Background: Metastatic dissemination can exist before a pathologically and clinically detectable manifestation. The\nstructural heterogeneity of colon cancer (CC) in histological sections with respect to the morphology of tumor\naggressiveness and composition of the tumor microenvironment raises the question of whether the microscopical\ntumor architecture enables a discrimination of groups with different metastatic potential. This would result in an\nassessment of the prognosis and provision of an ancillary tool for the therapeutic management after surgery,\nbeside the estimation of the local tumor extent.\nMethods: In order to identify predictive biomarkers for metastasis of locally advanced CC, which can easily be\nintegrated into the pathologist�s daily routine diagnostic activity, we determined tumor budding, peritumoral\ninflammation, extent of desmoplasia and necrosis, density of macro- and microvascular blood vessels and functional\nstate of lymphatics in the tumor center, invasive margin and tumor-free surrounding tissue in 86 non-metastatic,\nlymphogenous-metastatic and haematogenous-metastatic, subserosa-invasive CC.\nResults: Features influencing nodal metastasis in the univariate analysis included high tumor budding (p = 0.004),\nhigh large vessel density in the subserosa (p = 0.043), abundant desmoplasia (p = 0.049), non-finger-like desmoplastic\npattern (p = 0.051) and absent lymphocellular intratumoral inflammation (p = 0.084). In the multivariate analysis,\nwith the exception of large vessel density, these pathomorphological features were independent risk factors for\nlymphogenous metastasis (p = 0.023, p = 0.017, p = 0.037, p = 0.012, respectively) with a good discrimination ability\n(AUC of 0.853). Features associated with distant metastasis in the univariate analysis included high tumor budding\n(p = 0.002), low intratumoral small vessel density (p = 0.013), absent lymphocellular intratumoral inflammation\n(p = 0.048) and abundant necrosis (p = 0.073). In the multivariate analysis only tumor budding was an independent\npredictor for haematogenous metastasis (p = 0.007) with a good discrimination ability (AUC of 0.829).\nConclusions: Thus, mainly tumor budding but also the described structural characteristics of the peritumoral\ntissue appears to reflect the metastatic potential of locally advanced CC and therefore should be stated in\npathological reports.
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