Carcinoma of unknown primary (CUP) is a heterogeneous entity with different clinical and histological features. The aim of this study was to investigate the clinicopathological features and expression of proteins associated with carcinogenesis and tumor environment in different histological subtypes of CUP. Sixty-nine cases of CUP were subjected to immunohistochemistry for EGFR, phospho-EGFR, HER-2, phospho-HER-2, p53, ERCC1, RRM1, REDD1, HIF1α, COX-2, GLUT-1, 14-3-3σ, Phospho-mTOR, Phospho-S6, AMPKα1, Phospho-Akt, PDGF-β receptor, and caveolin-1, and fluorescence in situ hybridization for HER-2 gene amplification. Fourteen (20.3%) cases were poorly differentiated carcinoma, 24 (34.8%) were adenocarcinoma (AD), 17 (24.6%) were squamous cell carcinoma (SC), and 14 (20.3%) were undifferentiated carcinoma (UD). AD were mostly carcinomatosis type, while SC and UD were mostly nodal type (p < 0.001). SC showed more frequent EGFR overexpression (p < 0.001) and Glut-1 (p = 0.001). AD (p = 0.001) and carcinomatosis (p < 0.001) types showed shorter overall survival. SCs expressing Glut-1, HIF1α, and COX2 showed a poor prognosis (p = 0.048, 0.029, and 0.042, respectively). CUP shows various clinicopathological features according to the histological subtypes. SC is mainly associated with nodal metastasis in the head and neck, and frequent EGFR overexpression and Glut-1 expression. Glut-1, HIF1α, and COX2 expression in SC is associated with a poor prognosis.
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