1. Annals of Oncology
doi:10.1093/annonc/mdq411review
Gastric atrophy and risk of oesophageal cancer and
gastric cardia adenocarcinoma—a systematic review
and meta-analysis
F. Islami1,2,3
, P. Sheikhattari4
, J. S. Ren2
& F. Kamangar4,1
*
1
Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical sciences, Tehran, Iran; 2
International Agency for Research on Cancer, Lyon, France;
3
King’s College London, Thames Cancer Registry, London, UK; 4
Department of Public Health Analysis, School of Community Health and Policy, Morgan State
University, Baltimore, USA
Received 26 May 2010; revised 9 June 2010; accepted 11 June 2010
Background: Several studies have reported an association between gastric atrophy and upper gastrointestinal
cancers. Our aim was to summarise the available information and calculate the relative risks (RRs) associated with
gastric atrophy for gastric cardia adenocarcinoma (GCA), oesophageal squamous cell carcinoma (OSCC), and
oesophageal adenocarcinoma (OAC) by conducting a systematic review and meta-analysis.
Methods: We searched the PubMed and ISI-Web of Science databases, as well as the reference lists of the relevant
articles. Summary RRs and 95% confidence intervals (95% CI) were calculated using random-effects models for the
association between gastric atrophy, defined histologically or by serum pepsinogen markers, and OSCC, OAC, and
GCA.
Results: Eighteen articles were included in the meta-analysis; 13, 7, and 3 studies reported on GCA, OSCC, and
OAC, respectively. The overall RRs (95% CI) for the three cancer types were: GCA, 2.89 (2.09–3.98); OSCC, 1.94
(1.48–2.55); OAC, 0.51 (0.19–1.37). Several subgroup analyses showed the robustness of the results. In the majority
of the analyses, there was low to moderate heterogeneity.
Conclusions: This study found two- to threefold increased risk of OSCC and GCA but a possible reduced risk of
OAC in people with gastric atrophy. Further studies are needed to establish the association with OAC and causal
association with OSCC, and mechanisms of the increased risk need to be investigated for GCA.
Key words: cardia adenocarcinoma, gastric atrophy, gastric cancer, meta-analysis, oesophageal cancer,
pepsinogen
introduction
Each year more than 1 million people die of cancers of the
oesophagus and stomach [1]. The two predominant
histological types of oesophageal cancer, i.e. oesophageal
squamous cell carcinoma (OSCC) and oesophageal
adenocarcinoma (OAC), have distinct risk factors. For
example, alcohol consumption is a strong risk factor for OSCC
but not for OAC [2]. Likewise, risk factors are not necessarily
similar for the two main anatomic subgroups of gastric cancer,
i.e. gastric cardia adenocarcinoma (GCA) and noncardia gastric
adenocarcinoma (NCGA) [3]. For example, while Helicobacter
pylori is a strong risk factor for NCGA, the association of this
organism with GCA is less clear [4].
Atrophy of the gastric mucosa has long been known as a risk
factor for NCGA [5–7]. However, the association of atrophy
with OSCC, OAC, and GCA is less well studied. Until recently,
GCA constituted a minority of all gastric cancers [8, 9].
Therefore in most studies, due to small numbers, the GCA
results were either not reported or did not receive enough
scrutiny. Higher risk of OSCC was initially reported in patients
with pernicious anaemia [10], an autoimmune disease that
includes atrophy of the stomach, and also in case series of other
patients with atrophy [11]. However, it has received more
attention in the past few years after a Swedish case–control
study found a strong association [12]. OAC was rare until the
1990s [9, 13], and there are still relatively few studies that have
investigated the association between atrophy and this type of
cancer.
Gastric atrophy is characterised by loss of specialised glands
in the stomach and their replacement by metaplastic cells and
interstitial fibrosis [14]. Therefore, this condition can be
diagnosed using histological examination. With the advent of
atrophy, specialised gastric cells in gastric fundus that produce
pepsinogen 1 (PG1) are replaced by metaplastic cells of antral
type. While serum PG1 level is reduced in gastric atrophy,
review
*Correspondence to: Dr F. Kamangar, Department of Public Health Analysis, School of
Community Health and Policy, Morgan State University, 4530 Portage Avenue Campus,
Room 302-D, Baltimore, MD, USA. Tel: +1-443-885-4788; Fax: +1-443-885-4309;
E-mail: farin.kamangar@morgan.edu
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Annals of Oncology Advance Access published September 22, 2010
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2. pepsinogen 2 (PG2) level remains stable or is even increased
because PG2 is produced in the mucosa of the gastric cardia,
fundus, antrum, and duodenum [15]. Therefore, atrophy can
also be diagnosed with low serum PG1 or a low ratio of serum
PG1 to PG2 (PG1:PG2 ratio).
