Cancer of the oral cavity is widespread in humans with about 275,000 (176,000 men and 99,000 women) new cases per year (1). About 127,000 subjects die as a result of this cancer each year. The age-standardized incidence is about 6.3 per 100,000 in men and 3.2 per 100,000 in women. Compared to other sites, the ratio of mortality and incidence of 0.46 is high. Such a high ratio points to the fact that we are currently not in a good position to cure this malignancy and that there is potential for new successful therapeutic and preventive strategies (2).

There are several areas with high incidence of cancer of the oral cavity. According to recent estimates from national cancer registries (1), in men, the highest age-adjusted rates are found in Papua New Guinea (40.9 per 100,000), Solomon Islands (34.1 per 100,000), Sri Lanka (24.5 per 100,000), and Botswana (23.1 per 100,000). Other regions with high incidence of about 12 per 100,000 are Southcentral Asia and Western Europe. More specific data from regional registries from the high incidence countries indicate that regional hot spots exist.

Overall, the time trend of cancer of the oral cavity was stable since the 1970s. In the United States, a decline in older whites was observed, whereas in African Americans and younger whites, an increase was seen (3). In some countries, the incidence of oral cancer is increasing (4). Most (95%) of the cancers are squamous cell carcinomas. Cancers appearing in the parotis and other salivary glands (C07, C08) of the mouth are mostly adenocarcinomas and should be considered as a separate entity in etiologic studies.

The low ratio of female-to-male incidence seems to be directly related to the gender-specific distribution of the major risk factors. Tobacco smoking and alcohol drinking are being consistently linked to this cancer site in observational epidemiologic studies that are almost uniformly of the case-control design. Both habits are positively interrelated, but more evidence is needed to conclude that they follow the multiplicative model (5). In other areas of the world, particularly Southeast Asia, chewing of tobacco and betel nuts is positively related to the occurrence of this malignancy (6). Furthermore, tobacco and betel chewing are often the main causative agents for this malignancy in countries with low alcohol consumption (7). However, low intake of fruits and vegetables has been related to increased risk, albeit mostly in case-control studies (8). Thus, the recent expert evaluation on fruit and vegetables by the International Agency of Research on Cancer (IARC) called for prospective studies to clarify the relation between diet and risk of this carcinoma due to the methodologic problems with the retrospective case-control design. Precancerous lesions such as oral leukoplakia are linked with the risk factors for oral cancer. It has been shown that smoking cessation decreases the prevalence of precancerous lesions (9). However, intervention with vitamin A and beta-carotene does not seem to be a successful treatment (10). Cancer of the lip seems to be caused in part by heavy sunlight exposure (11). This may be one of the factors that drive the occurrence of this cancer in countries such as Australia.

Cancer of the pharynx lining of the upper GI tract includes the oropharynx (C10) and the hypopharynx (C13). In the recent tabulation of incident cancer cases worldwide (1), about 130,000 new cases of incident pharynx cancer are reported, excluding the nasopharynx. The latter, with about 80,000 new cases per year, should be separated from the GI site of the pharynx due to another anatomic localization and different etiology, and thus is not considered further in this chapter. The ratio of mortality to incidence of cancer of the pharynx is 0.64. The age-standardized incidence of pharyngeal cancer worldwide was calculated to be 3.8 per 100,000 in men and 0.8 per 100,000 in women, with men having a distinct higher frequency in the more developed regions.

High incidence on the countrywide scale was seen in 2002 in men in Hungary (16.9 per 100,000), France (15.4 per 100,000), Luxembourg (13.1 per 100,000), and Slovakia (11.1
per 100,000), as well as in Bangladesh (12.5 per 100,000) and India (9.6 per 100,000) (1).

Reports on time trends give a mixed picture. Since the 1980s in the United States, a decrease in pharyngeal cancer has been observed (12,13), whereas in other areas of the world, such as Japan, pharyngeal cancer is increasing (14,15). The high incidence of this cancer in Europe is the result of past increases in incidence (16). Pharyngeal cancer seems to be high in India for a longer time period (17).

There is the common view that the incidence and mortality of pharyngeal cancer is going along with the degree and trend in alcohol and tobacco use in a population (12,13,14,18,19). Tobacco use includes chewing and smoking. However, the distribution and time trends of the two major risk factors also leave room for further hypotheses on how incidence of pharyngeal cancer can be influenced by dietary or occupational exposures.

