ESMO Preceptorship Gastrointestinal Tumours Valencia October 2017

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1 ESMO Preceptorship Valencia October 2017 Gastrointestinal Tumours

2 I have no conflicts of interest to declare Fátima Carneiro

3 Gastrointestinal tumours Multidisciplinary management, standards of care and future perspectives Fátima Carneiro IPATIMUP & Medical Faculty/Centro Hospitalar São João Porto, Portugal FMUP/CHSJ

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6 Risk of gastric cancer development H. pylori virulent genotypes (vaca; CagA) 15 to 17 IL-1 gene polymorphism 3.3 H. pylori virulence & IL-1B polymorphism 87 Gene-environment interaction Machado et al. Gastroenterology 121: 823, 2001 Figueiredo et al, JNCI 94: 1680, 2002 Helicobacter pylori infection Epstein Barr Diet Smoking Environment (Epi)Genetic alterations Gastric Carcinoma Polymorphisms: Mucin genes Pro-inflammatory genes Mutations in low or high penetrant genes

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8 Gastroenterology 2014 special issue

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10 The stomach displays a diverse microbiota when H. pylori is absent or low in abundance H. pylori negative stomach H. pylori positive stomach 2% 1%1% 11% 1% <1% 11% 30% Firmicutes Actinobacteria Firmicutes Actinobacteria Bacteroidetes Proteobacteria Fusobacteria Others Bacteroidetes Proteobacteria (H. pylori) 47% 96% Andersson et al., PLoS ONE 2008

11 The stomach displays a diverse microbiota when H. pylori is absent or low in abundance Stomach H. pylori - Stomach H. pylori + Resident or transient populations of ingested microbes?? Andersson et al., PLoS ONE 2008

12 Figueiredo et al, 2017

13 METAGENOMICS

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15 European Helicobacter Study Group 2015 European Helicobacter and Microbiota Study group

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17 Precursor lesions Sporadic cancer Hereditary cancer Molecular pathology CnAG CAG Metaplasia Dysplasia (macroscopy; grade; differentiation) Gastric adenocarcinoma

18 Chronic gastritis

19 Duodenal ulcer Diffuse antral gastritis Asymptomatic 90% Focal atrophy Helicobacter pylori infection Host & environmental factors Gastric ulcer Multifocal atrophic gastritis IM Asymptomatic 90% IM Dysplasia Gastric cancer

20 Chronic gastritis Antrum Incisura Gland atrophy and multifocal IM Body

21 Classification of chronic gastritis OLGA staging Rugge M et al. Dig Liver Dis 40: 650, 2008

22 Classification of chronic gastritis OLGIM staging Capelle L et al. Gastrointest Endosc 71: 1150, 2010

23 Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer (Prospective study mean follow-up: 7.7 years) HP infection _ + + _ CAG + + Gastric cancer Cases/incidence rate 0 19/107 24/238 2/871 HR (95% CI) _ (1) 7.13 ( ) 14.51( ) ( ) p= Ohata H et al. Int J Cancer 109:138, 2004

24 Helicobacter pylori Eradication to Prevent Gastric Cancer in a High-Risk Region of China A Randomized Controlled Trial Prospective, randomized, placebo-controlled, population-based primary prevention study of 1630 healthy carriers of H. pylori infection Overall H. pylori eradication 7 gastric cancers Placebo 11 gastric cancers p=0.33 Patients without precancerous lesions on presentation H. pylori eradication 0 gastric cancers Placebo 6 gastric cancers p=0.02 Wong BC et al JAMA 291: 187, 2004

25 H. pylori infection Normal mucosa H. pylori strain virulence (vaca s1, m1, caga+) Chronic superficial gastritis Enhanced chronic inflammatory response Host susceptibility (IL1B-511*T / IL1RN*2/*2) (TNFA-308*A) Chronic atrophic gastritis Intestinal metaplasia Dysplasia Intestinal carcinoma

26 Dixon MF et al: Classification and grading of gastritis. Am J Surg Pathol 20(10):1161, 1996

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29 Gastric dysplasia - WHO classification (2010) Odze RD et al. Premalignant lesions of the digestive system. In: WHO Classification of Tumours of the Digestive System, Fouth Edition. Bosman FT, Carneiro F, Hruban RH and Theise ND (eds), IARC Press: Lyon, 2010; Pp

30 LOW- AND HIGH-GRADE DYSPLASIA Minimal architectural disarray Mild/moderate cytological atypia Nuclei are elongated, polarised, basally located Mitotic activity is mild/moderate. Pronounced architectural disarray High nucleus:cytoplasm ratio Numerous mitoses, often atypical Nuclei frequently extend towards the luminal half of the gland

31 Intestinal type MORPHOLOGIC TYPE Gastric type Columnar cells Pencilate nuclei Hipercromatic nuclei Cuboidal cells Oval, vesicular nuclei Clear, eosinophilic cytopasm WHO 4th Edition, 2010

32 HE MUC5AC MUC6 MUC2 CD10 CDX2 Intestinal phenotype

33 HE MUC5AC MUC6 MUC2 CD10 CDX2 Gastric/foveolar phenotype

34 Comparison between grade and immunophenotypes Grade High grade (n=25) Low grade (n=35) Immunophenotype Gastric (n=24) Intestinal(n=22) Hybrid(n=14) 15* 63% 9 37% * coexistent intramucosal carcinoma in 8 cases 4 18% 18 82% 6 43% 8 57% p value Gastric differentiation is associated with high-grade dysplasia and coexistence of intramucosal carcinoma. Baldaia H et al. Virchows Archiv 461 (Suppl 1): S7-S8, 2012

35 WHO 2010 introduction Precursor lesions of invasive neoplasia (intraepithelial neoplasia) of the tubal gut Intraepithelial neoplasia encompasses all premalignant lesions, with or without typical characteristics of dysplasia; the term dysplasia is only used when a morphologically identifiable lesion exists. Dysplasia is the term used to indicate histologically unequivocal neoplastic epithelium without evidence of tissue invasion.

