Sporadic fundic gland polyps with epithelial dysplasia : evidence for preferential targeting for mutations in the adenomatous polyposis coli gene

Abstract

Gastric fundic gland polyps (FGPs) occur in two distinct clinicopathological scenarios: sporadic and familial adenomatous polyposis (FAP) associated. FAP-associated FGPs arise through somatic second hit alterations of the adenomatous polyposis coli (APC) gene and frequently demonstrate epithelial dysplasia (Am J Pathol 2000, 157:747-754). Sporadic FGPs, in contrast, tend to contain beta-catenin gene mutations and only infrequently show dysplasia (Am J Pathol 2001, 158:1005-1010). However, sporadic FGPs with dysplasia have not been previously investigated. We studied 13 sporadic FGPs with surface/foveolar low-grade dysplasia or changes indefinite for dysplasia for alterations in the APC/beta-catenin pathway, using chromosome 5q allelic loss assays and direct DNA sequencing of the mutation cluster region in exon 15 of APC and the phosphorylation region in exon 3 of beta-catenin. In addition, to evaluate for possible additional genetic alterations in FGPs, all cases were evaluated for microsatellite instability using fluorescent-based amplification of a standard panel of five microsatellite markers. Alterations in APC were present in seven (53.8%) FGPs, including two cases with bi-allelic APC inactivation (truncating intragenic mutation plus 5q allelic loss), two cases with APC mutation only, and three cases with 5q allelic loss only. In contrast, only two (15.4%) FGPs contained stabilizing beta-catenin mutations. All 13 FGPs were microsatellite stable. These results indicate that sporadic FGPs with dysplasia/indefinite for dysplasia are molecularly similar to FAP-associated FGPs, and are dissimilar to the more common sporadic nondysplastic FGPs. Mutations in APC and beta-catenin, despite occurring in the same genetic pathway, show differing biological properties, a phenomenon that has previously been demonstrated in colorectal neoplasms. The lack of microsatellite instability in FGPs in this study and of K-ras mutations in a previous study suggests that secondary genetic alterations are rare in both dysplastic and nondysplastic FGPs.

Figure 1.

Histological appearance of a nondysplastic FGP. A: At low power, the FGP shows characteristic, cystically dilated, and budded oxyntic glands. B: At higher power, the surface and foveolar epithelium overlying the dilated glandular compartment is composed of nondysplastic gastric mucin cells, with small, basally oriented nuclei and abundant apical mucin.

Figure 2.

Histological features of sporadic FGPs with dysplasia. A: At low power, the characteristic architecture of a FGP is seen. However, the surface appears hyperchromatic in comparison with the FGP in Figure 1 ▶ . B: Low-grade dysplasia of the surface/foveolar epithelium. The nuclei are enlarged, hyperchromatic, and crowded, and there is decreased cytoplasmic mucin content. C: Epithelial changes indefinite for dysplasia. The cytological features are intermediate between those of the nondysplastic FGP in Figure 1 ▶ and the FGP with low-grade dysplasia in B. D: The attenuated parietal cells and chief cells lining the dilated oxyntic glands do not demonstrate dysplasia.

Figure 3.

Bi-allelic APC inactivation in a sporadic FGP graded as indefinite for dysplasia (case SD2). A: DNA sequencing chromatogram showing deletion of base (A) from a 6-base poly(A) tract spanning codons 1554 to 1556. B: Allelic loss on chromosome 5q is also present (shown here after amplification with the microsatellite marker D5S299). The ratio of smaller allele (arrow) to larger allele (arrowhead) is inverted in the FGP as compared to the patient’s normal tissue because of loss of smaller allele. Allelic loss can also be appreciated on the sequencing chromatogram in A.

Figure 4.

β-catenin missense mutation in a sporadic FGP graded as indefinite for dysplasia. DNA sequencing chromatogram shows a codon 33 TCT (serine)→TGT (cysteine) mutation in case SD7. This mutation would be expected to result in stabilization of β-catenin protein because of loss of a serine phosphorylation site. A mixture of the mutant and wild-type is present, reflective of the dominant nature of β-catenin mutations.