Multiple Endocrine Neoplasias - MEN

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Content

Multiple Endocrine Neoplasia 1 (MEN1)

Indications for Testing

  • Diagnostic testing for patients with clinical or biochemical evidence diagnosis of MEN1
  • Presymptomatic testing of at-risk family members is advised when a specific MEN1 mutation has been identified in an affected relative

Laboratory Testing

  • Initial biochemical testing can identify tumor presence
    • Carcinoid tumor – testing depends on tumor location
      • ACTH, gastrin, βhCG, somatostatin, pancreatic polypeptide, serotonin, histamine, tachykinins
    • Parathyroid tumor – calcium and parathyroid hormone (PTH)
    • Gastrinoma tumor – gastrin and gastric acid output measures
    • Insulinoma and other pancreatic tumors – chromogranin A, glucagon, serum insulin, and C-peptide levels
    • Anterior pituitary tumor – prolactin and insulin-like growth factor-1 (IGF-1); additional anterior pituitary testing based on symptoms
    • Pheochromocytoma – metanephrines
    • VIPoma – vasoactive intestinal peptide
  • Genetic testing
    • MEN1 mutation analysis
      • Confirms MEN1 
      • Likelihood of detecting a germline MEN1 mutation increases in proportion to the number of main tumors found in patient
        • MEN1 mutation seldom found in patient with no family history and single MEN1-associated tumor
      • ~20-55% of families with familial isolated hyperparathyroidism (FIHP) have germline MEN1 mutations
      • If the specific familial mutation has already been identified in a relative, testing can be performed on at-risk family members using familial mutation targeted sequencing
    • For patients with overlap symptoms or MEN1 presentation without MEN1 gene, consider testing for CDKN1B (MEN4)

MEN2A and 2B

Indications for Testing

  • Typical tumor presentation (MTC or pheochromocytoma) and family history

Laboratory Testing

  • Biochemical testing
  • Genetic testing
    • RET mutation analysis 
      • Confirms presence of mutation in patient with MTC or pheochromocytoma
      • Presymptomatic testing of at-risk family members
      • For additional RET information, please refer to ARUP's MEN2 and RET database, which documents RET sequence changes relevant to MEN2 syndromes

Familial Medullary Thyroid Carcinoma (FMTC)

Indications for Testing

  • Family history of MTC in multiple generations without the presence of pheochromocytoma or parathyroid adenoma/hyperplasia

Laboratory Testing

  • RET mutation analysis to confirm a clinical diagnosis and allow for presymptomatic testing of family members

Multiple Endocrine Neoplasia 1 (MEN1)

  • Periodic screening for MEN1-associated endocrine tumors beginning in early childhood and continuing for life (NCCN, 2014)
    • Consider annual testing for the following
      • Parathyroid tumor
      • Pancreatic neuroendocrine tumor
      • Bronchial carcinoid/thymic carcinoid previously
        • Chest imaging at 1-3 years
      • Pituitary
        • Previous pituitary – MRI at 3-5 years
        • No previous pituitary
          • IGF-1
        • Prolactin
  • Risk for malignant progression of MEN1-associated tumors depends on tumor type
    • Malignancy uncommon before early adulthood

Multiple Endocrine Neoplasia 2 (MEN2)

Multiple endocrine neoplasia (MEN) syndromes are characterized by tumors involving multiple endocrine glands. Subtypes MEN1 and MEN2 are distinguished by clinical features and molecular testing. MEN2 includes the additional subtypes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). 

