Accuracy of Laryngeal Examination during Upper Gastrointestinal Endoscopy for Premalignancy Screening: Prospective Study in Patients with and without Reflux Symptoms

• Introduction
• Patients and Methods
• Design of the Study
• Patients Recruited and Inclusion Criteria
• Patients Excluded from the Study
• Gastroenterologists’ Examination
• ENT Specialists’ Examination
• Results
• Gastroenterologists’ Examination
• ENT Specialists’ Examination of Video Recordings
• ENT Specialists’ Standard Laryngeal Examination
• Statistical Results
• Discussion
• Conclusions
• References

Background and Study Aims: Gastroesophageal reflux disease may be associated with laryngeal damage caused by reflux material. The aim of this study was to investigate the accuracy of laryngeal examinations during routine upper gastrointestinal endoscopy as a method of screening for major laryngeal injury in a series of patients with reflux symptoms.
Patients and Methods: A total of 100 consecutive patients with reflux symptoms and 100 control individuals underwent upper gastrointestinal endoscopy with standard or high-resolution magnifying video endoscopes. Any laryngeal abnormalities were initially identified by the gastroenterologist before the scope was inserted into the esophagus. All of the examinations were recorded on video and subsequently reevaluated by an otorhinolaryngologist. All of the patients underwent standard laryngoscopy as a reference procedure.Results: All of the patients completed the study. The sensitivity, specificity, negative predictive value, and positive predictive value of the preliminary laryngeal exploration for detecting laryngeal abnormalities (such as laryngitis and vocal leukoplakia) were 90 %, 90 %, 92 %, and 89 %, respectively. High-resolution magnifying endoscopy had a higher sensitivity and specificity than standard endoscopy for detecting laryngeal pathology. Two patients were found to have laryngeal leukoplakia.
Conclusions: This study shows that preliminary diagnosis of laryngeal disorders can be accurately carried out by the gastroenterologist when patients are undergoing upper endoscopy for reflux symptoms. This approach could also be helpful for the timely diagnosis of major reflux-related laryngeal disease.

Introduction

Gastroesophageal reflux disease (GERD) is a frequent disorder characterized by various clinical manifestations due to the abnormal reflux of gastric contents from the stomach into the esophagus. Although the most vulnerable tissue is the epithelium in the distal esophagus [1], reflux may also reach the proximal esophageal segment and then the larynx. There have been many reports of laryngeal damage caused by gastroesophageal acid or biliary reflux, with patients presenting with a wide range of symptoms and varying degrees of severity and frequency [2] [3] [4] [5] [6]. Some manifestations of this condition (such as laryngitis and laryngeal cancer) are being increasingly recognized [7] [8] [9] [10] [11] [12].

However, GERD may be overlooked as the underlying mechanism of laryngeal damage, as the typical reflux symptoms may be absent despite abnormal esophageal exposure to acid [3]. Poelmans et al. recently demonstrated that patients with ear, nose, and throat (ENT) symptoms suspected to be related to reflux have a higher prevalence of esophagitis than typical reflux patients and that this is associated with a better response to antisecretory therapy [13].

This prospective and controlled study was carried out in order to evaluate the potential accuracy of preliminary screening for laryngeal damage in patients with reflux symptoms undergoing upper gastrointestinal endoscopy.

Patients and Methods

Design of the Study

Two gastroenterologists (G.C., R.C.) were initially trained by ENT specialists in searching for and recognizing laryngeal damage. The training consisted of at least seven laryngeal examinations per day for a 2-month period. The ENT specialists provided instruction in how to examine the laryngopharyngeal area, reviewing the most common pathological findings (such as laryngitis, vocal leukoplakia, and laryngeal cancer).

The study required the consecutive enrolment of patients who were undergoing upper gastrointestinal endoscopy due to typical reflux symptoms or for other reasons (in patients who served as control individuals). After a preliminary, blinded laryngeal evaluation by gastroenterologists during upper gastrointestinal endoscopy, all video recordings of the laryngeal examinations were reevaluated by independent ENT specialists in order to confirm or revise the preliminary findings. All of the enrolled patients underwent standard laryngoscopy as a reference procedure.

