Abstract
Background:
Oral leukoplakia is a precancerous disorder that is common among residents in Linxian. However, the associations between oral leukoplakia and upper gastrointestinal cancers have not been reported. We investigated the relationships between oral leukoplakia and upper gastrointestinal cancers in the Linxian General Population Trial cohort.
Methods:
The Linxian General Population Trial cohort, with 29,584 healthy adults enrolled in 1985 and followed through the end of 2012. With collected baseline data, hazard ratios (HR) and 95% confidence intervals (95% CI) for developing upper gastrointestinal cancers were estimated using Cox proportional hazard models.
Results:
During 28 years of follow-up, we confirmed a total of 2,924 incident esophageal squamous cell carcinoma (ESCC) cases, 1,644 gastric cardia cancers and 590 gastric non-cardia cancers. Overall, participants with oral leukoplakia had significantly higher risk of developing ESCC (HR=1.18, 95% CI: 1.08, 1.29). Among individuals ≤52 years old at baseline, oral leukoplakia was associated with elevated risk of ESCC (HR=1.31, 95%CI: 1.15, 1.49). No significant associations were observed for gastric cardia or non-cardia cancers in either all subjects or subgroups.
Conclusions:
Oral leukoplakia was associated with increased risk of ESCC, particularly in younger population. Future studies are needed to confirm these findings.
Keywords: oral leukoplakia, esophageal squamous cell carcinoma, gastric cardia carcinoma, gastric non-cardia carcinoma, Linxian General Population Trial
1. Introduction
Esophageal cancer ranked as the 6th leading cause of cancer death worldwide in 2008, causing an estimated 406, 000 deaths, while gastric cancer was the 4th, killing 738,000 persons [1]. Nearly 52% of all esophageal cancer and 42% of the world’s gastric cancer occur in China [1]. Within Linxian county and the surrounding Taihang Mountain region in north central China, rates of upper gastrointestinal (UGI) cancers are particularly high, and historically have been reported to be responsible for over 20% of all deaths.
The etiology of UGI cancers in Linxian and other high-risk regions remains unclear, but studies have shown a role for numerous dietary deficiencies [2-5] and genetic susceptibility [6-7], and have suggested that environmental carcinogens [8] and thermal damage [9, 10] are also involved. Associations between oral hygiene and UGI cancers have previously been reported by us [11, 12] and others [13, 14]. Oral leukoplakia is an established precursor lesion associated with high risk of oral squamous cell carcinoma [15]. In the 1970s, oral leukoplakia was also reported in a few families with tylosis who also had esophageal squamous cell cancers [16, 17]. Although oral leukoplakia is common in Linxian, little prospective data for the association between oral leukoplakia and UGI cancers are available.
This study aimed to examine the associations between oral leukoplakia and risk of esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC) and gastric non-cardia carcinoma (GNCC) in the Linxian General Population Trial cohort in China.
2. Methods
2.1. Study population and data collection
The detailed description of Linxian General Population Trial cohort has been reported in the previous studies [18, 19]. Briefly, the General Population Trial enrolled subjects between 40-69 years old from the general population of four communes in Linxian in 1985. Finally, a total of 29,584 healthy individuals were randomized and received up to four daily vitamin or mineral supplement combinations for 5.25 years, beginning in March 1986. Individuals who had cancer, debilitating disease, or required daily medications were excluded. All participants were interviewed providing data on age, smoking, alcohol, family history of cancer and other variables, and given a brief physical examination that included an inspection of oral cavity, performed by a village doctor.
Age and sex were recorded from the participants’ ID cards. Individuals’ weight and height were measured during physical examination and body mass index (BMI) was calculated as weight in kilogram divided by height in meter squared. Smoking was defined as regular cigarette or pipe use for at least six months (including ever and current smokers), and alcohol drinking was defined as any consumption in the previous 12 months (The possible responses for drinkers could range from “several times per year” to “several times per day”). Family history of cancer was considered positive if a cancer was reported in at least one first-degree relative, including parents, siblings or offspring. Oral leukoplakia was characterized by white spots or patches in the mucous membranes inside the mouth after ruling out all other possible causes (such as oral candidiasis and lichen planus).
