AIRTUM 2016

Nel mondo

Oltre il 70% dei casi insorgono nei paesi in via di sviluppo, circa
met dei casi insorge in Asia (soprattutto in Cina).

La mortalit pi alta stimata per Asia (28.1 per 100,000 negli

uomini, 13.0 per 100,000 nelle donne), la pi bassa in Nord
America (2.8 e 1.5 rispettivamente)
 In Europa

ECO, European Cancer Observatory. International Agency for Research on Cancer http://eu-cancer.iarc.fr, accessed on 19/04/2011
Sopravvivenza

stomaco
Stomaco
 Classificazione istologica
del carcinoma gastrico

Lauren 1965 Goseki 1992

Nakamura 1968 Nagayo 1994
Mulligan 1972 Carneiro 1995
Ming 1977 WHO 2000
 WHO 2010
Classification of gastric carcinoma

Gastric carcinomas are a biologically and

genetically heterogeneous group of tumours.
They are characterized by broad morphological
heterogeneity with respect to pattern of architecture
and growth, cell differentiation and histogenesis.

The heterogeneity of gastric carcinomas is

reflected in part by the diversity of the various
Histopathological classification schemes on record.
Although the most commonly used are those of
WHO and Lauren, several other schemes have
been proposed.
 WHO 2010
Classification of gastric carcinoma

Adenocarcinoma
papillary
tubular
mucinous
poorly cohesive
mixed
Others
Papillary adenocarcinoma

This type is composed of

elongated finger-like processes
lined by cilindrical or cuboidal cells
supported by fibrovascular
connective tissue cores.

The invading edge of the tumor is

usually sharply demarcated.
Tubular adenocarcinoma

This type is composed of dilated or

slit like and branching tubules of
varying diameter.

The degree of nuclear atypia

varies from low- to high-grade.

The degree of desmoplasia varies

and may be conspicuous.
Mucinous adenocarcinoma

This tumour is composed of

malignant epithelium and
extracellular mucinous pools.

By convention, the tumour shows

more than 50% extracellular
mucin.
 Poorly cohesive carcinoma
Poorly cohesive carcinomas are
composed of neoplastic cells that are
isolated or arranged in small
aggregates.
These encompass:
a)Signet-ring cell type
a tumour composed predominantly
or exclusively of signet-ring cells.

b)Other cellular variants

the neoplastic cells may resemble
histiocytes or lymphocytes;
they may show deeply eosinophilic
cytoplasm; the nuclei may be irregular
and bizare.
Poorly cohesive carcinoma
Mixed adenocarcinoma

These carcinomas dysplay a mixture

of discrete morphologically identifiable
glandular (tubular/papillary)
and signet-ring/poorly cohesive
cellular histological component.

Any discrete histological component

should be reported.
 Uncommon histological variants
(about 5% of gastric cancers)
Adenosquamous Squamous

Hepatoid Undifferentiated
Gastric carcinoma with lymphoid stroma
This tumour, also reported as
lymphoepithelioma-like carcinoma
or medullary carcinoma, is
characterized by poorly developed
tubular structures associated with
a prominent lymphoid infiltration of
the stroma.
Characteristics:
-proximal stomach/gastric stumps
-EBV 80% of cases
-good prognosis
Specimens taken at operation for gastric cancer on 1344 patients were
studied in the Department of Pathological Anatomy, University of
Turku in 1945-1964.
In the series 53 per cent of the tumours (715cases) were found to
belong to a main type consisting mainly of tumours of adenomatous
structure. The name intestinal-type gastric carcinoma was used for
this group because all tumours of this strutural type occur as primary
colon cancer as well.
Another main type, 33 per cent (441 cases) differed from the intestinal
type both in general and cellular structure. These tumours were called
diffuse gastric carcinoma in view of their manner of growth.
In the remaining 14 per cent (188 cases), the structure of the carcinoma
differed from both main types.

