In our study, morphological characteristics were found to be distributed differently among right and left sided HPs. In particular, the presence of crypt dilatation, horizontal crypts, serration in the lower third of crypts, and a high serration index were associated with a proximal HP location. Recent studies have identified an HP variant that is distinguished from classic HPs on the basis of multiple morphological features. These lesions, termed sessile serrated adenomas (SSAs), show a predilection for the proximal colon and have been linked with MSI-H CRC.2,18
A high proportion of right sided HPs show the features of SSAs.2,18
However, it is unclear whether SSAs and HPs are fundamentally different lesions, or represent a continuous spectrum of “serrated polyps”. In an earlier study, increased expression of CEA and altered sialic acid composition co-segregated with certain morphological features that have now been associated with SSAs.19
The aim of our present study was to determine whether functional markers expressed by right and left sided HPs highlight biological differences that are not only more diagnostically discriminating than the subtle morphological changes described by others, but may also serve as evidence that proximal and distal HPs are biologically distinct lesions.
Early studies indicated that HPs are age related lesions, but these dealt only with HPs in the rectum.21
The finding of a full decade of difference in age between patients with proximally versus distally located HPs was unexpected, given the predominance of right sided bowel cancers in older patients.22
It has been estimated that only one in 25 right sided HPs will progress to an MSI-H CRC.6
The relatively young age of subjects with right sided HPs in our study suggests that the lesions may remain unchanged for many years before malignant transformation.
No significant differences were found between left and right sided polyps in terms of staining with either mPAS or antibodies against SLex
. It is known that changes occur in the structure of sialic acid (loss of O
-acetylation) secreted by malignant colorectal epithelium,19,23–27
and that these changes may be revealed by mPAS staining. SLex
is detectable in cancerous and precancerous lesions but not in normal colorectal mucosa. The basis for this observation is the same change in sialic acid structure (loss of O
-acetylation) that renders SLex
Because no significant difference was detected between the right and left sided HPs, which nevertheless differed from the normal colorectal mucosa (results not shown), it appears that these mucin histochemical alterations are not specific for the anatomical site of origin of HPs. The trend towards increased sialic acid abnormality in right sided HPs might assume significance in a larger series. However, the findings suggest that proximal and distal HPs are related lesions that differ quantitatively rather than qualitatively. It would be of interest to examine the mucin core proteins present in right versus left sided HPs because a previous study by Biemer-Hüttmann et al
found that serrated polyps were associated with upregulation of intestinal mucin MUC2 and gastric mucin MUC5AC, both of which are known to be upregulated in mucinous MSI-H cancers.5
“The increased serration seen in right sided hyperplastic polyps in our present study may be explained by a greater antiapoptotic effect in this subgroup”
Staining with anti-CEA antibody yielded no significantly different results for either intensity or distribution between the two groups of polyps. Previous studies have found increased CEA expression in HPs,16,19
a finding that parallels the commonly observed increase in CRCs.19,28,29
This increased expression of CEA, a GPI linked transmembrane protein implicated in cell signalling,28
could conceivably serve as an indicator of potentially neoplastic progression, even though it does not seem to be differentially expressed in right versus left sided HPs. The lack of a difference in numbers of IELs present in polyps from opposite sides of the colon suggests that lymphocytes are not recruited in abnormally large numbers to areas of hyperplasia, but only with the advent of dysplasia.
The lack of a significant difference in proliferation zone length between distal and proximal HPs, as indicated by staining for the proliferation inducible Ki-67 antigen, implies that expansion of this zone may be common to all subsets of HPs. An increase in cell proliferation, without an accompanying increase in the rate of anoikis (exfoliation induced apoptosis at mucosal surfaces), would represent a possible mechanism for the development of glandular serration.6
The increased serration seen in right sided HPs in our present study may be explained by a greater antiapoptotic effect in this subgroup. It is possible that the observed morphological disparity results from different underlying mechanisms for inhibiting apoptosis. This is supported by the fact that apoptosis inhibition by mutated K-ras is linked to the Akt/protein kinase B mediated inhibition of BAD and caspase 9, whereas BRAF mutation blocks caspase activation downstream of BAD mediated cytochrome c release.30,31
BRAF mutation occurs more frequently in large, right sided HPs occurring in the condition hyperplastic polyposis.32
Take home messages
- There was a significant association between proximal hyperplastic polyps (HPs) and the presence of horizontal crypts, crypt dilatation, serration in lower crypt thirds, and a high serration index
- These findings suggest that right and left sided HPs differ mainly in terms of growth regulation rather than cellular differentiation, implying that these lesions belong to a continuous spectrum of serrated polyps that differ quantitatively rather than qualitatively
- The structural differences found in the right sided polyps may be attributable to pressure from increased cell numbers within individual crypts, in turn reflecting a more profound impairment of apoptosis
With respect to staining for 5-MeC, the lack of a significant difference in the upper, middle, or lower areas of the crypts from right versus left sided polyps indicates a more or less common DNA methylation status in polyps from either side of the colorectum. This particular feature was evaluated because, on the one hand, MSI-H colorectal cancers are associated with hypermethylation in the promoters of certain genes33–37
whereas, on the other hand, global hypomethylation has been associated with many cancers.20,34,38–43
Although no consistent methylation differences were apparent, it is notable that only epithelial nuclei from HPs located in the distal colorectum were found to be globally methylated to a greater extent than those of their stromal counterparts. All right sided HPs contained either equally or less methylated epithelial nuclei. A possible explanation for this could be the previous suggestion that global hypermethylation may result from increased methylation at sites of DNA damage, which decreases the general availability of methyltransferases.44
In conclusion, this investigation has shown a significant association between proximal HPs and the presence of horizontal crypts, crypt dilatation, serration in lower crypt thirds, and a high serration index. This is consistent with findings by others.2,14,18
Because the main differences in our study proved to be morphological, rather than functional, it appears that proximal HPs show an exaggerated imbalance of cellular proliferation rather than a dysregulation of cellular differentiation compared with their distal counterparts. The structural differences found in the right sided polyps may be attributable to pressure from increased cell numbers within individual crypts, in turn reflecting a more profound impairment of apoptosis.