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High Risk Lesions in the Stomach
Marc C. Winslet and S. Frances Hughes
Aims
To identify high risk lesions and explore pathology.
Introduction
Gastric cancer remains a common cause of death worldwide, but the incidence is declining [1]. There is evidence to support a stepwise sequence of histological changes in gastric carcinogenesis from inflammatory gastritis, gastric atrophy to intestinal metaplasia, dyspla- sia and finally intestinal type gastric carcinoma [2]. Dysplasia may also arise de novo in non- metaplastic glands as a precursor of diffuse type gastric carcinoma.
Atrophic Gastritis and Gastric Atrophy
Atrophic gastritis is a common condition whose incidence increases directly with age [4].
Screening studies of a healthy Japanese popula- tion revealed atrophic gastritis in over half the study population with the vast majority related to the presence of Helicobacter pylori [3].
Figures of 15–30% are recorded in Western pop- ulations. One to three per cent of patients with inflamed gastric mucosa will have evidence of
atrophic gastritis and cohort studies indicate this occurs almost exclusively in the presence of preceding chronic gastritis. Chronic gastritis is frequently found in association with gastric cancer, but whether it is itself precancerous is debatable. Gastric atrophy is defined as the loss of gastric acid producing glands, which develops as a progression from chronic atrophic gastritis.
Atrophic gastritis has been classified into two major groups, autoimmune type A, which is associated with pernicious anaemia, and envi- ronmental type B.
Type A chronic atrophic gastritis is an autoimmune disease associated with disorders of the thyroid and adrenal glands. The changes in type A occur predominantly in the fundus and body with antral sparring and may be found in patients with or without overt perni- cious anaemia. Initially pathological changes are superficial, affecting the foveolar mucosal region, with subsequent progression to the deeper layers and destruction of parietal and chief cells. End-stage disease results in gastric atrophy, achlorhydria and hypergastrinaemia [4]. Autoantibodies to intrinsic factor result in megaloblastic anaemia due to B12 deficiency.
The incidence of gastric carcinoma in patients with pernicious anaemia is three to four times that of the general population, with 2% of patients with pernicious anaemia developing overt gastric cancer [5].
Type B atrophic gastritis is more prevalent and increases with age. It is seen with greatest
frequency in areas with the highest incidence of gastric cancer. It is multifocal in nature and usually arises from the antrum and body. In type B atrophic gastritis, gastric acid secretion may be low, normal or increased. The vast majority of patients are asymptomatic, but type B disease may be associated with non-steroidal anti-inflammatory drugs (NSAIDs), alcohol, smoking and biliary reflux. The major aetiolog- ical agent is Helicobacter pylori infection. The prevalence of H. pylori infection varies from 40 to 80% and is influenced by associated eco- nomic factors. It causes gastritis in almost all cases, irrespective of symptomatology and is strongly implicated in the pathogenesis of gastric cancer [6]. The presence of H. pylori results in inflammation, apoptosis and direct gland injury followed by regeneration in the majority of cases.
In others, functional glands lose the ability to regenerate, resulting in fibrosis and atrophy.
Simultaneously the chief and mucus cells of the stomach are replaced by intestinal type epithe- lium containing goblet cells. These two markers, subsequently influenced by external factors, are the forerunner of intestinal type gastric carci- noma. The risk of developing cancer in the pres- ence of atrophic gastritis is 10% over 10 years.
The Influence of Bacterial, Genetic and Environmental Factors in Atrophic Gastritis and Gastric Atrophy
Cancer risk may vary with different strains of H. pylori, with the maximal extent of gastric atrophy associated with the cytotoxin-associ- ated gene A (Cag A) gene product. Cag A may be associated with an exaggerated inflammatory response and increased epithelial cell prolifera- tion, abnormal mucus secretion and mutation induction. The vacuolating cytotoxin (Vac A) gene product also has a positive influence on the development of carcinoma, with possible poly- morphism influencing whether ulceration or neoplasia develops [7].
