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Gastric carcinoma

C. Fenoglio-Preiser F. Carneiro P. Correa P. Guilford R. Lambert F. Megraud

N. Muñoz S.M. Powell M. Rugge M. Sasako M. Stolte H. Watanabe

Definition

A malignant epithelial tumour of the stomach mucosa with glandular differentiation. Its aetiology is multifactorial; most commonly it develops after a long period of atrophic gastritis.

Tumours of the oesophagogastric junction are dealt with in the preceding chapter.

ICD-O codes

Adenocarcinoma 8140/3

Intestinal type 8144/3

Diffuse type 8145/3

Papillary adenocarcinoma 8260/3

Tubular adenocarcinoma 8211/3

Mucinous adenocarcinoma 8480/3

Signet-ring cell carcinoma 8490/3

Epidemiology

Geographical distribution

Gastric cancer was the second commonest cancer in the world in 1990, with an estimated 800,000 new cases and 650,000 deaths per year; 60% of them occurred in developing countries {1469}. The areas with the highest incidence rates (> 40/100,000 in males) are in Eastern Asia, the Andean regions of South America and Eastern Europe. Low rates (< 15/100,000) are found in North America, Northern Europe, and most countries in Africa and in Southeastern

Asia {1471}. There is about a 20-fold difference in the incidence rates when comparing the rates in Japan with those of some white populations from the US and those of some African countries. A predominance of the intestinal type of ade-nocarcinoma occurs in high-risk areas, while the diffuse type is relatively more common in low-risk areas {1296}.

Time trends

A steady decline in the incidence and mortality rates of gastric carcinoma has been observed worldwide over the past several decades, but the absolute number of new cases per year is increasing mainly because of the aging of the population {1296}. Analysis of time trends by histological types indicates that the incidence decline results from a decline in the intestinal type of carcinoma {1296}.

Age and sex distribution

Gastric carcinoma is extremely rare below the age of 30; thereafter it increases rapidly and steadily to reach the highest rates in the oldest age groups, both in males and females. The intestinal type rises faster with age than the diffuse type; it is more frequent in males than in females.

Diffuse carcinoma tends to affect younger individuals, mainly females; it frequently has hereditary characteristics, perhaps modulated by environmental influences {1738, 1633}.

Aetiology

Diet

Epidemiological studies in different populations show that the most consistent association is diet. This is especially true of intestinal type carcinomas. An adequate intake of fresh fruits and vegetables lowers the risk {1450}, due to their antioxidant effects. Ascorbic acid, carotenoids, folates and tocopherols are considered active ingredients. Salt intake strongly associates with the risk of gastric carcinoma and its precursor lesions {869}.

Other foods associated with high risk in some populations include smoked or cured meats or fish, pickled vegetables and chili peppers.

Alcohol, tobacco and occupational exposures to nitrosamines and inorganic dusts have been studied in several populations, but the results have been inconsistent.

Bile reflux

The risk of gastric carcinoma increases 5-10 years after gastric surgery, especially when the Bilroth II operation, which increases bile reflux, was performed.

Fig. 3.01 Worldwide annual incidence (per 100,000) of stomach cancer in males. Fig. 3.02 The mortality of stomach cancer is decreasing worldwide, including Numbers on the map indicate regional average values. countries with a high disease burden.

H. Pylori Infection

Ascorbic Acid

ß-Carotene

Ascorbic Acid

ß-Carotene

Cell Damage (DNA, lipids, mitochondria...)

Apoptosis

Nitrate Reductase

Apoptosis

Atrophic gastritis

Cell Damage (DNA, lipids, mitochondria...)

Repair

Diet. Saliva Acid (HCI)

Nitrate Reductase

Diet. Saliva Acid (HCI)

Fig. 3.03 Pathogenetic scheme of carcinogenesis in the stomach.

Helicobacter pylori infection

The most important development in the epidemiology of adenocarcinoma is the recognition of its association with Helicobacter pyloriinfection. Strong epi-demiological evidence came from three independent prospective cohort studies reporting a significantly increased risk in subjects who 10 or more years before the cancer diagnosis had anti-H. pylorianti-bodies, demonstrable in stored serum samples {1371, 1473, 519}. At the pathological level, H. pylorihas been shown to induce the phenotypic changes leading up to the development of adenocarcino-ma (i.e. mucosal atrophy, intestinal metaplasia and dysplasia) in both humans and in experimental animals {1635, 350, 2069}.

A prolonged precancerous process, lasting decades, precedes most gastric cancers. It includes the following sequential steps: chronic gastritis, multifocal atrophy, intestinal metaplasia, and intraepithelial neoplasia {342}. Gastritis and atrophy alter gastric acid secretion, elevating gastric pH, changing the flora and allowing anaerobic bacteria to colonize the stomach. These bacteria produce active reductases that transform food nitrate into nitrite, an active molecule capable of reacting with amines, amides and ureas to produce carcinogenic N-nitroso compounds {2167}. H. pyloriacts as a gastric pathogen and it is important in several steps in the car cinogenic cascade. H. pylori is the most frequent cause of chronic gastritis. It decreases acid-pepsin secretion and interferes with anti-oxidant functions by decreasing intragastric ascorbic acid (AA) concentrations. The organisms predominantly occur in the mucus layer overlying normal gastric epithelium. They are absent in areas overlying intestinal metaplasia where neoplasia originates. Thus, H. pylori's carcinogenic influences are exerted from a distance, via soluble bacterial products or the inflammatory response generated by the infection. H. pylori genome. H. pylori is genetically heterogeneous, and all strains may not play the same role in the development of malignancy. Strains containing a group of genes named cag pathogenicity island {264} induce a greater degree of inflammation than strains lacking these genes. The mechanism involves epithelial production of interleukin 8 via a nuclear factor KappaB pathway. There is an association between an infection with a cag positive H. pylori strain and the development of gastric carcinoma {1549}.

The determination of the complete DNA sequence of two H. pylori strains has shown other similar 'islands' are also present in the H. pylori genome. Research is ongoing to determine whether strain-specific genes located in one of these islands named the plasticity zone, or outside on the rest of the chromo some, could be associated with gastric carcinogenesis. H. pylorican also produce a vacuolating cytotoxin named VacA. This cytotoxin, responsible for epithelial cell damage, also associates with gastric carcinogenesis {1771}. The aetiological role of H. pylori in gastric carcinogenesis was confirmed when inoculation of a cag and VacA positive strain was able to induce intestinal metaplasia and gastric carcinoma in Mongolian gerbils {2069}. Excessive cell proliferation. Cell replication, a requisite of carcinogenesis, potentiates action of carcinogens targeting DNA. The higher the replication rate, the greater the chance that replication errors become fixed and expressed in subsequent cell generations. Spontaneous mutations lead to subsequent neoplastic transformation, but whether or not they cause epidemic increases in cancer rates is debatable. The latter is better explained by the presence of external or endogenous carcinogens. Proliferation is higher in H. pylori infected than in non-infected stomachs; it declines significantly after infection eradication {187} supporting the mitogenic influence of H. pylorion gastric epithelium. Ammonia, a substance stimulating cell replication, is abundantly liberated by the potent urease activity of H. pylori in the immediate vicinity of gastric epithelium. Oxidative stress. Gastritis is associated with increased production of oxidants and reactive nitrogen intermediates, including nitric oxide (NO). There is an increased expression of the inducible isoform of nitric oxide synthase in gastritis {1157}. This isoform causes continuous production of large amounts of NO. NO can also be generated in the gastric lumen from non-enzymatic sources. Acidification of nitrite to NO produces the reactive nitrogen species dinitrogen tri-oxide (N2O3), a potent nitrosating agent that forms nitrosothiols and nitrosamines {628}. Nitrosated compounds are recognized gastric carcinogens in the experimental setting.

Interference with antioxidant functions.

