Achalasia and Risk of Esophageal Squamous Cell Carcinoma and Adenocarcinoma in a Multinational Study

BACKGROUND & AIMS: Achalasia appears to increase the risk of esophageal squamous cell carcinoma, but existing evidence relies on small studies that did not adjust for this cancer's main risk factors (ie, smoking and alcohol overconsumption). Whether achalasia increases the risk of esophageal adenocarcinoma, whose main risk factor is gastroesophageal reflux disease (GERD), is even more uncertain. This study aimed to clarify these associations. METHODS: A population-based case-control study was conducted in 5 Nordic countries from 1987 to 2023. Esophageal cancer cases (n = 35,604) were matched to 10 times as many background population controls by age, sex, calendar year, and country (n = 355,869). Conditional logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for smoking and alcohol, and additionally for GERD in a mechanistic model. All variables came from national health data registries. RESULTS: Achalasia was present in 137 cases (96 squamous cell carcinomas and 41 adenocarcinomas) and 230 controls (99 squamous cell carcinomas and 131 adenocarcinomas). Achalasia was associated with a strongly increased risk of esophageal squamous cell carcinoma (OR, 9.46; 95% CI, 7.07-12.65). A moderate association was found for esophageal adenocarcinoma (OR, 3.05; 95% CI, 2.14-4.35), which attenuated after adjustment for GERD (OR, 1.44; 95% CI, 0.99-2.09). Achalasia treated with myotomy or dilation was associated with an even stronger association with esophageal squamous cell carcinoma (OR, 16.33; 95% CI, 11.26-23.67), but not with esophageal adenocarcinoma after adjustment for GERD (OR, 1.32; 95% CI, 0.76-2.30). CONCLUSIONS: Achalasia appears strongly and independently associated with esophageal squamous cell carcinoma. The association with esophageal adenocarcinoma is less strong and seems to be largely explained by GERD.