Risk of multiple squamous cell carcinomas both in the esophagus and the head and neck region
Manabu Muto *,
Mari Takahashi,
Atsushi Ohtsu,
Satoshi Ebihara 1,
Shigeaki Yoshida and
Hiroyasu Esumi 2
Division of Digestive Endoscopy and Gastrointestinal Oncology and 1 the Division of Head and Neck Surgery, National Cancer Center Hospital East, 6-5-1 kashiwanoha Kashiwa, 277-8577 Japan and 2 National Cancer Center Research Institute East, Kashiwa, Japan
* To whom correspondence should be addressed Email: mmuto{at}east.ncc.go.jp
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Abstract
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While multiple squamous cell carcinomas are often observed in the esophagus and the head and neck region and confound us about the favorable treatments, the reason why some patients are more likely to develop multiple cancers remains obscure. We statistically analyzed clinical factors in 203 patients with newly diagnosed squamous cell carcinoma, to assess the risk of multiple cancers for the establishment of an effective prevention and screening programs. Widespread epithelial oncogenic alterations were assessed as multiple lugol-voiding lesions (multiple LVL) using lugol chromoendoscopy. Genetic polymorphisms of alcohol dehydrogenase type 3 (ADH3) and aldehyde dehydrogenase type 2 (ALDH2) were identified by PCRrestriction fragment length polymorphism analysis. Forty patients had synchronous multiple cancers and the remaining 163 had solitary cancer. Presence of multiple LVL was the only independent risk factor for multiple cancers [relative risk (RR) = 67; 95%CI, 15310]. Multiple LVL was observed in only smoking drinkers. Among them, a multivariate analysis demonstrated that the ALDH2 deficiency allele (RR = 5.7; 95%CI, 2.811.6) and the slow metabolizing ADH3 allele (RR = 1.9; 95%CI, 1.17.9) were the independent risk factors for multiple LVL. Combination of these alleles lead to increase the risk of multiple LVL. In conclusion, an episode of multiple LVL is a remarkable high risk for multiple cancers both at the esophagus and the head and neck region. The interaction between drinking and the ALDH2 deficiency allele increases the risk. In addition, the slow metabolizing ADH3 allele enhances the risk. Prohibiting the use of alcohol and early detection of cancer are strongly recommended for such individuals.
Abbreviations: ALDH2, aldehyde dehydrogenase type 2; ADH3, aldehyde dehydrogenase type 3; LVL, lugol-voiding lesions; RR, relative risk
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Introduction
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In the esophagus and the head and neck region, multiple development of primary squamous cell carcinomas and widespread epithelial oncogenic alterations, including carcinoma in situ, dysplasia and hyperkeratosis have long been a recognized phenomena and have been explained by the field cancerization theory, which was proposed by Slaughter et al. (1) in 1953. Although many epidemiological studies have attributed drinking and smoking to this phenomenon for more than five decades (16), the reason why some patients are more likely to develop multiple cancers remains obscure. The second primary lesion is identified either simultaneously with the primary lesion (synchronous) or after a period of time (metachronous). Synchronous multiple primary cancers in the esophagus and the head and neck region particularly confound surgeons, radiologists and oncologists about the favorable treatments for each tumor and also adversely affect the survival and quality of life in the patients (7,8). Therefore, identification of the critical risk factors is very important for the prevention and earlier detection of multiple primary lesions.
Widespread epithelial oncogenic alterations surrounding the primary cancer have been ascribed to a histopathological progression pathway to squamous cell carcinoma (9,10). Therefore, data on these lesions is important to understand the mechanism of field cancerization phenomenon. However, previous studies mainly focused on only primary cancers (26,11,12) and little is known about the factors that predispose the epithelium to such lesions. Clinically, lugol chromoendoscopy can visualize such epithelial changes as multiple lugol-voiding lesions (multiple LVL), since dysplastic or hyperkeratotic epithelium does not stain with lugol iodine solution and appears white or pink in color, whereas normal epithelium is stained brown (13,14). We have previously reported that episodes of multiple LVL were precursors for a second primary esophageal cancer in patients with head and neck cancer (1416). However, the prevalence of multiple LVL in patients with multiple cancers and those with solitary cancer in the esophagus and the head and neck region has not been known. To assess the critical risk factor for multiple cancers from the point of view of field cancerization phenomenon, we analyzed the patients with cancer in the esophagus and/or the head and neck region.
