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{{Stomach cancer}}
{{Stomach cancer}}
==Overview==
==Overview==
The pathophysiology of stomach cancer depends on histologic subtypes.
There are many molecular causes of gastric cancer; [[Helicobacter pylori|H. pylori]] and gastric cancer have strong correlation. This is related to [[Nitric oxide|nitric oxides]] accumulation produced by inflammatory cells responding to H. pylori infection. The pathophysiology of stomach cancer depends on histologic subtypes. ''[[Ras oncogene|K-ras]]'' [[mutations]] is found in [[Invasive (medical)|invasive]] [[Cancer|cancers]] and intestinal [[metaplasia]]. Inactivation of [[P53 (protein)|p53]] in gastric [[epithelial cells]] reduce their ability to undergo [[apoptosis]]. [[DNA]] [[methylation]] of [[gene]] promoters can silence the expression of ''[[CDH11|CDH1]]. [[Beta-catenin]] [[mutation]] is a frequent cause of [[Wnt signaling pathway|Wnt]] pathway activation in gastric cancer. Diffuse gastric carcinomas do not have a [[precancerous]] lesion. They are highly [[Metastasis|metastatic]] with a poorer [[prognosis]] than [[Intestine|intestinal]] cancers. When the entire [[stomach]] wall is infiltrated, it results in a rigid thickened stomach wall called [[Linitis plastica|linitis plastica.]] There are many associated diseases to gastric cancer; Hereditary diffuse gastric cancer, Gastric Adenocarcinoma and Proximal Polyposis of the Stomach, [[Lynch syndrome]], [[Familial adenomatous polyposis]], [[Li-Fraumeni syndrome]]'', [[Peutz-Jeghers syndrome|''Peutz Jeghers syndrome'']], [[Juvenile polyposis syndrome|J''uvenile polyposis'']], ''Hereditary breast and [[Ovarian cancer|ovarian cancer syndrome]]'', [[Cowden syndrome|''Cowden's syndrome'']]. There are five gross pathology types of gastric cancer; Superficical, ulcerative, infiltrative ulcerative, diffuse infiltrative, and unclassified. There are two major histological classifications for gastric cancer; Japanesse classification and WHO classification. Generally, the main two types are;  Intestinal type adenocarcinoma and diffuse type [[adenocarcinoma]].  


== Physiology of stomach ==
== Physiology of gastric acid secretion ==
* The stomach consists of two functional areas; oxyntic and pyloric glands. The oxyntic area contains parietal cells that produce gastric acid.  
* The [[stomach]] consists of two functional areas; [[Oxyntic cells|oxyntic]] and [[pyloric glands]]. The [[Oxyntic cells|oxyntic area]] contains [[parietal cells]] that produce [[gastric acid]].  
* The antrum contains pyloric glands that secrete gastrin and somatostatin.
* [[Parietal cells]] are filled with [[Secretory component|secretory]] [[vesicles]] that coalesce with stimulation to form channels that drain to the apical lumen.<ref name="pmid12500969">{{cite journal| author=Yao X, Forte JG| title=Cell biology of acid secretion by the parietal cell. | journal=Annu Rev Physiol | year= 2003 | volume= 65 | issue=  | pages= 103-31 | pmid=12500969 | doi=10.1146/annurev.physiol.65.072302.114200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12500969  }}</ref>
* '''SECRETION OF ACID AND PEPSIN'''   parietal cells are filled with secretory vesicles that coalesce with stimulation to form channels that drain to the apical lumen [9].   The secretory membrane lining these structures contains the hydrogen-potassium-ATPase acid-secreting pump.  This pump is always active, but exists in a short-circuited state in resting vesicles because the pathway necessary for transporting potassium to the apical surface for exchange with hydrogen is not present or active. With stimulation, this pathway for potassium-chloride cotransport becomes active, allowing hydrogen-potassium exchange to occur [10-13]. '''Gastrin'''  Gastrin enhances gastric acid secretion from parietal cells by increasing synthesis of histamine.[15-18].   Gastrin is the best identified trophic regulator of parietal cell mass in humans. This relationship is evidenced by the presence of gastric hypertrophy in gastrinoma patients who have chronic exposure to elevated gastrin levels (picture 1), and atrophy of the parietal cell mass with antrectomy, which decreases gastrin levels.  '''Histamine'''   Gastrin is the primary stimulus to histamine release from ECL cells.  Stimulated ECL cells promptly degranulate, with release of histamine and pancreastatin from the vesicles; this is followed by an increase in histamine synthesis [17].   gastric mast cells outnumber ECL cells, gastrin has only been demonstrated to release histamine from ECL cells [36].  Inhibitors of the histamine-forming enzyme histidine decarboxylase (HDC) block the acid secretory response to gastrin, but not to histamine [24]. Furthermore, both H2 receptor deficient mice and HDC-knockout mice have near normal basal acid secretion, a preserved acid secretory response to cholinergic agents, an absent acid secretory response to exogenous gastrin, and hypergastrinemia [23,24].  '''Somatostatin'''   Somatostatin is an inhibitor of acid secretion.  [42].  The secretion of somatostatin is increased by gastric acid and by gastrin itself.   The major function of somatostatin is to modulate the feedback inhibition of the acid secretory response to gastrin [43]. 
* The secretory membrane contains [[Hydrogen potassium ATPase|hydrogen-potassium-ATPase]] acid-secreting pump. With stimulation, [[Hydrogen potassium ATPase|hydrogen-potassium]] exchange occur. The collected [[hydrogen]] unifies with chloride forming [[hydrochloric acid]].<ref name="pmid16149129">{{cite journal| author=Geibel JP| title=Role of potassium in acid secretion. | journal=World J Gastroenterol | year= 2005 | volume= 11 | issue= 34 | pages= 5259-65 | pmid=16149129 | doi= | pmc=4622792 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16149129  }}</ref>
* The [[antrum]] contains [[pyloric glands]] that secrete [[gastrin]] and [[Somatostatin|somatostatin.]]
* [[Gastrin]] enhances [[gastric acid]] secretion from [[parietal cells]] by increasing synthesis of [[histamine]].<ref name="pmid9845587">{{cite journal| author=Kidd M, Modlin IM, Tang LH| title=Gastrin and the enterochromaffin-like cell: an acid update. | journal=Dig Surg | year= 1998 | volume= 15 | issue= 3 | pages= 209-17 | pmid=9845587 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9845587 }}</ref>
* [[Somatostatin]]''':''' The secretion of [[somatostatin]] is increased by [[gastric acid]] and [[gastrin]] level.<ref name="pmid1682134">{{cite journal| author=Shulkes A, Read M| title=Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms. | journal=Endocrinology | year= 1991 | volume= 129 | issue= 5 | pages= 2329-34 | pmid=1682134 | doi=10.1210/endo-129-5-2329 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1682134  }}</ref>


