ESMO Preceptorship Gastrointestinal Tumours · ESMO Preceptorship Gastrointestinal Tumours Valencia 06-07 October 2017. I have no conflicts of interest to declare Fátima Carneiro

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ESMO Preceptorship

Gastrointestinal

Tumours

Valencia

06-07 October 2017

I have no conflicts of interest to declare

Fátima Carneiro

ESMO Preceptorship ― Gastrointestinal Tumours

Pathology and carcinogenesis


Fátima CarneiroIPATIMUP

& Medical Faculty/Centro Hospitalar São João

Porto, Portugal

FMUP/CHSJ



Gastrointestinal tumoursMultidisciplinary management, standards of care and future perspectives



• ESMO Preceptorship ― Gastrointestinal Tumours

• Pathology and carcinogenesis

• Helicobacter pyloriinfection• Epstein Barr• Diet• Smoking

Environment(Epi)Genetic alterations

GastricCarcinoma

Gene-environment interaction

Risk of gastric cancer development

H. pylori virulent genotypes (vacA; CagA) 15 to 17IL-1 gene polymorphism 3.3H. pylori virulence & IL-1B polymorphism 87

Machado et al. Gastroenterology 121: 823, 2001 Figueiredo et al, JNCI 94: 1680, 2002

• Polymorphisms: Mucin genesPro-inflammatory genes

• Mutations in “low” or “high” penetrant genes







Gastroenterology 2014 – special issue



The stomach displays a diverse microbiota when H. pylori is absent or low in abundance

30%

47%

11%

11%1% <1%

Firmicutes

Actinobacteria

Bacteroidetes

Proteobacteria

Fusobacteria

Others

2%1%

1%

96%

Firmicutes

Actinobacteria

Bacteroidetes

Proteobacteria (H. pylori)

Andersson et al., PLoS ONE 2008

H. pylori positive stomach H. pylori negative stomach



The stomach displays a diverse microbiota when H. pylori is absent or low in abundance

Resident or transient populations of ingested microbes??

Stomach H. pylori -

Stomach H. pylori +

Andersson et al., PLoS ONE 2008



Figueiredo et al, 2017

METAGENOMICS





European Helicobacter Study Group

European Helicobacter and Microbiota Study group

2015





Sporadic cancer

Hereditary cancer

Molecular pathology

Precursor lesions

• CnAG• CAG• Metaplasia • Dysplasia• Gastric adenocarcinoma

(macroscopy; grade; differentiation)



Chronic gastritis



Helicobacter pyloriinfection

Diffuse antral gastritis Asymptomatic90%

Multifocal atrophic gastritis Asymptomatic90%

Host & environmental factors

Duodenal ulcer

Focal atrophy

Gastric ulcer

IM Dysplasia Gastric cancer

IM



Chronic gastritis

Antrum

Incisura

Body

Gland atrophy and multifocal IM



Classification of chronic gastritisOLGA staging

Rugge M et al. Dig Liver Dis 40: 650, 2008



Classification of chronic gastritisOLGIM staging

Capelle L et al. Gastrointest Endosc 71: 1150, 2010



Progression of chronic atrophic gastritis associated with Helicobacter pylori

infection increases risk of gastric cancer(Prospective study – mean follow-up: 7.7 years)

Ohata H et al. Int J Cancer 109:138, 2004

HP infection _ + + _

CAG _ _ + +

Gastric cancerCases/incidence rate 0 19/107 24/238 2/871HR (95% CI) _ (1) 7.13 (0.95-53.33) 14.51(1.96-107.70) 61.85 (5.60-682.64)

p=0.0007



Helicobacter pylori Eradication to Prevent

Gastric Cancer in a High-Risk Region of ChinaA 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



Chronic superficial gastritis

H. pylori infection

H. pylori

strain virulence(vacA s1, m1, cagA+)

Host

susceptibility(IL1B-511*T / IL1RN*2/*2)

(TNFA-308*A)

Intestinal metaplasia

Dysplasia

“Intestinal” carcinoma

Chronic atrophic gastritis

Enhanced chronic

inflammatory response

Normal mucosa



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







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 10-12.

