Introduction

Achalasia is a chronic idiopathic condition characterized by the absence of esophageal peristalsis and reduced relaxation of the lower esophageal sphincter, causing progressive dysphagia and weight loss. EA has been investigated as a potential risk factor for esophageal cancer (EC); squamous cancer due to chronic inflammation related to stasis due to poor esophageal emptying and adenocarcinoma due to uncontrolled gastroesophageal reflux after treatment [1]. Longstanding disease, repeated treatment, age and male sex have been addressed as the most relevant risk factors [2], but no clear effect size estimation from large sample cohorts has been provided so far [3].

Aims & Methods

We conducted a retrospective cohort study, accessing the global federated health research network “TriNetX”, that provides access to electronic medical records from approximately a hundred million patients across large healthcare organizations (HCOs). The analysis was performed on March 25^th 2025 on the Global collaborative network on achalasia patients, based on the ICD-10 code (K22.0), from January 1^st 2000 until January 31^st 2024. We first investigated the incidence rate (cases/1000 persons-year) and cumulative prevalence of EC in an achalasia cohort in a span of 25 years. Then we inferred the risk of EC, by comparing the achalasia cohort with control population, using propensity score nearest neighbor greedy matching, for relevant covariates. Kaplan-Meyer (KM) analysis with censoring, Hazard Ratios (HRs) and Risk Difference (RD) estimation for EC risk were calculated. Log Rank test was used to compare Kaplan-Meyer curves. Further sub-group analysis was implemented between two population of achalasia patients, treated (with endoscopic/surgical myotomy or pneumatic dilation) and treatment-naïve.

Results

Among a cohort of 68,115 achalasia patients in a span of 25 years of follow-up, the cumulative prevalence of EC was 0.83% (increasing from 0.23% to 0.72% between 2000-2005 and 2020-2025) with an overall incidence rate of 0.87 cases/1000persons-year (increasing from 0.52 to 1.43 between 2000-2005 and 2020-2025). After 1:1 propensity score matching, 63,686 EA patients were compared with 63,686 control subjects (mean age 58.3±19.2 years, M 45%, previous history of malignant GI neoplasm 5.8%, alcohol users 2.1%; PPI use 35%; all p>0.05). The total number of EC occurrences were 517 (risk 0.008) in EA group compared to 86 (risk 0.001) in the control group, resulting in a RD of 0.007 (0.006-0.008, 95%CI, p<0.0001) and an HR of 6.7 (5.3-8.4, 95%CI, p<0.00001). At KM analysis, survival probability was 97.5% in achalasia group compared to 99.6% in controls in more than 20 years of follow-up (log rank test p<0.00001). In subgroup analysis of 4,166 treated vs untreated achalasia patients, the risk of EC after treatment (26 total cases) was considerably higher in the first group with a RD of 0.003 (0.001-0.006 95%CI, p=0.037) and a HR 2.46 (1.26-4.80, 95%CI, p<0.009) in a mean follow-up of 1,031.8 days.

Conclusion

The results from this large population analysis from multicenter global database with 20 years of follow-up of achalasia confirm the higher risk of EC in long-standing achalasia compared with healthy subjects. Furthermore, an in-depth analysis apparently indicated that the risk of EC is higher after treatment of achalasia, suggesting the need of prolonging the endoscopic surveillance, particularly in patients after treatment.

References

1. Zaninotto G, Rizzetto C, Zambon P, Guzzinati S, Finotti E, Costantini M. Long-term outcome and risk of oesophageal cancer after surgery for achalasia. Br J Surg. 2008 Dec;95(12):1488-94. doi: 10.1002/bjs.6413. PMID: 18991316.
2. Oude Nijhuis RAB, Zaninotto G, Roman S, Boeckxstaens GE, Fockens P, Langendam MW, Plumb AA, Smout A, Targarona EM, Trukhmanov AS, Weusten B, Bredenoord AJ. European guidelines on achalasia: United European Gastroenterology and European Society of Neurogastroenterology and Motility recommendations. United European Gastroenterol J. 2020 Feb;8(1):13-33. doi: 10.1177/2050640620903213. PMID: 32213062; PMCID: PMC7005998.
3. Ponds FA, Moonen A, Smout AJPM, Rohof WOA, Tack J, van Gool S, Bisschops R, Bredenoord AJ, Boeckxstaens GE. Screening for dysplasia with Lugol chromoendoscopy in longstanding idiopathic achalasia. Am J Gastroenterol. 2018 Jun;113(6):855-862. doi: 10.1038/s41395-018-0064-1. PMID: 29748564.

Disclosure

E.V. received speaker and/or consulting fees from Sanofi/Regeneron, Falk Pharma, Apollo Therapeutics, and Aurora Biofarma. EVS received consulting fees from Dr Falk Pharma and Reckitt Benckiser; research support from Medtronic and Diversatek Healthcare. AJB received research funding from BMS, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Uniquity, Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Uniquity, Reckitt, AlfaSigma and AstraZeneca. All other authors did not have any disclosures.