From dysfunction to malignancy: The inflammatory pathway linking achalasia to esophageal cancer

This review article published in LabMed Discovery delves into the complex and clinically significant connection between achalasia, a chronic esophageal motility disorder, and the subsequent development of esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC). Although achalasia is a rare condition, its association with an elevated long-term cancer risk makes understanding its pathological progression critically important for early diagnosis and intervention.

The authors begin by explaining achalasia’s pathophysiology: a disorder marked by impaired relaxation of the lower esophageal sphincter (LES) and the absence of peristalsis in the esophageal body. This leads to chronic stasis of food and liquids in the esophagus, resulting in dilation, mucosal irritation, and persistent inflammation. Over time, this stagnant environment fosters microbial overgrowth, chemical irritation, and continuous mucosal damage—factors that can eventually trigger dysplasia and malignant transformation.

Central to the article is the idea that chronic inflammation is the main driver in the progression from benign motility disorder to cancer. The authors describe how repeated irritation activates key inflammatory mediators such as interleukins, TNF-α, and NF-κB, which create a pro-carcinogenic microenvironment. Oxidative stress and DNA damage further accelerate the transformation of normal epithelial cells into neoplastic ones.

The review also explores genetic and molecular alterations observed in achalasia patients at higher risk of cancer. These include mutations in tumor suppressor genes (e.g., p53), overexpression of oncogenes, and epigenetic modifications that suppress DNA repair and apoptosis. Histopathological evidence shows that even in non-symptomatic patients, long-term achalasia can lead to basal cell hyperplasia, squamous dysplasia, and eventually carcinoma in situ.

Clinically, the article notes that symptoms of esophageal cancer may be masked by pre-existing achalasia symptoms, such as dysphagia and weight loss, which can delay cancer diagnosis. The latency period between achalasia onset and cancer development is often decades, making long-term surveillance essential. The authors review current screening strategies—including endoscopic monitoring and imaging—and recommend early and regular surveillance, especially in patients with longstanding achalasia, failure to respond to treatment, or other risk factors such as male sex and older age.

The review concludes by calling for a more proactive approach in managing achalasia patients. This includes raising awareness among clinicians, integrating molecular biomarkers into routine monitoring, and developing personalized screening protocols. The authors suggest that understanding the inflammatory and molecular mechanisms behind the achalasia-to-cancer sequence is essential not only for early detection but also for developing preventive therapies.

In summary, the article provides a comprehensive and clinically relevant review of how a non-malignant motility disorder can evolve into a deadly malignancy through a cascade of inflammatory and molecular events. It underscores the importance of long-term monitoring and highlights opportunities for intervention that could ultimately reduce cancer burden in this high-risk group.