Class III β-tubulin isotype (β III) in the adrenal medulla: II. Localization in primary human pheochromocytomas

Background: The Class III β-tubulin isotype (β III) is expressed specifically in central and peripheral nervous system neurons at various stages of neuronal differentiation. We have shown previously that β III is expressed in a differentiation-dependent manner in human neuroblastomas arising in the adrenal medulla and sympathetic chains (Katsetos et al., Clin Neuropathol 13:241-255, 1994). The neuronal distribution of β III in the developing and mature human adrenal medullae is detailed in the companion article (Katsetos et al., 1998A). Methods: We have compared the localization of the neuronal β III to S-100 protein, a sustentacular cell marker, in 14 formalin-fixed, paraffin-embedded primary human pheochromocytomas of the adrenal medulla and 14 adrenocortical tumors (adenomas and carcinomas). Results: In pheochromocytomas, β III staining was present in all tumors, but the number of stained cells varied in the two neural neoplastic phenotypes. Although the majority of chromaffin-like cells were β III-positive, there was a lack of β III in one-third of the tumor cells. Compared to chromaffin- like phenotypes, neuronal (ganglion-like cells) were invariably β III- positive. Stromal sustentacular cells, stromal fibroblasts, and tumor blood vessels were β III-negative. Sustentacular cells in pheochromocytomas were S-100 protein-positive, but β III-negative. Primary adrenocortical tumors were β III-negative with the exception of rare β III-positive cells demonstrated in one case. Conclusions: The distribution of β III in human pheochromocytomas of the adrenal gland is differentiation-dependent, closely recapitulating chromaffin cell and neuronal phenotypes of the normal adrenal medulla. Our findings indicate that β III may be used as one of the adjuvant neural markers in the differential diagnosis of adrenal tumors, i.e., pheochromocytoma versus adrenocortical carcinoma. The occurrence of rare β III-positive cells in cortical carcinomas is exceptional and probably represents the acquisition of a divergent neuroendocrine phenotype. The significance of the latter is unclear, although it may constitute a marker for malignancy.