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Gastroesophageal and Laryngopharyngeal Reflux Associated with Laryngeal Malignancy: a Systematic Review and Meta-Analysis

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Gastroesophageal and Laryngopharyngeal Reflux Associated with Laryngeal Malignancy: a Systematic Review and Meta-Analysis Accepted Manuscript Gastroesophageal and Laryngopharyngeal Reflux Associated with Laryngeal Malignancy: A Systematic Review and Meta-Analysis Sean M. Parsel, DO, Eric L. Wu, MD, Charles A. Riley, MD, Edward D. McCoul, MD, MPH PII: S1542-3565(18)31150-9 DOI: https://doi.org/10.1016/j.cgh.2018.10.028 Reference: YJCGH 56150 To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 8 October 2018 Please cite this article as: Parsel SM, Wu EL, Riley CA, McCoul ED, Gastroesophageal and Laryngopharyngeal Reflux Associated with Laryngeal Malignancy: A Systematic Review and Meta-Analysis, Clinical Gastroenterology and Hepatology (2018), doi: https://doi.org/10.1016/ j.cgh.2018.10.028. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Title : Gastroesophageal and Laryngopharyngeal Reflux Associated with Laryngeal Malignancy: A Systematic Review and Meta-Analysis Sean M. Parsel, DO 1, Eric L. Wu, MD 1, Charles A. Riley, MD 2, and Edward D. McCoul, MD, MPH 1, 3, 4 1 Tulane University School of Medicine, Department of Otolaryngology—Head and Neck Surgery, New Orleans, LA 2 Weill Cornell Medical Center, Department of Otolaryngology—Head and Neck Surgery, New York, NY 3 Ochsner Clinic Foundation, Department of Otorhinolaryngology, New Orleans, LA 4 University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA Short title: Reflux and Laryngeal Malignancy Grant support: none Correspondence Edward D. McCoul, MD, MPH 1514 Jefferson Highway, CT-4 New Orleans, LA 70121 Phone: (504) 842-4080 Fax: (504) 842-3979 [email protected] MANUSCRIPT Financial disclosures or conflicts of interest: No authors have any financial disclosures of conflicts of interest to report. Abbreviations BE: Barret esophagus CI: confidence interval GERD: gastroesophageal reflux disease HNSCC: head and neck squamous cell carcinoma HPV: human papilloma virus ICD: International Classification of Disease LPR: laryngopharyngeal reflux MINORS: Methodological Index for Non-Randomized Studies NSND: nonsmokers and nondrinkers OR: odds ratio PICOS: Population,ACCEPTED Intervention, Control, Outcome, and Study Design PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis RSI: Reflux Symptom Index ACCEPTED MANUSCRIPT Author Contributions SMP: systematic review of literature, data analysis, manuscript preparation, critical revision of manuscript ELW: systematic review of literature CAR: manuscript preparation, data analysis EDM: study concept and design, manuscript preparation, critical revision of manuscript MANUSCRIPT ACCEPTED ACCEPTED MANUSCRIPT Background & Aims: Gastric reflux could lead to chronic mucosal inflammation and contribute to development of laryngeal malignancies, although there is controversy over this association. We performed a systematic review and meta-analysis to assess this relationship and determine risk of laryngeal malignancy in patients with reflux disease. Methods: We performed a systematic review and meta-analysis, searching MEDLINE, EMBASE, and Web of Science databases from 1900 through April 9, 2018 for observational studies of adults reporting associations between gastroesophageal reflux disease (GERD) and/or laryngopharyngeal reflux and the risk of having or developing laryngeal malignancies. An itemized assessment of the risk of bias was conducted for each study that met inclusion criteria. The meta-analysis was performed using the Mantel-Haenszel method with random effects to account for heterogeneity. We performed subgroup analyses to determine effect of reflux type, study design, diagnostic method, and confounding variables Results: Of the 957 studies that were identified during systematic review, 18 case– control studies met the criteria for analysis. Our meta-analysis demonstrated that reflux disease significantly increased the risk of laryngeal malignancy (odds ratio, 2.47; 95% CI, 1.90–3.21; P<.00001; I 2 = 94%). This association remained when we controlled for patient smoking and drinking (odds ratio, 2.07; 95% CI, 1.26–3.41). There was no statistically significant difference in risk of laryngeal malignancies between patients with GERD vs laryngopharyngeal reflux ( P=.44). Conclusions: In a systematic review and meta-analysis, we found a significant association between reflux disease and the presenceMANUSCRIPT of laryngeal malignancy. Prospective studies should be performed to examine this relatio nship. KEY WORDS: LPR, PICOS, esophagus, laryngeal