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MC2024-06 and a Specialist in Radiosurgery at Mayo Clinic, a Facilitated Appointment Can Be Made by Calling Figure 3 MAYO CLINIC NEUROSCIENCE UPDATE 3 SPECIAL EDITION CLINICALUPDATE Focus on Endocrinology CURRENT TRENDS IN THE PRACTICE OF MEDICINE Treatment Strategies for Multiple Endocrine Neoplasia Type 1 Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder that Points to Remember affects tumorigenesis in at least 8 endocrine and nonendocrine tissues. The true prevalence of I The major clinical manifestations in MEN 1 is likely underestimated but varies from multiple endocrine neoplasia type 1 0.2 to 2 per 100,000 population. The major clinical (MEN 1) include the “3 Ps”: primary manifestations in MEN 1 include “the 3 Ps”: hyperparathyroidism, pancreatic and primary hyperparathyroidism (HPT), pancreatic duodenal neuroendocrine tumors, and and duodenal neuroendocrine tumors, and pituitary tumors. pituitary tumors (Figure 1). Expression of the disease rarely occurs before the age of 10 years, I MEN1 gene testing, most often using and most often the syndrome presents itself direct DNA sequencing, is clinically between the ages of 20 and 40 years. Two of the available in at least 4 molecular genetics 3 major lesions must be present to confirm the laboratories in North America. clinical diagnosis in a proband. In the members of I a known MEN 1 kindred, the presence of 1 major The preferred surgical approach for the MEN 1 patient with primary hyperparathyroidism is subtotal parathyroidectomy with transcervical Hyperprolactinemia thymectomy. Acromegaly Inside This Issue Cushing’s syndrome I Pancreatic and duodenal endocrine Minimally Invasive Primary HPT tumors remain the number 1 cause of Parathyroidectomy. 3 Nonmedullary tumor-related death in MEN 1 patients. thyroid tumors Percutaneous I Morbidity may be reduced and survival Ethanol Injection prolonged with early detection of to Treat Recurrent pancreatic and duodenal endocrine Differentiated Miscellaneous tumors tumors in at-risk MEN 1 family members, Thyroid Cancer . 5 Thymic carcinoids Lung carcinoids hence the importance of presymptomatic Adrenocortical tumors Skin lesions Stereotactic Functioning/nonfunctioning GI carcinoids testing. Radiosurgery for Patients lesion is diagnostic. Genetic testing confirms the With Pituitary clinical diagnosis. Adenomas . 6 The gene responsible for MEN 1 was identified in 1997 and is located on chromosome 11q13. The Islet cell tumors Functioning/nonfunctioning MEN1 gene encodes a nuclear protein referred to Duodenal carcinoids as menin. Menin interacts with other proteins (usually gastrin-producing, ZES) involved in transcription and cell growth. Therefore, MEN1 acts as a tumor suppressor gene. Figure 1. Manifestations of MEN 1. GI, gastrointestinal; MEN1 gene testing, most often using direct DNA HPT, hyperparathyroidism; ZES, Zollinger-Ellison syndrome. sequencing, is clinically available in at least MAYO CLINIC CLINICAL UPDATE 2 4 molecular genetics laboratories in North kindred members, and more than 80% of MEN 1 America. Germline mutations may be absent in up patients have histologic changes within the to 20% of indexed cases, and linkage analysis can be pancreas. All pancreatic and duodenal endocrine used to track the disease alleles through the family. tumors are capable of malignant transformation, and this is especially true for nonfunctioning Pituitary Tumors tumors. When discovered clinically, nearly 50% of Pituitary tumors in MEN 1 family members occur these tumors have metastasized to regional lymph less frequently than primary HPT or pancreatic nodes, liver, or both at the time of exploration. and duodenal neuroendocrine tumors. Up to 60% Insulinoma associated with endogenous of MEN 1 patients may develop pituitary hyperinsulinism is the most common functioning neoplasms. Mean age at diagnosis of the pituitary primary endocrine tumor in MEN 1 patients tumor is 38 years, with a range of 12 to 83 years. In younger than 25 years. Although these patients the majority of MEN 1 patients, the pituitary often have multiple pancreatic tumors, typically tumors are macroadenomas, most of which are only 1 or 2 of the tumors are the source of insulin prolactinomas (60%). Monitoring for pituitary excess. Although insulinomas are most often tumor development in patients with MEN 1 benign, there is no effective medical therapy, should include yearly measurement of serum and without surgery, including an extended prolactin and insulin-like growth factor 1 and distal pancreatectomy and pancreatic head imaging the pituitary by MRI every 2 to 3 years. tumor enucleation, hormonal sequelae remain Primary Hyperparathyroidism debilitating and life threatening. Most MEN 1 patients develop hypercalcemia and In MEN 1 patients, glucagonomas, VIPomas, primary HPT by the fourth decade