World J. Surg. 15, 228-234, 1991
World Journal of Surgery 9 1991 by the Soci6t6 Internationale de Chirurgie
The Epidemiology of Gastric Cancer Pelayo Correa, M.D. Department Of Pathology, Louisiana State University Medical Center, New Orleans, Louisiana, U.S.A. The etiology of gastric carcinoma, especially its "epidemic" or "intestinal" type is reviewed. The prevailing etiologic hypothesis, based on the selective targeting of etiologic agents in different points of the chain of causation, is described. Support for the hypothesis is updated, based on descriptive and analytical epidemiologic studies as well as on recently obtained laboratory and experimental evidence. Primary and secondary prevention measures are hriefly discussed.
It seems ironic that our understanding of the natural history of gastric cancer is improving considerably at the same time that the impact of the disease in certain Western affluent populations is decreasing. As a world health problem, however, gastric cancer occupies a very prominent position. Multidisciplinary research on gastric cancer in many countries has contributed valuable information on cancer etiology, which may be applicable to cancer of other sites. A general perspective of the state of the art in gastric cancer is attempted in this article through a brief review of the descriptive epidemiology, pathology, precancerous process, etiologic factors, and prevention aspects of the disease. Descriptive Epidemiology
As of 1980, gastric cancer was the most frequent malignant disease in the world, with 682,400 new cases per year [1]. This incidence calculation excludes skin cancer, for which world incidence figures are lacking. The incidence rate of lung cancer has been increasing worldwide and is expected to surpass gastric cancer soon after 1980. With the prominent exception of Japan, gastric cancer displays higher rates in populations of low socioeconomic standards. The gradual decline in gastric cancer rates in many populations may be a reflection of improving economic conditions. In some affluent societies, there are some indications that the decline in gastric cancer rates may not continue indefinitely and the actual number of new cases may be increasing. In the Supported by grant no. P01-CA-28842 of the National Cancer Institute, NIH, USPHS. Reprint requests: Pelayo Correa, M.D., Department of Pathology, Louisiana State University Medical Center, 1901 Perdido Street, New Orleans, Louisiana 70112, U.S.A.
United States of America, the number of new cases rose by 8% from 22,900 in 1976 to 24,700 in 1986 [2]. For many years, Japan displayed the highest death rates for gastric cancer in the world as shown in Figure 1, but the decline in their rates has given Costa Rica first place in the latest tabulations of WHO data as shown in Figure 2 [3]. Chile occupies third place in such tabulations, reflecting the high rates in the Andean regions in Latin America. Northern European countries also have high rates. Gastric cancer is the most frequent neoplasm in China, but no yearly rates are available from WHO sources [4]. Pathology
Two main types of gastric carcinoma have been recognized as having independent epidemiologic characteristics. The most common type in populations at high risk has been called the intestinal type because it resembles intestinal carcinomas and usually arises in areas of the mucosa which have previously become intestinalized. It is also the type that has been decreasing in frequency most markedly in industrialized nations and, because of that trend, it has also been called the epidemic type [5]. In other classifications it has received the names of "expansive" or well-differentiated adenocarcinoma [6]. This type is the main subject of this review. The other common type has been called "diffuse," "infiltrative," or poorly-differentiated. This type is predominant in populations at low risk and is becoming relatively more frequent in populations with marked declines in the intestinal type, as shown in Figure 3 for Norway [7]. The Precancerous Process
Little is known about the precancerous lesions for the diffuse carcinomas, most of which make their appearance in otherwise normal mucosa. Two types of lesions have been proposed as precursors of diffuse carcinoma: the so-called globoid dysplasia [8] and the nonmetaplastic dysplasia [9]. The intestinal type of carcinoma is considered the end result of a prolonged precancerous process in which the following lesions appear to develop in a sequential manner: superficial gastritis, atrophy, small intestinal metaplasia, colonic metaplasia, dysplasia, and, finally, invasive carcinoma [10]. The corn-
P. Correa: Epidemiology of Gastric Cancer
229
Fig. 1. Map of gastric cancer incidence in the world around 1970. Reproduced with permission o f publisher [39]. RATE PER 100.0O0POPL'LATION
MALE
I COSTARICA 2 3 4 5 6 7 8 9 10 ll 12 13 14 15 16 17 I8 19 20 21 22 23 24 Z5
26 27 28 29 31 32 33 34 35 ]6 37 $$ 40 41
0
I0
20
]
30
40
50
FEMALE
0
I0
20
30
l COSTARICA
JAPAN I CHILE l l l [ l l l POLAND ~ HUNGARY ~ PORTUGAL ~ 1 SINGAPORE CZECHOSLOVAKIA ~ BULGARIA ~ AUSTRIA ~ ITALY l ROMANIA" I GERMAN D R. / YUGOSLAVIA m URUGUAY ~ GERMANY, F R. I SPAIN" ~ 1 1 FINLAND l NETHERLANDS ~ NORTHERN IRELAND ~ ENGLAND& WALF..S ~ SCOTLAND ~ IRELAND J GUATEMALA" l ARGENTINA ~ BELGIUM" ~ NORWAY ~ PUERTO RICO J SWITZERLAND l ISRAEL l FRANCE i SWEDEN 1 N E W ZEALAND 1 HONGKONG | GREECE B DENMARK i U 5,. N O N W H I T E ~l AUSTRALIA L1 CANADA 1 CL'RA I U S., W H I T E t i
1964
2 3 4 5 6 7 8 9 t0 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
JAPAN
[
~
GUATEMALA"
CHILE PORTUGAL BULGARIA HUNGARY SINGAPORE CZECHOSLOVAKIA AUSTRIA POLAND ITALY lUll GERMAND.R. / GERMANY,F.R. l FINLAND l YUGOSLAVIA B~B ROMANIA/~ ~1 SPAIN" SCOTLAND i IRELAND URUGUAY NORWAY 1 E N G L A N D & WALES l BELGIUM ~ 1 NETHERLANDS I ARGENTINA 1 NORTHERN IRELAND mR HONG KONG 1 PUERTO RICO SWITZERLAND I SWEDEN II GREECE DENMARK 1 ISRAEL l FRANCE 1 U.S., NONWHITE I N E W ZEALAND 9 AUSTRALIA 9 CUBA lib CANADA 9 U.S.. WHITE II
Fig. 2. Mortality rates of gastric cancer: 19841985. Reproduced with permission of publisher [3].
