What cancers are associated with Multiple Endocrine Neoplasia (MEN)?

Cancers Associated with Multiple Endocrine Neoplasia (MEN) Syndromes

Multiple Endocrine Neoplasia syndromes are characterized by specific patterns of neuroendocrine tumors that vary by subtype, with MEN1 primarily associated with parathyroid adenomas, pancreatic neuroendocrine tumors, and pituitary tumors, while MEN2 is characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenomas. 1

MEN1 Associated Tumors

MEN1 is caused by pathogenic variants in the MEN1 gene on chromosome 11q13 and is characterized by:

Major Manifestations:

• Parathyroid adenomas (95% of patients) - most common presenting feature 1
• Pancreatic neuroendocrine tumors (40-75% of patients)
  • Gastrinomas (most common)
  • Insulinomas
  • VIPomas
  • Glucagonomas
  • Non-functioning pancreatic NETs
• Pituitary neuroendocrine tumors (30-55% of patients)
  • Prolactinomas (most common)
  • Growth hormone-secreting adenomas
  • Other pituitary tumors (<5% of cases)

Other Associated Tumors:

• Adrenocortical adenomas (35% of patients) 1
• CNS neoplasms (ependymomas and meningiomas) 1
• Carcinoid tumors (thymic and bronchial) 1
• Cutaneous manifestations (angiofibromas, lipomas, collagenomas) 1
• Leiomyomas 1

MEN2 Associated Tumors

MEN2 is caused by pathogenic variants in the RET proto-oncogene and is divided into two main subtypes:

MEN2A:

• Medullary thyroid carcinoma (MTC) - nearly 100% penetrance 1
• Pheochromocytoma (50% risk) 1
• Parathyroid adenomas/hyperplasia (20-30% risk) 1
• Cutaneous lichen amyloidosis (in some variants) 2
• Hirschsprung's disease (in some variants) 1, 2

MEN2B:

• Medullary thyroid carcinoma - earlier onset and more aggressive than in MEN2A 1
• Pheochromocytoma (50% risk) 1
• Mucosal neuromas (oral and ocular) 1
• Intestinal ganglioneuromatosis (40% of patients) 1
• No parathyroid involvement 1

MEN4 Associated Tumors

MEN4 is caused by pathogenic variants in the CDKN1B gene and features:

• Parathyroid tumors
• Pituitary adenomas
• Reproductive organ tumors
• Adrenal and renal tumors 1, 3

HPT-JT Syndrome Associated Tumors

HPT-JT Syndrome is caused by pathogenic CDC73 variants and includes:

• Parathyroid tumors (with higher malignancy potential)
• Ossifying fibromas of the jaw
• Renal tumors
• Uterine tumors 1

Clinical Implications and Screening

The tumor spectrum varies significantly between MEN subtypes, necessitating different surveillance approaches:

• For MEN1: Screening should begin as early as age 5 for prolactin and age 10 for calcium levels 1
• For MEN2: Prophylactic thyroidectomy is recommended based on RET mutation risk stratification, with highest risk mutations requiring surgery in infancy 1

Genotype-Phenotype Correlations

• MEN1 has no clear genotype-phenotype correlations 1
• MEN2 demonstrates strong genotype-phenotype correlations with specific RET mutations predicting disease aggressiveness and tumor spectrum 1, 2

Important Clinical Considerations

• Any individual with two or more MEN1-associated tumors should be referred for genetic testing 1
• Gastrinoma alone is sufficient to warrant genetic testing for MEN1 1
• Any patient with MTC should be evaluated for MEN2 1
• Early identification of mutation carriers allows for prophylactic interventions that can significantly reduce morbidity and mortality 1

The recognition of these tumor patterns is crucial for early detection and management of affected individuals, as well as for screening of at-risk family members.