Small Bowel Epithelial Precursor Lesions: A Focus on Molecular Alterations

Abstract

The wider use of gastrointestinal endoscopic procedures has led to an increased detection of small intestinal preneoplastic and neoplastic epithelial lesions, most of which are identified in the duodenum and ampullary region. Like their malignant counterparts, small intestinal glandular precursor lesions, which include adenomas and hamartomas, may arise sporadically or be associated with hereditary tumor syndromes, such as familial adenomatous polyposis, MUTYH-associated polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome. In addition, dysplastic, preinvasive lesions have been observed adjacent to small bowel adenocarcinomas complicating immune-related disorders, such as celiac or Crohn's disease. Adenomatous lesions may exhibit an intestinal-type, gastric-type, or, very rarely, serrated differentiation, related to different molecular pathogenetic mechanisms. Finally, in the background of multiple endocrine neoplasia 1 syndrome, precursor neuroendocrine growths have been described. In this review we offer a comprehensive description on the histo-molecular features of the main histotypes of small bowel epithelial precursors lesions, including: (i) sporadic adenomas (intestinal-type and gastric-type; non-ampullary and ampullary); (ii) syndromic adenomas; (iii) small bowel dysplasia in celiac and Crohn's disease; (iv) serrated lesions; (v) hamartomatous lesions; and (vi) neuroendocrine precursor lesions.

Keywords: APC; Crohn’s disease; GNAS; adenoma; ampulla; celiac disease; hamartoma; neuroendocrine; polyposis; small intestine.

Figure 1

Mutational path from dysplastic precursor lesions to duodenal adenocarcinoma (gastric type and intestinal type). APC: adenomatous polyposis coli; BRAF: v-raf murine sarcoma viral oncogene homolog B1; CIMP: CpG island methylator phenotype; GNAS: guanine nucleotide binding protein, alpha stimulating; HER2: human epidermal growth factor receptor 2; HGD: high grade dysplasia; KRAS: kirsten rat sarcoma; LGD: low grade dysplasia; MSI: microsatellite instability; TP53: tumor protein p53; Wnt: wingless-related integration site.

Figure 2

Non-ampullary and ampullary sporadic, glandular precursor lesions. (A) Sporadic non-ampullary, low-grade, intestinal-type adenoma. (B) Sporadic non-ampullary, low-grade foveolar-type adenoma. (C,D) Sporadic non-invasive intra-ampullary papillary-tubular neoplasm, with admixed low grade (C) and high grade (D) dysplastic foci. Patients signed informed consent regarding publishing their data before having their endoscopic/surgical procedure.

Figure 3

Precursor epithelial (glandular and neuroendocrine) lesions occurring in a background of hereditary tumor syndromes or immune-mediated disorders. (A) MUTYH-associated polyposis syndrome-associated non-ampullary duodenal adenoma showing high grade dysplasia. (B) Cytokeratin 7 positive ileal flat dysplasia adjacent to a small bowel adenocarcinoma associated to Crohn’s disease. (C) Peutz-Jeghers polyp. (D) Gastrin cell preneoplastic lesions in a patient affected by multiple endocrine neoplasia type 1 syndrome-related duodenal gastrinomas, including enlarged nodules and microinvasive lesions, in close relationship with linear and nodular gastrin cell hyperplasia of Brunner’s glands. Patients signed informed consent regarding publishing their data before having their endoscopic/surgical procedure.