Gastric adenocarcinoma and proximal polyposis of the stomach: diagnosis and clinical perspectives

Abstract

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a recently described, rare gastric polyposis syndrome. It is characterized by extensive involvement of the fundus and body of the stomach with fundic gland polyps sparing the antrum and lesser curvature, an autosomal dominant inheritance pattern with incomplete penetrance, and a significant predisposition for the development of gastric adenocarcinoma. Due to the recent discovery of APC promotor IB mutations (c.-191T>C, c.-192A>G, and c.-195A>C), which reduce binding of the transcription factor Yin Yang 1 (YY1) and transcriptional activity of the promotor, as its underlying genetic perturbation, GAPPS has been added to the growing molecular class of APC-associated disorders. Recent reports on family members afflicted by gastric polyposis due to GAPPS have described the development of metastatic cancer or the presence of invasive gastric adenocarcinoma in total gastrectomy specimens after variable periods of endoscopic surveillance emphasizing the need for an improved understanding of the to-date poorly characterized natural history of the syndrome. There are, however, currently no guidelines on screening, timing of prophylactic gastrectomy, or endoscopic surveillance for GAPPS available. In this review, we summarize the clinical, pathological, and genetic aspects of GAPPS as well as management approaches to this rare cancer predisposition syndrome, highlighting the need for early recognition, a multidisciplinary approach, and the creation of prospective family registries and consensus guidelines in the near future.

Keywords: APC promotor IB variant; APC-associated disorder; fundic gland polyp; gastric adenocarcinoma predisposition; gastrointestinal polyposis.

Figure 1

Endoscopy findings of gastric polyposis due to GAPPS. Notes: (A) Polyps immediately visible after passage through gastroesophageal junction. (B) Gastric cardia (retroflexed scope), (C) fundus, and (D) corpus of the stomach involved by extensive polyposis with heterogenous polyp size. (E) Pathognomonic feature of sparing of the gastric antrum from gastric polyps. (F) No duodenal involvement. Abbreviation: GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach.

Figure 2

Gastric polyposis of the fundus and body of the stomach with pathognomonic sparing of the antrum and lesser curvature in a GAPPS proband with confirmed c.-191T>C APC gene promotor IB variant. Notes: (A) Carpet of polyps involving upper four-fifth of the stomach including cardia, fundus, and body; arrow indicates gastroesophageal junction. (B) Uninvolved antrum, forceps lifts pylorus. (C) Gastric polyps at cardia not extending into esophagus (arrow indicates esophageal mucosa). (D) Linitis plastica due to HDGC causing enlarged folds and “polypoid” appearance without involvement of the distal stomach. (E) Irregular enlarged folds with intact mucosa due to HDGC. (F) Sagittal section shows tumor submucosal tumor infiltration (arrow). Abbreviations: GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; HDGC, hereditary diffuse gastric cancer.

Figure 3

Histopathology of fundic gland polyps in GAPPS. Notes: (A) Fundic gland polyp with flattened cuboidal epithelium with focal area of low-grade dysplasia (black arrows) and high-grade dysplasia (white arrows) from total gastrectomy specimens of a GAPPS proband with confirmed c.-191T>C APC gene promotor IB variant. (B) Fundic gland polyp with low-grade and (C) high-grade dysplasia in gastrectomy specimens (inset 20×). Abbreviations: GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; HDGC, hereditary diffuse gastric cancer.

Figure 4

Selective loss of APC gene promotor IB function by large genomic deletions or point mutations. Notes: Schematic representation showing inactivation of promoter 1B of APC by genomic deletions (blue bars) or hotspot mutations in the YY1-binding motif (listed by nucleotide position relative to promotor, in blue). As examples, length and position of previously described large deletions in relation to the promotor IB reported (blue bars, from top to bottom) by Rohlin et al, Snow et al, Kadiyska et al, and Lin et al are shown. Reprinted from The American Journal of Human Genetics, vol 98, Li J, Woods SL, Healey S, et al., Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant, pages 830–842, copyright (2016), with permission from Elsevier.