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Università degli Studi di Pavia
AA 2005 - 2006
Corso Integrato Geriatria ed Oncologia
Insegnamento Oncologia Medica
GASTRIC CANCER. I.
Prof. Alberto Riccardi
GASTRIC ADENOCARCINOMA
* incidence and mortality rates markedly ↓ over past 70 yrs;
- 1930: gastric cancer → 1st cause of cancer - related
deaths in American men (by a factor of 2) and 3rd cause in
women (behind tumors of uterine cervix and breast);
- in USA, mortality dropped in men from 28 to 5.0 and in
↓ worldwide);
women from 27 to 2.3 / 100,000 population (↓
* nonetheless, in 1996, 22,800 new cases diagnosed and
11,800 pts died;
* incidence varies widely among different countries, being
comparatively high in Japan, China, Chile, and Ireland (with
still decreased incidence and mortality)
GASTRIC ADENOCARCINOMA
GASTRIC ADENOCARCINOMA
(Cancer Statistics, 2000, females)
* age - adjusted death rates for gastric cancer in 2000 in 45 countries
[no = per 100,000 population (rank among 45 countries)];
- rates in USA, Canada and United Kingdom compared with selected
countries (including 15 countries with highest death rates)
GASTRIC ADENOCARCINOMA
(Cancer Statistics, 2000, males)
* age - adjusted death rates for gastric cancer in 2000 in 45 countries
[no = per 100,000 population (rank among 45 countries)];
- rates in USA, Canada and United Kingdom compared with selected
countries (including 15 countries with highest death rates)
GASTRIC ADENOCARCINOMA
(Cancer Statistics, females, 2003)
* age - adjusted
cancer death
rates in USA from
1930 to 1999 in
selected sites:
- steady ↓ in
death rates for
stomach, breast
and colorectal
cancers;
- from 1960 to
1998, continual ↑
in death rates for
lung cancer
stomach
GASTRIC ADENOCARCINOMA
(Cancer Statistics, males, 2003)
* age - adjusted
cancer death rates in
United States from
1930 to 1999 in
selected sites; ;
- similar ↓ in death
rates from gastric
cancer;
- ↑ in death rates for
lung cancer from 1930
to 1990 with a
continual decrease
during the 1990s
stomach
GASTRIC ADENOCARCINOMA
Epidemiology
* an environmental exposure, beginning early
in life, probably related to development of GC,
with dietary carcinogens being most likely
factor(s):
- risk of GC greater among lower socio economic classes;
- migrants from high - to low - incidence
nations maintain their susceptibility to GC (while
risk for their offspring ~ that of new homeland)
RISK FACTORS AND PATHOGENESIS
GASTRIC ADENOCARCINOMA
Risk factors. I.
* diet (high in dry salted, smoked or preserved foods
and low in fruits and vegetables);
* bacteria (including Helicobacter pylori infection);
* advanced age;
* male gender;
* atrophic gastritis and intestinal metaplasia;
* pernicious anemia;
* cigarette smoking;
* Menetrier's disease (giant hypertrophic gastritis),
and
* gastric adenomatous polyps and familial polyposis
GASTRIC ADENOCARCINOMA
Etiology. I. Diet and bacteria
* relationship between dietary patterns and
development of GC:
- long - term ingestion of high concentrations
of nitrates in dried, smoked and salted foods;
- bacteria convert nitrates to carcinogenic
nitrites (= nitrosamines)
Nitrate - converting bacteria as a factor in
causation of gastric carcinoma
GASTRIC ADENOCARCINOMA
Etiology. II. Bacteria and favoring growth factors
* exogenous bacteria (= partially decayed foods,
especially consumed by lower socioeconomic classes);
- endogenous bacteria (such as Helicobacter pylori),
whose growth results from loss of gastric acidity:
* favoring factors:
- partial gastrectomy to control benign peptic ulcer
disease (15 - 20 yrs earlier) abolishes acid - producing cells
of gastric antrum;
- achlorhydria, atrophic gastritis and pernicious anemia
(= precancerous situations) in elderly (in pts with atrophic
gastritis, usual gastric mucosa replaced by intestinal - type
cells → intestinal metaplasia → cellular atypia and
eventual neoplasia)
HELICOBACTER PYLORI IN A GASTRIC PIT
˚
NATURAL HISTORY OF
HELICOBACTER PYLORI
INFECTION. I.
