Gastric Carcinoma

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Gastric Carcinoma

Carcinoma gastrico localmente avanzato:

terapie integrate

ASPETTI EMERGENTI NELLA

CARATTERIZZAZIONE

ANATOMOPATOLOGICA

Vincenzo Canzonieri, M.D.

Anatomia Patologica


Gastric Carcinoma

Exocrine-Endocrine Modulation in Gastric

Cancer

Post CTRT Pathological Response


Exocrine-Endocrine Modulation in

Gastric Cancer

Epithelial

stomach

cancers

Exocrine cell (Exo-cell) type

(adenomas and carcinomas)

Endocrine cell (End-cell) type

(carcinoid tumors and

endocrine cell carcinomas)

It has been suggested that the origin of stomach common carcinomas

is from a progenitor cell specializing towards an Exo-cell lineage.

Tatematsu et al., Cancer Sci 2005


However, there have been several reports that chromogranin A (CgA)

and synaptophysin (Syn), generic End-cell differentiation markers,

were immunohistochemically found in about 15-70% of common

stomach carcinomas, suggesting the possibility of both Exo-cell and

End-cell differentiation.

Such a mixture of Exo-cell and End-cell lineages could have

implications on the histogenesis of common carcinomas.

Park et al., Int J C 1992

Qvigstad et al., Histoch J 2000

Naritomi et al., Anticancer Res 2003

Tatematsu et al., Cancer Sci 2005

Takenaka et al., Histol Histopatol 2007

Lewin K. Carcinoid tumors and the mixed (composite)

glandularendocrine cell carcinomas. AmJ Surg Pathol

1987;11(Suppl 1):71–86.

1) Composite (or mixed) glandular-endocrine tumor with both elements in more

or less equal proportions

2) Amphicrine tumors with dual differentiation within the same cell.

3) Collision tumors where the two components are juxtaposed but not admixed.


Volante et al Virchows Arch (2006) 449:499–506


(CgA/Syn +)

AC (Adenocarcinoma) = 0%

ACNED (Adenocarcinoma with Neuroendocrine Differentiation ) < 20%

LCNEC (Large Cell Neuroendocrine Carcinoma) > 20%

The presence of (N)Endocrine differentiation in gastric adenocarcinomas

ultimately deals with prognostic definition and, possibly, with therapy

decision making.

Jiang et al., Am J Surg Pathol 2006


CRO series

103 Common Gastric Cancers


Methods

Immunohistochemistry was performed with automated immunostainer

Benckmark XT (Ventana) using CgA and Syn antibodies.

Ten microscopic fields at 40x original magnification were randomly

chosen and at least 100 tumor cells were counted for each field. The

cases were stratified according to the percentage of CgA/Syn positive

tumor cells (0%, 1-20%, >20%) in each section.


CgA


CgA


(= AC)

(= ACNED) (= LCNEC)

CgA/Syn +

0%

CgA/Syn +

≤ 20%

CgA/Syn +

> 20%

Age

Mean

SD

67.8 ± 10.4 64.3 ± 11.4

62.3 ± 11.3

Range 50-84 40-94 49-85

Sex

Male 17 39* 7

Female 20 13 7

Diagnosis

Adenocarcinoma 28 35 8

Undifferentiated

carcinoma

9 17 6

Presence of (N)Endocrine differentiation in 66/103 cancers

(64,1%): 52/103 ACNED and 14/103 LCNED.


(= AC)

(= ACNED) (= LCNEC)

CgA and Syn 0%

CgA and/or

Syn 1-20%

CgA and/or

Syn >20%

Histopathological

Grading

G1 + G2

G3

G4

Primary Tumor

T1 + T2

T3 + T4

Regional Lymph

Nodes

N0

N+

3

25

9

6

31

10

27

8

27

17

13

39

16

36

0

8

6

2

12

8

6


(= AC)

(= ACNED) (= LCNEC)

CgA and Syn 0%

CgA and/or

Syn 1-20%

CgA and/or

Syn >20%

Distant Metastasis

M0

M1

Clinical stage

I

II

III

IV

33

4

1

14

18

4

45

7

6

16

23

7

13

1

1

6

6

1

CgA/Syn expression is homogeneously distributed stage by stage.


The presence of (N)Endocrine differentiation in common

gastric carcinomas correlates with increased relapses and

mortality


Survival by CgA/Syn expression

(CgA/Syn expression: 0%___ / ≤ 20% _ _ / >20% _ __ _)

AC= 66

ACNED

=52

LCNEC

=14

The prognosis of LCNEC is significantly worse than prognosis

of ACNED or AC.


