The incidence rates for esophageal cancer vary internationally more than any other cancer, with more than 50-fold difference between high- and low-rate areas over the world. In most parts of the world, esophageal cancer is relatively uncommon, with the annual incidence rates below 5 cases per 100 000 persons-year. In the United States, esophageal cancer ranked at 15th in the number of cases in 2010 [4
] whereas in parts of north China it was the most common cancer with its incidence and mortality rates exceeding 100 cases per 100 000 persons-year [5
]. Esophageal cancer typically occurs in one of the two forms, squamous cell carcinoma, and adenocarcinoma. The natural histories of and risk factors for squamous cell carcinoma and adenocarinoma of the esophagus appear to differ substantially. Squamous cell carcinoma develops as the result of a sequence of histopathological changes that typically involves esophagitis, atrophy, dysplasia, carcinoma in situ and finally, invasive cancer [6
]. Alcohol consumption, tobacco use, and deficiencies in certain nutrients present in fresh fruits or vegetables have been identified as the main risk factors for esophageal squamous cell carcinoma, especially in high-risk populations [7
]. Most adenocarcinomas, however, arise from glandular cells that are present at the junction of the esophagus and stomach. The gastroesophageal reflux disease causes chronic inflammation, resulting in Barrett’s esophagus, a condition that occurs when the esophagus is damaged and its inner lining replaced by the glandular cells because of the continued exposure to stomach acid [9
]. Patients with Barrett’s esophagus have esophageal cancer incidence rate of 7 per 1000 per year [10
], which is more than 100-fold that for the rate in the general population in the United States [11
]. Since treatment successes have been limited and esophageal cancers still are usually fatal, regardless of cell type, modifiable factors, if identified having chemopreventive effect, can be applied for the prevention and control of this malignancy. Tea drinking has been studied for its potential for anticarcinogenesis in the esophagus in experimental animals as well as humans.
3.1 Inhibition of esophageal tumorigenesis in experimental animals
The cancer-inhibitory activities of green tea extract and green tea polyphenols have been studied in different models of oral-digestive tract carcinogenesis. Morse et al. [12
] compared the inhibitory effects of the polyphenol fractions of green tea, EGCG, and the polyphenol fraction of black tea, theaflavins. The tea fractions were administered in the drinking water at concentrations of 360 and 1200 ppm for 2 wk before administration of the esophageal carcinogen N
-nitrosomethylbenzylamine (NMBA). NMBA was administered subcutaneously in 10% dimethyl sulfoxide three times weekly for 5 wk. Twenty-five weeks after NMBA administration began, rats treated with NMBA only had an esophageal tumor incidence of 100% and a multiplicity of 3.3±0.4 tumors per rat. The proportion of rats developing tumors was not significantly reduced by any of the four tea fractions at the concentrations tested. However, the 1200 ppm concentrations of each tea fractions in the drinking water produced some reduction in esophageal tumor multiplicity. The rates of esophageal tumor formation were significantly reduced at 360 and 1200 ppm by EGCG and theaflavins [12
Wang et al. [13
] carried out a similar experiment to investigate the effects of green tea and black tea, when given either during or after carcinogen treatment, on esophageal tumorigenesis in male Sprague–Dawley rats. Rats were treated with NMBA (2.5 mg/kg, s.c., twice weekly) for 5 wk; 39 wk after the initial dose of NMBA, 65% of the rats had esophageal tumors with an average of 1.4±0.3 tumors per rat. In the groups of rats receiving 0.6% decaffeinated green tea or decaffeinated black tea (6 mg tea solids per mL) as the sole source of drinking fluid during the NMBA-treatment period, esophageal tumor incidence, and multiplicity were reduced by approximately 70%. When the tea preparations were given after the NMBA treatment period, the esophageal papilloma incidence and multiplicity were reduced by approximately 50%. In a second experiment, NMBA was given to rats at a dose of 3.5 mg/kg (s.c., twice weekly) for 5 wk; after 16 wk, the tumor incidence was 82% and tumor multiplicity was 6.7±1.2 tumors per rat. In the groups of rats receiving 0.9% regular green tea or decaffeinated green tea after the NMBA treatment period, tumor multiplicity was decreased by more than 55%. The volume per tumor was reduced by approximately 60% in the rats receiving 0.9% regular green tea. Histological analysis indicated that both the incidence and multiplicity of esophageal carcinoma was decreased by both regular and decaffeinated green tea by approximately 20% and 60–70%, respectively [13
]. The above results indicate that both green tea and black tea can inhibit the tumorigenic action of NMBA during the period of carcinogen treatment and the subsequent molecular events important for esophageal tumorigenesis.