* HP found worldwide (prevalence,
up 100%, in developing countries;
* HP products in stomach mucosa
control acidity of environment and
induce inflammation → several
gastric diseases (weakening of
mucosal barrier eventually result in
ulceration);
* major cause of chronic gastritis
and associated with duodenal
ulcer (90% of pts), gastric ulcer
(70% of pts) and ?gastric cancer
(?60% of pts)
NATURAL HISTORY OF HELICOBACTER PYLORI INFECTION. II.
* most HP strains (= type
I; e.g. strain 26695)
causing disease contain
cag (= cytotoxin associated Ag)
chromosomal
pathogenicity island (~
37,000 bp and 29 genes);
- cag island splits into 2
parts, with most cag
arranged genes involved
in secretory machinery
translocating protein
CagA (cytotoxin * most genes involved in 2 major processes:
associated Ag A) into
cytoplasm of gastric
- translocation of CagA from bacterium to host cell
epithelial cells;
- production of IL - 8 (chemotactic for neutrophils
and lymphocytes and angiogenic) by gastric cells
NATURAL HISTORY OF HELICOBACTER PYLORI INFECTION. III.
* HP usually acquired in
childhood;
* acute HP infection (gray) →
transient, rarely diagnosed hypo chlorhydria;
- persistent infection → chronic
gastritis (green) in most pts (80 90%, without symptoms);
* variable further clinical course:
hypocloridria
- pts with ↑ acid output (red) →
antral gastritis predisposing to
duodenal ulcer;
- pts with ↓ acid output (black) →
gastritis in stomach’s body
predisposing to gastric ulcer and (more rarely) to gastric carcinoma;
[* HP infection induces mucosa - associated lymphoid tissue (MALT),
possibly leading to malignant lymphoma]
Pathogen - host interactions in
pathogenesis of HP infection. I.
* integral role of host response to
HP in induction of damage to
gastric epithelium:
- during early phase of infection,
binding of HP to epithelial cells (EC)
(especially by BabA and by strains
harboring cag pathogenicity island)
→ production of IL - 8 and other
chemokines by EC [e.g., epithelial cell - derived neutrophil - activating
peptide 78 (ENA - 78) and growth related oncogene (GRO - α)];
- nuclear factor - κB (NF - κB) and
early - response transcription factor activator protein 1 (AP - 1) =
intracellular messengers involved in
this process
Pathogen - host interactions in
pathogenesis of HP Infection. II.
* chemokines secreted by
epithelial cells bind to proteoglycan
scaffolding → gradient by
polymorphonuclear cells (PMN) are
recruited;
* chronic phase of HP gastritis
associates an adaptive lymphocyte
response with initial innate
response;
[- lymphocyte recruitment
facilitated by chemokine mediated expression of vascular
addressins [e.g., vascular - cell
adhesion molecule 1 (VCAM - 1)]
and intercellular adhesion molecule
1 (ICAM - 1), required for
lymphocyte extravasation]
Pathogen - host interactions in
pathogenesis of HP Infection. III.
* macrophages participating in IL 8 production → proinflammatory
cytokines involved in activation of
recruited cells [especially T helper
cells (Th0, Th1, Th2), that respond
with a biased Th1 response to HP;
- in turn, Th1 - type cytokines such
as interferon - γ (INF - γ) →
expression of class II major
histocompatibility complexes
(MHC) and accessory molecules B7
- 1 and B7 - 2 by epithelial cells →
epithelial cells competent for
antigen presentation
Pathogen - host interactions in
pathogenesis of HP infection. IV.