0% ≤ 20% > 20% 0% ≤ 20% > 20%

(N)Endocrine differentiation in common gastric carcinomas

significantly correlates with increased relapse rate and mortality,

even when cases are stratified for clinical stages.


Mature fenotypes

Immunohistochemistry

Gastric

phenotype

Intestinal phenotype

MUC5AC

MUC2

Exo-cell

MUC6

G

Villin

CD10

I

CgA /Syn+

End-cell

Gastrin

Somatostatin

e-G

Glucagon-like peptide-1 (GLP1)

Gastric inhibitory polypeptide (GIP)

e-I


CRO series

Methods

Ten microscopic fields at 40x original magnification were

chosen and at least 100 tumor cells were counted for each

field. The cases were stratified according to any

percentage of positive tumor cells for each marker in each

section.

Maturely differentiated

Exocrine phenotypes

16/103 Exo-G (15,5%)

22/103 Exo-I (21,4%)

64/103 Exo-GI (62,1%)

1/103 Exo-Null (


MUC2

MUC5AC


Gastrin

Somatostatin


Diagnostic and Prognostic

Relevance

Maturely differentiated EXO-cell phenotype

Univariate and multivariate analysis of survival revealed the G-

phenotype tumor to be associated with a significantly poorer

outcome than the I-phenotype tumor (p < 0.05).

Tajima et al., Oncology 2001

Tajima et al., Br J Cancer 2004

No data for maturely differentiated (N)END-cell

phenotype and coordinate pattern with EXO-cell

phenotype


Maturely differentiated

Exocrine phenotype

16/103 Exo-G (15,5%)

22/103 Exo-I (21,4%)

64/103 Exo-GI (62,1%)

1/103 Exo-Null (


Maturely differentiated

Endocrine phenotype

26/66 End-G (39,4%)

21/66 End-I (31,8%)

5/66 End-GI (7,6%)

14/66 End-Null (21,2%)


Conclusions






Significant cut-off value for (N)Endocrine differentiation in common

gastric carcinomas is fixed to 20% CgA/Syn positive cells.

CgA/Syn expression is a negative prognostic factor for relapse-free

survival and disease specific survival in common gastric carcinomas.

When cases are stratified for clinical stage (I and II vs III and IV),

prognostic value of CgA/Syn still remains statistically significant.

Exocrine mature differentiation of gastric type is a negative prognostic

factor.

Endocrine mature differentiation of gastric type is associated with

poorer prognosis in CgA/Syn positive tumors.


Definition of Post-CTRT

Pathological Response

Bain et al. The Oncologist,2010


Histopathologic Investigation

Standardized Protocol

Becker at al Cancer 2003;98:1521–30.

• Photographic documentation, and photocopy of the specimen

• Measurement of macroscopically identifiable residual tumor

• The entire macroscopic identifiable tumor or the area of the stomach with

scarring indicating the site of the previous tumor (the tumor bed) was crosssectioned

serially at 0.5 cm intervals

• Tissue sections were stained with hematoxylin and eosin, elastic von Gieson

stain, and periodic acid–Schiff (PAS) stain

• van Gieson stain was used to distinguish between tumor desmoplasia and

scarring as a result of chemotherapy

• PAS stain was used to help distinguish signet ring cells from histiocytes

• Immunohistochemistry for cytokeratins was used in cases in which epithelial

cells were not identifiable.


Pathological Response

Mandard and Becker scoring systems for histopathological

response in gastroesophageal cancer

Grade Description

Mandard regression grade

1. Absence of residual cancer, fibrosis extending through different areas of

esophageal wall

2. Rare residual cancer cells scattered through fibrosis

3. Increase in number of residual cancer cells but fibrosis still predominant

4. Residual cancer outgrowing fibrosis

5. Absence of regressive changes

Becker regression grade

1a

1b

No residual tumor/tumor bed

10% residual tumor/tumor bed

2 10%–50% residual tumor/tumor bed

3 50% residual tumor/tumor bed


Becker at al Cancer

2003;98:1521–30.


Morbidity, Mortality, and Pathological

Response in Patients With Gastric

Cancer Preoperatively Treated With

Chemotherapy or Chemoradiotherapy

V Valenti et al.


Thanks

Lorenzo Memeo IOM

Tiziana Perin CRO

Cristina Colarossi IOM

Laura Del Col CRO

Renato Talamini CRO

Roberto Sigon CRO

Renato Cannizzaro CRO

Eleonora Aiello IOM

Angela Buonadonna CRO

Fabrizio Italia SR

Daniela Massi Univ. Firenze

Antonino Carbone CRO

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