Stomach cancer pathophysiology

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

The pathophysiology of stomach cancer depends on histologic subtypes.

Pathophysiology

Molecular effect of H.pylori:

• There is a strong correlation between H. pylori seropositivity and gastric cancer incidence. [34,35].
• Regression of premalignant lesions has been demonstrated with eradication of H. pylori.[38,39],
• This is related to nitric oxides accumulation produced by inflammatory cells responding to H. pylori infection. [41]
• Nitric oxides may induce abnormalities in the DNA of epithelial cells.[43]

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

Oncogenes

• K-ras mutations is found in invasive cancers, and intestinal metaplasia. [51]
• Hepatocyte growth factor receptor c-met oncogene, encoding the h is supported by the finding that gene expression is found in intestinal-type gastric cancers. Effector protein CagA made by H.pylori modulates c-met receptor signal transduction pathways. [53].[52]

Tumor suppressor genes

• Almost 50% of gastric cancers have alterations in genes TP53, TP73, APC, TFF, DCC, LOH, and FHIT.  [50,54-67]
• Inactivation of p53 in gastric epithelial cells may reduce their ability to undergo apoptosis. [61]

• Abnormalities are found in intestinal-type , intestinal metaplasia and dysplasia, and H. pylori-associated chronic gastritis. [54,55,59,60,68].
• Mutations in the APC gene are found in intestinal-type gastric cancers [70]. APC mutations alternate the Wnt/cateninsignaling pathway. [71]
• The trefoil factor family (TFF) is normally expressed in the gastroduodenal mucosa. 72 Loss of TFF1 expression has been observed in gastric carcinomas [74].

Cell cycle regulatory molecules

• Cyclin E overexpression is found in gastric carcinomas. [75,76]
• Cyclin E and Cyclin dependent kinase inhibitor 1B are cell-cycle regulators. [76,78].

Epigenetic events

• DNA methylation of gene promoters can silence the expression of CDH1. [50,62,81,82]
• Hypermethylation of the Reprimo gene has been found in the plasma of patients with gastric cancer and can be used as biomarkers in the detection of early gastric cancer. [89]

Beta-catenin/Wnt signaling

• Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. [95]
• Beta-catenin is a part of Wnt signaling pathway which regulates coordination of individual 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.

• APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. [94,96].

Diffuse-type gastric cancer

• Diffuse gastric carcinomas do not have a precancerous lesion/
• They are highly metastatic with a poorer prognosis than intestinal cancers.  [109,110]When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastic. (image 1).
• Intracellular mucin is accumulating pushing the nucleus giving the histological figure of signet ring carcinoma.
• The E-cadherin gene (CDH1) encodes a transmembrane cellular adhesion protein. Its cytoplasmic tail interacts with catenins making the adhesion. [119].
• Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers. [127-130].
• Prostate stem cell antigen gene is also involved in regulating gastric epithelial cell proliferation. [132].

Apoptosis pathway

Neutrophil activation 

• H. pylori infection results in the migration of neutrophils to the site of infection and adhesion to the surface epithelium.
• The neutrophils produce nitric oxide synthase which damage DNA.
• CD11a/CD18- and CD11b/CD18-neutrophils interact with intercellular adhesion molecule-1 (ICAM-1)  [31].
• Epithelial cells respond by signaling pathways leading to apoptosis, proliferation, differentiation, and autophagy.

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 [33] [32]
• 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 [36].
• 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. [43].

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).
• 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.
• 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.
• 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, 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.

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.
• It is characterized by incomplete penetrance.

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.

An autosomal dominant inheritance pattern has been noted in many such families.

Other hereditary cancer syndromes:

• Lynch syndrome (hereditary nonpolyposis colorectal cancer),
• Familial adenomatous polyposis (FAP)
• Li-Fraumeni syndrome
• Peutz Jeghers syndrome
• juvenile polyposis
• Hereditary breast and ovarian cancer syndrome
• Cowden's syndrome

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.

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 (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".

World Health Organization histological classification of gastric tumors:

Types	Histological features
Epithelial tumors	Adenoma Carcinoma Adenocarcinoma Intestinal type Diffuse type Papillary adenocarcinoma Tubular adenocarcinoma Mucinous adenocarcinoma Signet-ring cell carcinoma Adenosquamous carcinoma Squamous cell carcinoma Small cell carcinoma Undifferentiated carcinoma Carcinoid (well differentiated endocrine neoplasm)
Non-epithelial tumors	Leiomyoma Schwannoma Granular cell tumour Glomus tumour Leiomyosarcoma GI stromal tumour 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