Layers of epithelial cells originally line the esophagus. Thus, most of the cancers appearing in this organ are diagnosed as squamous cell carcinomas. However, over time the morphologic appearance of the cells can change and metaplastic tissues can appear, particularly in the lower part of the esophagus. The cancers appearing from these tissues are often adenomas that might have a different etiology and are therefore described separately.

The available worldwide statistics cover the whole organ, recording about 462,000 new cases of incidence esophageal cancers in 2002 (315,394 men and 146,723 women) (1). In the same year, about 386,000 deaths due to esophageal cancer were estimated. This results in a ratio of mortality to incidence of 0.84. Thus, esophageal cancer is by far the most deadly cancer in the upper GI tract. Cancer rates of more then 20 age-standardized incident cases per 100,000 on a country level can be found in Ethiopia, Kenya, South African Republic, China, Mongolia, Kazakhstan, Turkmenistan, and Fuji (1).

The time trends seem to differ in various parts of the world. In developed countries such as the United States, squamous cell carcinomas decrease while adenocarcinomas increase (20). Detailed data from the United States show that African Americans have twice the rates of esophageal cancer as whites and that squamous cell carcinoma was more prevalent in African Americans and women than in white men (21). In Africa, esophageal cancer rates appear to be remaining stable since the 1990s or are even increasing (22,23), and an often sharp decrease in incidence is reported from Southcentral and Southeast Asian countries since the 1970s and 1990s, respectively (24,25).

Tobacco and alcohol use are the major risk factors of this disease, followed by diet (26). In some areas, betel nut chewing contributes substantially to risk (27).

Adenocarcinoma of the esophagus is a malignant epithelial tumor with glandular differentiation, arising predominantly from Barrett’s intestinal metaplasia of the mucosa in the lower third of the esophagus or the esophagus gastric junction. Because adenocarcinoma originating from the distal esophagus may infiltrate the gastric cardia and adenocarcinoma of the gastric cardia may grow into the distal esophagus, distinction between these entities, particularly in tumors involving the esophagus gastric junction is relatively difficult in clinical practice (28). During the healing process of chronic inflammatory injury typically associated with gastroesophageal reflux disease, in the Barrett’s intestinal metaplasia, the normal esophagus epithelium is replaced by columnar epithelium.

Since the 1980s, incidence rates of adenocarcinoma of esophagus (ACE) have been increasing in both genders in developed countries. ACE is the fastest rising malignancy among white men in the United States, with a relative increase even higher than that observed for breast cancer, malignant melanoma, or prostate cancer. From 1975 to 2001, the incidence of ACE increased sixfold in the United States, from 4 to 23 cases per million (29). As a consequence of this increase and a parallel decrease of squamous cell carcinoma, ACE in whites is the most frequent type of esophageal cancer since 1990 in the United States (30). From 1996 to 2000, adenocarcinoma in white males represented 65.7% of total cases of esophageal cancer, whereas the rate was only 18% for Asian and Pacific Islanders and 9.4% for blacks (31). Similar increasing trends have been observed in Canada and several European countries (32). Although part of the large increase could be associated with improved case ascertainment due to a wider practice of endoscopy and/or reclassification of related cancers, it has been shown that the lower third of the esophagus is the only location with increased incidence and that a similar trend has been observed for mortality of esophageal adenocarcinoma that rose sevenfold from 2 to 15 deaths per million for the same period (29).

The incidence rate of ACE varies markedly among ethnicities and gender. In the United States, the incidence of ACE in white men was double of that in Hispanic men and over four times higher than in blacks, Asians, and Native Americans (33). Rates of women in all ethnicities are significantly lower than for men, although similar ethnic patterns persist by gender. The incidence rate of esophageal cancer in whites in the United States is seven times higher in men than in women (33). However, the increasing trends of ACE vary by age, being more pronounced among older rather than younger men (34). Although incidence of ACE is higher among whites than blacks, an inverse relation with socioeconomic status has been observed, even after adjusting for all recognized risk factors (35).

Reflux of acidic gastric juice is the most important etiologic factor for Barrett’s esophagus and ACE (36), although reflux of bile and pancreatic juice may play also a role (37). Normally, gastroesophageal junctional anatomic structures, swallowing-induced peristalsis, and the esophageal sphincter serve as protective barriers against the retrograde escape of gastric acid. Another recognized risk factor of ACE is obesity. The rapidly increasing incidence rate of ACE in the United States coincides with the increasing incidence of obesity and gastroesophageal reflux disease in this population (30). Smoking and low consumption of fruit and vegetables seem to be modest risk factors, while alcohol consumption does not seem to be associated with risk or may be a weak risk factor (38). There is some evidence that Helicobacter pylori infection may protect against ACE (39).