* tumor necrosis factor - α (TNF- α) (red)
↑ cytotoxin VacA- and Fas- mediated
apoptosis induced by → disruption of
epithelial barrier → facilitation of
translocation of bacterial antigens →
further activation of macrophages
(cytokines produced by macrophages
also alter mucus secretion → HP mediated disruption of mucous layer);
* cytokines produced in gastric mucosa
(green) → changes in gastric - acid
secretion / homeostasis (dashed lines);
β and IFN - γ ↑ gastrin
* TNF - α, IL - 1β
release, stimulating parietal and
enterochromaffin cells and thus acid
secretion;
* TNF- α also induces ↓ no. of antral D cells → decreased somatostatin production
= indirectly ↑ acid production (LPS = lipopolysaccharide)
Potential outcomes
of sequencing
of Helicobacter pylori genome
GASTRIC ADENOCARCINOMA
Etiology. III. Other factors
* gastric ulcers and adenomatous polyps (but
unconvincing data on a cause / effect relationship = e.g.,
inadequate clinical distinction between benign gastric
ulcers and small ulcerating GC);
- Menetrier's disease (extreme hypertrophy of gastric
rugal folds mimics polypoid lesions, but does not represent
true adenomatous polyps);
- blood group A have ↑ incidence of GC than blood
group 0 individuals (possibly due to # in mucous secretion
of various ABO groups → greater or lesser mucosal
protection from carcinogens);
- no association between duodenal ulcers and GC
PATHOLOGY
GASTRIC CANCER
Pathology. I.
* 85%
= adenocarcinomas (diffuse and
intestinal type);
* 15% = non - Hodgkin's lymphomas and
gatrointestinal stromal tumors (GIST, formerly
called “leiomyosarcomas”)
GASTRIC CANCER
Pathology. II.
Polyps
GASTRIC CANCER
Pathology. III.
Leiomyoma
(gastrointestinal
stromal cell tumor,
GIST?)
GASTRIC ADENOCARCINOMA
Pathology. IV. Carcinoma, diffuse type
* cell cohesion absent, with individual cells
infiltrating and thickening stomach wall without
forming a discrete mass;
- more often in younger pts, develops
throughout stomach, including cardias → loss of
distensibility of gastric wall (“linitis plastica” or
"leather bottle" appearance), with a far more
ominous prognosis
GASTRIC ADENOCARCINOMA
Pathology. V. Carcinoma, diffuse type
* right: low power view, with poorly
differentiated cancer arising from mucosa
and diffusely infiltrating all layers of gastric
wall;
* left: ↑ magnification, with effacement of
lamina propria of gastric mucosa
GASTRIC ADENOCARCINOMA
Pathology. VI. Carcinoma, diffuse type
* linitis plastica carcinoma diffusely infiltrates entire gastric wall
without forming an intraluminal mass;
* wall typically thickened ~ 2 - 3 cm, with leathery, inelastic
consistency
GASTRIC
ADENOCARCINOMA
Pathology. VII.
Carcinoma, diffuse type
Linitis plastica
(scirrhous)
GASTRIC ADENOCARCINOMA
Pathology. VIII. Carcinoma, diffuse type
GASTRIC ADENOCARCINOMA
Pathology. IX. Carcinoma, diffuse type
GASTRIC ADENOCARCINOMA
Pathology. X. Carcinoma, intestinal type
cohesive neoplastic cells forming gland like tubular structures:
- frequently ulcerative;
- more commonly in antrum - prepylorus,
cardia - fundus and lesser curvature of
stomach, and
- often preceeded by prolonged pre cancerous process
*
GASTRIC ADENOCARCINOMA
Pathology. XI. Carcinoma, signet ring cells
GASTRIC ADENOCARCINOMA
Pathology. XII. Neuroendocrine carcinoma
typical light and electron microscopy of carcinoid tumor, with
numerous, fairly uniformly sized neurosecretory granules
GASTRIC
ADENOCARCINOMA
Pathology. XIII. Borrmann
gross classification
I = polypoid;
II = ulcerating;
III = ulcerating infiltrating;
IV = infiltrating
GASTRIC ADENOCARCINOMA
Pathology. XIV. Ulcerating carcinoma
GASTRIC
ADENOCARCINOMA
Pathology. XV.
Ulcerating
carcinoma
GASTRIC ADENOCARCINOMA
Pathology. XVI. Polypoid carcinoma
GASTRIC
ADENOCARCINOMA
Pathology. XVII.
Polypoid carcinoma
Carcinoma of cardia
Carcinoma of fundus
GASTRIC
ADENOCARCINOMA
Pathology. XVIII.
