Health Risk Appraisal Models for Mass Screening of
Esophageal Cancer in Japanese Men
Tetsuji Yokoyama,1Akira Yokoyama,2Yoshiya Kumagai,4Tai Omori,3
Hoichi Kato,5,6Hiroyasu Igaki,6Toshimasa Tsujinaka,9Manabu Muto,10
Masako Yokoyama,7and Hiroshi Watanabe8
1Department of Technology Assessment and Biostatistics, National Institute of Public Health, Saitama, Japan;
2National Hospital Organization Kurihama Alcoholism Center;
Kawasaki Municipal Hospital, Kanagawa, Japan;
Information Services, National Cancer Center and
7Mitsukoshi Health and Welfare Foundation;
3Departments of Gastroenterology and Surgery,
4Kumagai Satellite Clinic;
6Surgery Division, National Cancer Center Hospital;
8Department of Surgery, School of Medicine, Keio University,
9Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan;
10Department of Gastroenterology and Hepatology, School of Medicine, Kyoto University, Kyoto, Japan
5Center for Cancer Control and
Background: Because early squamous cell carcinoma
(SCC) of the esophagus is detectable by endoscopic
esophageal iodine staining with high accuracy and is
easily treated by endoscopic mucosectomy, it is
important to develop efficient methods for screening
candidates for the endoscopic examination. Inactive
aldehyde dehydrogenase-2 (ALDH2) is a very strong
risk factor for esophageal SCC in alcohol drinkers and
thus may be suitable as a screening tool.
Purpose: To assess the performance of health risk
appraisal (HRA) models in screening for esophageal
SCC in the Japanese male population.
Methods: Two types of HRA models were developed
based on our previous case-control study, which
included assessment of ALDH2 activity and selected
risk factors (HRA-G and HRA-F: activities of ALDH2
assessed by genotype and questionnaire for alcohol
flushing, respectively). Each individual’s risk of
esophageal SCC was calculated quantitatively as a
risk score. The sensitivity and specificity of the HRA
models at various cutoff values of risk score was
estimated by a leave-one-out cross-validation. The
positive predictive value was estimated assuming
the prevalence of esophageal SCC in the whole
population to be 0.17% or 0.39% according to
Results: When individuals ranked in the top 10% of the
HRA-F risk score was screened, the sensitivity was
57.9% and positive predictive value was 0.93% or 2.12%
according to the above assumptions, respectively. The
sensitivity was slightly better by the HRA-G model
than by the HRA-F model.
Conclusion: The HRA models may provide an impor-
tant approach to early intervention strategies to control
esophageal SCC in Japanese men.
Biomarkers Prev 2008;17(10):2846–54)
Because early squamous cell carcinoma (SCC) of the
esophagus and oropharyngolarynx can be treated by
endoscopic mucosectomy (1, 2) or endoscope-guided
mucosectomy (3), it is important to develop methods to
identify individuals at increased risk of cancer of the
upper aerodigestive tract to provide detailed examina-
tions by the upper aerodigestive tract endoscopy
combined with esophageal iodine staining. Without
using the esophageal iodine staining, more than half of
intraepithelial or mucosal esophageal SCC would be
missed (2, 4). A possible approach to mass screening of
high-risk individuals is to classify them according to
exposure to risk factors such as heavy alcohol drinking
and smoking. However, the prevalence of drinkers and
smokers in Japanese men is so high (e.g., 35.7% of men
drink every day and 43.3% are current smokers in 2004;
ref. 5) that it is not practical to conduct detailed
endoscopic examinations on all of them; therefore, a
more effective screening method is required.
A mutant allele encoding an inactive subunit of
aldehyde dehydrogenase-2 (ALDH2*2) is prevalent
(42%) in the Japanese population (6), and the ALDH2
genotype determines an individual’s blood acetaldehyde
concentration (7). Acetaldehyde has been established as a
carcinogen in experimental animals (8) and is suspected
of playing a critical role in cancer development in
humans (9). Case-control studies in Japanese (10-13)
and Taiwanese (13-16) individuals and prospective
studies in which esophageal iodine staining has been
used in Japanese alcoholics (17-19) have consistently
shown a very strong link between the risk of esophageal
SCC and alcohol drinking in people possessing the
ALDH2*1/*2 genotype. Alcohol drinking together with
the ALDH2*1/*2 genotype has been reported to be a risk
factor for multiple cancerization in the upper aerodiges-
tive tract (13, 17, 19-21) and for oropharyngolaryngeal
SCC (13, 18, 20, 22, 23). The IARC has recently concluded
that substantial mechanistic evidence in humans with
inactive ALDH2 indicates that acetaldehyde derived
Cancer Epidemiol Biomarkers Prev 2008;17(10). October 2008
Received 5/1/08; revised 6/27/08; accepted 7/28/08.
