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A high plasma level of leptin might activate the production of
inflammatory cytokines, such as TNF-alpha, IL-2, and IL-6,
which might contribute to the development of dysplastic BE
and the progression of tumor (Dvorak et al. 2007; FernadezRiejos et al. 2010; Tselepis et al. 2002).
Cigarette smoking is moderately associated with the
development of EAC. A pooled analysis from 10 populationbased case-control studies and two cohort studies demonstrated an OR of 1.96 and 2.18 for EAC and esophagogastric
junctional adenocarcinoma, respectively. Furthermore, there
was a strong dose–response association between pack years of
cigarette smoking and EAC (p < 0.001) (Cook et al. 2010). This
association has been confirmed by a recent meta-analysis, with
a relative risk of 1.66 in former smokers and 2.34 in current
smokers (Wang et al. 2017). Unlike ESCC, alcohol consumption is not associated with EAC (Anderson et al. 2009).
Though diet has been proposed as a possible risk factor for
EAC, the evidence is inconclusive. A large prospective cohort
study did not show a significant inverse association between
total fruit and vegetable intake and EAC risk (hazard ratio
(HR): 0.98), except for spinach intake (Freedman et al. 2007).
On the contrary, processed meat intake was associated with an
increased risk of EAC (Salehi et al. 2013).
Risk Factors for Esophageal Squamous Cell
Carcinoma
Non-modifiable Risk Factors
The gender predilection for ESCC depends on geographical
areas. The male-to-female ratio is approximately 4:1 in the
United States and nearly 1:1 in China and Iran (Abnet et al.
2018). It is most prevalent in central Asia, spanning China,
northern Iran, and Turkey (esophageal cancer belt).
Genetic factors might play a role in ESCC development, as
shown in a population-based case-control study in Taixing,
China. It demonstrated an almost doubled risk of ESCC in
individuals with a positive family history of esophageal cancer
among first-degree relatives (OR: 1.85). The ESCC risk was
further increased by eight-fold if both parents had esophageal
cancer (Chen et al. 2015). Although no specific gene mutation
has been strongly attributed to ESCC, several studies did identify germline mutation in PLCE1, TP53, HLA class II,
CDKN2A, cyclin D1, CDK4/6, RB1, NFE2L2, CHEK1, CHEK2,
NOTCH1, and NOTCH3 (Abnet et al. 2010; Cheng et al. 2016;
Gao et al. 2014; Wang et al. 2010). Although none of these are
currently being applied clinically, the research area in genomic
study is expanding, especially since the emergence of genomewide association study (GWAS).
Tylosis (Howel–Evans syndrome) and to some extent achalasia
have a strong link with ESCC. Tylosis is a rare autosomal dominant disease characterized by hyperkeratosis of the palms and
soles, and there is a 90% risk of ESCC in late-onset tylosis (Marger
and Marger 1993). Achalasia carries up to 50-fold increased risk of
ESCC, especially after 10 years of the initial diagnosis
(Leeuwenburgh et al. 2010; Meijssen et al. 1992). Patients with
head and neck squamous cell carcinoma (HNSCC) also have an
increased risk of ESCC. A population-based cohort study showed
that among patients with HNSCC, the excess risk of second cancer, calculated by using the standardized incidence ratio, was 21.8
for esophageal cancer (Jain et al. 2013). Other prospective studies
have shown a prevalence of synchronous or metachronous ESCC
of 3.8% to 14.9% (Chaber-Ciopinska et al. 2016).
Modifiable Risk Factors
A strong association between cigarette smoking and alcohol consumption has been linked to the development of ESCC, with a
three- to five-fold increased risk of ESCC in current smokers as
compared to non-smokers (Wang et al. 2017). Additionally,
studies around the globe have observed a six- to nine-fold
increased risk of ESCC with excess alcohol intake (Garidou et al.
1996; IARC Working Group on the Evaluation of Carcinogenic
Risks to Humans 2012; Lagergren et al. 2000; Pan et al. 2017).
Furthermore, both these lifestyle factors seem to have a synergistic effect in further increasing the ESCC risk up to 12-fold and
19-fold in men and women, respectively (Castellsague et al. 1999).
Regarding the role of diet in ESCC, a potential causal relationship has been found with consuming pickled vegetables
(OR: 2.08) (Islami et al. 2009b) and drinking high-temperature
beverages (Islami et al. 2009a), while a higher intake of fruits
and vegetables seems to have protective effect (Engel et al. 2003;
Howard et al. 2014).
Precursor Lesion: Barrett’s Esophagus
BE is a precursor lesion for EAC in the metaplasia–dysplasia–adenocarcinoma sequence, with a prevalence of approximately 0.8%
in the general population and 3% in those with GERD (Qumseya
et al. 2019). The diagnosis of BE requires the endoscopic appearance of metaplastic columnar epithelium (described as salmonpink color) above the gastroesophageal junction, replacing the
normal distal squamous epithelial lining (see Figure 1), together
with histopathological confirmation (intestinal metaplasia with
or without goblet cells) from esophageal biopsies (Fitzgerald et al.
2014). On the basis of the maximal length endoscopically, BE can
be divided into short (<3cm) and long segments (≥3cm).
BE is more prevalent in males and typically diagnosed after their
sixth decade of life. In a retrospective cross-sectional study
involving 155,641 patients undergoing upper gastrointestinal
endoscopy, the BE yield increased steeply from the third decade of
life (2.1%) to the sixth decade (9.3%) and then plateaued thereafter
(Rubenstein et al. 2010a). Other significant risk factors for BE are
white race, chronic GERD, central obesity, cigarette smoking, and
a family history of BE/EAC (Sanghi and Thota 2019).
The risk of EAC in BE increases with increasing BE length and
grade of dysplasia. In a study involving 1017 patients, the annual
cancer transition rates for patients with long (≥3 cm), short (<3
3 SCREENING, SURVEILLANCE, AND PREVENTION OF ESOPHAGEAL AND GASTRIC CANCERS 45
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Figure 1 Endoscopic view of salmon-pink coloured of columnar lined
esophagus, consistent with Barrett’s esophagus. The Prague classification
is C1, M4 (Schoofs et al. 2017/Hellenic Society of Gastroenterology).
cm), and ultra-short (<1 cm) BE were 0.22%, 0.03%, and 0.01%,
respectively (Pohl et al. 2016). A recent meta-analysis of 2694
patients demonstrated an annual progression rate of BE to adenocarcinoma of 0.54% (Singh et al. 2014b). Concerning the grade of
dysplasia, the annual risk of EAC with non-dysplastic BE is 0.33%,
increasing to 0.54% for low-grade dysplasia and steeply rising to
7% for high-grade dysplasia (Shaheen et al. 2016). A meta-analysis in 2017 concluded that the risk of progression to high-grade
dysplasia or EAC was higher with the presence of low-grade dysplasia in BE (OR: 4.2) (Krishnamoorthi et al. 2018).