==Pathophysiology==
==Pathophysiology of gastric cancer==


=== '''Molecular effect of H.pylori:''' ===
=== '''Molecular effect of H.pylori:''' ===
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* The [[E-cadherin]] [[gene]] (CDH1) encodes a [[Transmembrane protein|transmembrane cellular adhesion protein]]. Its [[Cytoplasm|cytoplasmic]] tail interacts with [[Catenin|catenins]] making the adhesion.
* The [[E-cadherin]] [[gene]] (CDH1) encodes a [[Transmembrane protein|transmembrane cellular adhesion protein]]. Its [[Cytoplasm|cytoplasmic]] tail interacts with [[Catenin|catenins]] making the adhesion.
* [[Somatic]] [[mutations]] in the ''[[CDH11|CDH1]]'' gene by hypermethylation, [[mutation]], and [[loss of heterozygosity]] are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.<ref name="pmid16555931">{{cite journal| author=Ramos-de la Medina A, More H, Medina-Franco H, Humar B, Gamboa A, Ortiz LJ et al.| title=Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer. | journal=Rev Esp Enferm Dig | year= 2006 | volume= 98 | issue= 1 | pages= 36-41 | pmid=16555931 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16555931  }}</ref>  
* [[Somatic]] [[mutations]] in the ''[[CDH11|CDH1]]'' gene by hypermethylation, [[mutation]], and [[loss of heterozygosity]] are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.<ref name="pmid16555931">{{cite journal| author=Ramos-de la Medina A, More H, Medina-Franco H, Humar B, Gamboa A, Ortiz LJ et al.| title=Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer. | journal=Rev Esp Enferm Dig | year= 2006 | volume= 98 | issue= 1 | pages= 36-41 | pmid=16555931 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16555931  }}</ref>  
* Prostate stem cell antigen gene is also involved in regulating gastric [[Epithelium|epithelial cell]] proliferation.<ref name="pmid18488030">{{cite journal| author=Study Group of Millennium Genome Project for Cancer. Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T et al.| title=Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. | journal=Nat Genet | year= 2008 | volume= 40 | issue= 6 | pages= 730-40 | pmid=18488030 | doi=10.1038/ng.152 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18488030  }}</ref>
* Prostate stem cell antigen [[gene]] is also involved in regulating gastric [[Epithelium|epithelial cell]] proliferation.<ref name="pmid18488030">{{cite journal| author=Study Group of Millennium Genome Project for Cancer. Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T et al.| title=Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. | journal=Nat Genet | year= 2008 | volume= 40 | issue= 6 | pages= 730-40 | pmid=18488030 | doi=10.1038/ng.152 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18488030  }}</ref>


