Multiple Endocrine Neoplasia Type 2 (MEN2) Guidelines

In 2015, the American Thyroid Association (ATA) published revised guidelines for the diagnosis and treatment of medullary thyroid carcinoma (MTC) that included recommendations for management of multiple endocrine neoplasia type 2 (MEN2). ^[1] The National Comprehensive Cancer Network (NCCN) includes recommendations for diagnosis and treatment of MEN2 in its guidelines for thyroid cancer and its guideline for neuroendocrine and adrenal tumors. ^{[9, 24]}

Diagnosis

According to NCCN guidelines, the criterion for a clinical diagnosis of MEN2A is two or more MEN2A-associated tumors (medullary thyroid carcinoma [MTC], adrenal pheochromocytoma) in an individual or in a first-degree relative. Other physical findings include lichen planus amyloidosis and Hirschsprung disease. ^[9]

The criteria for clinical diagnosis of MEN2B includes the presence of the following ^[9] :

• MTC
• Pheochromocytoma
• Mucosal neuromas of the lips and tongue
• Medullated corneal nerve fibers
• Ectopic lenses
• Distinctive faces with enlarged lips
• Marfanoid body habitus
• Inability to cry tears

Evaluation

NCCN guidelines recommend offering a MEN2 clinical evaluation to individuals with a clinical diagnosis or suspicion of MEN2, even those with a negative RET genetic test. At-risk relatives should also be offered evaluation even if RET mutation has not been identified or if RET genetic testing has not been performed in the affected family member. Clinical evaluation should include the following tests ^[9] :

• Biochemical tests of hormone levels
• Imaging tests to localize MEN2-associated tumors
• Genetic counseling and testing

Genetic Testing

Predictive RET gene testing is the clinical standard of care for all individuals with a positive family history of MEN2 because of the very high risk of early-onset MTC in affected individuals, including children. ^[25]

The ATA guidelines recommend offering genetic counseling and genetic testing for RET germline mutations to the following individuals ^[1] :

• First-degree relatives of patients with confirmed hereditary MTC
• Parents whose infants or young children have the classic phenotype of MEN2B
• Patients with cutaneous lichen amyloidosis
• Infants or young children with Hirschsprung disease (HD) and exon 10  RET germline mutations, and adults with MEN2A and exon 10 mutations who have symptoms suggestive of HD

The NCCN guidelines recommend genetic counseling and RET testing for the following individuals ^[9] :

• Patients diagnosed with MTC or clinically diagnosed with MEN2 or primary C-cell hyperplasia
• At-risk relatives of patients with known germline  RET mutation

Screening

The ATA guidelines recommend screening for pheochromocytoma by measuring free plasma metanephrines and normetanephrines or 24-hour urinary metanephrines and normetanephrines. Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results. The following patients should be screened ^[1] :

• Children in the high risk (ATA-H) and highest risk (ATA-HST) categories by age 11 years 
• Children in the moderate risk (ATA-MOD) category by age 16
• Women with MEN2 who are planning a pregnancy or are pregnant; if detected, pheochromocytoma should be treated prior to the third trimester

Before surgery for MTC, both the ATA and NCCN guidelines recommend screening for coexisting pheochromocytoma. ^{[24, 1]}  

Treatment 

The ATA and NCCN guidelines recommend removal of pheochromocytoma prior to surgery for MTC or hyperparathyroidism to prevent a possible hypertensive crisis. ^{[24, 1]}

Pheochromocytoma should be resected by laparoscopic or retroperitoneoscopic adrenalectomy. Subtotal adrenalectomy to preserve adrenal cortical function should be considered as an alternative procedure. Patients with no adrenal glands require glucocorticoid and mineralocorticoid replacement therapy and should be carefully monitored to ensure that their steroid levels are adequate. Patients should be educated regarding the risk of adrenal crisis and wear a bracelet or a necklace indicating that they have no adrenal glands and are on corticosteroid replacement therapy. Glucocorticoid supplementation will be required if they become severely ill or are injured. ^[1]  