Screening
Screening for Barrett’s Esophagus
Patients with esophageal cancer usually present late due to the
lack of symptoms during the early stages of cancer. Screening
aims to detect the precursor lesions and subsequently offers
close surveillance or early eradication treatment. In a prospective Dutch cohort study, EAC was detected at a significantly
earlier stage during endoscopic surveillance for BE as compared to the general population (92% vs. 15%). This study has
also shown a greater five-year survival benefit in the surveillance group as compared to the general population, that is, 74%
vs. 15%, respectively (Kastelein et al. 2016).
However, population-based or mass endoscopic screening is
not deemed to be efficient or cost effective and is not recommended by major gastrointestinal societies in the United States,
the United Kingdom, and Europe (Li et al. 2019). Nevertheless,
these societies do advocate screening for BE in high-risk individuals. The American College of Gastroenterology (ACG) and
the British Society of Gastroenterology (BSG) recommend BE
screening for patients with chronic (>5 years) and/or frequent
(≥weekly) GERD symptoms who have three or more of the
following risk factors: being male, being 50 years old or older,
being Caucasian, being a tobacco smoker, being obese, and
having first-degree relatives with a family history of BE or EAC
(Shaheen et al. 2016). BSG further recommends lowering the
threshold of these multiple risk factors in the presence of that
family history (Fitzgerald et al. 2013). Although the Asia Pacific
consensus has acknowledged the above recommendation from
the West, the experts did not suggest BE screening based on
prolonged GERD symptoms. This is due to low disease prevalence and burden in the Asia Pacific region. Furthermore, the
majority of symptomatic patients will usually be subjected to
diagnostic oesophagogastroduodenoscopy (OGD) anyway to
exclude peptic ulcer disease or malignancy (Fock et al. 2016).
For individuals subjected to BE screening, one-time OGD is
the gold standard procedure, together with four-quadrant
biopsies at the suspected BE site for every 1–2 cm as per Seattle
protocol (Levine et al. 1993). In the case of moderate-to-severe
esophagitis, repeat endoscopy is warranted (usually by 2–3
months) after proton pump inhibitor therapy to ensure resolution and subsequently perform the biopsy protocol as indicated
(Shaheen et al. 2016). One limitation of BE screening is the lack
of typical GERD symptoms in nearly 50% of the patients diagnosed with EAC (Rubenstein et al. 2010b). Additionally, a
systematic review demonstrated that only 4.7% of EAC patients
who underwent resection had been previously diagnosed with
BE (Dulai et al. 2002). Therefore, the current screening strategy
that mainly targets individuals with GERD symptoms might
have a limited impact on reducing the incidence of EAC and
the mortality rate (Mansour et al. 2017).
Other Screening Methods for Barrett’s Esophagus –
Currently Unproven for Clinical Use
Another potential limitation of screening is the application
of OGD as a screening tool. Although generally safe, OGD is
associated with small risk of complications such as sedation
risk, aspiration, bleeding, perforation, and discomfort during/after the procedure. The associated cost is another limiting factor. Alternative screening tools have been explored,
including unsedated transnasal endoscopy (uTNE), cytology
retrieval devices, esophageal capsule endoscopy, and biomarkers. uTNE can be performed with topical anesthesia
without sedation. This greatly improves patients’ comfort,
safety, and willingness to undergo BE screening (Jobe et al.
2006; Peery et al. 2012, 2012; Shariff et al. 2012; Thota et al.
2005). When comparing with gold standard OGD, uTNE had
excellent sensitivity (98%) and specificity (91%) for detecting the columnar lined esophagus for intestinal metaplasia
(IM), with 100% specificity (Peery et al. 2012). It is also much
cheaper than sedated OGD, as shown in a randomized controlled trial, with a mean cost difference of USD 1386.72
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(Moriarty et al. 2018). These advantages encourage the use of
uTNE as a BE screening tool at the hospital, at the bedside
office, or in mobile community settings.
One of the non-invasive methods of BE screening that use a
cytology sampling device is a cytosponge. It is a mesh surrounded by a gelatin capsule attached to a string and passed
transorally (Ross-Innes et al. 2015). The capsule dissolves five
minutes post-ingestion and expands the mesh to a sphere of 3
cm. The collected distal esophageal samples is then stained
with Trefoil Factor 3 (TFF3), a biomarker for specialized IM
(Maitra et al. 2020). A cytosponge with TFF3 had a sensitivity
of 73.3% and a specificity of 93.8% for detecting BE (Kadri et al.
2010). When compared with screening OGD, a cytosponge can
reduce the cost by 27–29% (Heberle et al. 2017). In addition to
TFF3, other biomarkers for BE can be applied to improve the
sensitivity, such as TFPI2, TWIST1, ZNF345, and ZNF569
(Chettouh et al. 2018; Pohl et al. 2016). However, two of the
larger trials (BEST 1 and 2) excluded short segment noncircumferential BE, which is considered important in the USA
(Chandar et al. 2020). Furthermore, the analysis of immunohistochemistry on cytology which is qualitative and requires
considerable expertise, not widely available. To circumvent
these problems competitor devices such as EsophaCap (another
sponge on the string device but smaller), uses methylated DNA
biomarkers to provide greater quantifiable (and perhaps less
subjective) information (Chandar et al. 2020). EsoCheck uses a
different swallowable encapsulated balloon which only deploys
in the high-risk lower esophageal sphincter area and then the
balloon inverts back into the capsule sheath before withdrawal
to minimize contamination with more proximal cells as in contemporary sponge methods (Chandar et al. 2020).
New different technologies have been invented and evaluated in pilot studies, with promising sensitivity, such as esophageal capsule endoscopy (EsohaCap) and balloon cytology (Falk
et al. 1997; Iyer et al. 2018; Moinova et al. 2018). Esophageal
capsule endoscopy is a non-invasive, unsedated imaging technique that allows the visualization of the esophageal mucosa.
From a meta-analysis with pooled participants of 618 patients,
capsule endoscopy showed a moderate sensitivity of 77% and
specificity of 86% (Bhardwaj et al. 2009). It is safe and easy to
conduct, and currently various sample collection designs and
lower cost versions are being trialed.