Several host factors may influence suscepti- bility to neoplasia. There may be a genetic susceptibility to the degree of inflammation induced by H. pylori. There may also be a vari- able response in terms of gastric acid secretion leading to severe atrophy, a reduction in parietal
cell mass, increasing hypoacidity and increased (pre-) malignant potential. HLA status may influence the development of atrophic gastritis.
A variety of environmental factors have been implicated in the development of gastric atrophy. In vitro studies, have shown that sodium chloride increases mutagenicity of nitrosamine-related food as well as inflamma- tory changes and atrophy. It may act as a co-carcinogen with H. pylori. The formation of nitrosamines promotes atrophic gastritis and intestinal metaplasia. Antioxidants such as ascorbic acid and vitamin E may inhibit the conversion of nitrates to such mutagens [8].
Duodenogastric reflux promotes bacterial proliferation and mutagen production. Long- term acid suppression may increase atrophic gastritis.
Pathology
The precise definition of atrophic gastritis, other than the absence of gastric glands, is con- troversial, resulting in problems in classifica- tion, diagnosis and prognosis.
Unfortunately there are few cellular markers associated with atrophic gastritis or gastric atrophy. Indirect markers of proliferation such as AgNORS (silver staining nucleolar organising regions) have been shown to be increased. There is little to confirm changes in p53 mutation in the premalignant stomach and their significance remains unclear.
Serological markers in the form of pepsino- gen 1 and 2 ratio may be associated with a pro- gression to gastric atrophy [9].
Pepsinogen 1 is normally secreted by T cells in the corpus, with low levels indicating gastric atrophy. Pepsinogen 2 normally originates in the antral glands but may also be secreted by pre-neoplastic or neoplastic cells. A low pepsinogen 1:2 ratio is a reliable marker for atrophic gastritis. This ratio is significantly lower in the presence of H. pylori. Serum gastrin is a marker of the degree of gastric atrophy in the presence of H. pylori.
Natural History
The proportion of patients with atrophic gastritis who progress to atrophy is unknown whilst the transition from superficial gastritis to atrophic gastritis is approximately 5% per year.
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The cancer risk varies and is highest in type B with extensive mulifocal involvement. The risk is proportionate to the degree of atrophy, which predisposes to intestinal metaplasia. This pro- gression in turn is influenced by factors such as age, the presence of bile reflux and antioxidants.
Management
There may be some benefit in recommending a reduced salt intake and increased vitamin C supplementation in high cancer risk areas but both factors may only influence the disease process at a fairly late stage.
Whilst H. pylori eradication may help in peptic ulcer disease, the benefits in relation to gastric cancer are controversial and unproven [10]. Eradication may cause regression of intestinal metaplasia, but similar findings for atrophic gastritis and atrophy are unconfirmed.
Gastric atrophy with associated dense inflam- matory infiltrate is reversible by eradication therapy unless replacement is with fibroblasts.
The role for H. pylori eradication is convincing in association with mucosa associated lymphoid tumours (MALT) and there is a strong argu- ment for eradication after early gastric cancer resection in order to reduce the rate of recur- rence [11].
The histological interpretation of endoscopic biopsies is difficult due to surrounding inflam- mation. Eradication of H. pylori with subsequent 6-monthly biopsies is required. As the available natural history data indicates that progression from atrophic gastritis to atrophy occurs over years, as does the progression from early gastric cancer to advanced disease, the policy of serial surveillance and biopsy seems appropriate. The frequency remains controversial but 5-yearly, increasing to 3-yearly in high risk areas and individuals, may be appropriate [12].
Intestinal Metaplasia
Intestinal metaplasia is the functional morpho- logical transformation of gastric epithelial and glandular secretory type cells to intestinal absorptive type epithelium containing goblet cells. This is the forerunner of intestinal-type gastric carcinoma.
Intestinal metaplasia is classified according to the type of mucins produced and crypt
histology. Type I or complete intestinal meta- plasia resembles small bowel mucosa and pro- duces neutral sialomucins. Type II has goblet cells containing acid mucins with columnar cells secreting sialomucins. Type III or incomplete intestinal metaplasia resembles colonic mucosa with distorted crypts and produces sulpho- mucins. Type III carries the highest risk of malignant transformation. Intestinal metaplasia is usually multifocal and invariably associ- ated with H. pylori. Such cells are thought to arise from mutation of undifferentiated stem cells.
