Gheorghe Bălan
Multistep gastric carcinogenesis (Correa
cascade)
Normal mucosa – non-atrophic gastritis –
atrophic gastritis – intestinal metaplasia –
dysplasia - carcinoma
•Atrophic gastritis
•Intestinal metaplasia
•Epithelial dysplasia – penultimate stage
of gastric carcinogenesis (premalignant
lesion)
•Gastric dysplasia/atypia – unequivocal
neoplastic non-invasive epithelial alteration
•Frequent association between dysplastic
epithelium and gastric carcinoma
•Nakamura, Nagayo (late 1960s-early 1970);
atypia
•Grundmann (1975); dysplasia
•Are commonly found in medical practice
•There are no international recommendations
to guide clinicians
•Subsequent heterogenicity of practice
•Failure to diagnose patients with curable
forms of cancer
•Identification and surveillance lead to early
dianosis of gastric cancer
• Diagnostic assessment
• Treatment
• Follow-up
Diagnostic assessement :
• Conventional white light endoscopy cannot
accurately differentiate and diagnose preneoplastic gastric conditions
- antral nodularity/absence of rugae/visible
vessels/thin, white mucosal deposits (aspects
of unestablished value)
•New high resolution endoscopes – no more
reliable
•Magnification chromoendoscopy (MCE) and
norrow band imaging (NBI), with or without
magnification – improve the diagnosis of
gastric preneoplastic conditions/lesions
- methylene blue/indigo carmine/acetic acid/
hematoxylin
•MCE cannot be recommended for routine
performance
Narrow band imaging
- method under evaluation
- no agreement on NBI patterns associated
with gastric precancerous lesions
- requires some level of expertise
- is not practicable in an everyday clinical
setting
•Biopsy sampling
- For adequate staging and grading of gastric
precancerous conditions, at least four nontargeted biopsies of two topographic sites (at the
lesser and greater curvature, from the antrum
and the corpus) should be taken; additional
target biopsies of lesions
- Systems for histopathological staging may be
useful for categorization of risk of progression to
gastric cancer
Histological findings :
- neoplastic epitelium without evidence of
tissue invasion ;
- correct diagnosis and grading of dysplasia are
critical ;
- large variability of histological protocols
(intra/interobserver) ;
- differences between Japanes and EU/NA
pathologists
Histological findings (WHO classification)
•Negative for intraepithelial neoplasia/dysplasia
•Indefinite for intraepithelia neoplasia/dysplasia
•Low grade intraepithelial neoplasia/dysplasia
•High grade intraepithelial neoplasia/dysplasia
•Intramucosal invasive neoplasia/intramucosal
carcinoma
•Negative for intraepitelial neoplasia/displasia
- chronic atrophic gastritis
- intestinal metaplasia
•Indefinite for IEN/dysplasia
- doubt about neoplastic or non-neoplastic
lesion ( reactive or regenerative) ; requires
aditional biopsies
•Low grade intraepithelial neoplasia/dysplasia
- minimal architectural disarray
- mild-to-moderate cytological atypia
(elongated nuclei, polarized, basally located,
mild-to-moderate mitotic activity)
• High grade intraepitelial neoplasia/dysplasia
- neoplastic cells (cuboidal, high nucleusto-cytoplasm ratio and mitotic activity,
amphophilic nucleoli, pronounced arch.