Polypoid carcinoma
Carcinoma of antrus
GASTRIC ADENOCARCINOMA
Pathology. XIX. Topography
antrum and prepylorus
cardia and fundus
lesser curvature
greater curvature
entire stomach
~ 30%
~ 35%
~ 20%
~ 3 - 5%
~ 5 - 10%
GASTRIC ADENOCARCINOMA
Pathology. XX.
* ↓ incidence of cancer of distal half of
stomach (especially intestinal type);
- no ↓ in diffuse type GC (10% of pts);
* cancer of cardia and gastroesophageal
junction rising (dramatically under 40 yrs, in
last 2 decades)
“EARLY” GASTRIC CANCER
GASTRIC ADENOCARCINOMA
Pathology. XXI. Early gastric cancer
* early gastric cancer = depth of invasion limited
to mucosa or submucosa, regardless of LN
involvement (gross pathology: type I = polypoid;
type IIa = elevated; type IIb = flat; type IIc =
depressed; type III = excavated);
* advanced gastric cancer = disease penetrates
muscolar layer, usually associated with
contiguous or distant spread [gross pathology
(Borrmann classification): I = polypoid; III =
ulcerating; III = ulcerating - infiltrating; IV =
infiltrating]
GASTRIC ADENOCARCINOMA
Pathology. XXII. Early gastric cancer
* early GC → limited to mucosa and submucosa;
* advanced GC → tumor penetrates beyond submucosa
GASTRIC ADENOCARCINOMA
Pathology. XXIII. Early gastric cancer
macroscopically
divided
into three types
GASTRIC ADENOCARCINOMA
Pathology. XXIV.
Early gastric cancer, elevated
GASTRIC
ADENOCARCINOMA
Pathology. XXV.
Early gastric cancer,
excavated
GASTRIC ADENOCARCINOMA
Pathology. XXVI. Is early gastric cancer an
“early” stage of advanced gastric cancer
* ?early gastric cancer could be a different
disease than advanced gastric cancer (because
an inability to invade);
* observation indicating that early gastric cancer
becomes advanced gastric cancer:
- retrospective analysis of sequential X rays;
- pts who refused surgery for early gastric cancer
and developed advanced cancer;
- animal studies
GASTRIC ADENOCARCINOMA
Pathology. XXVII.
* % of pts with GC with lymph node involvement
↑ as depth of invasion ↑ from mucosa to serosa;
* 5 - yr survival ↓ as depth of invasion ↑
GENETICS
GASTRIC ADENOCARCINOMA
Genetics. I.
incidence of diffuse GC similar in most
populations;
- intestinal GC predominates in high - risk
geographic regions (accounting for declining of
GC);
* different etiologic factor(s) involved in these
two subtypes?
*
GASTRIC ADENOCARCINOMA
Genetics. II.
* multiple genetic and epigenetic alterations
in oncogenes, tumour - suppressor genes, cell cycle regulators, cell adhesion molecules, DNA
repair genes, genetic instability and telomerase
activation implicated in multistep process of
human stomach carcinogenesis;
- combinations of alterations # in two
histological types of GC → distinct
carcinogenetic pathways in well - differentiated
(intestinal - type GC) and poorly differentiated
(diffuse - type GC)
GENETIC STEPS
OF GASTRIC ADENOCARCINOMA
GENETIC STEPS OF INTESTINAL TYPE
GASTRIC ADENOCARCINOMA
GENETIC STEPS OF DIFFUSE TYPE
GASTRIC ADENOCARCINOMA
Diffuse type
GASTRIC ADENOCARCINOMA
Genetics. III. Intestinal - type GC
* in multistep process of intestinal - type
carcinogenesis, genetic pathway divided into 3
subpathways:
- intestinal metaplasia → adenoma →
carcinoma;
- intestinal metaplasia → carcinoma, and
- de novo;
* infection with HP is a strong trigger for
hyperplasia of hTERT+ (human telomerase reverse
transcriptase, regulating human telomers and
senescence) “stem cells” in intestinal metaplasia
Telomeres and telomerase
* telomere = extension of DNA at chr ends, generated by
telomerase reverse transcriptase (TERT, which uses an internally
bound RNA loop as a template);
[usually, “Hayflick limit” of ~ 50 - 70 division cycles for human
diploid cells mediated by telomere length]
Schematic structure of telomere - repair complex
