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Inhibin/Activin ßB-Subunit Expression in Pheochromocytomas Favors Benign Diagnosis¹

Department of Pathology, Haartman Institute, University of Helsinki (K.S., J.A., R.V., A.I.K., P.H., J.L.), and HUCH Laboratory Diagnostics (K.S., J.A., R.V., A.I.K., P.H., J.L.) and Departments of Internal Medicine (V.I.) and Surgery (C.H.), Helsinki University Central Hospital, FIN-00014 Helsinki; and Department of Pediatrics, Kuopio University Hospital (R.V., J.L.), FIN-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Dr. Kaisa Salmenkivi, Haartman Institute, Department of Pathology, P.O. Box 21, University of Helsinki, FIN-00014 Helsinki, Finland. E-mail address: kaisa.salmenkivi{at}helsinki.fi

Malignancy of pheochromocytomas is difficult to estimate on the basis of histopathological features. Good prognostic markers are not available. In our search for new markers to differentiate malignant pheochromocytomas from benign ones we tested the value of inhibin/activin subunit expression. Inhibins are heterodimeric glycoproteins consisting of an -subunit and either a ßA- or a ßB-subunit. Activins are composed of ß-subunits only.

Immunohistochemically inhibin/activin ßB-subunit was strongly positive in the normal adrenal medulla, but the cortex was negative. A striking difference was found in inhibin/activin ßB expression between benign and malignant pheochromocytomas. The majority of benign adrenal tumors (27 of 30) showed strong or moderate immunoreactivity, whereas all seven malignant tumors were negative or only weakly positive for inhibin/activin ßB-subunit. The percentage of positively staining cells varied greatly in extraadrenal pheochromocytomas and in those benign tumors that showed over 5 mitoses/10 high power fields, necrosis, or capsular or vascular invasion, here called borderline tumors. Inhibin/activin ßB messenger ribonucleic acid was also found in pheochromocytomas. However, no significant differences in messenger ribonucleic acid levels were found in various types of tumors. Weak immunohistochemical positivity for inhibin/activin ßA-subunit was detected in the adrenal cortex, but the medulla and most of the pheochromocytomas were negative.

Our data show that inhibin/activin ßB-subunit is expressed in normal adrenal medullary cells. Strong staining is found in most benign adrenal pheochromocytomas, whereas malignant tumors are almost negative. This suggests that loss of inhibin/activin ßB-subunit expression in pheochromocytomas may be used as an indicator of malignant potential.

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