Implication for second primary cancer from visible oral and oropharyngeal premalignant lesions in betel-nut chewing related oral cancer

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1 Received: 31 August 2016 Revised: 22 October 2016 Accepted: 10 February 2017 DOI: /hed ORIGINAL ARTICLE Implication for second primary cancer from visible oral and oropharyngeal premalignant lesions in betel-nut chewing related oral cancer Shyun-Yu Liu, DDS 1 I-Jung Feng, PhD 2 Yu-Wei Wu, PhD 3,4 Ching-Yuan Chen, MS 5 Chao-Nan Hsiung, MS 3,4,6 Hsueh-Wei Chang, PhD 7,8,9 Che-Yi Lin, DDS 10 Min-Te Chang, DDS 1 Hsi-Chien Yu, DDS 11 Sheng-Yang Lee, PhD 12,13 Ching-Yu Yen, MS 1,12 1 Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Tainan, Taiwan 2 Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan 3 Center for Teeth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan 4 College of Oral Medicine, Taipei Medical University, Taipei, Taiwan 5 Department of Electrical Engineering, Southern Taiwan University, Tainan, Taiwan 6 College of Science and Technology, Taipei Medical University, Taipei, Taiwan 7 Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 8 Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan 9 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan 10 Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Lioying, Tainan, Taiwan 11 Department of Dentistry, Chiali Chi Mei Hospital, Tainan, Taiwan 12 School of Dentistry, Taipei Medical University, Taipei, Taiwan 13 Division of Orthodontics, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan Correspondence Ching-Yu Yen, Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, No. 901, Zhonghua Road, Yongkang District, Tainan City 710, Taiwan. ycysmc@gmail.com Abstract Background: Visible oral and oropharyngeal premalignant lesions may be used to monitor for a second primary oral cancer. To control for bias, we focused on the visible oral and oropharyngeal premalignant lesions of patients with oral cancer with a positive betel-nut chewing habit. Visible oral and oropharyngeal premalignant lesions that can predict second primary oral cancers were studied. Methods: Nine hundred ninety-seven patients with positive betel-nut chewing habits and oral cancer were enrolled in this retrospective cohort study. We analyzed the relevance of their visible oral and oropharyngeal premalignant lesion incidence and relative clinicopathological variables to the development of a second primary oral cancer. Results: cancer risk was significantly higher in patients with positive visible oral and oropharyngeal premalignant lesions (P <.0001), especially in younger patients (P ; 40 years: adjusted odds ratio [OR] 2.66; years: adjusted OR 2.61). The heterogeneous leukoplakia was (adjusted OR 2.17) higher than homogeneous leukoplakia. Conclusion: The predictive value and practicality of visible oral and oropharyngeal premalignant lesions make it a potentially valuable marker in follow-ups of patients with a positive betel-nut chewing habit with oral cancer, especially young patients with heterogeneous leukoplakia. KEYWORDS erythroplakia, leukoplakia, oral and oropharyngeal, premalignant lesion, second primary oral cancer 1428 VC 2017 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/hed Head & Neck. 2017;39:

2 LIU ET AL INTRODUCTION Betel-nut (also known as betel-quid) chewing is popular among adult men in Taiwan and southern Asia. The neoplasia it engenders might contribute about 50% of all malignancies in some countries. 1,2 Betelnut chewing with or without tobacco (smoking or chewing) is the major risk factor for high-prevalence oral premalignant disease. In 1 recent nationwide Taiwanese survey, 3 the oral leukoplakia incidence rate was high, and the mean patient age was years. The high premalignancy rate and the younger patients in the study population might have affected the course and outcomes of oral cancer treatment. One major barrier to comprehensive treatment for oral cancer is the increased risk of a second primary tumor after the index tumor has been eradicated. The published second primary tumor rate in respiratory and upper digestive tracts are 11.2%-17.6%, 4 6 and 2%-3% per person-years in patients with head and neck cancer. 