Intestinal metaplasia and atrophic gastritis may occur together or independently and increase with age. This may be due in part to the relationship with H. pylori. The relationship between intestinal metaplasia and H. pylori infestation is variable, with reduced positivity reported in patients with type III disease. Its overall role may be as an initiator or co-factor [13]. The relationship between intestinal meta- plasia and Cag A is variable. Glycentin, an intestinal polypeptide hormone that promotes intestinal metaplasia, is increased in mucosa associated with H. pylori.
As with atrophic gastritis, antioxidants may play an important role in aetiology. Vitamin C inhibits the conversion of nitrates to nitroso- mutagens, which encourage the progression of atrophic gastritis to intestinal metaplasia.
Patients with intestinal metaplasia have reduced serum levels of Vitamin C and increased nitroso compound concentrations.
Vitamin E may also reverse intestinal meta- plasia but the site of action is unknown. In Japan, a diet rich in dried fish, low in Vitamin A and with a high pickle intake also promotes intestinal metaplasia.
Bile reflux may promote intestinal metaplasia in the presence of H. pylori by raising the gastric pH and increasing bacterial proliferation and mutagenic expression.
Natural History
The progression of gastric atrophy to intestinal metaplasia is dependent on alteration of the gastric milieu. The subsequent development of neoplasia in patients with intestinal metapla- sia appears to be dependent on histological subtype, distribution and the expression of genotypic and phenotypic markers.
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There is some evidence to suggest that the risk of cancer is increased in type III intestinal metaplasia compared to type I but this is not universally supported [14]. This uncertainty may be compounded by the progression of type I to type III intestinal metaplasia as a reflection of prolonged mucosal injury [15].
The more widespread the intestinal metapla- sia, the greater the proportion of type III with possible increased malignant potential.
Various cellular markers have been advo- cated to identify high risk metaplasia including the presence of sulphomucins, PCNA (prolifer- ating cell nuclear antigen) expression and mucin peptide core antigens including MUC II.
Cellular proliferation is raised in premalig- nant lesions, with type III intestinal metaplasia having the highest index with increased apop- tosis compared to type I. Variable p53 muta- tions have been reported. This on the whole is a late event detectable predominantly in dys- plasia and not in earlier premalignant lesions.
pS2 protein expression may be an early event in the development of intestinal-type gastric cancer, with 100% positivity in type I intestinal metaplasia [16]. The transforming growth factor (TGF) beta receptor abnormalities, due to microsatellite instability, appear to be impor- tant in gastric carcinogenesis. The epidermal growth factor (EGF) R2 receptor is overex- pressed in gastric cancer. TGF-␣ and EGF R1 overexpression has been observed in intestinal metaplasia with malignant change, but not in metaplasia alone.
Management
The management strategies for intestinal meta- plasia are similar to those for atrophic gastritis.
There is evidence to suggest that a diet high in the antioxidant vitamin C may be beneficial.
As well as inhibiting the growth of H. pylori, vitamin C inhibits production of nitrosomuta- gens by the increased bacteria resulting from reduced gastric acidity.
Low vitamin E levels have been reported in association with gastric cancer, with evidence to suggest that regression of intestinal metaplasia may be achieved with a diet rich in vitamin E.
Regression in intestinal metaplasia has been reported after eradication of H. pylori but this finding was not universal. Macroscopically intestinal metaplasia appears as small grey
plaques. In view of our understanding of the natural history of gastric carcinoma, there is evi- dence to suggest that surveillance endoscopy every 5 years may be appropriate, with increased frequency in high risk individuals and areas.
Dysplasia
Dysplasia may be defined as an area of epithe- lium where atypical cellular proliferation is occurring with loss of orderly maturation of cells. The area is marked by atypical glandular formation, pleomorphic nuclei and increased mitosis dependent on degree. The grading of dysplasia into mild, moderate or severe is dependent on the severity of these changes.
