At a Glance

Multiple Endocrine Neoplasia Type 2B (MEN2B) is a syndrome composed of medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas, and marfanoid features. Predisposition to this syndrome is caused by germline mutations in the RET proto-oncogene. Unlike MEN2A, primary hyperparathyroidism is not a feature of MEN2B, and the two syndromes arise from different mutations in RET. Medullary thyroid carcinoma is characterized by proliferation of calcitonin-secreting thyroid C-cells. MTC in MEN2B is typically more aggressive than in MEN2A, and early preventive surgery to remove the thyroid gland and associated lymph nodes is a critical point for clinical management.

Clinical features of MTC may include a thyroid nodule, along with symptoms of local spread, such as hoarseness or shortness of breath. Pheochromocytoma can present as sustained or episodic hypertension, along with episodic headache, diaphoresis, palpitations, tachycardia, and anxiety. The characteristic neuromas may present as gastrointestinal (GI) symptoms, and the marfanoid habitus is also useful for early clinical diagnosis.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

MTC is diagnosed by morphologic and immunohistochemical analysis of fine-needle aspirate thyroid material, and serum calcitonin should be elevated (although calcitonin may also be produced by other tumor types and is not in itself diagnostic). In the context of a positive diagnosis of MTC, the most important test to order is a genetic analysis of the RET proto-oncogene to determine if a germline mutation can be detected. A calcium challenge test can also be used to detect increased number of C-cells. In this assay, a rapid calcium infusion is performed and both calcium and calcitonin are measured at 0, 5, 10, 15, and 30 minutes.

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For the diagnosis of pheochromocytoma, fractionated metanephrines (urine and/or serum) should be ordered along with chromogranin A. Metanephrines are derived from the methylation of epinephrine and norepinephrine, and, because of their longer half-life, they represent a superior analyte for measurement than unmethylated catecholamines. Plasma metanephrines have traditionally been more difficult to measure than urine metanephrines because of their low levels; however, the advent of HPLC-mass spectrometry-based assays has significantly improved the detection limits, as well as eliminating some drug interferences (note that acetaminophen is a known interference with older HPLC-electrochemical detection).

Annual screening of patients for fractionated metanephrine levels is clinically important for early identification of pheochromocytoma, and the age at which screening should start is indicated by the specific RET mutation that has been identified.(Table 1)

Table 1.
Calcitonin Plasma metanephrine RET protooncogene mutation testing
Increased in medullary thyroid carcinoma; FNA morphology should also be used for diagnosis of MTC Increased if a pheochromocytoma is present Presence of known mutation confirms risk and can distinguish MEN2A from MEN2B

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

DNA testing of the RET proto-oncogene is not affected by any medications. Plasma levels of metanephrine and normetanephrine are elevated by monoamine oxidase (MAO) inhibitors, as well as amphetamines, ephedrines, albuterol, cocaine, lidocaine, anesthetic gases, and withdrawal from a variety of sedatives. Urine metanephrines have been reported to be increased by tricyclic antidepressants and levodopa, as well as by extreme endogenous stress.

Although normetanephrine is generally increased by tricyclic antidepressants and nonselective alpha blockers, metanephrine is not affected and is a more significant analyte in the case of MEN2-associated pheochromocytoma. Chromogranin A levels may be elevated because of proton pump inhibitor (PPI) administration, as well as renal or liver failure. For any analyte measured by radioimmunoassay, recent administration of radioactive material may interfere with the results. All immunoassays may have falsely elevated values due to endogenous interfering antibodies.

What Lab Results Are Absolutely Confirmatory?

Germline testing for RET proto-oncogene mutations is the most important diagnostic study. Different mutations are associated with MEN2A and MEN2B, although both syndromes lead to a predisposition to MTC and pheochromocytoma. Given the risk of MTC, including early metastasis in approximately 15% of patients, a positive test for RET mutation in a patient or clinically unaffected family member, including young children, is a strong indication for thyroid removal with central lymph node dissection to prevent the development of MTC.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Following surgery for medullary thyroid carcinoma, calcitonin levels may be used as a tumor marker to assess disease recurrence. If a pheochromocytoma is the presenting malignancy in a patient without known MTC or hyperparathyroidism, fractionated plasma metanephrines may indicate the likelihood of MEN2A. Specifically, elevations in metanephrine (as opposed to isolated elevations in normetanephrine) are associated with NF1 and MEN2-related pheochromocytoma and may, therefore, be useful prior to the acquisition of genetic testing results. If a bilateral pheochromocytoma is surgically removed, it may be necessary to utilize laboratory measurements of adrenocortical hormones to guide replacement therapy and ensure that acute adrenal insufficiency does not occur.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

As with all tumor markers measured by immunoassay, calcitonin measurements over time to detect disease recurrence should be performed by the same laboratory using the same assay whenever possible. If it is necessary to change laboratories and/or platforms, both the old and new assays should be performed on a crossover sample to rebaseline the patient.