In this systematic review and meta-analysis, we have
examined the association between gastric atrophy, defined
histologically or by serum pepsinogen markers, and OSCC,
OAC, and GCA.
methods
selection of studies
We searched the PubMed and ISI-Web of Science databases for all case–
control or cohort studies published in English language on the association
of gastric atrophy with oesophageal cancer and GCA risk. We used the
following terms to search the PubMed database (esophag* OR oesophag*
OR gastric OR stomach OR cardia) AND (cancer OR carcinoma OR
adenocarcinoma) AND (‘‘gastritis, atrophic’’ [MeSH] OR (gastric atrophy)
OR pepsinogen) AND ((case–control) OR (case–control) OR (cohort) OR
(prospective)). Equivalent terms were used to search text words in the ISI-
Web of Science database. All results were updated on 4 January 2010. Using
this approach, 416 and 273 publications were retrieved from the PubMed
and ISI-Web of Science databases, respectively. After considering the
matching articles in the two databases as a single article, 552 publications
remained for further evaluation. Eleven additional publications were found
by manual search of the bibliographies of the relevant original and review
articles and added to list. After exclusion of 542 non-relevant articles, three
articles [16–18] were excluded because the original or updated information
was available in 18 full-text publications that were finally included in the
meta-analysis [7, 12,19–34]. More detailed information on the study
selection process is presented in supplemental File 1 (available at Annals of
Oncology online). To reduce the possibility of missing the published articles,
at least two of the authors reviewed each publication. We contacted the
authors of one study [28] as further information was required.
data extraction and statistical analysis
Where data were available, we extracted information on first author, place
and year of the study, and other study characteristics such as study design
and the control selection method. We also extracted the following
information by cancer subtype, when applicable: the number of cases and
controls; the crude and adjusted relative risks (RRs), i.e. any ratio measures
of effect, including odds ratio, and 95% confidence intervals (CI); and the
variables for which the results were adjusted.
We used both random-effects models (DerSimonian–Laird method) and
fixed-effects models (Mantel–Haenszel method) to calculate summary RRs
and 95% CIs. Because both models yielded qualitatively similar results, we
only present those from random-effects models. When an individual study
presented both crude and adjusted RRs and 95% CIs, we used the
maximally adjusted results.
We compared gastric atrophy status among cases and controls. The
status was determined by direct examination of the gastric tissue specimens
or by the level of PG1 or PG1:PG2 ratio in serum samples. Different cut-off
points were used for the serologic tests. When results for several cut-off
points were presented, we used those that were in more concordance with
the cut-off points in other studies, i.e. PG1 < 28 to £ 70 lg/l and PG1:PG2
ratio < 2 to £ 3. If the study reported both PG1 level and PG1:PG2 ratio, we
used the latter, because PG1:PG2 ratio may be a more accurate indicator for
gastric atrophy than PG1 level [35]. One study that used histology reported
the results for gastric atrophy, intestinal metaplasia, and dysplasia separately
[33]. We combined the results using a fixed-effects model.
We conducted several subgroup analyses. All the included studies were
from Asia, Europe, and the United States. It has been suggested that the
association between H. pylori and GCA may vary between Western and
Eastern countries [36]. Since H. pylori is an important cause of atrophy, we
chose to conduct the analyses by geographic region. Several studies
recruited their control participants from those who referred to
gastroenterology clinics. As the rate of gastric atrophy in those hospital-
based controls might be different from the rate in the general population,
we performed subgroup analyses that included only population-based
controls. Consistent with our previous meta-analyses [37, 38], we present
the results for larger studies, defined as those with standard errors < 0.5,
separately. Since the association between gastric atrophy and oesophageal
and cardia cancer could be confounded by other factors, we also calculated
and present the summary of adjusted RRs (95% CIs) for studies in which
the results were controlled (by matching or adjustments) for the main risk
factors, i.e. age for all cancers, tobacco and alcohol use for OSCC, and
tobacco use and body mass index or total energy intake (as an indirect
indicator of body mass index) for OAC and GCA. As the sensitivity of PG1
level and PG1:PG2 ratio for detection of gastric atrophy may be different,
the studies that reported PG1:PG2 ratio were also analysed separately.
We used Begg and Mazumdar’s method to calculate P for rank
correlation and Egger’s weighted regression method to calculate P for
publication bias. We also plotted Begg’s funnel plot to examine small study
effects. To examine heterogeneity among studies, the Q-statistic (using
Mantel–Haenszel weights) and the I2
statistic were calculated. Throughout
the article, two-sided P < 0.05 was considered as statistically significant.
results
Table 1 shows summary characteristics of the 18 studies
included in this meta-analysis, of which 13, 7, and 3 studies
reported on GCA, OSCC, and OAC, respectively. Except for
two studies in which histological examination of the stomach
tissue was used to determine gastric atrophy, the other studies
measured pepsinogen level in serum samples. The majority of
the studies (n = 14) were population based.
gastric cardia adenocarcinoma
Thirteen studies were included in this analysis (Figure 1A and
Table 2). The overall RR (95% CI) was 2.89 (2.09–3.98). The I2
statistic was 34%, suggesting little to moderate heterogeneity,
and the P value associated with the Q-statistic was 0.11 (Table
2). Neither Begg and Mazumdar’s method (P for rank
correlation = 1.00) nor Egger’s weighted regression method (P
for bias = 0.65) showed evidence for publication bias. Begg’s
funnel plot for the association is shown in supplemental Figure
S1A (available at Annals of Oncology online).