and location of mutations
* TERC, TERT,
dyskerin, NOP10,
NHP2 and GAR1
constitute
telomerase ribo nucleoprotein
complex;
* mutations of
amino acids
denoted by their
single - letter
codes
Yamaguchi H et al N Engl J Med 2005; 352: 1413 - 24
GASTRIC ADENOCARCINOMA
Genetics. IV. Intestinal - type GC
* infection with HP is
a strong trigger for
hyperplasia of hTERT+
(Human Telomerase
Reverse Transcriptase,
regulating human
telomers and cell
senescence) “stem
cells” in intestinal
metaplasia →
adenoma →
carcinoma sequence;
→ replication
* genetic instability and hyperplasia of hTERT+ “stem cells”→
error (at D1S191 locus), DNA hypermethylation (D17S5 locus), pS2 loss,
β loss, CD44 abnormal transcripts and p53 mutation;
RARβ
- all these epi- and genetic alterations in > 30% of incomplete intestinal
metaplasias and common in intestinal - type GC
GASTRIC ADENOCARCINOMA
Genetics. V. Intestinal - type GC
* adenoma →
carcinoma sequence
in ~ 20% of gastric
adenomas, with
additional events
including APC and p53
mutations, loss of
heterozygosity (LOH),
reduced p27 and
cyclin E expression
and presence of c met 6.0 - kb transcripts;
* advanced intestinal - type gastric cancer associated with further
events (including c - erbB gene amplification, DCC loss, 1q LOH, p27 loss,
reduced tumour growth factor (TGF) - β type I receptor expression and
reduced nm23 expression)
GASTRIC ADENOCARCINOMA
Genetics. V. Intestinal - type GC
* de - novo pathway for carcinogenesis of
well - differentiated GC involves LOH and
abnormal expression of p73 gene (responsible
for development of foveolar - type gastric
cancers with pS2 expression)
GASTRIC ADENOCARCINOMA
Genetics. VI. Diffuse - type GC
* loss of E - cadherin, LOH at chr 17p and mutation or LOH of
p53 preferentially involved in development of poorly
differentiated GC
ROLE OF CADHERINS IN ESTABLISHING MOLECULAR LINKS
BETWEEN ADJACENT CELLS
* cadherin dimers
gather at adherens
junctions to form a
zipper - like structure
that maintains
adjacent cells in close
contact;
* cadherins linked to
cytoskeleton through
cytoplasmic catenins
(essential for normal
cadherin function and
formation of adherens
junctions);
- cadherin linked to β - catenin (or related plakoglobin) and α catenin associated with actin microfilaments
GASTRIC ADENOCARCINOMA
Genetics. VII. Diffuse - type GC,
Hereditary forms
germline mutations in E - cadherin (CDH1)
gene (on chr 16, inherited in autosomal
dominant pattern and coding for cell
adhesion proteins) linked to high incidence
of occult gastric cancers in young
asymptomatic carriers → ~ 70% lifetime risk
for hereditary diffuse gastric adeno carcinoma
*
Model for development of
hereditary diffuse gastric cancer
* gastric mucosa in CDH1 (E - cadherin
gene) germline mutation carriers is
normal until second CDH1 allele is
inactivated or repressed (second hit) by
transcriptional downregulation;
[- promoter hypermethylation is one
mechanism for downregulation
(transcription factor mediated events
also play a role, including environmental
and physiological factors such as diet,
carcinogen exposure, ulceration and
gastritis)];
- since downregulation may occur in
multiple cells, multifocal tumors develop;
- tumor expands slowly until additional genetic events, possibly combined with
an altered microenvironment → clonal expansion and disease progression;
[- because second hit does not involve somatic, irreversible, mutation of second
CDH1 allele, it is possible that early stage lesions is reversible]
RECEPTOR TYROSINE KINASE AND PROLIFERATION AND TISSUE EXPANSION
* receptor tyrosine
kinases (RTKs) = main
positive regulators of
proliferation and tissue
expansion (through
downstream pathways
including ras - MAPK and
PI3K / Akt cascade);
* RTKs negatively act on