7,8 Men are at a higher risk then are women. 6 Smoking significantly affected the incidence of the development of second primary tumors in 1 case-control study. 9 In addition, betel-nut chewing habits increased the risk of second primary tumors, and 70% of the second primary lesions were oral and oropharyngeal. 10 The field cancerization concept 4 was used to interpret the phenomenon of multiple tumors in patients with oral cancer; in that study, premalignant lesions surrounding the cancerous area mucosa were common in histology examinations. An expanding and genetically altered mucosal field surrounded the primary tumor and shares its carcinogenic characteristics. Premalignant lesions often remain after the primary tumor was resected. 11,12 There was a high percentage of histological abnormality on the mirror-image mucosa from the oral cancer and premalignant cells, even though the mirror-image mucosa looked grossly normal. 13,14 The preneoplastic mucosa cells were distributed in the field more than 7 cm from the excised tumor in 25% of the patients. 15 Furthermore, in clinically healthy-looking mucosa, only the premalignant lesion cells proliferated sufficiently to become visible enough for the second field tumor to be identified. 11 Although the genetic alternations in the cancerous field forecast the risk of a malignant tumor, it was detectable only using an invasive tissue harvest and costly laboratory procedures, both of which are impractical for routine long-term follow-up programs. We recognized the transformation potential of the premalignant lesions. Nevertheless, visible oral and oropharyngeal premalignant lesion might require more complicated treatment. The predicted value of (visible oral and oropharyngeal premalignant lesions) in patients with oral cancer seems important, but it has not yet been studied in depth. Most patients with oral cancer in Taiwan have a positive betel-nut chewing habit, and they were followed up by oral surgeons, but only the oral and oropharyngeal areas are well recorded. To avoid bias, we focused on the oral and oropharyngeal areas and the betel-nut chewing habit-positive population to precisely estimate the implications of visible oral and oropharyngeal premalignant lesions for second primary oral cancers. We investigated the clinical and pathological characteristics and patterns of visible oral and oropharyngeal premalignant lesions and the association between visible oral and oropharyngeal premalignant lesions and second primary oral cancers. 2 MATERIALS AND METHODS This retrospective cross-sectional study was approved by the Institutional Review Board of Chi Mei Medical Center (IRB: ). The inclusion criteria were: (1) a first histopathological diagnosis between 2001 and 2010 at Chi Mei Medical Center of oral squamous cell carcinoma (OSCC; International Classification of Disease, Revision 9, Clinical Modification codes and ) between 2001 and 2010 at Chi Mei Medical Center; (2) having had no surgery, radiotherapy, or chemotherapy, or a targeted drug treatment before the OSCC diagnosis; and (3) having a betel-nut chewing habit. The clinicopathologic variables were recorded; the index tumor stage was based on the sixth American Joint Committee on Cancer criteria. To clearly identify visible oral and oropharyngeal premalignant lesions, patients with submucous fibrosis and oral lichen planus were excluded from this study. Lesions were visually inspected under white light. Visible oral and oropharyngeal premalignant lesions were classified as homogeneous or heterogeneous leukoplakia or as erythroplakia, as appropriate. If multiple visible oral and oropharyngeal premalignant lesionswerefound,onlythehighestgradelesionwasregistered(eg, erythroplakia over homogeneous leukoplakia and heterogeneous leukoplakia over homogeneous). All of the visible oral and oropharyngeal premalignant lesions were subsequently surgically removed. Second primary oral cancers were defined based on Warren and Gates criteria 16 :(1) each tumor must present a definite picture of malignancy; (2) each tumor must be distinct and at least 3 cm away from the index tumor or occur at an interval of at least 3 years; and (3) the probability of one of the multiple tumors being a recurrence or a metastasis must be excluded. The patients were asked to visit the clinic every month for the first 2 years, and every 3 months for the subsequent 3 years, to undergo a mapping physical examination to have their oral and oropharyngeal mucosa checked. The location of the tumor and when it was found were recorded. All patients were followed up for at least 3 years or until death. 