Multiple endocrine neoplasia type 1 (MEN1) is characterized by the development 
of endocrine tumors of the parathyroid and pituitary glands, pancreas, and 
duodenum. Less frequently occurring tumors associated with MEN1 include 
non-endocrine tumors such as lipomas and angiofibromas. An increased incidence 
of thyroid neoplasms, leiomyomas, adrenal cortical hyperplasia, hepatic focal 
nodular hyperplasia, and renal angiomyolipoma has been noted in the MEN1 
population. The pathogenesis of non-neuroendocrine tumors in MEN1 is unknown. We 
report a complex clinical course and a detailed morphologic and genetic analysis 
of a series of tumors that developed in a patient with MEN1. All tumors were 
microdissected and analyzed for loss of heterozygosity of the MEN1 gene. A 
germline mutation of the MEN1 gene was detected, and deletions of the MEN1 gene 
were consistently detected in multiple neuroendocrine tumors involving the 
parathyroid glands and the pancreas and a hepatic neuroendocrine tumor 
metastasis, as predicted by Knudson's "two hit" hypothesis. Two hits of the MEN1 
gene were also detected in esophageal leiomyoma tissue, suggesting that 
tumorigenesis was directly related to the patient's underlying MEN1. In 
contrast, follicular thyroid adenoma, papillary thyroid carcinoma, hepatic focal 
nodular hyperplasia, and adrenal cortical hyperplasia consistently showed 
retained heterozygosity of the MEN1 gene with flanking markers and an intragenic 
marker. Therefore, these tumors appear to develop along pathogenetic pathways 
that are different from classical MEN1-associated tumors.