Best Practice & Research Clinical Gastroenterology 29 (2015) 885e893

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Gastroenterology

Early esophageal cancer screening in China

Qin-Yan Gao, M.D., Ph.D., Jing-Yuan Fang, M.D., Ph.D. *
Division of Gastroenterology and Hepatology, Ren-Ji Hospital, Shanghai Jiao-Tong University School of
Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology,
Ministry of Health, State Key Laboratory of Oncogene and Related Genes, 145 Middle Shandong Rd, Shanghai
200001, China

a b s t r a c t
Keywords:
Esophageal cancer In China, the incidence of esophageal cancer (EC) and its related
Screening mortality are high. Screening strategies aiming at early diagnosis
China can improve the prognosis. Researches on detection of early EC,
especially in China are reviewed. Compared to esophageal balloon
cytology or routine endoscopy, chromoendoscopy with Lugol's
staining and biopsy appears to be the gold standard for early EC
diagnosis in China today. Narrow-band imaging endoscopy,
Confocal Laser endomicroscopy and other novel diagnostic ap-
proaches are more and more widely used in developed urban
areas, but cost and lack of essential training to the endoscopists
have made their use limited in rural areas. No specific biomarkers
or serum markers were strongly commended to be used in
screening strategies currently, which need to be evaluated in
future. Trials on organized screening have been proposed in some
regions of china with high disease prevalence. Screening in these
areas has been shown to be cost effective.
© 2015 Elsevier Ltd. All rights reserved.

Esophageal cancer (EC). one of the most common malignant tumors, has a high incidence and
mortality rate. EC is prominent in Ethiopia, China and Mongolia, and occurs more frequently in males
than in females [1]. According to population-based cancer registration data of the National Central
cancer registry (NCCR), collected in 2011, the incidence rate of EC was 21.62/100,000, which ranks it as
the sixth most common malignant tumor in China [2]. The incidence and mortality rate of EC vary

* Corresponding author. Tel.: þ86 21 53882450; fax: þ86 21 63266027.

E-mail address: jingyuanfang@yahoo.com (J.-Y. Fang).

http://dx.doi.org/10.1016/j.bpg.2015.09.018
1521-6918/© 2015 Elsevier Ltd. All rights reserved.
886 Q.-Y. Gao, J.-Y. Fang / Best Practice & Research Clinical Gastroenterology 29 (2015) 885e893

largely between urban and rural areas in China, being higher in rural than in urban areas (incidence
rate 13.46 vs. 30.19/100,000; mortality rate 10.67 vs. 22.12/100,000) [2].
There are two types of esophageal cancer, based on histopathology: squamous cell carcinoma (SCC)
and adenocarcinoma (AC). SCC is the major histological type in Western and Asian countries [3,4]. AC is
more often found in developed countries, and currently accounts for more than 80% of new EC cases in
the United States [5]. It is worth noting that in the recent decades, the incidence of AC has increased
rapidly and has even surpassed that of SCC in western countries. Currently, the incidences of AC and of
SCC are approximately equal [1].
Although the incidence of EC has declined because of elevated socioeconomic levels, prognosis is
very poor. Early EC is asymptomatic and most patients do not realize they have it until progressive
dysphagia and weight loss have occurred. The rich submucosal lymphatics of the esophagus also
accelerate early spread of cancer cells [6,7]. Therefore, in China, the overall five-year survival rate for
advanced EC is only around 10%e20% [8,9]. However, after conventional surgery and endoscopic
resection, the five-year survival rates of early-stage asymptomatic EC can reach 90% or above [10e12].
Thus, screening strategies for the early detection of precursor lesions and early EC are crucial.

Selection of screening subjects

According to the risk factors of EC, epidemiological characteristics and socioeconomic levels of
China, individuals should be considered at high-risk of developing EC and recommended to do a
screening test when they met the following criteria: (1) Age 40 years; with any of the following
criteria (2) from an area prone to EC (3) with upper gastrointestinal symptoms; (4) family history of EC;
(5) personal history of precancerous lesions or diseases of EC; and (6) high-risk factors of EC (e.g.,
smoking, heavy drinking and a history of SCC of the head and neck or upper respiratory tract) [13].