2.2. Follow up for cancer
During the trial period, village doctors visited all subjects monthly, and an International Endpoints Review Committee consisting of experts in cytology, pathology, surgery, and radiology from the US and China reviewed all endpoints and confirmed 85% of cancer diagnoses based on histology, cytology or x-rays. During the post-trial follow-up, a similar review was performed by Chinese experts. All esophageal cancers were squamous cell carcinomas; gastric cardia cancers were adenocarcinomas that occurred in the proximal three cm of the stomach and gastroesophageal junction; and gastric non-cardia cancers were adenocarcinomas located more distally [20].
2.3. Statistical analysis
We tested the differences of oral leukoplakia prevalence between groups using nonparametric Kruskal-Wallis Test and Chi Square Test. Cox Proportional Hazard Regression Models were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI). Potential confounders included age at baseline (continuous variable), sex (men or women), smoking (yes (regular cigarette or pipe use for at least six months) or never), alcohol drinking (yes (any consumption of alcohol in the previous 12 months) or never), BMI (continuous variable), education (never or less than 5 years or primary school or tertiary high school/ higher education or unknown), family history of cancer (positive (defined as reporting a cancer in at least one first-degree relative) or negative) and commune (Rencun, Yaocun, Hengshui or Donggang). Stratification analyses were performed by age at baseline (<52 and ≥52, based on the median age), sex (men or women), smoking (yes or no) and drinking (yes or no). Tests of trend were conducted by assigning individuals’ oral leukoplakia numbers as a continuous variable and entering this variable into the models. All analyses were performed using SAS software (version 9.2, SAS Institute Inc. Cary, North Carolina). All tests were two-sided test and the significant level was 0.05.
3. Results
A total of 29,449 individuals were included in the final analysis. At baseline, 7,105 persons were confirmed with oral leukoplakia. During 28 years of follow-up, we identified 2,924 incident ESCC cases, 1,644 GCC cases, and 590 GNCC cases.
Compared with subjects without oral leukoplakia, those with leukoplakia were younger (51.4 vs 52.0 years), were more often male (76.7% vs 34.3%), had a relatively lower median BMI (21.9 vs 22.0 kg/m2), were more likely to have higher education (13.6% vs 7.8%), were more commonly smokers (61.4% vs 20.2%) and drinkers (35.3% vs 19.7%), and were more likely to have a positive family history of cancer (36.5% vs 33.7%). (Table 1)
Table 1.
Baseline demographic characteristics by oral leukoplakia in the Linxian General Population Trial Cohort
| Oral leukoplakia |
|||
|---|---|---|---|
| Yes | No | P value | |
| Age (Mean±SD) | 51.4±8.7 | 52.0±8.9 | <0.001 |
| Sex, n (%) | |||
| Men | 5452 (76.7) | 7668 (34.3) | <0.001 |
| Women | 1653 (23.3) | 14676 (65.7) | |
| BMI, Mean±SD (kg/m2) | 21.9±2.2 | 22.0±2.6 | 0.032 |
| Education level, n (%) | |||
| Never | 1982 (27.9) | 9831 (44.0) | |
| Less than 5 years | 2753 (38.7) | 6430 (28.8) | <0.001 |
| Primary school | 1072 (15.1) | 2079 (9.3) | |
| Tertiary high school or higher education | 962 (13.6) | 1742 (7.8) | |
| Unknown | 366 (4.7) | 2263(10.1) | |
| Smoking, n (%) | |||
| No | 2740 (38.6) | 17824 (79.8) | <0.001 |
| Yes | 4365 (61.4) | 4520 (20.2) | |
| Alcohol drinking, n (%) | |||
| No | 4597 (64.7) | 17942 (80.3) | <0.001 |
| Yes | 2508 (35.3) | 4402 (19.7) | |
| Family history of cancer, n (%) | <0.001 | ||
| No | 4508 (63.5) | 14808(66.3) | |
| Yes | 2597 (36.5) | 7536(33.7) | |
Table 2 presents the associations between oral leukoplakia and risk of all three UGI cancers. We found a significant association between oral leukoplakia and risk of ESCC. Compared with individuals without oral leukoplakia, subjects with leukoplakia had an 18% higher risk of ESCC incidence (HR=1.18, 95% CI: 1.08, 1.29). This significant association was present in both men and women (for men: HR=1.19, 95% CI: 1.06, 1.32; for women: HR=1.19, 95% CI: 1.02, 1.39). There was no statistically significance for gender difference. No significant associations were observed between oral leukoplakia and risk of GCC and GNCC.