Patients Recruited and Inclusion Criteria

Between April 2004 and February 2005, patients who were undergoing upper gastrointestinal endoscopy for the first time, due to typical reflux symptoms (such as heartburn or acid regurgitation, or both) were considered eligible for inclusion in the study. Of 1465 patients who were referred to the endoscopy unit for routine upper gastrointestinal endoscopy, 100 (9 %) were included in the study.

In the same outpatient setting and over the same period, a further 100 patients who had not reported heartburn or acid regurgitation during the preceding year were enrolled as a control group. These patients were undergoing upper endoscopy for various reasons: 47 for malabsorption symptoms (diarrhea, abdominal pain, unexplained iron-deficiency anemia), 46 due to a recent onset of pain referable to the stomach, and seven for weight loss.

The reflux questionnaire developed by Locke et al. was used to identify heartburn and acid regurgitation [14]. Heartburn was defined as “a burning feeling that rises through the chest” and acid regurgitation as “liquid coming back into the mouth, leaving a bitter or sour taste.” A patient was deemed to be suffering from reflux symptoms when he or she reported having had heartburn or acid regurgitation, or both, on a regular basis (at least twice a week) during the preceding year, irrespective of its severity or duration. Extraesophageal symptoms such as hoarseness, chronic throat clearing, or coughing, together with a history of tobacco and alcohol habits, were recorded on the basis of direct interviews with the patients. With regard to tobacco use, patients were classified as nonsmokers (persons with no history of smoking) or smokers (including those who were smokers at the time of the evaluation and persons who had smoked previously but quit before the evaluation). Alcohol intake was recorded as the mean number of standard drinks consumed per day (one standard drink = 12 g of absolute alcohol) [15]. Patients were therefore divided into nondrinkers (including patients who were teetotallers or who occasionally drank small quantities of alcohol) and drinkers (including men or women who habitually drank three or more drinks per day or two or more drinks per day, respectively).

The study was conducted in accordance with the humane and ethical research principles set forth in the Helsinki guidelines, and started after oral approval was received from the relevant local institutional board. Informed written consent was obtained from all participants to carry out the preliminary endoscopic laryngeal examination and to prolong the endoscopic procedure from 1 min up to 2 min. Written consent was also obtained from each patient to undergo an additional free examination (such as laryngoscopy).

Patients Excluded from the Study

A total of 1265 patients who underwent upper gastrointestinal endoscopy in the same study period were not considered eligible for this study. These included 33 patients who were referred for severe upper gastrointestinal disorders (such as gastric cancer), 22 patients with dysphagia or with any known esophageal motility disorder, 495 in-patients who were undergoing multiple treatment for multiple-organ diseases (ischemic heart disease, diabetes, etc.), 121 patients who did not consent to the study conditions, and 461 patients who had previously undergone upper gastrointestinal endoscopy or ENT examinations. A total of 121 patients with reflux symptoms who were or had been receiving acid-suppressing therapy and 12 patients who reported allergies were also excluded.

Gastroenterologists’ Examination

All of the examinations included in the study were conducted by the same skilled endoscopist (G.C.), who randomly used a standard video endoscope (Fujinon EG-200FP, Fuji Photo Optical Ltd, Omiya, Japan) or a commercially available high-resolution magnifying video endoscope (Fujinon EG-485ZH). The latter instrument provides high-resolution images (using an 850 000-pixel chip) with an optical magnification of 200 × and adjustable digital image magnification over a continuous range up to 2.0 ×. The preset digital magnification used in this study was 1.5 × or 2 ×. Five minutes before the start of the examination, each patient was requested to gargle at least twice with 0.4 % benoxinate hydrochloride to induce local laryngeal anesthesia. Before the scope was inserted into the esophagus, a careful laryngeal exploration was carried out with the video endoscope. The presence of at least one of several signs - such as hyperemia, edema, or hypertrophy of the posterior commissure of the larynx (the interarytenoid fold) - was considered to represent laryngitis. These signs, together with major laryngeal abnormalities (leukoplakia and tumorous lesions) were carefully investigated. All of the laryngeal video examinations were recorded using a DVD recorder (Philips Electronics N.V., Eindhoven, Netherlands). The Los Angeles classification was used to assess the degree of esophagitis [16] [17].

