Multiple Endocrine Neoplasia Type 2 (MEN 2)

• MEN 2A
• MEN 2B
• Familial medullary carcinoma of thyroid

The underlying problem for all the MEN syndromes is failure of a tumour suppressor gene. The genetic defect in MEN 2 is on chromosome 10 (10q11.2) and has also been identified both for MEN 2A and MEN 2B.^1,2

MEN 2A is also known as Sipple's syndrome.

• Those who are not identified by screening usually present in the 4th and 5th decades.
• Parathyroid hyperplasia occurs in up to 80% of patients with MEN 2A, but less than 20% have hypercalcaemia. The remainder are identified at the time of thyroidectomy.
• Nephrolithiasis, nephrocalcinosis or renal failure may occur.
• Parathyroidectomy should be performed in those with hypercalcaemia and in the remaining patients grossly enlarged glands should be removed at the time of thyroidectomy.

Has the characteristic features of mucosal neuromas and a habitus suggestive of Marfan's syndrome.

• Patients tend to present much earlier than MEN 2A. This allows early intervention, as the neuromas usually predate MTC and phaeochromocytoma.
• Almost all patients have a Marfan's-like habitus, usually associated with skeletal abnormalities, particularly slipped femoral epiphysis.
• Delayed puberty is a common feature of the syndrome.
• Neuromas are commonly ocular and oral, causing whitish-yellow or pink nodules on the anterior aspect of the tongue, lips, and eyelids, with thickening of the mucosa and often eversion of the lower lids.
• Neuromas in the gut can cause an acquired Hirschsprung's disease in MEN 2, especially MEN 2B, and they may require surgery.³
• The nasal bridge may be broadened. Pedunculated neuromas are found on the mucosa of the cheek, and the corneal nerves are thickened and medullated. Involvement of peripheral motor and sensory nerves can cause a peroneal muscular atrophy (Charcot-Marie-Tooth disease) type picture. Intestinal ganglioneuromatosis affects about 75% of cases.
• Neuromas involve the autonomic nerves of both the myenteric and submucosal plexi and can cause poor suckling with failure to thrive, altered bowel habit, recurrent pseudo-obstruction, toxic megacolon, and occasionally dysphagia and vomiting, possibly due to achalasia.

This may occur alone without other features.

Familial medullary cell carcinoma of thyroid

MTC is a tumour of the C cells of the thyroid which secrete calcitonin, and this acts as a tumour marker.

• Only 25% of cases are familial.
• The sporadic 75% tend to be unilateral and the familial 25% bilateral in familial MTC and in MEN 2A.
• Familial MTC alone (without the other features) is the most benign form of MTC.⁴ MTC in association with MEN 2B is the most malignant form of the disease.
• In MEN 2 the initial thyroid lesion is C-cell hyperplasia, which has been found as early as the age of 3 years in MEN 2A and may be present at birth in MEN 2B. Over the subsequent 5 to 10 years microscopic MTC develops and finally gross tumours become apparent. MTC typically presents as a neck mass or neck pain at about age 15 to 20 years. However, more than 50% of such patients already have cervical lymph node metastases.

Phaeochromocytoma

• Phaeochromocytoma occurs in 50% of MEN 2.
• About 70% are bilateral, almost all are benign, and they are rarely extra-adrenal.
• They produce excessive adrenaline secretion, so that palpitation and other beta-adrenergic symptoms predominate initially.
• Hypertension is a late feature, but often present by the time of diagnosis.

Carney complex

Carney complex is a distinct rare type of MEN characterized by primary pigmented adrenocortical disease, pituitary adenoma, Sertoli-cell tumours, thyroid nodules, and additional nonendocrine features. The most commonly associated features are cardiac and skin myxomas, melanotic schwannomas and lentigines.

• Screening test for pheochromocytoma is 24 hours urine for elevated catecholamines and catecholamine metabolites, especially vanillyl-mandelic acid (VMA).
• Clinical suspicion or elevated urinary catecholamine values demand an abdominal MRI scan. A further test may be MIBG (131I-meta-iodo-benzyl-guanidine) scintigraphy if initial tets are positive because of the high frequency of multiple tumours.
• MTC is suspected with an elevated plasma calcitonin concentration. This is a specific and sensitive marker. In provocative testing, plasma calcitonin concentration is measured before and 2 and 5 minutes after intravenous administration of calcium.
• Thyroid tumours can be investigated by ultrasound if under 2cm in diameter and by a combination of CT and MRI if larger.⁵
• Parathyroid abnormalities are diagnosed when there are simultaneously elevated serum calcium and parathyroid hormone (PTH) levels with an elevated urinary calcium to creatinine ratio.

