Multiple Endocrine Neoplasias - MEN

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).

Tabs Content

Clinical Overview

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)
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

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
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
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
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
    - Hypercortisolism
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
  - Meningiomas
  - Ependymomas
- Muscle tumors
  - Leiomyomas

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 Lab Tests

Preferred initial test to confirm diagnosis of MEN1

Clinical sensitivity: combined testing ~94%

90% sequencing
4% deletion/duplication

Not evaluated: regulatory region variants, deep intronic variants, breakpoints of large deletions/duplications, and variants in genes other than MEN1

Diagnostic errors can occur due to rare sequence variations

Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication 2005360

Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Diagnostic and predictive test for MEN2A and MEN2B

Clinical sensitivity

MEN2A: 95%
MEN2B: 98%

Not evaluated: regulatory region variants, deep intronic variants, large deletions/duplications, and RET exons other than 5, 8, 10, 11, 13-16

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

Useful when a pathogenic familial variant identifiable by sequencing is known

Consultation with a genetics counselor is advised

Familial Mutation, Targeted Sequencing 2001961

Method: Polymerase Chain Reaction/Sequencing

Related Tests

Aid in diagnosis of adrenal insufficiency and determining the presence of anterior pituitary tumors

Adrenocorticotropic Hormone 0070010

Method: Quantitative Electrochemiluminescent Immunoassay (ECLIA)

Diagnose and monitor familial medullary thyroid carcinoma (FMTC)

Secondary test to assist in diagnosing multiple endocrine neoplasia type 2 (MEN2) and FMTC

Calcitonin 0070006

Method: 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

Chromogranin A 0080469

Method: Quantitative Enzyme Immunoassay

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

Chromosome FISH, Metaphase 2002299

Method: Fluorescence in situ Hybridization

Aid in detection of insulinoma

C-Peptide, Serum or Plasma 0070103

Method: Quantitative Chemiluminescent Immunoassay

Aid in diagnosis of carcinoid and gastrinoma tumors

Gastrin 0070075

Method: Quantitative Chemiluminescent Immunoassay

Aid in diagnosis and monitoring of glucagonoma

Glucagon 0099165

Method: Quantitative Radioimmunoassay

Use to diagnose and manage diabetes mellitus (DM) and other carbohydrate metabolism disorders

Glucose, Plasma or Serum 0020024

Method: Quantitative Enzymatic

Aid in evaluation of patient with allergic signs and symptoms, such as anaphylaxis; may assist in diagnosing and monitoring of mast-cell activation disorders

Histamine, Plasma 0070036

Method: Quantitative Enzyme-Linked Immunosorbent Assay

Aid in diagnosis of growth hormone excess or deficiency disorders

Insulin-Like Growth Factor 1 (IGF-1) with Calculated Z-Score 2007698

Method: Quantitative Chemiluminescent Immunoassay

Aid in detection of insulinoma

Insulin, Fasting 0070063

Method: Quantitative Chemiluminescent Immunoassay

Use to assess cardiovascular disease risk and guide therapy

Lipid Panel 0020421

Method: Quantitative Enzymatic

Panel includes cholesterol, triglycerides, HDL cholesterol, LDL cholesterol (calculated), non-HDL cholesterol, VLDL cholesterol (calculated), appearance chemistry

First-line test in suspected pheochromocytoma

Metanephrines, Plasma (Free) 0050184

Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Acceptable initial test to confirm diagnosis of MEN1 but does not detect deletions/duplications

Not evaluated: regulatory region variants, deep intronic variants, breakpoints of large deletions/duplications, variants in genes other than MEN1

Diagnostic errors can occur due to rare sequence variations

Clinical sensitivity: 90%

Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing 2005359

Method: Polymerase Chain Reaction/Sequencing

Aid in diagnosis and monitoring of pancreatic neuroendocrine tumors

Pancreatic Polypeptide 0099436

Method: Quantitative Radioimmunoassay

Use to evaluate calcium dysregulation

Parathyroid Hormone, Intact with Calcium 0070172

Method: Quantitative Electrochemiluminescent Immunoassay

Screening for anterior pituitary tumor

Prolactin 0070115

Method: Quantitative Chemiluminescent Immunoassay

Evaluate for kidney dysfunction in patients with known risk factors (eg, hypertension, diabetes, obesity, family history of kidney disease)