230
World J. Surg. Vol. 15, No. 2, Mar./Apr. 1991
40
Oe=,thrate
gee 100 000
T
30
10
1940-44
1952-$3
1964-66 Time
Intest ,n,II --'--
Diffuse =
Other
Fig. 3. Age-adjusted mortality rates of gastric cancer in Norwegian males, by histologic type. Reproduced with permission of publisher [7].
Fig. 5. Small intestinal metaplasia. The gastric mucosa is replaced by intestinal type epithelium with alternating goblet cells and absorptive cells with a distinct brush border.
Fig. 4. Multifocal chronic atrophic gastritis. Section of gastric antrum showing loss of glands and hyperplasia of gland necks.
ponents of the precancerous process constitute the nosologic complex of multifocal atrophic gastritis, whose prevalence is very high in populations at high risk. This type of gastritis is to be distinguished from other entities such as the diffuse corporal (type A) gastritis confined to Northern European populations with a high prevalence of pernicious anemia or the diffuse antral gastritis which accompanies duodenal ulcer and which is not known to increase gastric cancer risk [11], Multifocal atrophic gastritis first appears as multiple foci of chronic inflammation
and atrophy located in the area of the incisura angularis and in the vicinity of the antrum-corpus junction. Hyperplasia of gland necks, a response to the loss of epithelial cells, is observed off and on in the early as well as in the more advanced stages of the precancerous process. As age advances, these foci coalesce and progressively make their appearance in the distal and proximal lesser curvature, the antral walls, and the corpus. The foci are then the site of intestinal metaplasia which, in younger individuals, almost exclusively resembles small intestinal mucosa: it consists of enterocytes with absorptive brush borders alternati[~, with goblet cells; Paneth cells are seen, sialomucins are secreted, and intestinal dissacharidases are abundant. This type of metaplasia has also been called " c o m p l e t e " [12] or type I [13]. As the process advances, such metaplastic foci acquire colonic phenotype, lose their absorptive cells, digestive enzymes, and secrete sulfated mucins. This colonic type of metaplasia has also been called "incomplete" or type III [12, 13]. In such a background, dysplastic foci make their appearance; they are occasionally associated with small foci of carcinoma which are not necessarily in the same area of the dysplasia, Most small carcinomas, when discovered, are sur-
P. Correa: Epidemiology of Gastric Cancer
Fig. 6. Colonic metaplasia. Metaplastic cells are columnar, contain numerous cytoplasmic mucin vacuoles of different sizes, and have no discernible brush border.
rounded by areas of colonic metaplasia. Figures 4-7 illustrate these precursor lesions. Recent results from a population cohort followed up for over 5 years in the rural Andean region of Narifio, Colombia, have given support to the sequential nature of the precursor lesions described above. Independent evaluation of each parameter showed that the most advanced lesion was regularly accompanied by the less advanced one. Both progression and regression changes were observed in the cohort over the years of observation with the net result of a slow overall progression. This phenomenon is shown by a net progression rate of 3.3 per 100 person years, representing a net gain of 1.7 for atrophic gastritis, 0.9% for metaplasia, and 0.7% for dysplasia. Etiologic Factors
Investigators from different scientific disciplines working in different countries have identified risk factors for gastric cancer which have led to the postulation of the etiologic hypothesis outlined in Figure 8. As seen in the diagram, several etiologic agents have been recognized as acting in different points of the chain of causa-
231
Fig. 7. Moderate adenomatous dysplasia. Closely-packed metaplastic glands with large, elongated, and pseudostratified nuclei.