=== Apoptosis pathway ===
=== Apoptosis pathway ===
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* ''[[Helicobacter pylori|H. pylori]]'' infection results in the migration of [[neutrophils]] to the site of infection and adhesion to the surface [[epithelium]].
* ''[[Helicobacter pylori|H. pylori]]'' infection results in the migration of [[neutrophils]] to the site of infection and adhesion to the surface [[epithelium]].
* The [[Neutrophil|neutrophils]] produce [[nitric oxide synthase]] which damage [[DNA]].  
* The [[Neutrophil|neutrophils]] produce [[nitric oxide synthase]] which damage [[DNA]].  
* [[CD11a]]/[[CD18]]- and [[CD11b]]/CD18[[Neutrophil|-neutrophils]] interact with [[intercellular adhesion molecule-1]] (ICAM-1).<ref name="pmid11556297">{{cite journal| author=Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M et al.| title=Helicobacter pylori infection and the development of gastric cancer. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 11 | pages= 784-9 | pmid=11556297 | doi=10.1056/NEJMoa001999 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11556297  }}</ref>
* [[CD11a]]/[[CD18]]- and [[CD11b]]/CD18[[Neutrophil|-neutrophils]] interact with [[intercellular adhesion molecule-1]] ([[ICAM-1]]).<ref name="pmid11556297">{{cite journal| author=Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M et al.| title=Helicobacter pylori infection and the development of gastric cancer. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 11 | pages= 784-9 | pmid=11556297 | doi=10.1056/NEJMoa001999 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11556297  }}</ref>
* [[Epithelial cells]] respond by signaling pathways leading to [[apoptosis]], proliferation, differentiation, and autophagy.
* [[Epithelial cells]] respond by signaling pathways leading to [[apoptosis]], [[proliferation]], differentiation, and [[autophagy]].


==== '''Apoptotic pathways''' ====
==== '''Apoptotic pathways''' ====
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* Germline truncating mutations in the ''CDH1'' gene, which encodes the cell adhesion protein E-cadherin, have been identified HDGC is inherited as an autosomal dominant trait with high penetrance.<ref name="pmid25979631">{{cite journal| author=van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N et al.| title=Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. | journal=J Med Genet | year= 2015 | volume= 52 | issue= 6 | pages= 361-74 | pmid=25979631 | doi=10.1136/jmedgenet-2015-103094 | pmc=4453626 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25979631  }}</ref>
* Germline truncating mutations in the ''CDH1'' gene, which encodes the cell adhesion protein E-cadherin, have been identified HDGC is inherited as an autosomal dominant trait with high penetrance.<ref name="pmid25979631">{{cite journal| author=van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N et al.| title=Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. | journal=J Med Genet | year= 2015 | volume= 52 | issue= 6 | pages= 361-74 | pmid=25979631 | doi=10.1136/jmedgenet-2015-103094 | pmc=4453626 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25979631  }}</ref>
* The cumulative risk for gastric cancer by age 80 for ''CDH1'' mutation carriers is up to 70 percent in men and up to 56 percent in women.<ref name="pmid26072394">{{cite journal| author=van der Post RS, Vogelaar IP, Manders P, van der Kolk LE, Cats A, van Hest LP et al.| title=Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1. | journal=Gastroenterology | year= 2015 | volume= 149 | issue= 4 | pages= 897-906.e19 | pmid=26072394 | doi=10.1053/j.gastro.2015.06.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26072394  }}</ref>
* The cumulative risk for gastric cancer by age 80 for ''CDH1'' mutation carriers is up to 70 percent in men and up to 56 percent in women.<ref name="pmid26072394">{{cite journal| author=van der Post RS, Vogelaar IP, Manders P, van der Kolk LE, Cats A, van Hest LP et al.| title=Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1. | journal=Gastroenterology | year= 2015 | volume= 149 | issue= 4 | pages= 897-906.e19 | pmid=26072394 | doi=10.1053/j.gastro.2015.06.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26072394  }}</ref>
* Promoter hypermethylation, mutation, and loss of heterozygosity. The end result is loss of expression of the cell adhesion molecule E-cadherin.
* Promoter [[Methylation|hypermethylation]], [[mutation]], and [[loss of heterozygosity]]. The end result is loss of expression of the [[cell adhesion]] molecule [[E-cadherin]].
* The risk of gastric cancer in asymptomatic carriers of a pathogenetic ''CDH1 ''mutation who belong to families with highly penetrant hereditary diffuse gastric cancer is sufficiently high to warrant prophylactic gastrectomy.
* The risk of gastric cancer in asymptomatic carriers of a pathogenetic ''[[CDH11|CDH1]] ''[[mutation]] who belong to families with highly penetrant hereditary diffuse gastric cancer is sufficiently high to warrant prophylactic [[gastrectomy]].
* Women in these affected families are also at high risk of developing breast cancer, predominantly lobular. The cumulative risk of breast cancer to age 80 for ''CDH1'' mutation carriers is approximately 42 percent, and like the gastric cancers, the increased relative risk starts early.
* Women in these affected families are also at high risk of developing [[breast cancer]]. The cumulative risk of [[breast cancer]] to age 80 for ''[[CDH11|CDH1]]'' mutation carriers is 42 percent.


