The Rising Rate of Nonsmokers Among Laryngeal Carcinoma Patients: Are We Facing a New Disease? Hagit Shoffel-Havakuk, MD ; Karla O’Dell, MD ; Michael M. Johns III MD; Lindsay Reder, MD ; Margarita Popova; Doron Halperin, MD; Edit Feldberg, MD; Yonatan Lahav, MD Objectives/Hypothesis: Laryngeal squamous cell carcinoma (SCC) is strongly associated with tobacco smoking. With the rising awareness of tobacco’s adverse health effects, we have witnessed a global decrease in tobacco use. Nevertheless, laryn- geal SCC remains prevalent and includes a subset of patients lacking the traditional risk factors. Study Design: A two-center retrospective cohort. Methods: Medical records of patients diagnosed with laryngeal SCC between 2009 and 2016 were reviewed. Data collected included demographics, smoking status, and tumor site. Patients who have never smoked were designated as nonsmokers. Results: The study included 330 patients with laryngeal SCC, of whom 75 (22.7%) were nonsmokers; this rate was rela- tively similar for each of the two institutions independently (21.9% and 25%). There were 285 patients with glottic SCC and 45 with supraglottic SCC. All nonsmoking patients in this cohort had glottic SCC, representing 26.3% (75/285) of the glottic SCC cases. The rate of female patients was significantly higher among nonsmokers. Of the patients with glottic SCC, females represented 25.3% (19/75) of the nonsmokers compared with 12.4% (26/210) of the smokers (P = .008). Mean age at diagno- sis was 60.2  17.5 years for nonsmoking glottic SCC patients and 63.6  12.4 years for smokers (P = .280). However, non- smokers demonstrated a distinct age distribution pattern. Nonsmoking females with glottic SCC demonstrated a bimodal age distribution pattern; 73.7% (14/19) were age <40 years or >75 years at diagnosis. Conclusions: The rate of laryngeal SCC in nonsmokers is higher than what has previously been reported, representing a growing proportion, and may suggest a shift in etiology. Knowing that laryngeal SCC in nonsmokers predominantly affects the glottis, and that females and age extremities are more vulnerable, the traditional screening paradigm should be revised. Key Words: Nonsmoker, laryngeal carcinoma, glottic carcinoma, female, young, elderly. Level of Evidence: 4 Laryngoscope, 00:1–8, 2019 INTRODUCTION Laryngeal squamous cell carcinoma (SCC) is strongly associated with tobacco smoking and alcohol abuse. 1–4 Specifi- cally, for glottic SCC, tobacco smoking is considered the major cause and of a much greater influence. 3,4 During the past two decades, with the rising awareness of tobacco’ s adverse health effects, along with the achievements of tobacco-control pro- grams, we have witnessed a global decrease in tobacco use. The worldwide prevalence of daily smoking decreased between 1990 and 2015 from 34.9% to 25.0% in males and from 8.2% to 5.4% in females, representing 28.4% and 34.4% reductions, respectively. 5 Similar trends were also reported in the United States; tobacco smoking among adults has decreased from 20.9% in 2005 to 15.5% in 2016, representing a 25.8% reduction. 6 Despite the global decline in tobacco use, laryngeal SCC remains prevalent, and the number of new laryngeal cancer cases is more stable than the decline in smoking rates. The rate of new cases of laryngeal cancer in the United States was 3.2 per 100,000 in 2005 and 2.5 per 100,000 in 2015 (21.9% reduction) 7 ; moreover, the annual deaths related to laryngeal cancer in the United States demonstrated merely a minor change, from 1.2 deaths per 100,000 in 2005 to 1.0 deaths per 100,000 in 2015 (16.7% reduction). 7 These figures raise the question of whether this rela- tive stability in new cases of laryngeal cancer can be attrib- uted to population aging alone or there are other emerging risk factors besides tobacco smoking. Indeed, recent evi- dence suggests that a subset of laryngeal SCC patients lac- king the traditional risk factors is growing. 8 Although an early study that collected data on laryngeal SCC patients diagnosed between 1960 and 2006 described a rate of 3.8% nonsmokers, 9 two presentations at the 2017 Combined Oto- laryngology Spring Meetings indicated considerably higher rates in recent years. One study on laryngeal SCC patients diagnosed between 2003 and 2013 described a nonsmoker rate of 13% 10 ; another study described an increasing rate of From the Department of Otolaryngology–Head and Neck Surgery (H.S.-H.), Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine (H.S.-H.), Tel Aviv University, Tel Aviv, Israel; USC Voice Center, Department of Otolaryngology–Head and Neck Surgery (K.O., M.M.J., M.P.), University of Southern California, Los Angeles, California; Department of Otolaryngology, Head and Neck Surgery (L.R.), Southern California Permanente Medical Group, Los Angeles, California; and the Department of Otolaryngology–Head and Neck Surgery (D.H., Y.L.) and Department of Pathology (E.F.), Kaplan Medical Center, Rehovot, and the Hebrew University, Jerusalem, Israel. Editor’s Note: This Manuscript was accepted for publication on April 23, 2019. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Hagit Shoffel-Havakuk, MD, Department of Otolaryngology–Head and Neck Surgery, Rabin Medical Center Affiliated with Tel Aviv University, 39 Ze’ev Jabotinsky Street, Petah Tikva, Israel. E-mail: shoffel@gmail.com DOI: 10.1002/lary.28067 Laryngoscope 00: 2019 Shoffel-Havakuk et al.: Nonsmokers and Laryngeal Carcinoma 1 The Laryngoscope © 2019 The American Laryngological, Rhinological and Otological Society, Inc.