Table 2.
Crude and adjusted hazards ratios (HR) and 95% confidence intervals (CI) for the associations between oral leukoplakia and upper gastrointestinal cancers in the Linxian General Population Trial
| ESCC | GCC | GNCC | |||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| n | HR (95%CI) | Pinteraction | n | HR (95%CI) | Pinteraction | n | HR (95%CI) | Pinteraction | |
| Crude | 2924 | 1.33 (1.23,1.45) | - | 1644 | 1.44 (1.30,1.60) | - | 590 | 1.42 (1.19,1.69) | - |
| Age- and sex-adjusted |
- | 1.27 (1.16,1.38) | - | - | 1.08 (0.97,1.21) | - | - | 1.06 (0.88,1.27) | - |
| Fully adjusted* | - | 1.18 (1.08,1.29) | - | - | 1.04 (0.92,1.16) | - | - | 1.01 (0.83,1.23) | - |
| Age | |||||||||
| <52 | 1344 | 1.31 (1.15, 1.49) | 0.243 | 734 | 1.12 (0.94, 1.33) | 0.231 | 250 | 1.02 (0.76, 1.38) | 0.944 |
| ≥52 | 1580 | 1.08 (0.95, 1.22) | 910 | 0.96 (0.82, 1.12) | 340 | 1.00 (0.77, 1.29) | |||
| Sex | |||||||||
| Men | 1400 | 1.19 (1.06,1.32) | 0.928 | 1008 | 1.05 (0.93,1.20) | 0.701 | 367 | 1.06 (0.86,1.32) | 0.473 |
| Women | 1524 | 1.19 (1.02, 1.39) | 636 | 0.97 (0.75, 1.25) | 223 | 0.84 (0.53, 1.35) | |||
| Smoking | |||||||||
| No | 1932 | 1.21(1.07, 1.37) | 0.616 | 952 | 0.97 (0.81, 1.16) | 0.415 | 329 | 0.83 (0.59, 1.15) | 0.210 |
| Yes | 992 | 1.16 (1.03, 1.32) | 692 | 1.09 (0.94, 1.27) | 261 | 1.16 (0.91, 1.49) | |||
| Alcohol drinking | |||||||||
| No | 2244 | 1.20 (1.08, 1.34) | 0.653 | 1216 | 1.05 (0.91, 1.21) | 0.380 | 441 | 1.02 (0.80, 1.28) | 0.803 |
| Yes | 680 | 1.15 (0.97, 1.35) | 428 | 0.99 (0.81, 1.21) | 149 | 1.02 (0.72, 1.43) | |||
Abbreviations: ESCC, esophageal squamous cell carcinoma; GCC, gastric cardia carcinoma; GNCC, gastric non-cardia carcinoma.
Adjusted for age at baseline, sex, smoking, drinking, BMI, family history of cancer, education, and commune.
