Overlapping expression of immunohistochemical markers and synaptophysin mRNA in pheochromocytomas and adrenocortical carcinomas. Implications for the differential diagnosis of adrenal gland tumors.

BACKGROUND: The differential diagnosis of cortical versus medullary tumors of the adrenal gland may be a problem in diagnostic pathology. Conflicting results have been reported about the distribution of various immunohistochemical markers in the normal as well as neoplastic adrenal cortex and medulla.

EXPERIMENTAL DESIGN: Archival, formaldehyde-fixed, and paraffin-embedded material comprising 27 adrenocortical carcinomas (ACC, meeting Weiss' histologic criteria), 28 pheochromocytomas (PCC), and adjacent nontumorous tissue (13 glands) were analyzed by immunogold-silver staining for the expression of polysialic acid (poly Sia), cytokeratins (CK), synaptophysin (SYN), chromogranin A (CrgA), somatostatin (SOM), calcitonin (CT), and the "adrenocortical marker" D11. Further, SYN mRNA expression was studied by nonradioactive in situ hybridization using digoxigenin-labeled oligonucleotide probes.

RESULTS: In the normal adrenal gland, poly Sia was exclusively detected in the medulla and in cortical nerves. In ACCs, SYN immunoreactivity was present in 23 of 27 tumors (85%), D11 was present in 22 of 27 (81%), poly Sia was present focally in 8 of 27 (29%), and CK was present in 7 of 27 (25%). Synthesis of SYN in ACCS was demonstrated by mRNA in situ hybridization. Immunoreactivity for CrgA, SOM, or CT was not detectable. No difference of the marker profiles was seen in the nine clinically hormone-producing (three androgen, five corticosteroid, one mineralocorticoid) ACCs compared with the clinically silent tumors. In PCCs, all 28 tumors were immunoreactive for poly Sia and SYN; CrgA was detectable in 26 of 28 (93%), CT was detectable in 6 of 28 (21%), and SOM was detectable in 2 of 28 (7%) tumors. Staining for D11 or CK was undetectable. By immunohistochemistry, no distinction was possible between the 4 clinically malignant, the 6 multiple endocrine neoplasia type 2A-associated, and the 18 sporadic benign PCCs.

CONCLUSIONS: Poly Sia of the neural cell adhesion molecule is consistently detected in normal adrenal medullary cells as well as in PCCs, and is occasionally focally expressed in ACCs. CrgA, CK, and D11 are reliable markers to immunohistochemically distinguish ACC from PCC. Immunoreactivity for SYN and detection of its mRNA in the majority of ACCs indicates the existence of tumor cells sharing both cortical and medullary features. Such focal neuroendocrine differentiation in ACCs can lead to confusion with PCCs.