Polymorphism in the genes for alcohol metabolism, particularly for alcohol dehydrogenase type 3 (ADH3) and aldehyde dehydrogenase type 2 (ALDH2), has been well studied (1721) and alters the rate of metabolism. Fast metabolizing ADH3 encoded by the ADH3-1 allele and inactive ALDH2 encoded by the ALDH2-2 allele appeared to have an important role in alcohol-associated carcinogenesis (2225). Herein, we investigated whether the genetic polymorphism of ADH3 and ALDH2 were potential risk factors for multiple cancers both in the esophagus and the head and neck region along with episodes of multiple LVL. We also identified the factors that predispose the epithelium to widespread oncogenic alternations.
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Materials and methods
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Patients
We analyzed 203 consecutive patients with newly diagnosed squamous cell carcinoma in the esophagus or the head and neck regions between September 1999 and August 2001. There were 177 male and 26 female subjects. The median age was 61 years (range, 2986 years).
Multiple primary cancers that synchronously developed in both the esophagus and head and neck region were classified as multiple cancers. Cases with multicentric cancers in only a single organ, the esophagus or the head and neck region, were classified as solitary cancer, which refers to cancer in a single organ, because in some cases, it was difficult to distinguish multicentric cancer from intra-organic metastasis or migration. Of these, 40 patients had synchronous multiple primary cancers and the remaining 163 patients had solitary cancer. All the multiple cancers were diagnosed at initial work-up. Distribution of a second primary cancer in the head and neck region was as follows: 20 in hypopharynx, 11 in oropharynx, 7 in oral cavity and 2 in larynx. Among the patients with solitary cancers, 74 had head and neck cancer alone (18 in hypopharynx, 13 in oropharynx, 8 in larynx, 19 in tongue and 16 in oral cavity) and the remaining 89 had esophageal cancer alone.
This study was approved by the institutional review boards of National Cancer Center at Tokyo. All patients provided written informed consent before enrolment. A fixed questionnaire, which aimed to obtain detailed drinking and smoking habits, was used for the interview. Taking into account the different ethanol concentration, alcohol consumption was estimated as the average amount of ingested pure alcohol for every drinking day (g pure alcohol/day): 179 patients (88%) had a drinking habit and median daily ethanol consumption was 65 g (range, 0324). Indicators of tobacco use, including the average number of cigarettes smoked/day and the duration of smoking in years was calculated as the smoking index: 182 patients (90%) had a smoking habit and median smoking index was 960 (range, 04400). Drinkers and smokers were defined as patients who drank >5 days in a week and smoked every day, respectively. Drinkers and smokers who had ceased drinking and smoking for >5 years before enrolment were categorized as ex-drinkers and ex-smokers, respectively. Non-drinkers and non-smokers were defined as patients who never used or who only rarely used alcohol and tobacco, respectively.
Lugol chromoendoscopy
All patients underwent lugol chromoendoscopy. Video endoscope (model Q200, Q230 and Q240, Olympus Optical Co., Ltd, Tokyo, Japan) was used throughout the examination. After a conventional examination,
10 ml of a 1.5% lugol iodine solution was sprayed over the entire esophageal mucosa using a catheter as described previously. All procedures were recorded on a digital filing system. Lugol voiding pattern of the background mucosa was reviewed and evaluated by a single endoscopist (M.M.) who was blinded to the results of genetic analysis. Multiple LVL was defined as lesions in which innumerable well-defined, irregular shaped lugol unstained lesions were observed throughout the entire esophageal mucosa.