The screening method involving the use of blood samples for
detecting circulating microRNAs (miRNAs) has been explored
recently. miRNAs are endogenous, small non-coding RNAs that
regulate cell growth, differentiation, proliferation, apoptosis,
and metabolism and perform as post-transcriptional regulators of gene expression (Aalami et al. 2021). These miRNAs are
dysregulated and altered, and their presence in the blood could
serve as a biomarker for BE and early AEC. A pilot study of
41 patients with BE and 15 controls that used a panel of four
circulating miRNAs (miRNA-95-3p, -136-5p, -194-5p, and
-451a) revealed a sensitivity and specificity of 78% and 86%,
respectively (Bus et al. 2016). Another circulating miRNA that
has been studied is miR-21. It has the highest pooled sensitivity
and specificity (72% and 82%, respectively) for gastrointestinal
cancers, such as colorectal cancer, gastric cancer, hepatocellular carcinoma, and esophageal cancer (Chettouh et al. 2018).
However, it cannot discriminate between subgroups of gastrointestinal cancers and, therefore, is not useful as a screening
biomarker. Nevertheless, it might play a role in monitoring disease progression or treatment response.
Screening for Esophageal Squamous Cell
Carcinoma
Unlike EAC, there are no established guidelines to screen for
ESCC, either in the West or in the East, due to variable incidence
rates and limited evidence to support mortality benefits or
cost-effectiveness (Li et al. 2019). Nonetheless, a few studies have
been conducted in high-incidence regions (≥30 cases per 100,000
persons per year) in China to evaluate the efficacy of ESCC
screening. A cohort study in Cixian, China, demonstrated a
significant reduction in both the incidence of esophageal cancer
and mortality from esophageal cancer through 10 years of follow-up, with an HR of 0.61 and 0.45, respectively (Wei et al.
2015). A recent multicenter population-based cohort study with a
larger sample size (113,340 screened individuals) involving six
areas in China confirmed the effectiveness of a one-time endoscopic screening program. Through 10 years of follow-up, incidence and mortality rates of esophageal cancer were significantly
reduced by 27% and 57%, respectively (Chen et al. 2021).
Comparing 12 different ESCC screening methods in terms of cost
in China, the authors suggested two screening strategies. In areas
with low-income levels and limited health-care access, it was recommended that a patient will undergo one screening endoscopy
at the age of 50 years. Subsequently, the patient will undergo surveillance at five years and three years for low-grade dysplasia and
high-grade dysplasia, respectively. However, in areas with higher
income levels and better health-care access, the recommendation
was as follows: three screening endoscopies at five-year intervals
starting at the age of 40 years, with subsequent equivalent surveillance of dysplasia (Yang et al. 2012). In regard to the screening
endoscopic technique, chromoendoscopy with Lugol iodine
staining is the gold standard to detect dysplasia or early ESCC.
The sensitivity of Lugol chromoendoscopy in detecting
high-grade dysplasia is excellent when compared with standard
white-light endoscopy (96% vs. 62%) (Lao-Sirieix and Fitzgerald
2012). Some experts recommend endoscopic screening in the
subgroup of patients with pre-existing high-risk conditions that
predispose them to ESCC (e.g., HNSCC, tylosis, and achalasia),
although there is no clear-cut, evidence-based guidance regarding
the screening starting age and surveillance interval periods.
Surveillance for Barrett’s Esophagus
Patients diagnosed with BE are recommended to undergo
subsequent surveillance endoscopy so any dysplasia can be
detected in a timely manner, that is, before the invasion of the
3 SCREENING, SURVEILLANCE, AND PREVENTION OF ESOPHAGEAL AND GASTRIC CANCERS 47
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submucosa, when the risk of lymph node metastases is significantly increased (Shaheen et al. 2016). The endoscopic technique is similar to the screening endoscopy as described earlier.
In addition, a targeted biopsy should be performed for any
visible or suspected dysplastic lesions, such as nodules or
ulcers. If the biopsy indicates dysplasia, the finding should be
confirmed by two pathologists (one of them should specialize
in the gastrointestinal system).
In a large cohort study of BE patients (N = 29,536) in the
United States, BE surveillance showed better EAC outcomes
over a mean follow-up of five years. Compared with EAC
patients diagnosed by non-BE surveillance endoscopy (n =
215), EAC patients from the BE surveillance program (n = 209)
were diagnosed at an earlier stage (74.7% vs. 56.2%), had lower
cancer-related mortality (34% vs. 54%), and had a trend to
receive esophagectomy (51.2% vs. 42.3%) (El-Serag et al. 2016).
The current BE surveillance guidelines vary slightly according
to the gastrointestinal societies. Most of the recommendations
are based on the degree of dysplasia and the length of BE. Those
recommendations are summarized in Table 2.
Advanced Imaging Techniques in Barrett’s
Esophagus Surveillance
Detection for dysplasia might be hampered by inadequate sampling and interpretative error. To improve the detection rate of
dysplasia in BE patients, several advanced endoscopic imaging
techniques have been studied and meet the criteria for the preservation and incorporation of valuable endoscopic innovations
(PIVI) released by the American Society of Gastrointestinal
Endoscopy (ASGE), that is, per-patient sensitivity ≥ 90%, specificity ≥ 80%, and negative predictive value ≥ 98% for detecting
high-grade dysplasia or EAC (Shaheen et al. 2016). One of
those techniques is acetic acid chromoendoscopy. Acetic acid
will trigger a chemical reaction with the proteins in the cytoplasm when sprayed onto the BE. Acetylation of the cytoplasmic proteins will then result in aceto-whitening of Barrett’s
mucosa. Non-neoplastic segments remain white, while neoplastic areas appear as red spots and are, therefore, easily identified and biopsied (Bhandari et al. 2017). Advantages of acetic
acid chromoendoscopy are that it is a quick procedure and easy
to learn and acetic acid is low in cost. A meta-analysis of nine
prospective studies concluded a high diagnostic accuracy for
detecting high-grade dysplasia and EAC in patients with BE.
The pooled sensitivity, specificity, positive likelihood ratio, and
negative likelihood ratio were 92%, 96%, 25%, and 8%, respectively (Coletta et al. 2016).
Virtual chromoendoscopy has been applied in BE surveillance, resulting in increased dysplastic lesion recognition,
lesser biopsy, and reduced total cost (Pascarenco et al. 2016).
