Immunohistochemistry of COUP-TFI: an adjuvant diagnostic tool for the identification of corticotroph microadenomas Zachary M. Bush Æ Maria-Beatriz S. Lopes Æ Isa M. Hussaini Æ John A. Jane Jr. Æ Edward R. Laws Jr. Æ Mary Lee Vance Published online: 13 June 2009 Ó Springer Science+Business Media, LLC 2009 Abstract Cushing’s disease is caused by an ACTH-pro- ducing pituitary tumor, and accounts for 10–15% of pitu- itary tumors. The majority of corticotroph tumors are microadenomas ( \ 10 mm), and accurate histologic iden- tification of these tumors can be challenging because of their small size and the presence of nests of normal corti- cotroph cells in the anterior pituitary. Retinoic acid has been shown to inhibit ACTH production and induce apoptosis in corticotroph tumor cells. The expression of the orphan nuclear receptor COUP-TFI antagonizes retinoic acid signaling and has been shown to be expressed in normal corticotroph cells, but absent in corticotroph tumor cell lines. We analyzed 34 corticotroph tumor specimens by immunohistochemistry using a goat polyclonal IgG antibody with epitope mapping to the N-terminus of human COUP-TFI. Segments of normal pituitary in each of the 34 specimens demonstrate COUP-TFI immunoreactivity in normal corticotroph cells. Twenty-nine of 34 ACTH producing tumors were immunonegative for COUP-TFI. All of the tumors measuring less than 5 mm by preopera- tive MRI were COUP-TFI immunonegative. Two tumors, measuring 9 and 11 mm, showed consistent ( [ 90%) expression of COUP-TFI, and three adenomas (5, 11, and 18 mm) showed heterogenous (20–80%) expression of COUP-TFI. Immunohistochemistry of COUP-TFI may be a useful adjuvant diagnostic tool in distinguishing corti- cotroph microadenomas from nests of normal corticotroph cells in the anterior pituitary. Furthermore, this study identifies two unique corticotroph tumor populations which differ in their expression of COUP-TFI, the presence of which occurs more frequently in macroadenomas. Keywords Cushing’s Á COUP-TFI Á Diagnosis Á Pathology Á Corticotroph Introduction Cushing’s disease is caused by an adrenocorticotropic hormone (ACTH)-producing pituitary tumor, and accounts for 10–15% of all pituitary tumors [1]. Current evidence suggests that corticotroph adenomas are derived from clonal expansion of mutated somatic cells, and non-random methylation patterns suggest the majority arise from a single cell [2, 3]. As with most other pituitary adenomas, corticotroph tumors are very slow growing and are uni- versally non-malignant, though aggressive local invasion may occur. The natural history of pituitary adenomas is unique in that not all microadenomas become macroade- nomas, and macroadenomas are often stable in size, and can even spontaneously resolve [4]. More than 80% of corticotroph tumors are microadenomas ( \ 10 mm) at the time of diagnosis. Z. M. Bush (&) Á M. L. Vance Division of Endocrinology and Metabolism, University of Virginia Health System, P.O. Box 801408, Charlottesville, VA 22908-1408, USA e-mail: zmb8e@virginia.edu M.-B. S. Lopes Á I. M. Hussaini Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908-1408, USA J. A. Jane Jr. Department of Neurosurgery, University of Virginia Health System, Charlottesville, VA 22908-1408, USA E. R. Laws Jr. Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA 123 Pituitary (2010) 13:1–7 DOI 10.1007/s11102-009-0189-8