All of the video recordings were independently reevaluated by another gastroenterologist (R.C.), who was blinded to the patients’ clinical conditions and provided an independent diagnosis concerning the laryngeal field. In the event of a discrepancy in the image scoring for a given patient, the two gastroenterologists discussed the findings and formulated a common score.

ENT Specialists’ Examination

All recordings of laryngeal examinations were independently reevaluated by two professional ENT specialists (S.A., M.R.), who were blinded to the endoscopic findings and to the patients’ clinical conditions. The same signs of laryngitis (such as hyperemia, edema, or hypertrophy of the posterior commissure) and laryngeal cancer [18] were identified and recorded. The ENT specialists expressed a judgment on the accuracy of the laryngeal examination carried out by the gastroenterologists. In particular, the laryngeal examination was considered: poor, when laryngeal details could not be evaluated and/or visualized; good, when the laryngeal examination was sufficient to establish a diagnosis; or fully satisfactory, when the ENT specialists considered that the laryngeal examination was in accordance with their personal standards.

Finally, 1 week after the gastrointestinal evaluation, all of the included patients underwent standard laryngoscopy by two other ENT specialists (J.G., E.D.C.) using a nasopharyngolaryngofiberscope (Pentax FNL-10RP3, Pentax Medical, Montvale, New Jersey, USA). The ENT specialists were blinded to the preliminary findings and to the patients’ clinical conditions. In the event of a discrepancy in the image scoring for a given patient, the two ENT specialists (J.G., E.D.C.) discussed the findings and formulated a common score.

Statistical analysis. Data for continuous variables are presented as means plus or minus standard deviation. Statistical analyses were carried out using the Statistical Package for the Social Sciences program, version 10.1.0 for Windows (SPSS, Inc., Chicago, Illinois, USA). Statistical significance was considered to be represented by the rejection of null hypotheses at the P < 0.05 level. The correlation between the results obtained by the initial laryngeal exploration conducted by the gastroenterologists and the standard ENT evaluation was analyzed by either parametric analysis (Pearson’s product-moment correlation coefficient, r) or nonparametric analysis (Spearman’s rank-order correlation coefficient, rho). Interobserver variability was assessed using kappa statistics, which measures the level of agreement after correction for chance agreement. Sensitivity, specificity, and positive and negative predictive values for the preliminary endoscopic evaluation of the larynx were calculated, with the standard laryngoscopy examination being used as the gold standard.

Results

Table [1] summarizes the general characteristics and habits of the patients and control individuals. The patients’ overall compliance with the study was excellent, with all of the patients completing the preliminary examination and undergoing upper gastrointestinal endoscopy. No adverse events were observed with benoxinate. The two gastroenterologists established the same initial diagnosis in 163 patients (81 %). In the remaining 37 laryngeal examinations, the gastroenterologists discussed the findings and formulated a common score.

The average time spent evaluating the larynx before inserting the scope into the esophagus was 51 ± 12 s. The ENT specialists (S.A., M.R.) considered the technique used by the gastroenterologists to conduct the preliminary laryngeal exploration as good or fully satisfactory in all of the patients examined (100 %). The kappa coefficient between gastroenterologists and ENT specialists (S.A., M.R.) in the preliminary laryngeal exploration during endoscopy was 0.89, indicating excellent agreement over and above the level of chance.

Gastroenterologists’ Examination

Patients. Of 100 patients with reflux symptoms, 50 underwent upper endoscopy with the high-resolution magnifying video endoscope (ME group) and 50 with the standard video endoscope (SE group). The preliminary laryngeal exploration identified signs of laryngitis in 83 patients (83 %). Of these, two (2 %) had areas of leukoplakia on the vocal cords, associated with signs of posterior laryngitis (Figure [1]). The larynx was considered normal in the remaining 17 patients (17 %).

