www.esmo.org
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
Pathology and carcinogenesis
Fátima CarneiroIPATIMUP
& Medical Faculty/Centro Hospitalar São João
Porto, Portugal
FMUP/CHSJ
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Gastrointestinal tumoursMultidisciplinary management, standards of care and future perspectives
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
• 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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Gastroenterology 2014 – special issue
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Figueiredo et al, 2017
METAGENOMICS
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
European Helicobacter Study Group
European Helicobacter and Microbiota Study group
2015
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Sporadic cancer
Hereditary cancer
Molecular pathology
Precursor lesions
• CnAG• CAG• Metaplasia • Dysplasia• Gastric adenocarcinoma
(macroscopy; grade; differentiation)
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Chronic gastritis
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Helicobacter pyloriinfection
Diffuse antral gastritis Asymptomatic90%
Multifocal atrophic gastritis Asymptomatic90%
Host & environmental factors
Duodenal ulcer
Focal atrophy
Gastric ulcer
IM Dysplasia Gastric cancer
IM
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Chronic gastritis
Antrum
Incisura
Body
Gland atrophy and multifocal IM
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Classification of chronic gastritisOLGA staging
Rugge M et al. Dig Liver Dis 40: 650, 2008
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Classification of chronic gastritisOLGIM staging
Capelle L et al. Gastrointest Endosc 71: 1150, 2010
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Dixon MF et al: Classification and grading of gastritis. Am J Surg Pathol 20(10):1161, 1996
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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)
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
HE
CDX2CD10MUC2
MUC6MUC5AC
Intestinal phenotype
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
HE
CDX2CD10MUC2
MUC6MUC5AC
Gastric/foveolar phenotype
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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.
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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?).
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Low & highgrade dysplasia
Intramucosal carcinoma
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Time related progression of premalignant lesions to gastric cancer
De Vries et al. Gastroenterology 2008
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Branching and budding of glands
Intraluminal necrotic debris
Fused or cribriforming glands
Intramucosal invasive neoplasia/intramucosal
carcinoma
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Thanks for your attention
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
Normal gastric mucosa
Chronic gastritis
Chronic atrophic gastritis
Intestinal metaplasia
Gastric carcinoma
Other host and environmental factors
Helicobacter pylori
Helicobacter pylori and gastric carcinogenesis
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and 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:
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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
Chronic atrophic 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
ESMO Preceptorship ― Gastrointestinal Tumours
Pathology and carcinogenesis
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