We explored the application of TFE3 immunostaining and TFE3 mRNA expression in the differential diagnosis and prognostication of adrenal cortical tumors and distinction of the latter from clear cell renal cell carcinoma (ccRCC) which show significant morphologic overlap. TFE3 immunostaining was performed on a large cohort of samples including 40 adrenal cortex tissues, 95 adrenocortical adenoma (ACA), 11 adrenocortical carcinoma (ACC), 53 ccRCC, and 18 pheochromocytomas. TFE3 was compared with other immunomarkers melan-A, inhibin-α, synaptophysin, chromogranin A, CAIX and CD10. One hundred percent normal adrenal cortices and 94% ACA were strongly and diffusely stained for TFE3 while no ACC showed diffuse staining. TFE3 is thus useful in distinguishing ACA from ACC. TFE3 is also useful in separating ACC from ccRCC as 64% ACC showed partial, while only 7% of ccRCC showed partial TFE3 staining. Only 1 pheochromocytoma showed focal weak TFE3 staining. Results also demonstrated superiority of TFE3 over other commonly used immunomarkers. TFE3 gene rearrangement testing by fluorescence in situ hybridization showed no rearrangement in 6 TFE3 positive adrenal tumors. TFE3 mRNA were analyzed by the Cancer Genome Atlas database and we found TFE3 mRNA expression correlated with overall patient survival in ACC. Our study showed usefulness of TFE3 in distinguishing ACA from ACC, and ACC from ccRCC. TFE3 is superior over other commonly used immunomarkers for adrenal tumors. In addition, decreased TFE3 immunoexpression and TFE3 mRNA expression may carry poor prognostic implication in adrenal tumors.
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