Pancreas

• Autosomal dominant syndrome characterized by inactivating MEN1 gene mutations, leading to multiple endocrine tumors (NETs) and other tumor types
• Classic triad of pituitary, parathyroid and pancreatic tumors (the 3 Ps)

• MEN1 gene was first identified in 1997 and is located on chromosome 11q13 (Science 1997;276:404)
• Menin, the protein product of MEN1, is a tumor suppressor gene involved in regulating cell proliferation, apoptosis and maintaining genome integrity (F1000Res 2017;6:73)
• Menin is conserved across species, from Drosophila to humans; however, it does not show homology with any other known protein (Cancer Genet 2016;209:36)
• Truncation, frameshift, nonsense mutations or large deletions (including those in intronic areas leading to splice site defects) cause MEN1 gene loss and a lack of menin, resulting in uncontrolled endocrine cell proliferation
• 12 MEN1 gene mutations were initially identified and > 1,800 mutations have been identified to date (F1000Res 2017;6:73)
• 75% of MEN1 mutations are inactivating (F1000Res 2017;6:73)
• 5 - 20% of individuals may not harbor mutations in the MEN1 gene coding region, suggesting alternative genetic mechanisms (Cancer Genet 2016;209:36)
• 2 hit hypothesis suggests that germline MEN1 mutation combined with a somatic mutation leads to tumorigenesis
• There is no direct genotype phenotype correlation between the type of MEN1 mutation and the specific types of tumors that develop (F1000Res 2017;6:73)

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• Endocrine tumors are found in parathyroid, anterior pituitary, pancreas / gastrointestinal tract, adrenal cortex and thymus
• Parathyroid adenomas cause hypersecretion of parathyroid hormone (PTH), leading to hypercalcemia with symptoms such as gastrointestinal pain, cognitive dysfunction and renal stones
• Pituitary adenomas may cause visual field defects due to optic chiasm compression or extraocular muscle involvement
• Functional pituitary adenomas can cause Cushing disease (adrenocorticotropic hormone [ACTH] secreting tumors), Nelson syndrome (postadrenalectomy ACTH overproduction), acromegaly (excess growth hormone), hyperprolactinemia (prolactin secreting adenomas)
• Patients with gastrinomas, typically found in the duodenum, may have Zollinger-Ellison syndrome (excess stomach acid, severe peptic ulcers)
• Primary gastrinomas may be microadenomas but lymph node metastases can be much larger (J Pediatr Genet 2016;5:89)
• Tumors in the adrenal cortex and thymus can occur, though they are less common
• Nonendocrine tumors: skin lesions (angiofibromas, collagenomas), epididymomas, meningiomas

• Osteoporosis, terminal tuft erosion (distal phalanges) and nephrolithiasis in patients with parathyroid adenomas and hypercalcemia
• Calvarial thickening, frontal bossing, enlarged sinuses (especially frontal sinuses), enlarged sella turcica, prognathic mandible and increased vertebral fractures in patients with acromegaly due to pituitary adenoma
• PanNETs are usually well circumscribed, solid and avidly enhancing lesions (Radiol Clin North Am 2016;54:441)
• Sensitivity of imaging technique for PanNETs: endoscopic ultrasound (EUS) ~90%, computed tomography (CT) 63 - 82%, magnetic resonance imaging (MRI) 85 - 100% (AJR Am J Roentgenol 2021;217:245, Ann Gastroenterol 2015;28:193)

Contributed by R. Peter Powell, M.D.

AFIP images

Contributed by R. Peter Powell, M.D. and Wei Chen, M.D., Ph.D.

