Value of narrow band imaging endoscopy in early mucosal head and neck cancer

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1 ORIGINAL ARTICLE Value of narrow band imaging endoscopy in early mucosal head and neck cancer Yen Chun Lin, MD, 1 Wen Hung Wang, MD, PhD, 1 * Kam Fai Lee, MD, 2 Wan Chi Tsai, PhD, 3 Hsu Huei Weng, MD, MPH, PhD 4,5 1 Department of Otolaryngology Head and Neck Surgery, Chang Gung Memorial Hospital at Chiayi, Taiwan and Chang Gung University College of Medicine, Chiayi County, Taiwan, 2 Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Taiwan and Chang Gung University College of Medicine, Chiayi County, Taiwan, 3 Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Kaohsiung, Taiwan, 4 Department of Diagnostic Radiology, Chang Gung Memorial Hospital at Chiayi, Taiwan; and Chang Gung University College of Medicine, Chiayi County, Taiwan, 5 Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi County, Taiwan. Accepted 6 September 2011 Published online 31 January 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to show the investigated prevalence rate of brownish spots of early cancer under narrow band imaging (NBI) in different sites/types of the epithelium. Methods. In all, 125 adults with early mucosal cancer underwent NBI examination. Four types of epithelium were categorized: keratinized thick stratified squamous (type 1), nonkeratinized thin (type 2a) or very thick (type 2b) stratified squamous, and pseudo-stratified ciliated columnar epithelium (type 3). Results. The prevalence rate of brownish spots in early cancer of the nasopharynx, oral cavity, oropharynx, hypopharynx, and epiglottis were 11.1%, 15.9%, 21.4%, 100%, and 100%, respectively. Type 2a epithelium (odds ratio [OR], 76.45; 95% confidence interval [CI], ) was a significant predictive factor for the brownish spots. Conclusion. The brownish spots have higher reliability for screening in early cancer of the mouth floor, hypopharynx, and epiglottis, but not in other mucosal sites. Mucosal sites with type 2a epithelium have a higher tendency of demonstrating brownish spots. VC 2012 Wiley Periodicals, Inc. Head Neck 34: , 2012 KEY WORDS: endoscopy, epithelium, head and neck, narrow-band imaging (NBI), screening The use of narrow band imaging (NBI) is currently considered of great benefit in detecting superficial mucosal lesions over the pharyngeal mucosa. 1 It provides better detection of irregular microvascular patterns (brownish spots) of carcinoma compared to conventional laryngoscope (p <.05) through better visualization of the demarcation line (p <.05) 2 because the narrow band blue light, which has a short wavelength (415 nm), penetrates the mucosa and highlights the superficial vasculature. Moreover, the blue filter is designed to correspond to the peak absorption spectrum of hemoglobin, which enhances the image of capillary vessels on the surface mucosa. Thus, superficial mucosal lesions that are usually not detected by regular white-light endoscopy can be identified based on their neoangiogenetic vasculature pattern using the blue light in NBI. 3 A literature review shows that the effectiveness of NBI in the early detection of head and neck squamous cell carcinoma (SCC) of the larynx, 3 mouth floor, 4 oropharynx, and hypopharynx 5,6 has been documented through the years. They all use brownish spots as the typical image pattern for detecting early cancerous lesions such that brownish spots seem to have become a gold standard in identifying early mucosal head and neck cancer. However, a previous *Corresponding author: W. Wang, Department of Otolaryngology Head and Neck Surgery, Chang Gung Memorial Hospital at Chiayi, Taiwan and Chang Gung University College of Medicine, Chiayi County, Taiwan. ent.taiwan@gmail.com study 7 in the nasopharynx has shown that only 33.3% (3 of 9) of patients with American Joint Committee on Cancer T1 classification primary nasopharyngeal carcinoma (NPC) can be identified using the brownish spots pattern. In addition, some mucosal sites in the head and neck region have not yet been mentioned, including alveolus, tonsil, tongue base, and epiglottis. Thus, the primary question is whether or not brownish spots are a universal image pattern that can be used to screen for early or occult cancer of the head and neck. There are also different covering epithelia of the mucosa in different regions of the head and neck, 8 including keratinized thick, nonkeratinized