Renal Function Panel 0020144

Method: 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

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108

Method: 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

Thyroid Stimulating Hormone 0070145

Method: Quantitative Chemiluminescent Immunoassay

Preferred serotonin test when diagnosing carcinoid tumors is whole blood

Serotonin, Serum 0080397

Method: Quantitative High Performance Liquid Chromatography

Aid in diagnosis of VIPoma

Vasoactive Intestinal Peptide 0099435

Method: 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

C-Peptide, Other 3000529

Method: Quantitative Chemiluminescent Immunoassay

C-Peptide, 30 Minutes 2013558

Method: Quantitative Chemiluminescent Immunoassay

C-Peptide, 60 Minutes 2013560

Method: Quantitative Chemiluminescent Immunoassay

C-Peptide, 120 Minutes 2013562

Method: Quantitative Chemiluminescent Immunoassay

C-Peptide, 180 Minutes 2013564

Method: Quantitative Chemiluminescent Immunoassay

Beta-hCG, Serum Quantitative 0070025

Method: Chemiluminescent Immunoassay

Calcium, Ionized, Serum 0020135

Method: Ion-Selective Electrode/pH Electrode

Calcium, Serum or Plasma 0020027

Method: Quantitative Spectrophotometry

Electrolytes, Urine 0020498

Method: Quantitative Ion-Selective Electrode

Somatostatin Quantitative, Plasma 2010001

Method: Quantitative Extraction/Immunoassay

Medical Experts

Best, Hunter, PhD, Medical Director, Molecular Genetics and Genomics; Scientific Director, NGS and Biocomputing at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Mao, Rong, MD, FACMG, Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

Tvrdik, Tatiana, MS, LCGC, PhD, Sequencing Analyst, Genomics at ARUP Laboratories

References

Guidelines

Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001; 86(12): 5658-71. PubMed
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: Dec 2014. College of American Pathologists (CAP). Northfield, IL [Last Modified: Dec 2014; Accessed: Jun 2018]
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: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Revised: Jan 2016; Accessed: Jun 2017]
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: Jan 2016. College of American Pathologists (CAP) . Northfield, IL [Revised : Oct 2013; Accessed: Mar 2018]
Protocol for the Examination of Specimens from Patients with Primary Carcinoma of the Colon and Rectum. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised: Jan 2016; Accessed: Mar 2018]
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: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised: Jun 2014; Accessed: Mar 2018]
NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine and Adrenal Tumors. Version 4.2018. National Comprehensive Cancer Network. Fort Washington, PA [Updated: May 2018; Accessed: Jul 2018]
Protocol for the Examination of Specimens from Patients with Tumors of the Endocrine Pancreas. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Aug 2016. College of American Pathologists (CAP). Northfield, IL [Revised: Aug 2016; Accessed: July 2018]
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: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised: Oct 2013; Accessed: Mar 2018]
Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML, 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 MQ, Stratakis CA. Solid tumors associated with multiple endocrine neoplasias. Cancer Genet Cytogenet. 2010; 203(1): 30-6. PubMed

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

Duerr E, Chung DC. 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: Adam MP, Ardinger HH, Pagon RA, Wallace SE, eds. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Dec 2017; Accessed: Jul 2019]

Marquard J, Eng C. Multiple Endocrine Neoplasia Type 2. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Jun 2015; Accessed: Jul 2019]

Marsh DJ, 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 RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014; 386(1-2): 2-15. PubMed

Walls GV. 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

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Agarwal AM, Bentz JS, 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

Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, 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 RL, Durtschi JD, Stephens JE, Perez M, Voelkerding KV. 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 RL, Mao R, Highsmith E, Holtegaard LM, Wittwer CT. 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 RL, Mao R, Wittwer CT. Rapid diagnosis of MEN2B using unlabeled probe melting analysis and the LightCycler 480 instrument. J Mol Diagn. 2008; 10(2): 123-8. PubMed

Testing Algorithms

Educational Videos

Content Review:

June 2017

Last Update: October 2019

Multiple Endocrine Neoplasias - MEN

Diagnosis

Multiple Endocrine Neoplasia 1 (MEN1)

Indications for Testing

Laboratory Testing

MEN2A and MEN2B

Indications for Testing

Laboratory Testing

Familial Medullary Thyroid Carcinoma (FMTC)

Indications for Testing

Laboratory Testing

Monitoring

MEN1

MEN2

Background

MEN1

Epidemiology

Inheritance

Clinical Presentation

MEN2

Epidemiology

Inheritance

Clinical Presentation

MEN4

Epidemiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Hypocalcemia Testing Algorithm

Pheochromocytoma Testing Algorithm

Thyroid Nodules Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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Multiple Endocrine Neoplasias - MEN

Diagnosis

Multiple Endocrine Neoplasia 1 (MEN1)

Indications for Testing

Laboratory Testing

MEN2A and MEN2B

Indications for Testing

Laboratory Testing

Familial Medullary Thyroid Carcinoma (FMTC)

Indications for Testing

Laboratory Testing

Monitoring

MEN1

MEN2

Background

MEN1

Epidemiology

Inheritance

Clinical Presentation

MEN2

Epidemiology

Inheritance

Clinical Presentation

MEN4

Epidemiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Hypocalcemia Testing Algorithm

Pheochromocytoma Testing Algorithm

Thyroid Nodules Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult