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Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome
  1. D L Worthley1,
  2. K D Phillips2,
  3. N Wayte3,
  4. K A Schrader4,
  5. S Healey5,
  6. P Kaurah4,
  7. A Shulkes6,
  8. F Grimpen7,
  9. A Clouston7,
  10. D Moore8,
  11. D Cullen9,
  12. D Ormonde9,
  13. D Mounkley10,
  14. X Wen11,
  15. N Lindor12,
  16. F Carneiro11,
  17. D G Huntsman4,
  18. G Chenevix-Trench5,
  19. G K Suthers2,13
  1. 1Division of Digestive and Liver Diseases, Columbia University, New York, New York, USA
  2. 2SA Clinical Genetics Service, SA Pathology, South Australia, Australia
  3. 3School of Medicine, University of Queensland, Queensland, Australia
  4. 4Hereditary Cancer Program, BC Cancer Agency, British Columbia, Canada
  5. 5Queensland Institute of Medical Research, Queensland, Australia
  6. 6Department of Surgery, University of Melbourne, Victoria, Australia
  7. 7Royal Brisbane and Women's Hospital, Queensland, Australia
  8. 8Women's and Children's Hospital, South Australia, Australia
  9. 9St John of God Hospital, Western Australia, Australia
  10. 10Flinders Medical Centre, South Australia, Australia
  11. 11Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Faculty/Hospital S. João, Porto, Portugal
  12. 12Department of Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  13. 13Department of Paediatrics, School of Paediatrics & Reproductive Health, Faculty of Health Sciences, University of Adelaide, SA, Australia
  1. Correspondence to Dr Graeme Suthers, SA Clinical Genetics Service SA Pathology Women's & Children's Hospital, North Adelaide, SA 5006, Australia; graeme.suthers{at}health.sa.gov.au

Abstract

Objective The purpose of this study was the clinical and pathological characterisation of a new autosomal dominant gastric polyposis syndrome, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).

Methods Case series were examined, documenting GAPPS in three families from Australia, the USA and Canada. The affected families were identified through referral to centralised clinical genetics centres.

Results The report identifies the clinical and pathological features of this syndrome, including the predominant dysplastic fundic gland polyp histology, the exclusive involvement of the gastric body and fundus, the apparent inverse association with current Helicobacter pylori infection and the autosomal dominant mode of inheritance.

Conclusions GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma. It is characterised by the autosomal dominant transmission of fundic gland polyposis, including areas of dysplasia or intestinal-type gastric adenocarcinoma, restricted to the proximal stomach, and with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

  • Genetics
  • gastric adenocarcinoma
  • polyposis
  • gastric neoplasia
  • stem cells
  • intestinal stem cell
  • cancer
  • inflammation
  • molecular genetics
  • cancer genetics
  • cancer syndromes
  • oesophageal cancer
  • gastric cancer
  • histopathology
  • fatty liver
  • liver transplantation
  • paediatric gastroenterology
  • cancer prevention
  • cancer epidemiology
  • cancer registries
  • cancer susceptibility
  • family cancer
  • Helicobacter pylori
  • acid-related diseases
  • non-ulcer dyspepsia
  • genetic polymorphisms
  • colorectal cancer genes
  • microsatellite instability
  • cell cycle
  • gastrointestinal neoplasia
  • molecular pathology
  • polyposis

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Introduction

Fundic gland polyps (FGPs) are the most common gastric polyps. They are diagnosed in ∼5% of gastroscopies and account for up to 70% of all sampled gastric polyps.1 2 Sporadic FGPs are usually small (<5 mm), few in number (usually <10) and are restricted to the gastric body and fundus.3 FGPs are histologically characterised by prominent cystic spaces lined by flattened parietal, chief and mucous neck cells.3

FGPs are directly associated with chronic proton pump inhibitor (PPI) therapy and inversely associated with Helicobacter pylori infection, suggesting a possible connection between FGPs and perturbed gastric acid homeostasis.4 Fundic gland polyposis may also be a manifestation of inherited gastrointestinal polyposis syndromes, particularly familial adenomatous polyposis (FAP) which is characterised by hundreds to thousands of adenomatous polyps in the colorectum and, without colectomy, the almost inevitable development of colorectal cancer. Other inherited gastric polyp syndromes include MUTYH-associated polyposis (MAP), generalised juvenile polyposis syndrome (GJPS), Peutz–Jeghers syndrome (PJS) and Cowden syndrome.5 6 However, FGPs are relatively rare in MAP, an autosomal recessive disorder, and GJPS and PJS are often characterised by the presence of specific hamartomatous (rather than purely dysplastic fundic gland) polyps.5 6

Sporadic FGPs are usually innocuous, but syndromic FGPs can progress to dysplasia and gastric adenocarcinoma.7–9 Therefore, clinicians must distinguish patients with sporadic versus syndromic fundic gland polyposis so that additional scrutiny is provided for the latter without subjecting the majority of patients to needless investigation.