MEN1 (Wermer Syndrome)

Epidemiology

  • Incidence – 1/30,000
  • Age – onset is 20-45 years

Inheritance

  • Autosomal dominant inheritance – 10% of mutations are de novo
  • Germline mutations in the MEN1 gene on 11q13 are causative
    • Sequence analysis of MEN1 detects a germline mutation in 80-90% of familial cases and 65% of simplex patients (ie, a single occurrence of MEN1 syndrome in a family)
    • Approximately 1-4% of MEN1 mutations are large deletions
  • Variable expressivity
    • Penetrance for clinical features is age-related – 50% by 20 years and above 95% by 40 years
  • Genotype/phenotype associations have not been identified in MEN1

Clinical Presentation

  • Parathyroid tumors
    • Primary hyperparathyroidism develops in ~100% of patients by age 50
    • Typically involves all four parathyroid glands (unlike sporadic disease)
    • Signs – hypercalcemia, hyperparathyroidism
    • Symptoms – fatigue, anorexia, polydipsia, polyuria, bone lesions, abdominal pain, kidney stones
  • Gastroenteropancreatic (GEP) tumors
    • Develop in 20-55% of patients
    • Some are nonfunctional tumors
    • If functional tumor, symptoms depend on specific tumor type
      • Gastrinoma (~40%) – Zollinger-Ellison syndrome
        • Peptic ulcer disease, recurrent diarrhea, abdominal pain
      • Insulinoma (~10%) – pancreatic islet tumors; usually multiple
        • Hypoglycemia and related symptoms
      • Carcinoid tumors (~10%) – carcinoid syndrome
        • Flushing, wheezing, diarrhea, carcinoid heart disease
      • VIPoma (~2%) – Verner-Morrison syndrome
        • Watery diarrhea, hypokalemia, achlorhydria
      • Glucagonoma (~2%)
        • Hyperglycemia, skin rash, anorexia, diarrhea
  • Anterior pituitary tumors
    • 10-60% of patients; symptoms depend on the pituitary hormone produced
      • Prolactinoma (~20%) – most common
        • Females – amenorrhea and galactorrhea
        • Males – impotence or reduced libido
      •  Growth hormone tumor (~5%)
      •  Combination – prolactinoma/growth hormone tumor (~5%)
        • Combined symptoms
      •  Adrenal tumors (~2-5%) – most nonfunctioning
  • Other endocrine tumors
  • Non-endocrine tumors
    • Cutaneous tumors
      • Collagenoma and facial angiofibromas – 70-85% of patients
      • Lipomas – 30% of patients
      • Malignant melanoma
    • Central nervous system tumors
    • Muscle tumors
      • Leiomyomas

MEN2

Epidemiology

  • Incidence – 1/35,000
    • MEN2A – 70-80% of cases
    • FMTC – ~10-20% of cases
    • MEN2B – ~5% of cases

Inheritance

  • Autosomal dominant – 5% of MEN2A and 50% of MEN2B mutations are de novo
  • Caused by mutation in the RET proto-oncogene – refer to ARUP's MEN2 and RET database
  • Genotype/phenotype correlations – can help predict risk for aggressive MTC
  • Penetrance – varies by MEN2 subtype
    • ~100% for MTC

Clinical Presentation

  • MEN2A (Sipple syndrome)
    • MTC (~95%) – early onset; usually <35years 
    • Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches
      • Usually bilateral
    • Parathyroid tumors (~20-30%) – adenoma, hyperplasia
    • Lichen planus amyloidosis
  • MEN2B
    • MTC – childhood onset; aggressive; 100% of patients
    • Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches
      • Multiple and often bilateral
    • Skeletal deformities (eg, Marfanoid body type)
    • Eye abnormalities (eg, corneal thickening)
    • Mucosal and intestinal ganglioneuromatosis
    • Parathyroid tumors – uncommon
  • FMTC
    • MTC only – onset in middle age; 100% of patients
    • Considered a variant of MEN2 with decreased penetrance

MEN4

Epidemiology

  • Incidence – unknown, but rare
  • Inheritance
    • Autosomal recessive
    • Caused by CDKN1B mutation
      • Presents as phenocopy of MEN1 but lacks MEN1 gene
  • Penetrance – unknown