==== Gastric Adenocarcinoma and Proximal Polyposis of the Stomach ('''GAPPS)''' ====
==== Gastric Adenocarcinoma and Proximal Polyposis of the Stomach ('''GAPPS)''' ====
* GAPPS was characterized by the [[autosomal dominant]] transmission of fundic gland polyposis that is restricted to the proximal stomach, with no evidence of duodenal or colorectal polyposis or other hereditary gastrointestinal (GI) cancer syndrome.<ref name="pmid27573780">{{cite journal| author=Brosens LA, Giardiello FM, Offerhaus GJ, Montgomery EA| title=Syndromic Gastric Polyps: At the Crossroads of Genetic and Environmental Cancer Predisposition. | journal=Adv Exp Med Biol | year= 2016 | volume= 908 | issue=  | pages= 347-69 | pmid=27573780 | doi=10.1007/978-3-319-41388-4_17 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27573780  }}</ref>
* GAPPS was characterized by the [[autosomal dominant]] transmission of fundic gland polyposis that is restricted to the proximal [[stomach]], with no evidence of [[Duodenum|duodenal]] or colorectal polyposis or other hereditary gastrointestinal cancer syndrome.<ref name="pmid27573780">{{cite journal| author=Brosens LA, Giardiello FM, Offerhaus GJ, Montgomery EA| title=Syndromic Gastric Polyps: At the Crossroads of Genetic and Environmental Cancer Predisposition. | journal=Adv Exp Med Biol | year= 2016 | volume= 908 | issue=  | pages= 347-69 | pmid=27573780 | doi=10.1007/978-3-319-41388-4_17 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27573780  }}</ref>


==== '''Familial intestinal gastric cancer''' ====
==== '''Familial intestinal gastric cancer''' ====
* FIGC should be considered a potential diagnosis when histopathological reports denote intestinal-type gastric cancers that segregate within families without gastric [[polyposis]].<ref name="pmid27809451">{{cite journal| author=Choi YJ, Kim N| title=Gastric cancer and family history. | journal=Korean J Intern Med | year= 2016 | volume= 31 | issue= 6 | pages= 1042-1053 | pmid=27809451 | doi=10.3904/kjim.2016.147 | pmc=5094936 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27809451  }}</ref>
* FIGC should be considered a potential diagnosis when [[histopathological]] reports denote [[intestinal]]-type gastric cancers that segregate within families without gastric [[polyposis]].<ref name="pmid27809451">{{cite journal| author=Choi YJ, Kim N| title=Gastric cancer and family history. | journal=Korean J Intern Med | year= 2016 | volume= 31 | issue= 6 | pages= 1042-1053 | pmid=27809451 | doi=10.3904/kjim.2016.147 | pmc=5094936 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27809451  }}</ref>
==== '''Other hereditary cancer syndromes''':<ref name="pmid27809451" /> ====
==== '''Other hereditary cancer syndromes''':<ref name="pmid27809451" /> ====
* [[Lynch syndrome]] ([[hereditary nonpolyposis colorectal cancer]])
* [[Lynch syndrome]] ([[hereditary nonpolyposis colorectal cancer]])
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*Gastric [[adenocarcinoma]] is a malignant epithelial [[tumor]], originating from [[glandular]] epithelium of the [[gastric]] [[mucosa]]. It invades the [[gastric]] wall, infiltrating the [[muscularis mucosae]], the [[submucosa]] and hence the muscular propria. Histologically, there are two major types of gastric cancer (Lauren classification): intestinal type and diffuse type.
*Gastric [[adenocarcinoma]] is a malignant epithelial [[tumor]], originating from [[glandular]] epithelium of the [[gastric]] [[mucosa]]. It invades the [[gastric]] wall, infiltrating the [[muscularis mucosae]], the [[submucosa]] and hence the muscular propria. Histologically, there are two major types of gastric cancer (Lauren classification): intestinal type and diffuse type.
**Intestinal type adenocarcinoma: [[Tumor]] cells describe irregular tubular structures, harboring pluristratification, multiple lumens, and reduced stroma ("back to back" aspect). Often, it associates intestinal metaplasia in neighboring [[mucosa]]. Depending on glandular architecture, cellular pleomorphism and mucosecretion, [[adenocarcinoma]] may present 3 degrees of differentiation: well, moderate and poorly differentiated.
**Intestinal type adenocarcinoma: [[Tumor]] cells describe irregular tubular structures, harboring pluristratification, multiple lumens, and reduced stroma ("back to back" aspect). Often, it associates intestinal metaplasia in neighboring [[mucosa]]. Depending on glandular architecture, cellular pleomorphism and mucosecretion, [[adenocarcinoma]] may present 3 degrees of differentiation: well, moderate and poorly differentiated.
**Diffuse type [[adenocarcinoma]] (mucinous, colloid): [[tumor]] cells are discohesive and secrete mucus which is delivered in the [[interstitium]] producing large pools of mucus/colloid (optically "empty" spaces). It is poorly differentiated. If the [[mucus]] remains inside the [[tumor]] cell, it pushes the [[nucleus]] at the periphery - "signet-ring cell".
**Diffuse type [[adenocarcinoma]] (mucinous, colloid): [[tumor]] cells are discohesive and secrete [[mucus]] which is delivered in the [[interstitium]] producing large pools of mucus/colloid. It is poorly differentiated. If the [[mucus]] remains inside the [[tumor]] cell, it pushes the [[nucleus]] at the periphery signet ring cell.