Here we describe a new autosomal dominant syndrome characterised by fundic gland polyposis and gastric cancer. We refer to the syndrome as gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). This report documents the detailed clinical and pathological features of GAPPS in a large Australian family and in two smaller North American families. We propose diagnostic criteria and management strategies for GAPPS and examine potential factors that may contribute to the pathogenesis.

Methods

DNA and pathology samples were collected following informed written consent and approval by the local institutional review board. In lieu of BMJ Publishing Group consent forms being provided, all individual sex-specific information was removed from this description to reduce the probability of an individual being identified. Histopathology, where available, was reviewed and reported by a gastrointestinal pathologist (FC). Mutations in APC, MUTYH, CDH1, SMAD4, BMPR1A, STK11 and PTEN were excluded in all families by sequence analysis of exons and flanking regions as well as by assays for deletion or duplication of exons. Immunohistochemistry, microsatellite testing, gastrin amide and progastrin assays were performed using published methods.10 11 H pylori status was determined primarily by histopathology, although serology, rapid urease test on gastric biopsies and the urea breath test were performed in some patients. H pylori infection was considered to be present if detected on any test, and negative only if negative on all available tests with histological classification requiring a specific statement regarding the presence or absence of H pylori in the report. The association between H pylori and GAPPS was analysed by the Fisher exact test.

Results

This syndrome was first recognised in an Australian Caucasian family (family 1) and subsequently in one American family (family 2) and one Canadian family (family 3). The families were notable for the autosomal dominant transmission of fundic gland polyposis, the development of gastric cancer and by the exclusion of other causes of inherited polyposis by clinical, pathological and molecular means.

Family 1

The Australian proband was diagnosed at 33 years of age (figure 1, III-1). They presented to hospital with melaena without any significant past medical history. They had an upper gastrointestinal endoscopy that revealed florid gastric polyposis (figure 2A). The gastric polyps were predominantly <10 mm in diameter. The polyps (>100) carpeted the gastric body and fundus with relative sparing along the lesser curve of the stomach. The oesophagus, gastric antrum, pylorus and duodenum were normal. The colonoscopy was normal (table 1).

Figure 1

Family pedigrees with age at diagnosis; all individuals are shown as being of unknown sex, and only affected individuals are shown for family 1. In family 1 other malignancies included one case of cervical cancer and in family 3 one case each of leukaemia, brain, prostate and lung cancer. GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach.

Figure 2

Gastrectomy specimens III-1 (A) and IV-11 (B) from family 1, and III.19 from family 2 (C). The stomach in A is opened along the lesser curve, while B and C were opened along the greater curve. The gastro-oesophageal junction is on the right. Each reveals the typical proximal polyposis and antral and lesser curve sparing. D (proximal polyposis) and E (antral sparing) reveal the typical appearance at endoscopy (family 1, IV-2). (F) Typical fundic gap polyp (FGP) and focal area of dysplasia (inset) from family 1. (G) Hyperplastic gastric polyp (family 1). (H) FGP with dysplasia identified in a young member of family 1 (IV-2). (I) High grade dysplasia in the surface of an FGP from another member of family 1. (J) Intestinal-type gastric adenocarcinoma from family 1. (K) Typical FGP with adenomatous gastric polyp (inset) from family 2. (L) Immunohistochemistry for chromogranin performed on the gastric antrum from healthy control (left) compared with gastric antrum (right) and FGP (M) from individual IV-11, family 1.

Table 1

Clinical features of families 1–3

After 2 years of annual endoscopic surveillance the composite histopathology confirmed a predominant fundic gland polyposis including areas of dysplasia (figure 2F). In addition, amidst these FGPs there were occasional hyperplastic (figure 2G) and pure adenomatous polyps, as well as some mixed polyps containing discrete areas of FGP-like, adenomatous and hyperplastic features.