Grant support: Ministry of Health, Labour and Welfare of Japan grants-in-aid for
cancer research 12-12 and 16-11.
Requests for reprints: Tetsuji Yokoyama, Department of Technology Assessment and
Biostatistics, National Institute of Public Health, Wako, Saitama 351-0197, Japan.
Phone: 81-48-458-6226; Fax: 81-48-469-3875. E-mail: email@example.com
Copyright D 2008 American Association for Cancer Research.
from the metabolism of ethanol in alcoholic beverages
contributes to esophageal cancer (9). Because drinking
a small amount of alcohol results in acetaldehydemia
and unpleasant alcohol flushing responses in persons
with inactive ALDH2, the activity of ALDH2 can be
assessed by a simple questionnaire that asks about
both current and past facial flushing (24, 25). This simple
questionnaire about flushing as a marker of inactive
ALDH2 is a highly reliable means of detecting inactive
ALDH2 and predicting the risk of SCC in the upper
aerodigestive tract (11, 18, 22, 25-27).
Increased mean corpuscular volume (MCV) is associ-
ated with alcohol drinking, especially drinking by
inactive ALDH2 heterozygotes, and with smoking, low
body mass index, and poor nutrition, all of which
increase the risk of SCC in the upper aerodigestive tract
(26, 27). We showed recently that MCV is a marker for
drinkers who are at high risk of SCC in the upper
aerodigestive tract (18, 26-28).
Based on our previous case-control study of esopha-
geal SCC in Japanese men (12, 25), we developed simple
health risk appraisal (HRA) models that predicted an
individual’s risk of developing esophageal cancer based
on logistic regression analyses. In addition to drinking
habits, smoking habits, and diet, the HRA models
included either ALDH2 genotype or the results of a
simple questionnaire about alcohol flushing (26). Each
individual was ranked according to his risk of esophageal
SCC. Persons in the top 10% risk category for esophageal
SCC, as estimated by the HRA model that included
ALDH2 genotype, were selected with high sensitivity by
two simple criteria, that is, the combination of moderate/
heavy drinking plus ‘‘heavy smoking or alcohol flushing’’
and the combination of moderate/heavy drinking plus
‘‘heavy smoking or MCV z 99 fl’’ (26). If these models are
valid for the screening of high-risk individuals for
esophageal SCC, a detailed examination by endoscopy
of such high-risk individuals may provide an efficient
method for detecting early esophageal SCC. In the
present study, we assessed the performance of screening
methods with our HRA models in terms of sensitivity,
specificity, and positive predictive value (PPV) to identify
individuals with and without esophageal SCC.
Materials and Methods
Data of Case-Control Study
Study Subjects. We previously conducted a case-
control study of 234 male cases with esophageal SCC
and 634 male cancer-free controls and reported the
results (12). The case participants were male Japanese
patients with primary esophageal SCC undergoing
treatment at the National Cancer Center Hospital,
National Cancer Center Hospital East, Kawasaki
Municipal Hospital, or National Osaka Hospital. The
cancer-free controls were men who came to two Tokyo
clinics for annual health checkups, and most of them
were ordinary residents or workers living in Tokyo or
surrounding areas. The age-adjusted prevalences of
current smokers and habitual drinkers in the controls
were very similar to those in the Tokyo metropolis
assessed by the National Nutrition Survey in Japan, a
nationwide population-based survey using representa-
tive samples (29). Thus, the controls represented the
general population of Tokyo well, at least with regard to
drinking and smoking habits (12). The ethics committee
of each collaborating institute reviewed and approved
the proposal for this study, and each of the participants
gave his informed consent.
Measurement of Risk Factors. Each participant indepen-
dently completed a structured questionnaire concerning
his drinking, smoking, and dietary habits; those with
cancer were instructed to report on their habits before
they got sick. The contents of the questionnaire and the
method of calculating alcohol consumption (1 unit = 22 g,
the ethanol content of one serving of sake) were described
previously (12). The subjects were classified as never/rare
drinkers, ex-drinkers, or current drinkers who consumed
1 to 8.9 units/wk (light drinkers), 9 to 17.9 units/wk
(moderate drinkers), or z18 units/wk (heavy drinkers).
MCV was measured during the health checkups in the
Table 1. Risks of esophageal SCC according to select-
ed risk factors including ALDH2 genotype or alcohol
risks of esophageal
SCC, OR* (95%
Multivariate model including ALDH2 genotype
ALDH2 genotype Alcohol drinking
0 (not calculable)
0 (not calculable)
Multivariate model including alcohol flushing
* Simultaneously adjusted for all the variables (including age; not shown)
in each multiple logistic regression model. These ORs were estimated by
our previously reported case-control study. See refs. 12 and 25 for details.
cFrequent versus never/sometimes (reference).
bz30 versus <30 pack-years (reference).
xNot every day versus almost every day (reference).
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