Several systems have been devised but consid- erable inter-observer variation remains [17,18].
The presence of dysplastic epithelium implies irreversible inheritable change in the genome without phenotypic expression of malignancy with regard to its ability to invade.
Dysplasia may be divided into two types.
Type I or adenomatous dysplasia results from gastric atrophy via intestinal metaplasia and is a precursor for intestinal-type gastric carci- noma [17]. Type II arises in non-metaplastic glands and is associated with diffuse gastric cancer [17,18]. Non-metaplastic dysplasia may be seen in association with hyperplastic polyps, juvenile polyps and fundic gland polyps.
The presence of all grades of dysplasia increases with age. Dysplastic lesions may arise from progression of type III intestinal metapla- sia or from other lesions which do not contain metaplastic cells such as polyps. Non-metaplas- tic dysplasia is usually identified in focal lesions of the stomach but this may represent sampling bias. Dyplasia is probably most frequently iden- tified from macroscopically normal mucosa fol- lowed by gastric ulcers and then polypoid lesions [19].
Aetiology
As before, disease progression is influenced by the environment, with salt, the antioxidant beta carotene and tobacco smoking being influential.
The development of gastric cancer is related to the rate of proliferation and cell matura- tion, and expansion of the proliferative com- partment, abnormal differentiation with failure
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of normal cell maturation and the rate of apop- tosis [20,21].
The relationship between H. pylori and dys- plasia is unclear as previously discussed [22,23].
Previous partial gastrectomy for benign disease is associated with dysplasia in the gastric stump secondary to bile reflux, which may be premalignant. Two patterns of neoplasia have been described. Cancers in the gastric body are associated with intestinal metaplasia and dys- plasia while tumours in the stump arise from non-metaplastic dysplasia.
Markers of Dysplasia
The markers of dysplasia are those of cellular proliferation or increased apoptosis. There is evidence in well-differentiated tumours that both proliferation and apoptosis are increased whilst in poorly differentiated tumours there is an imbalance with more proliferation than apoptosis. There is evidence that apoptotic cells are more common in well rather than poorly differentiated tumours and that reduced apop- tosis may contribute to tumour progression.
Abnormalities in p53 are common in dyspla- sia with mutation in 15–17% of cases [24]. The cell adhesion molecule E-cadherin is also lost in gastric cancer, as is catenin through which it interacts with the intracellular cytoskeleton [25].
Natural History
Data on the natural history of dysplasia are poor but regression has been reported, ranging from 6% to 46% of cases [26,27]. This may be depen- dent on degree [19].
Progression of dysplasia to carcinoma is nor- mally reported at less than 10%. This again may be influenced by degree. Progression of mild to moderate dysplasia is seen in 5% of cases whilst progression from moderate to severe dysplasia may occur in 20% [28]. The widely varying outcomes of studies of the natural history of dysplastic lesions may partly be due to sampling errors on sequential biopsies as well as different interpretation of pathological grade.
Management
As before, chemoprevention with vitamin C may be beneficial even though nitrosomutagens
are not implicated in the progression of intesti- nal metaplasia to dysplasia. Carotenoids may be more important in the prevalence of the development of dysplasia [29].
The management of dysplastic lesions of the stomach depends on the macroscopic appear- ance of the lesion and its assigned grade.
When dysplasia is identified in a macroscop- ically normal area, providing it is low grade, surveillance can be safely adopted in view of the rates of progression [19]. Helicobacter pylori should be eradicated and repeat endoscopy should be performed at 3 months surveying the whole stomach. If the stomach is macroscopi- cally normal with no evidence of dysplasia and Helicobacter eradication is complete, sub- sequent surveillance by further endoscopy is only required for further symptoms.
The progression of moderate dysplasia to carcinoma is more common and further endo- scopic surveillance should be performed at one year. The high rate of progression of severe dysplasia suggests that some form of ablation should be undertaken. If the dysplasia is localised this may allow a more limited surgical resection.
