Presentation^[3]

• Patients may present with symptoms related to medullary thyroid carcinoma, hyperparathyroidism, or phaeochromocytoma. Virtually all patients have medullary thyroid carcinoma at the time of diagnosis, but may present with features of phaeochromocytoma or hyperparathyroidism.
• Symptoms may include hypertension, episodic sweating, diarrhoea, pruritic skin lesions or a lump in the neck (which may cause compressive symptoms).
• Hypercalcaemia may lead to constipation, polyuria, polydipsia, memory problems, depression, nephrolithiasis, glucose intolerance, gastro-oesophageal reflux, and fatigue.
• Phaeochromocytomas may present with hypertension and increased pulse rate, which may be constant or episodic. There may be episodes of sweating and headaches.
• Medullary thyroid carcinoma may cause diarrhoea.
• Chronic constipation.
• Cutaneous lichen amyloidosis in multiple endocrine neoplasia type 2A (MEN2A) presents with multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back.

MEN type 2A

MEN2A is also known as Sipple's syndrome.

• Those who are not identified by screening usually present in the fourth and fifth decades.
• Parathyroid hyperplasia occurs in up to 80% of patients with MEN2A, but less than 20% have hypercalcaemia. The remainder are identified at the time of thyroidectomy. Hyperparathyroidism is the least common manifestation of MEN2A and usually presents after the age of 30 years.^[3]
• 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.

MEN type 2B

• Patients tend to present much earlier than MEN2A. This allows early intervention, as the neuromas usually predate medullary thyroid carcinoma (MTC) and phaeochromocytoma.
• Almost all patients have a Marfan's-like habitus, usually associated with skeletal abnormalities, particularly slipped femoral epiphysis.
• MEN2B disease is also characterised by the development in early life of multiple mucosal neuromas. 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 appear as:^[4]
  • Glistening bumps around the lips, tongue, and lining of the mouth.
  • Bumps on the eyelids, which are often thickened - neuromas may also appear on the cornea and conjunctiva.
• 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, constipation, diarrhoea, recurrent pseudo-obstruction, toxic megacolon and, occasionally, dysphagia and vomiting, possibly due to achalasia.
• Patients with MEN2B disease also often develop spinal abnormalities, and abnormalities of the bones in the feet and thighs. Many have long limbs and loose joints. These features, along with thickened lips and eyelids are associated with Marfanoid habitus (the features of Marfan's syndrome). The nasal bridge may be broadened.
• Involvement of peripheral motor and sensory nerves can cause a peroneal muscular atrophy (Charcot-Marie-Tooth syndrome) type of picture.
• Delayed puberty is a common feature.

Medullary cell carcinoma of the thyroid^[5]

See also the separate Thyroid carcinoma article. In multiple endocrine neoplasia type 2 (MEN2) the initial thyroid lesion is C-cell hyperplasia, which has been found as early as the age of 3 years in MEN2A and may be present at birth in MEN2B. Over the subsequent 5 to 10 years microscopic medullary thyroid carcinoma (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.

• MTC may occur alone without other features of MEN2.
• MTC is a tumour of the C cells of the thyroid which secrete calcitonin, and this acts as a tumour marker.
• Inherited MTC accounts for 25% of cases of MTC, occurring in association with MEN types 2A and 2B, but non-MEN familial MTC also occurs.
• It may present with a thyroid lump. Local spread may cause hoarseness, dysphagia and dyspnoea. Diarrhoea may also occur.
• Metastases may occur, especially to the lung, liver and bone. Paraneoplastic syndromes are rare but may include Cushing's syndrome or carcinoid syndrome.
• Investigations include ultrasound scan, calcitonin levels (raised), fine-needle aspiration, and DNA testing for familial cases.
• Management: see separate Thyroid carcinoma article.
• Adverse prognostic indicators include older age, higher-grade lesions and incomplete surgical resection of the lesion.

Phaeochromocytoma^[6][7]

See also the separate Phaeochromocytoma article.

