Mixed-type gastric carcinomas exhibit more aggressive features and indicate the histogenesis of carcinomas

Abstract

To investigate the pathobiological behaviors of gastric mixed-type (MT) carcinomas and gastric carcinogenesis, the clinicopathological characteristics of MT carcinomas were analyzed and compared with intestinaltype (IT) and diffuse-type (DT) carcinomas. The expression of Ki-67, caspase-3, p53, fragile histine triad (FHIT), maspin, extracellular matrix metalloproteinase inducer (EMMPRIN), vascular growth factor (VEGF), MUC-2, 4, 5AC and 6, CD44, E-cadherin, β-catenin, and phosphorylated glycogen synthase kinase 3β-ser 9 (P-GSK3β-ser 9 ) was examined on tissue microarrays using immunohistochemistry. It was found that MT carcinomas exhibited large size, deep invasion, frequent local invasion, and lymph node metastasis in comparison with IT and DT carcinomas (p<0.05). All the markers except MUC-5AC showed higher expression in IT than DT carcinomas (p<0.05). The expression of maspin, EMMPRIN, VEGF, MUC-4, and membrane E-cadherin was stronger in MT intestinal than diffuse component (p<0.05). Immunoreactivities to Ki-67, EMMPRIN, and VEGF were weaker in IT carcinoma than in the MT intestinal portion (p<0.05), while the opposite was true for CD44, MUC-2, and MUC-6 (p< 0.05). The MT diffuse component displayed a higher expression of FHIT, VEGF, and P-GSK3β-ser 9 than DT carcinoma (p<0.05). The accumulative survival rate of the IT carcinoma patients was higher than the other types (p< 0.05). The invasive depth, venous invasion, lymph node, peritoneal or liver metastasis, and Lauren's classification were independent prognostic factors for gastric carcinomas (p<0.05). These findings suggested that MT carcinomas were also indicated to be more aggressive than IT and DT carcinomas. Significant differences were observed in the proliferation, apoptosis, angiogenesis, mucin secretion, and cell adhesion between IT and DT carcinomas, whereas only a few of these characteristics showed differences between the MT intestinal and diffuse parts, thus suggesting that both the MT components might originate from the stem cells with similar genetic traits, but follow different histogenic pathways.

The Clinicopathological Significance of Bmi-1 Expression in Pathogenesis and Progression of Gastric Carcinomas

“…In addition, the repression of Bmi-1 reverses the expression of epithelial mesenchymal transition markers and inhibits the Akt/GSK3β/Snail pathway (Guo et al, 2011). To clarify the prognostic significance of Bmi-1 expression, we here analyzed their relation with the survival of 309 patients with gastric carcinoma and found a negative relationship link between the positivity of Bmi-1 expression and favorable survival, in line with other reports (Zheng et al, 2008;Xiao et al, 2009;Liu et al, 2010;Yang et al, 2010;Zhang et al, 2010;Huber et al, 2011;Min et al, 2011;Zhang et al, 2012). It might be attributed to Bmi-1 overexpression in gastric cancer with more aggressive behaviors.…”

“…The cell cohesion is less apparent or absent in diffuse-type carcinoma and cancer cells diffusely spread in the gastric wall lesions. Tumors that contain approximately equal quantities of intestinal and diffuse components are called mixed carcinoma (Zheng et al, 2007;Zheng et al, 2008). Here, it was noted that Bmi-1 expression was higher in intestinal-than diffuse-type carcinomas, indicating that it might play an important role in intestinal-type carcinogenesis, but less in de novo carcinogenic pathway and underlie the molecular basis for differentiation of both carcinomas.…”

“…These sections were stained by haematoxylinand-eosin (HE) to confirm their histological diagnosis and other microscopic characteristics. Histological architecture of gastric carcinoma was expressed in terms of Lauren's classification (Zheng et al, 2007;Zheng et al, 2008). Furthermore, tumour size, depth of invasion, and lymph node metastasis were determined.…”

CDH1‐related hereditary diffuse gastric cancer syndrome: Clinical variations and implications for counseling

“…IGC or intestinal components are reported within the histological spectrum of HDGC. 30 A latent, nonproliferative, phase of SRCs has been suggested previously 31 and reasoned recently, 32 and is now strongly supported by the presence of SRCs 10 and 7 years prior to gastrectomy without progression to invasive cancer in two patients from one family. Remarkable is the variation in aggressiveness of the disease within this family.…”

DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis

“…Since the two major types show distinctively different phenotypic, epidemiologic and biologic characteristics, it is believed that different genetic alterations may be implicated in each histologic type of the classification (7). However, a considerable number of GCs accounting for 10-15% of cases, share the histologic features of these two types and are designated as mixed-type (8,9). Although this type of tumor shows poorer prognosis than the common intestinal-type GCs, it is difficult to define and to diagnose when these tumors are encountered in a small biopsy.…”