The identification of dysplasia in the presence of a discrete macroscopic lesion is managed differently. Severely dysplastic discrete gastric lesions should be removed. In the absence of invasive malignancy with lymph node involve- ment minimally invasive surgical or endoscopic techniques may be appropriate [30]. Eradica- tion of H. pylori reduces the incidence of further dysplastic lesions after resection of early gastric carcinoma and eradication should therefore be ensured after local resection.
Gastric Polyps
Gastric polyps have been classified into two major groups: the hyperplastic/regenerative polyps and the adenomas. The hyperplastic polyps account for 75–95% of all gastric polyps.
They arise from excessive regeneration of epithelium with no distinction between the polyp and normal gastric mucosa. Malignant transformation is rare. An associated indepen- dent carcinoma, however, may be seen in between 6.5% and 25% of cases.
Adenomas account for between 8% and 25% of gastric polyps. True neoplasms have a distinct margin from surrounding mucosa with 111
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associated intestinal metaplasia and frequent mitotic figures. Malignant transformation is seen in 6–75% with a lower incidence in small flat adenomas and an increased risk in adeno- mas over 2 cm in diameter.
The management of gastric polyps is largely dependent on size and histological findings on biopsy. Polyps less than 2 cm in diameter have a low malignant potential and do not require removal [31]. Ginsberg et al [32], however, have suggested that in a small number of patients there was a significant incidence of dysplasia or carcinoma in situ in all polyps over 0.5 cm in size. As biopsy sampling may be non-represen- tative, removal of all polyps greater than this size has been recommended. This area remains controversial and a pragmatic management pathway based on available criteria is required.
Questions
1. What is the suggested pathway to devel- opment of gastric cancer?
2. What role does H. pylori play?
3. Describe the types of intestinal metapla- sia.
4. What is recommended to treat and reverse these changes?
5. What type of gastric polyp is a high risk lesion?
References
1. Mayers WC, Damiano RJ, Rotoro FS, Postlethwait RW.
Adenocarcinoma of the stomach: changing patterns over the last 4 decades. Ann Surg 1987;205:1–8.
2. Correa P, Haenszell W, Cuello C et al. A model for gas- tric cancer epidemiology. Lancet 1975;ii:58–60.
3. Asaka M, Kudo M, Kato T, et al. Review article: long term Helicobacter pylori infection – from gastritis to gastric cancer. Aliment Pharmacol Ther 1998;12:9–15.
4. Siurala M, Lehtola J, Ihamaki T. Atrophic gastritis and its sequelae: results of 19–23 years follow up examina- tions. Scand J Gastroenterol 1974;9:441.
5. Hsing AW, Hansson LE, McLaughlin JK et al. Pernicious anaemia and subsequent cancer: a population based cohort study. Cancer 1993;71:745–50.
6. Parsonnet J, Friedman GD, Vandersteen DP et al.
Helicobacter pylori infection and the risk of gastric can- cer. N Engl J Med 1991;325:1127–31.
7. Atherton JC, Peek R, Tham KT et al. Clinical and patho- logical importance of heterogeneity in Vac A, the vacuolating cytotoxin gene of Helicobacter pylori.
Gastroenterology 1997;112:92–9.
8. Block G. Vitamin C and cancer prevention. The epi- demiological evidence. Am J Clin Nutr 1991;53:
2705–825.
9. Knight T, Greaves S, Wilson A et al. Variability in serum pepsinogen levels in an asymptomatic population. Eur J Gastroenterol Hepatol 1995;7:647–54.
10. Uemura N, Mukai T, Okamoto S et al. Helicobacter pylori eradication inhibits the growth of intestinal type of gastric cancer in its initial stage. Gastroenterology 1996;110:A282.
11. Wotherspoon AC, Doglioni C, Diss TC. Regression of primary low grade B cell gastric lymphoma of mucosa associated lymphoid tissue after eradication of Helicobacter pylori. Lancet 1993;342:575–7.
12. Sjoblom SM, Sipponen P, Jarvinen H. Gastroscopic fol- low up of pernicious anaemia patients. Gut 1993;34:
28–32.