Examples of virtual chromoendoscopy include narrow-band
imaging (NBI) (optical chromoendoscopy), Flexible Spectral
Imaging Color Enhancement (FICE) (digital chromoendoscopy), and i-Scan (digital chromoendoscopy), which are
available on Olympus, FujiFilm, and PENTAX endoscopy
systems, respectively. A meta-analysis found excellent results
of a pooled sensitivity, specificity, and negative predictive
value of 94.2%, 94.4%, and 97.5%, respectively (Thosani et
al. 2016). A newer technique, namely confocal laser endomicroscopy (CLE), provides real-time diagnostic information at
the cellular level. It requires intravenous fluorescence dye to
excite the tissue. Typically, 2.5 mL of a 10% solution is administered immediately before the endomicroscopic examination
(Pilonis et al. 2022). Probe-based CLE has a high specificity
(of 98%) for detecting dysplasia and EAC but a sensitivity
of only 67% (Shah et al. 2018). It is not widely used as yet
due to its high cost and the fact that considerable training is
required for the correlation between imaging and histology.
Additionally, mild adverse events from dye injection have also
been reported, including nausea, vomiting, mild epigastric
pain, transient hypotension, and rash, at the site of injection
(El-Serag et al. 2016).
Biomarkers for Barrett’s Esophagus and
Esophageal Adenocarcinoma
Since the annual progression rate from BE to high-grade dysplasia/EAC is low and endoscopy is costly and involves safety
issues, there is a pressing need for risk stratification biomarkers for BE in order to predict the likelihood of BE to
progress to high-grade dysplasia/EAC in a patient. Extensive
studies have revealed some potential risk biomarkers, although
none of them have been applied clinically as yet. Epigenetic
alterations, such as DNA hypermethylation in the promoter
region of genes, are among the potential biomarkers for BE
and EAC. A retrospective study by the Early Detection
Research Network (EDRN) found a few hypermethylated
DNA markers (tissue-based assay) associated with an increased
risk of progression from BE to high-grade dysplasia/EAC.
These markers were hypermethylated p16 (OR: 1.74), RUNX3
(OR: 1.80), and HPP1 (OR: 1.77) (Schulmann et al. 2005).
When these markers were combined with clinical features
such as gender, BE’s length, and histopathologic examination,
a prediction model was able to stratify BE patients into low,
intermediate, and high-risk groups (ROC curve: 0.8386 and
0.7910 for two-year and four-year prediction models, respectively) (Sato et al. 2008).
When assessing the role of miRNAs in risk stratification,
multiple miRNAs, such as miR-15b, miR-25, miR-31, mi-93,
miR-106b, miR-192, miR-194, miR-196a, miR-196b, miR203, miR-205, miR-215, miR-375, and let-7c, have shown an
association with the progression of BE along the metaplasia–dysplasia–carcinoma sequence (Bansal et al. 2011; Fassan et al. 2011;
Leidner et al. 2012; Luzna et al. 2011; Maru et al. 2009; RevillaNuin et al. 2013; Smith et al. 2011). However, the efficacy of these
markers is still suboptimal due to small-sample-sized studies,
heterogenicity among studies, and non-standardized methods of
detecting miRNAs (Grady et al. 2020).
techniques can be used to
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facilitate targeted biopsies
and increase detection rate
Advanced endoscopic imaging
chromoendoscopy, optical
Routine use of
of dysplasia.
chromoendoscopy,
autofluorescence endoscopy,
or confocal laser
endomicroscopy is not
advised.
without IM and dysplasia:
Surveillance every 3–5 years. In columnar-lined esophagus
needed.
BE < 1cm: no surveillance
endoscopy in 3–5 years. If
still no IM, consider
a) < 1cm: no surveillance.
b) ≥ 1cm and < 3cm: repeat
surveillance every 5 years.
BE ≥ 1cm and < 3cm:
discharge.
surveillance every 3 years.
BE ≥ 3cm and < 10cm:
BE ≥ 10cm: refer to BE expert
2–3 years.
3–5 years.
c) ≥ 3cm: surveillance every
BE < 3cm: surveillance every
center for surveillance
endoscopy.
2–3 years.
BE ≥ 3cm: surveillance every
medication and repeat
endoscopy in 6 months. If
Optimization of antireflux
Optimization of antireflux
repeat shows:
a) No dysplasia: return to
medication and repeat
endoscopy in 6 months.
dysplasia, return to
If subsequent biopsies show no
non-dysplastic BE protocol.
dysplasia, repeat endoscopy
in 6 months.
b) Persistent indefinite
non-dysplastic BE protocol.
chromoendoscopy over
white light endoscopy.
Recommends
Recommends both white light
SURVEILLANCE METHODS
BSG, 2013 & 2018 ACG, 2022 ASGE, 2019 ESGE, 2017 APC, 2016 AUS CPG, 2014
Table 2 Barrett’s esophagus surveillance guidelines.
Advanced imaging modalities
Do not recommend routine use
endoscopy and
chromoendoscopy.
No recommendation on the
such as chromoendoscopy, is
not superior to standard
white light endoscopy.
of confocal laser
endomicroscopy.
transepithelial sampling
(WATS-3D) in addition to
Suggest using wide-area
use of p53 staining and
TissueCypher in addition to
standard histopathology
immunostaining may
improve the diagnostic
Addition of p53
Seattle protocol.
examination.
reproducibility of dysplasia
in BE.
medication and repeat
Intensification of antireflux
endoscopy in 1–2 years.
years.
BE and without IM: repeat
BE < 3cm: surveillance every 5
in patients with IM at the
SURVEILLANCE PROTOCOL FOR NON-DYSPLASTIC BARRETT’S ESOPHAGUS
cardia or those with irregular
Surveillance not recommended
years.
BE ≥ 3cm: surveillance every 3
Z-line.
dysplasia: repeat endoscopy.
If no IM, discharge the
patient from surveillance.
BE < 3cm and without IM/
every 3–5 years.
BE < 3cm with IM: surveillance
BE ≥ 3cm: surveillance every
2–3 years.
MANAGEMENT OF DYSPLASIA AND EARLY CANCER
medication (twice daily) and
Intensification of antireflux
medication and repeat
Indefinite dysplasia
Optimization of antireflux
endoscopy.
repeat endoscopy in 6
months.
dysplasia, surveillance every
1 year.
In persistent indefinite
endoscopy in 6 months.
dysplasia, return to
non-dysplastic BE protocol.
If subsequent biopsies show no
endoscopies show no dysplasia,
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consider less frequent
surveillance follow up.
especially where LGD is
definite, multifocal, and
Surveillance every 6 months.
If 2 consecutive 6-monthly
surveillance.
Consider treatment or
If for treatment, endoscopic
interval can be broadened to
Repeat endoscopy in 6 months.