The cancer-inhibitory activities of tea can be offset by the high temperature of fluid. Li et al. [14
] arried out an experimental study to determine the effect of hot water on NMBA-induced rat esophageal tumorigenesis in rats that was given hot water (65°C) alone, NMBA injections alone, a combination NMBA and hot water, and with or without added EGCG for each of the three treatment. At week 20, the incidence and the number of tumors per rat were significantly increased in rats given hot water as compared with rats received NMBA injections only. EGCG treatment did not significantly reduce the number or the size of tumors as the temperature of added hot water increased, but slightly decreased the elevated prostaglandin E2 induced by NMBA. These data confirmed that the drinking of hot beverages increased the risk of esophageal carcinogenesis, and may abolish the inhibitory effects of EGCG on esophageal tumorigenesis [14
3.2 Green tea consumption and risk of esophageal cancer in humans
Given the thermal irritation of hot fluid including tea beverage to the esophagus, tea drinking, if consumed at high temperature, could cause damage to the esophageal epithelia and result in increased risk of esophageal cancer. In early 1970 s, epidemiological studies already suggested a link between tea consumed at high temperature and increased risk of esophageal cancer in humans [15
]. In 1974, De Jong et al. reported that subjects who drank burning tea had statistically significant almost three times the risk of esophageal cancer that of non-drinkers [16
]. Results on tea drinking and esophageal cancer risk from epidemiological studies with vigor in study design became available since 1990 s. In a case–control study in Shanghai, China, Gao et al. found that the consumption of burning-hot fluid (including green tea) was associated with statistically significantly fourfold increased risk of esophageal cancer compared with green tea drinkers who did not consumed burning-hot fluid [17
]. In a similar study, Wu et al. examined the effect of green tea temperature on risk of esophageal cancer in Jiangsu Province, China, a high incidence area of esophageal cancer. Compared with non-drinkers, high tea temperature was associated with statistically significant two to threefold increased risk of esophageal cancer [18
]. In a prospective cohort of more than 220 000 Japanese men and women with 15 y of follow-up, individuals who usually drank green tea at high temperature had a statistically significant 60% higher mortality of esophageal cancer than those who consumed green tea at moderate temperature [19
]. In a systemic review, Islami et al. examined the consumption of high-temperature beverages (coffee, tea, and maté) in relation to risk of esophageal cancer [20
]. Majority of the studies included showed an increased risk of esophageal cancer with high temperature of beverages consumed regardless of the type of beverages. Of the 12 studies included in the systemic review, 8 reported a statistically significantly elevated risk and one reported non-significant increase in risk of esophageal cancer associated with very hot tea intake. Two studies reported a decreased risk with hot tea drinking, but both were not statistically significant. The remaining one reported a null association between high-temperature tea intake and risk of esophageal cancer. These findings have clearly demonstrated the thermal effect of tea beverage on esophageal carcinogenesis.
Despite the thermal carcinogenic effect of tea beverage, a number of epidemiologic studies have examined the potential protective effect of green tea consumption on risk of esophageal cancer. In most of those studies, the tea temperature was not assessed, thus was not adjusted for. lists 15 epidemiological studies that examined the association between green tea intake. Thirteen studies were carried out in Chinese populations (10 in mainland China, 2 in Taiwan, and 1 in Singapore) and two in Japanese (both in Japan). Among the 15 studies, six reported a statistically significantly reduced risk of esophageal cancer associated with high level of tea consumption [17
]. Four studies reported a lower risk with green tea consumption for drinkers than non-drinkers, but the risk reduction was not statistically significant [26
]. Three studies reported a statistically significantly positive association between tea consumption and esophageal cancer risk [18
]. The remaining two studies reported a relative risk that was close to one [16
]. The inconsistent results of those studies could be, at least partly, due to the potential confounding effect of tea temperature. For example, a recent report from a population-based, large case–control study of esophageal cancer in Jiangsu Province, China, demonstrated that the elevated risk of esophageal cancer associated with green tea consumption was reduced considerably and some of the ORs became statistically non-significant after tea temperature was adjusted for, especially among current tea drinkers [18
A summary of studies on the association between green tea consumption and risk of esophageal cancer
Cigarette smoking and alcohol drinking, the two established risk factors for esophageal cancer, might further complicate the association between green tea consumption and esophageal cancer risk because green tea consumers are more likely to smoke cigarettes and drink alcoholic beverages. For example, in a prospective study of more than 18 000 middle-aged or older Chinese men in Shanghai, China [33
], 77% of men who smoked cigarettes and drank alcoholic beverages consumed green tea on a daily basis. In contrast, only 44% of men who neither smoked cigarettes nor drank alcoholic beverages consumed the similar amount of green tea (unpublished data). Gao et al. carried out a large, population-based case–control study of esophageal cancer in Shanghai, China [17