13. Cahill, RJ, Killgallen C, Beattie S et al. Gastric epithelial cell kinetics in the progression of normal mucosa to gas- tric carcinoma. Gut 1996;38:177–81.
14. Huang CB, Xu J, Huang JF, Meng XY. Sulphomucin colonic type intestinal metaplasia and carcinoma of the stomach. Cancer 1986;57:1370–5.
15. Silva S, Filipe MI, Pinho A. Variants of intestinal meta- plasia in the evolution of chronic atrophic gastritis and gastric ulcer. A follow up study. Gut 1990;31:1097–105.
16. Semba S, Yokozaki H, Yamamoto S et al. Microsatellite instability in precancerous lesions and adenocarcino- mas of the stomach. Cancer 1996;77:1620–7.
17. Jass JR. A classification of gastric dysplasia. Histo- pathology 1983;7:181–93.
18. Morson BC, Sobin LH, Grundmann E et al. Precancer- ous conditions and epithelial dysplasia in the stomach.
J Clin Pathol 1980;33:711–21.
19. Rugge M, Farinati F, Baffa R et al. Gastric epithelial dys- plasia in the natural history of gastric cancer: a multi- centre prospective follow-up study. Interdisciplinary group on gastric epithelial dysplasia. Gastroenterology 1994;107:1288–96.
20. Lipkin M. Biomarkers of increased susceptibility to gas- trointestinal cancer: new application to studies of can- cer prevention in human subjects. Cancer Res 1988;
48:235–45.
21. Moss SF, Calam J, Agarwal B et al. Induction of gastric epithelial cell apoptosis by Helicobacter pylori. Gut 1996;38:498–501.
22. The Eurogast study group. An international association between Helicobacter pylori infection with gastric can- cer. Lancet 1993;341:1159–62.
23. Parsonnet J, Friedman GD, Vandersteen DP et al.
Helicobacter pylori infection and the risk of gastric can- cer. N Engl J Med 1991;325:1127–31.
24. Brito MJ, Williams GT, Thompson H, Filipe MI.
Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa. Gut 1994;35:1697–700.
25. Shimoyama Y, Hirohashi S. Expression of E- and P- cadherin in gastric carcinomas. Cancer Res 1991;51:
2185–92.
26. Coma del Corral MJ, Pardo-Mindan FJ et al. Risk of can- cer in patients with gastric dysplasia. Cancer 1990;65:
2078–85.
27. Di Gregorio C, Morandi P, Fante R, De Gaetani C.
Gastric dysplasia. A follow up study. Am J Gastroenterol 1993;88:1714–19.
1111 2 3 4 5 6 7 8 9 1011 1 2 3 4 5 6 7 8 9 2011 1 2 3 4 5 6 7 8 9 3011 1 2 3 4 5 6 7 8 9 4011 1 2 3 4 5 6 7 8 9 5011 1 2 311
28. Kokkola A, Haapiainen R, Laxen F et al. Risk of gastric carcinoma in patients with mucosal dysplasia associ- ated with atrophic gastritis: a follow-up study. J Clin Pathol 1996;49:979–84.
29. Haenszel W, Correa P, Lopez A et al. Serum micronu- trient levels in relation to gastric pathology. Int J Cancer 1985;36:43–8.
30. Noda M, Kodama T, Atsumi M et al. Possibilities and limitations of endoscopic resection for early gastric cancer. Endoscopy 1997;29:361–5.
31. Papa A, Cammarota G, Tursi A et al. Histologic types and surveillance of gastric polyps. Hepatogastroenterol- ogy 1998;45:579–82.
32. Ginsberg GG, Al-Kawas FM, Fleischer DE et al. Gastric polyps; relationship of size and histology to cancer risk.
Am J Gastroenterol 1996;91:714–17.
111 2 3 4 5 6 7 8 9 1011 1 2 3 4 5 6 7 8 9 2011 1 2 3 4 5 6 7 8 9 3011 1 2 3 4 5 6 7 8 9 4011 1 2 3 4 5 6 7 8 9 5011 1 2 311