tion, The first step of the process, characterized by active inflammation, has been linked to 2 factors: excessive salty foods and infection with Helicobacter pylori. Excessive salt is probably the most consistent and better documented etiologic factor for gastric carcinoma: it has been reported independently in many countries in studies of ecologic correlations, analytical epidemiology, and experimental carcinogenesis [14-t7], Salting of foods appears to increase their capacity to produce mutagens after nitrosation [18]. Infection with Helicobacter pylori is excessively common and severe in populations at high gastric cancer risk. It is also prevalent in them since childhood. The infection is also observed in low-risk populations, but its prevalence is lower and its start observed at later ages [19, 20]. Although not a sufficient carcinogenic factor, Helicobacter infection may be an important contributory factor in populations exposed to other carcinogenic influences [21]. The second stage in the chain of causation is atrophy or gland loss, whose etiopathogenic mechanism is obscure. Although nutritional deficits have been proposed, no epidemiologic or experimental evidence for their causative role has been proposed. Experimentally, feeding excessively salty rice to mice has resulted in glandular atrophy [22]. The equivalent of atrophy or gland loss may be induced surgically in gastrectomy
232
World J. Surg. Vol. 15, No. 2, Mar./Apr. 1991
DI[ I
GASTRIC CAVITY
GASTRIC MUCOSA
PR[
normal i superficial
irritants
NaeI-Helicobacter
remove
irritants
gastritis
nutrition deficits (animal proteins)
V[ NI ION
antibodies gastrectomy
(vitamins)
~ ritis
I
improve nutrition
NOj
anti-oxidant deficit compounds (foods-drugs)
nitrogen
-
-
~
block nitrosation
bile
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NaCI
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promote differenti-
~
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r
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Fig. 8. Diagram of etiologic hypothesis. The progressive histopathologic changes are shown; the etiologic agents are depicted at the point of their presumed action. Indications for possible prevention are suggested.
procedures. It is also observed in patients with autoantibodies against parietal cells, as a component of the pernicious anemia syndrome. Once atrophy is established, the secretion of hydrochloric acid is reduced, the gastric pH is elevated, and anaerobic bacteria proliferate in the gastric microenvironment. Many such bacteria contain reductases which act on nitrate molecules present in the normal diet. This results in abundant nitrite molecules which have the capacity to nitrosate nitrogen containing compounds from food, medications, or bile salts. N-nitroso compounds are frequently mutagens and carcinogens. A highly potent mutagen N-nitroso-chloro-indol has been identified after nitrosation of fava beans (Vicia faba), the staple food of high-risk peasants in Narifio, Colombia [23]. Nitrosation of Japanese fish has resulted in compounds which induce gastric carcinomas in experimental rats [24]. It has been postulated that N-nitroso carcinogens synthesized in small amounts in the gastric cavity over a prolonged time period induce the successive mutations which lead to the precancerous lesions and finally to invasive carcinoma in the gastric epithelium [10, 25]. The best experimental model of gastric carcinogenesis utilized MNNG, a potent N-nitroso compound. It has been shown that feeding salt to experimental animals simultaneously with MNNG markedly potentiates the effect of the carcinogen [17].
Two general mechanisms of inhibition or retardation of the gastric carcinogenic process are being actively investigated. The first one involves vitamin C, which has the double role of blocking the synthesis of N-nitroso carcinogens and of retarding the progression of transformed cell clones through fibroplasia. The first role is based on the destruction of the nitrite molecules [26]. It has been recently reported that only the reduced form of vitamin C (ascorbic acid) is capable of reacting with and inactivating the nitrite molecules. The oxidized form of vitamin C (dehydro ascorbic acid) has no such role [27]. This observation may explain why vitamin C has been found as a risk factor for stomach cancer in some populations but not in others. The other mechanism of inhibition of gastric carcinogenesis is mediated through beta carotene and related compounds. Blood levels of carotenoids have been found to be remarkably low in patients with dysplasia in the population of Narifio, Colombia [28]. Beta-carotene and its related pigment cantaxantine (which is not a precursor of vitamin A) inhibit, to a considerable extent, experimental gastric carcinoma (but not early precursors) in rats receiving MNNG [29]. The above reports suggest that beta-carotene acts in the late stages of carcinogenesis, which gives support to their proposed mechanism of action as scavengers of free radicals [30]. Beta-carotene also increases cellto-cell communications through the widening of intercellular gap junction channels. This results in inhibition of the expression of malignant phenotypes in transformed cells connected to nontransformed cells through such junction channels [31]. This phenomenon may be specially relevant in the gastric mucosa where neighboring transformed and nontransformed cells are frequently found. Genetic Influences