Among the 83 patients with laryngeal abnormalities, only 18 (12 %) had extraesophageal symptoms. In particular, one patient with laryngeal leukoplakia reported a long-term history of heartburn and acid regurgitation, with no extraesophageal symptoms. Upper gastrointestinal endoscopy revealed erosive esophagitis in 31 of 100 patients (31 %): 18 with grade A esophagitis, five with grade B, four with grade C, and four with grade D. All of these 31 patients had signs of laryngitis (including the above-mentioned two patients with laryngeal leukoplakia), while 10 of them (32 %) reported extraesophageal symptoms.

Control individuals. Signs of laryngitis were found in only 13 of the 100 control patients, while the larynx was found to be normal in the remaining 87. None of the patients in the control group had erosive esophagitis. Four patients reported extraesophageal symptoms. The results are summarized in Table [2].

ENT Specialists’ Examination of Video Recordings

The reevaluation of the upper gastrointestinal endoscopy recordings by two ENT specialists (S.A., M. R.) identified the presence of laryngitis in 81 cases; among these, two patients had leukoplakia of the vocal cord. Among the control individuals, 15 patients (15 %) were found to have signs of laryngitis. The results are detailed in Table [2].

ENT Specialists’ Standard Laryngeal Examination

The standard laryngeal examination by ENT specialists (J.G., E.D.C.) showed the presence of laryngitis in 78 patients (78 %), two of whom had leukoplakia of the vocal cords, and in 16 control individuals (16 %). The patients with leukoplakia underwent cord decortication, and the histological examination showed moderate epithelial dysplasia in both cases.

Statistical Results

The statistical analyses were carried out with the standard laryngoscopy results being used as the reference standard. Taking all of the patients enrolled in the study into account, the sensitivity, specificity, negative predictive value, and positive predictive value of the preliminary laryngeal exploration conducted by the gastroenterologists were 90 %, 90 %, 92 %, and 89 %, respectively. The sensitivity, specificity, negative predictive value and positive predictive value of the preliminary laryngeal explorations reviewed by the ENT specialists on the video recordings were 90 %, 93 %, 81 %, and 92 %, respectively.

In comparison with standard laryngoscopy as the reference standard, no significant differences were found between standard and high-resolution magnifying endoscopy examinations for assessing the presence or absence of laryngeal abnormalities. There was a significant difference between the patients and control individuals with regard to the presence of laryngeal disorders (P < 0.001), while there were no significant differences with regard to sex, age, tobacco habits, or alcohol consumption between the two groups (Table [1]).

The results of the statistical analyses are detailed in Tables [2] - [4].

Discussion

This study shows that gastroenterologists can attempt a preliminary screening for laryngeal abnormalities in patients undergoing upper gastrointestinal endoscopy for reflux symptoms. The accuracy of this approach is demonstrated by the high sensitivity, specificity, negative predictive, and positive predictive values (90 %, 90 %, 92 %, and 89 %, respectively) obtained in the study population. The sensitivity and specificity values were only slightly higher (not significantly) when the gastroenterologists used a high-resolution magnifying video endoscope rather than a standard instrument (Table [3]).

Using a conventional endoscope, Mullhaupt et al. recently screened the laryngopharyngeal area in a series of unselected patients during routine upper gastrointestinal endoscopy and found a negative predictive value of 100 %, whereas the positive predictive value was only 43 % [18]. However, the reliability of the approach used for this type of study is questionable, as the assessment of laryngeal findings may vary widely from clinician to clinician [19], depending on the different endoscopist’s experience, the equipment used, and the time spent on specific training. In addition, signs such as laryngeal hyperemia and edema may be differently assessed by different observers.

The findings of the present study are in agreement with literature data showing a high prevalence of laryngeal signs and symptoms in patients with GERD [20] [21]. However, the high level of accuracy reached with the approach used here for detecting premalignant lesions (such as vocal leukoplakia; Figures [1], [2]) in two patients with reflux symptoms is a major achievement. It is important to underline the fact that both of these patients, in addition to having erosive esophagitis, were also heavy smokers. A preliminary laryngeal exploration was highly justified in these two patients due to the potentially dangerous effects of both tobacco habits and chronic reflux.