]. The study included more than 900 patients with recently diagnosed esophageal cancer and more than 1500 healthy control subjects. A statistically significantly reduced risk of esophageal cancer associated with green tea consumption was observed for women (odds ratio (OR) = 0.50; 95% confidence interval (CI) = 0.30–0.83), and the inverse green tea-risk association was dose dependent. However, the same study did not demonstrate a statistically significant inverse association between green tea intake and esophageal cancer risk for men (OR =0.80; 95% CI =0.58–1.09). This gender difference in green tea–esophageal cancer association could be due to the residual confounding effect of smoking and alcohol drinking because Chinese men consumed greater amounts of tobacco and alcohol than their female counterparts. When data were analyzed separately for those who neither smoked cigarettes nor drank alcoholic beverages, a statistically significant decreased risk of esophageal cancer for green tea consumption was observed in both men (OR =0.43; 95% CI =0.22–0.86) and women (OR =0.40; 95% CI = 0.20–0.77). Similarly, the study by Wu et al. demonstrated a statistically significantly inverse association between green tea consumption and the risk of esophageal cancer among never smokers (OR =0.7, 95% CI =0.5–0.9) or non-drinkers of alcoholic beverages (OR =0.8, 95% CI =0.6–1.1), but not in smokers or alcohol drinkers [18
]. These findings suggested that the residual confounding of cigarette smoking and alcohol intake might exist and mask the potential protective effect of green tea consumption against the risk of developing esophageal cancer even after they were adjusted for in the statistical regression models. It also is possible that the moderate protective effect of green tea consumption on esophageal cancer could be cancelled out by the strong adverse effects of cigarette smoking and alcohol consumption on the esophagus.
Data on green tea consumption and risk of specific histological types of esophageal cancer are scarce. Three epidemiological studies have examined the effect of green tea consumption on the risk of esophageal squamous carcinoma, the dominant histological type of esophageal cancer in high-risk area. A population-based case–control study involved 107 patients with esophageal squamous cell carcinoma and an equal number of sex- and age-matched control subjects in Jiangsu Province, China, reported that regular green intake was associated with a statistically significantly reduced risk of esophageal carcinoma (multivariate-adjusted OR =0.13, 95% CI =0.03–0.62, p
=0.01) compared with no consumption of green tea [24
]. A similar study involved 355 patients with esophageal squamous cell cancer and 408 healthy control subjects living in a different county of Jiangsu Province from those of the previous study found a similar protection (OR =0.26, 95% CI =0.07–0.94) for women, but not for men [29
]. As a matter of fact, the slightly increased risk of esophageal squamous cell carcinoma among men who consumed green tea regularly was due to the confounding effect of cigarette smoking and alcohol intake that were not adjusted for. A more recent study in Taiwan confirmed these findings; OR of esophageal squamous cell carcinoma for the consumption of ≥7 cups per week was 0.4 (95% CI =0.2–0.6) compared with <1 cup per week after adjustment for smoking and alcohol intake [25
]. There have been no studies that examined the association between green tea consumption and risk of esophageal adenocarcinoma. Data from studies that examine the association between green tea consumption and the risks of both esophageal squamous cell carcinoma and adenocarcinoma, respectively, are needed to show whether green tea consumption has differential effect on different histological type of esophageal cancer.
Epidemiologic studies of specific tea catechins in relation to the risk of esophageal cancer in humans are sparse. Sun et al. carried out a nested case–control study within the Shanghai Cohort Study, a prospective cohort of more than 18 000 men aged 45–64 y in 1986–1989 when subjects were recruited and information on dietary and lifestyle factors and blood and urine samples were collected. Using validated urinary biomarkers for tea polyphenol uptake and metabolism, the investigators demonstrated a decreased risk for both esophageal and gastric cancers for the presence of EGC in urine. The inverse association was stronger in non-smokers or non-drinkers of alcohol or among those with lower serum level of carotenes (OR =0.46, 95% CI = 0.26–0.84) [34
]. More population-based studies are warranted to confirm those findings.
There has been one report on an intervention study that examined the effect of decaffeinated green tea (DGT) on the inhibition of progression of esophageal precancerous lesions in a high-risk population in northern China [35
]. Two hundred patients with different severities of esophageal precancerous lesions were randomly assigned with equal likelihood to the treatment (given 5 mg DGT per day for 12 months) or placebo arm (given a placebo pill). At the beginning and the end of the treatment, esophageal biopsy specimens were taken at the middle and the lower thirds of the esophagus of each subject. Sixteen (25%) of the 63 patients in the DGT group who completed the study with evaluable biopsy specimens showed improvement of disease lesions in the middle-third esophagus while only did 9 (13%) of 71 patients in the placebo group. However, the difference was not statistically significant (p
=0.12). The distributions of lesions by severity in the low-third esophagus were comparable in the DGT and placebo group at the end of the study. The conclusion of this intervention study was that treatment with DGT had no effect on the alleviation of esophageal precancerous lesions and abnormal cell proliferation [35