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 pre- neoplastic 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 non- targeted 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 nucleus- to-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 cost- effectiveness of surveillance for premalignant gastric conditions worldwide

\ Patients with dysplasia Visible endoscopic lesion? Magnification chromoendoscopy and/or narrow band imaging (NBI) Grade of dysplasia Low grade H. pylori eradication NoYes High grade Staging and resection Follow - up 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? Magnification chromoendoscopy and/or narrow band imaging (NBI) Grade of dysplasia Low grade H. pylori eradication NoYes High grade Staging and resection Follow - up 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. inflammatory changes limited to the antrum and without gland atrophy and/or intestinal metaplasia are defined as diffuse antral gastritis. 2. 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 6- month 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