E - cadherin function →
disassembly of adherens
junctions;
- downstream elements of RTK signalling interact and activate Rho family
GTPases (Rac, Rho, Cdc42) system that interfere with cadherin - mediated
adhesion through changes in actin cytoskeleton;
* catenin p120 acts as regulator of cadherin function either promoting or
repressing E - cadherin - dependent adhesion
Pedigrees fulfilling
Hereditary Diffuse Gastric Cancer (HDGC) criteria
(examples)
* ≥ 2 pathologically documented cases of
diffuse gastric cancer in 1st- or 2nd- degree
relatives, with ≥ 1 diagnosed at < 50 yrs;
* ≥ 3 pathologically documented cases of
diffuse gastric cancer in 1st- or 2nd - degree
relatives of any age
SCHEMA TO GUIDE THE MANAGEMENT
OF FAMILIAL GASTRIC CANCER KINDREDS
FAMILY WITH PREDICTIVE GENETIC - TESTING (A)
AND SEQUENCE CHROMATOGRAM OF CDH1 (EXON 12) (B)
A) squares = male and circles = female members;
- = unaffected and = affected persons;
- slash = death and line under symbol = prophylactic gastrectomy;
- + sign = mutation+, - sign = mutation-, in parentheses = result of predictive testing;
- arrow identifies proband [age at diagnosis and death (in parentheses) under each
symbol];
B) codon 598 in yellow;
- pt IV - 2 = wild - type sequence and pt IV - 1 = heterozygous for C2095T mutation;
[- Opa = opal nonsense mutation (one of 3 nonsense codons predicting protein
truncation) (NL = normal sequence and Mut = mutation; N in nucleotide chromatogram
indicates that both C and T are present)]
GASTRIC ADENOCARCINOMA
Genetics. VIII.
from prophylactic gastrectomy in pts to
regular endoscopic surveillance with multiple
random biopsies → presence of microscopic
intrahepitelial carcinomas → early total
gastrectomy for this small pt’s population (lack
of other effective early tumor detection with less
aggressive approaches)
*
Early diffuse gastric cancers
from prophylactic - gastrectomy
specimens
A) superficial infiltrate of signet - ring
carcinoma cells (EE staining);
B) immunohistochemistry with Abs to
type IV collagen = invasive nature of
signet - cell infiltrates (thick
basement membrane under surface
epithelium and around both glands and
capillaries stains strongly; no distinct
staining around signet - ring cells);
C) signet - ring - cells infiltrate in
superficial lamina propria in gastric
cardia (PAS with diastase staining for
mucina);
D) epithelial nature of infiltrate
(immunohistochemistry for cytokeratin);
E) in situ signet - ring - cell lesions in
gastric cardia;
F, G, H) early diffuse gastric cancers
(EE)
CLINICAL FEATURES
GASTRIC ADENOCARCINOMA
Clinical features. I.
* usually no symptoms when superficial and surgically
curable;
* with more extensive tumors → insidious upper
abdominal discomfort (from a vague, postprandial
fullness to severe, steady pain), anorexia (often with slight
nausea) and weight loss;
* no early physical sign (finding of a palpable
abdominal mass generally indicates long - standing
growth and regional extension)
GASTRIC ADENOCARCINOMA
Clinical features. II.
* possible early symptoms (with superficial and
surgically curable tumors);
- nausea and vomiting (with tumors of pylorus);
- dysphagia (with lesions of cardia);
GASTRIC ADENOCARCINOMA
Clinical features. III.
* iron - deficiency anemia in men and of
occult blood in stool in both sexes → search for
an occult lesion in gastrointestinal tract
(especially in pts with atrophic gastritis or
pernicious anemia);
* unusual clinical features:
- migratory thrombophlebitis;
- microangiopathic hemolytic anemia, and
- acanthosis nigricans
GASTRIC ADENOCARCINOMA
Clinical features. IV. Acanthosis nigricans
GASTRIC ADENOCARCINOMA
Clinical features. V. Acanthosis nigricans
GASTRIC
ADENOCARCINOMA
Clinical features. VI.
Acanthosis nigricans