Clinical Presentation

  • Parathyroid tumors
  • Pituitary adenomas
  • Other MEN1 tumors are possible (eg, PNET tumors)

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication 2005360
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations

Regulatory region mutations, deep intronic mutations, breakpoints of large deletions/duplications, and mutations in genes other than MEN1 are not evaluated

Diagnostic errors can occur due to rare sequence variations

Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing 0051390
Method: Polymerase Chain Reaction/Sequencing

Limitations

Regulatory region mutations, deep intronic mutations, large deletions/duplications, and RET exons other than 5, 8, 10, 11, 13-16 are not evaluated

Diagnostic errors can occur due to rare sequence variations

Endocrine Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 13 Genes 2010193
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Diagnostic errors can occur due to rare sequence variations

Not determined or evaluated – Mutations in genes not included on the panel; deep intronic and regulatory region mutations; structural and numerical chromosomal abnormalities; breakpoints for large deletions/duplications

Deletions/duplications may not be detected in exon 1 in RET gene; exon 8 in PTEN gene; exons 4, 6, and 7 in STK11 gene

Lack of a detectable gene mutation does not exclude a diagnosis of hereditary endocrine cancer; not all predisposing genes are analyzed

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Follow Up

For assistance in ordering this test, contact a genetic counselor

Additional Tests Available

Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay

Beta-hCG, Serum Quantitative 0070025
Method: Chemiluminescent Immunoassay

Calcitonin 0070006
Method: Quantitative Chemiluminescent Immunoassay

Calcium, Ionized, Serum 0020135
Method: Ion-Selective Electrode/pH Electrode

Calcium, Serum or Plasma 0020027
Method: Quantitative Spectrophotometry

Chromogranin A 0080469
Method: Quantitative Enzyme Immunoassay

Chromosome FISH, Metaphase 2002299
Method: Fluorescence in situ Hybridization

C-Peptide, Serum or Plasma 0070103
Method: Quantitative Chemiluminescent Immunoassay

Electrolytes, Urine 0020498
Method: Quantitative Ion-Selective Electrode

Gastrin 0070075
Method: Quantitative Chemiluminescent Immunoassay

Glucagon 0099165
Method: Quantitative Radioimmunoassay

Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

IGF-1 (Insulin-Like Growth Factor 1) 0070125
Method: Quantitative Chemiluminescent Immunoassay

Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay

Metanephrines, Plasma (Free) 0050184
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Parathyroid Hormone, Intact with Calcium 0070172
Method: Quantitative Electrochemiluminescent Immunoassay

Lipid Panel 0020421
Method: Quantitative Enzymatic

Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

Renal Function Panel 0020144
Method: Quantitative Chemiluminescent Immunoassay/Quantitative Enzyme-Linked Immunosorbent Assay

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay

Somatostatin Quantitative, Plasma 2010001
Method: Quantitative Extraction/Immunoassay

Pancreatic Polypeptide 0099436
Method: Quantitative Radioimmunoassay

Histamine, Plasma 0070036
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Serotonin, Serum 0080397
Method: Quantitative High Performance Liquid Chromatography

Vasoactive Intestinal Peptide 0099435
Method: Quantitative Radioimmunoassay

Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing 2005359
Method: Polymerase Chain Reaction/Sequencing

Multiple Endocrine Neoplasia Type 1 (MEN1) Deletion/Duplication 2005346
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Guidelines

Brandi M, Gagel R, Angeli A, Bilezikian J, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri R, Libroia A, Lips C, Lombardi G, Mannelli M, Pacini F, Ponder B, Raue F, Skogseid B, Tamburrano G, Thakker R, Thompson N, Tomassetti P, Tonelli F, Wells S, Marx S. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001; 86(12): 5658-71. PubMed

NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Sep 2015]

Protocol for the Examination of Specimens from Patients with Carcinoma of the Endocrine Pancreas. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