of life. In and obviously malignant nonfunctioning tumors screened patients, HPT has been detected in warrant an aggressive surgical approach that patients as young as 19 years. Primary HPT is the includes an 80% distal pancreatectomy, splenectomy, initial clinical manifestation of MEN 1 in 60% to and lymphadenectomy, along with enucleation of 90% of patients, and the primary pathology is any residual tumors. Isolated liver metastases or a asymmetric hyperplasia or multiple adenomas finite number of multiple metastases can be involving all parathyroid glands. successfully managed with excellent control of The timing of parathyroidectomy is an important hormonal sequelae using a combination of hepatic issue. Primary HPT in MEN 1 patients involves all resection, radiofrequency thermoablation, and parathyroid tissue; thus, any treatment we provide hepatic artery embolization. Intramuscular is considered palliative at best. Attempts at octreotide and systemic chemotherapy can also be eradicating all parathyroid tissue can result in a used for palliation of advanced disease. treatment outcome far worse than the disease itself Gastrinomas are the most common functioning (permanent hypoparathyroidism). In patients with tumors in MEN 1 patients. Nearly one-third of mild disease, it is appropriate to delay surgery Zollinger-Ellison syndrome patients are MEN 1 until the serum calcium level is at least 1 mg/dL kindred members and more than 50% of MEN 1 higher than the upper limit of normal. patients have hypergastrinemia. Although medical The preferred surgical approach for an MEN 1 therapy with proton pump inhibitors is quite patient with primary HPT is subtotal parathyroid- effective for managing the hormonal effects of ectomy with transcervical thymectomy. Although gastrin excess, it does not prevent malignant recurrence rates are somewhat higher with this transformation and progression. More than 90% of approach compared with total parathyroidectomy gastrinomas in MEN 1 patients are duodenal in with immediate autotransplantation, the risk origin. The surgical approach involves a distal of permanent hypoparathyroidism is markedly pancreatectomy, lymphadenectomy, enucleation reduced (1%-2% vs 20%-30%). of residual tumors in the head of the pancreas, and exploratory duodenotomy to excise all visible and Pancreatic and Duodenal palpable duodenal carcinoid tumors. Neuroendocrine Tumors If you have questions about MEN 1 or if you Pancreatic and duodenal neuroendocrine tumors have a patient who might benefit from consultation represent the second most frequent classic with an endocrinologist and an endocrine surgeon manifestation in MEN 1 and remain the number at Mayo Clinic, a facilitated appointment can be 1 cause of tumor-related death. These neoplasms made by calling 800-313-5077. become clinically apparent in 50% to 75% of MAYO CLINIC CLINICAL UPDATE 3 Minimally Invasive Parathyroidectomy Primary hyperparathyroidism (HPT) is the most common cause of hyper- Points to Remember calcemia, affecting as many as 1 per I Minimally invasive parathyroidectomy may 1,000 women over the age of 60 years. be appropriate for up to two-thirds of Cure of primary HPT reliably benefits patients with primary hyperparathyroidism patients with osteoporosis or osteopenia undergoing initial surgical treatment. and those with subtle but clinically significant neuropsychiatric and I With minimally invasive muscular symptoms. These benefits parathyroidectomy, an outpatient may be expected regardless of the level procedure with local anesthesia is an Figure 1. The small, 3-cm incision of hypercalcemia, even when the serum option. site is locally anesthetized. calcium level is less than 11.0 mg/dL. Standard bilateral cervical exploration is I Minimally invasive parathyroidectomy is a safe and effective procedure, with a associated with a smaller incision, shorter cure rate higher than 95% and risk of hospitalization time, and faster recurrent laryngeal nerve damage or postoperative recovery. hypoparathyroidism of less than 1%. This high level of success in curing the disease and minimizing complications High-Quality Localization Techniques has led to patient-focused improvements The sensitivity and specificity of high-resolution, and has prompted a shift from standard real-time small parts ultrasonography are open surgical approaches to minimally approximately 70% and 90%, respectively, invasive techniques. Minimally invasive in adenoma localization, provided that highly parathyroidectomy (MIP) has emerged expert radiologists are performing the examination. as a popular method in endocrine surgery It is noninvasive and the most inexpensive (Figures 1-4). Several key advances preoperative localization technique. It is anatomically have facilitated the development of MIP: precise and capable
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