Despite a steady decline in the incidence of gastric cancer (GC) in the United States (30) and most other countries since the mid-1950s, GC remained in the year 2000 the fourth most frequent cancer and the second most common cause of cancer death in the world (40). It has been estimated that there are approximately 876,000 new cases (8.7% of the total) and 647,000 deaths (10.4% of cancer deaths) of GC each year. Almost two-thirds of them occur in developing countries (40). The highest incidence rates are observed in Japan, East Asia, the Andean regions of South America, and Eastern Europe, whereas the lowest rates are observed in North and East Africa, Northern Europe, and North America (40). In cancer deaths in the United States, GC ranks 10th among women and 11th among men (30), and approximately 90% are adenocarcinomas (31). It is now recognized that risk factors, time trends, and geographic distribution differ according to the anatomic localization of the tumor (proximal stomach or gastric cardia adenocarcinoma and distal stomach or noncardia adenocarcinoma)
and the main histologic types of the Lauren classification (intestinal and diffuse).

Although the incidence of noncardia gastric cancer declined in most countries of the world during the past decades (40), the incidence of cardia cancer remained stable (41) or rose in several European countries (42), Japan (43), and the United States (30). Similar increasing trends have been observed for adenocarcinomas at the gastroesophageal junction (34). The increase in cardia cancer is less marked than that in esophageal adenocarcinoma and may even be stabilized in the United States after 1988. It is not clear whether there was a change in risk between generations (cohort effect) or whether the change affected all age groups simultaneously (period effect) (32).

The incidence rate of cardia and noncardia stomach cancer varied markedly according to race and gender group. In the United States between 1996 and 2000, cardia adenocarcinoma accounted for 37% of all GC in white men, while it represented only 11% of GC in black men and Asian/Pacific Islanders, with substantially lower percentages of cardia adenocarcinoma among women than men for all racial groups (31). The incidence rate of cardia GC in whites in the United States was five times higher in men than in women, while the incidence of noncardia GC was 1.8-fold (30). The increasing trends of cardia adenocarcinoma also vary by age, with a much greater upward trend among older rather than younger men (35). Low socioeconomic status, which is a surrogate of lifestyle and environmental factors, has been related to excess risk of both cardia and noncardia gastric cancer (30).

Intestinal adenocarcinoma is the most frequent histologic type, particularly in high-incidence areas, and is considered responsible for most of the large international variation of GC (44). However, since the 1950s, the decline of gastric cancer has primarily been of the intestinal type, and consequently, the diffuse type has become relatively more common. A decrease in incidence of the intestinal types has been observed in the United States and Japan, while the diffuse type has increased in the United States (45) or has shown a stable trend in Japan (46). As a consequence of these changes, in some countries such as Finland, in patients younger than 60 years, the diffuse type has become more common than the intestinal type (47).

Different trends in cardia and noncardia gastric cancer suggest, at least in part, different etiologic factors. In fact, H. pylori infection is a recognized causal factor of noncardia but not of cardia gastric cancer (48). Obesity and gastroesophageal reflux disease are associated with cardia cancer (49). Tobacco smoking is associated with both cardia and noncardia cancer (50), and dietary factors are believed to play an important role, but differences according to anatomic subtypes are not yet well established.

Primary liver cancer includes hepatocellular carcinoma (HCC) as well as angiosarcoma, cholangiocarcinoma, and hepatoblastoma. HCC accounts for 90% of all cases (44). It is the fifth most common cancer throughout the world (44,51). In 2000, approximately 560,000 cases occurred, accounting for 5.6% of all cases of cancer. The incidence is highest in developing countries, where 80% of all patients are found (with 54% in China) (44,51). Liver cancer incidence is about three times higher among men than women (51,52). HCC is rarely detected in an early stage and is usually fatal within a few months (53). The disease has a 5-year survival rate of less than 5% (52).