Acta path. et microbiol. scandinav. 64, 31-49, 1965

The two histological main types of gastric carcinoma:
diffuse and so-called intestinal type carcinoma
Lauren P. Acta Pathol Microbiol Scand 64:31-49, 1965

Tipo intestinale Tipo diffuso

Pattern architetturale
 Tipo di crescita

Expanding Infiltrating
Lauren mixed type
Lauren mixed type
Lauren indeterminate type
 CORRELATION BETWEEN INTESTINAL-TYPE
AND DIFFUSE GASTRIC CARCINOMA AND
OTHER CHARACTERISTICS OF THE DISEASE
Sex. The great majority, 65 per cent of the cases with intestinal-type
carcinoma were men, 35 per cent women.
Age. The mean age of the patients with intestinal-type carcinoma
was 55.4 years, the age of the patients with diffuse carcinoma
being clearly lower, 47.7 years.
Macroscopic features. Of the intestinal type carcinomas 60 per cent
were described as polypous or fungating; the corresponding percentage in
diffuse carcinomas was 31 per cent. Intestinal-type carcinoma formed
rarely an infiltrate of the linitis plastica type (15 per cent) than diffuse
carcinoma (43 per cent).
Changes in the normal mucosa close to the tumour. Marked signs
of chronic atrophic, atrophic-hyperplastic, or hyperplastic gastritis in the
surrounding mucosa were encountered in 88 per cent of the intestinal type
and in 45 per cent of the diffuse carcinomas.
Acta path. et microbiol. scandinav. 64, 31-49, 1965
 Classificazione di Borrmann 1926

Polypoid

Fungating

Ulcerated

Infiltrative
Istologia tipo intestinale Istologia tipo diffuso
 Metaplasia intestinale

Istologia tipo intestinale Istologia tipo diffuso

The principal sinificance of differentiation between intestinal-
type and diffuse gastric carcinoma is, however, that the tumours
of these two types differ not only structurally but also in their
other characteristics. Such difference is not allowed for in the
purely descriptive histological types of gastric carcinoma in
common use. The observations made here motivate the
assumption that intestinal-type and diffuse carcinoma might
have an at least somewhat differing aetiology and patogenesis.

Acta path. et microbiol. scandinav. 64, 31-49, 1965

The two histological main types of gastric carcinoma:
diffuse and so-called intestinal type carcinoma
Lauren P. Acta Pathol Microbiol Scand 64:31-49, 1965

Tipo intestinale Tipo diffuso

The principal sinificance of differentiation between intestinal-
type and diffuse gastric carcinoma is, however, that the tumours
of these two types differ not only structurally but also in their
other characteristics. Such difference is not allowed for in the
purely descriptive histological types of gastric carcinoma in
common use. The observations made here motivate the
assumption that intestinal-type and diffuse carcinoma might
have an at least somewhat differing aetiology and patogenesis.

Acta path. et microbiol. scandinav. 64, 31-49, 1965

 E-Caderina

Istologia tipo diffuso Istologia tipo intestinale

Prof M. Rugge Padova
 Tipo Intestinale Tipo Diffuso
Epidemico Endemico
Maschi Femmine
Et media 60 a. Et media 50 a.
Esofitico Ulcerato-infiltrante
Strutture ghiandolari Cellule dissociate
Crescita expanding Crescita infiltrating
Atrofia/metaplasia int. Atrofia/metaplasia int.
Prognosi migliore Prognosi peggiore
Sporadico Eredo-familiare
HER2 + 20% Mutazione E-caderina
WHO 2010
Staining Surgical Biopsies HER2
intensity staining staining overexpression
score pattern pattern status