thin, or very thick stratified squamous epithelium and pseudostratified ciliated columnar epithelium. Hence, the secondary question is whether or not the different epidermal state can affect the appearance of brownish spots. The main purpose of this study was to investigate the prevalence rate of brownish spots of early cancerous lesions under NBI endoscopy in different mucosal sites/types of epithelium and to determine their reliability for screening early cancer. MATERIALS AND METHODS One hundred twenty-five adults (112 men, 13 women; mean age, years) underwent detailed NBI endoscopic, imaging, and histologic examinations at the Chang Gung Memorial Hospital at Chiayi to diagnose early (T1 classification SCC) or occult (carcinoma in situ 1574 HEAD & NECK DOI /HED NOVEMBER 2012

2 BROWNISH SPOTS ON NARROW BAND IMAGING IN HEAD AND NECK TABLE 1. Clinical characteristics and histopathology of early or patients with occult head and neck mucosal cancer with or without brownish spots under NBI endoscopy (number of patients 5 125). Group Total BS NBS p value No. of patients (29.6%) 88 (70.4%) Age, mean (SD), y 57.7 (24.3) 60.1 (18.5) 57.1 (22.5).831 Sex Male (31.3%) 77 (68.7%).236 Female 13 2 (15.4%) 11 (84.6%) Neck lymph node status (N classification) N N N N Histopathology Squamous cell carcinoma Carcinoma in situ Site of cancerous lesions (%) Nasopharynx 27 3 (11.1) 24 (88.9) <.0001 Oral cavity (15.9) 53 (84.1) <.0001 Buccal 23 2 (8.7) 21 (91.3) <.0001 Retro-molar trigon 5 2 (40) 3 (60) NS Dorsal surface of tongue 20 1 (5) 19 (95) <.0001 Lip 5 0 (0) 5 (100).004 Hard palate 2 0 (0) 2 (100) NS Floor of mouth 5 5 (100) 0 (0).004 Alveolar ridge 3 0 (0) 3 (100) NS Oropharynx 14 3 (21.4) 11 (78.6).008 Tonsil 5 0 (0) 5 (100).004 Soft palate 6 3 (50) 3 (50) NS Base of tongue 3 0 (0) 3 (100) NS Hypopharynx (100) 0 (0) <.0001 Epiglottis 4 4 (100) 0 (0).034 Abbreviations: NBI, narrow band imaging; BS, brownish spots group; NBS, non brownish spots group; NS, not significant (p >.05). [CIS]) mucosal head and neck cancer. The hospital s ethics committee approved the study and all of the patients provided written informed consents before biopsy. The TNM status of each tumor was classified according to the 2002 criteria of the American Joint Committee on Cancer. 9 The NBI system used was equipped with an ENF-V2 or VQ rhinolarynx videoscope (Olympus Medical Systems, Tokyo, Japan), a light source (CLV-160B; Olympus Medical Systems), and a central video system (CV-160B, Olympus Medical Systems). The system could easily switch between conventional and NBI views. One of 2 experienced otolaryngologists (Y.-C. L. or W.- H. W.) performed all endoscopic examinations in the outpatient clinic. The patients were examined while in a seated position. Before the endoscopy, the nasal cavity was anesthetized with 4% lidocaine hydrochloride spray. The use of decongestants at the time of endoscopy was only in the nasal cavity. The oral cavity and oropharynx were evaluated first in the white-light mode and later by the NBI system. Transnasal endoscopy was performed to screen the nasopharynx, base of the tongue, epiglottis, and hypopharynx. Any irregular microvascular pattern (brownish spots) was defined based on irregularly high density and thicker vessels with abnormal dilatation, abrupt alteration in caliber, and heterogeneity in shape. All of the patients underwent a tissue biopsy and the specimens were stained with hematoxylin-eosin stain for histopathologic examinations as performed by a single pathologist (K.-F. L.) blinded to the endoscopic findings. The results were presented as mean (6SD) for continuous variables and as percentages for categorical variables. Statistical differences were compared by the Fisher exact test for dichotomous variables. A p <.05 was considered statistically significant for nonparametric data analyzed by a single-tailed test. Logistic regression models were used to estimate the effect of type of epithelium on the likelihood of brownish spots. Statistical analyses were conducted using a statistical software package (SPSS statistical software, version 12; SPSS, Chicago, IL). RESULTS Patient characteristics Between July 2007 and December 2010, 125 patients with newly diagnosed early or occult mucosal head and neck cancer (including nasopharyngeal carcinoma, oral cavity cancer, orohypopharyngeal cancer, and epiglottic cancer) were enrolled (Table 1). Neck lymph node status (N classification) was 102, 14, 7, and 2 in patients for N0, N1, N2, and N3, respectively. The patients were divided into 2 groups based on the presence or absence of brownish spots under NBI endoscopy. The brownish spots group had 37 patients (35 men, 2 women; mean age, years) whereas the nonbrownish spots (NBS) group had 88 patients (77 men, 11 women; mean age, HEAD & NECK DOI /HED NOVEMBER