It has been suspected for a long time that genetic forces determine the susceptibility or the resistance to gastric cancer. In pernicious anemic families, a major dominant gene transmitted autosomally has been postulated [32]. The familial aggregation of gastric cancer unrelated to pernicious anemia has also been reported [33]. The susceptibility to chronic atrophic gastritis, the apparent key event in the early stages of gastric carcinogenesis, appears determined by a recessive autosomal gene whose expression is influenced by environmental factors. This is inferred from segregation analysis of precancerous lesions in the population of Narifio, Colombia, in which age and having an affected mother represent the suspected environmental influences [34]. Prevention
Primary prevention of gastric carcinoma should be based on the control of the etiologic agents. Avoiding salty foods should be a major concern in primary prevention. Some calcium salts, especially calcium lactate, may block the damaging effect of high sodium intake to a certain extent [35]. An adequate supply of fresh fruits and vegetables will provide sufficient amounts of reduced ascorbic acid and beta-carotene, strongly suspected to play a protective role. The same food items contain a variety of non-nutrients which inhibit carcinogenesis [36]. The control of Helicobacter infections, especially when associated with severe
P. Correa: Epidemiology of Gastric Cancer
gastritis, should be considered but its beneficial effects are only a matter of investigation at this point. Secondary prevention of gastric carcinoma has a role in subjects suspected to be at high risk because of advanced premalignant lesions such as dysplasia and, probably, colonic metaplaSia. Frequent endoscopies should be done in order to detect superficial carcinomas (early cancer in the Japanese nomenclature) which have an excellent prognosis after surgery [37]. The treatment of dysplasia itself (and of colonic metaplasia) is still a matter of controversy. The natural history of such lesions, especially the time required for transformation into invasive carcinoma, is poorly understood. Chemoprevention trials with antioxidants, anti-Helicobacter therapy, calcium salts, and dietary modifications are being proposed and, hopefully, might shed some light in this field. Markers of increased risk are provided by pepsinogen I and pepsinogen I/II ratios in the blood. Very low figures are good indicators of increased risk [38]. R6sum6
L'dtiologie du cancer gastrique, surtout de type "6pid6mique" ou "intestinal," est 6tudide. L'hypoth~se 6tiologique dominante, bas6e sur une succesion de stades d'agents 6tiologiques, est ddcrite. L'evidence en faveur de cette hypoth6se est mise jour, fond6e sur des 6tudes d'6pid6miologie descriptive et analytique, tout autant que sur les r6sultats r6cemment obtenus au laboratoire ou en exp6rimentation. Les mesures de prdvention principales et secondaires sont bri6vement discut6es. Resumen
Se revisa la etiologia del carcinoma gfistrico, especialmente de su tipo "epid6mico" o "intestinal." Se describe la hip6tesis etiol6gica prevalente, la cual se fundamenta en el enfoque sobre determinados agentes etiol6gicos en la cadena de factores causales. Se ha hecho una actualizaci6n del soporte a esta hip6tesis con base en estudios epidemiol6gicos descriptivos y en evidencia experimental reciente. Se discuten brevemente las medidas preventivas primarias y secundarias. References
1, Parkin, D.M., Stjerhsward, J., Muir, C.S.: Estimates of the worldwide frequency of twelve major cancers. Bull. W.H.O. 62:163, 1984 2. Cady, B., Rossi, R.L., Silverman, M.L., Piccione, W., Heck, T.: Gastric adenocarcinoma. A disease in transition. Arch. Surg. 124:303, 1989 3. Kurihara, M., Aoki, K., Hisamichi, S.: Cancer Mortality Statistics in the World 1950-1985, Nagoya, U. Nagoya Press, 1989 4. Atlas of Cancer Mortality in the People's Republic of China, Beifing, China Map Press, 1979 5. Mufioz, N., Correa, P., Cuello, C., Duque, E.: Histologic types of gastric carcinoma in high-risk and low-risk areas. Int. J. Cancer 3:809, 1968 6. Ming, S.C.: Gastric carcinoma. A pathobiological classification. Cancer 39:2475, 1977 7. Mufioz, N., Asvall, J.: Time trends of intestinal and diffuse types of gastric cancer in Norway. Int. J. Cancer 8:144, 1971 8. Borcbard, F.: Gastric dysplasia. Istocitopatologia 3:89, 1981 9. Ghand-Mnaymne, L., Paz, J., Roldan, E.: Dysplasia of nonmetaplastic gastric mucosa. Am. J. Surg. Path. 12:96, 1988
