| Esophageal squamous cell carcinoma (ESCC) is one of the most common carcinomas in the world. There are about 250 000 newly diagnosed patients with ESCC every year, ranking the 4th in carcinomas in China. Most areas have a low prevalence in China, but the south area of the Taihang Mountain, which is the boundary of He'nan, Shanxi, and Hebei has a high prevalence of 100/100 000. Linzhou City (originally named as Lin County) and Ci County have the highest prevalence and mortality of ESCC in China, as well as in the world. Furthermore, several other areas in China, such as Anxi County in Fujian Province, Nan'ao County in Guangdong Povince, Huai'an City in Jiangsu Province, Yanting County in Sichuan Province and Feicheng City in Shandong Province have high prevalence of ESCC too.The clinical characteristics of precancerous esophageal leasions are bidirectional and inconstant. In other words, the lesions may either develop into a carcinoma or stay in a certain stage for quite many years, even turn to normal status.Some investigations ever since 1970s have revealed the fact that the prevalence of other esophageal diseases is also higher in areas with high prevalence of ESCC than in other areas.An esophageal balloon-cytology screening was carried out in Lin County. Among the 12649 participants 38% showed hyperplasia, 21% showed atypical hyperplasia 1, 6% showed atypical hyperplasia 2, 2% showed near-carcinoma and 2% showed carcinoma. ESCC and other esophageal diseases have common risk factors. For instance, the prevalence rate of ESCC is higher in males than in females, and the prevalence rate of chronic esophageal inflammation is higher in males too; the prevalence rate is high in those who have an ESCC family history. The age of patients with gentle atypical hyperplasia, severe atypical hyperplasia and carcinoma gradually increased, indicating esophageal atypical hyperplasia is a transitional stage of ESCC.Many comparative studies between different areas or periods showed that the prevalence of ESCC is accordant with the prevalence of non-malignant esophageal diseases. The prevalence of esophageal inflammation, base cell hyperplasia and atypical hyperplasia is higher in areas with a high carcinoma rate than in areas with a low carcinoma rate. Two studies carried out in Linzhou City in 1980 and 2004 respectively found that there was no significant difference in ESCC prevalence, and that there was no significant difference in atypical hyperplasia prevalence too.Prospective studies in areas with high ESCC rate demonstrated the significant correlation between esophagitis, base hyperplasia and ESCC. A follow-up study of 30-78 months in the high incidence area of He'nan Province showed that 4.03% of the patients with esophagitis or simple hyperplasia and 33.87% of the patients with atypical hyperplasia developed ESCC. Another 15-year-follow- up revealed that the incidence rate of normal esophageal mucosa, gentle atypical hyperplasia, moderate atypical hyperplasia and severe atypical hyperplasia to ESCC are as follows, 2.4%, 5.0%, 8.3% and 10.3%, respectively.Through the observation on surgery specimens the developing process of ESCC can be found from simple hyperplasia to atypical hyperplasia and carcinoma in situ, and the features of surrounding tissues are related to the differentiation of ESCC. Many experimental studies on animals such as rats or dogs also demonstrated this process. One intervention study in Lin County showed that patients with severe hyperplasia subjected to drug interruption had a lower prevalence of ESCC than the control group, suggesting that intervention therapy on non-malignant esophageal lesions is effective to prevent ESCC. Obviously, it is important to study the development and risk factors of non-malignant lesions to decrease the prevalence and mortality of ESCC.ESCC is related with age and sex and geographical environment, with a higher incidence in countryside than cities and a higher incidence in mountain area than in champaign. Its influencing factors include life habits (such as smoking and drinking), carcinoma family history, and diet etc. It is difficult to calculate the disease probability to an individual only using traditional epidemiology. For example, among the people who smoke, drink and have a family history of ESCC, only a few develop ESCC. This phenomenon is caused by different hereditary susceptibilities, so it is necessary to study the influencing factors on the level of molecular biology.Studies