All subgroup analyses showed a statistically significant
association between gastric atrophy and GCA risk (Table 2).
The summary RR (95% CI) was 2.72 (1.67–4.44) for studies
from Asia, 3.07 (1.95–4.83) for studies from Europe/the United
States, 2.65 (1.84–3.81) for studies with population-based
controls, 2.73 (1.94–3.83) for large studies, 2.56 (1.54–4.25) for
studies with adjusted results, and 2.43 (1.78–3.32) for studies
that reported PG1:PG2 ratio. There was no evidence for
significant heterogeneity in the subgroup analyses, except for
the adjusted analyses, which showed a marginally significant
Q-statistic (P= 0.06). We also conducted an analysis after
excluding the two studies with fewer than 10 cases [19, 21]; the
results were the same as the overall estimates (data not shown).
review Annals of Oncology
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3. Table 1. Summary of studies on the association between gastric atrophy and risk of oesophageal and gastric cardia cancer
Study; country Case/control Studied cancer Method of diagnosis for atrophic
gastritisa
Adjusted
resultsb
Study design
Parsonnet et al. [7];
United States
30/30 GCA S: PG1 < 50 lg/l No Nested CCS (in a cohort of
subscribers to a medical
care program)
Hattori et al. [19]; Japan 1/4858 GCA S: PG1:PG2 ratio £ 3 and
PG1 £ 70 mg/l; PG1:PG2 ratio
< 3 and PG1 < 50 lg/l;
PG1:PG2 ratio £ 2 and
PG1 £ 30 lg/l
No Screening study among steel
workers, and follow-up for
one year
Fukuda et al. [20]; Japan 52/112 GCAc
S: PG1:PG2 ratio < 3;
PG1 < 30 lg/l
No H-B CCS
Ye et al. [12]; Sweden 75/449 OSCC S: PG1 < 28 lg/ld
Yese
P-B CCS
67/449 OAC
103/449 GCA
Watabe et al. [21]; Japan 2/6940 GCA S: PG1:PG2 ratio £ 3 and
PG1 £ 70 lg/l
No P-B screening study, and
follow-up for a mean
period of 4.7 year
Nomura et al. [22];
United States
29/334 GCA S: PG1:PG2 ratio £ 2;
PG1 £ 30 lg/l
No P-B CCS
Oishi et al. [23]; Japan 23/NAf
GCAc
S: PG1:PG2 ratio £ 3 and
PG1 £ 70 mg/L; PG1:PG2 ratio
£ 2 and PG1 £ 30 lg/l
Yes P-B Cohort
Knekt et al. [24]; Finland 32/63 GCA S: PG1 < 49 lg/l No Nested CCS (in a P-B cohort)
Palli et al. [25]; Several
European countries
54/200g
GCA S: PG1 22 lg/l No Nested CCS (in a P-B cohort)
Hansen et al. [26]; Norway 44/132 GCA S: PG1:PG2 ratio 2.5 No Nested CCS (in a cohort of
blood donors)
Anderson et al. [27]; Ireland 131/260 OAC S: PG1:PG2 ratio £ 3, and £7 Yese
CCS; H-B cases, P-B controls
92/260 GCA
Derakhshan et al. [28]; Iran 19/38 OAC S: PG1:PG2 ratio 2.5 No H-B CCS
53/53 GCA
Iijima et al. [29]; Japan 90/89 OSCC S: PG1:PG2 ratio 2;
PG1 25 lg/l
Yes H-B CCS
Yokoyama et al. [30]; Japan 90/180 OSCC S: PG1:PG2 ratio £ 3, and £ 2;
PG1 £ 70, and £ 30 lg/l
No P-B CCS among alcoholics
Kamangar et al. [31]; China 125/250 Moderate to severe
squamous dysplasia
S: PG1:PG2 ratio £ 3, £ 4, £ 9,
and £ 12; PG1 £ 30, £ 50,
£ 100, and £ 130 lg/l
No P-B screening study
Ren et al. [32]; China 323/974 OSCC S: PG1:PG2 ratio £ 3, £4, £5,
and £6; PG1 £ 50 lg/l
Yes Nested CCS (in a cohort of
participants in an
intervention trial)546/974 GCA
De Vries et al. [33]; the
Netherlands
126/NAf
OSCC Histology: gastric atrophy,
intestinal metaplasia, and
dysplasia
No Nationwide gastric
atrophy cohort
Akiyama et al. [34]; Japan 253/253 OSCC Histology: gastric mucosal
atrophy open-type 2 and 3
Yes H-B CCS
a
When several serological cut-offs were presented, the ones highlighted in bold font were used in the current meta-analysis.
b
Reporting relative risks controlled (by matching controls or doing adjustments in statistical models) at least for age for all cancers, as well as tobacco and
alcohol use for OSCC and tobacco use and body mass index or total energy intake (as an indirect indicator of body mass index) for OAC and GCA.
c
Adenocarcinoma in proximal one-third of the stomach.
d
Participants with high PG1 level (158 lg/l) were categorised separately. They were not included in the current analyses.
e
Also adjusted for at least one socioeconomic status indicator, e.g. education level.
f
The number of cases was compared with standardised incidence rates.
g
A total of 910 controls (approximately four controls for each case) were enrolled for a total of 233 gastric cancer cases (including noncardia cancers).