Methods of screening

Esophageal balloon or sponge cytology

Since the late 1950s, many studies were performed to develop early detection methods for EC,
among them, the most famous techniques has been the esophageal balloon or sponge cytology (Lawang,
which means “to pull a (fishing) net”). During the procedure, an inflatable balloon covered with nylon or
silk net is swallowed by the patients into the stomach, inflated, and pulled up while the size of the
balloon is regulated with a syringe connected to the balloon through tubing. At the upper esophageal
sphincter, the balloon is deflated and removed, and the attached cells are smeared directly onto the
slides to be stained for cytological screening [14]. This technique was widely used in China and accepted
as a diagnostic method by the WHO [15e17]. Studies comprizing large sample sizes found that balloon
cytology examination is easier, more economic and reproducible. The specificity of this technique can up
to 99e100%. However, its sensitivity is low (about 14e44%) and the concordance of EC by balloon
cytology and endoscopic biopsy histology is less than 50% [14,18,19]. Experience and skill are important
in cytological examination and biopsy targeting. A recent study of 15 years of follow-up showed that
balloon cytology examination remained a reliable method for early detection of EC and has accumulated
a valuable cytological bank, after long time follow-up, they also found some important markers for high-
risk subjects with predisposition to SCC which provide more useful information in clinical work [20].
However, this uncomfortable procedure has been phased out after the widely use of endoscopy.
Currently, it is not the best option for screening, but it can be used as a primary screening method before
endoscopy in areas prone to a high incidence of EC and with limited medical resources [13,21].

Endoscopy

1) Routine endoscopy

There is no doubt that esophagogastroduodenoscopy (EGD) with biopsy has become the standard
procedure for the early diagnosis of EC. Currently, the procedure is used widely in China. Several issues
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should be considered when screening EC with EGD, such as the limited acceptance of the procedure by
screening subjects, the complication rate, the cost and false negative rate of the diagnostic test [22]. The
accuracy of EGD to detect early cancer is a matter of debate. Studies reported that the sensitivity of EGD in
the diagnosis of EC in general clinical practice is 90.9% [23]; however, the overall missing rate of EC may up
to 7.8 % (95%CI 7.1e8.4) [24]. This rate may be even higher for early EC. Data from China showed that the
missing rate of early EC is nearly 50% [25]. The reason for the high missing rate may be failure of identify a
potential lesion, failure to recognize the significance of a lesion and choosing not to biopsy, and or taking
an insufficient number of biopsies. A high-resolution video fiberscope may help to improve the accurate
analysis of the mucosal lining in the esophagus. Moreover, training endoscopists to be familiar with the
features of early EC is very important. Although it is recommended that high quality figures should be
taken at least every 5cm in the esophagus [13], endoscopy units in China are currently facing increasing
pressure to perform more cases and reduce costs, making it difficult to perform in clinical practice.