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10. Correa, P.: A human model of gastric carcinogenesis. Cancer Res. 48:3554, 1988 11. Correa, P.: Chronic atrophic gastritis: A clinico-pathological classification. Am. J. Gastroenterol. 83:504, 1988 12. Matsukura, N., Suzuki, K., Kawachi, T., Aoyagi, M., Sugimura, T., Kitaoka, H., Numajiri, H., Itabashi, M., Hirota, T.: Distribution of marker enzymes and mucin in intestinal metaplasia in human stomachs and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomas. J. Natl. Cancer Inst, 65:231, 1980 13. Silva, S., Filipe, M.I.: Intestinal metaplasia and its variants in the gastric mucosa of Portuguese subjects: A comparative analysis of biopsy and gastrectomy material. Human Path. 17:988, 1986 14. Joossens, J.V., Geboers, J.: Nutrition and gastric cancer. Nutr. Cancer 2:250, 1981 15. Buiatti, E., Palli, D., Decarli, A., Amadori, D., Avellini, C., Bianchi, S., Bisemi, R., Cipriani, F., Cocco, P., Giacosa, A., Marubini, E., Puntoni, R., Vindigui, C., Fraumeni, J., Blot, L.: A case-control study of gastric cancer and diet in Italy. Int. J. Cancer 44:611, 1989 16. Graham, S., Hanghey, B., Marshall, J., Brasure, J., Zielezny, M., Freudenheim, J., West, D., Nolan, J., Wilkinson, G.: Diet in the epidemiology of gastric cancer. Nutr. Cancer 13:19, 1990 17. Shirai, T., Imaida, K., Fukishima, S., Hasegawa, R., Tatematsu, M.: Effect of NaCI, Tween 60 and low dose of N-Ethyl-N'-nitronitrosoguanidirie on gastric carcinogenesis of rats given a single dose of N-methyl-N'-nitro-nitrosoguanidine. Carcinogenesis 12: 1419, 1982 18. Rojas-Campo, N., Sigaran, M., Bravo, A.V., Jimenez-Ulate, F., Correa, P.: Salt enhances the mutagenicity of nitrosated black beans. Nutr. Cancer 14:1, 1990 19. Fox, J.G., Correa, P., Taylor, N., Zavala, D., Fontham, E., Janney, F., Rodriguez, E., Hunter, E., Diavolitsis, S.: Campylobacter pylori-associated gastritis and immune response in a population at increased risk of gastric carcinoma. Am. J. Gastroenterol. 84:775, 1989 20. Parsonnet, J.: The epidemiology of C. pylori. In Campylobacter Pylori in Gastritis and Peptic Ulcer Disease, M.J. Blaser, editor, New York, Igaku-shoin, 1989, pp. 51-60 21. Correa, P., Ruiz, B.: Campylobacter pylori and gastric cancer. In Campylobacter Pylori and Gastroduodenal Disease, B.J. Rathbone, R.V. Heatley, editors, London, Blackwell Scientific Publications, 1989, pp. 13%145 22. Kodama, M., Kodama, T., Suzuki, H., Kondo, K.: Effect of rice, salty rice diets on the structure of mouse stomachs. Nutr. Cancer 6:135, 1984 23. Yang, D., Tannenbaum, S.R., Buchi, G., Lee, G.C.M.: 4-chloro6-methoxyindole is a precursor of a potent mutagen that forms during nitrosation of the fava beans (Vicia faba). Carcinogenesis 5:1219, 1984 24. Weisburger, J.H., Marguardt, H., Hirota, N.: Induction of cancer of the glandular stomach by extract of nitrite treated fish. J. Natl. Cancer Inst. 64:163, 1980 25. Correa, P., Haenszel, W., Cuello, C., Archer, M., Tannenbaum, S.R.: A model for gastric cancer epidemiology. Lancet 2:58, 1975 26. Mirvish, S.S.: The etiology of gastric cancer: Intragastric nitrosamide formation and other theories. J. Natl. Cancer Inst. 71:629, 1983 27. Sobala, A.M., Schorah, C.J., Sanderson, M.: Ascorbic acid in the human stomach. Gastroenterology 97:357, 1989 28. Haenszel, W., Correa, P., Lopez, A., Cuello, C., Zarama, G., Zavala, D., Fontham, E.: Serum micronutrient levels in relation to gastric pathology. Int. J. Cancer 36:43, 1985 29. Santamaria, L., Bianchi, A., Ravetto, C., Arnaholdi, A., Santogati, G., Andreoni, L.: Prevention of gastric cancer induced with MNNG in rats fed supplemental carotenoids. J. Nutr. Growth Cancer 4:175, 1987 30. Burton, A.W., Ingold, K.U.: Beta-carotene: An unusual type of lipid antioxidant. Science 224:569, 1984 31. Bertram, J.S., Hossain, M.Z., Pung, A., Dundhang, J.E.: Development of in vitro system for chemoprevention research. Prev. Med. 18:562, 1989 32. Varis, K., Ihamaki, T., Lehtola, J., Sipponen, P., Kekki, M.,
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Isokoski, M., Sankkonen, M., Siurala, M.: Genetic aspects of gastritis-cancer relationship. Dtsch. Z. Verdau u Stefwechseldr. 38:51, 1978 33. Lehtola, J.: Family studies of gastric carcinoma with special reference to histologic types. Scand. J. Gastroenterol. 13:1, 1978 34. Bonney, G., Elston, R.E., Correa, P., Haenszel, W., Zavala, D., Zarama, G., Collazos, T., Cnello, C.: Genetic aspects of gastric carcinoma. I. Chronic atrophic gastritis. Genetic Epid. 3:213, 1986 35. Wargovich, M.J., Baer, A.: Basic and clinical investigations of dietary calcium in the prevention of colorectal cancer. Prey. Med. 18:672, 1989
World J. Surg. Vol. 15, No. 2, Mar./Apr. 1991 36. Wattenberg, L.W.: Chemoprevention of cancer. Cancer Res. 45:1, 1985 37. Bringaze, W.L., Chappuis, C.W., Cohn, I., Correa, P.: Early gastric cancer: 21 years experience. Ann. Surg. 204:103, 1986 38. Stemmermann, G.N., Samloff, I.M., Hayashi, T.: Pepsinogens I and II in carcinoma of the stomach: An immunochemical study. Appl. Path. 3:159, 1985 39. Correa, P.P., Tannembaum, S.R.: The microecology of gastric cancer. In N-Nitroso Compounds, R.A. Scanlan, S.R. Tannembaum, editors, American Chemical Society Symposium Series 174, 1981, pp. 321-329
World Journal of Surgery 9 1991 by the Soci6t6 Internationale de Chirurgie
The Epidemiology of Gastric Cancer Pelayo Correa, M.D. Department Of Pathology, Louisiana State University Medical Center, New Orleans, Louisiana, U.S.A. The etiology of gastric carcinoma, especially its "epidemic" or "intestinal" type is reviewed. The prevailing etiologic hypothesis, based on the selective targeting of etiologic agents in different points of the chain of causation, is described. Support for the hypothesis is updated, based on descriptive and analytical epidemiologic studies as well as on recently obtained laboratory and experimental evidence. Primary and secondary prevention measures are hriefly discussed.
