Pheochromocytoma in multiple endocrine neoplasia type II: an example of the two-hit theory of neoplasia.

Six kindreds in which pheochromocytomas were present as manifestations of the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type II were studied. The patients underwent bilateral total adrenalectomy with the finding that the pheochromocytomas were bilateral, multifocal, and associated with distinct medullary hyperplasia and reduction in the normal corticomedullary ratio-- features not usually seen in patients with sporadic pheochromocytoma. These findings were exemplified in recent cases of a 34-year-old woman and a 40-year-old man who both had undergone total thyroidectomy for medullary carcinoma of the thyroid. Diagnoses of pheochromocytoma were made by catecholamine studies, computerized tomography, and 131I meta-iodobenzylguanidine (MIBG) scan. Bilateral adrenalectomy was performed with the finding of multiple bilateral pheochromocytomas and adrenal medullary hyperplasia. As in hereditary medullary carcinoma of the thyroid, the histologic findings in pheochromocytomas of the MEN II syndrome are consistent with Knudson's two-mutational-event theory for the initiation of neoplasia, with adrenal medullary hyperplasia representing the manifestation of the first or genetic mutational event and being present invariably in the hereditary cases.