2) Chromoendoscopy

About 40 years ago, chromoendoscopy was introduced into clinical use as a novel method to
identify mucosal lesions [26]. Several types of chromoendoscopy stains are used in clinical practice.
Iodine staining was first used to detect early carcinoma of the cervix of the uterus [27]. Lugol's solution
contains iodine and potassium iodide, and is frequently used to detect esophageal mucosal lesions,
making it useful in early EC screening programs [28,29]. Compared with cytology balloons, its sensi-
tivity and specificity are superior, at 96% and 63%, respectively. Some data even showed that the
specificity could reach 100% after reviewing the histology [30]. In China, a high-risk population study in
1988 showed that after staining with Lugol's solution, 23% of the lesions containing high-grade dys-
plasias and 55% of the lesions containing low-grade dysplasias, which were missed by routine
endoscopy, could be detected, which suggested strongly a role for Lugol's staining in the early detection
of dysplastic lesions of the esophagus [6]. Unfortunately, there are limitations of using Lugol's solution
to screen patients for EC. One is the low sensitivity; reduced staining in normal esophageal tissue can
cause false-positive results. Possible reasons include: 1) mucus on the mucosal surface that can inhibit
the contact between iodine dye and epithelial cells; and 2) less intense staining in the proximal
esophagus, which, to prevent aspiration, can lead to a weakly stained mucosa [31]. Reported adverse
events are rare, such as iodine allergy, esophageal spasm, bronchospasm and retrosternal discomfort
[32]. In our experience, Lugol's staining is a safe and well-tolerated procedure. Biopsy guided by iodine
staining has become the gold standard for research and clinical diagnosis in China today [13,33].
Few studies of methylene blue staining chromoendoscopy in China have been reported. Several of
them estimated the value of combined staining with methylene blue and Lugol's solution. The results
showed that double staining might contribute to a higher rate of the early diagnosis of EC [34e36].

3) Narrow-band imaging (NBI) endoscopy

Adding NBI to routine endoscopy was helpful in the early detection of EC. The main advantage of
NBI is the improvement in visualization of the intrapapillary capillary loops (IPCL). Data from China
showed that NBI could classify the different esophageal IPCL, which indicated the feasibility of NBI for
effective diagnosis of esophageal inflammation and cancer [37]. Foreign studies showed that the ac-
curacy of NBI in screening for EC has been reported to be equal to that of iodine staining chro-
moendoscopy, while the specificity of NBI was higher, especially in SCC [28,38e40]. Performing NBI
endoscopy is quite simple, amounting to just pushing a button on the endoscope, without using any
solution. However, the experience of endoscopist is an important factor for achieving successful results.
One study from Japan indicated that compared with less experienced endoscopists, experienced
endoscopists achieved a significantly higher sensitivity for detecting high-grade squamous neoplasia of
esophagus using NBI [41]. The benefit of magnifying NBI endoscopy had been assessed in some studies.
This technique achieved more accurate assessment of early EC and reduced adverse symptoms, total
procedure time and esophageal observation time compared with Lugol chromoendoscopy [40].
Nevertheless, even without magnification, NBI endoscopy and Lugol's staining show equivalent per-
formances [42]. Overall, NBI has much higher specificity in the diagnosis of esophageal dysplasia when
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compared to Lugol's staining. In areas without sophisticated endoscopes, Lugol iodine should be used.
In China, NBI endoscopies are widely used in developed urban areas, but cost and lack of essential
training to the endoscopists have made its use limited in rural areas.

4) Confocal laser endomicroscopy (CLE)

CLE allows not only observation of living cells and tissue, but also of the vascular networks of the
mucosal layer in the gastrointestinal tract during endoscopy. With a 1000-fold magnifying ability, it
enables visualization of the cells of the esophageal squamous epithelium and IPCLs [43,44].
Compared with other kinds of endoscopy, the CLE technique has great advantages. First, it can pro-
vide detailed observation for not only the epithelial cells, but also microvascular patterns. Second, it
provides up to 1000-fold magnified imaging in vivo during the procedure, thus the alterations of the
shape and size of IPCLs can be observed clearly and easily. Third, it can reduce the biopsy rate, the
waiting time for pathology and the cost for repeat endoscopy [45,46]. Emphasizing the features of
both cells and capillary patterns make it more suitable for the diagnosis of esophageal tumors in the
early stage. However, its application requires an endoscopist experienced in image reading, and high
diagnostic accuracy also needs high quality images. In addition, the presence of moving artifacts
caused by the heartbeat and breathing might lead to an unsatisfactory quality of endomicroscope
image.
Recently, a novel diagnostic approach by 3-dimensional (3D) confocal endomicroscopic imaging
was invented by a Chinese medical team that permits the investigation of the degree of surface
maturation of the esophageal epithelium. Using special scoring criteria based on surface maturation,
intraepithelial neoplasms and non-neoplastic epithelial lesions can be distinguished clearly [47].
The reasons why the use of CLE is limited in China are similar to those stated for NBI; however, one
study confirmed that CLE can be learned quickly after a short training period [48].

