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).
Diagnosis
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
- 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)
- MEN1 mutation analysis
- 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
- Vasoactive intestinal polypeptide secreting tumor (VIPoma) – vasoactive intestinal peptide
- Carcinoid tumor – testing depends on tumor location
MEN2A and MEN2B
Indications for Testing
- Typical tumor presentation (familial medullary thyroid carcinoma [FMTC] or pheochromocytoma) and family history
- Refer to testing algorithms for pheochromocytoma and thyroid nodules
Laboratory Testing
- Genetic testing
- RET mutation analysis
- Confirms presence of mutation in patient with FMTC 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
- RET mutation analysis
- Biochemical testing
- Pheochromocytoma and medullary thyroid cancer evaluation prior to genetic testing
Familial Medullary Thyroid Carcinoma (FMTC)
Indications for Testing
- Family history of FMTC 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
Monitoring
MEN1
- Periodic screening for Multiple Endocrine Neoplasia 1 (MEN1)-associated endocrine tumors beginning in early childhood and continuing for life (NCCN, 2017)
- Consider annual testing for the following
- Parathyroid tumor
- Calcium (ionized)
- Electrolytes
- Parathyroid hormone
- Pancreatic neuroendocrine tumor
- Chromogranin A
- Other hormone testing based on syndrome presentation
- Gastrin
- Glucagon
- Pancreatic polypeptide
- Vasoactive intestinal peptide (VIP)
- Glucose/insulin
- Bronchial carcinoid/thymic carcinoid previously
- Chest imaging at 1-3 years
- Pituitary
- Previous pituitary – MRI at 3-5 years
- No previous pituitary
- Insulin-like growth factor-1 (IGF-1)
- Prolactin
- Parathyroid tumor
- Consider annual testing for the following
- Risk for malignant progression of MEN1-associated tumors depends on tumor type
- Malignancy uncommon before early adulthood
MEN2
- See Pheochromocytoma and Thyroid Cancer
Background
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 >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
- Vasoactive intestinal polypeptide secreting tumor (VIPoma) (~2%) – Verner-Morrison syndrome
- Watery diarrhea, hypokalemia, achlorhydria
- Glucagonoma (~2%)
- Hyperglycemia, skin rash, anorexia, diarrhea
- Gastrinoma (~40%) – Zollinger-Ellison syndrome
- 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%)
- Gigantism in children and acromegaly in adults
- Combination – prolactinoma/growth hormone tumor (~5%)
- Combined symptoms
- Adrenal tumors (~2-5%) – most nonfunctioning
- Prolactinoma (~20%) – most common
- 10-60% of patients; symptoms depend on the pituitary hormone produced
- Other endocrine tumors
- Adrenal cortical adenomas – 20-40% of patients
- Thyroid neoplasms – 8-25% of patients
- Pheochromocytoma – <1% of patients
- Nonendocrine tumors
- Cutaneous tumors
- Collagenoma and facial angiofibromas – 70-85% of patients
- Lipomas – 30% of patients
- Malignant melanoma
- Central nervous system tumors
- Muscle tumors
- Leiomyomas
- Cutaneous tumors
MEN2
Epidemiology
- Incidence – 1/35,000
- MEN2A – 70-80% of cases
- Familial medullary thyroid carcinoma (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 FMTC
- Penetrance – varies by MEN2 subtype
- MEN2A – 95%
- MEN2B and FMTC – nearly 100%
Clinical Presentation
- MEN2A (Sipple syndrome)
- FMTC (~95%) – early onset; usually <35years
- Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches
- Usually bilateral
- Parathyroid tumors (~20-30%) – adenoma, hyperplasia
- Lichen planus amyloidosis
- MEN2B
- FMTC – 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
- FMTC 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, pancreatic neuroendocrine tumors [PanNETs])
ARUP Laboratory Tests
Preferred initial test to confirm diagnosis of MEN1
Massively Parallel Sequencing
Diagnostic and predictive testing for MEN2 syndrome caused by pathogenic variants in the RET gene
Massively Parallel Sequencing
Useful when a pathogenic familial variant identifiable by sequencing is known
Consultation with a genetics counselor is required
Massively Parallel Sequencing
Aid in diagnosis of adrenal insufficiency and determining the presence of anterior pituitary tumors
Quantitative Electrochemiluminescent Immunoassay
Diagnose and monitor familial medullary thyroid carcinoma (FMTC)
Secondary test to assist in diagnosing multiple endocrine neoplasia type 2 (MEN2)and FMTC
Quantitative Chemiluminescent Immunoassay
Assay aids in monitoring but is not recommended for diagnosis of carcinoid tumors
May be useful in monitoring nonsecretory sympathetic and parasympathetic neuroendocrine tumors
Immunofluorescence
FISH probes for specific microdeletion/microduplication syndromes must be specified; if no specific syndrome is in question, genomic microarray should be ordered instead of screening multiple loci by FISH
Fluorescence in situ Hybridization (FISH)
Aid in detection of insulinoma
Quantitative Chemiluminescent Immunoassay
Aid in diagnosis of carcinoid and gastrinoma tumors
Quantitative Chemiluminescent Immunoassay
Aid in diagnosis and monitoring of glucagonoma
Quantitative Radioimmunoassay