In the subgroup analyses, we observed that risk for ESCC was increased for oral leukoplakia in both younger (<52 years) and older (≥ 52 years) age groups, although the HR reached statistical significant only in the younger group (HR=1.31, 95% CI: 1.15, 1.49). Results were also significant for risk of ESCC in both nonsmokers and smokers (HR=1.21, 95% CI: 1.07, 1.37 and HR=1.16, 95% CI: 1.03, 1.32, respectively). For the subgroup analysis by alcohol drinking, results were only significant for risk of ESCC among nondrinkers (HR=1.20, 95%CI: 1.08, 1.34), but not in alcohol drinkers (HR=1.15, 95%CI: 0.97, 1.35). No significant associations were observed for risk of GCC or GNCC in the subgroup analyses. (Table 2)
Table 3 summarizes the associations for the number of oral leukoplakia and risk of UGI cancers. Unilateral oral leukoplakia was associated with a12% higher risk of ESCC (HR=1.12, 95%CI: 1.00, 1.25, P<0.05), while risk in subjects with bilateral oral leukoplakia increased by 26% (HR=1.26, 95% CI: 1.12, 1.41), with evidence of a statistically significant monotonic trend (Ptrend<0.001). Neither unilateral oral leukoplakia, bilateral oral leukoplakia nor the trend for the number of oral leukoplakia were significantly associated with risk of GCC or GNCC (all P>0.05).
Table 3.
Hazards ratios (HR) and 95% confidence intervals (CI) for the associations between number of oral leukoplakia and upper gastrointestinal cancers in the Linxian General Population Trial
| ESCC | GCC | GNCC | ||||
|---|---|---|---|---|---|---|
|
| ||||||
| HR (95%CI) * | Ptrend | HR (95%CI) * | Ptrend | HR (95%CI) * | Ptrend | |
| Oral leukoplakia | ||||||
| No | 1.00 | 1.00 | 1.00 | |||
| Unilateral | 1.12(1.00, 1.25) | <0.001 | 0.99(0.85, 1.15) | 0.385 | 1.08(0.85, 1.37) | 0.802 |
| Bilateral | 1.26(1.12, 1.41) | 1.08(0.93, 1.24) | 0.95 (0.74, 1.21) | |||
Abbreviations: ESCC, esophageal squamous cell carcinoma; GCC, gastric cardia carcinoma; GNCC, gastric non-cardia carcinoma.
Adjusted for age at baseline, sex, smoking, drinking, BMI, family history of cancer, education, and commune.
4. Discussion
This is the first prospective study to examine the association between oral leukoplakia and risk of UGI cancers. Overall, a significant association between oral leukoplakia and risk of ESCC was found. Risk for ESCC was increased in men and women alike, and in both younger and older persons, although the association by age group was stronger and statistically significant only in the younger group. We also observed evidence of a significant monotonic trend for the number of oral leukoplakia and risk of ESCC (Ptrend<0.001). No associations with GCC or GNCC were seen in either all subjects or subgroups.
Several previous studies have reported that oral leukoplakia is a precancerous lesion, with an estimated annual rate of malignant transformation of 1.36%. Both the size and extent of oral leukoplakia are regarded to be risk factors for malignant transformation. Oral cavity is anatomically adjacent to the esophagus and stomach, and it is plausible that changes in the oral cavity could reflect changes in the UGI tract. Oral leukoplakia has been reported to have associations with genetic variants of the phase ? xenobiotic metabolism enzyme GSTT, p53 overexpression[21], and with variants of DNA repair genes[22], and these variants have also shown associations with risk of UGI cancers. In addition, many molecular factors are involved in malignant transformation between oral leukoplakia and cancer. The epidermal growth factor receptor (EGFR) was highly expressed in oral leukoplakia tissue [23, 24], and EGFR expression was also related to tumor stage, metastasis, and poor clinical outcome [25]. Thus several molecular alterations found in oral leukoplakia are similar to those seen in cancer.