It seems ironic that our understanding of the natural history of gastric cancer is improving considerably at the same time that the impact of the disease in certain Western affluent populations is decreasing. As a world health problem, however, gastric cancer occupies a very prominent position. Multidisciplinary research on gastric cancer in many countries has contributed valuable information on cancer etiology, which may be applicable to cancer of other sites. A general perspective of the state of the art in gastric cancer is attempted in this article through a brief review of the descriptive epidemiology, pathology, precancerous process, etiologic factors, and prevention aspects of the disease. Descriptive Epidemiology
As of 1980, gastric cancer was the most frequent malignant disease in the world, with 682,400 new cases per year [1]. This incidence calculation excludes skin cancer, for which world incidence figures are lacking. The incidence rate of lung cancer has been increasing worldwide and is expected to surpass gastric cancer soon after 1980. With the prominent exception of Japan, gastric cancer displays higher rates in populations of low socioeconomic standards. The gradual decline in gastric cancer rates in many populations may be a reflection of improving economic conditions. In some affluent societies, there are some indications that the decline in gastric cancer rates may not continue indefinitely and the actual number of new cases may be increasing. In the Supported by grant no. P01-CA-28842 of the National Cancer Institute, NIH, USPHS. Reprint requests: Pelayo Correa, M.D., Department of Pathology, Louisiana State University Medical Center, 1901 Perdido Street, New Orleans, Louisiana 70112, U.S.A.
United States of America, the number of new cases rose by 8% from 22,900 in 1976 to 24,700 in 1986 [2]. For many years, Japan displayed the highest death rates for gastric cancer in the world as shown in Figure 1, but the decline in their rates has given Costa Rica first place in the latest tabulations of WHO data as shown in Figure 2 [3]. Chile occupies third place in such tabulations, reflecting the high rates in the Andean regions in Latin America. Northern European countries also have high rates. Gastric cancer is the most frequent neoplasm in China, but no yearly rates are available from WHO sources [4]. Pathology
Two main types of gastric carcinoma have been recognized as having independent epidemiologic characteristics. The most common type in populations at high risk has been called the intestinal type because it resembles intestinal carcinomas and usually arises in areas of the mucosa which have previously become intestinalized. It is also the type that has been decreasing in frequency most markedly in industrialized nations and, because of that trend, it has also been called the epidemic type [5]. In other classifications it has received the names of "expansive" or well-differentiated adenocarcinoma [6]. This type is the main subject of this review. The other common type has been called "diffuse," "infiltrative," or poorly-differentiated. This type is predominant in populations at low risk and is becoming relatively more frequent in populations with marked declines in the intestinal type, as shown in Figure 3 for Norway [7]. The Precancerous Process
Little is known about the precancerous lesions for the diffuse carcinomas, most of which make their appearance in otherwise normal mucosa. Two types of lesions have been proposed as precursors of diffuse carcinoma: the so-called globoid dysplasia [8] and the nonmetaplastic dysplasia [9]. The intestinal type of carcinoma is considered the end result of a prolonged precancerous process in which the following lesions appear to develop in a sequential manner: superficial gastritis, atrophy, small intestinal metaplasia, colonic metaplasia, dysplasia, and, finally, invasive carcinoma [10]. The corn-
P. Correa: Epidemiology of Gastric Cancer
229
Fig. 1. Map of gastric cancer incidence in the world around 1970. Reproduced with permission o f publisher [39]. RATE PER 100.0O0POPL'LATION
MALE
I COSTARICA 2 3 4 5 6 7 8 9 10 ll 12 13 14 15 16 17 I8 19 20 21 22 23 24 Z5
26 27 28 29 31 32 33 34 35 ]6 37 $$ 40 41
0
I0
20
]
30
40
50
FEMALE
0
I0
20
30
l COSTARICA
JAPAN I CHILE l l l [ l l l POLAND ~ HUNGARY ~ PORTUGAL ~ 1 SINGAPORE CZECHOSLOVAKIA ~ BULGARIA ~ AUSTRIA ~ ITALY l ROMANIA" I GERMAN D R. / YUGOSLAVIA m URUGUAY ~ GERMANY, F R. I SPAIN" ~ 1 1 FINLAND l NETHERLANDS ~ NORTHERN IRELAND ~ ENGLAND& WALF..S ~ SCOTLAND ~ IRELAND J GUATEMALA" l ARGENTINA ~ BELGIUM" ~ NORWAY ~ PUERTO RICO J SWITZERLAND l ISRAEL l FRANCE i SWEDEN 1 N E W ZEALAND 1 HONGKONG | GREECE B DENMARK i U 5,. N O N W H I T E ~l AUSTRALIA L1 CANADA 1 CL'RA I U S., W H I T E t i
1964
2 3 4 5 6 7 8 9 t0 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
JAPAN
[
~
GUATEMALA"
CHILE PORTUGAL BULGARIA HUNGARY SINGAPORE CZECHOSLOVAKIA AUSTRIA POLAND ITALY lUll GERMAND.R. / GERMANY,F.R. l FINLAND l YUGOSLAVIA B~B ROMANIA/~ ~1 SPAIN" SCOTLAND i IRELAND URUGUAY NORWAY 1 E N G L A N D & WALES l BELGIUM ~ 1 NETHERLANDS I ARGENTINA 1 NORTHERN IRELAND mR HONG KONG 1 PUERTO RICO SWITZERLAND I SWEDEN II GREECE DENMARK 1 ISRAEL l FRANCE 1 U.S., NONWHITE I N E W ZEALAND 9 AUSTRALIA 9 CUBA lib CANADA 9 U.S.. WHITE II
Fig. 2. Mortality rates of gastric cancer: 19841985. Reproduced with permission of publisher [3].