The major risk factors for liver cancer are hepatitis B virus (HBV) and hepatitis C virus (HCV) (53,54,55,56). Excessive alcohol consumption, resulting in alcoholic cirrhosis, is also an important risk factor for liver cancer (53,54,55,56), as well as contamination of food with aflatoxins, a group of metabolites produced by the phylogenetically related Aspergillus flavus and Aspergillus parasiticus (54,56,57,58). In 1997, a World Cancer Research Fund International (WCRF International) expert panel concluded that contamination of food with aflatoxin probably increases risk (59) and that the evidence that regular high consumption of alcohol increases the risk of liver cancer, mediated by liver cirrhosis, was convincing. The panel noted that diets high in vegetables possibly decrease the risk of liver cancer. Evidence that selenium decreases and iron increases the risk of liver cancer was considered insufficient (59).

Apart from HBV and HCV, smoking is an established cause of liver cancer. The most effective means of preventing liver cancer is to avoid exposure to these viruses and not to use tobacco. The most effective dietary means of preventing liver cancer are limited consumption of alcohol and avoidance of food liable to be contaminated with aflatoxin (59).

The gallbladder is a small pear-shaped organ on the distal side of the liver at the right side of the abdomen. The gallbladder is connected to the liver by the hepatic duct. It is approximately 8 to 10 cm long and 3 cm wide. The function of the gallbladder is to store and concentrate bile that is produced in the liver before it is secreted into the intestines. In the intestines, the bile acids are required for the digestion of fatty foods. Bile consists of three major components: cholesterol, bile salts, and bilirubin. When the gallbladder does not function properly, the composition of bile is unbalanced, which leads to the formation of gallstones. The majority of stones are composed of cholesterol, whereas the others consist of bilirubin.

Gallbladder cancer is a rare, highly malignant tumor with a poor 5-year survival rate (60). It is difficult to diagnose this malignancy at an early stage due to its nonspecific symptoms (60). Gallbladder cancer has the highest incidence in adult women and elderly men and women (60).

There is a prominent geographic variability of gallbladder cancer incidence. The populations with the highest incidences are Chileans, Bolivians, Native Americans, Mexican Americans, and Central Europeans. Gallbladder cancer occurs rarely in the rest of the world (60).

There is not much evidence in support of the hypothesis that food and nutrition affects the risk of gallbladder cancer (60,61,62). Because obesity is a risk factor for gallstones, which are associated with an increased risk of gallbladder cancer, a higher body mass may play a role—either direct or indirect—in gallbladder cancer (59).

Pancreatic cancer is estimated to be the 12th most frequent incident cancer and cause of cancer death in the world (63). In Western European, it ranks 12th for cancer incidence and 7th for cancer mortality (63). In the United States, it ranks 11th for cancer incidence, but it is the 4th most common cause of cancer mortality for men and women (64). More than 9 out of 10 pancreatic cancers are ductal adenocarcinomas, with islet cell tumors constituting about 5% (65). There are no effective screening methods for pancreatic cancer; therefore, it is most often diagnosed at advanced stages, resulting in a 5-year relative survival rate of only 4.3%. The incidence of pancreatic cancer is generally higher in men compared with women (66). Internationally, rates of pancreatic cancer vary by 10- to 15-fold (66), with the highest rates in Northern and Eastern Europe and the lowest rates in Hong Kong (67). Rates have been increasing in Spain, Italy, and Japan, likely reflecting cigarette smoking patterns (67,68). Within the Untied States,
this is a site often noted for its relevance to cancer disparities, with both black men and black women experiencing incidence rates 30 to 40% higher than their white counterparts (69). This disparity may be due to differences in the prevalence of risk factors (70).

Of the few risk factors that have been identified, cigarette smoking is the most consistent (65). Chronic pancreatitis also predisposes to the disease (71,72). Type 2 diabetes mellitus and glucose intolerance have been consistently associated with pancreatic cancer (73,74). However, whether diabetes is etiologically involved in pancreatic carcinogenesis or the result of subclinical malignancy has been controversial. A modest positive association with obesity has been reported in the majority of studies (75). One recent prospective study that showed a twofold increased risk with fasting insulin concentrations measured up to 16.7 years prior to cancer diagnosis (76) may support the hypothesis that insulin and insulin resistance may be a potential mechanism that explains the diabetes and obesity associations. However, the effect of physical activity and dietary factors is unclear. Inverse associations have been reported for fruit and vegetable intake (66). Genetic susceptibility plays a role, with some cases being familial or related to hereditary familial atypical melanoma, Peutz-Jeghers syndrome, hereditary breast or ovarian cancer (BRCA1 and BRCA2), familial pancreatitis, cystic fibrosis, and hereditary nonpolyposis colon cancer (HNPCC) (77).