3 LIN ET AL. FIGURE 1. Identification of typical brownish spots as a neoplastic lesion by standard endoscopy (A, B, C, arrows), which was more difficult, and by narrow-band imaging (NBI) in the mouth floor (D, arrows), hypopharynx (E, arrows), and epiglottis (F, arrows). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 22.5 years). There were no statistically significant differences regarding age, sex, and neck lymph node status between the 2 groups. Histopathology results showed SCC in 121 patients and CIS in 4 (1 buccal mucosa and 3 hypopharynx). Identification of brownish spots by narrow band image in different mucosal sites Only 29.6% of the patients (37 of 125) with early or occult primary mucosal head and neck cancer had detectable brownish spots. The prevalence rates of brownish spots in early cancer of the nasopharynx, oral cavity, oropharynx, hypopharynx, and epiglottis were 11.1% (3 of 27), 15.9% (10 of 63), 21.4% (3 of 14), 100% (all of 17), and 100% (all of 4), respectively. The prevalence was significantly lower in the nasopharynx (11.1% vs 88.9%; p <.0001), oral cavity (15.9% vs 84.1%; p <.0001), and oropharynx (21.4% vs 78.6%; p ¼.008), and significantly much higher in the hypopharynx (100% vs 0%; p <.0001) and epiglottis (100% vs 0%; p ¼.034; Table 1). Using subsites of the oral cavity and oropharynx, typical brownish spots pattern of early mucosal cancer was most often identified in the mouth floor (100% vs 0%; p ¼.004; Figure 1) and less identified in the buccal mucosa (8.7% vs 91.3%; p <.0001), tongue (5% vs 95%; p <.0001), lip (0% vs 100%; p ¼.004), and tonsil (0% vs 100%; p ¼.004). There were no differences in the retromolar trigon (40% vs 60%; p >.05), hard palate (0% vs 100%; p >.05), alveolar ridge (0% vs 100%; p >.05), soft palate (50% vs 50%; p >.05), and base of tongue (0% vs 100%; p >.05; Figure 2). Identification of brownish spots by narrow band image in different types of the epithelium Furthermore, the prevalence rate could be classified based on the covering epithelium of the mucosa in different regions of the head and neck. 8 Type 1, keratinized thick stratified squamous epithelium (including gingiva, hard palate, and dorsal surface of the tongue), had a 3% (1 of 30) prevalence of brownish spots. Type 2a, nonkeratinized thin stratified squamous epithelium (including the floor of the mouth, ventral tongue, soft palate, palatine tonsils, base of the tongue, epiglottis, and hypopharynx), had a 72.5% (29 of 40) prevalence of brownish spots. Type 2b, nonkeratinized, very thick stratified squamous epithelium, including the retromolar trigon, labial, and buccal mucosa, had a 14.3% (4 of 28) prevalence. Type 3, pseudostratified ciliated columnar epithelium (including the nasopharynx and supraglottic larynx), had an 11.1% (3 of 27) prevalence. The prevalence of brownish spots in type 2a epithelium was significantly higher than those of types 1, 2b, and 3 (72.5% vs 3%, 14.3%, and 11.1%; p <.0001), which had no differences among them (p >.05). Using logistic regression to estimate the effect of epithelium type on the likelihood of brownish spots, type 2a epithelium (odds ratio [OR], 76.45; 95% confidence interval [CI], ; p ¼.000) was a significant predictive factor (Table 2). Type 2b (OR, 4.83; 95% CI, , p ¼ 0.171) and type 3 epithelium (OR, 3.63; 95% CI, 1576 HEAD & NECK DOI /HED NOVEMBER 2012

4 BROWNISH SPOTS ON NARROW BAND IMAGING IN HEAD AND NECK FIGURE 2. Identification of typical brownish spots as a neoplastic lesion by standard endoscopy (A, C, arrows) and by narrow-band imaging (NBI), which both were difficult, in the left buccal mucosa (B, arrows) and right lateral surface of the tongue (D, arrows). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] ; p ¼.278) were no difference to type 1 epithelium. DISCUSSION Most head and neck cancer cases encountered are in the late stages and, as such, can be easily detected by standard endoscopy. In contrast, superficial mucosal cancer in the early stages often has occult or shallow layer lesions that may be overlooked by standard endoscopy. Under NBI, superficial SCCs show several typical endoscopic findings, particularly an irregular microvascular pattern and a welldemarcated line between the normal epithelium and cancerous lesion. 