If no dysplasia, surveillance
Consider endoscopic ablation
resection for all visible
lesions. RFA should be
considered in the absence of
1 year. After 2 subsequent
endoscopies negative for
dysplasia, return to
present more than one
focal lesions.
endoscopy in 6 months to
If for surveillance, repeat
non-dysplastic BE protocol.
endoscopies, RFA should be
If LGD is found on subsequent
occasion.
confirm LGD.
offered.
visible lesions and T1a
adenocarcinoma: endoscopic
resection followed by BE
eradication (RFA,
Dysplasia associated with
visible lesions and T1a
adenocarcinoma: Endoscopic
Dysplasia associated with
endoscopic resection.
T1a adenocarcinoma:
T1b adenocarcinoma:
cryotherapy).
Selected patients with T1b
resection followed by
ablation.
endoscopic resection may be
a valid alternative to surgery
if the endoscopic resection
specimen meets all these
early adenocarcinoma may
also be offered endoscopic
resection, only if
esophagectomy is not
indicated.
criteria:
500um.
a) submucosal invasion <
differentiated.
b) well or moderate
c) absence of lymphatic/blood
vessels invasion.
in deep resection margin.
d) absence of tumor infiltration
SURVEILLANCE METHODS
BSG, 2013 & 2018 ACG, 2022 ASGE, 2019 ESGE, 2017 APC, 2016 AUS CPG, 2014
is recommended.
Repeat endoscopy in 6 months.
Endoscopic eradication therapy
Repeat endoscopy in 6 months.
RFA is recommended if
Low grade dysplasia
Repeat endoscopy in 6 months.
If LGD is found, RFA should be
every year.
If not undertaken, surveillance
persistent LGD. If not
undertaken, repeat
endoscopy at 12 months
from diagnosis, and the
offered. If RFA is not
undertaken, continue
surveillance every 6 months.
or alternatively surveillance
every 3 months.
Endoscopic eradication therapy
visible lesions and T1a
adenocarcinoma: Endoscopic
resection followed by
ablation.
adenocarcinoma, but at high
risk of surgery: endoscopic
annually thereafter.
Dysplasia associated with
without visible lesions:
endoscopic ablative
High grade dysplasia & Barrett’s related adenocarcinoma
HGD/intramucosal cancer
technique – RFA has a better
Good prognosis T1b
safety profile with
comparable efficacy.
therapy can be offered.
visible lesions and T1a
adenocarcinoma: Endoscopic
resection followed by
ablation.
Dysplasia associated with
adenocarcinoma, but at high
Good prognosis T1b
risk of surgery: endoscopic
therapy can be offered.
(Recommended biopsy is according to Seattle protocol, i.e., quadrantic biopsy every 2cm for non-dysplastic BE, and every 1cm for dysplastic BE).
ACG, American College of Gastroenterology; APC, Asia-Pacific Consensus; ASGE, American Society of Gastrointestinal Endoscopy; AUS CPG, Australian Clinical Practice Guidelines; BE, Barrett’s esophagus;
BSG, British Society of Gastroenterology; ESGE, European Society of Gastrointestinal Endoscopy; HGD, high-grade dysplasia; IM, intestinal metaplasia; LGD, low-grade dysplasia; RFA, radiofrequency
ablation
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Among the altered proteins studied in the risk stratification of
BE, altered TP53 has shown an encouraging result. In a recent
retrospective study (n = 561 BE patients), abnormal p53 expression was highly correlated with the TP53 mutation status (90.6%
agreement) and significantly associated with the progression of
BE. However, in a subsequent prospective validation cohort (n =
1487 BE patients), only 49.7% of the progressors had altered
TP53 immunostaining (Redston et al. 2022). Although none of
BE guidelines have recommended routine testing of TP53 as
part of risk stratification, the BSG guideline does have a grade B
recommendation to test the immunostaining of TP53 in cases
with indeterminate dysplasia (Fitzgerald et al. 2013).
Prevention
Primary prevention of esophageal cancer involves controlling
the modifiable risk factors, while secondary prevention primarily aims to prevent neoplastic progression of the precursor
lesions. For EAC, treatment of the GERD symptoms, cessation
of smoking, and weight loss to address obesity are important
preventive interventions. Although nearly half of the patients
diagnosed with EAC do not have classic GERD symptoms
(Barb et al. 2007), the severity and chronicity of GERD symptoms remain strong indicators for progression toward EAC. In
a population-based case-control study, the presence of reflux
symptoms increased the risk of EAC (OR: 3.61). This risk was
higher with the presence of hiatus hernia (which signifies silent
reflux) (OR: 5.85) and the highest in cases with both reflux and
hiatus hernia (OR: 8.11) (Wu et al. 2003). Therefore, the
treatment of GERD with acid suppression is vital to prevent the
chemical irritation of the distal esophagus by gastric acid and
bile. Proton pump inhibitors (PPIs) effectively control GERD
symptoms and potentially reduce the risk of high-grade dysplasia and EAC in patients with BE. A meta-analysis of seven
observational studies showed a 71% reduction in the risk of
high-grade dysplasia and EAC (OR: 0.29) with PPI therapy
(Singh et al. 2014a). A recent prospective study (AspECT trial)
with a median follow-up of 8.9 years has demonstrated the
superiority of 40 mg esomeprazole over 20 mg esomeprazole in
reducing the incidence of dysplasia and neoplastic lesions in
patients with BE (Jankowski et al. 2018) PPI. Although PPIs are
generally safe, possible long-term side effects, such as osteoporosis, pneumonia, infectious diarrhea, and dementia, may preclude its use as a chemopreventive agent. BSG guidelines
recommend the use of PPIs for symptom control only. However,
recent ACG guideline 2022 recommends once-daily PPI
therapy in patients with BE (Shaheen et al. 2022). In addition,
the AspECT trial demonstrated a significant effect of low dose
aspirin 300 mg, to decrease progression to high grade dysplasia
(Jankowski et al. 2018). This was also one of the first trials to
show an additive effect of two chemoprevention agents, high
dose twice a day PPI and once a day aspirin, to work synergistically to prevent death and high-grade dysplasia. This trial
cohort is being followed up in the AspECT Excel trial to see if
both agents need longer than nine years’ use to prevent the
development of EAC.
Since obese individuals are likely to have GERD, it is wise to
encourage the patients to reduce weight and adopt a healthier
dietary style. Randomized controlled trials have shown that
weight loss and visceral fat loss are associated with improved
GERD symptoms and a reduction in esophageal exposure to
Tygat 2002). A prospective population-based cohort study in
Norway (the HUNT study) examined the association between
weight loss and reduction in GERD symptoms in 29,610 individuals. The authors concluded that weight loss is dose-dependently associated with both the reduction in GERD symptoms
and an increase in treatment success with anti-reflux medication (OR: 1.98 and 3.95, respectively) (Ness-Jensen et al. 2013).