=== World Health Organization histological classification of gastric tumors: ===
=== World Health Organization histological classification of gastric tumors: ===
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|'''Special types'''
|'''Special types'''
|[[Carcinoid syndrome|Carcinoid tumor]]  
|[[Carcinoid syndrome|Carcinoid tumor]]  
Endocrine carcinoma
[[Endocrine]] carcinoma


Carcinoma with lymphoid stroma
Carcinoma with [[lymphoid]] stroma


Hepatoid adenocarcinoma
Hepatoid adenocarcinoma


Adenosquamous carcinoma  
[[Adenosquamous carcinoma]]


Squamous cell carcinoma  
[[Squamous cell carcinoma]]


Undifferentiated carcinoma
Undifferentiated carcinoma
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|'''Miscellaneous carcinoma'''
|'''Miscellaneous carcinoma'''
|Non-epithelial tumor
|Non-epithelial tumor
Gastrointestinal stromal tumor (GIST)  
[[Gastrointestinal stromal tumor]] (GIST)  


Smooth muscle tumor  
[[Smooth muscle]] tumor  


Neurogenic tumor  
[[Neurogenic]] tumor  


Miscellaneous non-epithelial tumors
Miscellaneous non-epithelial tumors


Lymphoma
[[Lymphoma]]


B-cell lymphoma
[[B-cell lymphoma]]


MALT (mucosa-associated lymphoid tissue) lymphoma
[[MALT lymphoma|MALT]] (mucosa-associated lymphoid tissue) [[lymphoma]]


Follicular lymphoma  
[[Follicular lymphoma]]


Mantle cell lymphoma  
[[Mantle cell lymphoma]]


Diffuse large B-cell lymphoma  
[[Diffuse large B cell lymphoma|Diffuse large B-cell lymphoma]]


Other B-cell lymphomas
Other [[B-cell lymphoma|B-cell lymphomas]]


T-cell lymphoma
[[T-cell lymphoma]]


Other lymphomas
Other lymphomas

Revision as of 21:44, 27 November 2017


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

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Overview

There are many molecular causes of gastric cancer; H. pylori and gastric cancer have strong correlation. This is related to nitric oxides accumulation produced by inflammatory cells responding to H. pylori infection. The pathophysiology of stomach cancer depends on histologic subtypes. K-ras mutations is found in invasive cancers and intestinal metaplasia. Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis. DNA methylation of gene promoters can silence the expression of CDH1. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. There are many associated diseases to gastric cancer; Hereditary diffuse gastric cancer, Gastric Adenocarcinoma and Proximal Polyposis of the Stomach, Lynch syndrome, Familial adenomatous polyposis, Li-Fraumeni syndrome, Peutz Jeghers syndrome, Juvenile polyposis, Hereditary breast and ovarian cancer syndrome, Cowden's syndrome. There are five gross pathology types of gastric cancer; Superficical, ulcerative, infiltrative ulcerative, diffuse infiltrative, and unclassified. There are two major histological classifications for gastric cancer; Japanesse classification and WHO classification. Generally, the main two types are; Intestinal type adenocarcinoma and diffuse type adenocarcinoma.

Physiology of gastric acid secretion

Pathophysiology of gastric cancer

Molecular effect of H.pylori:

  • The exact pathway for oncogenesis is not known but many trials supported the adenoma-carcinoma sequence.