cancer, head and neck cancer What You Need To Know Background: Gastroesophageal and laryngopharyngeal reflux can lead to chronic mucosal inflammation and increase risk for development of cancer. Researchers have reported a correlation between reflux and laryngeal carcinoma, but there is controversy over this association. Findings: In a meta-analysis of the literature, we found an association between reflux disease and laryngeal carcinoma. We found patients with reflux disease to be 2.47-fold more likely to have a diagnosis of laryngeal cancer. Implications for patient care: Although alcohol and tobacco use are established risk factors for laryngealACCEPTED cancer, other factors require identification. Awareness of a potential role for reflux in laryngeal carcinogenesis should prompt vigilance among clinicians to evaluate susceptible individuals and potentially mitigate risk through medical therapy. ACCEPTED MANUSCRIPT Background Laryngeal cancer is the 14 th most common cancer worldwide with approximately 157,000 new cases annually. 1 These cancers are often detected at advanced stages. 2 The aggressive nature of these cancers portends a poor 5-year overall survival rate at around 53%, with better survival for earlier stages. 3, 4 In order to improve detection, a better understanding of the risk factors involved in the development of laryngeal carcinoma is necessary, which in turn might improve survival and outcomes. The major identifiable risk factors implicated in the development of laryngeal malignancy are alcohol and tobacco use. However, other risk factors are thought to contribute to tumorigenesis. 1 In younger patients diagnosed with laryngeal cancer, tobacco and alcohol use are less commonly associated with the development of malignancy. 5 In the nonsmoking and nondrinking (NSND) population with head and neck cancers, there is a lesser degree of genetic mutatiMANUSCRIPTons compared with smokers and drinkers, suggesting alternate etiologies; however, the incidence of laryngeal subsite cancer is significantly less in this population. 6, 7 Human papilloma virus (HPV) infection is hypothesized to account for some of these malignancies; however, the incidence of HPV-induced laryngeal cancer remains substantially lower than with oropharyngeal cancer. 8 Other risk factors likely have a role in development of malignancy. Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) have been hypothesized to be risk factors for developing laryngeal carcinoma, though this association remainsACCEPTED incompletely defined. 9-11 Many of the prior studies have poor controls, leading to some controversy, and there is a paucity of literature examining the effects of reflux disease on the laryngeal mucosa while controlling for covariates. 12-14 15 ACCEPTED MANUSCRIPT Since the overwhelming majority of laryngeal cancers arise from the effects of smoking and drinking, finding a cohort without this exposure is difficult. Despite the lack of controls, early investigation suggests that laryngeal injury can occur from reflux of acidic and nonacidic gastric contents. 16 Further, animal models of acid exposure to upper airway mucosa have shown an increase growth in the number of tumors when the mucosa is exposed to hydrochloric acid (HCl) and pepsin. 17 Although HCl may play a role, much of the risk appears to be secondary to the effects of pepsin on the mucosa, which may lead to cellular injury. 18, 19 GERD has been linked to other types of cancers involving the aerodigestive tract. Specifically, there is a role in the development of esophageal adenocarcinoma where reflux is associated with development of Barrett esophagus (BE) and subsequent dysplasia and malignant transformation. 20-22 Study of hypopharyngeal mucosa exposed to gastric reflux in vitro has demonstrated inflammatoMANUSCRIPTry changes similar to that found in BE. 23-26 Other conditions leading to chronic and/or recurrent inflammatory insults have been implicated in the development of malignancy within the gastrointestinal tract including chronic hepatitis and hepatocellular carcinoma 27 as well as colon cancer and ulcerative colitis.28 This trend is also present in the upper aerodigestive tract, as allergic rhinitis and chronic rhinosinusitis have been associated with nasopharyngeal carcinoma. 29-31 Given the potential link between inflammation and the development of malignancy, ACCEPTEDthe relationship between reflux—either GERD or LPR—and laryngeal carcinoma was investigated. A previous systematic review examining reflux and the association of laryngeal and pharyngeal malignancies suggested a correlation between ACCEPTED MANUSCRIPT GERD and laryngeal
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