AA. Gastric C I 06. ppt - Università degli studi di Pavia

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 

women from 27 to 2.3 / 100,000 population (↓ worldwide); 

* 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


(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)


(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)

* 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 


(Cancer Statistics, females, 2003) 

stomach

* 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 


(Cancer Statistics, males, 2003) 

stomach


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


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


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


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 - 

associated Ag A) into 

cytoplasm of gastric 

epithelial cells; 

* most genes involved in 2 major processes: 

- translocation of CagA from bacterium to host cell 

- 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


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]


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


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); 

* TNF - α, IL - 1β and IFN - γ ↑ gastrin 

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


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”)


Pathology. II. 

Polyps


Pathology. III. 

Leiomyoma 

(gastrointestinal 

stromal cell tumor, 

GIST?)


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


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


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)


Pathology. VIII. Carcinoma, diffuse type


Pathology. IX. Carcinoma, diffuse type


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


Pathology. XI. Carcinoma, signet ring cells


Pathology. XII. Neuroendocrine carcinoma 

typical light and electron microscopy of carcinoid tumor, with 

numerous, fairly uniformly sized neurosecretory granules

GASTRIC 


Pathology. XIII. Borrmann 

gross classification 

I = polypoid; 

II = ulcerating; 

III = ulcerating - 

infiltrating; 

IV = infiltrating


Pathology. XIV. Ulcerating carcinoma

GASTRIC 


Pathology. XV. 

Ulcerating 

carcinoma


Pathology. XVI. Polypoid carcinoma

GASTRIC 


Pathology. XVII. 

Polypoid carcinoma 

Carcinoma of cardia 

Carcinoma of fundus

GASTRIC 


Pathology. XVIII. 

Polypoid carcinoma 

Carcinoma of antrus


Pathology. XIX. Topography 

antrum and prepylorus ~ 30% 

cardia and fundus ~ 35% 

lesser curvature ~ 20% 

greater curvature ~ 3 - 5% 

entire stomach ~ 5 - 10%


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


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]


Pathology. XXII. Early gastric cancer 

* early GC → limited to mucosa and submucosa; 

* advanced GC → tumor penetrates beyond submucosa


Pathology. XXIII. Early gastric cancer 

macroscopically 

divided 

into three types


Pathology. XXIV. 

Early gastric cancer, elevated

GASTRIC 


Pathology. XXV. 

Early gastric cancer, 

excavated


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


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


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?


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 


Diffuse type


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


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; 

* genetic instability and hyperplasia of hTERT+ “stem cells”→ replication 

error (at D1S191 locus), DNA hypermethylation (D17S5 locus), pS2 loss, 

RARβ loss, CD44 abnormal transcripts and p53 mutation; 

- all these epi- and genetic alterations in > 30% of incomplete intestinal 

metaplasias and common in 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; 


Genetics. V. Intestinal - type GC 

* 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)


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)


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


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)]


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


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)


Clinical features. II. 

* possible early symptoms (with superficial and 

surgically curable tumors); 

- nausea and vomiting (with tumors of pylorus); 

- dysphagia (with lesions of cardia);


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


Clinical features. IV. Acanthosis nigricans


Clinical features. V. Acanthosis nigricans

GASTRIC 


Clinical features. VI. 

Acanthosis nigricans

AA. Gastric C I 06. ppt - Università degli studi di Pavia

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