CCS, case–control study; GCA, gastric cardia adenocarcinoma; H-B, hospital based; OAC, oesophageal adenocarcinoma; OSCC, oesophageal squamous cell
carcinoma; NA, not applicable; PG1, pepsinogen 1; PG2, pepsinogen 2; PG1:PG2 ratio, pepsinogen 1 to pepsinogen 2 ratio; P-B, population based; S,
serological assessment.
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4. oesophageal squamous cell carcinoma
Figure 1B and Table 2 show the results for the association
between gastric atrophy and OSCC. Seven studies were
included in this analysis. The overall RR (95% CI) was 1.94
(1.48–2.55). The I2
statistic was 49%, suggesting moderate
heterogeneity, and the P value associated with the Q-statistic
was 0.07, showing a marginally significant heterogeneity (Table
2). There was no evidence for publication bias using either Begg
and Mazumdar’s method (P for rank correlation = 0.55) or
Egger’s weighted regression method (P for bias = 0.84). Begg’s
funnel plot for the association between gastric atrophy and
OSCC is shown in supplemental Figure S1B (available at Annals
of Oncology online).
In analyses by geographic region, P values associated with the
Q-statistic were 0.27 and 0.10 for studies from Asia and from
Europe/the United States, respectively, suggesting no significant
heterogeneity in each region (Table 2). The summary point
estimate was lower for studies from Asia (RR = 1.64; 95% CI:
1.21–2.23) than for studies from Europe/the United States (RR
= 2.71; 95% CI: 1.43–5.11). However, there were only two
studies from Europe/the United States. Summary RR (95% CI)
was 1.91 (1.33–2.73) for studies with population-based
controls, 1.95 (1.45–2.63) for large studies, and 2.10 (1.19–3.70)
for studies with adjusted results. For these subgroup analyses,
the heterogeneity was statistically significant or borderline
(Table 2). For the studies that used PG1:PG2 ratio to
detect gastric atrophy, the summary RR (95% CI) was 1.71
(1.08–2.69) and the P value associated with the Q-statistic did
not suggest a significant heterogeneity (P = 0.16).
oesophageal adenocarcinoma
Only three publications reported on the association between
gastric atrophy and OAC (Figure 1C and Table 2). The overall
summary RR (95% CI) was 0.51 (0.19–1.37). The I2
statistic
showed a moderate variation (55%) among study results,
but the Q-statistic did not suggest significant heterogeneity
(P = 0.11). Since very few studies were included in this
subgroup, we do not report results of analyses for publication
bias.
In subgroup analyses, each subgroup consisted of only one or
two studies. Of note, when we considered the two studies that
used PG1:PG2 ratio as the marker of atrophy, we observed
a statistically significant association between gastric atrophy
and OAC with no heterogeneity; the summary RR (95% CI)
was 0.29 (0.13–0.47) and the P value associated with the
Q-statistic was 0.99 (Table 2). Results of other subgroup
analyses were similar to the overall results, with high
heterogeneity in subgroups with two studies (data not shown).
discussion
The results of this meta-analysis showed a nearly twofold
increased risk of OSCC and threefold increased risk of GCA
associated with gastric atrophy. We found only three studies for
the association between OAC and atrophy but the results of
these studies showed no increased risk and perhaps they even
suggested a reduced risk.