disarray, lost of nuclear polarity
•Intramucosal invasive neoplasia/IM carcinoma
- carcinomas invade the lamina propria
- minimal or absent desmoplastic changes
- distinct structural anomalies ( marked
glandular crowding, excesive branching,
budding and fused cribriforming glands)
- increased risk of limphatic invasion and
lymphnode metastasis
Noninvasive assessement :
•Serum pepsinogen levels can predict extensive
atrophic gastritis
•In patients with low pepsinogen test levels,
H. Pylori serology may be useful for further
detection of high risk individuals
•Additional diagnostic factors :
- Family history of gastric cancer should be
taken into account in the follow-up of
precancerous conditions
- No clinical recommendations can be made
for targeted management based on another
factors (age, gender, H. pylori virulence
factors)
Surveillance
•Low grade dysplasia in the absence of an
endoscopically defined lesion – patients should
receive follow-up within 1 year after diagnosis;
in the presence of defined lesion – endoscopic
resection should be considered (more accurate
histological diagnosis)
Surveillance
•High grade dysplasia in the absence of
endoscopically defined lesions – immediate
reassessement with extensive biopsy sampling ;
surveillance at 6 months to 1 year is indicated
•The patients – high risk for rapid development
or for either syncronous invasive carcinoma
Treatment in the cases with endoscopically
defined lesions
• Endoscopic mucosal resection
•Surgery
Treatment
•Eradication of H. pylori
- Heals nonatrophic chronic gastritis/
partial regression of atrophic gastritis
- no reverse intestinal metaplasia/may slow
progression to neoplasia
- recommended for patients with previous
neoplasia after endoscopic/surgical treat.
Treatment (additional measures)
- COX-2 inhibitors cannot be suported to
decrease the progression risk of gastric
precancerous lesions ;
- Antioxidans (ascorbic acid, beta/caroten)
cannot be suported as a therapy to reduce
the prevalence of atrophic gastritis or
intestinal metaplasia
Cost-effectiveness
•H. pylori eradication is cost-effective after
endoscopic resection of early gastric cancer
•There is not an accurate estimation of costeffectiveness of surveillance for
premalignant gastric conditions worldwide
\
Patients with dysplasia
Visible endoscopic lesion?
No
Yes
Magnification chromoendoscopy and/or
narrow band imaging (NBI)
Grade of dysplasia
Low grade
High
grade
H. pylori eradication
Follow - up
Staging and
resection
Immediatly and 6 –
12 months
< 12 months
M. Dinis-Ribeiro, M. Areia et all. MAPS…Endoscopy 2012; 44: 74-94
\
Patients with dysplasia
Visible endoscopic lesion?
No
Yes
Magnification chromoendoscopy and/or narrow band
imaging (NBI)
Grade of dysplasia
Low grade
High
grade
H. pylori eradication
Follow - up
Staging and
resection
Immediatly and 6 –
12 months
< 12 months
M. Dinis-Ribeiro et all. MAPS…Endoscopy 2012; 44: 74-94
questions
 Which are the precancerous lesions of the
stomach? Which outcomes to prevent or avoid?
 Is there evidence to use endoscopic methods to
improve diagnosis?
 Which care should be taken on biopsies (number
and sites) for correct diagnosis and staging?
 Should other sources of data be added for staging?
 Is there evidence to use non-invasive methods to
improve diagnosis?
questions
 Should these patients be followed up?
 Does the type, the severity and the extension of the
lesion influence the prognosis of these patients?
 Is there a role for Hp eredication?
 Is there a role for other therapies?
 May these strategies be cost-effective?
recommendations
 Conventional white light endoscopy cannot accurately
diagnose MAPS (B)
 Slight unsignificant improvement for: NBI and
magnification endoscopy (B)
 At least 4 biopsies from proximal and distal stomach,
lesser and greater curvature (C)
 Low serum pepsinogen levels (C)
 Hp infection (C)
recommendations
 Family history of gastric cancer (B)
 Extensive atrophy or extensive intestinal metaplasia
(B)
 If H. pylori infection is present, eradication should be
offered to prevent high grade dysplasia or carcinoma
(B)
 Mild to moderate atrophy/intestinal metaplasia only
in antrum do not need follow-up
recommendations
 The use of COX-2 inhibitors or the use of dietary
supplementation with antioxidants are not endorsed
as approaches to decrease the risk of progression of
gastric precancerous lesions
 Patients with dysplasia or cancer within an
endoscopically visible lesion should undergo staging
and resection
Definitions and outcomes to
prevent
 Gastric carcinogenesis
 1. Patients with chronic atrophic gastritis or intestinal
metaplasia should be considered to be at higher risk for
gastric adenocarcinoma.
 2. High grade dysplasia and invasive carcinoma should be
regarded as the outcomes to be prevented when patients
with chronic atrophic gastritis or intestinal metaplasia are
managed.