0 1+ 2+ 3+
 Suggested HER2 testing algorithm
in GC/GEJ cancer

Patient tumour sample

IHC

0 +1 +2 +3
retest

FISH/SISH*

+ Eligible for trastuzumab

*cut off for FISH, SISH = HER2:CEP17 ratio 2

The majority of gastric cancers are associated with infectious
agents, including the bacterium Helicobacter pylori4 and
EpsteinBarr virus (EBV). The distribution of histological
subtypes of gastric cancer and the frequencies of H. pylori and
EBV associated gastric cancer vary across the globe.
A small minority of gastric cancer cases are associated
with germline mutation in E-cadherin (CDH1) 6 or mismatch
repair genes7 (Lynch syndrome), whereas sporadic mismatch
repair-deficient gastric cancers have epigenetic silencing of
MLH1 in the context of a CpG island methylator phenotype
(CIMP)8.
Molecular profiling of gastric cancer has been performed using
gene expression or DNA sequencing912, but has not led to a
clear biologic classification scheme. The goals of this study by
The Cancer Genome Atlas (TCGA) were to develop a robust
molecular classification of gastric cancer and to identify
dysregulated pathways and candidate drivers
of distinct classes of gastric cancer.
50%

10
%

20
%

20%
EBV MSI CIN GS
 Carcinoma gastrico: prognosi

Sopravvivenza a 5 anni: 20-40%

correlata a:
radicalit chirurgica
stadio

early gastric cancer: sopravvivenza a 5 anni 90%

advanced gastric cancer: sopravvivenza a 5 anni 15%

Early gastric cancer
Early gastric cancer
carcinoma invasivo che
non supera la sottomucosa
con o senza metastasi linfonodali
 Carcinoma gastrico iniziale
(early gastric cancer)

Carcinoma invasivo che non supera la

sottomucosa con o senza metastasi
linfonodali.

La sopravvivenza condizionata dalle

dimensioni, dal livello dinfiltrazione e dal
tipo di crescita.
Growth patterns and prognosis in early gastric cancer
superficial spreading and penetrating growth types
Kodama Y, Cancer 1983

< 4 cm., mucosa

sottomucosa focalmente

> 4 cm., mucosa

sottomucosa

< 4 cm., sottomucosa

exp., distruzione m. mucosa
inf., fenestrazioni m. mucosae
Growth patterns and prognosis in early gastric cancer
(167 cases; Kodama, 1983)

Super Small Pen A Pen B

Frequenza 45% 36% 10% 8%
N+ 11% 3% 25% 8%
Vene + 0% 0% 25% 0%
M. epatiche 1% 0% 25% 7%
Vivi a 10 a. 90% 91% 65% 100%
 Carcinoma gastrico avanzato
(advanced gastric cancer)

Carcinoma invasivo che supera la

sottomucosa.

La sopravvivenza dipende
principalmente dallo stadio (pTNM).
 Gastric cancer: survival rates by stage
National Cancer Data Base (33,085 cases)
Hundahi S.A. et al. Cancer 2000
100%

80% IA
IB
60%
II
40% IIIA
IIIB
20%
IV
0%
years 1 2 3 4 5
Mucos
a
Sottomucos
a
Muscolar
e

Sottosieros
a
Sieros
a
Gastrite autoimmune
5% gastriti croniche
corpo/fondo interessati
antro normale
Nord-europa
M:F= 1:3 ; 45-60 anni
acp anti cellule parietali e
anti fattore intrinseco
>gastrina <B12
tiroidite di Hashimoto
carcinoma: 0-2%
carcinoide: 3-10%
talora multipli
 Neuroendocrine neoplasms
of the stomach

Gastric NETs and NECs are classified on the

basis of criteria that are comon to all
gastrointestinal and pancreatic neuroendocrine
neoplasms.