5) Other kinds of endoscopy

Some special kinds of endoscopy are also used to screen early EC. For example, high-resolution
microendoscope (HRME), which provides subcellular resolution, images when used with a topical
fluorescent agent. It is easy to control by insertion through the endoscope's accessory channel and
provides gentle contact with the mucosa; thus providing clear features of cellular features, which help
the endoscopist to differentiate benign epithelium from neoplasia in real-time. The sensitivity and
specificity of HRME could reach 95% and 79% at a low cost [49]. A recent study revealed that HRME is
useful and cost-effective in endoscopic screening and surveillance programs for both average-risk and
high-risk populations [50].
The Fujinon intelligent color enhancement (FICE) is another new diagnostic method that can be
used to screen for EC. This technique uses a magnifying mode to determine tumor margins and depth
by observing the IPCL. In 2014, one study showed that compared with Lugol chromoendoscopy, the
positive rates of early esophageal squamous cell carcinoma examined by FICE or magnifying FICE were
significantly higher (92.6% and 96.3%, respectively) [51].
Additionally, autofluorescence imaging (AFI) is a non-invasive optical technique that is based on the
detection of tissue autofluorescence from endogenous fluorophores. Previous results suggested that
AFI could improve the visualization of esophageal neoplasia [52,53]. In China, a study of screening EC
by AFI showed that although the image quality was acceptable, the current system of AFI is not equal to
chromoendoscopy in sensitivity and positive predictive value (PPV) [13,54].
Recently, multiphoton microscopy has emerged as a potential diagnostic tool for imaging tissue
architecture and cellular morphology, based on two-photon excited fluorescence and second harmonic
generation. It has several advantages, such as enhanced imaging penetration depth, increased image
quality and reduced toxicity by the generation of auto-fluorescence images without the need for
fluorescent dyes [55].
Moreover, trimodal imaging, which comprises a combination of white-light endoscopy, auto-
fluorescence and NBI [56,57]; optical coherence tomography, which can produce a high-resolution
image of the epithelium [58,59]; elastic scattering spectroscopy, which is based on measurement of
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the epithelial elastic scattering index, have been used to screen early EC worldwide [60]. However, in
China, no studies of these methods using large sample have been reported. Further studies are needed
to determine whether these methods are also helpful for the early detection of EC [28].

Tumor markers and biomarkers

Serum markers for EC in clinical use, such as carcinoembryonic antigen, carbohydrate antigen (CA)
19-9, squamous cell carcinoma antigen, and CYFRA21-1 have been used in the diagnosis of EC for some
time; however, they are not sufficiently sensitive for early diagnostic purposes [61,62]. Therefore, a
noninvasive method for the early detection of EC is urgently needed, which would play an important
role in the management of patients. Many studies have focused on biomarker targets, such as p53 [63],
peroxiredoxin VI [64], heat shock protein 70 [65], CDC25B phosphatase [66], FOXP3 [67] and Anti-p16
autoantibodies [68]. One cohort study revealed that a panel of six tumor-associated antigens (p53, NY-
ESO-1, heat shock protein 70, etc) by enzyme-linked immunosorbent assay could differentiate early-
stage EC patients from normal controls with a sensitivity of about 45% (95% CI: 32e59%) and a spec-
ificity of 95% (95% CI: 89e98%) [69]. Although the sensitivity was not very high, it may act as an aid to
diagnose EC, especially in the early-stage.
In addition, microRNAs (miRs), which are small noncoding RNAs involved in posttranscriptional
regulation of mRNAs stability and protein translation, may play an important part in the progress of EC.
Fassan et al. found that let-7c, miR-192 and miR-215 could be biomarkers of early AC of the esophagus
[70]. Others found that miR-196a, miR-203 and miR205 might be related to the tumorigenic progress
from Barrett's esophagus through varying grades of dysplasia to AC of the esophagus [71,72]. In SCC of
the esophagus, Wu et al. ascertained that the expression levels of miR-143 and miR-145 were signif-
icantly decreased and were correlated with tumor invasion depth [73]. Unfortunately, research on the
relationship between squamous intraepithelial neoplasia (the most predictive marker for risk of EC)
and SCC of the esophagus are rare [74]. One study from China used the Serum surface-enhanced laser
desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS) and support vector machine
(SVM) algorithm to demonstrate that the different stages of esophageal carcinogenesis could be
discriminated. The results showed that the specificity and sensitivity of this novel model for a blind test
were 96.8% and 87.1%, respectively [75]. Therefore, there is a great potential to improve the detection of
SCC of the esophagus using this kind of combined biomarker model compared with only a single
biomarker. However, those specific biomarkers or serum markers need to be further evaluated in
multicenter, large sample and prospective trials.