Concerning anti-reflux surgery, the BSG guideline made a statement that “it is not superior to the pharmacological acid suppression for the prevention of neoplastic progression of BE, and
therefore should only be considered in patients with poor or
partial symptomatic response to PPIs” (Fitzgerald et al. 2013).
Notably, a proportion of obese patients have difficulty reducing
their body weight despite following dietary and lifestyle modification advice. Bariatric surgery is an effective intervention for
weight reduction, and the two most frequently performed procedures are Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). There is no official statement made either for or
against bariatric surgery as a preventive measure for BE/EAC.
However, it should be noted that although both RYGB and SG
have equivalent and good outcomes in terms of weight reduction
(Peterli et al. 2018; Salminen et al. 2018), SG might worsen preexisting GERD symptoms or even induce de novo GERD symptoms (Felsenreich et al. 2017; Genco et al. 2017; Mandeville et al.
2017). In fact, a recent meta-analysis of 46 studies found a 19%
increase in post-operative GERD, a 23% increase in de novo
reflux, a 28% increase in esophagitis, and an 8% increase in BE in
patients who had undergone SG (Yeung et al. 2020).
A few studies have looked at the role of aspirin, non-steroidal
anti-inflammatory drugs (NSAIDs), and statin as chemoprevention for EAC. A few observational studies have demonstrated a
protective effect of aspirin and NSAIDs against BE progression
to high-grade dysplasia/EAC (Corley et al. 2003; Gammon et al.
2004; Liao et al. 2012). In the AspECT trial, aspirin was found
to lengthen the time to reach the combined endpoint of death
(mortality from any cause, EAC, or high-grade dysplasia), but
only when patients using other NSAIDs were censored. The
study also revealed that a combination of 40 mg esomeprazole
with aspirin had a stronger effect as compared to 20 mg esomeprazole without aspirin (Jankowski et al. 2018). However, the primary outcome measured was the combined endpoint of deaths,
and the study did not demonstrate any significant results for
cancer-related outcomes. However, they did reduce high grade
dysplasia and death from all causes including aspiration related
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pneumonia. Due to unclear benefit/risk profile and a lack of
concrete evidence, BSG and ACG have made no recommendation regarding the use of aspirin and other NSAIDs as chemoprevention for EAC.
A meta-analysis of 13 studies demonstrated a significant
pooled reduction (28%) in the incidence of EAC among statin
users. The benefit was further increased (41% in EAC incidence
reduction) in a subgroup of patients with BE (in 5 studies)
(Singh et al. 2013b). However, the authors acknowledged that
there was considerable heterogeneity among studies. In a nested
case-control study among US veterans with BE, statin use was
associated with a decreased risk of EAC with an adjusted OR of
0.65 (Nguyen et al. 2015). Although currently available evidence
from observational studies indicates the protective effect of
statin in preventing BE progression, the sole use of statin as chemoprevention is currently not routinely recommended.
Similarly, the primary prevention of ESCC would revolve
around avoiding the precipitating risk factors, such as cigarette
smoking, excessive alcohol intake, and high intake of pickled
foods and hot drinks. Patients should be encouraged to adopt a
healthier lifestyle, with increased consumption of fruits and
vegetables. The evidence of PPIs, aspirin, NSAIDs, and statin as
chemoprevention for ESCC is conflicting and scanty (Alexandre
et al. 2016; Arai et al. 2021; Nielsen et al. 2012), and therefore
their use is not advocated for now.
Gastric Cancer
Risk Factors for Gastric Cancer
Non-modifiable Risk Factors
Risk factors for gastric cancer vary according to the tumor location within the stomach, that is, cardia and non-cardia regions.
Common non-modifiable risk factors for both types of gastric
cancers include advanced age, male gender, and family history.
Epidemiological data from the United States showed that a
higher proportion of individuals (70%) diagnosed with gastric
cancers were in the age group of 55–84 years (Karimi et al.
2014). Males have a predilection, with a five- and two-fold
higher risk for cardia and non-cardia gastric cancer, respectively, as compared to females (Brown and Devesa 2002). This
male predominance might be explained by experimental and
observational studies that have shown a potential protective
effect of estrogens and the harmful effect of anti-estrogen
drugs, such as tamoxifen, on the development of gastric cancer.
Additionally, women seem to develop gastric cancer at a similar
rate as men after menopause, but with a 10–15-year lag
(Camargo et al. 2012; Derakhshan et al. 2009; Karimi et al.
2014; Sheh et al. 2011).
Race or ethnicity poses an important non-modifiable risk
factor for gastric cancer. Data from the United States registry (Surveillance, Epidemiology, and End Results Registry
1992–2009) showed a nearly doubled incidence rate in nonwhite Americans compared with white Americans: whites
7.4/100,000; Asian/Pacific Islanders 15.6/100,000; Africans
12.8/100,000; Hispanics 12.9/100,000 (Lui et al. 2014). Within
the Asian American subgroup, Korean and Japanese Americans
had a much higher incidence rate (Kim et al. 2016). Globally,
four countries that have a high gastric cancer incidence (defined
as an age-standardized rate ≥20/100,000) are South Korea
(39.6/100,000); Mongolia (33.1/100,000); Japan (27.5/100,000);
and China (20.7/100,000) (Rawla and Barsouk 2019).
Although most gastric cancer cases are sporadic, in 10% of
the cases, the presence of family history is observed. The odds
ratio for the risk of developing gastric cancer in individuals
with first-degree relatives with gastric cancer ranges from 2 to
10 (La Vecchia et al. 1992; Palli et al. 1994; Shin et al. 2010;
Yaghoobi et al. 2010). A small percentage of gastric cancer cases
with a positive family history are thought to arise from the
hereditary syndrome. A few hereditary syndromes are associated with an increased risk of gastric cancer, with the highest
risk being carried by hereditary diffuse gastric cancer (HDGC)
syndrome. It is characterized by autosomal dominant inheritance, with a germline mutation in the CDH1 tumor suppression gene at chromosome 16q22 that encodes E-cadherin
(Rawla and Barsouk 2019). HDGC syndrome is associated with
an estimated 70% lifetime risk of gastric cancer in men and a
56% risk in women (frequently early onset, before the age of 40
years) (Hansford et al. 2015). In addition, there is a 50% lifetime risk of lobular breast cancer and an increased risk of signet-ring cell colorectal cancer (Roberts et al. 2019). Other
syndromes associated with an increased gastric cancer risk
include Peutz–Jeghers syndrome (29% lifetime risk), juvenile
polyposis (21% lifetime risk), Lynch syndrome (6–13% lifetime
risk), hereditary breast/ovarian cancer syndrome (2.6–5.5%
lifetime risk), and familial adenomatous polyposis (0.5–2%
lifetime risk) (Chun and Ford 2012).