2.1 Statistical analysis To compare clinicopathological categorical characteristics between groups, chi-square tests and the Fisher s exact tests were used, as appropriate. The risks of developing a second primary oral cancer in the positive visible oral and oropharyngeal premalignant lesion and negative visible oral and oropharyngeal premalignant lesion groups were evaluated using logistic regression analysis. Crude odds ratios (ORs) and adjusted ORs with corresponding 95% confidence intervals (CIs) are presented. The subgroups were stratified by age and sex. SAS version 9.4 for Windows was used for all analyses. Significance was set at P <.05 (2-tailed). 3 RESULTS One thousand one hundred patients were identified with OSCC and 997 patients (90.64%) had a positive betel-nut chewing habit. Age was

3 1430 LIU ET AL. TABLE 1 Betel-nut chewing habit in the background population Betel-nut chewing Betel-nut chewing habit-positive habit-negative Variables No. of patients (%) No. of patients (%) P value Total no. of patients (90.64) 103 (9.36) Age, y, mean (SD) (10.74) (12.37) (89.08) 19 (10.92) (92.69) 53 (7.31) > (84.58) 31 (15.42) Sex.1104 Female 50 (84.75) 9 (15.25) Male 947 (90.97) 94 (9.03) Stage I 343 (89.09) 42 (10.91).0913 II 200 (90.50) 21 (9.50) III 153 (95.63) 7 (4.38) IV ABC 301 (90.12) 33 (9.88) Differentiation grade.0003 Well differentiated 345 (89.15) 42 (10.85) Moderately differentiated 489 (92.26) 41 (7.74) Poorly differentiated 69 (77.53) 20 (22.47) Index tumor site.0142 Tongue 288 (87.27) 42 (12.73) Gingiva 108 (87.10) 16 (12.90) Buccal mucosa 380 (93.14) 28 (6.86) Others 221 (92.86) 17 (7.14) Drinking habit <.0001 Yes 960 (95.52) 45 (4.48) No 37 (38.95) 58 (61.50) Smoking habit <.0001 Yes 969 (95.28) 48 (4.72) No 28 (33.73) 55 (66.27) Visible oral and oropharyngeal premalignant lesion-positive Yes 236 (92.91) 18 (7.09) No 761 (89.95) 85 (10.05).1771 cancer-positive tumor.0052 Yes 157 (96.32) 6 (3.68) No 840 (89.65) 97 (10.35) significantly (P ; chi-square test) associated with being betelnut chewing habit-positive, as were the grade of differentiation, index tumor site, drinking and smoking habits, and second primary oral cancers (Table 1). 3.1 Visible oral and oropharyngeal premalignant lesions and second primary oral cancers in patients with positive betel-nut chewing habits There were 236 patients (23.67%) with visible oral and oropharyngeal premalignant lesions. The clinicopathologic characteristics of age, index tumor stage, grade of betel-nut chewing habit differentiation, and index tumor site were significantly associated with visible oral and oropharyngeal premalignant lesions (chi-square test or Fisher s exact test; Table 2). One hundred fifty-seven patients (15.75%) with positive betel-nut chewing habits also had second primary oral cancer-positive lesions. Age, index tumor stage, index tumor site, and drinking and smoking habits were significantly associated with having second primary oral cancer-positive lesions (P <.05; Table 2). 3.2 Association between patients with visible oral and oropharyngeal premalignant lesions and second primary oral cancer in patients with a positive betel-nut chewing habit During the follow-up period, 64 patients (40.76%) with visible oral and oropharyngeal premalignant lesion-positive tumors and 93 patients