10,11 In the literature, this is documented as the demarcated brownish area with scattered spots typically observed by NBI mode in cancerous or precancerous lesions of the orohypopharyngeal mucosa. 1,12,13 The current study indicates that the screening pattern of brownish spots by NBI endoscopy is feasible and allows the otolaryngologists to detect nearly all early mouth floor, hypopharyngeal, and epiglottic cancers. However, when applying NBI to identify early NPC and other oral cavity cancers, the frequency of brownish spots is much lower than expected (11.1% in the nasopharynx and 15.9% in the oral cavity). To date, there is no documentation of NBI application on early or occult mucosal cancers in the head and neck region. According to clinical observations, there are still some regions where brownish spot patterns are rarely seen. The most possible reasons are variations of the epidermis state and interference of lymphoid tissue in the identification of subepithelial microvascular architecture. For example, the floor of the mouth, ventral tongue, soft palate, epiglottis, vocal cords, hypopharynx, and esophagus are covered by nonkeratinized thin stratified squamous epithelium 8,14 and they display a high prevalence of brownish spots (72.5%; 29 of 40). The current study shows that nonkeratinized thin stratified squamous epithelium has a significant likelihood of having brownish spots than other types of epithelium (OR, 76.45; 95% CI, ). However, there were 2 special conditions. First, although the palatine tonsils and lingual tonsils (base of tongue) are also lined by nonkeratinized stratified TABLE 2. Factors predicting likelihood of brownish spots based on different types of epithelium. Type of epithelium Odds ratio 95% CI p value Type (Reference) (Reference) Type 2a Type 2b Type Abbreviations: CI, confidence interval; type 1, keratinized thick stratified squamous epithelium; type 2a, nonkeratinized thin stratified squamous epithelium; type 2b, nonkeratinized very thick stratified squamous epithelium; type 3, pseudostratified ciliated columnar epithelium. HEAD & NECK DOI /HED NOVEMBER

5 LIN ET AL. squamous epithelium, 15 theirs are not uniform and contain rich lymphoid tissue leading to absence of spots (0 of 8). Second, although the buccal mucosa and retromolar trigon are also lined by the same epithelium, these are too thick (500 lm) 8 and display only 14.3% (4 of 28) prevalence of brownish spots. The alveolus, hard palate, and dorsal surface of the tongue are all covered by thick, keratinized epithelium 8,14 and have much lower prevalence (3%; 1 of 30). There were 4 patients with histopathologically diagnosed CIS in the brownish spots group but none in the NBS group. Whether or not all lesions will display brownish spots when lesions can be detected earlier in the CIS stage warrants a larger case series to confirm. In the nasopharynx, there is 1 previous case of irradiated NPC with early recurrence successfully detected by NBI endoscopy. 16 However, a recent study shows that only 8.8% of the identified T1 category primary NPCs have subepithelial microvascular architecture (brownish spots). 7 It is possible that brownish spots are 1 of the early neovasculature signs and they are difficult to identify in more advanced tumors. Lymphoid hyperplasia, if present, may obscure superficial lesions. Because the fine structure of the nasopharyngeal mucosa can be identified by NBI, there is higher sensitivity and specificity when NPC is diagnosed using the mucosal microsurface structure (light crests and side-difference pattern) instead of the subepithelial microvascular architecture (brownish spots) visualized by NBI endoscopy. 7 Thus, the data here reveal that NBI is effective in increasing the sensitivity, negative predictive value, and accuracy for NPC due to the easy identification of the microvascular architecture and mucosal microsurface structure simultaneously by NBI, including detecting tortuous microvessels, fine white lines on the surface crests, and easy comparisons with both sides of the nasopharynx. 7 In the oral cavity, different regions have different mucosal structures. 