• Phaeochromocytoma occurs in 50% of MEN2. Pheochromocytomas in patients with MEN2 are usually found in the adrenals after presentation of medullary thyroid cancer.
• About 70% are bilateral, almost all are benign, and they are rarely extra-adrenal.
• They produce excessive adrenaline secretion leading to tachycardia, palpitations, hypertension and headache.
• Investigations include plasma concentrations of free metanephrines (or free metanephrines in urine), and imaging with CT or MRI. False-positive CT/MRI studies can occur and the specificity of CT/MRI may vary from 50-90%. Positron emission tomography (PET) is also used for diagnosis.
• Treatment is surgical and laparoscopic surgery is increasingly used. Overall, half of the patients with malignant phaeochromocytomas remain alive for five years.

Carney complex

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

Diagnosis of multiple endocrine neoplasia type 2

• Screening test for phaeochromocytoma 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 metaiodobenzylguanidine (MIBG) scan is useful for localising pheochromocytomas.^[3]
• Medullary thyroid carcinoma (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 initially by ultrasound and fine-needle aspiration.
• Parathyroid abnormalities are diagnosed when there are simultaneously elevated serum calcium and parathyroid hormone levels with an elevated urinary calcium to creatinine ratio.

Screening for multiple endocrine neoplasia type 2

The two types of molecular diagnosis for MEN2 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 98-99% predictive accuracy and, in individuals identified as at low risk of developing MEN2, less frequent screening would be reasonable. In families in whom a mutation has been characterised, affected individuals can be identified by mutation screening.

Screening, to identify affected individuals and for early detection of thyroid, parathyroid and adrenal disease, reduces both morbidity and mortality in MEN2:^[3]

• Annual 24-hour urine collections for catecholamine concentrations to detect phaeochromocytoma at the earliest age possible.
• Annual testing of serum calcium and parathyroid hormone levels should begin at age 10 years.
• Recurrence of medullary thyroid carcinoma (MTC) should be monitored with calcitonin, carcinoembryonic antigen (CEA) and provocative calcitonin testing with the pentagastrin stimulation test, with serial measurements of serum calcitonin measured. False-positive and false-negative results have been reported.^[3]

Management

General principles

In multiple endocrine neoplasia type 2 (MEN2) the goals of management are:

• Identify individuals with germline RET-disease-causing mutations associated with MEN2 before symptoms develop.
• Reduce morbidity and mortality in the highest-risk individuals through either prophylactic thyroidectomy or screening for medullary thyroid carcinoma (MTC), and through screening for phaeochromocytoma and parathyroid disease before symptoms develop.

Operating on patients with phaeochromocytoma or carcinoid syndrome can present a great challenge for the anaesthetist.^[8]

Counselling of patients with MEN is important so that they know what to expect and why continued follow-up is so important.^[9] Leaflets and various sources of information for patients are very valuable.

MEN2A

• 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 MEN2 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.
• Total thyroidectomy has been recommended for patients as young as 3 years for MEN2A if they contain the genetic mutation.^[3]
• Hyperparathyroidism: subtotal parathyroidectomy is advised, along with cervical thymectomy because of the increased risk of supernumerary parathyroid glands. Persistent or recurrent hyperparathyroidism is unusual and less likely to occur in MEN2A patients than in MEN1 patients.^[3]

MEN2B

• 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. In patients with the genetic mutation for MEN2B, total thyroidectomy is recommended in infancy.^[3]
• 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 carcinoembryonic antigen (CEA).^[10]

Prognosis

• Patients with multiple endocrine neoplasia type 2B (MEN2B) tend to do worse than those with MEN2A, as the medullary thyroid carcinoma (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 MEN2B who present with clinically apparent MTC. Their 10-year survival is about 50%, and death from metastatic disease in the mid-twenties is common.

Other syndromes associated with endocrine neoplasia

There are other syndromes which overlap with the multiple endocrine neoplasia (MEN) syndromes:

• Phaeochromocytomas may be associated with pancreatic islet-cell tumours alone, or in combination with other syndromes eg with prolactinoma as a mixed MEN syndrome.
• Von Hippel-Lindau syndrome^[11] is associated with a high incidence of phaeochromocytomas, islet-cell tumours, cerebellar haemangioblastomas, 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 (MTC).