Although the small bowel comprises about 75% of the length of the GI tract and is exposed to a wide variety of potentially noxious endogenous and exogenous substances, malignant tumors of the small bowel are unusual and account for only 1% to 5% of all GI tract malignancies (78). Data from cancer registries participating in the Surveillance, Epidemiology, and End Results (SEER) program in the United States from 1973 to 1990 (79) showed that the average annual incidence rate was 9.9 per million people. Carcinoid tumors and adenocarcinomas were the most common histologic subtypes, with average annual incidence rates of 3.8 and 3.7 per million people, respectively, followed by lymphomas (1.1 per million people) and sarcomas (1.3 per million people). For all histologic subtypes, men had higher rates than women. Most tumors occurred in older adults; more than 90% of cases occurred in people older than 40 years (79). The incidence of small bowel tumors has risen slowly over time. Small intestinal adenocarcinoma resemble large bowel adenocarcinoma in that they both arise from adenomatous polyps, co-occur in the same individuals, and have a similar pattern of incidence rates by country.

An association of Crohn’s disease and cholecystectomy with small intestine adenocarcinoma is hypothesized, but the analytic epidemiology of small intestine malignancies has not received much attention because of small numbers. One case-control study conducted among 36 cases with small intestinal cancer (19 adenocarcinoma and 17 malignant carcinoid tumors) and 52 controls with nonmalignant conditions showed a four- to fivefold increased risk with cigarette smoking and alcohol consumption (80).

Colorectal cancer is one of the most common types of cancer in the world. Colon and rectal cancers accounted for about 1 million new cancer cases in 2002 (9.4% of the world total) (1). The age-standardized incidence rates for colorectal cancer ranges from around 60 in the Czech Republic and Hungary to less than 5 per 100,000 in Middle Africa and Southcentral Asia (1,40). In general, the incidence of colorectal cancer is increasing rapidly in countries where overall risk was formerly low (especially in Japan), whereas in high-risk countries, trends are either gradually increasing, stabilizing (Northern and Western Europe), or declining with time (81). Unlike most cancer sites, colorectal cancer incidence is not so different in men and women (ratio, 1.2:1). Colorectal cancer incidence ranks fourth in frequency in men and third in women (1). Survival estimates (in men) at 5 years are 65% in North America, 54% in Western Europe, 34% in Eastern Europe, and 30% in India (81). Given the overall relatively good prognosis, prevalence is second only to that of breast cancer worldwide, with an estimated 2.8 million persons living with colorectal cancer diagnosed in the past 5 years (81).

There is at least a 25-fold variation in occurrence of colorectal cancer worldwide. The highest incidence rates are in North America, Australia/New Zealand, Western and Eastern Europe, and affluent Asian countries (e.g., Japan). Incidence tends to be low in Africa and nonaffluent Asian countries and intermediate in southern parts of South America (40). The geographic distribution of colon and rectal cancer is similar, although the variation between countries is more striking for colon cancer. In high-risk populations, the ratio of colon to rectal cancer incidence is 2:1 or more. In low-risk countries, colon and rectal cancer rates are similar. Genetic differences, different environmental exposures, or both may explain the large geographic differences for colorectal cancer. Migrants’ studies that evaluate tumor risk in populations moved from low- to high-risk areas show that the incidence of colorectal cancer increases rapidly within the first generation, implying that environmental factors constitute a major component of risk. Japanese individuals born in the United States now have higher rates than those of whites in the United States, and the rates in Japanese individuals living in Hawaii and Los Angeles are among the highest in the world (82). These rates may be attributable to interplay between Westernized dietary habits and genetic susceptibility to these dietary factors (83).

Although there is clear evidence of genetic predisposition to colorectal cancer, genetic syndromes such as familial adenomatous polyposis (FAP) and HNPCC may explain less than 10% to 15% of all colorectal cancer. It is estimated that dietary habits may account for 50% to 60% of all colorectal cancer cases (59). Epidemiologic studies find consistent evidence that physical inactivity and a body mass index (BMI) of more than 25 kg/m² may increase colon cancer risk. A relatively high intake of alcohol and high consumption of red and processed meat and low consumption of fruits and vegetables probably increases risk of colon and rectal cancer. High consumption of dairy products and a high intake of calcium and vitamin D may reduce risk (59,84,85). Regular use of aspirin and other nonsteroidal anti-inflammatory drugs as well as hormone replacement therapy tend to decrease risk, whereas longtime cigarette smoking increases risk of colorectal cancer (85).