Introduction
Intestinal-type gastric adenocarcinomas are the most
common type of gastric tumor, and are preceded by a series of
precancerous lesions, beginning with chronic atrophic gastritis,
prior to progression to intestinal metaplasia, dysplasia and
finally developing into gastric cancer (1). Gastric endoscopy and biopsy
collection are frequently used in the diagnosis of chronic atrophic
gastritis; however, this procedure is highly invasive. For this
reason, numerous experimental and meta-analysis studies have been
conducted in order to identify an effective serological screening
method for chronic atrophic gastritis (2–6).
However, the level of variation in the results of
these studies have made it difficult to identify a standardized
method for the effective diagnosis of chronic atrophic
gastritis.
Currently, commercially available serological
screening tests identify four main molecular markers: Pepsinogen I
(PGI, 30–160 mg/l), whose concentration levels in the blood reflect
the structure and function of the mucosa of the gastric body
(corpus); pepsinogen II (PGII, 3–15 g/l), whose concentration
levels are associated with the structure and function of the mucosa
of the stomach; gastrin-17b (G17b, 1–7 pmol/l), whose concentration
levels reflect the structure and function of the antrum mucosa of
the stomach and Helicobacter pylori (HPAbG, <30 EIU),
which is responsible for gastric mucosal atrophy and
dysfunction.
The evaluation of the ratio of PGI:PGII, and the
detected combinations of these markers should provide adequate and
complete information regarding the structure and function of the
gastric mucosa (7). The present
study therefore aimed to evaluate the positive predictive value of
such commercial serological screening kits via comparison with data
from histological evaluation.
Materials and methods
Patients
In the present study, 123 patients (mean age 53±14
years), who gave their informed consent and had been referred by
their general practitioner for endoscopy, were enrolled at the
Institute for Cancer Cure and Research, the International Cancer
Institute 'G. Pascale' Foundation (Naples, Italy). They donated
blood and underwent an endoscopy. A total of 13 patients (six
females and seven males; mean age 51±16 years) were selected due to
discrepancies observed between serological and histological
analyses. The study was approved by the ethics committee of INT
Fondazione Pascale.
Determination of biological marker
expression
All blood samples were tested for antibodies against
H. pylori, PGI, PGII and G17b using a
GastroPanel® commercial ELISA kit (cod. 601300; Biohit
HealthCare, Helsinki, Finland) assay. The final report contained
the results of biological marker expression levels, including the
cut-off values outlined in Table
I.
 | Table IPatients selected according to the
discrepancy between serological screening results (indicated by
cut-off values of HPAbG, PGI, PGII, PGI/PGII and G17b) and
histological phenotypes according to the OLGA staging system (from
stage 0 to 4). |
Table I
Patients selected according to the
discrepancy between serological screening results (indicated by
cut-off values of HPAbG, PGI, PGII, PGI/PGII and G17b) and
histological phenotypes according to the OLGA staging system (from
stage 0 to 4).
| Pt | Serological screening
| Diagnosis | OLGA staging system
|
|---|
| PGI
(30–165μg/l) | PGII
(3–15μg/l) | PGI/PGII (3–20) | G17b (1–10
pmol/l) | HPAbG (<30
EIU) | SCORE
ANTRUM/ANGULARIS INCISURA | SCORE
CORPUS | Stage |
|---|
| 1 | 94.9 | 15.0 | 6.3 | 19.9 | 99.0 | NON ATROPHIC
GASTRITIS | 2 | 2 | 3 |
| 2 | 109.0 | 10.3 | 10.6 | 0.8 | 2.1 | NORMAL | 2 | 2 | 3 |
| 3 | 91.5 | 11.4 | 8.0 | 1.6 | 119.4 | NON ATROPHIC
GASTRITIS | 3 | 2 | 3 |
| 4 | 103.5 | 8.0 | 12.9 | 3.8 | 0.7 | NORMAL | 3 | 1 | 3 |
| 5 | 54.3 | 6.4 | 8.5 | 2.6 | 2.1 | NORMAL | 2 | 2 | 3 |
| 6 | 121.3 | 13.7 | 8.9 | 14.9 | 115.5 | NON ATROPHIC
GASTRITIS | 3 | 2 | 3 |
| 7 | 190.4 | 19.0 | 10.0 | 25.3 | 59.5 | NON ATROPHIC
GASTRITIS | 2 | 2 | 3 |
| 8 | 55.3 | 3.1 | 17.8 | 1.9 | 68.9 | NON ATROPHIC
GASTRITIS | 3 | 3 | 3 |
| 9 | 179.7 | 11.6 | 15.5 | 8.6 | 82.5 | NON ATROPHIC
GASTRITIS | 2 | 2 | 3 |
| 10 | 197.2 | 23.7 | 8.3 | 18.6 | 14.8 | NORMAL | 2 | 3 | 3 |
| 11 | 25.0 | 4.5 | 5.6 | 13.7 | 6.1 | ATROPHIC
GASTRITIS | 1 | 1 | 1 |
| 12 | 20.3 | 11.6 | 1.7 | 40.0 | 104.5 | ATROPHIC
GASTRITIS | 1 | 1 | 1 |
| 13 | 0.0 | 3.5 | 0.0 | 40.0 | 9.7 | ATROPHIC
GASTRITIS | 2 | 1 | 2 |
Histological examination
The stomach mucosa was evaluated using routine
methods, and biopsies were taken from the corpus, antrum and
angularis incisura for histological examination. Formalin-fixed,
