Studies investigating the relationship between malignancy and DM have revealed conflicting results on the association between DM and esophagus cancer, and other cancers [8, 23–39]. Based on histology, the distribution of squamous cell carcinoma and adenocarcinoma varies among different geographic areas. Most of studies on esophageal cancer have been conducted on adenocarcinoma of the esophagus for the populations in Western countries [8, 23–42]. The positive association between the risk of esophagesl cancer and DM in the meta-analysis conducted by Huang et al consisted of 15 studies from Western countries and two studies from Asian countries . More than 80% of esophagus cancer cases in the Asian are squamous cell carcinoma . Whether the risk of squamous cell carcinoma of esophagus has a relationship with DM has not been well explored. Our study makes up for the gap because the previous study found that the squamous cell carcinoma is the major type of esophageal cancer in Taiwan, accounting as high as 95% of patients with the disease .
The present population-based case-control study failed to find a significant association between DM and esophagus cancer in Taiwan. Regardless no association was found between DM and esophageal cancer, this study shows several co-morbidities were much more prevalent in cases than in controls. Consistent with other studies [26, 27, 37–39], we also found heavy alcohol drinking is the strongest risk factor associated with esophageal cancer. A Korean study found a relative risk of 5.62 for mortality from esophageal cancer . Japanese have an OR of 15 for esophageal caner among high alcohol consumers . The risk may increase further to approximately 70-fold higher for those with alcohol flushing response, indicating individuals with difficulty to metabolite alcohol are at a much higher risk for the cancer. The exact mechanism of how alcoholic beverage is associated with esophagus cancer risk is not clear. Although ethanol has not been shown as carcinogenic in laboratory animals, it may act through its major metabolite, acetaldehyde, a carcinogen in animal models [27, 38, 43–45]. The dose-response relationship with alcohol strongly indicates it as an independent risk factor, particularly for esophagus squamous–cell cancer [26, 37, 39].
Esophageal cancer is significantly associated with esophageal ulcer and esophageal reflux, and medications in this study. Both esophageal ulcer and esophageal reflux are likely the earlier signals for the subsequent development of the cancer of esophagus due to esophageal stricture formation, such as acid peptic and medication-induced. Peptic strictures account for most of esophageal strictures [46–49]. Purdy et al. found esophageal mucosa injury is associated with sloughing esophagitis, chronic debilitation and medications . García Rodríguez et al. have also reported that long term pharmacological gastric acid suppression is associated with the risk of oesophageal and gastric adenocarcinoma . In this study, anti-diabetes drugs and other NSAIDs are significantly associated with the disease.
This study was conducted using insurance claims data, a few limitations should be considered. First, smoking is an important factor associated with esophageal cancer. But, this information is not available in the insurance claims. However, we are able to identify patients with the diagnosis of alcoholism. There is strong relationship between drinking and smoking. And we did find alcoholism is an indicator that may well predict the cancer. Second, this case-control study enrolled study subjects with and without esophageal cancer identified from 2000 to 2009. The frequency matched study design fails to observe age difference between cases and controls. However, we have also conducted an unmatched analysis by randomly sampling controls, which revealed a mean age of 15.4 years younger in the controls. This analysis also showed that DM is not a factor associated with esophageal cancer. Therefore, the frequency matched samples are representative of the insured population. Finally, the insurance registry does not provide the information on histological type and genotype of the cancer. We were unable to differentiate whether the associated risk factors different between squamous cell carcinoma and adenocarcinoma among study subjects. It is likely that the small portion of adenocarcinoma may not change the association between DM and the risk of esophageal cancer in the present study.