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background: Accurate diagnosis, early detection, and differentiation of lung adenocarcinoma from mesothelioma; particularly the epithelioid subtype is needed to allow better management thus to improve their prognosis.Aim of our study was to assess applicability of CPA4, UHRF1, glypican-1 and CD90 expression by immunohistochemistry to differentiate between lung adenocarcinoma and epithelioid mesothelioma in addition to detection of their prognostic roles and relation to patients' survival. Methods: We collected samples from 30 patients diagnosed with lung adenocarcinoma and 30 patients diagnosed with epithelioid mesothelioma. For the immunohistochemistry, sections of all collected samples were incubated with CPA4, UHRF1, glypican-1 and CD90 to assess their diagnostic accuracy. RESULTS: A highly significant association was detected between positive CPA4, UHRF1 expression in lung adenocarcinoma and their diagnostic accuracy (p value <0.001). Also, highly significant association was detected between positive CD90, Glypican 1 expression in epithelioid mesothelioma and their diagnostic accuracy (p value <0.001). CPA4 expression was associated with shorter OS rate (P value 0.019, 0.009) UHRF1 expression was associated with shorter OS rate (P value=0.009) Conclusions: CPA4, UHRF1, glypican-1 and CD90 were considered novel biomarkers that have important roles in differentiation between epithelioid malignant mesothelioma and adenocarcinoma of the lung with high sensitivity and specificity. [ABSTRACT FROM AUTHOR]