Protocol for the Examination of Specimens from Patients with Carcinomas of the Thyroid Gland. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: October 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Appendix. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: February 2010. College of American Pathologists (CAP) . Northfield, IL [Accessed: Sep 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Colon and Rectum. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Sep 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Small Intestine and Ampulla. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Sep 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Stomach. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: February 2010. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

Protocol for the Examination of Specimens from Patients with Tumors of the Brain/Spinal Cord. No AJCC/UICC TNM Staging System. Protocol web posting date: June 2008; Protocol effective date: February 2009 . No AJCC/UICC TNM Staging System. Protocol web posting date: June 2008; Protocol effective date: February 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

Thakker R, Newey P, Walls G, Bilezikian J, Dralle H, Ebeling P, Melmed S, Sakurai A, Tonelli F, Brandi M, Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012; 97(9): 2990-3011. PubMed

General References

Almeida M, Stratakis C. Solid tumors associated with multiple endocrine neoplasias. Cancer Genet Cytogenet. 2010; 203(1): 30-6. PubMed

DeLellis R. Parathyroid tumors and related disorders. Mod Pathol. 2011; 24 Suppl 2: S78-93. PubMed

Duerr E, Chung D. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab. 2007; 21(1): 1-14. PubMed

Giusti F, Marini F, Brandi M. Multiple Endocrine Neoplasia Type 1. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Feb 2015; Accessed: Nov 2015]

Marquard J, Eng C. Multiple Endocrine Neoplasia Type 2. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Jun 2015; Accessed: Nov 2015]

Marsh D, Gimm O. Multiple endocrine neoplasia: types 1 and 2. Adv Otorhinolaryngol. 2011; 70: 84-90. PubMed

Nosé V. Familial thyroid cancer: a review. Mod Pathol. 2011; 24 Suppl 2: S19-33. PubMed

Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer. 2010; 9(3): 449-57. PubMed

Thakker R. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014; 386(1-2): 2-15. PubMed

Walls G. Multiple endocrine neoplasia (MEN) syndromes. Semin Pediatr Surg. 2014; 23(2): 96-101. PubMed

Zhang Y, Nosé V. Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 2011; 18(3): 206-18. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Agarwal A, Bentz J, Hungerford R, Abraham D. Parathyroid fine-needle aspiration cytology in the evaluation of parathyroid adenoma: cytologic findings from 53 patients. Diagn Cytopathol. 2009; 37(6): 407-10. PubMed

ARUP Scientific Resource for Research and Education. Multiple endocrine neoplasia and MEN1 missense variants. ARUP Laboratories, University of Utah. Salt Lake City, UT [Accessed: Nov 2012]

Margraf R, Calderon F, Mao R, Wittwer C. RET mutation scanning update: exon 15. Clin Chem. 2009; 55(11): 2059-61. PubMed

Margraf R, Crockett D, Krautscheid P, Seamons R, Calderon F, Wittwer C, Mao R. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat. 2009; 30(4): 548-56. PubMed

Margraf R, Durtschi J, Stephens J, Perez M, Voelkerding K. Determination of RET Sequence Variation in an MEN2 Unaffected Cohort Using Multiple-Sample Pooling and Next-Generation Sequencing. J Thyroid Res. 2012; 2012: 318232. PubMed

Margraf R, Mao R, Highsmith E, Holtegaard L, Wittwer C. RET proto-oncogene genotyping using unlabeled probes, the masking technique, and amplicon high-resolution melting analysis. J Mol Diagn. 2007; 9(2): 184-96. PubMed

Margraf R, Mao R, Wittwer C. Rapid diagnosis of MEN2B using unlabeled probe melting analysis and the LightCycler 480 instrument. J Mol Diagn. 2008; 10(2): 123-8. PubMed

Marquard J, Eng C. Multiple Endocrine Neoplasia Type 2. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Jun 2015; Accessed: Nov 2015]

Medical Reviewers

Last Update: December 2015