Multiple Endocrine Neoplasia Type 1 (MEN1) Workup

Updated: Oct 31, 2017
  • Author: Catherine Anastasopoulou, MD, PhD, FACE; Chief Editor: George T Griffing, MD  more...
  • Print
Workup

Approach Considerations

The recognition, localization, staging and follow-up of MEN1 NETs are performed by tumor marker measurements in serum and urine, and by imaging, such as computed tomography (CT) scan of chest, abdomen and pelvis, magnetic resonance imaging (MRI) of chest, abdomen and liver, endoscopic ultrasounds (EUS) of stomach and abdomen, contrast-enhanced abdominal CT and non-contrast MRI of the head.

Next:

Laboratory Studies

Laboratory studies in patients known to have multiple endocrine neoplasia type 1 (MEN1) screen for different hormones associated with potential MEN1 tumors.

Gastrinomas

Fasting gastrin 10 times over the gastrin normal upper limit of 100 pg/mL, in presence of hyperchloryhydia or pH <2. If fasting gastrin levels are below the diagnostic level of 1000 pg/mL, gastrin stimulation test by 12h- fasting intravenous injection of secretin is useful in establishing the diagnosis of gastrinoma. A gastrin increase of 120-500 pg/mL with respect to baseline value and a gastrin rise of 110 pg/mL immediately after secretin infusion strongly suggest gastrinoma; approximately 90% of patients with gastrinoma have a positive secretin test. [8]

Insulinomas

A supervised 72-hour fast is used most often to confirm this diagnosis. Increased plasma insulin occurs with hypoglycemia. Elevated C-peptide and proinsulin levels occur. Screening should start by age 5 years. Exclude the presence of oral hypoglycemic agents.

Glucagonomas

Elevated serum glucagon levels and hyperglycemia are present. Diagnosis may occur incidentally with imaging studies. Screening should start in children younger than 10 years.

Vasoactive intestinal polypeptidomas (VIPomas)

Watery diarrhea with hypokalemia and achlorhydria can occur. Elevated serum levels of vasoactive intestinal polypeptide with excess stool volume of 0.5-1L per day during fasting can establish the diagnosis. Screening should start in children younger than 10 years.

Pancreatic polypeptidomas (PPomas)

PPomas are not associated with a clinical syndrome. Pancreatic polypeptide levels are elevated. Chromogranin A levels can be elevated in any pancreatic neuroendocrine tumor. Screening should begin by age 10 years.

Carcinoid tumors

Elevated levels of chromogranin A, calcitonin, corticotropin, or urinary 5-hydroxyindoleacetic acid (5-HIAA) can occur. However, screening depends on radiological imaging, as no biochemical abnormality has been consistently observed. [1]

Pituitary tumors

Assess growth hormone levels (insulinlike growth factor-1 [IGF-1]) and prolactin. Screening should begin by age 5 years.

Hyperparathyroidism

The serum calcium is elevated, while the parathyroid hormone level is elevated or inappropriately normal. Screening should start by age 8 years. Patients with hypercalcemia should undergo continuous surveillance, including annual 24-hour urine calcium measurement and imaging studies (see below).

Previous
Next:

Imaging Studies

Primary hyperparathyroidism

Radiographs in patients with hyperparathyroidism may reveal bone abnormalities, as seen in the images below. Patients with hypercalcemia should undergo annual screening that includes imaging of the urinary tract and dual-energy x-ray absorptiometry (DXA) for evaluation of bone mineral density (BMD).

Anteroposterior radiographic view of the right han Anteroposterior radiographic view of the right hand in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1) and primary hyperparathyroidism. This image shows subperiosteal bone resorption along the radial aspects of the middle phalanges (arrows).
Bilateral, anteroposterior radiographic views of t Bilateral, anteroposterior radiographic views of the hands in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1) and primary hyperparathyroidism. These images show subperiosteal bone resorption along the radial aspects of the middle phalanges.

Pituitary tumors

Magnetic resonance imaging (MRI), with attention to the sella turcica region (pancreatic protocol), is the screening test of choice. [19] Patients should also be screened every 3 years starting at age 5 years.

Gastrinomas

Biochemical evidence should be present to justify pursuing radiological evaluation. The majority of multiple endocrine neoplasia type 1 (MEN1) gastrinomas are multiple tumors localized in the submucosa of the proximal duodenum, and most are missed by conventional imaging surveillance (CT scan, MRI, and endoscopic ultrasonography [EUS]).

Somatostatin receptor scintigraphy (SRS) has a sensitivity range for gastrinomas of 70-90%. SRS findings can be enhanced by selective arterial secretagogue testing with secretin or calcium infusion. (In 10% of cases of gastrinomas, secretin is not diagnostically useful.)

EUS helps detect tumors in the pancreatic head but rarely in the duodenal wall. It is more sensitive than CT scanning or transabdominal ultrasonography.

Insulinomas

Biochemical evidence should be present before pursuing radiological evaluation. Tumors are generally localized by CT scan, MRI, or EUS of the pancreas body and tail. MRI is the imaging tehcnique of choice for periodical surveillance. SRS findings may be positive in up to 50% of patients with insulinomas. SRS is best used in conjunction with single-photon emission CT (SPECT) scanning.