Modifiable Risk Factors
The most important risk factor for gastric cancer (and it is
modifiable) is Helicobacter pylori infection. In 1994, H. pylori
was classified as a class 1 carcinogen by the International
Agency for Research on Cancer (IARC), given its pathogenic
role in the development of gastric cancer (IARC Working
Group on the Evaluation of Carcinogenic Risks to Humans
1994). Colonization and subsequent infectivity of H. pylori in
the stomach would trigger gastric inflammation and if left
untreated would lead to chronic gastritis. Over time, this
condition can progress to gastric atrophy and intestinal metaplasia, two important precursors of gastric cancer. A metaanalysis of 12 studies revealed a higher risk of non-cardia
gastric cancer with the H. pylori infection (OR: 2.97) compared
with cardia gastric cancer (OR: 0.99) (Helicobacter and Cancer
Collaborative Group 2001). Although gastric cancer is detected
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in approximately 1% of individuals with H. pylori infection (de
Vries and Kuipers 2007), more than 90% of individuals diagnosed with gastric cancer had a history of H. pylori infection
(Kato et al. 2007). The type of H. pylori strain and the duration
of the infection have also been shown to further influence the
risk of gastric cancer. Individuals with the cagA positive strain
of H. pylori (Azuma et al. 2004; Matos et al. 2013) and a history
of childhood H. pylori infection (Kikuchi et al. 1995; Mitchell et
al. 1992) are at a higher risk of getting gastric cancer.
Other modifiable risk factors for gastric cancer, although
less significant than H. pylori infection, are dietary intake, cigarette smoking, alcohol consumption, and obesity. Dietary patterns implicated in the development of gastric cancer include
moderate–high salt intake (relative risk: 1.41–1.68) (D’Elia
et al. 2012) (HR: 2.67) (Shikata et al. 2006), pickled/smoked/
dried foods (Tsugane S. 2005), a Western/unhealthy diet rich
in starchy and fatty foods (OR: 1.51) (Bertuccio et al. 2013),
and meat intake (association between meat intake and noncardia gastric cancer, HR: 3.52 for total meat intake, 1.73 for
red meat, and 2.45 for processed meat) (Gonzalez et al. 2006).
Consumption of fruit, vegetables, and vitamin C (HR: 0.5)
seems to provide a protective effect against gastric cancer
(Larsson et al. 2006; Riboli and Norat 2003; You et al. 1988).
A meta-analysis of 42 studies showed an increased risk of
both cardia (relative risk: 1.87) and non-cardia (relative risk:
1.60) gastric cancers with cigarette smoking (Ladeiras-Lopes et
al. 2008). Another meta-analysis of alcohol consumption and
risk of gastric cancer showed a dose-dependent relationship,
albeit the risk was much lower compared to dietary factors and
cigarette smoking. The pooled relative risk for heavy alcohol
drinkers (≥4 drinks/day) was 1.20, as compared to casual
alcohol drinkers, 1.07 (Tramacere et al. 2012). Regarding obesity, a meta-analysis of 10 cohort studies revealed an increased
risk of gastric cancer with excess body weight (BMI ≥ 25), with
an OR of 1.22. When stratified according to the subgroup, its
risk seems to be significant in gastric cancer arising from the
cardia region (OR: 1.55) rather than from the non-cardia
region (1.18) (Yang et al. 2009).
Precursor Lesions: Atrophic Gastritis and
Intestinal Metaplasia
Atrophic gastritis (AG) and IM are well-known precursors of
gastric cancer, as proposed in Correa’s cascade model (Correa
1992). Both terms are defined histologically, with AG characterized by a loss of gastric glandular cells due to chronic inflammation of gastric mucosa (predominantly associated with H.
pylori infection) or other causes, such as environmental factors
and autoimmunity (Crafa et al. 2018). Atrophy can present as
focal, multifocal, or diffuse patterns in the stomach. The loss of
glandular cells in AG is usually replaced by IM, which is an
intestinal-type epithelium lined by Paneth, goblet, and absorptive cells (Park ad Kim 2015).
A prospective population-based cohort study in the
Netherlands showed that the incidence of gastric cancer
increased as the premalignant gastric lesions progressed.
Among individuals with atrophic gastritis, the annual incidence of gastric cancer was 0.1%, followed by 0.25% for
individuals with intestinal metaplasia, 0.6% for individuals
with mild–moderate dysplasia, and 6% for individuals with
severe dysplasia (de Vries et al. 2008). In terms of the relative
risk of gastric cancer in patients with H. pylori infection and
AG, the risk was higher in moderate (relative risk: 1.7) and
severe atrophies (relative risk: 4.9) as compared to none/mild
atrophy (Uemura et al. 2001). The same cohort study also
demonstrated a significantly higher risk of gastric cancer in
the presence of gastric IM (relative risk: 6.4) (Uemura et al.
2001). A large-population-based study from Germany replicated the gastric cancer risk from these precursor lesions
(hazard ratio of 32.4 for the combination of AG and H. pylori
infection) (Chen et al. 2016). IM can be subdivided histologically into complete and incomplete types. The incomplete type of IM shows a higher risk of progression to gastric
cancer (relative risk of 4–11 when compared to the complete
type) (Gonzalez et al. 2013).
Screening
Population-based screening for gastric cancer is not advocated,
except for high-incidence countries. Indeed, Japan and South
Korea are the only two countries implementing a nationwide
screening program for gastric cancer at the moment. Japan’s
screening program was initiated regionally in 1960 and formally enrolled nationwide in 1983 (Li et al. 2019). Fifty years of
age and above is used as the cut-off screening age, and at the
early stage of the program, individuals were screened by radi-
onward, the Japanese guidelines recommended the use of both
radiographic and endoscopic techniques for the screening,
because of increasing evidence of the efficacy of endoscopy as a
screening method (Hamashima 2018). South Korea launched
its nationwide screening program in 1999 and adopted a similar screening strategy, albeit at a lower screening age, of 40
years and above (Jun et al. 2017).
The screening program in these high-incidence countries
has shown promising outcomes in support of its effectiveness.