230
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40
Oe=,thrate
gee 100 000
T
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Fig. 3. Age-adjusted mortality rates of gastric cancer in Norwegian males, by histologic type. Reproduced with permission of publisher [7].
Fig. 5. Small intestinal metaplasia. The gastric mucosa is replaced by intestinal type epithelium with alternating goblet cells and absorptive cells with a distinct brush border.
Fig. 4. Multifocal chronic atrophic gastritis. Section of gastric antrum showing loss of glands and hyperplasia of gland necks.
ponents of the precancerous process constitute the nosologic complex of multifocal atrophic gastritis, whose prevalence is very high in populations at high risk. This type of gastritis is to be distinguished from other entities such as the diffuse corporal (type A) gastritis confined to Northern European populations with a high prevalence of pernicious anemia or the diffuse antral gastritis which accompanies duodenal ulcer and which is not known to increase gastric cancer risk [11], Multifocal atrophic gastritis first appears as multiple foci of chronic inflammation
and atrophy located in the area of the incisura angularis and in the vicinity of the antrum-corpus junction. Hyperplasia of gland necks, a response to the loss of epithelial cells, is observed off and on in the early as well as in the more advanced stages of the precancerous process. As age advances, these foci coalesce and progressively make their appearance in the distal and proximal lesser curvature, the antral walls, and the corpus. The foci are then the site of intestinal metaplasia which, in younger individuals, almost exclusively resembles small intestinal mucosa: it consists of enterocytes with absorptive brush borders alternati[~, with goblet cells; Paneth cells are seen, sialomucins are secreted, and intestinal dissacharidases are abundant. This type of metaplasia has also been called " c o m p l e t e " [12] or type I [13]. As the process advances, such metaplastic foci acquire colonic phenotype, lose their absorptive cells, digestive enzymes, and secrete sulfated mucins. This colonic type of metaplasia has also been called "incomplete" or type III [12, 13]. In such a background, dysplastic foci make their appearance; they are occasionally associated with small foci of carcinoma which are not necessarily in the same area of the dysplasia, Most small carcinomas, when discovered, are sur-
P. Correa: Epidemiology of Gastric Cancer
Fig. 6. Colonic metaplasia. Metaplastic cells are columnar, contain numerous cytoplasmic mucin vacuoles of different sizes, and have no discernible brush border.
rounded by areas of colonic metaplasia. Figures 4-7 illustrate these precursor lesions. Recent results from a population cohort followed up for over 5 years in the rural Andean region of Narifio, Colombia, have given support to the sequential nature of the precursor lesions described above. Independent evaluation of each parameter showed that the most advanced lesion was regularly accompanied by the less advanced one. Both progression and regression changes were observed in the cohort over the years of observation with the net result of a slow overall progression. This phenomenon is shown by a net progression rate of 3.3 per 100 person years, representing a net gain of 1.7 for atrophic gastritis, 0.9% for metaplasia, and 0.7% for dysplasia. Etiologic Factors
Investigators from different scientific disciplines working in different countries have identified risk factors for gastric cancer which have led to the postulation of the etiologic hypothesis outlined in Figure 8. As seen in the diagram, several etiologic agents have been recognized as acting in different points of the chain of causa-
231
Fig. 7. Moderate adenomatous dysplasia. Closely-packed metaplastic glands with large, elongated, and pseudostratified nuclei.
tion, The first step of the process, characterized by active inflammation, has been linked to 2 factors: excessive salty foods and infection with Helicobacter pylori. Excessive salt is probably the most consistent and better documented etiologic factor for gastric carcinoma: it has been reported independently in many countries in studies of ecologic correlations, analytical epidemiology, and experimental carcinogenesis [14-t7], Salting of foods appears to increase their capacity to produce mutagens after nitrosation [18]. Infection with Helicobacter pylori is excessively common and severe in populations at high gastric cancer risk. It is also prevalent in them since childhood. The infection is also observed in low-risk populations, but its prevalence is lower and its start observed at later ages [19, 20]. Although not a sufficient carcinogenic factor, Helicobacter infection may be an important contributory factor in populations exposed to other carcinogenic influences [21]. The second stage in the chain of causation is atrophy or gland loss, whose etiopathogenic mechanism is obscure. Although nutritional deficits have been proposed, no epidemiologic or experimental evidence for their causative role has been proposed. Experimentally, feeding excessively salty rice to mice has resulted in glandular atrophy [22]. The equivalent of atrophy or gland loss may be induced surgically in gastrectomy
232
World J. Surg. Vol. 15, No. 2, Mar./Apr. 1991
DI[ I
GASTRIC CAVITY
GASTRIC MUCOSA
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normal i superficial
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(vitamins)
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-
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Fig. 8. Diagram of etiologic hypothesis. The progressive histopathologic changes are shown; the etiologic agents are depicted at the point of their presumed action. Indications for possible prevention are suggested.
procedures. It is also observed in patients with autoantibodies against parietal cells, as a component of the pernicious anemia syndrome. Once atrophy is established, the secretion of hydrochloric acid is reduced, the gastric pH is elevated, and anaerobic bacteria proliferate in the gastric microenvironment. Many such bacteria contain reductases which act on nitrate molecules present in the normal diet. This results in abundant nitrite molecules which have the capacity to nitrosate nitrogen containing compounds from food, medications, or bile salts. N-nitroso compounds are frequently mutagens and carcinogens. A highly potent mutagen N-nitroso-chloro-indol has been identified after nitrosation of fava beans (Vicia faba), the staple food of high-risk peasants in Narifio, Colombia [23]. Nitrosation of Japanese fish has resulted in compounds which induce gastric carcinomas in experimental rats [24]. It has been postulated that N-nitroso carcinogens synthesized in small amounts in the gastric cavity over a prolonged time period induce the successive mutations which lead to the precancerous lesions and finally to invasive carcinoma in the gastric epithelium [10, 25]. The best experimental model of gastric carcinogenesis utilized MNNG, a potent N-nitroso compound. It has been shown that feeding salt to experimental animals simultaneously with MNNG markedly potentiates the effect of the carcinogen [17].
