Multiple Endocrine Neoplasia Type 2 (MEN2) Treatment & Management

Multiple endocrine neoplasia type 2 (MEN2) is treated with surgery. The surgical procedures for individual components of MEN2 are as follows:

• Parathyroidectomy
• Thyroidectomy
• Adrenalectomy
• Cryoablation for inoperable thyroid massess

Radiation therapy either as primary or adjuvant therapy for various tumorsPreoperative medical treatment may consist of prostaglandin inhibitors to alleviate diarrhea that may be associated with medullary thyroid cancer.

Evaluation for pheochromocytomas is important because these should be removed before other elective surgical interventions. This evaluation can be performed before parathyroidectomy or thyroidectomy under a single general anesthetic if the patient is stable. 

Hypercalcemia

Patients presenting with severe hypercalcemia should first be hydrated, after which they may be treated with furosemide. If they remain severely hypercalcemic, consider treatment with calcitonin, denosumab, ^[19] or bisphosphonates (eg, pamidronate, zoledronic acid). While bisphosphonates are most commonly used, cinacalcet, a calcimimetic, can also be effective at reducing serum calcium levels. These patients need urgent parathyroidectomy once calcium levels have been lowered, ideally below 14 mg/dL. Patients who are not surgical candidates may also benefit from cinacalcet.

Thyroid supplementation

Thyroid hormone supplementation is necessary following total thyroidectomy in carriers of RET mutations or following a diagnosis of medullary thyroid carcinoma.

Deterrence/prevention

Start annual 24-hour urine collections for catecholamine concentrations to detect pheochromocytoma at the earliest age possible. Begin annual testing of serum calcium and PTH levels at age 10 years.

Outpatient care

Monitor patients for recurrence of medullary thyroid carcinoma with calcitonin and carcinoembryonic antigen (CEA), and consider provocative calcitonin testing.

Perform annual screening for hyperparathyroidism with serum calcium and parathyroid hormone (PTH) levels in MEN2A patients. Obtain urinary catecholamine levels on an annual basis to assess for pheochromocytoma. Carefully monitor medication dosage and adverse effects.

Consultations

Consultations with the following specialists may be necessary:

• Geneticist
• Endocrinologist
• Oncologist

 With nearly 100% penetrance of medullary thyroid carcinoma (MTC) 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 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 MTC 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.

Hyperparathyroidism is the least common manifestation of MEN2A. It usually manifests in patients older than 30 years. Histologically, the parathyroid glands in MEN2A patients consist of a chief-cell hyperplasia; this hyperplasia is asymmetrical in terms of parathyroid size.

To reduce the risk of postoperative hypocalcemia, remove only grossly abnormal parathyroid glands. If all parathyroid glands are enlarged, a subtotal parathyroidectomy is advocated, leaving an approximately 60-mg remnant. Perform a cervical thymectomy because of the increased risk of supernumerary parathyroid glands. ^[20]

Persistent or recurrent hyperparathyroidism is unusual and less likely to occur in MEN2A patients than in MEN1 patients.

While all MEN2A patients may have bilateral adrenal medullary hyperplasia, the tumors may or may not be present bilaterally at the time of initial operation. In this situation, a unilateral adrenalectomy avoids the risk of addisonian crisis and improves the quality of life, as patients will not require replacement therapy. The advent of laparoscopic adrenalectomy has substantially decreased the morbidity of adrenalectomy.  

Cortical sparing is a surgical technique in which the surgeon leaves a small amount of vascularized unilateral or bilateral adrenal tissue that will be sufficient to maintain the normal function of the adrenal cortex for a prolonged period of time. Cortical-sparing adrenal surgery is increasingly performed, based on the very low risk of malignancy and the high probability of maintaining normal adrenal cortical function. In a review by Castinetti et al, glucocorticoid function was normal in 57–100% of patients treated for bilateral pheochromocytoma with at least one adrenal-sparing surgery. ^[14]  

The overall risk of recurrence of pheochromocytoma following cortical-sparing adrenal surgery is estimated as 0–21%. A study of 533 patients with MEN2-associated pheochromocytoma did not find any significant difference in the rate of recurrence between patients treated by total or partial adrenalectomy. In the cortical-sparing group, recurrence developed in the operated gland in four of 153 (2.6%) patients after a mean follow-up of 10 years; in the adrenalectomy group, recurrence occurred in 11 of 717 (1.5%) patients after a mean follow-up of 13 years. ^[21]

Patients should be monitored lifelong for evidence of recurrent disease. After an initial follow-up visit, patients may be evaluated at 6 months, then yearly if they are asymptomatic.

Evaluations should include the following:

• Physical examination
• 24-hour urine catecholamine, metanephrine, and vanillylmandelic acid levels
• CEA level
• Calcitonin level
• Serum calcium level

If recurrent hypercalcemia is suggested, consider patients for repeat cervical exploration.

If pheochromocytoma is suggested, evaluate patients for surgical resection. This tumor is likely in the remaining contralateral adrenal, although workup should include a CT scan and an MIBG scan to evaluate for recurrence at the resected area or at an extra-adrenal site. Recurrences in the resected area are more common if a subtotal adrenalectomy was performed initially.

The management of patients with calcitonin/CEA elevations has been controversial. Resect any palpable cervical disease. Some practitioners have advocated routine cervical ultrasonography with exploration for any evidence of recurrence. Many patients remain asymptomatic with elevated calcitonin levels for 20 years or longer.

Calcitonin and CEA doubling times provide sensitive markers for progression and aggressiveness of metastatic medullary thyroid carcinoma. Calcitonin doubling times less than 6 to 12 months are associated with poor survival, while doubling times > 24 months are associated with a very favorable prognosis. ^{[22, 23]} A tumor volume doubling time of ≤1 year is associated with poorer overall survival.

Complications of MEN2 include the following: 

• Usual surgical complications
• Persistent disease
•  Hypertensive emergency/urgency during pheochromocytoma surgery
• Hypoglycemia
• Hypocalcemia
• Hypothyroidism
• Recurrent laryngeal nerve injury 

Consultation with the following services is indicated for patients with MEN2:

• Endocrinology
• Surgical oncology
• Otorhinolaryngology
• Genetics
• Social work

Endocrinology should be consulted perioperatively for management of MEN2, especially for blood pressure variation and for management of potential postoperative complications, in addition to usual standard of care.

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. ^{[24, 1]}  

Risk stratification

The 2009 ATA guidelines stratified risk level of RET carriers into four categories, A through D, based on the increasing aggressiveness of the particular mutations. Due to some confusion and lack of uniformity with other staging guidelines, the 2015 revised ATA guidelines transition category D to “highest risk” (HST), transition category C to “high risk” (H), and combine categories B and A into “moderate risk”. The risk stratification, screening schedules, and prophylactic thyroidectomy schedules are described in the table below. ^[1]

Table. Revised ATA MTC Risk Levels and Pediatric Recommendations (Open Table in a new window)

CEA=carcinoembryonic antigen;  Ctn=calcitonin; MEN=multiple endocrine neoplasia; US=ultrasound

Surveillance

The American Society of Clinical Oncology (ASCO) recommends the following screening tests for individuals with MEN2:

• Yearly blood tests for ionized calcium and parathyroid hormone levels, beginning in childhood (MEN2A)

• Yearly blood tests for catecholamines and catecholamine metabolites (metanephrine and normetanephrine), beginning in childhood 

• Magnetic resonance imaging (MRI) or computerized tomography (CT or CAT) scan of the abdomen to detect pheochromocytomas, every 4 to 5 years or when abnormal catecholamine or metanephrine levels are detected.