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 leads 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 he 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].
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 muscularis 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 |
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| 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 tumorAdenoma Malignant epithelial tumorCommon 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 |