PATHOLOGY OF GASTRIC CANCER

Fátima Carneiroi3S/Ipatimup & Medical Faculty/Centro Hospitalar São João, Porto, Portugal

DISCLOSURE OF INTEREST

No conflicts of interest to declare

CANCER STAGING (UICC& AJCC), 8th EDITION

Eighteen expert panels and 7 cores (420contributors from 181 institutions, 22countries and 6 continents)

TUMOURS AT THE ESOPHAGOGASTRIC JUNCTION (EGJ)

Staged as gastric cancer Staged as esophageal cancer

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 4th edition, 2010

Gregory Y. LauwersFátima Carneiro David Y. Graham Maria-Paula Curado Silvia FranceschiElizabeth Montgomery Masae TatematsuTakenori Hattori

ICD-O Code Adenocarcinoma 8140/3 Papillary adenocarcinoma 8260/3 Tubular adenocarcinoma 8211/3 Mucinous adenocarcinoma 8480/3 Poorly cohesive carcinoma 8490/3 (Signet-ring cell carcinoma and variants)Mixed carcinoma 8255/3

Papillary Tubular

Mucinous

Poorly cohesive

Mixed

Poorly cohesive(signet ring cell)

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 4th edition, 2010

The same frame for the classification of major types of gastric cancer was kept

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 5th edition, 2019

Tubular adenocarcinoma.The tumour is composed of dilated tubules invading themuscle layer.

Papillary carcinoma The tumour consists of elongated finger-like processes with fibrovascular connective tissue cores, lined by columnar cells.

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 5th edition, 2019

Poorly cohesive carcinoma, signet-ring cell typeThe tumour is composed predominantly of signet-ring cells; theneoplastic cells are larger at the superficial part of the mucosa

Poorly cohesive carcinoma NOSThe tumour consists of poorly cohesive cells of non–signet-ring cell type that invade the gastric wall widely, with markeddesmoplasia.

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 5th edition, 2019

Mixed carcinoma

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 5th edition, 2019

HISTOLOGICAL CLASSIFICATIONS OF GASTRIC CANCERLaurén(1965)

Nakamura(1968)

JGCA(2017)

WHO(2018)

Intestinal Differentiated Papillary: papTubular 1, well-differentiated: tub1Tubular 2, moderately-differentiated: tub2

PapillaryTubular, well-differentiatedTubular, moderately-differentiated

Indeterminate Undifferentiated Poorly 1 (solid type): por 1 Tubular, poorly-differentiated (solid)

Diffuse Undifferentiated Signet ring cell carcinoma (SRC): sigPoorly 2 (non-solid type): por2

Poorly cohesive, SRC typePoorly cohesive, NOS

Intestinal/diffuse/indeterminate Differentiated/Undifferentiated

Mucinous Mucinous

Mixed Description according to the proportion(e.g. por2>sig>tub2)

Mixed

Not defined Not defined Special type:Adenosquamous carcinomaSquamous cell carcinomaUndifferentiated carcinomaCarcinoma with lymphoid stromaHepatoid adenocarcinomaAdenocarcinoma with enteroblasticdifferentiation Adenocarcinoma of fundic gland type

Histological variants:Adenosquamous carcinomaSquamous cell carcinomaUndifferentiated carcinomaCarcinoma with lymphoid stromaHepatoid carcinomaAdenocarcinoma with enteroblastic differentiationAdenocarcinoma of fundic gland typeMicropapillary adenocarcinoma

*JGCA, Japanese Gastric Cancer Association {978-4-307-20375-3}. **Table prepared in collaboration with Prof. Ryoji Kushima, Japan

WHO, 5th edition

Laurén(1965)

Nakamura(1968)

JGCA(2017)

WHO(2018)

Intestinal Differentiated Papillary: papTubular 1, well-differentiated: tub1Tubular 2, moderately-differentiated: tub2

PapillaryTubular, well-differentiatedTubular, moderately-differentiated

Indeterminate Undifferentiated Poorly 1 (solid type): por 1 Tubular, poorly-differentiated (solid)

Diffuse Undifferentiated Signet ring cell carcinoma (SRC): sigPoorly 2 (non-solid type): por2

Poorly cohesive, SRC typePoorly cohesive, NOS

Intestinal/diffuse/indeterminate Differentiated/Undifferentiated

Mucinous Mucinous

Mixed Description according to the proportion(e.g. por2>sig>tub2)

Mixed

Not defined Not defined Special type:Adenosquamous carcinomaSquamous cell carcinomaUndifferentiated carcinomaCarcinoma with lymphoid stromaHepatoid adenocarcinomaAdenocarcinoma with enteroblasticdifferentiation Adenocarcinoma of fundic gland type

Histological variants:Adenosquamous carcinomaSquamous cell carcinomaUndifferentiated carcinomaCarcinoma with lymphoid stromaHepatoid carcinomaAdenocarcinoma with enteroblastic differentiationAdenocarcinoma of fundic gland typeMicropapillary adenocarcinoma