8 First, there is the masticatory mucosa (keratinized areas) found in the hard palate, gingival, and vermilion border. Second, the lining or reflecting mucosa (nonkeratinized areas) is found on the cheeks, alveolar mucosa, vestibular fornix, mouth floor, soft palate, and ventrum of the tongue. Third, the dorsum of the tongue has specialized mucosa. From literature review, the most usual locations include the floor of the mouth, 5,17 20 followed by the ventral tongue, 17,21 23 hard palate, 17,21 gingival, 22 buccal mucosa, 22 and lower lip. 22 The current study also reveals that all of the early cancer in the floor of the mouth significantly displays brownish spots (p ¼.004). The most possible reason is that the very thin nonkeratinized epithelium (100 lm) 8 in the floor of the mouth is different from the keratinized or thick oral cavity. Other sites without significant or demonstrable brownish spots are the buccal mucosa, lips, and dorsal tongue (p <.05; Table 1), which have very thick epithelium up to 500 lm. 8 In the oropharynx and hypopharynx, since Muto et al 1 first stressed the importance of NBI endoscopic detection of superficial carcinoma at oropharyngeal and hypopharyngeal mucosal sites in 18 patients in 2004 and Watanabe et al 12 screened the oropharynx and hypopharynx of 217 consecutive patients with esophageal cancer to conclude that the NBI system might improve sensitivity by 2-fold over conventional methods in Several studies have been published to further confirm the effectiveness of NBI in patients with primary unknown cervical lymph node metastasis, 24 and in detecting metachronous superficial pharyngeal cancer in patients with esophageal SCC 25 after chemotherapy and/or radiotherapy. 26,27 NBI also diagnoses the extent of advanced oropharyngeal and hypopharyngeal cancer. 28 Brownish spots in the hypopharynx are mainly located in the pyriform sinus, 1,2,12,21,27 postcricoid area, 21 and lateral pharyngeal wall. 27 In the oropharynx, they are mainly in the anterior tonsillar pillar, 18,26 superior and posterior wall, 21 and the soft palate. 27 In the larynx, the first study regarding the application of NBI to diagnose laryngeal cancer focused on vocal cord region, from Watanabe et al, 6 showed that sensitivity and specificity is 91.3% and 91.6%, respectively. They claimed that NBI endoscopy seems to be a very promising diagnostic tool for diagnosing laryngeal malignant disease. However, the value of NBI in diagnosing early cancer in epiglottic region is still unknown. The mucosal type of the epiglottis is nonkeratinized thin stratified squamous epithelium, which is similar to the mouth floor and hypopharynx. In contrast, the supraglottic larynx belongs to the pseudostratified ciliated columnar epithelium. Unfortunately, there are not enough patients with vocal cord malignancies or other supraglottic laryngeal cancers to analyze differences between these 2 types of epithelium. The 4 cases diagnosed with epiglottic cancer all demonstrate brownish spot areas. Hence, there is a strong correlation to the epidermal state. Traditionally, NBI seems to be considered a tool that would be more relevant to the office examination of earlier more questionable lesions that may or may not require a biopsy. These viewpoints are correct in screening early cancer of the mouth floor, hypopharynx, and epiglottis according to our current study. That is, when we see an early lesion without brownish spots in the buccal mucosa, tongue, lip, tonsil region, and mucosal sites with type 1, 2b, and 3 epithelium, we still need to pay attention to the high possibility in which cancer occurs. However, further studies are warranted to investigate the mechanism of brownish spots occurrence in the different types of epithelium and subsites. CONCLUSION To our knowledge, this is the first study to document the prevalence of brownish spots in different subsites for early mucosal head and neck cancer. The brownish spots have a higher frequency of occurrence in screening early cancer in the mouth floor, hypopharynx, epiglottis, and mucosal sites with nonkeratinized thin stratified squamous epithelium. Therefore, even brownish spots have not presented in screening other mucosal sites under NBI, we still need to pay attention to the high possibility in which cancer occurs. REFERENCES 1. Muto M, Nakane M, Katada C, et al. Squamous cell carcinoma in situ at oropharyngeal and hypopharyngeal mucosal sites. Cancer 2004;101: HEAD & NECK DOI /HED NOVEMBER 2012

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