on surgery specimens showed that angiopoietin-2 (Ang2) is highly expressed in many carcinoma tissues. It has been reported that Ang2 is higher in ESCC tissues than in surrounding and normal tissues, but no information about the Ang2 level is reported in the serum of different esophagus diseases.Studies on influencing factors of ESCC mostly adopt case-control designs, in which the experiment group consisted of pathologically diagnosed patients and the control group consisted of healthy people or non-carcinoma inpatients. Selection bias was inevitable in these studies because the esophagus mucosa of the controls were not examined. The influencing factors of non-malignant esophageal lesions were seldom studied, and no multi-stage case-control study in a high incidence community was reported on precarcinomaous diseases and ESCC.From 1970s to 1990s, malignant neoplasms investigations in Shandong Province were carried out for three times. The results showed that the prevalence rate of ESCC was high in Feicheng City and Ningyang County, relatively high in their surrounding areas and low in the east. A study in 1990-1992 showed that ESCC in Shandong Province accounted for 15.44% and ranked the 4th in all carcinomas, with a mortality of 18.22/100000. The retrospective analysis showed that the mortality of ESCC in Feicheng City in 1970-1974, 1985-1989, 1990-1992, and 1997-1999 was 63.19, 71.68, 66.87 and 82.33/100,000 respectively, and the standard mortality (standardized by the population data of 1964 in China) was 45.37, 46.67, 51.21, 46.32/100000 respectively. The ratio of male to female was 2: 1. The mortality of ESCC was 71.07/100000 and the standard mortality was 34.64/100,000 in the period of 2000-2004, showing a declining incidence in recent years.The death surveillance and comparative study with low prevalence areas have been carried out but no intervention has been given in Feicheng City. In 1999 the report system on carcinoma occurrences and deaths was established, and in 2003 it was authorized as one of the ten sustainable development model areas for the early screening and prevention of ESCC.ObjectiveThe purpose of the present study was to provide theoretical bases and suggestions to decline the ESCC incidence in people with high risk. The epidemiological characteristics and influencing factors of ESCC and other esophageal lesions were analyzed; the associations of aldehyde dehydrogenase-2 (ALDH2) and vitamin D receptor (VDR) genes with ESCC and other esophageal diseases were studied by a gene-environment design; and the level of angiopoietin-2 were detected in normal controls and patients with different esophageal lesions to calculate its possibility as a biomolecular marker.Methods1 Definition of different stages of ESCCIn the present study the esophageal carcinoma was referred as ESCC and its development process were divide into the following stages: normal mucosa, esophagitis, basal cell hyperplasia, displasia (mild, moderate, and severe), early carcinoma (including carcinoma in situ), and advanced carcinoma.2 Risk factors for different stages of ESCCFrom Oct. 2004 to Oct. 2005, the residents of 40-69 years old in a town of Feicheng City participated in a free screening program. Investigation contents were as follows: (1) Questionnaire investigation included general information, such as sex, age, .culture, marriage condition, profession, family average income; family history of gastric, esophageal and other carcinomas; life habits, such as smoking and drinking habits; and diet, such as staple food, non-staple food, vegetables, fruit and their nutrient elements. (2) 5 ml venous blood was collected at 9-10 am after a 12-h fast from each participant. The sample was centrifuged for 10 min at 3000 r/min to separate plasma and obtain blood cells. (3) I-staining esophageal endoscope examination was made by seasoned endoscope doctors. Subjects with normal esophageal mucosa consisted of control group and those whose esophageal tract was not I-stained were pathologically examined. The pathological results were classified into seven categories: esophagitis, basal cell hyperplasia, mild atypical hyperplasia, moderate atypical hyperplasia, severe atypical hyperplasia, carcinoma in situ, and early carcinoma. Cases of carcinoma (including some ESCC patients accepting surgery in Peoples' Hospital of Feicheng City), hyperplasia and esophagitis were selected as index groups respectively, and subjects with normal esophageal mucosa were selected as control group. The epidemiological features of esophageal diseases and the frequency distribution of possible influencing factors were analyzed and described. 