The carcinogenetic impact of risk factors on esophageal cancer (EC) may differ according to the portion of the esophagus where the tumor occurs. It is unclear why more esophageal squamous cell carcinomas (SCC) developed in the middle location. We carried out a multicenter case-control study in Taiwan to assess anatomical subsite risk discrepancy for this neoplasm in regard to the consumption of alcohol, tobacco and betel quid. Four hundred forty seven incident patients with pathology-proven SCC of the esophagus (107 were upper-third [U/3-EC], 199 middle-third [ M/3-EC] and 141 lower-third [L/3-EC] cases), as well as 1, 022 gender, age and study hospital matched controls were analyzed by unordered polytomous logistic regression. All consumption of the three substances was related to the development of each subsite of EC, with a heterogeneously higher risk for current smokers (adjusted odds ratio (AOR) = 6.2) found in M/3-EC and for current chewers, in U/3-EC ( AOR = 4.9). The joint risk of contracting lower two-third EC for drinking and smoking appeared to significantly surpass those estimated by a multiplicative interaction model. Concomitant exposure to these two agents brought the risks of EC at all three subsites up to 10- to 23.9-fold an additional tobacco-free betel quid to a 30.3- to 75.0-fold. In conclusion, tumor subsite discrepancy risk is related to prolonged exposure to tobacco and betel quid with inflorescence . Alcohol interacts with tobacco in a stronger supra-multiplicative way in the middle portion of the esophagus, probably explaining why esophageal SCC occurs more commonly at this anatomical location. (c) 2007 Wiley- Liss , Inc. ; 附設醫院外科部 ; 醫學院附設醫院 ; 期刊論文