Gastric atrophy is a known risk factor for NCGA. In Pelayo
Correa’s model, published over two decades ago, atrophy is in
the pathway to intestinal type gastric carcinogenesis [39]. We
found a considerable number of studies reporting on the
association between gastric atrophy and GCA; nearly all studies
showed increased risk. As gastric cardia is located between the
NOTE: Weights are from random effects analysis
Overall
Anderson
Nomura
Watabe
Fukuda
Ye
Author
Hattori
Ren
Oishi
Knekt
Parsonnet
Palli
Hansen
Derakhshan
2.89 (2.09, 3.98)
2.21 (0.97, 5.03)
2.57 (1.01, 6.55)
0.73 (0.04, 15.18)
5.21 (2.49, 10.91)
4.50 (2.50, 7.80)
RR (95% CI)
8.72 (0.35, 214.26)
1.58 (0.95, 2.63)
2.77 (1.32, 5.81)
1.85 (0.55, 6.16)
5.00 (0.60, 42.80)
11.00 (3.00, 40.90)
1.56 (0.60, 4.09)
3.05 (1.32, 7.06)
100.00
9.48
8.03
1.07
10.79
14.05
%
Weight
0.97
15.40
10.75
5.52
2.08
4.87
7.75
9.25
1.5 2 5 10
NOTE: Weights are from random effects analysis
Overall
Author
Akiyama
Yokoyama
Kamangar
Ren
Iijima
Ye
de Vries
1.94 (1.48, 2.55)
RR (95% CI)
1.57 (1.03, 2.39)
1.53 (0.92, 2.56)
1.80 (0.58, 5.53)
1.10 (0.59, 2.04)
3.30 (1.60, 7.00)
4.30 (1.90, 9.60)
2.15 (1.81, 2.56)
100.00
Weight
%
18.93
15.57
5.03
12.38
9.80
8.56
29.73
1.5 2 5 10
C. Oesophageal adenocarcinoma
NOTE: Weights are from random effects analysis
Overall
Ye
Author
Anderson
Derakhshan
100.00
42.82
%
Weight
30.04
27.15
0.51 (0.19, 1.37)
1.10 (0.50, 2.50)
RR (95% CI)
0.29 (0.08, 1.01)
0.29 (0.07, 1.16)
1.1 .5 2
A. Gastric cardia adenocarcinoma
B. Oesophageal squamous cell carcinoma
Figure 1. Forest plots for the association of gastric atrophy with
oesophageal and gastric cardia cancers. Studies are sorted in order of
publication year. (A) Gastric cardia adenocarcinoma. (B) Oesophageal
squamous cell carcinoma. (C) Oesophageal adenocarcinoma.
review Annals of Oncology
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5. oesophagus and stomach, misclassification of GCA as
oesophageal and gastric noncardia adenocarcinoma, and vice
versa, is possible. This can influence the observed association in
our study. However, we do not expect a substantial influence
because it is unlikely that all studies had high rates of such
a misclassification. The direction and magnitude of increased
risk is similar to what has been reported for NCGA [4].
Atrophy may increase the risk of GCA through the same
mechanisms that it may increase the risk of NCGA. However, it
has been suggested that there may be two types of GCA, one
associated with H. pylori whose risk is increased with atrophy,
and one that resembles OAC, on which gastric atrophy may
have no or a protective effect [26]. Whereas this is an intriguing
hypothesis, we were not able to examine it in the current meta-
analysis because most studies did not provide information
stratified jointly by H. pylori and atrophy. However, our results
establish that overall atrophy substantially increases the risk of
GCA.
An association between atrophy of the gastric mucosa and
OSCC, a cancer outside the stomach, was not expected or
extensively studied until recently. The results of our study,
while indicating heterogeneity in strength of association, show
that nearly all seven published studies have found a point
estimate of higher than one for the risk. Several hypotheses
have been suggested to explain why such association may exist.
Atrophy of the mucosa leads to reduced acid production in
the stomach, proliferation of the bacteria, and perhaps
increased production of acetaldehyde and N-nitroso
compounds [40–42]; these latter two chemicals may act as risk
factors for OSCC [43, 44]. We would like to note that it is
unclear that the association between atrophy and OSCC is
causal. One study that found an RR of 2.16 (95% CI: 1.81–2.56)
for the association of gastric atrophy, intestinal metaplasia, and
dysplasia with OSCC also found an increased risk of small cell
carcinoma of the lung (RR = 1.86; 95% CI: 1.65–2.09) [33]. The
authors suggested that both associations may be attributable to
another common factor, such as smoking. However,
consistency of association across studies suggested by this meta-
analysis; dose–response relationship shown by some studies
[30, 31]; the presence of associations after adjusting for some
potential confounders, including smoking; and proposed
biological mechanisms discussed above argue for a causal
relationship. Some studies [32, 33] did not find a dose–
response relationship. For example, one study found that
although atrophy increased the risk of OSCC, the severity of
atrophy did not increase OSCC risk in a dose–response manner
[33]. However, lack of a dose–response relationship does not
exclude the possibility of a causal relationship as atrophy itself
may be sufficient to increase OSCC risk and progression to
metaplasia or dysplasia may not be consequential.
There were too few studies to establish or refute an
association between gastric atrophy and OAC. However, the
results of these studies point to a reduced risk of OAC in
patients with atrophy. If such an inverse association is
established, it may be due to reduced acid production and
reduced acid reflux from the stomach to the oesophagus, and it
may explain why carrying H. pylori is inversely associated with
risk of OAC [37]. The association between gastric atrophy and
OAC can be further studied in large prospective cancer studies
[45] and in a number of epidemiological studies that have been
established in the past two decades to study the risk factors of
OAC [46–50].