Another noteworthy finding in this study is that 52 of 83 patients with laryngitis (63 %) had no erosion of the esophageal mucosa. On the basis of these data, it appears that inflammation of the laryngeal epithelium (when defense mechanisms are absent) is more frequent than erosive esophagitis in patients with chronic reflux symptoms. However, future studies are needed in this area to delineate these associations better [22], since the criteria used to assess laryngitis and esophagitis differ. For example, the Los Angeles classification of esophagitis does not consider simple aspects of inflammation, such as edema and mucosal hyperemia, as representing esophagitis [16] [17], while various degrees of erythema and edema of the laryngeal epithelium are taken into consideration, to assess laryngitis - making precise laryngoscopic diagnosis highly subjective [18].

In the present study, the majority of patients with laryngeal abnormalities (88 %) did not report laryngeal symptoms (such as chronic hoarseness, throat clearing, or coughing) and would probably never have undergone ENT check-up examinations. This finding appears to be the most important message of the study, as it emphasizes the potential role that gastroenterologists can have in conducting preliminary laryngeal evaluations during upper endoscopy in a group of patients (such as those with reflux disease) in whom laryngeal disorders may be completely asymptomatic.

Conclusions

With sound experience, gastroenterologists may be able to detect findings similar to those identified by ENT specialists examining the larynx with a flexible video gastroscope. Future studies will be necessary in order to investigate the cost-benefit ratio of a preliminary laryngeal examination of this type, and whether the use of high-resolution magnifying video endoscopes is justified in this category of patients. It is also important to point out that patients affected by laryngeal abnormalities necessarily have to be referred to an ENT specialist after initial screening by the gastroenterologist. Gastroenterologists can never replace ENT specialists in the management of laryngeal disorders.

Competing interests: None

References

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G. Cammarota, M.D.