Smoking [26] and alcohol drinking [27] have all been related to increased risk of oral leukoplakia, as have deficiencies of beta-carotene [28]. Further, supplementation with vitamin A and beta-carotene [29, 30] and consumption of fresh vegetables have been associated with reduced risk of oral leukoplakia[31]. Risk factors for oral leukoplakia in Linxian are not all similar to those reported from other areas. In Linxian women seldom consume tobacco or alcohol. Despite this, 10% of women had oral leukoplakia. Thus, smoking, and alcohol drinking cannot explain oral leukoplakia in Linxian. Linxian residents have a low socioeconomic status and poor nutritional status as a result of limited intake of fresh vegetables, fruits, meats, and eggs [2]. It seems possible, even likely, that the multiple nutrient deficiencies observed in Linxian contribute to the development of oral leukoplakia. Risk factors for oral leukoplakia in Linxian were also associated with higher risk of ESCC and gastric cancer. Smoking, for example, was related to increased risk of ESCC, GCC, and GNCC in an earlier report from the Linxian General Population Trial cohort [2]. Such shared risk factors suggest potential association between oral leukoplakia and UGI cancers.
As further potential evidence for this association, a previous case series from United Kingdom reported that most ESCC cases had evidence of pre-leukoplakia or leukoplakia in their oral mucosa[17]. Case reports are weak evidence for causality, however, and the present study represents the first analytic epidemiological study to investigate the association between oral leukoplakia and UGI cancers. In our study, oral leukoplakia was associated with risk of ESCC, while no association was seen with GCC or GNCC. From an anatomic perspective, the esophagus is closest to the mouth, the cardia next closest, and the non-cardia farthest. Thus, the associations we observed for oral leukoplakia and UGI cancer sites might be plausible.
This study has several strengths, including the prospective design, large sample size, and long-term follow-up. One limitation was the diagnosis of primary exposure (oral leukoplakia), which was based on visual inspection by village doctors who were trained but only modestly experienced in diagnosing this disease. Inaccurate diagnosis, however, would more likely have resulted in an over-diagnosis of oral leukoplakia, which should have biased the results towards the null. In addition, we only had single assessment of baseline oral leukoplakia, which could contribute to misclassification of oral leukoplakia status.
In summary, this first prospective study of oral leukoplakia and UGI cancers found that oral leukoplakia was significantly associated with risk of ESCC, especially among younger individuals. Further studies of evaluating the association between oral leukoplakia and UGI cancers are warranted.
Research highlights.
We investigated the associations between oral leukoplakia and UGI cancers.
Participants with oral leukoplakia had higher risk of ESCC.
Oral leukoplakia was not associated with elevated risk of GCC and GNCC.
Acknowledgement
We thank the participants and staff of the General Population Trial Cohort Study for their valuable contributions. Participants did not receive compensation, and staffs were not compensated outside of their salaries.
Founding: The work was supported by in part by National Cancer Institute contracts (N01-SC-91030 and N01-RC-47701 to the Cancer Institute, Chinese Academy of Medical Sciences); in part by the Intramural Research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; and in part by Cancer Institute, Chinese Academy of Medical Sciences. The sponsors had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Abbreviations
- UGI
upper gastrointestinal
- ESCC
esophageal squamous cell carcinoma
- GCC
gastric cardia carcinoma
- GNCC
gastric non-cardia carcinoma
- BMI
body mass index
- HR
hazard ratios
- 95% CI
95% confidence intervals
- EGFR
epidermal growth factor receptor
Footnotes
Publisher's Disclaimer: 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 citable 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.
Trial registration: The trial is registered with ClinicalTrials.gov, NCT00342654
Conflict of interest
None declared.
Ethical approval This study was approved by the Institutional Review Boards of US National Institutes of Health and the Chinese Academy of Medical Science, and all participants gave informed consent for the use of their blood samples and all data.
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