Laboratory methods
Genomic DNA was extracted from peripheral lymphocytes using a DNA isolation kit for mammalian blood (Boehringer Mannheim, IN). The ADH3 and ALDH2 genotypes were analyzed by the PCRrestriction fragment length polymorphism method as described previously (15).
Statistical analysis
The Fisher's exact test and Student's t-test were used to compare categorical variables and continuous variables, respectively. A univariate logistic regression model was used to identify the risk factors for multiple cancers and multiple LVL. Univariate risk factors with a significance level <0.1 were entered into a multivariate logistic regression analysis. The level of significance for the multivariate model was set at 0.05. All tests of significance were two-tailed. All statistical analyses were performed with Stat View software package for Macintosh (version 5).
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Results
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Table I shows the characteristics of the patients with multiple cancers or solitary cancer. All the patients with multiple cancers had both drinking and smoking habits. Smoking index and daily ethanol consumption did not show any difference between the two groups. Presence of multiple LVL was quite frequent in those with multiple cancers compared with those with solitary cancer (93 and 18%, respectively). Among the 40 patients with multiple cancers, 32 (80%) were heterozygous for ALDH2-1/2-2, 8 (20%) were homozygous for ALDH2-1 and there was no patient who was homozygous for ALDH2-2. In contrast, among the 163 patients with solitary cancer, 65 (39.9%) were heterozygous for ALDH2-1/2-2, 94 (57.6%) were homozygous for ALDH2-1 and only 4 (2.5%) were homozygous for ALDH2-2.
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Table I. Patient characteristics with multiple or solitary squamous cell carcinoma(s) in the esophagus and the head and neck region
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In a univariate analysis of the risk of multiple cancers, presence of multiple LVL and the ALDH2-2 allele were significant factors (Table II). In particular, the risk of the presence of multiple LVL was remarkably high [relative risk (RR) = 57.0, 95%CI 16.4197.6]. A multivariate analysis shows that the presence of multiple LVL was the only risk factor for the multiple cancers.
When drinking and smoking habits were compared with the presence or absence of multiple LVL, only the smoking drinkers had multiple LVL (Table III). We therefore investigated the critical determinant of the development of multiple LVL among the subgroup of smoking drinkers. Logistic regression analysis showed that the ALDH2-2 allele and the ADH3-2 allele were independent risk factors for multiple LVL (RR = 5.7, 95%CI 2.811.6; RR = 2.9, 95%CI 1.17.9, respectively, Table IV). When the genotypes of ADH3 and ALDH2 were combined, the RR for multiple LVL was increased depending on whether they had the ADH3-2 allele, ALDH2-2 allele, both or neither (Table V). This significant tendency was noted in the analysis for multiple cancers (Table V).
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Table IV. Risk of multiple LVL in patients with squamous cell carcinoma in the esophagus and/or the head and neck region among smoking drinkers
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Table V. RR of multiple LVL and multiple cancers in combination of ALHD2 and ADH3 genotypes among smoking drinkers
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Discussion
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In this study, we observed a strong association between widespread epithelial oncogenic alterations, which was recognized as multiple LVL, and multiple cancers in the esophagus and the head and neck region. This may indicate that episodes of multiple LVL are precursors for multiple cancers in these regions. In addition, multiple LVL was observed only in the smoking drinkers. These findings are consistent with the suggestion that the phenomenon of field cancerization may be caused by the use of alcohol and tobacco. However, two-thirds (61.6%) of the smoking drinkers did not develop multiple LVL in this study. Similarly, the smoking drinkers do not always develop multiple cancers in the general population. This indicates that alcohol consumption and smoking may not directly affect the risk of multiple LVL.