4 LIU ET AL TABLE 2 Clinicopathologic variables analysis in visible oral and oropharyngeal premalignant lesion and second primary oral cancer No. of patients (%) No. of patients (%) Variables Visible oral and oropharyngeal premalignant lesion-positive Visible oral and oropharyngeal premalignant lesion-negative P value cancer-positive cancer-negative P value Total no. of patients (23.67) 761 (76.33) 157 (15.75) 840 (84.25) Age, y, mean (SD) 49.4 (9.34) 51.6 (11.10) (9.25) (10.95) (23.23) 119 (76.77) (21.29) 122 (78.71) (25.89) 498 (74.11) 108 (16.07) 564 (83.93) >60 26 (15.29) 144 (84.71) 16 (9.41) 154 (90.59) Sex Female 7 (14.00) 43 (86.00) 5 (10.00) 45 (90.00) Male 229 (24.18) 718 (75.82) 152 (16.05) 795 (83.95) Index tumor stage I 121 (35.28) 222 (64.72) < (18.95) 278 (81.05).0249 II 51 (25.50) 149 (74.50) 36 (18.00) 164 (82.00) III 28 (18.30) 125 (81.70) 24 (15.69) 129 (84.31) IV ABC 36 (11.96) 265 (88.04) 32 (10.63) 269 (89.37) Differentiation grade Well differentiated 112 (29.40) 269 (70.60) 68 (19.43) 313 (80.57) Moderately differentiated 116 (21.68) 419 (78.32) 81 (16.40) 454 (83.60) Poorly differentiated 8 (9.88) 73 (90.12) 8 (9.88) 73 (90.12) Index tumor site Buccal mucosa 108 (28.80) 267 (71.20) 70 (18.67) 305 (81.33) Tongue 58 (20.00) 232 (80.00) 44 (15.17) 246 (84.83) Gingiva 28 (25.93) 80 (74.07) 12 (11.11) 96 (88.89) Others 42 (18.75) 182 (81.25) 31 (13.84) 193 (86.16) Drinking habit Yes 227 (23.65) 733 (76.35) 156 (16.25) 804 (83.75) No 9 (24.32) 28 (75.68) 1 (2.70) 36 (97.30) Smoking habit Yes 228 (23.53) 741 (76.47) 156 (16.10) 813 (83.90) No 8 (28.57) 20 (71.43) 1 (3.57) 27 (96.43) cancer <.0001 Yes 64 (40.76) 93 (59.24) No 172 (20.48) 668 (79.52) Visible oral and oropharyngeal premalignant lesion-positive and visible oral and oropharyngeal premalignant lesion-negative: patients with and without visible oral and oropharyngeal premalignant lesion. cancer-positive and second primary oral cancer-negative: patients with and without second primary oral cancer. (59.24%) with visible oral and oropharyngeal premalignant lesionnegative tumors were diagnosed as having second primary oral cancer-positive tumors (Table 2). Patients with visible oral and oropharyngeal premalignant lesions had a significantly (P <.0001) higher risk of developing second primary oral cancer-positive tumors than did patients with visible oral and oropharyngeal premalignant lesion-negative tumors (OR 2.67; 95% CI and adjusted OR 2.62; 95% CI ). Patients in both the 40 year and the year age groups separately had OR 2.60 (95% CI ) and OR 1.84 (95% CI ) higher odds than patients in the >60 year group did. After adjustment, the significantly higher risk was still discovered for patients younger than age 40 comparing them with patients older than 60 (adjusted OR 2.27; 95% CI ). However, no statistically significant higher/lower risk of second primary oral cancer was discovered in the sex, and drinking and smoking habits variables (Table 3). Further, an age-stratified analysis showed a significantly higher risk of positive second primary oral cancer for patients with visible oral and oropharyngeal premalignant lesions <60 year group (OR 2.80; 95% CI ; adjusted OR 2.66; 95% CI in the 40 year group; and in the year group OR 2.65; 95% CI ; and adjusted OR 2.61; 95% CI in the year group; Table 4). Visible oral and oropharyngeal premalignant lesion-positive male patients also had 2.59 times significantly higher risk of having a second primary oral cancer (OR 2.59; 95% CI and adjusted odds ratio 2.51; 95% CI ) than

5 1432 LIU ET AL. TABLE 3 Logistic regression analysis for second primary oral cancer showing crude and adjusted odds ratios and 95% confidence intervals Total no. of patients cancer-positive No. of patients (%) Crude OR (95% CI) Adjusted OR (95% CI) Visible oral and oropharyngeal premalignant lesion Yes 64 (27.12) 2.67 ( ) a 2.62 ( ) a No 93 (12.22) Age, y (21.29) 2.60 ( ) a 2.27 ( ) a (16.07) 1.84 ( ) a 1.60 ( ) >60 16 (9.41) Sex Female 5 (10.00) 0.58 ( ) 0.76 ( ) Male 152 (16.05) Drinking habit Yes 156 (16.25) No 1 (2.70) 6.98 ( ) 5.06 ( ) Smoking habit Yes 156 (16.10) No 1 (3.57) 5.18 ( ) 1.57 ( ) Abbreviations: CI, confidence interval; OR, odds ratio. Visible oral and oropharyngeal premalignant lesion-positive and visible oral and oropharyngeal premalignant lesion-negative: patients with and without visible oral and oropharyngeal premalignant lesion. cancer-positive and second primary oral cancer-negative: patients with and without second primary oral cancer. a Adjusted odds ratio is adjusted for age, sex, and drinking and smoking habits. visible oral and oropharyngeal premalignant lesion-negative men (Table 4). For 236 patients with positive visible oral and oropharyngeal premalignant lesions, analysis of the morphological typing was further performed. Significant results showed that the odds of a second primary oral cancer are 1.92 times higher on the patients with heterogeneous leukoplakia than on the patients with homogenous leukoplakia (OR 1.92; 95% CI and adjusted OR 2.17; 95% CI ; Table 5). 