Gastric dysplasia - WHO classification (2010)



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 towardsthe luminal half of the gland



Inte

stin

al t

ype

Gas

tric

typ

e

WH

O –

4th

Edition, 2

010

MORPHOLOGIC TYPE

• Columnar cells• Pencilate nuclei• Hipercromatic nuclei

• Cuboidal cells• Oval, vesicular nuclei• Clear, eosinophilic cytopasm



HE

CDX2CD10MUC2

MUC6MUC5AC

Intestinal phenotype



HE

CDX2CD10MUC2

MUC6MUC5AC

Gastric/foveolar phenotype



GradeImmunophenotype

p value

Gastric (n=24) Intestinal(n=22) Hybrid(n=14)

High grade (n=25)

15*63%

418%

643%

Low grade(n=35)

937%

1882%

857%

0.010* coexistent intramucosal carcinoma in 8 cases

Comparison between grade and immunophenotypes

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



WHO 2010 introductionPrecursor lesions of invasive neoplasia

(intraepithelial neoplasia) of the tubal gut

• “Intraepithelial neoplasia” encompasses allpremalignant lesions, with or without typicalcharacteristics of dysplasia; the termdysplasia is only used when a morphologicallyidentifiable lesion exists.

• Dysplasia is the term used to indicatehistologically unequivocal neoplastic epitheliumwithout evidence of tissue invasion.



WHO 2010 introductionPrecursor lesions of invasive neoplasia

(intraepithelial neoplasia) of the tubal gut

• The use of the term carcinoma in situ for columnarprecursor lesions is strongly discouraged (includedin high grade dysplasia).

• Intramucosal adenocarcinoma is the term used forlesions that show invasion into the lamina propriaor muscularis mucosa but not into the submucosa(what qualifies as evidence of invasion?).



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/dysplasia5.Intramucosal invasive neoplasia/intramucosal

carcinoma

*In stomach, and as far as these guidelines are concerned, category 1 includes lesions such as atrophic chronic gastritis and intestinal metaplasia.

WHO – 4th Edition, 2010

Intraepithelial neoplasia versus Dysplasia



Low & highgrade dysplasia

Intramucosal carcinoma



Time related progression of premalignant lesions to gastric cancer

De Vries et al. Gastroenterology 2008



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 3rd 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



Branching and budding of glands

Intraluminal necrotic debris

Fused or cribriforming glands

Intramucosal invasive neoplasia/intramucosal

carcinoma



Vienna classification ofgastrointestinal epithelialneoplasia

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 beyondSchlemper RJ et al: The Vienna classification of gastrointestinal epithelial neoplasia.Gut 47: 251, 2000Stolte M: The new Vienna classification of epithelial neoplasia of the gastrointestinal tract: advantadges and disavantadges. Virchows Archiv 442: 99, 2003

4 Non-invasive high grade neoplasia

5

4.1 High grade adenoma/dysplasia

4.2 Non-invasive carcinoma (in situ)

4.3 Suspicion of invasive carcinoma

4.4 Intramucosal carcinoma

Invasive neoplasia (Submucosalcarcinoma or beyond)

The new Vienna classification



Thanks for your attention



Normal gastric mucosa

Chronic gastritis


Intestinal metaplasia

Gastric carcinoma

Other host and environmental factors

Helicobacter pylori

Helicobacter pylori and gastric carcinogenesis



BabA (blood group antigen-binding adhesin) (Ilver et al, Science 1998)

- recognizes H-type I and Lewis b.

H type 1

Lewis b

- binds sialyl-Lewis x and sialyl-Lewis a.

Sialyl-Lewis a

Sialyl- Lewis x

Glycan mediated Helicobacter pylori adhesion to gastric mucosa> H. pylori needs to establish a close contact with the gastric epithelial cells

Magalhães A et al. Expert Rev Proteomics, 7:307; 2010.Magalhães A et al. BJMBR, 43:611, 2010

(Mahdavi et al., Science, 2002)

SabA (Sialic acid binding adhesin)

Molecular mechanisms underlying the glycan-mediated adhesion and infection of Helicobacter pylori:



Helicobacter pylori induces alterations in the glycosylation of the gastricmucosal leading to the synthesis of sialylated Lewis antigens, the ligands ofSabA.

Normal gastric mucosa

Chronic gastritis


Helicobacter pylori

Sialyl- Lewis x

Sialyl- Lewis x

Molecular mechanisms underlying the glycan-mediated adhesion and infection of Helicobacter pylori:

Magalhães A et al. Expert Rev Proteomics, 7:307; 2010.Magalhães A et al. BJMBR, 43:611, 2010



Japanese group classification

Group 1 Normal tissue or nonneoplastic lesionGroup 2 Indefinite for neoplasiaGroup 3 AdenomaGroup 4 Neoplastic lesion suspected to be carcinomaGroup 5 Carcinoma

Japanese diagnostic criteriaStructural 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 cryptcomplexity with crowding, branching glandular epithelium, fused glands,budding, a cribriform pattern, and variability of crypt size and shape

Documents

ESMO Preceptorship Gastrointestinal Tumours · ESMO Preceptorship Gastrointestinal Tumours Valencia 06-07 October 2017. I have no conflicts of interest to declare Fátima Carneiro