Two general mechanisms of inhibition or retardation of the gastric carcinogenic process are being actively investigated. The first one involves vitamin C, which has the double role of blocking the synthesis of N-nitroso carcinogens and of retarding the progression of transformed cell clones through fibroplasia. The first role is based on the destruction of the nitrite molecules [26]. It has been recently reported that only the reduced form of vitamin C (ascorbic acid) is capable of reacting with and inactivating the nitrite molecules. The oxidized form of vitamin C (dehydro ascorbic acid) has no such role [27]. This observation may explain why vitamin C has been found as a risk factor for stomach cancer in some populations but not in others. The other mechanism of inhibition of gastric carcinogenesis is mediated through beta carotene and related compounds. Blood levels of carotenoids have been found to be remarkably low in patients with dysplasia in the population of Narifio, Colombia [28]. Beta-carotene and its related pigment cantaxantine (which is not a precursor of vitamin A) inhibit, to a considerable extent, experimental gastric carcinoma (but not early precursors) in rats receiving MNNG [29]. The above reports suggest that beta-carotene acts in the late stages of carcinogenesis, which gives support to their proposed mechanism of action as scavengers of free radicals [30]. Beta-carotene also increases cellto-cell communications through the widening of intercellular gap junction channels. This results in inhibition of the expression of malignant phenotypes in transformed cells connected to nontransformed cells through such junction channels [31]. This phenomenon may be specially relevant in the gastric mucosa where neighboring transformed and nontransformed cells are frequently found. Genetic Influences
It has been suspected for a long time that genetic forces determine the susceptibility or the resistance to gastric cancer. In pernicious anemic families, a major dominant gene transmitted autosomally has been postulated [32]. The familial aggregation of gastric cancer unrelated to pernicious anemia has also been reported [33]. The susceptibility to chronic atrophic gastritis, the apparent key event in the early stages of gastric carcinogenesis, appears determined by a recessive autosomal gene whose expression is influenced by environmental factors. This is inferred from segregation analysis of precancerous lesions in the population of Narifio, Colombia, in which age and having an affected mother represent the suspected environmental influences [34]. Prevention
Primary prevention of gastric carcinoma should be based on the control of the etiologic agents. Avoiding salty foods should be a major concern in primary prevention. Some calcium salts, especially calcium lactate, may block the damaging effect of high sodium intake to a certain extent [35]. An adequate supply of fresh fruits and vegetables will provide sufficient amounts of reduced ascorbic acid and beta-carotene, strongly suspected to play a protective role. The same food items contain a variety of non-nutrients which inhibit carcinogenesis [36]. The control of Helicobacter infections, especially when associated with severe
P. Correa: Epidemiology of Gastric Cancer
gastritis, should be considered but its beneficial effects are only a matter of investigation at this point. Secondary prevention of gastric carcinoma has a role in subjects suspected to be at high risk because of advanced premalignant lesions such as dysplasia and, probably, colonic metaplaSia. Frequent endoscopies should be done in order to detect superficial carcinomas (early cancer in the Japanese nomenclature) which have an excellent prognosis after surgery [37]. The treatment of dysplasia itself (and of colonic metaplasia) is still a matter of controversy. The natural history of such lesions, especially the time required for transformation into invasive carcinoma, is poorly understood. Chemoprevention trials with antioxidants, anti-Helicobacter therapy, calcium salts, and dietary modifications are being proposed and, hopefully, might shed some light in this field. Markers of increased risk are provided by pepsinogen I and pepsinogen I/II ratios in the blood. Very low figures are good indicators of increased risk [38]. R6sum6
L'dtiologie du cancer gastrique, surtout de type "6pid6mique" ou "intestinal," est 6tudide. L'hypoth~se 6tiologique dominante, bas6e sur une succesion de stades d'agents 6tiologiques, est ddcrite. L'evidence en faveur de cette hypoth6se est mise jour, fond6e sur des 6tudes d'6pid6miologie descriptive et analytique, tout autant que sur les r6sultats r6cemment obtenus au laboratoire ou en exp6rimentation. Les mesures de prdvention principales et secondaires sont bri6vement discut6es. Resumen
Se revisa la etiologia del carcinoma gfistrico, especialmente de su tipo "epid6mico" o "intestinal." Se describe la hip6tesis etiol6gica prevalente, la cual se fundamenta en el enfoque sobre determinados agentes etiol6gicos en la cadena de factores causales. Se ha hecho una actualizaci6n del soporte a esta hip6tesis con base en estudios epidemiol6gicos descriptivos y en evidencia experimental reciente. Se discuten brevemente las medidas preventivas primarias y secundarias. References
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