Multiple Endocrine Neoplasia Type 1

MEN 1 is a well-established inherited endocrine disorder characterized by parathyroid hyperplasia, pituitary adenoma, and pancreatic neuroendocrine tumors. Studies indicate that the genetic defect in patients with MEN 1 is localized to the long arm of chromosome 11 and linked to the skeletal muscle glycogen phosphorylase gene.20'21 Evidence from these studies suggests that the development of endocrine tumors in patients with MEN 1 conforms to Knudson's two-hit model of neoplasm formation with an inherited mutation in one chromosome unmasked by a somatic deletion or mutation of the other normal chromosome, thereby removing the suppressor effects of the normal gene.22 In contrast, in sporadic patients with pancreatic neuroendocrine tumors, tumors do not appear to develop by homozygous inactiva-tion of the same gene.21

Furthermore, growth factors have been identified in the plasma of patients with MEN 1. A circulating blood factor that was mitogenic for parathyroid cells in tissue culture has been identified,23 and a subsequent study demonstrated that the factor was similar to fibroblast growth factor.24 In addition, patients with MEN 1 are susceptible to other tumors, including bronchial, thymic, and intestinal carcinoid tumors; thyroid adenomas; adrenal adenomas; and multiple lipomas.14 Thus, the complete pathogenesis of the multiple endocrine tumors in MEN 1 patients is not completely understood.

In patients with MEN 1, primary hyperparathyroidism is the most common clinical condition, occurring in approximately 95% of individuals.14 Functional pancreatic neuroendocrine tumors are the next most common condition, occurring in approximately 80% of patients.14 Finally, approximately 35% of individuals with MEN 1 develop a pituitary adenoma, most commonly a prolactinoma.14 Gastrinoma and insulinoma are the most common functional neuroendocrine pancreatic tumors in MEN 1 patients, accounting for approximately 50% and 20% of the neuroendocrine tumor syndromes, respectively.25 Nonfunctional pancreatic endocrine tumors and pancreatic polypeptide (PP)-producing tumors (PPomas) may be the most common pancreatic neuroendocrine tumors in MEN 1 patients because these tumors are almost always identified on careful histologic studies of the pancreas.26'27 Of the rare pancreatic neuroendocrine tumors, MEN 1 is present in approximately 3% of patients with glucagonoma, 1% of patients with VIPoma, 33% of patients with tumors that secrete growth hormone-releasing factor (GRF) (GRFoma), and 5% of patients with somatostatinoma.14 Essentially, any pancreatic neuroendocrine tumor may occur in individuals with MEN 1; therefore, when evaluating a patient with a known neuroendocrine tumor, the possibility of unrecognized MEN 1 should be considered. The best way to determine the presence of MEN 1 is to question the patient carefully about family history, search for lipomas, and measure serum levels of calcium, gastrin, glucose, PP, and prolactin. If MEN 1 is present, multiple neuroendocrine tumors are identified within the pancreas,26 27 and resection of the neuroendocrine tumor and the portion of pancreas near it is indicated. Somatostatinomas and other rare pancreatic neuroendocrine tumors, unlike insulinomas, are almost always malignant.28"34 Therefore, in patients with localized, potentially curable disease, pancreatic resection—either Whipple's procedure for pancreatic head tumors or subtotal pancreatectomy for pancreatic body and tail tumors—is indicated.

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