Use to diagnose and manage diabetes mellitus (DM) and other carbohydrate metabolism disorders
Quantitative Enzymatic Assay
Aid in evaluation of patient with allergic signs and symptoms, such as anaphylaxis; may assist in diagnosing and monitoring of mast-cell activation disorders
Quantitative Enzyme-Linked Immunosorbent Assay
Aid in diagnosis of growth hormone excess or deficiency disorders
Quantitative Chemiluminescent Immunoassay
Aid in detection of insulinoma
Quantitative Chemiluminescent Immunoassay
Use to assess cardiovascular disease risk and guide therapy
Quantitative Enzymatic Assay
First-line test in suspected pheochromocytoma
Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Aid in diagnosis and monitoring of pancreatic neuroendocrine tumors
Quantitative Radioimmunoassay
Use to evaluate calcium dysregulation
Quantitative Electrochemiluminescent Immunoassay (ECLIA)
Screening for anterior pituitary tumor
Quantitative Chemiluminescent Immunoassay
Evaluate for kidney dysfunction in patients with known risk factors (eg, hypertension, diabetes, obesity, family history of kidney disease)
Quantitative Chemiluminescent Immunoassay/Quantitative Enzyme-Linked Immunosorbent Assay
Panel includes albumin, calcium, carbon dioxide, creatinine, chloride, glucose, phosphorous, potassium, sodium, and blood urea nitrogen (BUN) and a calculated anion gap value
Assess thyroid function
Identify risk in patients with palpable thyroid nodules
Quantitative Electrochemiluminescent Immunoassay
Reflex pattern: if the thyroid stimulating hormone is outside the reference interval, then thyroxine, free (free T4) testing will be added
Preferred test for screening and monitoring of thyroid function
Quantitative Chemiluminescent Immunoassay
Preferred serotonin test when diagnosing carcinoid tumors is whole blood
Quantitative High Performance Liquid Chromatography
Aid in diagnosis of VIPoma
Quantitative Radioimmunoassay
Aid in the detection of insulinoma
May aid in distinguishing type 1 from type 2 diabetes mellitus (DM) in ambiguous cases
Do not use to diagnose DM
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Ion-Selective Electrode/pH Electrode
Quantitative Spectrophotometry
Quantitative Ion-Selective Electrode
Quantitative Extraction/Immunoassay
References
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Almeida MQ, Stratakis CA. Solid tumors associated with multiple endocrine neoplasias. Cancer Genet Cytogenet. 2010;203(1):30-36.
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Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86(12):5658-5671.
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DeLellis RA. Parathyroid tumors and related disorders. Mod Pathol. 2011;24 Suppl 2:S78-93.
GeneReviews - Multiple Endocrine Neoplasia Type 1
Giusti F, Marini F, Brandi ML. Multiple endocrine neoplasia type 1. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews, University of Washington; 1993-2022. [Last update: Mar 2022; Accessed: Dec 2022]
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Marsh DJ, Gimm O. Multiple endocrine neoplasia: types 1 and 2. Adv Otorhinolaryngol. 2011;70:84-90.
NCCN - Neuroendocrine Tumors
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and adrenal tumors. Version 4.2018. [Updated: May 2018; Accessed: Jul 2018]
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Nosé V. Familial thyroid cancer: a review. Mod Pathol. 2011;24 Suppl 2:S19-33.
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Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab. 2007;21(1):1-14.
CAP - Brain/Spinal Cord
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with tumors of the brain/spinal cord. No AJCC/UICC TNM Staging System. [Posted: Dec 2014; Accessed: Feb 2020]
CAP - Thyroid
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with carcinomas of the thyroid gland. Version 3.2.0.0. [Posted: Jan 2016; Accessed: Mar 2020]
CAP - Neuroendocrine Tumors (Carcinoid Tumors) of the Appendix
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the appendix. [Posted: Oct 2013; Accessed Feb 2020]
CAP - Primary Carcinoma of the Colon and Rectum
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. [Posted: Feb 2020; Accessed: Mar 2021]
CAP - Neuroendocrine Tumors (Carcinoid Tumors) of the Stomach
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the stomach, Version 4.0.0.0. [Posted: Oct 2013; Accessed Feb 2020]
CAP - Pancreas (Endocrine)
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with tumors of the endocrine pancreas. Version 3.3.0.1. [Posted: Aug 2016; Accessed: Mar 2020]
GeneReviews - Multiple Endocrine Neoplasia Type 1
Giusti F, Marini F, Brandi ML. Multiple endocrine neoplasia type 1. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews, University of Washington; 1993-2022. [Last update: Mar 2022; Accessed: Dec 2022]
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Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer. 2010;9(3):449-457.
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Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
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Zhang Y, Nosé V. Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 2011;18(3):206-218.
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