Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a 'fusion' pathway to colorectal cancer

Abstract

Aim: To establish and explain the pattern of molecular signatures across colorectal polyps.

Methods and results: Thirty-two sessile serrated adenomas (SSA), 10 mixed polyps (MP), 15 traditional serrated adenomas (SA), 49 hyperplastic polyps (HP) and 84 adenomas were assessed for mutation of KRAS and BRAF and aberrant expression of p53. The findings were correlated with loss of expression of O-6-methylguanine DNA methyltransferase (MGMT). KRAS mutation occurred more frequently (26.5%) than BRAF mutation (4.8%) in adenomas (P < 0.001) and particularly in adenomas with villous architecture (50%). Loss of expression of MGMT correlated with KRAS mutation in small tubular adenomas (P < 0.04). BRAF mutation was frequent in HPs (67%) and SSAs (81%), while KRAS mutation was infrequent (4% and 3%, respectively). Of MPs and SAs, 72% had either BRAF or KRAS mutation. Aberrant expression of p53 was uncommon overall, but occurred more frequently in MPs and SAs (12%) than adenomas (1%) (P < 0.04) and there was concordant loss of expression of MGMT.

Conclusions: Molecular alterations that are characteristic of the serrated pathway and adenoma-carcinoma sequence can co-occur in a minority of advanced colorectal polyps that then show morphological features of both pathways. These lesions account for only 2% of colorectal polyps, but may be relatively aggressive.

Figure 1

A, Serrated adenoma (SA) (BRAF mutation) with a ‘hyperplastic’ appearance but with architectural and cytological features of a non-adenomatous form of dysplasia. The latter include marked epithelial serration and surface papillarity and nuclei that are ovoid, vesicular and contain a prominent nucleolus (inset). The columnar cells (inset) contain apical mucin droplets, similar to sessile SA (SSA). B, Mixed polyp (BRAF mutation) comprising SSA (left) and SA with high-grade dyplasia showing back-to-back glands (right) and aberrant expression of p53 (inset). C,D, Two mixed polyps (MPs) (both SA/tubulo-villous adenoma and with KRAS mutation) in which the serrated epithelium has an adenomatous appearance as evidenced by elongated hyperchomatic nuclei with marked stratification and a dark amphophilic cytoplasm. The pure adenomatous component is not shown. E,F, Low- and medium-power images of a SA (KRAS mutation) in which complex microacini have resulted in markedly serrated epithelial contours. The epithelium comprises numerous goblet cells and absorptive-type columnar cells with eosinophilic cytoplasm and is reminiscent of the goblet cell variant of hyperplastic polyp. These examples illustrate the range of appearances and genetic changes that are encompassed by ‘traditional’ SA.

Figure 2

High-power field of a serrated adenoma with high-grade dysplasia (A) in which there is aberrant nuclear expression of p53 (B) and loss of nuclear expression of O-6-methylguanine DNA methyltransferase (C).