Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder that affects tumorigenesis in at least 8 types of endocrine and nonendocrine tissues.
Geoffrey B. Thompson, M.D., of the Department of Surgery at Mayo Clinic, says: "The true prevalence of MEN 1 is likely underestimated but varies from 0.2 to 2.0 per 100,000 people. The major clinical manifestations in MEN 1 include the 3 P's:
"Expression of the disease rarely occurs before age 10 years, and most often, the syndrome presents between the ages of 20 and 40 years. Two of the 3 major lesions must be present for the clinical diagnosis in a proband. In family members of a known MEN 1 kindred, however, the presence of 1 major lesion is diagnostic. Clinical diagnosis is confirmed with genetic testing."
Noralane M. Lindor, M.D., of the Department of Medical Genetics at Mayo Clinic, says: "The gene responsible for MEN 1 (MEN1) was identified in 1997 and is located on chromosome 11q13. MEN1 encodes a nuclear protein referred to as menin. Menin acts as a tumor suppressor gene to influence gene transcription, cell proliferation, apoptosis, and genomic instability.
"More than 400 different mutations have been reported to date, with no clinically useful genotype-phenotype correlations confirmed. Of these mutations, 90% are inherited and 10% arise de novo. MEN1 mutational analysis is clinically available and has about a 90% detection rate. In kindreds with undetectable mutations, linkage analysis may still be utilized to track the disease alleles through the family."
Pituitary tumors in MEN 1 family members are less frequent than primary HPT or pancreatic and duodenal neuroendocrine tumors.
William F. Young Jr., M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic, explains: "Pituitary neoplasms may develop in up to 60% of MEN 1 patients. The mean age at diagnosis of the pituitary tumor is 38 years, with a range from 12 to 83 years.
"In the majority of MEN 1 patients, the pituitary tumors are macroadenomas, most (60%) of which are prolactinomas. Monitoring for pituitary tumor development in MEN 1 should include measurement of serum prolactin and insulinlike growth factor 1 concentrations yearly and imaging the pituitary with magnetic resonance imaging every 2 to 3 years."
Most MEN 1 patients will have hypercalcemia and primary HPT by the fourth decade of life. In screened patients, the mean age at detection of HPT has been reported to be as low as 19 years.
Dr. Thompson notes: "Primary HPT is the initial clinical and biochemical manifestation of MEN 1 in 60% to 90% of patients. In MEN 1 patients, the pathologic features are that of asymmetrical hyperplasia or multiple adenomas involving all parathyroid glands. The timing of parathyroidectomy is an important issue. MEN 1-related primary HPT involves all parathyroid tissue, and thus any treatment we provide is considered palliative at best. Attempts at eradicating all parathyroid tissue can result in a treatment that is far worse than the disease (resulting in permanent hypoparathyroidism).
"In patients with mild disease, it is appropriate to delay surgery until the serum calcium level is 1 mg/dL or more above the upper limit of the reference range. The preferred surgical approach for a MEN 1 patient with primary HPT is a subtotal parathyroidectomy with transcervical thymectomy. Although recurrence rates are somewhat higher than for total parathyroidectomy with immediate autotransplantation, the risk of permanent hypoparathyroidism is markedly reduced (1% to 2% versus 20% to 30%)."
Pancreatic and duodenal neuroendocrine tumors represent the second most frequent manifestation in MEN 1 and continue to be the No. 1 cause of tumor-related death.
Dr. Thompson highlights: "Pancreatic and duodenal neuroendocrine neoplasms become clinically apparent in 50% to 75% of kindred family members, and more than 80% of MEN 1 patients have histologic changes within the pancreas. Insulinoma associated with endogenous hyperinsulinism is the most common functioning pancreatic neuroendocrine tumor in MEN 1 patients younger than 25 years. Although these patients often have multiple pancreatic tumors, typically only 1 or 2 tumors are the source of insulin excess.
"All pancreatic and duodenal endocrine tumors are capable of malignant transformation, and this capability is especially true for nonfunctioning tumors. MEN 1 patients with glucagonomas, neuroendocrine tumors that hypersecrete vasoactive intestinal polypeptide, and obviously malignant nonfunctioning tumors warrant an aggressive surgical approach that includes an 80% distal pancreatectomy, splenectomy, and lymphadenectomy, along with enucleation of any residual tumors.
"Isolated liver metastases or a finite number of multiple metastases can be successfully managed with excellent control of hormonal sequelae through a combination of hepatic resection, radiofrequency thermoablation, and hepatic artery embolization. Octreotide and systemic chemotherapy can also be used for palliation of advanced disease."
Gastrinomas represent the most common functioning tumors in MEN 1 patients. Nearly one-third of patients with Zollinger-Ellison syndrome are MEN 1 kindred members and more than 50% of MEN 1 patients have hypergastrinemia.
Dr. Thompson explains: "Although medical therapy with proton pump inhibitors is effective for managing the hormonal sequelae of gastrin excess, it does nothing to prevent malignant transformation or progression, or both. More than 90% of gastrinomas in MEN 1 patients are duodenal in origin. The surgical approach involves a distal pancreatectomy, lymphadenectomy, enucleation of residual tumors in the head of the pancreas, and an exploratory duodenotomy to excise all visible and palpable duodenal carcinoid tumors."