3 Effect of ALDH2 and VDR genes on different stages of ESCCBased on the results of esophageal endoscope and pathological examination, subjects were classified into 5 groups: ESCC, atypical hyperplasia, basal cell hyperplasia, esophagitis and normal. DNA of some samples was genotyped for ALDH2 and VDR polymorphisms. Reasons for choosing these two genes were that they are respectively associated with the alcohol metabolism and nutrition deficiency, which were found as two possible risk factors of ESCC in our former studies. In addition, given that smoking and drinking may be associated with esophageal diseases, the effect of the two genes combined with smoking and drinking was also analyzed.4 Association of serum Ang-2 level with the process of ESCCSerum Ang-2 of 261 normal subjects, patients with esophagitis, hyperplasia, early carcinoma and advanced carcinoma was tested to analyzed.5 Statistical analysisQualitative data were compared by relative ratio and chi-square test was used to evaluate differences in the frequency distributions of various potential risk factors among different stages of ESCC. Polynomial Logistic regression was used to analyze risk factors. The observation indexes were odds ratios (ORs) and 95% confidence intervals (95%C/s). The serum angiopoietin-2 level was described as (x|-)±s. ANOVA was used to compare the differences among different groups. The association of serum Ang-2 with the process of ESCC were calculated with rank correlation .All data were input and analyzed by SPSS 12.0.Results1 A total of 3253 subjects participated in the enscope screening. Data from 5 cases were incomplete and were excluded. The examination result was as follows: early carcinoma, 20; hyperplasia, 266; esophagitis, 144; and normal mucosa, 2818. In addition, we selected 51 inpatients with ESCC, so the carcinoma group included 71 patients. There were significant differences among different groups in terms of sex, age, culture and family average income. However, there were no differences in terms of marriage or occupation.2 After adjustment of sex, age, culture, and family average income, the OR ofsmoking to nonsmoking was the highest in ESCC group but had no statisticalsignificance. The OR of smoking index >500 was 2.3 (95%CI: 1.10-4.86) and 1.5(95%CI: 1.01-2.18) in ESCC group and hyperplasia group respectively, which reached the significant level.3 The OR of drinking to nondrinking in ESCC group and hyperplasia group was 2.8 (95%CI: 1.35-5.76) and 1.8 (95%CI: 1.08-5.87) respectively, which reached the significant level. According to drinking index, drinking was associated with ESCC in >30 and <30 levels, with ORs of 3.1 (95%CI: 1.35-5.76) and 2.5(95%CI: 1.12-5.69) respectively. In addition, OR of drinking index <30 reached significant level in esophagitis group.4 If nonsmoking+nondrinking was used as the baseline (OR=1.0) , it was found that smoking+drinking was significantly associated with ESCC (OR:2.S,95%CI: 1.18-6.64).5 The population attributable risk proportion (PARP) of smoking+drinking in ESCC, hyperplasia, and esophagitis groups was 36.8%, 11.5%, and 26.3% respectively.6 Family history of ESCC was significantly associated with all the three kinds of esophageal lesions, with ORs of 2.0(95%CI: 1.09-3.60),1.8(95%CI: 1.27-2.45),1.8( 95%CI: 1.17-2.72) respectively. The OR for ESCC history of first-degree relatives was2.6(95%CI: 1.36-4.85) ,2. (95%CI: 1.43-2.99) and 1.8 (95%CI:1.13-3.03) in early ESCC, hyperplasia ,and esophagitis groups respectively.7 To analyze the combined effect of ESCC family history with smoking, ESCC family history alone had no significant relation with ESCC, but the OR for ESCC family history+smoking was 3.3 (95%CI: 1.33-8.31)8 To analyze the combined effect of ESCC family history with drinking, ESCC family history alone had no significant relation with ESCC, hyperplasia and esophagitis , but the ORs of family history+drinking were 5.8 ( 95%CI: 1.40-3.77) ,2.3 (95%CI: 2.21-15.04), 3.3 (95%CI: 1.73-6.33) for the three diseases respectively.9 Meat increased the risk of ESCC, but soybean, fish, oil, celery, eggplant, kidney bean, green pepper, fat, crude fibre, ash and calcium decreased the risk; wheat, oil and heat were risk factors for esophageal hyperplasia, but leek had protective effect against it; oil and heat were risk factors