Pituitary oncocytoma is a subtype of nonfunctioning pituitary adenomas with the potential to be locally invasive. Currently, surgery is the most effective treatment, whereas functional pituitary adenomas can be treated by drugs. We analyzed the invasiveness of pituitary oncocytomas to identify biomarkers that may be useful for guiding future therapeutic decision making. To identify important biomarkers of pituitary oncocytomas, 20 oncocytomas that were negative for hormone-specific immunostaining were confirmed by anti mitochondria antibody immunostaining and electron microscopy. Our clinical phenotype data showed a prominent male predilection (85%). These tumors were classified as invasive or noninvasive based on preoperative magnetic resonance imaging, intraoperative records, and pathology slide. We observed significantly different expression profiles between pituitary oncocytomas (n = 3) and normal pituitary glands (n = 3). A total of 1937 genes were differentially expressed between the pituitary oncocytomas and normal pituitary glands. Among these 1937 genes, 954 were up-regulated and 983 were down-regulated in pituitary oncocytomas. The most significantly altered gene, claudin-9 (CLDN9), was further confirmed by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical staining in 10 invasive pituitary oncocytoma samples and 10 noninvasive pituitary oncocytoma samples. High levels of CLDN9 were found in the pituitary oncocytomas, whereas low levels were detected in normal pituitary glands. In addition, the CLDN9 expression level was higher in invasive oncocytomas compared with noninvasive oncocytomas. Bioinformatics Gene Ontology analysis was performed to better understand the critical role of CLDN9 in the development and progression of oncocytomas. Consequently, CLDN9 may be an important biomarker for invasive pituitary oncocytomas. (C) 2014 Elsevier Inc. All rights reserved.