*JGCA, Japanese Gastric Cancer Association {978-4-307-20375-3}. **Table prepared in collaboration with Prof. Ryoji Kushima, Japan

HISTOLOGICAL CLASSIFICATIONS OF GASTRIC CANCER

Laurén(1965)

Nakamura(1968)

JGCA(2017)

WHO(2018)

Intestinal Differentiated Papillary: papTubular 1, well-differentiated: tub1Tubular 2, moderately-differentiated: tub2

PapillaryTubular, well-differentiatedTubular, moderately-differentiated

Indeterminate Undifferentiated Poorly 1 (solid type): por 1 Tubular, poorly-differentiated (solid)

Diffuse Undifferentiated Signet ring cell carcinoma (SRC): sigPoorly 2 (non-solid type): por2

Poorly cohesive, SRC typePoorly cohesive, NOS

Intestinal/diffuse/indeterminate Differentiated/Undifferentiated

Mucinous Mucinous

Mixed Description according to the proportion(e.g. por2>sig>tub2)

Mixed

Not defined Not defined Special type:Adenosquamous carcinomaSquamous cell carcinomaUndifferentiated carcinomaCarcinoma with lymphoid stromaHepatoid adenocarcinomaAdenocarcinoma with enteroblasticdifferentiation Adenocarcinoma of fundic gland type

Histological variants:Adenosquamous carcinomaSquamous cell carcinomaUndifferentiated carcinomaCarcinoma with lymphoid stromaHepatoid carcinomaAdenocarcinoma with enteroblasticdifferentiationAdenocarcinoma of fundic gland typeMicropapillary adenocarcinoma

*JGCA, Japanese Gastric Cancer Association {978-4-307-20375-3}. **Table prepared in collaboration with Prof. Ryoji Kushima, Japan

WHO, 5th edition

HISTOLOGICAL CLASSIFICATIONS OF GASTRIC CANCER

JGCA, JAPANESE GASTRIC CANCER ASSOCIATION (2017)

WHO classification (2018)Poorly cohesive carcinoma, SRC Poorly cohesive carcinoma, NOS

POORLY COHESIVE CARCINOMA: MUTATIONAL SIGNATURESHeterogeneity of poorly cohesive carcinoma

HISTOLOGICAL CLASSIFICATIONS OF GASTRIC CANCERLaurén(1965)

Nakamura(1968)

JGCA(2017)

WHO(2018)

Intestinal Differentiated Papillary: papTubular 1, well-differentiated: tub1Tubular 2, moderately-differentiated: tub2

PapillaryTubular, well-differentiatedTubular, moderately-differentiated

Indeterminate Undifferentiated Poorly 1 (solid type): por 1 Tubular, poorly-differentiated (solid)

Diffuse Undifferentiated Signet ring cell carcinoma (SRC): sigPoorly 2 (non-solid type): por2

Poorly cohesive, SRC typePoorly cohesive, NOS

Intestinal/diffuse/indeterminate Differentiated/Undifferentiated

Mucinous Mucinous

Mixed Description according to the proportion(e.g. por2>sig>tub2)

Mixed

Not defined Not defined Special type:Adenosquamous carcinomaSquamous cell carcinomaUndifferentiated carcinomaCarcinoma with lymphoid stromaHepatoid adenocarcinomaAdenocarcinoma with enteroblasticdifferentiation Adenocarcinoma of fundic gland type

Histological variants:Adenosquamous carcinomaSquamous cell carcinomaUndifferentiated carcinomaCarcinoma with lymphoid stromaHepatoid carcinomaAdenocarcinoma with enteroblastic differentiationAdenocarcinoma of fundic gland typeMicropapillary adenocarcinoma

*JGCA, Japanese Gastric Cancer Association {978-4-307-20375-3}. **Table prepared in collaboration with Prof. Ryoji Kushima, Japan

WHO, 5th edition

Histological variants:Adenosquamous carcinoma (separate chapter)

Squamous cell carcinoma (separate chapter)

Undifferentiated carcinoma (separate chapter)

• Carcinoma with lymphoid stroma

• Hepatoid carcinoma

• Adenocarcinoma with enteroblastic differentiation

• Adenocarcinoma of fundic gland type

• Micropapillary adenocarcinoma

Invasive micropapillary adenocarcinomaThe tumour clusters display the characteristic inside-out growth pattern, with the luminal pole of the cells present on the outer surface of the cluster

Adenocarcinoma with enteroblastic differentiationThe glands consist of the columnar neoplastic cells characterized byglycogen-rich clear cytoplasm, reminiscent of fetal gut epithelium(variant of hepatoid carcinoma)

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 5th edition, 2019

Gastric carcinoma with lymphoid stroma (EBV-positive gastric cancer)Cancer cells form small nests or fused glands, accompanied by abundant lymphocyte infiltration. Nuclei of carcinoma cells are positive by in situ hybridization targeting EBV-encoded small RNA (EBER). Nuclei of infiltrating lymphocytes are negative.

