Multiple Endocrine Neoplasia Type 1 (MEN1) Diagnosis and Management

Definition and Prevalence

• Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare genetic disorder with an estimated prevalence of 1:20,000-40,000 in the general population 1
• Disease penetrance for a first manifestation among MEN1 carriers is high: 45% by age 30, 82% by age 50, and 96% by age 70 1

Major Clinical Features

• Primary hyperparathyroidism (PHPT) is the most common manifestation, occurring in 95% of MEN1 patients, typically presenting as parathyroid adenomas (usually multiglandular) 1, 2
• Pancreatic neuroendocrine tumors occur in 40-75% of patients, including gastrinomas, insulinomas, and other rare types 1, 2

Genetics

• MEN1 is caused by pathogenic variants in the MEN1 tumor-suppressor gene located on chromosome 11q13 1, 2
• The gene encodes the protein menin, which functions in cell-cycle control, transcriptional regulation, and maintenance of genomic stability 1

Diagnostic Criteria

• Clinical diagnosis of MEN1 is predicated on the identification of at least two of the major constituent tumors 1, 2
• Genetic testing is indicated for any person with two or more constituent MEN1 tumors, or any person with one MEN1 tumor and a first-degree relative with MEN1 3

Surveillance Recommendations

• Early detection through surveillance is critical as delays in diagnosis are associated with increased morbidity and mortality 4
• Surveillance should begin at an early age, as tumors have been diagnosed as young as 5 years old 1

Special Considerations

• MEN1 was previously thought to be an adult-onset disorder, but 17% of MEN1-associated tumors are diagnosed before age 21 1
• Recent data suggest that 42% of MEN1 patients in the second decade of life may possess clinically occult (non-functioning) pancreatic NETs 1

Pitfalls to Avoid

• Failing to screen for other MEN1-associated tumors when one component is identified, especially in young patients 3

Management of Multiple Endocrine Neoplasia Type 1 (MEN1)

Diagnosis and Screening

• The American College of Medical Genetics recommends genetic testing for MEN1 mutation in first-degree relatives of patients with MEN1, given the autosomal dominant inheritance pattern 5, 6
• The National Comprehensive Cancer Network (NCCN) suggests that patients with MEN1 should undergo biochemical screening for pancreatic islet cell tumors every 2 years, starting from age 5 7, 8
• The Journal of Internal Medicine recommends measurement of total calcium (corrected for serum albumin) as part of the screening protocol for MEN1 9

Surgical Management

• The NCCN recommends complete resection of functional and non-functional pancreatic tumors >2 cm, with negative margins and regional lymph node dissection 8
• The Journal of Internal Medicine suggests that insulinomas should be resected regardless of size due to metabolic complications (hypoglycemia) 8
• The Clinical Cancer Research journal recommends parathyroidectomy (subtotal or total) for hyperparathyroidism in MEN1 patients, in consultation with an endocrinologist and consideration of referral to a high-volume parathyroid surgeon 9, 10

Medical Management

• The NCCN recommends somatostatin analogs, targeted radionuclide therapy, locoregional treatments (ablation, chemoembolization), and chemotherapy for advanced or metastatic disease 8, 5
• The Gut journal suggests that sunitinib or everolimus may be used for progressive advanced disease 5

Multidisciplinary Approach

• The Gut journal recommends that management of MEN1 should be performed in multidisciplinary teams in referral centers, including specialists in neuroendocrine tumors, surgeons, radiologists, nuclear medicine specialists, histopathologists, and clinical nurse specialists 5, 8, 9

Management of Multiple Endocrine Neoplasia (MEN) Syndrome

Diagnostic Workup

• Biochemical screening must include serum calcium, parathyroid hormone, chromogranin A, and gastrin, as recommended by the European Neuroendocrine Tumor Society, for accurate diagnosis and management of MEN syndrome 11
• Imaging studies should employ a multimodality approach, including CT or MRI of abdomen for pancreatic tumors, somatostatin receptor scintigraphy for detecting metastases, and endoscopic ultrasound for small pancreatic lesions, as suggested by the National Comprehensive Cancer Network (NCCN) 11

Medical Management

• Chemotherapy may be considered for aggressive tumors in patients with unresectable or metastatic disease, according to the American Society of Clinical Oncology (ASCO) 11

Critical Organizational Structure

• Coordinate care through specialized centers with a multidisciplinary team, including endocrinologists, dedicated endocrine surgeons, clinical geneticists, radiologists, and specialized nurse coordinators, as recommended by the Endocrine Society 12, 13, 14
• Assign specialized paramedics or nurse coordinators to guarantee periodic examination, coordinate nationwide guidance, and prevent interruption of surveillance that delays intervention and worsens outcomes, as suggested by the European Society of Endocrinology 12, 13, 14
• Provide patient education materials through newsletters, internet resources, and patient support groups to address emotional distress and practical issues regarding employment and insurance, according to the American Cancer Society 14

Prevention of Common Pitfalls

• Never delay referral for suspected hereditary endocrine syndromes, as interruption of surveillance affects quality of life and impairs life expectancy, as recommended by the National Institute of Health (NIH) 14

Associated Tumor Types and Extrapancreatic Manifestations in MEN 1

Pancreatic Neuroendocrine Tumor Subtypes

• VIPomas, glucagonomas, and other rare functional pancreatic neuroendocrine tumor subtypes have been reported in individuals with MEN 1, although they are far less common than gastrinomas and insulinomas. 15

Pituitary Tumor Spectrum

• Non‑prolactin‑secreting pituitary adenomas represent fewer than 5 % of all pituitary tumors observed in MEN 1 patients. 15

Dermatologic Manifestations

• Cutaneous angiofibromas, lipomas, and collagenomas are frequent skin findings in MEN 1 carriers. 15

Adrenal Findings

• Adrenocortical adenomas are identified in approximately 35 % of individuals with MEN 1. 15