Gastric adenocarcinoma: pathomorphology and molecular pathology

Abstract

Two types of gastric adenocarcinoma can be distinguished histopathologically: the diffuse and the intestinal type. Molecular pathology supports this theory by showing differences in the genetic pathways of both tumor types. In addition to known pathomorphological factors of prognosis, e.g., depth of tumor infiltration, number of lymph node metastases and resection margins, a few genes have been suggested to have prognostic impact in gastric carcinoma. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1), the cell cycle regulator cyclin E, epidermal growth factor (EGF), the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-catenin. Gene amplification and protein overexpression of the growth factor receptors c-erbB-2 and K-sam may be prognostic factors for intestinal-type and diffuse-type gastric cancer, respectively. In addition, genetic instability is commonly seen. There has long been evidence for a genetic predisposition to gastric cancer by epidemiological studies and case reports. Very recently, germ line mutations of E-cadherin have been identified that are responsible for a dominantly inherited form of diffuse-type gastric cancer and could be used to identify individuals that are at high risk.

Hypermethylation of tumor suppressor genes (p16INK4A, p14ARF and APC) in adenocarcinomas of the upper gastrointestinal tract

“…However, our findings fit into the currently considered concept that significant differences in the molecular aberrations exist between the diffuse and glandular subtypes of gastric cancer. 3,28 In our study, hypermethylation of p16 INK4A was correlated with complete loss of p16 INK4A protein expression with high statistical significance, a finding that underlines the functional relevance of p16 INK4A hypermethylation in upper gastrointestinal ADC. However, we found exceptions in both directions, i.e., hypermethylation-negative tumors exhibiting complete loss of p16 INK4A protein expression as well as hypermethylation-positive tumors exhibiting retained protein expression.…”

THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling

“…On the other hand, the WHO types 'undifferentiated carcinoma' and 'signet ring cell carcinoma', as well as the 'infiltrative' type of Ming, generally match the diffuse type. [7][8][9] The two Laurén types reveal several divergent clinical and molecular characteristics, including their etiology, epidemiology, carcinogenesis and progression, mRNA and/or protein expression profile, gene copy numbers, microsatellite instability, loss of heterozygosity and mutation profile. 8 Thus, it is widely accepted that they represent distinct disease entities that may benefit from different therapeutic approaches.…”

Correlation of c-erbB-2, EGF and EGFR expression with postoperative survival of patients with advanced carcinoma of the stomach.

“…The EGF family members exhibit a similar range of biological activity induced by binding and activation of the EGF receptor [21]. Although the role of growth factors in oncogenesis of the alimentary tract diseases has been recently in the focus of attention, it is still not completely elucidated [22][23][24]. In the current study, a low immunohistochemical reaction to c-erbB-2 was observed in 78% of cases, mainly in the intestinal-type Table1.…”