for esophagitis.10 If ALDH2 A/A genotype was used as the baseline (OR=1.0) , G/G genotype was significantly associated with atypical hyperplasia and basal cell hyperplasia, with OR the highest in basal cell hyperplasia group (6.6; 95%:CI: 2.19-20.07). To analyze the combined effect of genotype with drinking, nondrinking+A/A was used as the baseline (OR=1.0), drinking+G/G was significantly associated with atypical hyperplasia (OR=2.8; 95%:CI: 1.02-7.86) and basal cell hyperplasia (OR=16.1; 95%:CI: 2.01-129.39).11 VDR genotype showed no significant relationship with all esophageal diseases, and no synthetic effect was found with smoking and drinking.4.12 The sAng-2 levels were 22.0±5.5, 21.3±3.2, 20.5±3.3, 24.0±5.0, and 29.8±5.0 U/ml in normal, esophagitis, hyperplasia, early ESCC, and advanced ESCC groups respectively. It was significantly higher in early ESCC than hyperplasia group (P=0.009).12 The proportion of the level of sAng2 higher than normal was 7.7%, 6.8%, 2.4%, 23.1% and 78.6% respectively in esophagitis, hyperplasia, early carcinoma and advanced carcinoma groups. A positive correlation was found between serum Ang-2 level and ESCC process (r=0.206), suggesting that serum Ang-2 level increases with the development of esophageal disease.Conclusions1 Traditional epidemiology investigation found that risk factors for nonmalignant, precancerous and cancerous diseases were different. The results were: (1) ESCC: smoking, drinking and family history of ESCC; (2) hyperplasy: smoking and family history of ESCC; (3) esophagitis: drinking and family history of ESCC. Diet and nutritional ingredient had association with all esophageal diseases. There was interaction between drinking, smoking and family history at all stages of the disease.2 The environment-gene analysis found that risk factors for nonmalignant, precancerous and cancerous diseases were different too. ALDH2 G/G had association with atypical hyperplasia and base cell hyperplasia, the combination of G genotype with smoking increases the risk of ESCC and atypical hyperplasia, and ALDH2 G/G interacted with drinking at all stages of esophageal diseases. VDR genetype had no association with esophageal diseases.3 Traditional epidemiology investigation found that the ORs of various risk factors in ESCC group were higher than that in esophagitis and hyperplasy group. While the ALDH2-environment analysis found that the effect of risk factors was more evident in the hyperplasy group. 4 The level of the antibodies against sAng2 had some association with precarcinomaous lesion of esophageal epithelium mucosa and it may be useful to the long-term monitoring of high risk individuals.Meaning and creativity1 In this study, the controls and patients came from the same community of high incidence of ESCC, and they possessed similar environment and customs, so their data are comparable. All diseases are determined by endoscope and pathological examination, and the possibility of misclassification is small. All patients were newly found, so they provided information with little recall bias, and their lifestyle, such as smoking and drinking did not change because of the disease. In a word, the results of this study is dependable.2 According to the development process of ESCC, we designed the multiple sequence case-control study. The influencing factors of each stage were analyzed by the combination of traditional and molecular epidemiology. The result will be helpful to learn the pathological process of ESCC and provide epidemiology method for ESCC prevention in high-incidence areas. Furthermore, no report was found about the systemic study on the factors of precancerous esophageal diseases in high-incidence aeras, so the result can provide scientific proofs to prevent precancerous diseases in these areas.Shortcomings and suggestions1 Shortcomings1.1 When the influencing factors were combined to analyze, some layers had not enough samples to estimate their ORs, so the result in the present study should be validated in the further studies.1.2 The samples for the two genes were not completely same and their synthetic effect was not analyzed.2 SuggestionsIn order to establish a dynamic monitoring system for high-risk individuals and find ideal indexes for early screening of ESCC, we suggest studying the development of nonmalignant esophageal diseases, make intervention in high-incidence areas and observe the change of some biological markers.
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