Table 2. Summary statistics for the association between gastric atrophy and oesophageal and gastric cardia cancers
Number
of studies
I2
(%)a
P valueb
Random-effects,
RR (95% CI)
Gastric cardia adenocarcinoma
Overall analysis 13 34 0.11 2.89 (2.09–3.98)
Studies from Asia 6 41 0.13 2.72 (1.67–4.44)
Studies from Europe and the United States 7 33 0.18 3.07 (1.95–4.83)
Population-based studies 11 34 0.13 2.65 (1.84–3.81)
Large studies (standard error 0.5) 8 42 0.10 2.73 (1.94–3.83)
Adjusted results 4 59 0.06 2.56 (1.54–4.25)
Studies using PG1:PG2 ratio 9 14 0.32 2.43 (1.78–3.32)
Oesophageal squamous cell carcinoma
Overall analysis 7 49 0.07 1.94 (1.48–2.55)
Studies from Asia 5 22 0.27 1.64 (1.21–2.23)
Studies from Europe and the United States 2 63 0.10 2.71 (1.43–5.11)
Population-based studies 5 54 0.07 1.91 (1.33–2.73)
Large studies (standard error 0.5) 6 57 0.04 1.95 (1.45–2.63)
Adjusted results 4 69 0.02 2.10 (1.19–3.70)
Studies using PG1:PG2 ratio 4 42 0.16 1.71 (1.08–2.69)
Oesophageal adenocarcinoma
Overall analysis 3 55 0.11 0.51 (0.19–1.37)
Studies using PG1:PG2 ratio 2 0 0.99 0.29 (0.13–0.47)
a
Higgins I2
statistic for heterogeneity
b
P value for chi-square test for heterogeneity (Q-statistics).
CI, confidence interval; PG1:PG2 ratio, pepsinogen 1 to pepsinogen 2 ratio; RR, relative risk.
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6. To test the robustness of the results, we conducted several
subgroup analyses. The increased risk of OSCC and GCA
with atrophy was observed regardless of the geographic site
of the study, design of the study (population based or
hospital based), size of the study, adjustments, and method
of ascertainment of atrophy. Therefore, the results seemed
robust. For OSCC, the association was somewhat stronger
in studies from Europe and the United States than those
conducted in Asia, but this difference was mainly related to
one study [32].
This meta-analysis has several strengths, including an
extensive search, careful examination of the studies by at least
two of the authors, the large number of studies included for
OSCC and GCA, and subgroups analyses that showed
robustness of the results. One limitation of the meta-analysis
was the relatively small number of studies for OAC. It is also
subject to limitations that may be associated with any meta-
analysis, including combining heterogeneous populations and
results [51]; however, as mentioned earlier, there was low to
moderate heterogeneity among studies and subgroup analyses
yielded results similar to the overall analysis. Histological
examination of gastric biopsy specimen and using serum
PG1:PG2 ratio are not perfect methods for diagnosis of gastric
atrophy. The first method is subject to observer variation and
sampling error [35]. There is no unanimous agreement on the
best cut-off points for the second method; furthermore, this
method may not allow for appropriate location of gastric
atrophy without other additional tests, such as examination of
gastrin-17 levels in serum [52, 53]. However, among the
available tools to diagnose gastric atrophy in epidemiological
studies, these two methods are the best tests and have
comparable efficacy [35]. Although the large majority of the
studies used PG1 or PG1:PG2 ratio as indicators of atrophy,
they used different definitions for atrophy. While heterogeneity
in definition may be a weakness, it may also be a strength,
because it could reveal the influence of cut-off points on the
associations. Within the range of cut-off points used, the large
majority of the studies showed increased risk of OSCC and
GCA regardless of the exact cut-off point.
In summary, we found two- to threefold increased risk of
OSCC and GCA but a possible reduced risk of OAC in people
with gastric atrophy. Further studies are needed to establish
the association with OAC and casual association with OSCC,
and mechanisms of the increased risk need to be investigated
for GCA.
funding
Work by F. I. was supported by a PhD fellowship from the
International Agency for Research on Cancer.
acknowledgement
We thank Dr M. H. Derakhshan for providing us with more
detailed information on the results of their study.
disclosure
The authors declare no conflict of interest.
references
1. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality,
and prevalence across five continents: defining priorities to reduce cancer
disparities in different geographic regions of the world. J Clin Oncol 2006; 24:
2137–2150.
2. Blot WJ, McLaughlin JK, Fraumeni JF. Esophageal Cancer. In Schottenfeld D,
Fraumeni JF (eds), Cancer Epidemiology and Prevention. New York: Oxford
University Press, 2006; 697–706.
3. Forman D, Burley VJ. Gastric cancer: global pattern of the disease and an
overview of environmental risk factors. Best Pract Res Clin Gastroenterol 2006;
20: 633–649.
4. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter
pylori: a combined analysis of 12 case control studies nested within prospective
cohorts. Gut 2001; 49: 347–353.
5. Nomura AM, Stemmermann GN, Samloff IM. Serum pepsinogen I as a predictor
of stomach cancer. Ann Intern Med 1980; 93: 537–540.
6. Stemmermann GN, Samloff IM, Nomura AM, Heilbrun LK. Serum pepsinogens I
and II and stomach cancer. Clin Chim Acta 1987; 163: 191–198.