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 5th edition, 2019

Gastric adenocarcinoma of fundic-gland typeSubmucosal invasion in the central portion of the tumor Neoplastic cells of immature fundic-gland type

WHO CLASSIFICATION OF TUMOURS OF THE DIGESTIVE SYSTEM, 5th edition, 2019

MOLECULAR CLASSIFICATION OF GASTRIC CANCER (TCGA)

The Cancer Genome Atlas (TCGA) project; Nature 2014

MOLECULAR CLASSIFICATION OF GASTRIC CANCER (ACRG)

Asian Cancer Research Group. Cristescu R et al: Nature Medicine 21; 449, 2015

A PROTEIN AND MRNA EXPRESSION-BASED CLASSIFICATION OF GASTRIC CANCER

Ahn S et al. Am J Surg Pathol 41:106, 2017Setia M et al. Mod Pathol 29:772, 2016

EBER

HER2 IHCISH

WHAT IS MISSING IN MOLECULAR CLASSIFICATION OF GASTRIC CANCER

HER2 IN GASTRIC CARCINOMA: PROGNOSTIC AND/ORPREDICTIVE FACTOR

Prognostic factor?NO (44%)

YES (56%)

HER2 amplificationin intestinal-type gastric carcinoma

Blood born metastasesPoor prognosis

David L et al; Mod Pathol 5:384, 1992Barros-Silva J et al; Br J Cancer 100: 487,2009

Predictive factorToGA TrialHER-2 overexpression in 22% of advanced gastric cancers; improved survival in patients treated with with trastuzumabASCO 2009 (LBA 4509)

EVALUATION OF HER2 STATUS

ImmunohistochemistryIn situ hybridization

MINIMUM BIOPSY SET FOR HER2 EVALUATION

Tominaga N et al. Gastric Cancer 2016. doi: 10.1007/s10120-015-0502-3

IT IS NOT ONLY THE QUALITY BUT ALSO THE QUANTITY

RESISTANCE TO HER2 TARGETED THERAPY IN GASTRIC CANCER

• Patients initially respond to HER2 targeted therapy but eventually becomeresistant to treatment.

• Individual tumours with similar clinical stage have different clinical outcomes.

Putative causes• Heterogeneity of HER2 expression• HER2 copy number in ctDNA• ERBB2/EGFR co-amplification

Lee HE et.al. Eur J Cancer 2013; Kim J et al J Clin Invest 2014; Kwak EL et al Cancer Discov 2015; . Wang et al. Eur J Cancer 2018, 88: 92-100

Mismatch Repair Deficiency (MMRd)

Microsatellite Instability (MSI)Next Generation Sequencing (NGS)• Instability signatures

• Instability burden(correlation with overall survival)

(Immunohistochemistry)

(Fluorescent Multiplex PCR)

MSI IN GASTRIC CARCINOMA

Survival of patients

Molecular marker of good prognosis in sporadic gastric cancer (caused by hMLH1promoter hypermethylation)

MSI IN GASTRIC CARCINOMA

IMPACT OF MSI-H STATUS IN RESPONSE TO STANDARD CHEMOTHERAPY

MAGIC trialPoor prognosis (overall survival) in patients submitted to chemoterapy and surgery (MSI-H)

IMPACT OF MSI-H STATUS IN RESPONSE TO STANDARD CHEMOTHERAPY

Experience of MSKC (NY-US)

Patients with MSI-H tumors suffered rapiddisease progression on standard cytotoxictherapy, with a significantly shorter PFS on first-line chemotherapy when compared with non-MSI-H tumors.

GASTRIC CANCER AND IMMUNE CHECKPOINT BLOCKADE

Predictive biomarkers

MSI-high status PD-L1 expression

Le DT et al. Science 2017; Kulangara K. Arch Pathol Lab Med 2018; Kim ST. Nat Med 2018

PD-1

Predictive biomarkers

EBV+ and MSI-high status

Le DT et al. Science 2017; Kulangara K. Arch Pathol Lab Med 2018; Kim ST. Nat Med 2018

PD-1

GASTRIC CANCER AND IMMUNE CHECKPOINT BLOCKADE

CLINICAL RELEVANCE OF MOLECULAR DIAGNOSIS

Eur J Cancer. 2017 Nov;86:305-317.

Dig Liver Dis. 2016 Nov;48(11):1283-1289

CLINICAL RELEVANCE OF MOLECULAR DIAGNOSIS

TAKE HOME LESSONS

1) Established predictive biomarkers: HER2 (anti-HER2 therapy in patients with unresectable or metastatic/recurrent HER2-positive GC)

2) Biomarkers partly established and/or under development:a. MSI status and conventional chemotherapy;b. Biomarkers for cancer immunotherapy (targeting of the PD-L1/PD-1 axis)

• MSI-high and EBV + • PD-L1 expression• Tumour mutational load

Thanks for your attention