paraffin-embedded sections (5 µm), were stained with
hematoxylin/eosin by automated instruments (Stainer AUS124; Bio
Optica, Milan, Italy) and the results were interpreted using a
light microscope, observing a minimum of 10 fields (Leica DM 1000;
Leica Microsystems GmbH, Heidelberg, Germany). Histological
parameters were outlined according to the 'Operative Link for
Gastritis Assessment (OLGA) Staging System', which was defined by
an international group of gastroenterologists and pathologists. The
OLGA staging system defines the histological phenotypes of
gastritis according to a scale of progressively increasing risk of
gastric cancer, from lowest (stage 0) to highest (stage 4)
(8). To minimize disagreement
amongst pathological diagnoses of chronic atrophic gastritis, two
independent reviews of each biopsy were required from two
pathologists, culminating in a final consensus diagnosis for each
patient.
Results
Intestinal-type gastric adenocarcinomas are preceded
by a series of precancerous lesions, initiating with chronic
atrophic gastritis (9). The
development of techniques to effectively perturb the progression of
such diseases represents a potentially significant public health
benefit, reducing the associated economic burden of medical
expenses and relieving the suffering of patients.
In the present study, 123 patients were enrolled to
evaluate a commercial kit for the serological determination of
chronic atrophic gastritis, compared with histological
analysis.
The results indicated a significant discrepancy
between the results of serological screening and histological
evaluation amongst 13 of the 123 patients (10.6%; Table I and Fig. 1).
 | Figure 1Histology of the antrum (left) and the
corpus (right) of the thirteen discrepant patients identified.
Magnification: 1) Left ×60, right 20×; 2) left ×60, right ×60; 3)
left ×60, right ×40; 4) left ×60, right ×40; 5) left ×40, right
×40; 6) left ×60, right ×60; 7) left ×60, right ×40; 8) left ×60,
right ×40; 9) left ×60, right ×60; 10) left ×60, right ×40; 11)
left ×60, right ×40; 12) left ×60, right ×60; 13) left ×40, right
×60. |
Ten patients (8.1%) were identified to be negative
following serological screening (normal phenotype or non-atrophic
gastritis) and positive at histology (OLGA stage ≥3) (Table I and Fig. 1). Amongst these patients, four
exhibited a normal serological phenotype and six demonstrated
non-atrophic gastritis. By contrast, three patients (2.4%) revealed
a positive serological screening indicative of atrophic gastritis,
while the histological examination was considered negative (OLGA
stage ≤2). One case exhibited histology indicating stage 2 atrophic
gastritis and two cases exhibited histology indicating stage 1
atrophic gastritis (Table I and
Fig. 1).
Discussion
Numerous studies have demonstrated the sensitivity
and specificity of serological screening tests for chronic atrophic
gastritis, determining a range of cut-off values used in commercial
kits (10).
However, the significant levels of variation
described in experimental studies, despite numerous validation
studies (11), may also be present
in standardized commercial methods. This may be due to
discrepancies in population characteristics, for example country of
origin or patient selection criteria, and also to variations in the
cut-off values used (11).
In particular, in the present study, the patients
evaluated represented a select group, often exhibiting clinical
disease, which represents a common limitation amongst studies of
various screening tests (11–13).
Studies have yielded conflicting results regarding
the use of the biomarkers evaluated in the present study. For
example, serological evaluation of PGI, PGII, the ratio of PGI and
PGII and serum gastrin revealed that only the ratio of PGI to PGII
was reliable, demonstrating a specificity of 87% and a sensitivity
of 77% for the detection of chronic atrophic gastritis (12). However, even in this example, the
study was limited by the recruitment of a patient cohort presenting
with dyspeptic symptoms (for endoscopy), which may increase the
probability of gastric atrophy identification. Furthermore, in
alternative studies conducted on selected populations, the positive
predictive value of serum PG for gastric cancer was demonstrated to
be low (13).
In conclusion, although existing commercial tests
for chronic atrophic gastritis are suggested to be highly sensitive
and specific, the results of the present study revealed that they
may not have the positive predictive value that has been previously
reported.
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