Ascorbic acid (AA), an antioxidant, is actively transported from blood to the gastric lumen by unknown mechanisms. Its putative anti-carcinogenic role is by preventing oxidative DNA damage. H. pyloriinfected individuals have lower AA intragastric concentrations than non-infected subjects. Following H. pylori treatment, intragastric AA concentrations increase to levels resembling those of non-infected individuals {1613}. DNA damage. Free radicals, oxidants and reactive nitrogen species all cause DNA damage {344}. These usually generate point mutations, the commonest being G:C^A:T, the commonest type of transformation in cancer with a strong link to chemical carcinogenesis. Peroxynitrite forms nitro-guanine adducts that induce DNA damage, generating either DNA repair or apoptosis. The latter process removes cells containing damaged DNA from the pool of replicating cells in order to avoid introduction of mutations into the genome and an associated heightened cancer risk. NO impairs DNA repair by compromising the activity of Fpg, a DNA repair protein. Thus, NO not only causes DNA damage but it also impairs repair mechanisms designed to prevent the formation of genetic mutations. As noted, cell proliferation increases in H. pyloriinfection. This increased replication is balanced by increased cell death. It is likely that the increased mitoses are a response to increased epithelial loss. However, the replicative rate exceeds apoptotic rates in patients infected with the virulent cagA vacA s1a H. pylori {1481} suggesting that cell loss also occurs via desquamation in patients infected by toxigenic H. pylori strains. Antitoxin derived from H. pylori also induces apoptosis. In patients with H. pylorigastritis, treatment with anti-oxi-dants attenuates the degree of apoptosis and peroxynitrite formation {1481}. It seems more than coincidental that dietary nitrite, nitrosamines and H. pylori-induced gastritis share so much chemistry and their association with cancer. As this process is chronic, the opportunity for random hits to the genome to occur at critical sites increases dramatically.

testinal complaints such as dyspepsia. Among patients in Western countries who have endoscopic evaluations for dyspepsia, however, gastric carcinoma is found in only 1-2% of cases (mostly in men over the age of 50). Symptoms of advanced carcinoma include abdominal pain that is often persistent and unrelieved by eating. Ulcerated tumours may cause bleeding and haematemesis, and tumours that obstruct the gastric outlet may cause vomiting. Systemic symptoms such as anorexia and weight loss suggest disseminated disease.

The lack of early symptoms often delays the diagnosis of gastric cancer. Consequently, 80- 90% of Western patients with gastric cancers present to the physician with advanced tumours that have poor rates of curability. In Japan, where gastric cancer is common, the government has encouraged mass screening of the adult population for this tumour. Approximately 80% of gastric malignancies detected by such screening programs are early gastric cancers. However, many individuals do not choose to participate in these screening programs, and consequently only approximately 50% of all gastric cancers in Japan are diagnosed in an early stage.

Imaging and endoscopy

Endoscopy is widely regarded as the most sensitive and specific diagnostic test for gastric cancer. With high resolution endoscopy, it is possible to detect slight changes in colour, relief, and architecture of the mucosal surface that suggest early gastric cancer. Endoscopic detection of these early lesions can be improved with chromoendoscopy (e.g. using indigo carmine solution at 0.4 %). Even with these procedures, a substantial number of early gastric cancers can be missed {745A}.

Gastric cancers can be classified endo-scopically according to the growth pattern {1298, 63} The patterns I. II and III of superficial cancer (Fig. 3.03) reflect the gross morphology of the operative specimen. The risk of deep and multifocal penetration into the submucosa and the risk of lymphatic invasion is higher in type IIc, the depressed variant of type II. Infiltration of the gastric wall (linitis plastica) may not be apparent endoscopically. This lesion may be suspected if there is limited flexibility of the gastric wall. Diagnosis may require multiple, jumbo biopsies. The depth of invasion of the tumour is staged with endoscopic ultrasound. A 5-layer image is obtained at 7.5/12 MHz: in superficial (T1) cancer the second hyper-echoic layer is not interrupted. Radiology with barium meal is still used in mass screening protocols in Japan, followed by endoscopy if an abnormality has been detected. For established gas-

Localization

The most frequent site of sub-cardial stomach cancer is the distal stomach, i.e. the antro-pyloric region. Carcinomas in the body or the corpus of the stomach are typically located along the greater or lesser curvature.

Clinical features

Symptoms and signs

Early gastric cancer often causes no symptoms, although up to 50% of patients may have nonspecific gastroin-

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