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Histopathologic Features of the Tumor Budding in Adenocarcinoma of the Lung: Tumor Budding As an Index to Predict the Potential Aggressiveness

Introduction: The term tumor budding has been applied to single cells or small clusters of up to four cells within the stromal tissue at the invasive margin of colorectal cancers. This morphologic feature is increasingly being recognized as an adverse prognostic factor. The purpose of this study was to evaluate the clinicopathologic significance of tumor budding in adenocarcinomas of the lung. Methods: We investigated the relationship between tumor budding and clinicopathologic parameters of adenocarcinomas of the lung and the prognostic significance of tumor budding by reviewing the cases of 201 consecutive patients who had undergone complete resection of adenocarcinoma of the lung measuring 30 mm or less in diameter. We examined immunohistochemical profile of budding cells (BCs) by immunohistochemical staining with 14 antibodies. Results: Tumor budding was observed in 78 (43.1%) of the 181 cases with invasive adenocarcinoma. The presence of tumor budding was significantly associated with lymph node metastasis (p = 0.005), pathologic stage (p < 0.001), vascular invasion (p = 0.003), lymphatic invasion (p = 0.009), and pleural invasion (p = 0.029). Examination of the relation between the presence of tumor budding and the predominant histologic subtype revealed that the predominant papillary subtype was significantly associated with the presence of tumor budding (p = 0.0023), whereas the predominant bronchioloalveolar carcinoma subtype was significantly associated with the absence of tumor budding (p < 0.001). The overall 5-year survival rates of the group with budding and the group without budding was 67.5% and 88.3%, respectively, and difference was significant (p = 0.0057). Compared with cancer cells forming nests, BCs displayed reduced expression of cellular adhesion molecule, E-cadherin, and β-catenin (p < 0.05 and p < 0.05, respectively) and increased expression of laminin5-γ2 (p < 0.05). However, BCs displayed reduced expression of differentiation marker, surfactant protein A (p < 0.05). Multivariate analysis revealed that tumor budding was significant independent prognostic factor of the small-sized adenocarcinoma of the lung. Conclusions: Our data showed that tumor budding in adenocarcinoma of the lung is a distinct morphologic feature that has biologic and prognostic significance.