EUS (see image below) has a reported detection sensitivity of up to 94%. Selective arterial calcium stimulation with hepatic venous sampling is often required, as patients with MEN1 are likely to have multiple lesions. Intraoperative ultrasonography can be helpful.

Endoscopic ultrasonogram in a patient with an insu Endoscopic ultrasonogram in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV). (From: Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. Jun 25 1992;326(26):1721-6.)

Parathyroid tumors

Parathyroid gland imaging with a sestamibi scanning is of limited benefit, as all parathyroid glands may be affected and neck exploration is required regardless. An example of a positive scan is illustrated (see image below).

Technetium-99m sestamibi scan (99mTc MIBI) in a pa Technetium-99m sestamibi scan (99mTc MIBI) in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These images demonstrate persistent abnormal activity of the inferior right parathyroid gland that is consistent with an adenoma.

Pancreatic neuroendocrine tumors (pNETs)

The sensitity of EUS is much higher than that of MRI for the detection of pNETs; EUS can identify tumors in 55% of asymptomatic patients. Annual MRI, CT scanning, or EUS screening is recommended. Adrenal gland imaging should be undertaken at the same time. Radiological screening should start before age 10 years.

Nonfunctioning neuroendocrine tumors

A combination of MRI, CT scan, and EUS of the abdomen is suggested every year. Improving sensitivity and specificity of imaging techniques have resulted in increased identification of nonfunctioning tumors in MEN1. [8]

Thymic and bronchial carcinoid tumors

CT scanning or MRI of the chest is recommended every 1-2 years. CT scan is more sensitive (about 95%). Screening should begin by age 15 years.

Previous
Next:

Other Tests

Genetic testing

MEN1 syndrome is caused by inactivating mutations of the tumor suppressor gene MEN1, positionally cloned in 1997 at 11q13 locus. The identification and genetic characterization of the causative gene opened the possibility of genetic testing and early diagnosis of the disease.

Sequence analysis of the MEN1 gene for mutations provides the best evidence of gene carrier status. This genetic test is performed in several commercial laboratories. Genetic testing for MEN1 mutations is recommended for the following individuals [1] :

  • Clinical index cases with 2 or more MEN1-associated endocrine tumors
  • Asymptomatic first-degree relatives of a known MEN1 mutation carrier
  • First-degree relatives of a MEN1 mutation carrier with symptoms, signs, and biochemical or radiological evidence of MEN1 associated tumor(s)

Asymptomatic members of a mutation-bearing family should undergo genetic screening as early as possible, preferably before the age of 5 years. All individuals offered MEN1 mutation testing should be provided with genetic counseling before testing. A positive MEN1 genetic test is an indication for periodic screening with biochemical and imaging studies for MEN1-associated tumors, and for the early initiation of surgical and/or pharmacological treatment. [1]

With the development of new techniques such as multiplex ligation-dependent probe amplification (MLPA), new mutations of the MEN1 gene are being discovered, which increases the sensitivity of genetic analysis. In the past, genetic testing has failed to identify MEN1 mutations in 10-30% of patients who meet the clinical criteria for the diagnosis of MEN1 (eg, presence of at least two MEN1-associated tumors: primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, pituitary tumors). [15] Such patients are termed phenocopies.

The presence of a phenocopy should be suspected in presence of a negative MEN1 genetic test, by sequencing, gene dosage, and 11q13 haplotype analyses. Phenocopies are estimated to account for up to 5% of MEN1-like cases, mainly associated with features of parathyroid and pituitary disease. [20]

Patients with mutations in the cyclin-dependent kinase inhibitor (CDKN1B) gene are found to have different clinical course from patients with MEN1 mutations. These patients develop parathyroid and anterior pituiary tumors but are at lower risk of developing pancreatic neuroendocrine tumors (pNET). [21]

Previous
Next:

Histologic Findings

The parathyroid glands show diffuse or nodular proliferations of chief cells, with some oncocytic cells. Usually, all 4 glands are involved and show signs of hyperplasia.

Neuroendocrine tumors of the pancreas manifest with numerous microadenomas, usually in the pancreatic tail. The tumors display a trabecular pattern and may show conspicuous connective-tissue stroma. Immunohistochemically, expression of multiple hormones is found. Pancreatic polypeptide and glucagon are expressed most often, followed by insulin and, rarely, gastrin. Nesidioblastosis and islet cell hyperplasia are not features of multiple endocrine neoplasia type 1 (MEN1), as previously thought.

Most duodenal tumors are located proximally. They stain for gastrin and can metastasize to regional lymph nodes.

The presence of diffuse hyperplasia of enterochromaffinlike (ECL) cells in the stomach is often associated with carcinoid tumors of considerable size (rarely metastases).

Pituitary tumors are found in the anterior part of the gland and are usually single. Most are macroadenomas, and one third show invasive features with infiltration of tumor cells through surrounding pituitary tissue.

Previous