4 DISCUSSION Almost all of our patients (90.4%) were betel-nut chewing habitpositive. The mean age of the patients with positive betel-nut chewing habits with OSCC was 51.1 years, and that of betel-nut chewing habitnegative patients was 53.0 years (P <.0001). The risk of oral mucosal neoplastic change caused by chewing betel nuts has been reported in many articles, 2,10,17 which also claim that the neoplastic change is even worse when a betel-nut chewing habit is combined with tobacco smoking or a drinking habit or both. The positive betel-nut chewing habit rate was highest in our year group, our largest group of patients; this echoes the national oral cancer registry of Taiwan, which says that the peak incidence rate is in the year group. Compared with the data from the United States, 18 more than half of the patients with oral cancer were >60. A more intensive follow-up might be necessary in highrisk populations. The study by de Vries et al 6 reported that men had a significantly higher second primary tumor incidence rate than did women (21.4% vs 12%), but, in our series, the sex difference was not significant. Patients with positive betel-nut chewing habits have higher drinking and smoking rates than do betel-nut chewing habit-negative patients. One study 19 reported that heavy tobacco and alcohol use are directly responsible for the second primary tumor of the upper aerodigestive tract and lung, and that second primary tumors developed even after patients had quit smoking. 20 The visible oral and oropharyngeal premalignant lesion and second primary oral cancer rates were as high as 23.7% and 15.8%. Overall, 32.9% of the patients with positive betel-nut chewing habits with OSCC had at least one other oral and oropharyngeal lesion in our study. The oral mucosa field change rate was high in patients with a positive betel-nut chewing habit and OSCC. In addition to the visible oral and oropharyngeal premalignant lesion-positive and second primary oral cancer-positive rates being significantly high, the index tumor stage and the level of tumor cell differentiation grade were also significant factors: patients with early-stage disease often live a relatively long time, during which there is an increase in the risk of visible oral and oropharyngeal premalignant lesions and second primary oral cancers developing, and patients tumor cells with moderately and well differentiation grade seem to be significantly affected over time, but this notion requires additional studies for confirmation. In patients with OSCC, genetic alternations are common in the oral mucosa, despite its distance from the primary tumor Parts of

6 LIU ET AL TABLE 4 Stratified logistic regression analysis of the association between visible oral and oropharyngeal premalignant lesion and second primary oral cancer Total cancer-positive No. of patients (%) Crude OR (95% CI) Adjusted OR (95% CI) Age, y 40 Visible oral and oropharyngeal premalignant lesion-positive 13 (36.11) 2.80 ( ) a 2.66 ( ) a Visible oral and oropharyngeal premalignant lesion-negative 20 (16.81) Visible oral and oropharyngeal premalignant lesion-positive 47 (27.01) 2.65 ( ) a 2.61 ( ) a Visible oral and oropharyngeal premalignant lesion-negative 61 (12.25) >60 Visible oral and oropharyngeal premalignant lesion-positive 4 (15.38) 2.00 ( ) 1.96 ( ) Visible oral and oropharyngeal premalignant lesion-negative 12 (8.33) Sex Female Visible oral and oropharyngeal premalignant lesion-positive 2 (28.57) 5.33 ( ) 4.48 ( ) Visible oral and oropharyngeal premalignant lesion-negative 3 (6.98) Male Visible oral and oropharyngeal premalignant lesion-positive 62 (27.07) 2.59 ( ) a 2.51 ( ) a Visible oral and oropharyngeal premalignant lesion-negative 90 (12.53) Abbreviations: CI, confidence interval; OR, odds ratio. Visible oral and oropharyngeal premalignant lesion-positive and visible oral and oropharyngeal premalignant lesion-negative: patients with and without visible oral and oropharyngeal premalignant lesion. cancer-positive and second primary oral cancer-negative: patients with and without second primary oral cancer. a Adjusted OR is adjusted for age and sex. tumor-adjacent and tumor-distant samples have aberrant protein profiles. 