Oncogenes

Tumor suppressor genes

Cell cycle regulatory molecules

Epigenetic events

{{#ev:youtube|_aAhcNjmvhc}}

Beta-catenin/Wnt signaling

  • Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer.[19]
  • Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation.
  • Beta-catenin is normally bound to protein complexes in the cell membrane that are involved in normal intercellular adhesions.

{{#ev:youtube|oweNT288BXo}}

Diffuse-type gastric cancer

Apoptosis pathway

Neutrophil activation 

Apoptotic pathways

  • Apoptosis occurs as a protective mechanism to prevent replication of mutated DNA which leads to atrophy of epithelium so called atrophic gastritis which returns to normal following eradication therapy.[25]
  • H. pylori enhances expression of the Fas receptor on gastric epithelial cells and may mediate apoptosis through signaling mechanisms related to the Fas death receptor.
  • Another trial supported that the source of tumorigenesis is from bone marrow-derived cells that differentiate into gastric epithelial cells in the presence of H. pylori.[26]

{{#ev:youtube|SyvOPXeg4ig}}

 
 
 
 
 
 
 
 
Helicobacter pylori infection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory response
secretes IL-8 ,IL-1b
 
 
 
 
Production of
alkaline ammonia
 
 
 
 
Production of urease
bacterial phospholipase A
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infux of neutophils and macrophages
release of lysosomal enzymes
leukotrienes (LT)and
reactive oxygen
 
 
 
 
inhibition of D-cells
leads to inappropriate release of somatostatin
and hypergastrinemia
 
 
 
 
Production of urease
,phospholipase
A and C
release toxic metabolities
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mucosal injury
 
 
 
 
 


Associated disorders

Familial predisposition

  • Although most gastric cancers are sporadic, 10 percent of cases are familial.

Hereditary diffuse gastric cancer

  • Clinical criteria for HDGC as described by the International Gastric Cancer Linkage Consortium (IGCLC).[27]
  • Germline truncating mutations in the CDH1 gene, which encodes the cell adhesion protein E-cadherin, have been identified HDGC is inherited as an autosomal dominant trait with high penetrance.[28]
  • The cumulative risk for gastric cancer by age 80 for CDH1 mutation carriers is up to 70 percent in men and up to 56 percent in women.[29]
  • Promoter hypermethylation, mutation, and loss of heterozygosity. The end result is loss of expression of the cell adhesion molecule E-cadherin.
  • The risk of gastric cancer in asymptomatic carriers of a pathogenetic CDH1 mutation who belong to families with highly penetrant hereditary diffuse gastric cancer is sufficiently high to warrant prophylactic gastrectomy.
  • Women in these affected families are also at high risk of developing breast cancer. The cumulative risk of breast cancer to age 80 for CDH1 mutation carriers is 42 percent.

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS)

  • GAPPS was characterized by the autosomal dominant transmission of fundic gland polyposis that is restricted to the proximal stomach, with no evidence of duodenal or colorectal polyposis or other hereditary gastrointestinal cancer syndrome.[30]

Familial intestinal gastric cancer

Other hereditary cancer syndromes:[31]

Gross pathology

Type Description
Type 0  (superficial) Typical of T1 tumors
Type 1 (mass) Polypoid tumors sharply demarcated from the

surrounding mucosa

Type 2 (ulcerative) Ulcerated tumors with raised margins

surrounded by a thickened gastric wall with

clear margins

Type 3 (infiltrative ulcerative)

Ulcerated tumors with raised margins,

surrounded by a thickened gastric wall

without clear margins

Type 4 (diffuse infiltrative)

Tumors without marked ulceration or raised

margins, the gastric wall is thickened and

indurated and the margin is unclear

Type 5 (unclassifiable)

Tumors that cannot be classified into any of the

above types

Video shows growth pathology of gastric cancer

{{#ev:youtube|ih-npVIJA6U}}

Image shows gastric adenocarcinoma linitis plastica, source: Case courtesy of Dr Andrew Ryan, Radiopaedia.org, rID: 16159


Histopathology

  • Gastric adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. It invades the gastric wall, infiltrating the muscularis mucosae, the submucosa and hence the muscular propria. Histologically, there are two major types of gastric cancer (Lauren classification): intestinal type and diffuse type.
    • Intestinal type adenocarcinoma: Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, and reduced stroma ("back to back" aspect). Often, it associates intestinal metaplasia in neighboring mucosa. Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiated.
    • Diffuse type adenocarcinoma (mucinous, colloid): tumor cells are discohesive and secrete mucus which is delivered in the interstitium producing large pools of mucus/colloid. It is poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery signet ring cell.