7. Parsonnet J, Samloff IM, Nelson LM et al. Helicobacter pylori, pepsinogen, and
risk for gastric adenocarcinoma. Cancer Epidemiol Biomarkers Prev 1993; 2:
461–466.
8. Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in
the United States. Surg Oncol Clin N Am 2002; 11: 235–256.
9. Steevens J, Botterweck AA, Dirx MJ et al. Trends in incidence of oesophageal
and stomach cancer subtypes in Europe. Eur J Gastroenterol Hepatol 2010; 22:
669–678.
10. Hsing AW, Hansson LE, McLaughlin JK et al. Pernicious anemia and subsequent
cancer. A population-based cohort study. Cancer 1993; 71: 745–750.
11. Rakic S, Dunjic MS, Pesko P, Milicevic M. Atrophic chronic gastritis in
patients with epidermoid carcinoma of the esophagus. J Clin Gastroenterol
1993; 17: 84.
12. Ye W, Held M, Lagergren J et al. Helicobacter pylori infection and gastric
atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus
and adenocarcinoma of the gastric cardia. J Natl Cancer Inst 2004; 96:
388–396.
13. Corley DA, Buffler PA. Oesophageal and gastric cardia adenocarcinomas:
analysis of regional variation using the Cancer Incidence in Five Continents
database. Int J Epidemiol 2001; 30: 1415–1425.
14. Rugge M, Correa P, Di Mario F et al. OLGA staging for gastritis: a tutorial. Dig
Liver Dis 2008; 40: 650–658.
15. Samloff IM, Taggart RT. Pepsinogens, pepsins, and peptic ulcer. Clin Invest Med
1987; 10: 215–221.
16. Shikata K, Kiyohara Y, Kubo M et al. A prospective study of dietary salt intake
and gastric cancer incidence in a defined Japanese population: the Hisayama
study. Int J Cancer 2006; 119: 196–201.
17. Iijima K, Koike T, Abe Y et al. Extensive gastric atrophy: an increased risk factor
for superficial esophageal squamous cell carcinoma in Japan. Am J
Gastroenterol 2007; 102: 1603–1609.
18. de Vries AC, van Grieken NC, Looman CW et al. Gastric cancer risk in patients
with premalignant gastric lesions: a nationwide cohort study in the Netherlands.
Gastroenterology 2008; 134: 945–952.
19. Hattori Y, Tashiro H, Kawamoto T, Kodama Y. Sensitivity and specificity of mass
screening for gastric cancer using the measurement of serum pepsinogens. Jpn
J Cancer Res 1995; 86: 1210–1215.
20. Fukuda H, Saito D, Hayashi S et al. Helicobacter pylori infection, serum
pepsinogen level and gastric cancer: a case-control study in Japan. Jpn J
Cancer Res 1995; 86: 64–71.
21. Watabe H, Mitsushima T, Yamaji Y et al. Predicting the development of gastric
cancer from combining Helicobacter pylori antibodies and serum pepsinogen
status: a prospective endoscopic cohort study. Gut 2005; 54: 764–768.
22. Nomura AM, Kolonel LN, Miki K et al. Helicobacter pylori, pepsinogen, and
gastric adenocarcinoma in Hawaii. J Infect Dis 2005; 191: 2075–2081.
23. Oishi Y, Kiyohara Y, Kubo M et al. The serum pepsinogen test as a predictor of
gastric cancer: the Hisayama study. Am J Epidemiol 2006; 163: 629–637.
review Annals of Oncology
6 | Islami et al.
byguestonOctober15,2010annonc.oxfordjournals.orgDownloadedfrom

7. 24. Knekt P, Teppo L, Aromaa A et al. Helicobacter pylori IgA and IgG antibodies,
serum pepsinogen I and the risk of gastric cancer: changes in the risk with
extended follow-up period. Int J Cancer 2006; 119: 702–705.
25. Palli D, Masala G, Del Giudice G et al. CagA+ Helicobacter pylori infection and
gastric cancer risk in the EPIC-EURGAST study. Int J Cancer 2006; 120:
859–867.
26. Hansen S, Vollset SE, Derakhshan MH et al. Two distinct aetiologies of cardia
cancer; evidence from premorbid serological markers of gastric atrophy and
Helicobacter pylori status. Gut 2007; 56: 918–925.
27. Anderson LA, Murphy SJ, Johnston BT et al. Relationship between Helicobacter
pylori infection and gastric atrophy and the stages of the oesophageal
inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR
case-control study. Gut 2008; 57: 734–739.
28. Derakhshan MH, Malekzadeh R, Watabe H et al. Combination of gastric atrophy,
reflux symptoms and histological subtype indicates two distinct aetiologies of
gastric cardia cancer. Gut 2008; 57: 298–305.
29. Iijima K, Koike T, Abe Y et al. Gastric hyposecretion in esophageal squamous-cell
carcinomas. Dig Dis Sci 2009; 55: 1349–1355.