Surveillance

Surveillance intervals for patients with pheochromocytomas following a complete resection include the following ^[9] :

• History, physical examination with blood pressure, and tumor markers measured after 3 to 12 months, then every 6 months for the first 3 years and annually for up to 10 years
• Chest CT with or without contrast, abdominal/pelvic CT or MRI with contrast, or FDG-PET/CT can be considered

The ATA guidelines include the following recommendations for the management of hyperparathyroidism in patients with MEN2A ^[1] :

• Patients in the high and moderate risk (ATA-H and ATA-MOD) categories should be screened for hyperparathyroidism at the time of screening for pheochromocytoma 
• Only visibly enlarged parathyroid glands should be resected. If all four glands are enlarged, surgical options include subtotal parathyroidectomy with a piece of one gland left in situ on a vascular pedicle or total parathyroidectomy with a heterotopic autograft. 
• Patients who develop hyperparathyroidism subsequent to thyroidectomy for MTC should have localization studies performed prior to repeat neck surgery.
• When repeat surgery is performed, all enlarged parathyroid glands should be removed, and parathyroids of normal size should be left in situ. If only one enlarged parathyroid gland is identified and there is histological documentation that three parathyroid glands have been removed previously, a portion of the enlarged gland should either be left in situ with an adequate blood supply or grafted to a heterotopic site. 

Hypoparathyroidism is a common complication of thyroidectomy. NCCN guidelines recommend 4-gland exploration and selective resection of abnormal parathyroid glands. Normal parathyroid glands should be left intact when possible. Subtotal parathyroidectomy is recommended when all glands appear abnormal. After subtotal or total parathyroidectomy, calcium levels should be evaluated to screen for parathyroid tumors. ^[9]  

Prevention of medullary thyroid cancer:

Both ATA and NCCN guidelines recommend prophylactic thyroidectomy for individuals who have a documented RET mutation and are at risk for aggressive medullary thyroid carcinoma. ^{[1, 24]}

Medullary Thyroid Carcinoma Surgery

With nearly 100% penetrance of medullary thyroid carcinoma in MEN 2A patients, surgical intervention is recommended in all patients who are identified to carry the MEN2A gene. With genetic analysis available, these patients are often found to have an earlier stage of disease, with many patients having only parafollicular C-cell hyperplasia.

Total thyroidectomy has been recommended for patients as young as 3 years for MEN2A if they contain the genetic mutation. In patients with the RET genetic mutation for MEN 2B, total thyroidectomy is recommended in infancy because medullary thyroid carcinoma behaves more aggressively in these patients.

In contrast to patients with sporadic cases of medullary thyroid carcinoma, who have solitary tumors, patients with MEN2A have bilateral and multifocal disease.

Surgical strategies

The extent of surgery is controversial. Total thyroidectomy with central neck dissection is recommended for all patients with proven or probable medullary thyroid carcinoma. The need for either a unilateral or a bilateral modified neck dissection is controversial.

The inclusion of a modified neck dissection has been recommended for patients with palpable jugular chain lymphadenopathy. Some surgeons advocate a routine modified neck dissection. Others sample the jugular chain intraoperatively and proceed with dissection only if histologic evidence of metastatic disease is found on frozen section.

Children often do not require a node dissection, because their disease is at the hyperplasia stage and has not reached metastatic potential. Moreover, patients undergoing prophylactic thyroidectomy do not require lymphadenectomy.

Patients who have late-stage medullary thyroid cancer with symptomatic or progressive disease who are not surgical candidates may benefit from treatment with vandetanib, a tyrosine-kinase inhibitor that inhibits vascular endothelial growth factor and epidermal growth factor.

Persistent or recurrent calcitonin elevation

The treatment of persistent or recurrent elevations of calcitonin with random testing or following pentagastrin stimulation has been a clinical dilemma. Some investigators have found calcitonin levels to remain stable for approximately 5 years and have recommended surgical excision only for clinically apparent disease. Others have found that 66% of patients with node-positive disease died secondary to medullary thyroid carcinoma and advocate a more aggressive approach to follow-up care and surgery.