World Health Organization histological classification of gastric tumors:

Types Histological features
Epithelial tumors
  • Carcinoid (well differentiated endocrine neoplasm)
Non-epithelial tumors Leiomyoma

Schwannoma

Granular cell tumor

Glomus tumor

Leiomyosarcoma

GI stromal tumor

Benign

Uncertain malignant potential

Malignant

Kaposi sarcoma

Malignant lymphomas Marginal zone B-cell lymphoma of MALT-type

Mantle cell lymphoma

Diffuse large B-cell lymphoma

Japanese histological classification of gastric tumors:

Types Histological features
Epithelial tumors
Benign epithelial tumor

Adenoma

Malignant epithelial tumor

Common type

Papillary adenocarcinoma

Tubular adenocarcinoma

Well-differentiated

Moderately differentiated

Poorly differentiated adenocarcinoma

Solid type

Non-solid type

Signet-ring cell carcinoma

Mucinous adenocarcinoma 

Special types Carcinoid tumor

Endocrine carcinoma

Carcinoma with lymphoid stroma

Hepatoid adenocarcinoma

Adenosquamous carcinoma

Squamous cell carcinoma

Undifferentiated carcinoma

Miscellaneous carcinoma Non-epithelial tumor

Gastrointestinal stromal tumor (GIST)

Smooth muscle tumor

Neurogenic tumor

Miscellaneous non-epithelial tumors

Lymphoma

B-cell lymphoma

MALT (mucosa-associated lymphoid tissue) lymphoma

Follicular lymphoma

Mantle cell lymphoma

Diffuse large B-cell lymphoma

Other B-cell lymphomas

T-cell lymphoma

Other lymphomas

Metastatic tumor

Tumor-like lesion

Hyperplastic polyp

Fundic gland polyp

Heterotopic submucosal gland

Heterotopic pancreas

Inflammatory fibroid polyp

Gastrointestinal polyposis

Familial polyposis coli, Peutz–Jeghers syndrome

Adrenocortical carcinoma,source: Public Domain, https://commons.wikimedia.org/w/index.php?curid=182915
signet ring appearance gastric cancer, source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=502927


Video shows microscopic pathology of gastric cancer {{#ev:youtube|lRvq1fEW8sY}} {{#ev:youtube|lWeECaiEfSs}}