Istituto di Medicina Interna, Policlinico Universitario A. Gemelli

Largo A. Gemelli 8 · 00168 Rome · Italy

Fax: +39-06-35502775

Email: gcammarota@rm.unicatt.it

References

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  CrossrefPubMedSearch in Google Scholar
• 2 Wong W M, Fass R. Extraesophageal and atypical manifestations of GERD.  J Gastroenterol Hepatol. 2004;  19 (Suppl 3) S33-43
  CrossrefPubMedSearch in Google Scholar
• 3 Fass R, Achem S R, Harding S. et al . Supra-oesophageal manifestations of gastro-oesophageal reflux disease and the role of night-time gastro-oesophageal reflux.  Aliment Pharmacol Ther. 2004;  20 (Suppl 9) 26-38
  CrossrefPubMedSearch in Google Scholar
• 4 Vaezi M F. Sensitivity and specificity of reflux-attributed laryngeal lesions: experimental and clinical evidence.  Am J Med. 2003;  115 (Suppl 3A) 97S-104S
  PubMedSearch in Google Scholar
• 5 Ormseth E J, Wong R K. Reflux laryngitis: pathophysiology, diagnosis, and management.  Am J Gastroenterol. 1999;  94 2812-2817
  CrossrefPubMedSearch in Google Scholar
• 6 Jaspersen D, Kulig M, Labenz J. et al . Prevalence of extra-esophageal manifestations in gastro-esophageal reflux disease: an analysis based on the ProGERD Study.  Aliment Pharmacol Ther. 2003;  17 1515-1520
  CrossrefPubMedSearch in Google Scholar
• 7 Qadeer M A, Colabianchi N, Vaezi M F. Is GERD a risk factor for laryngeal cancer?.  Laryngoscope. 2005;  115 486-491
  CrossrefPubMedSearch in Google Scholar
• 8 Weaver E M. Association between gastroesophageal reflux and sinusitis, otitis media, and laryngeal malignancy: a systematic review of the evidence.  Am J Med. 2003;  115 (Suppl 3) 81S-89S
  PubMedSearch in Google Scholar
• 9 Mercante G, Bacciu A, Ferri T. et al . Gastroesophageal reflux as a possible co-promoting factor in the development of the squamous-cell carcinoma of the oral cavity, of the larynx and of the pharynx.  Acta Otorhinolaryngol Belg. 2003;  57 113-117
  PubMedSearch in Google Scholar
• 10 Lewin J S, Gillenwater A M, Garrett J D. et al . Characterization of laryngopharyngeal reflux in patients with premalignant or early carcinomas of the larynx.  Cancer. 2003;  97 1010-1014
  CrossrefPubMedSearch in Google Scholar
• 11 Cammarota G, Galli J, Cianci R. et al . Association of laryngeal cancer with previous gastric resection.  Ann Surg. 2004;  240 817-824
  CrossrefPubMedSearch in Google Scholar
• 12 El-Serag H B, Hepworth E J, Lee P. et al . Gastroesophageal reflux disease is a risk factor for laryngeal and pharyngeal cancer.  Am J Gastroenterol. 2001;  96 2013-2018
  CrossrefPubMedSearch in Google Scholar
• 13 Poelmans J, Feenstra L, Demedts I. et al . The yield of upper gastrointestinal endoscopy in patients with suspected reflux-related chronic ear, nose, and throat symptoms.  Am J Gastroenterol. 2004;  99 1419-1426
  CrossrefPubMedSearch in Google Scholar
• 14 Locke G R, Talley N J, Weaver A L. et al . A new questionnaire for gastroesophageal reflux disease.  Mayo Clin Proc. 1994;  69 539-547
  PubMedSearch in Google Scholar
• 15 Secretary of Health and Humanservices . Effects of alcohol on fetal and postnatal development.  In: Ninth Special Report to the U.S. Congress on Alcohol and Health. Washington, DC; Dept. of Health and Human Services 1997: 193-246 (NIH publication 97 - 4017)
  Search in Google Scholar
• 16 Armstrong D, Bennett J R, Blum A L. et al . Endoscopic assessment of esophagitis: a progress report on observer agreement.  Gastroenterology. 1996;  111 85-92
  CrossrefPubMedSearch in Google Scholar
• 17 Lundell L R, Dent J, Bennett J R. et al . Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification.  Gut. 1999;  45 172-180
  CrossrefPubMedSearch in Google Scholar
• 18 Mullhaupt B, Jenny D, Albert S. et al . Controlled prospective evaluation of the diagnostic yield of a laryngopharyngeal screening examination during upper gastrointestinal endoscopy.  Gut. 2004;  53 1232-1234
  CrossrefPubMedSearch in Google Scholar
• 19 Branski R C, Bhattacharyya N, Shapiro J. The reliability of the assessment of endoscopic laryngeal findings associated with laryngopharyngeal reflux disease.  Laryngoscope. 2002;  112 1019-1024
  CrossrefPubMedSearch in Google Scholar
• 20 Malagelada J R. Supra-oesophageal manifestations of gastro-oesophageal reflux disease.  Aliment Pharmacol Ther. 2004;  19 (Suppl 1) 43-48
  CrossrefPubMedSearch in Google Scholar
• 21 Tauber S, Gross M, Issing W J. Association of laryngopharyngeal symptoms with gastroesophageal reflux disease.  Laryngoscope. 2002;  1112 879-886
  PubMedSearch in Google Scholar
• 22 Diaz-Rubio M, Moreno-Elola-Olaso C, Rey E. et al . Symptoms of gastro-oesophageal reflux: prevalence, severity, duration and associated factors in a Spanish population.  Aliment Pharmacol Ther. 2004;  19 95-105
  CrossrefPubMedSearch in Google Scholar

G. Cammarota, M.D.

Istituto di Medicina Interna, Policlinico Universitario A. Gemelli

Largo A. Gemelli 8 · 00168 Rome · Italy

Fax: +39-06-35502775

Email: gcammarota@rm.unicatt.it