Approach Considerations
Early detection of neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN1) is very important and should be pursued systematically to promote better treatment options and improve the final prognosis as much as possible. [22] The recognition, localization, staging, and follow-up of NETs involves tumor marker measurements in serum and urine and imaging studies such as the following:
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Computed tomography (CT) scan of chest, abdomen and pelvis
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Magnetic resonance imaging (MRI) of chest, abdomen and liver
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Endoscopic ultrasound (EUS) of stomach and abdomen
-
Contrast-enhanced abdominal CT
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Non-contrast MRI of the head
Laboratory Studies
Laboratory studies in patients known to have MEN1 are used to screen for the hormones associated with potential MEN1 tumors.
Gastrinomas
A fasting gastrin level 10 times over the normal upper limit of 100 pg/mL, in presence of hyperchloryhydia or pH < 2, indicates the presence of a gastrinoma. If fasting gastrin levels are below the diagnostic level of 1000 pg/mL, gastrin stimulation test by 12-hr fasting intravenous injection of secretin is useful in establishing the diagnosis of gastrinoma. A gastrin increase of 120-500 pg/mL over 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. [9]
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).
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).
Multiple endocrine neoplasia type 1 (MEN1). Anteroposterior radiographic view of the right hand in a patient with MEN1 and primary hyperparathyroidism shows subperiosteal bone resorption along the radial aspects of the middle phalanges (arrows).
Multiple endocrine neoplasia type 1 (MEN1). Bilateral, anteroposterior radiographic views of the hands in a patient with MEN1 and primary hyperparathyroidism 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, is the screening test of choice. [23] Screening MRI scans should be performed every 3 to 5 years, starting at age 5 to 10 years. [1]
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.
Multiple endocrine neoplasia type 1 (MEN1). 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).
Multiple endocrine neoplasia type 1 (MEN1). Technetium-99m sestamibi scan (99mTc MIBI) in a patient with MEN1 demonstrates 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. [9]
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.
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] :
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Clinical index cases with 2 or more MEN1-associated endocrine tumors
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Asymptomatic first-degree relatives of a known MEN1 mutation carrier
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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). [17] 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. [24]
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). [25]
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. Parathyroid cancer has also been reported but is very rare. [26]
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.
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Multiple endocrine neoplasia type 1 (MEN1). Sagittal (left image) and coronal (right image), T1-weighted magnetic resonance images of the brain in a patient with MEN1 show a pituitary macroadenoma (arrows).
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Multiple endocrine neoplasia type 1 (MEN1). Indium-111 (111In) octreotide scan in a patient with MEN1 demonstrates abnormal activity in the pituitary macroadenoma (curved arrow), parathyroid adenoma (straight arrow), and gastrinoma metastases throughout the abdomen (arrowheads).
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Multiple endocrine neoplasia type 1 (MEN1). Technetium-99m sestamibi scan (99mTc MIBI) in a patient with MEN1 demonstrates persistent abnormal activity of the inferior right parathyroid gland that is consistent with an adenoma.
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Multiple endocrine neoplasia type 1 (MEN1). Computed tomography (CT) scan of the pancreas in a patient with MEN1 and a gastrinoma shows a pancreatic head mass (large, white arrow), as well as a low-attenuating lesion in the liver (small, black arrowhead) that indicates metastases. Note the calcifications of the right renal medullary pyramids (medullary nephrocalcinosis; black arrows) in this nonenhanced CT scan.
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Multiple endocrine neoplasia type 1 (MEN1). 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.)
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Multiple endocrine neoplasia type 1 (MEN1). Computed tomography (CT) scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (From: Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, Mo: Mosby-Year Book; 1993: 272.)
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Multiple endocrine neoplasia type 1 (MEN1). Anteroposterior radiographic view of the right hand in a patient with MEN1 and primary hyperparathyroidism shows subperiosteal bone resorption along the radial aspects of the middle phalanges (arrows).
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Multiple endocrine neoplasia type 1 (MEN1). Bilateral, anteroposterior radiographic views of the hands in a patient with MEN1 and primary hyperparathyroidism show subperiosteal bone resorption along the radial aspects of the middle phalanges.
Tables
Tumor |
Age at which to begin screening (yr) |
Blood tests (annual) |
Imaging studies |
Insulinoma |
5 |
Fasting glucose, insulin |
– |
Anterior pituitary |
5 |
Prolactin, IGF-I |
MRI (every 3 yr) |
Parathyroid |
8 |
Calcium, PTH |
– |
Other pancreatic neuroendocrine tumors |
< 10 |
Chromogranin-A; pancreatic polypeptide, glucagon, VIP |
MRI, CT, or EUS (annually) |
Adrenal |
< 10 |
Only in patients with symptoms or signs of a functioning tumor and/or tumor >1 cm identified on an imaging study |
MRI or CT (annually with pancreatic imaging) |
Thymic and bronchial carcinoid |
15 |
None |
CT or MRI (every 1-2 yr) |
Gastrinoma |
20 |
Gastrin (± gastric pH) |
– |
CT = computed tomography; EUS = endoscopic ultrasound; IGF-1 = Insulin-like growth factor 1; ( MRI = magnetic resonance imaging; PTH = parathyroid hormone; VIP = vasoactive intestinal peptide Adapted from Thakker RV, et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep. 97(9):2990-3011. [1] |
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