title: Increased expression of cyclooxygenase-2 in malignant pheochromocytomas.
abstract: Pheochromocytomas are rare tumors of the adrenal medulla or the paraganglion system. There are no histological or chemical markers available that define the malignant behavior of these tumors; so far only the discovery of metastases reveals malignancy. Cyclooxygenase (Cox) is the key enzyme in conversion of arachidonic acid to PGs, and two isoforms, Cox-1 and Cox-2, have been identified. Cox-2 has been associated with carcinogenesis, and it is overexpressed in many human malignancies. We have now investigated the expression 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 the medulla was negative as detected by immunohistochemistry. Interestingly, all malignant pheochromocytomas (n = 8), regardless of the primary location of the tumor, showed moderate or strong Cox-2 immunoreactivity, whereas 75% of the benign adrenal tumors (n = 36) showed no or only weak immunopositivity. The staining was negative or weak in 79% of the adrenal tumors that showed histologically suspicious features (n = 24), but had not metastasized. Most of the pheochromocytoma samples studied also expressed low levels of Cox-2 mRNA. Our data show that normal adrenal medulla does not express Cox-2 immunohistochemically. However, strong Cox-2 protein expression was found in malignant pheochromocytomas, whereas most benign tumors expressed Cox-2 only weakly. To our knowledge, this is the first report on Cox-2 expression in pheochromocytomas and enhanced expression in malignant pheochromocytomas. These findings suggest that negative or weak Cox-2 expression in pheochromocytomas favors benign diagnosis.
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki and HUCH Laboratory Diagnostics, Helsinki University Central Hospital, FIN-00014 Helsinki, Finland. kasai.salmenkivi@helsinki.fi
authors.forename: K
authors.initials: K
authors.lastname: Salmenkivi
authors.forename: C
authors.initials: C
authors.lastname: Haglund
authors.forename: A
authors.initials: A
authors.lastname: Ristimäki
authors.forename: J
authors.initials: J
authors.lastname: Arola
authors.forename: P
authors.initials: P
authors.lastname: Heikkilä
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000201:enzymology* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015152:Blotting, Northern; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D010673:Pheochromocytoma / Q000201:enzymology* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases