Increased expression of cyclooxygenase-2 in malignant pheochromocytomas

Pheochromocytomas are rare tumors of the adrenal medulla or the paraganglio n system. There are no histological or chemical markers available that defi ne the malignant behavior of these tumors; so far only the discovery of met astases reveals malignancy. Cyclooxygenase (Cox) is the key enzyme in conve rsion of arachidonic acid to PGs, and two isoforms, Cox-1 and Cox-2, have b een identified. Cox-2 has been associated with carcinogenesis, and it is ov erexpressed in many human malignancies. We have now investigated the expres sion of Cox-2 in normal adrenal gland, in 92 primary pheochromocytomas and in six metastases using immunohistochemistry and Northern blot and Western blot analyses. Cox-2 protein was expressed in the adrenal cortex, whereas t he medulla was negative as detected by immunohistochemistry. Interestingly, all malignant pheochromocytomas (n = 8), regardless of the primary locatio n of the tumor, showed moderate or strong Cox-2 immunoreactivity, whereas 7 5% of the benign adrenal tumors (n = 36) showed no or only weak immunoposit ivity. The staining was negative or weak in 79% of the adrenal tumors that showed histologically suspicious features (n = 24), but had not metastasize d. Most of the pheochromocytoma samples studied also expressed low levels o f Cox-2 mRNA. Our data show that normal adrenal medulla does not express Cox-2 immunohist ochemically. However, strong Cox-2 protein expression was found in malignan t pheochromocytomas, whereas most benign tumors expressed Cox-2 only weakly . To our knowledge, this is the first report on Cox-2 expression in pheochr omocytomas and enhanced expression in malignant pheochromocytomas. These fi ndings suggest that negative or weak Cox-2 expression in pheochromocytomas favors benign diagnosis.