Lymphovascular invasion is associated with poor survival in gastric cancer: an application of gene-expression and tissue array techniques

Abstract

Objectives: To examine a population-based cohort for the association between clinicopathologic predictors of survival and immunohistochemical markers (IHC), and to assess changes in gene expression that are associated with lymphovascular invasion (LVI).

Summary background data: LVI has been associated with poor survival and aggressive tumor behavior. The molecular changes responsible for the behavior of gastric cancer have yet to be determined. Characterization of IHC markers and gene expression profiles may identify molecular alterations governing tumor behavior.

Methods: : Clinicopathologic and survival data of 114 patients were reviewed. Archival specimens were used to construct a multitumor tissue array that was subjected to IHC of selected protein targets. Correlation of IHC with tumor thickness (T status), LVI and prognosis was studied. Microarray analysis of fresh gastric cancer tissue was conducted to examine the gene expression profile with respect to LVI.

Results: In a multivariate analysis, nodal status (N), metastasis (M), and LVI were independent predictors of survival. LVI was associated with a 5-year survival of 13.9% versus 55.9% in patients in whom it was absent. LVI correlated with advancing T status (P = 0.001) and N status (P < 0.001). IHC staining of cyclooxygenase-2 (COX-2) correlated with T status, tumor grade, lymph node positivity, and IHC staining of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Microarray analyses suggested differential expression of oligophrenin-1 (OPHN1) and ribophorin-II (RPNII) with respect to LVI.

Conclusion: LVI was an independent predictor of survival in gastric cancer. Expression of COX-2 may facilitate tumor invasion through MMP-2 and MMP-9 activation. OPHN1 and RPN II appeared to be differentially expressed in gastric cancers exhibiting LVI. The reported function of OPHN1 and RPN II makes these gene products promising candidates for future studies involving LVI in gastric cancer.

FIGURE 1. A, Immunohistochemical staining of COX-2 in a gastric cancer multitumor tissue array (magnification ×10). A, COX-2 immunoreactivity is evident (2+) in the cytoplasm of the tumor cells. B, Immunohistochemical staining of COX-2 in a gastric cancer multitumor tissue array (magnification ×10). B, COX-2 negative immunoreactivity.

FIGURE 2. A: Immunohistochemical staining of MMP-9 in a gastric cancer multitumor tissue array (magnification ×10). A, MMP-9 immunoreactivity is evident (2+) in the cytoplasm of the tumor cell. B, Immunohistochemical staining of MMP-9 in a gastric cancer multitumor tissue array (magnification ×10). B, MMP-9 negative immunostaining.

FIGURE 3. The relationship between LVI and disease-specific survival in a population of patients with resected gastric cancer. The 5-year survivals of LVI-positive patients (n = 68, solid line) and LVI-negative patients (n = 37, dashed line) were 13.9% ± 8.4% versus 55.9% ± 16.7% respectively.

FIGURE 4. Relationship of LVI with tumor thickness and lymph node status in a cohort of 114 patients with gastric cancer. The number above each bar represents the percentage of patients with LVI within each stage category. The chart demonstrates a significant association between advancing T status (P = 0.001) and advancing N status (P < 0.001) with LVI.