Early detection and early treatment program in China

Based on the effective and successful methods for the early detection of EC, a strategy for EC control
in high-risk areas in China was proposed. Some programs have been started by the Chinese govern-
ment. One of them was proposed around the Taihang Mountains, Linxian, Cixian and Yangchen, and
approximately 300,000 people from these three stations were chosen for field studies [76]. The high-
risk population was defined based on the criteria shown above and they were screened by endoscopy
with iodine staining and multiple biopsy. After that adults with normal, mild and moderate dysplasia
would be followed up and examined again in 5.5 and 3 years. A pilot study diagnosed 3.5% cases with
EC and 0.9% cases with gastric cancer, and among those cancers, 89.5% were at an early stage. The cost
of each examination was low because the living standards were low in these areas. The cost of each
endoscopy was only cost $10, while the cost of treatment for the late stage of EC was calculated to be
about $800. Therefore, the program was demonstrated as effective for decreasing the mortality from
EC.
In addition, another study was held in 2011e2014 [77]. The seven participating cities and counties
were Linzhou, Jiyuan, Huixian, Yanshi, Neixiang, Hebi and Xunxian. 36,154 people between 40 and 69
years old defined as high-risk population were screened. 2.42% of cases were found to have cancers,
and among them 84.5% were at the early stage.
In 2015, a population-based, community assignment study were evaluated the utility of endoscopic
screening on EC [78]. About 45,000 people were enrolled. Study showed that the overall cumulative
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incidence of EC in the endoscopically screened group (4.17%) and cumulative mortality (3.35%) is lower
than in the control group (5.92% and 5.05%, respectively).
Thus screening, and early detection and treatment, open up a new direction in cancer prevention.
Although there is no national program of EC screening is in progress, these studies may provide useful
information on how a national screening program can be conducted.
In summary, screening can detect potential invasive and early stage cancer, and increase treatment
efficacy. Among high-risk populations, there are many people with early-stage EC or precancerous
conditions who do not have any presenting symptoms. Therefore in China, EC endoscopic screening
has been demonstrated to be effective in urban areas of China. However, policy makers should consider
the cost-benefit of screening, uptake rate of subjects, utilization of health resources and economic
implications when choosing appropriate screening strategies.

Practice points

 Esophageal cancer (EC) has a high incidence and mortality rate in China
 Early EC is asymptomatic and most patients do not realize until progressive symptoms have
occurred.
 Screening programs or strategies aiming at early diagnosis can improve the prognosis

Research agenda

 Although NBI, CLE or other diagnostic approaches demonstrated to be effective in detection

of early EC, expensive cost and lack of essential training have made their use limited.
 Noninvasive biomarkers or serum markers for EC detection need to be further evaluated in
multicenter, large sample and prospective trials.
 Cost-benefit of screening, acceptability in the population, local health resources and eco-
nomic level should be considered when choosing appropriate screening strategies.

Conflict of interest

None.

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