MEN 2A

• Screening using pentagastrin-stimulated calcitonin, probably identifies all cases before MTC has developed. Total thyroidectomy can be performed at the C-cell hyperplasia or microscopic MTC stage, and this should cure all patients. Screening to identify affected individuals and for early detection of thyroid and adrenal disease reduces both morbidity and mortality in MEN 2.⁶
• The pentagastrin test identifies microscopic MTC, 70% being detected before the age of 20, and, if a second test is positive, total thyroidectomy should be performed.
• Screening should commence at the age of 3 years and continue annually. The risk of developing MTC falls below 5% after the age of 35 and so screening can be performed less frequently thereafter.

MEN 2B

• Screening for MTC is not necessary, as all affected patients should have thyroidectomy.
• Serum calcium should be measured at annual screening to identify overt hyperparathyroidism.
• The two types of molecular diagnosis for MEN 2 are mutation analysis and linkage analysis of the RET proto-oncogene (chromosomal locus 10q11). Such testing is highly accurate and sensitive for presymptomatic identification of at-risk individuals in order to reduce morbidity and mortality through early intervention. Genetic linkage analysis has 98 to 99% predictive accuracy, and in individuals identified as at low risk of developing MEN 2 less frequent screening would be reasonable.
• In families in whom a mutation has been characterised affected individuals can be identified by mutation screening.

General principles

In MEN 2 the goals of management are:

• Identify individuals with germline RET -disease-causing mutations associated with MEN 2 before symptoms develop.
• Reduce morbidity and mortality in the highest risk individuals through either prophylactic thyroidectomy or screening for MTC, and through screening for phaeochromocytoma and parathyroid disease before symptoms develop
• Provide appropriate treatment for those who already have tumors. The management issues vary by MEN 2 subtype.

Operating on patients with pheochromocytoma or carcinoid syndrome can present a great challenge for the anaesthetist.⁷

Risk-based management using genetic alterations and biological markers can be used to categorize tumours into low-, intermediate- or high-risk and treatment can be tailored accordingly.⁸

MEN 2A

• The treatment for adrenal medullary hyperplasia or phaeochromocytoma is bilateral adrenalectomy, since the incidence of bilateral disease is high, and the mortality from phaeochromocytoma in MEN 2 about 15%, usually due to sudden death.
• If an adrenal lesion is identified at the same time as MTC, the adrenalectomy should be performed first.
• All patients should be operated on to prevent later morbidity from hypercalcaemia and there are two surgical approaches. Subtotal parathyroidectomy may be performed, but hyperparathyroidism will almost always recur, necessitating excision of the remaining parathyroid tissue. However, most surgeons would perform total parathyroidectomy, either with autotransplantation of one gland to the forearm, which can later be removed if hyperparathyroidism recurs, or with immediate replacement therapy with 1alpha-hydroxycholecalciferol.

MEN 2B

• In MEN 2B thyroidectomy with lymph node clearance should be performed at the earliest possible age in individuals with the phenotypic features, since MTC is biologically aggressive in these patients and has been reported as early as 15 months of age, with metastases by the age of 3 years.
• The role of prophylactic thyroidectomy in children carrying a MEN 2 gene is controversial. A significant number of patients with MEN 2A or 2B who undergo thyroidectomy in childhood for MTC have persistent or recurrent disease long-term. The genetic diagnosis of patients with these syndromes may allow for prophylactic surgery before the development of biochemical or clinical evidence of MTC. This approach is safe, but longer clinical follow-up will be necessary to confirm that MTC has been cured.⁹
• In those patients not identified by screening, thyroidectomy should still be performed, unless there are distant metastases, usually to lung or liver. It is probable that in all patients with palpable tumours, metastases to local lymph nodes will be present, so a central lymph node dissection should also be performed, probably with lateral node sampling to look for further spread.
• The most useful markers in the follow-up of MTC are plasma calcitonin and carcino-embryonic antigen (CEA).¹⁰

Counselling of patients with MEN is important so that they know what to expect and why continued follow-up is so important.¹¹ Leaflets and various sources of information for patients are very valuable.

• Patients with MEN 2B tend to do worse than those with MEN 2A, as the MTC is more aggressive.
• The prognosis is poor in this group, with recurrent disease in about 20% of patients with clinically occult but macroscopic MTC and in over 60% of those with palpable MTC.
• It is particularly poor in individuals with MEN 2B who present with clinically apparent MTC. Their 10 year survival is about 50%, and death from metastatic disease in the mid-twenties is common.

There are other syndromes which overlap with the multiple endocrine neoplasia syndromes.

• Phaeochromocytomata may be associated with pancreatic islet-cell tumours alone, or in combination with other syndromes e.g. with prolactinoma as a mixed MEN syndrome.
• Von Hippel-Lindau syndrome¹² is associated with a high incidence of phaeochromocytomata, islet-cell tumours, cerebellar haemangioblastomata, retinal angiomata and renal cell carcinoma.
• Neurofibromatosis type I (von Recklinghausen's syndrome) is often associated with phaeochromocytoma and rarely, with duodenal somatostatinoma and medullary thyroid carcinoma.