Adults (>= 18 years old) with a strong clinical suspicion (solid and/or liquid dysphagia and weight loss) at selected anatomical cancer sites or with confirmed incident primary EC or gastro-esophageal junction cancer according to the International Classification of Diseases for Oncology, 3rd edition, identified at the participating clinics and hospital, were eligible. Patients with a second or relapse EC and those who were mentally, emotionally, or physically unable to give consent were excluded. Eligible topography sites were: cervical esophagus (C15.0), upper third of the esophagus (C15.3), middle third of the esophagus (C15.4), lower third of the esophagus (C15.5), overlapping lesion of esophagus (C15.8), esophagus unspecified (C15.9), and cardia, NOS (cardio-esophageal junction, esogastric junction, gastro-esophageal junction) (C16.0).
For patients enrolled at the endoscopy clinics, the initial diagnosis was based on clinical suspicion, but a final diagnosis relied on histological or cytological confirmation. In patients consenting to donate biopsy specimens at endoscopy, three samples were taken and used to generate two formalin-fixed, paraffin-embedded (FFPE) blocks, and diagnosis slides, and the third sample for fresh tissue preservation. A majority of patients recruited at TAH were referred from other hospitals for treatment and did not have tumor tissue archived at TAH. For these patients, the diagnosis was based on histology slides or FFPE blocks, if these materials were available from the referral hospitals and patients consented to release of these specimens, or on a copy of the pathology report from the referral hospitals.
A slightly larger proportion of cases (36%) than controls (26%) were ever qat users (S1 Table), whereas duration of use among consumers did not differ much between cases (mean, 30 years) and controls (mean, 31 years). Overall, very few qat users had used qat for less than 10 years. The median retention time of the qat wad in the mouth during a chewing session was 4 hours in both cases and in controls. A higher proportion of cases (11%) than of controls (2.3%) retained the qat wad in the mouth overnight. Smoking during qat chewing sessions was reported in 16.4% of cases and in 11.3% of controls. Reporting of ever alcohol use was slightly higher in controls (41%) than in cases (30%), possibly related to the religious affiliation (S2 Table). Although the overall distribution of reported consumed staple food items did not differ between cases and controls, a slightly higher proportion of cases (21.9%) than controls (12%) specified kocho as the staple food. Kocho (qocho) is a local flatbread made using the starch obtained from the trunk of the false banana plant (Ensete ventricosum), fermented for several months and subsequently cooked in a griddle. Consumption of very salty food was more commonly reported by cases (26%) than by controls (1.5%).
A non-significant 2-fold elevation in risk of EC was seen in ever qat chewers compared with never users in unadjusted conditional analysis (odds ratio [OR] = 2.12; 95% confidence interval [CI]: 0.94, 4.74)) (Table 2), although this association disappeared after accounting for differences in tobacco use, consumption of alcohol and green vegetables, education level, and religion (OR = 0.95; 95% CI: 0.22, 4.22). No clear trend was observed between duration of qat use and risk of EC (Table 2). Tobacco use was associated with a more than 2-fold increase in risk of EC (OR = 2.62; 95% CI: 1.16, 5.92), the association in the adjusted model showed a larger magnitude but a lower precision, becoming non-significant (OR = 3.31; 95% CI: 0.53, 20.62) (Table 2). We did not observe a clear trend in EC risk with duration of tobacco use (Table 2). In sensitivity analysis according to control type, we observed a statistically significant elevation in risk of EC associated with ever tobacco use when including healthy visitor-type controls (OR = 3.02; 95% CI: 1.04, 8.77; p = 0.04) but not when limiting to hospital controls (OR = 1.75; 95% CI: 0.56, 5.51; p = 0.34) in fully adjusted unconditional logistic regression models. The association of qat chewing and risk of EC was also evaluated after stratifying by tobacco use. The risk of EC in ever qat users was elevated and statistically significant among never tobacco users (OR = 5.81; 95% CI: 1.21, 27.9) but not among ever tobacco users (OR = 0.76; 95% CI: 0.12, 4.61) (Table 2) in univariate analysis. After adjusting for differences in consumption of alcohol and green vegetables, education level, and religion, the risk of EC in ever qat users remained elevated but with a very wide confidence interval including 1 (OR = 6.75; 95% CI: 0.48, 96). The p-value for the interaction term between ever qat use and ever tobacco use was 0.06.
Ever alcohol use was associated with a reduction in risk of EC (OR = 0.45; 95% CI: 0.21, 0.96) according to the unadjusted risk estimate, but the odds ratio increased to 2.3 (95% CI: 0.32, 16.53) after adjusting for tobacco use, consumption of green vegetables, education level, and religion (Table 3). Staple foods reported to have been consumed one year before the interview, or one year before the endoscopy or diagnosis, were suggestive of an elevation in risk of EC. Subjects who specified kocho as the staple food had a statistically significantly elevated EC risk in univariate analysis only (Table 3). Low consumption of green vegetables was associated with an increased risk of EC, with subjects consuming green vegetables less than once a week (OR = 3.57; 95% CI: 1.31, 9.71) or not at all (OR = 12.47; 95% CI: 2.91, 53) having a substantially higher risk of EC compared with those with daily consumption. These results were corroborated after adjusting for confounders (Table 3). Saltiness of food and smokiness inside the home were associated with an increased risk of EC in unadjusted analysis, whereas in adjusted analysis an elevation in risk remained only for saltiness of food (Table 3).
Education level and religion were strongly associated with risk of EC (Table 3). More educated people had a lower risk of EC compared with illiterate people, even when the level of education did not reach complete schooling. Christians had a lower risk of EC compared with Muslims. Accounting for differences in tobacco use, alcohol use, and consumption of green vegetables did not affect the statistically significant association of education level and religion with risk of EC (Table 3). Thus, education level and religion were associated with EC independently of these specific lifestyle/dietary factors.