36 WHO 2010 introduction Precursor lesions of invasive neoplasia (intraepithelial neoplasia) of the tubal gut The use of the term carcinoma in situ for columnar precursor lesions is strongly discouraged (included in high grade dysplasia). Intramucosal adenocarcinoma is the term used for lesions that show invasion into the lamina propria or muscularis mucosa but not into the submucosa (what qualifies as evidence of invasion?).

37 Intraepithelial neoplasia versus Dysplasia Recognizing that the terminology of dysplasia is entrenched in the European and particularly North-American literature, as well as in clinical practice, WHO considers that intraepithelial neoplasia and dysplasia should be considered as synonymous terms. The following categories should thus be considered: 1.Negative for intraepithelial neoplasia /dysplasia* 2.Indefinite for intraepithelial neoplasia /dysplasia 3.Low -grade intraepithelial neoplasia/dysplasia 4.High-grade intraepithelial neoplasia/dysplasia 5.Intramucosal invasive neoplasia/intramucosal carcinoma WHO 4th Edition, 2010 *In stomach, and as far as these guidelines are concerned, category 1 includes lesions such as atrophic chronic gastritis and intestinal metaplasia.

38 Low & high grade dysplasia Intramucosal carcinoma

39 Time related progression of premalignant lesions to gastric cancer De Vries et al. Gastroenterology 2008

40 Pathologic criteria of carcinoma in Japan Differential diagnosis between adenoma and adenocarcinoma is made on the basis of the cellular and structural atypia Kushima R, The 3 rd Korean GI Endoscopists & Pathologists Conference 2010 Western perspectives in the diagnosis of intramucosal carcinoma Defines carcinoma that invades lamina propria Desmoplastic changes (minimal or absent) Single infiltrating cells in the lamina propria Distinct structural anomalies, such as - marked glandular crowding - excessive branching - budding - intraluminal necrotic debris WHO classification of tumors of the digestive system 2010

41 Intramucosal invasive neoplasia/intramucosal carcinoma Branching and budding of glands Intraluminal necrotic debris Fused or cribriforming glands

42 Vienna classification of gastrointestinal epithelial neoplasia The new Vienna classification 1 Negative for neoplasia/dysplasia 2 Indefinite for neoplasia/dysplasia 3 Non-invasive low grade neoplasia (low grade adenoma/dysplasia) 4 Non-invasive high grade neoplasia 4.1 High grade adenoma/dysplasia 4.2 Non-invasive carcinoma (in situ) 4.3 Suspicion of invasive carcinoma 5 Invasive neoplasia 5.1 Intramucosal carcinoma 5.2 Submucosal carcinoma or beyond 4 Non-invasive high grade neoplasia Schlemper RJ et al: The Vienna classification of gastrointestinal epithelial neoplasia.gut 47: 251, 2000 Stolte M: The new Vienna classification of epithelial neoplasia of the gastrointestinal tract: advantadges and disavantadges. Virchows Archiv 442: 99, High grade adenoma/dysplasia 4.2 Non-invasive carcinoma (in situ) 4.3 Suspicion of invasive carcinoma 4.4 Intramucosal carcinoma Invasive neoplasia (Submucosal carcinoma or beyond)

43 Thanks for your attention

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45 Helicobacter pylori and gastric carcinogenesis Normal gastric mucosa Other host and environmental factors Helicobacter pylori Chronic gastritis Chronic atrophic gastritis Intestinal metaplasia Gastric carcinoma

46 Molecular mechanisms underlying the glycan-mediated adhesion and infection of Helicobacter pylori: Glycan mediated Helicobacter pylori adhesion to gastric mucosa > H. pylori needs to establish a close contact with the gastric epithelial cells SabA (Sialic acid binding adhesin) (Mahdavi et al., Science, 2002) - binds sialyl-lewis x and sialyl-lewis a. BabA (blood group antigen-binding adhesin) (Ilver et al, Science 1998) - recognizes H-type I and Lewis b. Sialyl-Lewis a H type 1 Lewis b Sialyl- Lewis x Magalhães A et al. Expert Rev Proteomics, 7:307; Magalhães A et al. BJMBR, 43:611, 2010

47 Molecular mechanisms underlying the glycan-mediated adhesion and infection of Helicobacter pylori: Helicobacter pylori induces alterations in the glycosylation of the gastric mucosal leading to the synthesis of sialylated Lewis antigens, the ligands of SabA. Normal gastric mucosa Helicobacter pylori Chronic gastritis Sialyl- Lewis x Chronic atrophic gastritis Sialyl- Lewis x Magalhães A et al. Expert Rev Proteomics, 7:307; Magalhães A et al. BJMBR, 43:611, 2010

48 Japanese group classification Group 1 Normal tissue or nonneoplastic lesion Group 2 Indefinite for neoplasia Group 3 Adenoma Group 4 Neoplastic lesion suspected to be carcinoma Group 5 Carcinoma Japanese diagnostic criteria Structural and cytological abnormalities are necessary for diagnosis of GC regardless of the presence of invasion. Features of cytological abnormality Features of structural abnormality included increased crypt complexity with crowding, branching glandular epithelium, fused glands, budding, a cribriform pattern, and variability of crypt size and shape