24 Oral mucosa dysplasia usually shows copy number aberrations in specific chromosomal regions on mucosal cells that seemed to be healthy; however, these aberrations indicated early carcinogenesis. 25 Early molecular alienation is microscopic change in a small area 26 that cannotbedetectedorfollowedupindailyclinicalpractice:itrequires expensive and complicated immunocytochemical quantitative assessment. Visible oral and oropharyngeal premalignant lesions are neoplastic cells that have proliferated sufficiently to be clinically identifiable. Monitoring the proliferation field might have profound implications for cancer prevention or might allow physicians to discover the malignant transformation at an earlier stage. 27,28 Age-stratified logistic regression analysis showed significant differences in the incidence of second primary oral cancer-positive tumors, the stronger effect was in the 40 year group of patients with positive visible oral and oropharyngeal premalignant lesions than in year group, and finally in the >60 year group of patients with positive visible oral and oropharyngeal premalignant lesions. Moreover, combined with drinking and smoking habits, that hazard was even higher: these are the personal characteristics associated with visible oral and TABLE 5 Logistic regression analysis, stratified by morphologic grade of visible oral and oropharyngeal premalignant lesion-positive patients, of crude and adjusted odds ratios and 95% confidence intervals for being second primary oral cancer-positive, analysis morphologic grade of visible oral and oropharyngeal premalignant lesion Visible oral and oropharyngeal premalignant lesion-positive patients (n 5 236) cancer-positive patients Crude OR (95% CI) Adjusted OR (95% CI) Leukoplakia Homogenous, no. (%) 30 (21.74) Heterogeneous, no. (%) 33 (34.74) 1.92 ( ) a 2.17 ( ) a Erythroplakia, no. (%) 1 (33.33) 1.80 ( ) 1.58 ( ) Abbreviations: CI, confidence interval; OR, odds ratio. a Adjusted odds ratio is adjusted for age and sex.

7 1434 LIU ET AL. oropharyngeal premalignant lesion in patients with second primary oral cancer-positive tumors. Clinical investigation, the grade of visible oral and oropharyngeal premalignant lesion, and heterogeneous leukoplakia present a greater risk than homogeneous leukoplakia, which might also indicate a risk for developing a second primary oral cancer. High-grade visible oral and oropharyngeal premalignant lesions as well as heterogeneous leukoplakia and erythroplakia should be interpreted as signs that suggest a need to closely follow-up with the patients. That might allow us to create a profile of a high-risk group: young, with multiple carcinogenic personal habits, and positive visible oral and oropharyngeal premalignant lesions. These characteristics of patients with positive visible oral and oropharyngeal premalignant lesions are good predictive indicators of second primary oral cancer and can easily be used in routine follow-ups. A method for predicting visible oral and oropharyngeal premalignant lesions and second primary oral cancers has not yet been developed. 5 CONCLUSION Our preliminary findings on how visible oral and oropharyngeal premalignant lesions affect second primary oral cancer patterns in betel-nut chewing habit-related OSCC show that visible oral and oropharyngeal premalignant lesions are strongly and positively related to second primary oral cancers, especially in younger patients and in patients with multiple potential carcinogenic personal habits. If the visible oral and oropharyngeal premalignant lesion is heterogeneous, the risk of developing a second primary oral cancer is higher. Although our findings require confirmation in future studies with more patients with negative betel-nut chewing habits, visible oral and oropharyngeal premalignant lesions are powerful follow-up indicators. 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