Most neuroendocrine neoplasms of the stomach

are NETs and arise predominantly in the corpus-
fundus region.
 Gastric NETs
Type I associated with autoimmune
chronic atrophic gastritis

Type II associated with MEN1 and

Zollinger-Ellison syndrome

Type III sporadic

Others serotonin-producing NET

gastrin-producing NET
Gastric NET Type I

75% of gastric NENs

M:F 1:2.5
Mean age 63 years (range 15-88 y)
Gastric fundus/body
Back-ground of A-CAG
Typically small < 1 cm, and multiple
Hyperplasia of antral gastrin cells
ECL-cell hyperplasia/dysplasia in
the fundic peritumoral mucosa
ECL-cell hyperplasia/dysplasia
Gastric NET Type II
6% of gastric NENs
M:F 1:1
Mean age 50 years (range 28-67 y)
Gastric fundus/body
MEN1 Zollinger-Ellison syndrome
Usually multiple and < 1.5 cm in size
Hyperplasia of antral gastrin cells
ECL-cell hyperplasia/dysplasia in the
fundic peritumoral mucosa
Gastric NET Type III

13% of gastric NENs

M:F 2.8:1
Mean age 55 years (range 21-68 y)
Gastric fundus/body
Sporadic
Usually single and >2 cm in size
Normal surrounding mucosa
Gastric NEC

5-15% of gastric NENs

M:F 2:1
Mean age 63 years (range 41-61 y)
Any part of the stomach
Sporadic
Usually single and >2 cm in size
Evidence for progression from NET to
NEC has only rarely been
demonstrated
Normal surrounding mucosa
Gastrite autoimmune: tumore neuroendocrino
Pepsinogeno I e Pepsinogeno II
I pepsinogeni sono precursori dellenzima pepsina. Il
pepsinogeno I viene prodotto dalle cellule della zona alta dello
stomaco (tecnicamente corpo-fondo). Esiste una correlazione
tra la perdita di queste cellule (perdita che si pu avere in caso
di atrofia gastrica) e il livello di pepsinogeno I. Il pepsinogeno II
prodotto dallintero stomaco e dal duodeno. Vista la diversa
localizzazione delle cellule che producono i due pepsinogeni, il
rapporto tra pepsinogeno I e pepsinogeno II permette di stabilire
la zona dello stomaco affetta dalla patologia.
La Gastrina 17 un ormone prodotto dalle cellule della parte bassa
dello stomaco (antro) e la sua liberazione regolata da un
meccanismo
a feed-back negativo ai livelli di pH gastrico e di pepsinogeni.
Un basso livello di gastrina 17 indice di aumento della secrezione
acida gastrica, correlato per lo pi a malattia da reflusso gastro-
esofageo;
Un incremento della Gastrina 17 indice del tentativo di stimolare la
produzione di acido cloridrico in caso di gastrite atrofica del corpo-
fondo; in questo caso si associa a bassi livelli di pepsinogeno I.
Questultima situazione di frequente riscontro in soggetti con
patologia autoimmune tiroidea (Tiroidite di Hashimoto) nei quali ci si
pu attendere,
in un quinto dei casi, la concomitante presenza di gastrite atrofica
autoimmune, diagnosticabile con Gastropanel.
LHelicobacter pylori vive a livello della mucosa
gastrica. 20-50% della popolazione infetto da
questo batterio. Linfezione da Helicobacter
pylori pu provocare un'infiammazione cronica
dello stomaco e la sua presenza associata allo
sviluppo dellulcera gastrica e duodenale.
L'Helicobacter pylori , inoltre, uno dei fattori
che favorisce lo sviluppo del cancro e del
linfoma gastrico.
Helicobacter pylori classificato come
carcinogeno di classe degli
La determinazione 1. anticorpi anti-
Helicobacter pylori permette di valutare
lavvenuto contatto con il batterio.
A chi consigliato il GastroPanel

Il GastroPanel consigliato ai soggetti:

di tutte le et con disturbi digestivi e
problemi di acidit;
di tutte le et con reflusso gastrico,
difficolt a deglutire e tosse;
con pi di 45 anni per lo screening di stati
precancerosi;
con familiari affetti da cancro gastrico.
Nel test GastroPanel, vengono determinate, in un
campione di sangue, le concentrazioni di quattro
marcatori biologici: il pepsinogeno I (PGI), il
pepsinogeno II (PGII), la gastrina-17b (G17b) e gli
anticorpi anti-Helicobacter pylori. Il pepsinogeno I
(PGI), il pepsinogeno II (PGII) e la gastrina-17b
(G17b) sono secreti dalle cellule della mucosa
gastrica.
HP
 Linfomi Gastrici

