We read the paper entitled “GERD and Upper Aerodigestive Tract (UADT) Cancer Risk: A Systematic Review and Meta-Analysis” 1. In this meta-analysis, Huang et al. suggested that GERD was significantly associated with laryngeal cancer. They did not find significant associations for pharyngeal, oropharyngeal, hypopharyngeal, or esophageal carcinoma. Authors concluded that GERD is associated to an increased risk of laryngeal cancer, suggesting further investigation into reflux-related carcinogenesis in the UADT in high- risk populations. We thank the authors for this study. In this letter, we wish to draw attention to many methodological points. The diagnosis of laryngopharyngeal reflux disease (LPRD) is based on the identification of hypopharyngeal reflux events (HREs) after a full esophageal column, leading to the deposit of digestive enzymes into the UADT 2. GERD diagnosis relies on esophageal acid exposure time or esophageal findings 3, using different criteria than LPRD since these are distinct diseases 2, 4, with GERD limited to the esophagus. Of the studies included in the meta-analysis, the LPRD diagnosis was not confirmed through the identification of HREs at the hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring 2. The lack of consideration of the difference between GERD and LPRD in the meta-analysis in a major limitation because without identified HRE, the causality between LPRD and cancer cannot be established. Experimental and some selected clinical studies showed that pepsin and bile salts are both involved in the development of laryngeal and hypopharyngeal cancers through the activation of the NF-κB pathway 5. The meta-analysis findings suggesting an association between GERD and laryngeal cancer—but no association with other head and neck malignancies—are biased by the inclusion of patients with GERD alone or GERD with concomitant LPRD, likely representing only acidic LPRD, which does not reflect the majority of LPRD cases 2, 6. The failure to identify the actual proportion of patients in included studies presenting both GERD and LPRD constitutes a major methodological flaw. Mechanistic links between reflux and head and neck cancer development should be investigated in representative populations, given that most LPRD patients lack GERD and exhibit alkaline laryngopharyngeal reflux 2, 6, 7. Currently, establishing or refuting a causal association between LPRD, refluxed enzymes, and head and neck malignancies remains extremely challenging. The establishment of a potential mechanistic association (causality) requires future translational studies documenting LPRD with HEMII-pH and related refluxed gastroduodenal enzymes in tumor samples to determine their role in the development of UADT cancer through understanding the underlying biomolecular cellular mechanisms. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Lechien et al. (Fri,) studied this question.