We found significant independent and interactive effects of the genetic polymorphisms of ALDH2 and ADH3 on the development of multiple LVL. Combination of inactive ALDH2 and slow metabolizing ADH3 leads to an increased risk of multiple LVL. This combined effect was significantly noted in the risk of multiple cancers. These results strongly indicate that episodes of multiple LVL are precursors for multiple cancers. Yokoyama et al. (26) reported a strong linkage of inactive ALDH2 to the susceptibility for multiple cancers in male Japanese drinkers with esophageal or oropharyngeal cancers. They also reported a similar association between inactive ALDH2 and the risk of multiple intra-esophageal and esophageal cancer with oropharyngolaryngeal and/or stomach cancers in Japanese male alcoholics (27). These reports indicate that inactive ALDH2 plays an important role in the susceptibility of the upper aerodigestive tract to multiple cancers. However, these reports focused on the multiple cancers alone. Our present data further demonstrate that inactive ALDH2 along with slow metabolizing ADH3 is a critical determinant for the susceptibility to widespread epithelial oncogenic alterations. Since these alterations have been considered as pre-neoplastic lesions, we believe that it is the ultimate mechanism of development of multiple cancers in the esophagus and the head and neck region.
In contrast, it has been well known that the genetic polymorphisms of ALDH2 have a strong relationship with individual drinking behaviors in Orientals (28,29). In individuals with inactive ALDH2, the blood acetaldehyde concentration after drinking is
6-fold of those with active ALDH2 (30). Therefore, inactive ALDH2 has been known to play a protective role in alcohol consumption because it produces unpleasant reactions after drinking, such as facial flushing, palpitations, headache, vomiting and sweating (28,29). However, most patients with inactive ALDH2 in this study have a long history of drinking habit (>30 years). It would be important to elucidate the reason why those with inactive ALDH2 could be heavy drinkers.
The effects of polymorphism of the ADH3 gene on the risk of head and neck cancer have also been studied (3134). However, it remains controversial. The enzyme encoded by the ADH3-1 allele metabolizes ethanol to acetaldehyde 2.5 times faster than those with the ADH3-2 allele (17). Therefore, acetaldehyde accumulation by the fast metabolizing ADH3, have been reported to increase the risk of alcohol-associated cancer (22,31,35). However, in this study, the ADH-2 allele and not the ADH3-1 allele, modified the risk of the phenomenon of field cancerization. This might be attributed to the fact that acetaldehyde accumulation in the individuals with the ADH3-2 allele is so slow that they could drink without unpleasant reactions to acetaldehyde. On subsequent gradual accumulation of acetaldehyde, those with inactive ALDH2 could not eliminate it. Finally, they could increase the acetaldehyde level (16) and also the risk of the phenomenon of field cancerization. Therefore, we strongly recommend the individuals at risk to refrain from drinking to prevent the development of multiple cancers.
We have previously reported that multiple LVL are closely associated with synchronous and metachronous second primary esophageal cancers in the patients with head and neck cancer (14). The present study shows that multiple LVL is significantly associated with multiple cancers both in the esophagus and the head and neck region. From the point of view of the field cancerization phenomenon we need to look for a second primary cancer in the head and neck region among the patients with esophageal cancer, particularly those having multiple LVL in the background mucosa. Matsubara et al. (36) reported that patients with esophageal cancer had a remarkably high risk of subsequent head and neck cancer after esophagectomy. They also reported that an early detection of second malignancies allowed less invasive treatment with a favorable outcome. If we could detect a second primary cancer in the earlier stage, it would be of great benefit for the patients at high risk for multiple cancers. In such cases, multiple LVL could be a good biomarker for high risk.
For more than five decades, the field cancerization phenomenon has been explained by the effects of long-term exposure to tobacco smoke and alcohol alone. However, patients with squamous cell carcinomas in the esophagus or the head and neck region do not always develop multiple cancers even if they consume alcohol and cigarettes. This study clearly demonstrates that the interaction between drinking and the genetic polymorphism of alcohol metabolizing enzymes is the critical determinant. Our findings may provide a new insight into the understanding of the mechanism of the field cancerization phenomenon, and also provide a new preventive strategy and an early detection strategy for multiple cancers in the esophagus and the head and neck region.
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Acknowledgments
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This work was supported by Grant-in-Aid for Cancer Research 12-12f from Ministry of Health, Labor and Welfare.
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Received November 13, 2004;
revised January 1, 2005;
accepted January 24, 2005.