, with a negative surface epithelium. In contrast, all classical adenomas, either low grade or high grade, showed strong surface staining. Among 11 high grade SAs, seven showed a “dysplastic” pattern with strong surface staining, and four showed a normal pattern.
These results suggest that SAs may be a heterogeneous group of tumours that includes lesions close to HP, especially when only low grade dysplasia is present, but also high grade lesions with a similar pattern as high grade classical adenomas, and probably a similar risk of malignant transformation. It is interesting to note that the same relation between SAs, HP, and adenomas has been noted regarding the apoptotic pattern.6 Increased expression of MMR proteins has also been noted in precancerous skin lesions.7 Therefore, it may be hypothesised that intense surface expression of MMR proteins is a marker of neoplastic proliferation. This possibility has to be tested prospectively in various precancerous lesions, and also in regenerative non-neoplastic changes.
We acknowledge the financial support of the French Society of Pathology.
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