Gastric cancer was detected at earlier stages during the screening period (40% in Japan and 46–67% in Korea) (Lee et al.
2006; Mizoue et al. 2003). The risk of gastric cancer was also
found to be lower in the screened individuals compared to the
unscreened ones (relative risk: 0.52–0.72 in Japan and 0.79 in
Korea) (Hamashima 2018). Most importantly, recent data from
Japan have shown a downward trend in the age-adjusted incidence and mortality rates (Sekiguchi et al. 2021).
In China, rather than conducting a mass-screening program
for the early detection of gastric cancer, they follow a modified
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high-risk population strategy, in which individuals aged 40–69
years living in selected high-risk regions are invited for screening. Examples of such areas are Yangzhong (initiated in 2006),
Linqu County in Shandong (2008), Zhuanghe County in
Liaoning (2008), Huai River Basin (2008), and Wuwei County
in Gansu (2010) (Fan et al. 2021). Most studies evaluating the
effectiveness of screening programs in China have shown
favorable outcomes, including increased detection of early
gastric cancer and reduced incidence and cancer-specific
mortality rates (Chen et al. 2021; Wei et al. 2015; Zhang et al.
2018). The first ever Chinese multicenter cluster-randomized
trial of endoscopic screening for esophageal and gastric cancers
was launched in 2015 and is currently in the follow-up phase.
The initial baseline data were encouraging, in which the diagnostic yield of both cancers was higher in high-risk areas than
in non-high-risk areas (esophagus: 0.9% vs. 0.1%, stomach:
0.9% vs. 0.3%). The same went for the early detection rate
(esophagus: 92.9% vs. 53.3%; stomach: 81.5% vs. 33.3%) (Zeng
et al. 2020). Hopefully, the end-of-trial analysis will provide the
much-awaited result of the effectiveness of population-based
screening of esophageal and gastric cancers.
Endoscopic screening and endoscopic surveillance for individuals with the gastric-cancer-associated hereditary syndrome
are recommended, given the increased lifetime risk for gastric
cancer. For HDGC, endoscopic screening is defined for individuals who have undergone endoscopy who do not know their
mutation status or do not have pathogenic CDH1 mutation.
Endoscopic surveillance is termed for individuals with CDH1
mutation positivity undergoing endoscopy (van der Post et al.
2015). For individuals with HDGC who have undergone endoscopic screening, the guideline recommends repeating endoscopy annually if the gastric biopsy is negative for signet ring cell
carcinoma. In individuals with positive CDH1 mutation, prophylactic gastrectomy at the ages of 20–30 years is advocated.
However, if gastric biopsy indicates the presence of signet ring
cell carcinoma and surgery is delayed or refused, annual endoscopic surveillance is recommended, and prophylactic gastrectomy should be re-emphasized (Pilonis et al. 2021). Identifying
the subtle gastric lesions in HDGC patients is endoscopically
challenging. The rate of a diagnosis miss is as high as 60%, even
with the use of high-definition endoscopy and NBI (Pilonis et
al. 2021). During endoscopy, the stomach should be meticulously inspected, with sufficient endoscopic time spent (30
minutes), but before the endoscopy, the stomach should be
thoroughly cleansed with saline and anti-foaming agent. An
extensive mapping biopsy protocol is recommended, with 5
biopsies in the antrum, the transitional zone, the fundus, and
the cardia and 10 biopsies in the gastric body (Blair et al. 2020).
Regarding other hereditary syndromes, Li et al. recommended the following (Li et al. 2019):
1
Peutz–Jeghers syndrome: The first screening OGD should
be performed at the age of eight years and continued endoscopic surveillance conducted every 2–3 years if gastric polyps
are present. If no gastric polyps are identified on the first OGD,
the next endoscopic surveillance should be at the age of 18
years and continued thereafter. After the age of 50 years,
patients are advised to undergo annual endoscopic screening.
2
Juvenile polyposis syndrome: The first screening OGD should
be performed in the mid-teens or when symptomatic. If no
polyps are detected, endoscopic surveillance is recommended
every three years. In the presence of a few gastric polyps, patients
should go for annual endoscopic surveillance. Prophylactic total
gastrectomy is recommended if multiple polyps are found.
Lynch syndrome: First screening OGD is recommended at
3
the age of 40 years and should be repeated every three years.
However, the latest BSG and ESGE guidelines do not recommend routine endoscopic surveillance for Lynch syndrome.
(Monahan et al. 2020; van Leerdam et al. 2019).
4 Li–Fraumeni syndrome: As per National Comprehensive
Cancer Network guidelines, the first screening OGD should be
performed at the age of 25 years or 5 years before the earliest
known gastric cancer. A surveillance interval of 2–5 years has
been suggested (Daly et al. 2021).
Screening Methods for Gastric Cancer
Screening modalities for gastric cancer include radiography,
endoscopy, and serology testing. Barium meals and fluorography have been used at the early stage of the screening program
in Japan and South Korea. Barium contrast is used to delineate
the gastric lining, and if any suspicious lesions are detected
radiographically, patients will be advised to proceed with
endoscopy. Although this technique is non-invasive, widely
available, and uncostly, the patient tolerance for the procedure
is low, affecting the participation rate in Japan (Hamashima
2014). In a large-population-based study in Korea, the sensitivity and specificity of barium meals were found to be 36.7%
and 96.1%, respectively, (Choi et al. 2012), while in Japan, they
were 89.3% and 91.4%, respectively (Hamashima et al. 2015).
Nowadays, this radiographic modality in Japan and Korea has
been largely replaced by endoscopy due to its better efficacy.
Evidence of the efficacy of endoscopic screening for gastric
cancer, as opposed to radiography, is plenty. Endoscopic screening exhibits a higher detection rate of gastric cancer (Matsumoto
2007; Tashiro et al. 2006), higher sensitivity and specificity
(Daly et al. 2021; Hamashima 2014), and a higher reduction rate
in mortality and is more cost effective (Cho et al. 2013) and has
a better acceptance rate as compared to radiographic screening
(Lee et al. 2015). A thorough endoscopic inspection of the
gastric mucosa is paramount to increase the detection rate of
precursor lesions and early gastric cancer. Endoscopically, AG
features that should be sought out include pale mucosa, loss of
gastric folds, prominence of vessels, and presence of atrophic
border (Kohoutova et al. 2021). Gastric IM is much more difficult to appreciate. The appearance of gray-white mildly elevated
plaques surrounded by patchy pale areas on standard whitelight endoscopy and “marginal turbid band with light blue crest”
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