30. Yokoyama A, Omori T, Yokoyama T et al. Chronic atrophic gastritis
and metachronous gastric cancer in Japanese alcoholic men with
esophageal squamous cell carcinoma. Alcohol Clin Exp Res 2009; 33:
898–905.
31. Kamangar F, Diaw L, Wei WQ et al. Serum pepsinogens and risk of esophageal
squamous dysplasia. Int J Cancer 2009; 124: 456–460.
32. Ren JS, Kamangar F, Qiao YL et al. Serum pepsinogens and risk of gastric and
oesophageal cancers in the general population nutrition intervention trial cohort.
Gut 2009; 58: 636–642.
33. de Vries AC, Capelle LG, Looman CW et al. Increased risk of esophageal
squamous cell carcinoma in patients with gastric atrophy: independent of the
severity of atrophic changes. Int J Cancer 2009; 124: 2135–2138.
34. Akiyama T, Inamori M, Iida H et al. Macroscopic extent of gastric mucosal
atrophy: increased risk factor for esophageal squamous cell carcinoma in Japan.
BMC Gastroenterol 2009; 9: 34.
35. Weck MN, Brenner H. Association of Helicobacter pylori infection with chronic
atrophic gastritis: meta-analyses according to type of disease definition. Int J
Cancer 2008; 123: 874–881.
36. Dawsey SM, Mark SD, Taylor PR, Limburg PJ. Gastric cancer and H. pylori. Gut
2002; 51: 457–458.
37. Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-
analysis. Cancer Prev Res (Phila Pa) 2008; 1: 329–338.
38. Islami F, Ren JS, Taylor PR, Kamangar F. Pickled vegetables and the risk of
oesophageal cancer: a meta-analysis. Br J Cancer 2009; 101: 1641–1647.
39. Correa P. A human model of gastric carcinogenesis. Cancer Res 1988; 48:
3554–3560.
40. McColl KE, Watabe H, Derakhshan MH. Sporadic gastric cancer; a complex
interaction of genetic and environmental risk factors. Am J Gastroenterol 2007;
102: 1893–1895.
41. Vakevainen S, Mentula S, Nuutinen H et al. Ethanol-derived microbial production
of carcinogenic acetaldehyde in achlorhydric atrophic gastritis. Scand J
Gastroenterol 2002; 37: 648–655.
42. Kodama K, Sumii K, Kawano M et al. Gastric juice nitrite and vitamin C in
patients with gastric cancer and atrophic gastritis: is low acidity solely
responsible for cancer risk? Eur J Gastroenterol Hepatol 2003; 15: 987–993.
43. Secretan B, Straif K, Baan R et al. A review of human carcinogens—Part E:
tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009; 10:
1033–1034.
44. Kamangar F, Chow WH, Abnet CC, Dawsey SM. Environmental causes of
esophageal cancer. Gastroenterol Clin North Am 2009; 38: 27–57, vii.
45. Carneiro F, Moutinho C, Pera G et al. Pathology findings and validation of gastric
and esophageal cancer cases in a European cohort (EPIC/EUR-GAST). Scand J
Gastroenterol 2007; 42: 618–627.
46. Shaheen NJ, Green B, Medapalli RK et al. The perception of cancer risk in
patients with prevalent Barrett’s esophagus enrolled in an endoscopic
surveillance program. Gastroenterology 2005; 129: 429–436.
47. Whiteman DC, Sadeghi S, Pandeya N et al. Combined effects of obesity, acid
reflux and smoking on the risk of adenocarcinomas of the oesophagus. Gut
2008; 57: 173–180.
48. Corley DA, Kubo A, DeBoer J, Rumore GJ. Diagnosing Barrett’s esophagus:
reliability of clinical and pathologic diagnoses. Gastrointest Endosc 2009; 69:
1004–1010.
49. Pandeya N, Williams G, Green AC et al. Alcohol consumption and the risks of
adenocarcinoma and squamous cell carcinoma of the esophagus.
Gastroenterology 2009; 136: 1215–1222.
50. Hoyo C, Schildkraut JM, Murphy SK et al. IGF2R polymorphisms and risk
of esophageal and gastric adenocarcinomas. Int J Cancer 2009; 125:
2673–2678.
51. Shapiro S. Meta-analysis/Shmeta-analysis. Am J Epidemiol 1994; 140:
771–778.
52. Storskrubb T, Aro P, Ronkainen J et al. Serum biomarkers provide an accurate
method for diagnosis of atrophic gastritis in a general population: the Kalixanda
study. Scand J Gastroenterol 2008; 43: 1448–1455.
53. Iijima K, Abe Y, Kikuchi R et al. Serum biomarker tests are useful in delineating
between patients with gastric atrophy and normal, healthy stomach. World J
Gastroenterol 2009; 15: 853–859.
Annals of Oncology review
doi:10.1093/annonc/mdq411 | 7
byguestonOctober15,2010annonc.oxfordjournals.orgDownloadedfrom