 3. Patients with endoscopically visible high grade
dysplasia or carcinoma should undergo staging and
adequate management
! development of so-called “intestinal” gastric
adenocarcinoma represents the culmination of an
inflammation–metaplasia–dysplasia–carcinoma
sequence, known as the Correa cascade of multistep
gastric carcinogenesis
 Mucosal gastric atrophy and intestinal metaplasia
confer a high risk for the development of gastric cancer
 Individuals may develop different phenotypes of
chronic gastritis due to different genetic profiles and
environmental exposure:
1.
2.
inflammatory changes limited to the antrum and without gland atrophy
and/or intestinal metaplasia are defined as diffuse antral gastritis.
gland atrophy and/or intestinal metaplasia distributed multifocally
including the lesser curvature of the corpus and fundus, are defined as
multifocal atrophic gastritis (this phenotype may be described as “extensive,”
whereas the term “marked” is used to define a severity grade at a particular
site)
Diagnosis and staging
1. Endoscopy
 Conventional white light endoscopy cannot accurately
differentiate and diagnose pre-neoplastic gastric
conditions
 Magnification chromoendoscopy and narrow band
imaging (NBI), with or without magnification,
improve the diagnosis of gastric preneoplastic
conditions/lesions
 Diagnostic upper gastrointestinal endoscopy should
include gastric biopsies sampling
Diagnosis and staging
2. Biopsy sampling
 at least 4 nontargeted biopsies of two topographic sites
(at the lesser and greater curvature, from both the
antrum and the corpus) should be taken and clearly
labelled in separate vials; additional target biopsies of
lesions should be taken; maximum 8
 Systems for histopathological staging may be useful for
categorization of risk of progression to gastric cancer
Diagnosis and staging
3. Noninvasive assessment
 Serum pepsinogen levels can predict extensive
atrophic gastritis
 In patients with low pepsinogen test levels,
Helicobacter pylori serology may be useful for further
detection of high risk individuals
Diagnosis and staging
4. Additional diagnostic factors
 Family history of gastric cancer should be taken into
account in the follow-up of precancerous conditions
 Even though diverse studies assessed age, gender, and
Hp virulence factors as well as host genetic variations,
no clinical recommendations can be made for targeted
 management based on these factors with regard to
diagnosis and surveillance
Surveillance
1. Dysplasia
 low grade dysplasia in the absence of an endoscopically
defined lesion should receive follow-up within 1 year
after diagnosis. In the presence of an endoscopically
defined lesion, endoscopic resection should be
considered, to obtain a more accurate histological
diagnosis
 high grade dysplasia in the absence of endoscopically
defined lesions, immediate endoscopic reassessment
with extensive biopsy sampling and surveillance at 6month to 1–year intervals is indicated
Surveillance
2. Atrophy or intestinal metaplasia
 endoscopic surveillance should be offered to patients
with extensive atrophy and/or intestinal metaplasia
 extensive atrophy and/or intestinal metaplasia should
receive follow-up every 3 years after diagnosis
 mild to moderate atrophy/intestinal metaplasia
restricted to the antrum there is no evidence to
recommend surveillance
Therapy
1. Eradication of Hp
 Hp eradication heals nonatrophic chronic gastritis and
it may lead to partial regression of atrophic gastritis
 In patients with intestinal metaplasia, H. pylori
eradication does not appear to reverse intestinal
metaplasia but it may slow progression to neoplasia,
and therefore it is recommended
 Hp eradication is recommended for patients with
previous neoplasia after endoscopic or surgical therapy
Therapy
2. Additional measures
 the use of cyclooxgenase-2 (COX-2) inhibitors cannot
be supported as an approach to decrease the risk of
progression of gastric precancerous lesions
 dietary supplementation with antioxidants cannot be
supported as a therapy to reduce the prevalence of
atrophy or intestinal metaplasia
Cost– effectiveness
 After endoscopic resection of early gastric cancer, Hp
eradication is cost-effective
 Available evidence does not allow an accurate
estimation of the cost–effectiveness of surveillance for
premalignant gastric conditions worldwide
conclusions