Given the multiple gastric polyps and the inherent difficulties of endoscopic surveillance the patient proceeded to total gastrectomy. This confirmed the mixed, albeit predominant FGP histopathology and excluded gastric adenocarcinoma. One dysplastic gastric polyp was tested and found to be microsatellite stable with normal expression of MLH1, MSH2, MSH6 and PMS2 on immunohistochemistry.

Three years after the gastrectomy the proband's children, then aged 10 (figure 1, IV-1) and 14 years (IV-2), were referred for upper gastrointestinal endoscopy (figure 2D,E); the younger child was being investigated for persistent dyspepsia. Both were diagnosed with fundic gland polyposis with multiple areas of focal dysplasia (figure 2H). Dysplasia was also observed in FGPs from other affected family members (figure 2I).

The malignant potential of this syndrome was appreciated shortly after when both a 33-year-old (IV-3) and a 48-year-old relative (III-24) of the proband were diagnosed with, and subsequently died from, intestinal-type gastric adenocarcinoma (figure 2J). They had been diagnosed with GAPPS prior to the diagnosis of cancer and IV-3 developed metastatic gastric adenocarcinoma despite endoscopic surveillance and multiple biopsies of the gastric polyposis. Both displayed the typical proximal polyposis of the stomach and both developed liver metastases.

The characteristic phenotype was ultimately documented among 20 members of the proband's family (figure 1); in addition there were six individuals of uncertain diagnosis with 4–30 FGPs each. The male:female ratio among affected family members was 1:2.3. There were four instances of male-to-male transmission, confirming the mode of transmission as autosomal dominant. Three obligate carriers (II-2, II-4 and II-11) had normal endoscopies performed at 72, 77 and 68 years of age, respectively. The upper gastrointestinal endoscopic, colonoscopic and H pylori findings are outlined in table 1.

At the time of this report, colonoscopy results were available from 13 affected family members. The proband's sibling (III-7) had the most advanced colorectal pathology, with eight simple tubular adenomas removed over a series of four colonoscopies. The largest was 7 mm. There were no cases of colorectal polyposis and notably no family history of colorectal cancer (table 1). One affected individual (IV-11) has had a capsule endoscopy that excluded polyps of the small intestine.

Of the seven affected family members in whom we had a medication history, only two had taken PPIs or H2-receptor antagonists prior to diagnosis. Of the six uncertain cases with multiple FGPs, at least five had a history of PPI therapy, highlighting the difficulty in differentiating syndromic from sporadic cases.

PPIs can cause gastric enterochromaffin-like (ECL) cell hyperplasia.12 To examine whether ECL cell hyperplasia was also a feature of GAPPS we compared chromogranin immunohistochemistry staining from the gastric antrum of two affected family members, neither of whom took PPIs, with antral samples taken from a healthy unrelated control patient. One patient with GAPPS demonstrated relative ECL cell hyperplasia in the gastric antral and FGP tissue relative to the control sample (figure 2L,M). Fasting serum levels of gastrin amide and progastrin (potential causes for ECL cell hyperplasia) were evaluated in two patients with GAPPS with intact stomachs. Both patients had normal circulating levels of these hormones (gastrin amide <50 pmol/l and progastrin <2.5 fmol/ml).10 Twenty-seven family members had H pylori results, excluding the uncertain cases. All of the affected family members that were evaluated for H pylori were negative (0 of 18) but four of the nine unaffected relatives (including two of the three obligate carriers) were positive for the infection (p=0.007).

Family 2

This Caucasian American family had a gastric phenotype identical to that of Family 1, with proximal fundic gland polyposis in seven relatives and three cases of intestinal-type gastric adenocarcinoma transmitted in an autosomal dominant fashion over three generations (figures 1 and 2). The proband was diagnosed with gastric polyposis at 34 years of age. They had a prophylactic gastrectomy at 48 years of age that showed the typical appearance of GAPPS (figure 2C). The proximal polyposis was characterised by the typical dysplastic FGPs and occasional hyperplastic polyps and adenomas (figure 2). Colonoscopy in the affected family members III-21 and III-23 excluded significant colorectal pathology (table 1).

Family 3

Family 3 was a Caucasian Canadian family with fundic gland polyposis carpeting the proximal stomach in at least three first-degree relatives (II-2, II-3 and II-4, figure 1). A fourth patient (I-4) was likely to have had proximal gastric polyposis, but gastroscopy to confirm this failed due to an obstructing proximal gastric adenocarcinoma. The cases occurred over two generations, and two patients were diagnosed with intestinal-type gastric adenocarcinoma with autosomal dominant inheritance. The youngest patient with gastric cancer was diagnosed at 34 years of age. The affected family member II-3 had a normal colonoscopy (table 1). The gastric histology (II-3) confirmed fundic gland polyposis with multifocal, low grade dysplasia.

