2005

Treatment Strategies for Multiple Endocrine Neoplasia Type 1

Points to Remember

• The major clinical manifestations in multiple endocrine neoplasia type 1 (MEN 1) include the "3 Ps": primary hyperparathyroidism, pancreatic and duodenal neuroendocrine tumors, and pituitary tumors.
• MEN1 gene testing, most often using direct DNA sequencing, is clinically available in at least 4 molecular genetics laboratories in North America.
• The preferred surgical approach for the MEN 1 patient with primary hyperparathyroidism is subtotal parathyroidectomy with transcervical thymectomy.
• Pancreatic and duodenal endocrine tumors remain the number 1 cause of tumor-related death in MEN 1 patients.
• Morbidity may be reduced and survival prolonged with early detection of pancreatic and duodenal endocrine tumors in at-risk MEN 1 family members, hence the importance of presymptomatic testing.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder that affects tumorigenesis in at least 8 endocrine and nonendocrine tissues. The true prevalence of MEN 1 is likely underestimated but varies from 0.2 to 2 per 100,000 population. The major clinical manifestations in MEN 1 include "the 3 Ps": primary hyperparathyroidism (HPT), pancreatic and duodenal neuroendocrine tumors, and pituitary tumors (Figure 1). Expression of the disease rarely occurs before the age of 10 years, and most often the syndrome presents itself between the ages of 20 and 40 years. Two of the 3 major lesions must be present to confirm the clinical diagnosis in a proband. In the members of a known MEN 1 kindred, the presence of 1 major lesion is diagnostic. Genetic testing confirms the clinical diagnosis.

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The gene responsible for MEN 1 was identified in 1997 and is located on chromosome 11q13. The MEN1 gene encodes a nuclear protein referred to as menin. Menin interacts with other proteins involved in transcription and cell growth. Therefore, MEN1 acts as a tumor suppressor gene. MEN1 gene testing, most often using direct DNA sequencing, is clinically available in at least 4 molecular genetics laboratories in North America. Germline mutations may be absent in up to 20% of indexed cases, and linkage analysis can be used to track the disease alleles through the family.

Pituitary Tumors

Pituitary tumors in MEN 1 family members occur less frequently than primary HPT or pancreatic and duodenal neuroendocrine tumors. Up to 60% of MEN 1 patients may develop pituitary neoplasms. Mean age at diagnosis of the pituitary tumor is 38 years, with a range of 12 to 83 years. In the majority of MEN 1 patients, the pituitary tumors are macroadenomas, most of which are prolactinomas (60%). Monitoring for pituitary tumor development in patients with MEN 1 should include yearly measurement of serum prolactin and insulin-like growth factor 1 and imaging the pituitary by MRI every 2 to 3 years.

Primary Hyperparathyroidism

Most MEN 1 patients develop hypercalcemia and primary HPT by the fourth decade of life. In screened patients, HPT has been detected in patients as young as 19 years. Primary HPT is the initial clinical manifestation of MEN 1 in 60% to 90% of patients, and the primary pathology is asymmetric hyperplasia or multiple adenomas involving all parathyroid glands.

The timing of parathyroidectomy is an important issue. Primary HPT in MEN 1 patients involves all parathyroid tissue; thus, any treatment we provide is considered palliative at best. Attempts at eradicating all parathyroid tissue can result in a treatment outcome far worse than the disease itself (permanent hypoparathyroidism). In patients with mild disease, it is appropriate to delay surgery until the serum calcium level is at least 1 mg/dL higher than the upper limit of normal.

The preferred surgical approach for an MEN 1 patient with primary HPT is subtotal parathyroidectomy with transcervical thymectomy. Although recurrence rates are somewhat higher with this approach compared with total parathyroidectomy with immediate autotransplantation, the risk of permanent hypoparathyroidism is markedly reduced (1%-2% vs 20%-30%).

Pancreatic and Duodenal Neuroendocrine Tumors

Pancreatic and duodenal neuroendocrine tumors represent the second most frequent classic manifestation in MEN 1 and remain the number 1 cause of tumor-related death. These neoplasms become clinically apparent in 50% to 75% of kindred members, and more than 80% of MEN 1 patients have histologic changes within the pancreas. All pancreatic and duodenal endocrine tumors are capable of malignant transformation, and this is especially true for nonfunctioning tumors. When discovered clinically, nearly 50% of these tumors have metastasized to regional lymph nodes, liver, or both at the time of exploration.

Insulinoma associated with endogenous hyperinsulinism is the most common functioning primary endocrine tumor in MEN 1 patients younger than 25 years. Although these patients often have multiple pancreatic tumors, typically only 1 or 2 of the tumors are the source of insulin excess. Although insulinomas are most often benign, there is no effective medical therapy, and without surgery, including an extended distal pancreatectomy and pancreatic head tumor enucleation, hormonal sequelae remain debilitating and life threatening.

In MEN 1 patients, glucagonomas, VIPomas, 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 using a combination of hepatic resection, radiofrequency thermoablation, and hepatic artery embolization. Intramuscular octreotide and systemic chemotherapy can also be used for palliation of advanced disease.

Gastrinomas are the most common functioning tumors in MEN 1 patients. Nearly one-third of Zollinger-Ellison syndrome patients are MEN 1 kindred members and more than 50% of MEN 1 patients have hypergastrinemia. Although medical therapy with proton pump inhibitors is quite effective for managing the hormonal effects of gastrin excess, it does not prevent malignant transformation and progression. 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 exploratory duodenotomy to excise all visible and palpable duodenal carcinoid tumors.