Morphological and Molecular Evidence for Target Transformation during the Evolution of Gastric Carcinoma (GC).
Javiera Torres, Emanuela Veras, David S Klimstra, Laura H Tang. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: GC is a heterogenous disease with several epidemiologic, anatomic, and histopathologic characteristics. However, it continues to be grouped and treated as a single malignancy. The recognizable morphologic alteration in GC may be evidence for pathogenic or molecular transformation to more aggressive disease. We investigated the correlation of morphologic evolution and biomarker expression in GC subtypes.
Design: 72 GCs with heterogenous features were evaluated and grouped by specific morphologic variants: 1) moderately differentiated (MD) tubular carcinoma, 2) poorly differentiated (PD) tubular carcinoma, 3) diffuse carcinoma, and 4) others (Table 1). 136 foci with designated morphologic subtypes were investigated by immunohistochemistry on tumor sections and on tissue microassays. Immunoreactivity was interpreted based on features of individual antibodies.
Table 1 Biomarker Expression in Morphologic Variants of Gastric Carcinoma
| ||p-MET||EGFR||IGFR||VEGF||p-ERK||p53||E-Cad Loss|
|All Variants (136)||40%||15%||25%||25%||45%||25%||25%|
|MD Tubular (67)||63%||60%||78%||87%||55%||42%||17%|
|PD Tubular (41)||35%||25%||13%||7%||23%||30%||37%|
|PD Diffuse (26)||2%||15%||9%||6%||22%||22%||44%|
|Other (2)|| || || || ||2%||6%||2%|
Results: Uniform expression/loss of any biomarkers in individual tumors was <10%. Growth factors and receptors (including Her2Neu) were expressed in significantly higher levels in MD tubular carcinomas (P<0.005); and they were markedly decreased in diffuse type when compared with tubular type as one entity (P<0.001). When individual markers were assessed in cases with biphasic morphologic subtypes present in the same tumor, 71% p-Met, 72%, IGFR, and 74% VEGF expression were lost in the PD component whereas they were expressed in the corresponding better differentiated component (p<0.01). E-cadherin loss was strongly associated with PD carcinoma of either tubular or diffuse subtype (p<0.001). There was no significant differential expression of p53 and pERK in tumor subtypes.
Conclusions: GC exhibits morphologic diversity, which is associated with both pathogenic evolution and genetic transformation. It appears that growth factors/receptors act as carcinogenesis drivers in early malignancy and in better differentiated tumors, whereas loss of this pathway may be associated with additional cell cycle dysfunction that may be responsible for morphologic transformation and associated aggressiveness of PD carcinomas. This dynamic series of regulatory/dysregulated events may explain why effective targeted therapeutic strategies are difficult to develop given the evolving molecular targets in GC.
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 153, Tuesday Morning