• MEN1 is an autosomal dominant disorder that is caused by mutations in the MEN1 gene, a tumor suppressor gene located on chromosome 11q13, which encodes the protein menin
• Over 1,500 germline and somatic MEN1 mutations (Neuroendocrinology 2021;111:609)
  • Germline mutations (inherited): heterozygous mutations are present in all cells of affected individuals
  • Somatic mutations (acquired): found in sporadic cases of parathyroid, pancreatic and pituitary tumors
  • Mutation types
    • Nonsense (30%) mutation leads to truncated, nonfunctional menin protein
    • Frameshift (40%) mutation disrupts protein reading frame, leading to loss of function
    • Missense (20%) mutation alters protein function without truncation
    • Large deletions / insertions (10%) result in complete gene loss
  • Other chromosome changes (e.g., translocations or amplifications in aggressive pancreatic neuroendocrine tumors)
• 2 hit hypothesis: first hit is germline MEN1 mutation; second hit is somatic deletion / mutation of the remaining normal MEN1 allele
• Fluorescence in situ hybridization (FISH), multiplex ligation dependent probe amplification (MLPA) and PCR sequencing can detect MEN1 deletions and mutations
• Diagnostic genetic testing for MEN1 mutations is recommended for family members of affected individuals or individuals with multiple MEN1 related tumors

A 38 year old man with a history of recurrent duodenal ulcers and nephrolithiasis presents for evaluation of new onset headaches and visual disturbances. His lab results reveal elevated parathyroid hormone (PTH), hypercalcemia, increased gastrin and prolactin levels. Which of the following is the most likely explanation for his symptoms?

1. Medullary thyroid carcinoma associated with RET mutation
2. Patient with MEN1 mutation and no tumor development at the time of evaluation
3. Patient with parathyroid adenoma, meningioma and epididymoma
4. Patient with parathyroid adenoma, pituitary adenoma and duodenopancreatic neuroendocrine tumor
5. Pituitary adenoma secreting adrenocorticotropic hormone (ACTH)

D. Patient with parathyroid adenoma, pituitary adenoma and duodenopancreatic neuroendocrine tumor. This patient's symptoms are most consistent with multiple endocrine neoplasia type 1 (MEN1), which is characterized by tumors of the parathyroid glands, pituitary gland and pancreatic / duodenal neuroendocrine tumors. The elevated PTH and hypercalcemia point toward a parathyroid tumor. The gastrin elevation and duodenal ulcer suggest a gastrinoma (duodenopancreatic neuroendocrine tumor). The elevated prolactin level suggests a pituitary adenoma. Answer E is incorrect because ACTH secreting pituitary adenomas lead to Cushing syndrome, not elevated prolactin level. Answer A is incorrect because medullary thyroid carcinoma (MTC) can be seen in MEN2, not MEN1. Answer B is incorrect because the patient's clinical signs and elevated gastrin, prolactin and PTH indicate the presence of tumors. Answer C is incorrect because meningiomas and epididymomas are not characteristic features of MEN1 meningiomas.

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Reference: MEN1 syndrome

A 45 year old woman presents with a history of recurrent kidney stones, fatigue and constipation. Laboratory studies show hypercalcemia, low phosphate levels and an elevated parathyroid hormone (PTH). Imaging evaluation shows an enlargement of the parathyroid gland and a well circumscribed pancreatic mass. Genetic testing confirms a mutation in the MEN1 gene. Which of the following best describes the function of the gene mutated in this patient?

1. DNA repair gene
2. Gene encoding a protein involved in calcium sensing
3. Oncogene encoding a receptor tyrosine kinase
4. Proto-oncogene involved in cell cycle progression
5. Tumor suppressor gene involved in transcription regulation

E. Tumor suppressor gene involved in transcription regulation. The MEN1 gene encodes menin, a tumor suppressor protein that regulates transcription and is involved in cellular proliferation and survival. Mutations in MEN1 lead to the development of endocrine tumors, commonly in the parathyroid glands, pancreas and pituitary glands. The patient's symptoms, including hypercalcemia, elevated PTH, enlargement of the parathyroid gland and a pancreatic mass, are consistent with MEN1 and its associated tumors, such as parathyroid adenomas and pancreatic neuroendocrine tumors. Answer D is incorrect because the MEN1 gene is a tumor suppressor gene. MEN1 mutations result in the loss of tumor suppression. Answer C is incorrect because oncogenes typically encode proteins that promote cell division or survival via receptor tyrosine kinases or other growth factors. However, MEN1 is a tumor suppressor gene. Answer B is incorrect because the MEN1 gene does not directly encode a protein involved in calcium sensing. Answer A is incorrect because the MEN1 gene is not directly involved in DNA repair.

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Reference: MEN1 syndrome