Zona marginale (MALT-linfoma) 40-

60%
Diffuso a grandi cellule B 30-
40%
Mantellare
Burkitt
Linfomi T
altri
Macroscopic features
 Microscopic Features

Spindle cell type (60%-70%) Epithelioid cell type (~20%) Mixed type (~10%)
Diagnosi differenziale

proteina S-100
Gastrointestinal stromal tumors: pathology
and prognosis at different sites
 GIST: risk assessment

Tumor rupture (spontaneous

or at the time of surgery)
(ESMO, 2009)

Coagulation necrosis

Hemorrhage

MIB-1 proliferation index

 KIT and PDGFRA
(Type III receptor tyrosine kinase)
KIT PDGFRA

Extracellular domain (EC)

Ex 9 (~9%)

Transmembrane domain

Iuxtamembrane domain (JM) Ex 11 (~70%) Ex 12 (~1%)

Tyrosine kinase domain I (TKI) Ex 13 (~1%) Ex 14 (~1%)

Tyrosine kinase domain II (TKII)

Ex 17 (~1%) Ex 18 (~8%)
Frequency of KIT and PDGFRA mutations

Wild-type
PDGFRA

KIT 75-85%

PDGFRA 5-10%
KIT
Wild-type 10-12%

KIT and PDGFRA mutations are mutually exclusive

GIST localization by mutation type

KIT exon 11
Wild-type

KIT exon 9

PDGFRA exon 18
D842V
 Prognostic and predictive value
Gene Incidence Predictive value Prognostic value
KIT
exon 9 10-15% Partial response (10-40%) No prognostic value
exon 11 65-70% Good response (70-80%) Unfavourable (deletions)
Favourable (substitutions,
duplications)
exon 13 1% Poor response Favourable
exon 17 <1% Poor response No prognostic value
PDGFRA
exon 12 1-2% Possible response Favourable
exon 14 <1% Possible response Favourable
exon 18 5-7% No response (D842V) Favourable
WT 10-12% Poor response No prognostic value
Genotyping of GIST for KIT and PDGFR
mutations could be useful for:
confirmation of diagnosis in KIT negative GIST
 KIT/PDGFRA wild-type GISTs
Sporadic GISTs > Small bowel
> Spindle cell morphology
BRAF mutation (7-13%)
Pediatric GISTs > Females
> Stomach (antrum)
Multiple GISTs
Epithelioid morphology
Frequent lymph node metastasis
GIST and NF1 > Small bowel
Multiple GISTs
Spindle cell morphology
Micro-GISTs / diffuse Cajal cell hyperplasia
Carneys triad Gastric GISTs (> multiple), paraganglioma,
pulmonary chondroma
Epithelioid morphology
Carney-Stratakis syndrome Gastric GISTs (multiple), paraganglioma
Epithelioid morphology
Germline mutations of the genes coding for
succinate-dehydrogenase (SDH) B, C, D
 Il ruolo del patologo per una corretta diagnosi
Il referto anatomo patologico deve essere conciso e
riproducibile; esso deve includere:

La diagnosi di GIST, che deve avvalersi delle

metodiche immunoistochimiche (CD117/DOG1)
La sede della neoplasia
Le dimensioni della neoplasia
Lindice mitotico (numero delle mitosi X 50HPF)
Leventuale presenza di rottura del tumore, emorragia
e/o necrosi
Lo stato dei margini di resezione chirurgica (RX, R0,
R1, R2)
(Lanalisi delle mutazioni)
 GISTs are defined as cellular spindle cells, epithelioid or
biphasic mesenchimal tumors of the GI tract, omentum
and mesentery that express the KIT protein as detected
using immunohistochemistry.
Miettinen M. Virchows Arch 438:1-12, 2001.

Kit