References

  1. ↑ Yao X, Forte JG (2003). "Cell biology of acid secretion by the parietal cell". Annu Rev Physiol. 65: 103–31. doi:10.1146/annurev.physiol.65.072302.114200. PMID 12500969.
  2. ↑ Geibel JP (2005). "Role of potassium in acid secretion". World J Gastroenterol. 11 (34): 5259–65. PMC 4622792. PMID 16149129.
  3. ↑ Kidd M, Modlin IM, Tang LH (1998). "Gastrin and the enterochromaffin-like cell: an acid update". Dig Surg. 15 (3): 209–17. PMID 9845587.
  4. ↑ Shulkes A, Read M (1991). "Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms". Endocrinology. 129 (5): 2329–34. doi:10.1210/endo-129-5-2329. PMID 1682134.
  5. ↑ Eslick GD, Lim LL, Byles JE, Xia HH, Talley NJ (1999). "Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis". Am J Gastroenterol. 94 (9): 2373–9. doi:10.1111/j.1572-0241.1999.01360.x. PMID 10483994.
  6. ↑ Mera R, Fontham ET, Bravo LE, Bravo JC, Piazuelo MB, Camargo MC; et al. (2005). "Long term follow up of patients treated for Helicobacter pylori infection". Gut. 54 (11): 1536–40. doi:10.1136/gut.2005.072009. PMC 1462952. PMID 15985559.
  7. ↑ Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B; et al. (1996). "Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants". Cancer Res. 56 (14): 3238–43. PMID 8764115.
  8. ↑ Yasui W, Oue N, Kuniyasu H, Ito R, Tahara E, Yokozaki H (2001). "Molecular diagnosis of gastric cancer: present and future". Gastric Cancer. 4 (3): 113–21. doi:10.1007/s101200100001. PMID 11760076.
  9. ↑ Smith MG, Hold GL, Tahara E, El-Omar EM (2006). "Cellular and molecular aspects of gastric cancer". World J Gastroenterol. 12 (19): 2979–90. PMC 4124370. PMID 16718776.
  10. ↑ Ushiku T, Chong JM, Uozaki H, Hino R, Chang MS, Sudo M; et al. (2007). "p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma". Int J Cancer. 120 (1): 60–6. doi:10.1002/ijc.22275. PMID 17058198.
  11. ↑ Ashktorab H, Ahmed A, Littleton G, Wang XW, Allen CR, Tackey R; et al. (2003). "p53 and p14 increase sensitivity of gastric cells to H. pylori-induced apoptosis". Dig Dis Sci. 48 (7): 1284–91. PMID 12870784.
  12. ↑ Kodama M, Murakami K, Okimoto T, Sato R, Watanabe K, Fujioka T (2007). "Expression of mutant type-p53 products in H pylori-associated chronic gastritis". World J Gastroenterol. 13 (10): 1541–6. PMC 4146896. PMID 17461446.
  13. ↑ Nakatsuru S, Yanagisawa A, Furukawa Y, Ichii S, Kato Y, Nakamura Y; et al. (1993). "Somatic mutations of the APC gene in precancerous lesion of the stomach". Hum Mol Genet. 2 (9): 1463–5. PMID 8242071.
  14. ↑ Leung WK, Yu J, Chan FK, To KF, Chan MW, Ebert MP; et al. (2002). "Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues". J Pathol. 197 (5): 582–8. doi:10.1002/path.1147. PMID 12210076.
  15. ↑ Bani-Hani KE, Almasri NM, Khader YS, Sheyab FM, Karam HN (2005). "Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer". Clin Cancer Res. 11 (4): 1447–53. doi:10.1158/1078-0432.CCR-04-1730. PMID 15746045.
  16. ↑ Takano Y, Kato Y, van Diest PJ, Masuda M, Mitomi H, Okayasu I (2000). "Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases". Am J Pathol. 156 (2): 585–94. doi:10.1016/S0002-9440(10)64763-3. PMC 1850035. PMID 10666388.
  17. ↑ Yasui W, Sentani K, Motoshita J, Nakayama H (2006). "Molecular pathobiology of gastric cancer". Scand J Surg. 95 (4): 225–31. doi:10.1177/145749690609500403. PMID 17249269.
  18. ↑ Bernal C, Aguayo F, Villarroel C, Vargas M, Díaz I, Ossandon FJ; et al. (2008). "Reprimo as a potential biomarker for early detection in gastric cancer". Clin Cancer Res. 14 (19): 6264–9. doi:10.1158/1078-0432.CCR-07-4522. PMID 18829507.
  19. ↑ Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C; et al. (2002). "beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer". Cancer Res. 62 (12): 3503–6. PMID 12067995.
  20. ↑ Lowy AM, Clements WM, Bishop J, Kong L, Bonney T, Sisco K; et al. (2006). "beta-Catenin/Wnt signaling regulates expression of the membrane type 3 matrix metalloproteinase in gastric cancer". Cancer Res. 66 (9): 4734–41. doi:10.1158/0008-5472.CAN-05-4268. PMID 16651426.
  21. ↑ Graziano F, Humar B, Guilford P (2003). "The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice". Ann Oncol. 14 (12): 1705–13. PMID 14630673.
  22. ↑ Ramos-de la Medina A, More H, Medina-Franco H, Humar B, Gamboa A, Ortiz LJ; et al. (2006). "Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer". Rev Esp Enferm Dig. 98 (1): 36–41. PMID 16555931.
  23. ↑ Study Group of Millennium Genome Project for Cancer. Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T; et al. (2008). "Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer". Nat Genet. 40 (6): 730–40. doi:10.1038/ng.152. PMID 18488030.
  24. ↑ Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M; et al. (2001). "Helicobacter pylori infection and the development of gastric cancer". N Engl J Med. 345 (11): 784–9. doi:10.1056/NEJMoa001999. PMID 11556297.
  25. ↑ Xia HH, Talley NJ (2001). "Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis". Am J Gastroenterol. 96 (1): 16–26. doi:10.1111/j.1572-0241.2001.03447.x. PMID 11197247.
  26. ↑ Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H; et al. (2004). "Gastric cancer originating from bone marrow-derived cells". Science. 306 (5701): 1568–71. doi:10.1126/science.1099513. PMID 15567866.
  27. ↑ Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H; et al. (2015). "Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond". JAMA Oncol. 1 (1): 23–32. doi:10.1001/jamaoncol.2014.168. PMID 26182300.
  28. ↑ van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N; et al. (2015). "Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers". J Med Genet. 52 (6): 361–74. doi:10.1136/jmedgenet-2015-103094. PMC 4453626. PMID 25979631.
  29. ↑ van der Post RS, Vogelaar IP, Manders P, van der Kolk LE, Cats A, van Hest LP; et al. (2015). "Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1". Gastroenterology. 149 (4): 897–906.e19. doi:10.1053/j.gastro.2015.06.003. PMID 26072394.
  30. ↑ Brosens LA, Giardiello FM, Offerhaus GJ, Montgomery EA (2016). "Syndromic Gastric Polyps: At the Crossroads of Genetic and Environmental Cancer Predisposition". Adv Exp Med Biol. 908: 347–69. doi:10.1007/978-3-319-41388-4_17. PMID 27573780.
  31. ↑ 31.0 31.1 Choi YJ, Kim N (2016). "Gastric cancer and family history". Korean J Intern Med. 31 (6): 1042–1053. doi:10.3904/kjim.2016.147. PMC 5094936. PMID 27809451.

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