Inhibin/activin beta B-subunit expression in pheochromocytomas favors benign diagnosis

Malignancy of pheochromocytomas is difficult to estimate on the basis of hi stopathological features. Good prognostic markers are not available. In our search for new markers to differentiate malignant pheochromocytomas from b enign ones we tested the value of inhibin/activin subunit expression. Inhib ins are heterodimeric glycoproteins consisting of an alpha -subunit and eit her a betaA- or a betaB-subunit. Activins are composed of beta -subunits on ly. Immunohistochemically inhibin/activin betaB-subunit was strongly positive i n the normal adrenal medulla, but the cortex was negative. A striking diffe rence was found in inhibin/activin betaB expression between benign and mali gnant pheochromocytomas. The majority of benign adrenal tumors (27 of 30) s howed strong or moderate immunoreactivity, whereas all seven malignant tumo rs were negative or only weakly positive for inhibin/activin betaB-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 betaB messenger ribonucleic acid was al so found in pheochromocytomas. However, no significant differences in messe nger ribonucleic acid levels were found in various types of tumors. Weak im munohistochemical positivity for inhibin/activin betaA-subunit was detected in the adrenal cortex, but the medulla and most of the pheochromocytomas w ere negative. Our data show that inhibin/activin betaB-subunit is expressed in normal adr enal medullary cells. Strong staining is found in most benign adrenal pheoc hromocytomas, whereas malignant tumors are almost negative. This suggests t hat loss of inhibin/activin betaB-subunit expression in pheochromocytomas m ay be used as an indicator of malignant potential.