Discussion

The key clinical features of GAPPS are fundic gland polyposis of the stomach with occasional hyperplastic and adenomatous polyps, sparing of the gastric antrum, the development of intestinal-type gastric adenocarcinoma and the autosomal dominant mode of inheritance. It is important to note that the malignant potential of gastric polyps in GAPPS appeared to be significantly higher than in FAP, where malignant transformation is rare in Western populations.8 We recommend the following diagnostic criteria for GAPPS: (1) gastric polyps restricted to the body and fundus with no evidence of colorectal or duodenal polyposis; (2) >100 polyps carpeting the proximal stomach in the index case or >30 polyps (the greatest number of FGPs in our uncertain cases) in a first-degree relative of another case; (3) predominantly FGPs, some having regions of dysplasia (or a family member with either dysplastic FGPs or gastric adenocarcinoma); and (4) an autosomal dominant pattern of inheritance. Exclusions include other heritable gastric polyposis syndromes and use of PPIs. In patients on PPIs we recommend repeating the endoscopy off therapy.

GAPPS is distinct from other inherited causes of gastric polyposis. Attenuated FAP, FAP and MAP are defined by their colorectal phenotype, and MAP has autosomal recessive inheritance. We acknowledge that attenuated FAP may have an extremely mild colorectal phenotype.13 It is important to note, however, that even the relative with the most severe colorectal phenotype had <10 colorectal adenomas (>40 years of age)13 and that there were no cases of colorectal cancer or duodenal polyps. While patients with PJS may have FGPs, the predominant fundic gland polyposis, the intestinal-type gastric cancer and polyp distribution distinguished these families from hereditary diffuse gastric cancer, GJPS, PJS and Cowden syndrome. Furthermore, coding mutations were excluded in APC, MUTYH, CDH1, SMAD4, BMPR1A, STK11 and PTEN. Autosomal dominant Ménétrier disease was excluded by histopathological review of the gastrectomy specimens.14

The typical gastric phenotype was evident from 10 years of age and the earliest gastric cancer occurred at 33 years of age. The syndrome was also characterised, however, by incomplete penetrance, with three elderly obligate carriers having normal endoscopies. There appeared to be some degree of anticipation in the Australian family, with younger and more severe cases occurring in the second and third generations, but this might be due to changing environmental factors or ascertainment bias rather than an underlying unstable mutation. The gastrointestinal polyposis was restricted to the oxyntic mucosa of the gastric body and fundus. It is important to note that the pylorofundal mucosal junction is not limited by the incisura angularis but can extend along the lesser curve even to the gastric cardia.15 This explains the consistent lesser curve sparing. It is uncertain whether GAPPS reflects an abnormality of gastric acid homeostasis, with the polyposis mediated in part through endocrine or paracrine effects on the oxyntic mucosa, or is an inherent abnormality of growth and differentiation, possibly mediated through disturbed Wnt signalling.16 While there was relative antral ECL cell hyperplasia in one affected family member, circulating gastrin amide and progastrin levels were normal. There appeared to be an inverse association between GAPPS and H pylori infection. It is uncertain, however, whether H pylori is protective against GAPPS or is just less common due to a disturbed gastric luminal environment. This study's reliance on gastric histology would not have excluded prior H pylori infection.

The clinical management of GAPPS families must balance the limitations of endoscopic surveillance, the patient-specific risk of morbidity associated with prophylactic surgery and the risk of gastric cancer within the specific family. In each of these families the risk of gastric cancer was sufficient for many clinicians to recommend gastrectomy. All first-degree relatives of affected patients were advised to have an upper gastrointestinal endoscopy and colonoscopy.

GAPPS represents a new autosomal dominant gastric cancer syndrome. The authors would welcome notification of any families that fulfil the GAPPS criteria so that, through collaboration, the genetic basis of this novel and challenging syndrome can be found.

Acknowledgments

We would like to thank Dr Jonathan Beesley for his assistance, the clinical genetics services and pathology laboratories of Western Australia, Queensland and South Australia and most importantly the members of these families.

References

Footnotes

  • Funding This study received support from the National Health and Medical Research Council of Australia.

  • Competing interests None.

  • Ethics approval This study was appoved by the local institutional review board.

  • Provenance and Peer review Not commissioned; externally peer reviewed.

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