Multiple endocrine neoplasia type 2 (MEN2) is a rare familial cancer syndrome caused by mutations in the RET proto-oncogene. The underlying problem for all the MEN syndromes is failure of a tumour suppressor gene. The genetic defect in MEN2 is on chromosome 10 (10q11.2) and has also been identified both for MEN2A and MEN2B.[1, 2]The prevalence of MEN2 is about 1 in 35,000.
There is an association between medullary thyroid cancer (MTC) and phaeochromocytoma. MEN2 is further divided into MEN2A and MEN2B, with the following distinctions:
- Phenotype - MEN2A patients do not have the phenotypical abnormalities of mucosal neuromas and Marfanoid habitus found in MEN2B patients.
- MTC - MEN2A patients have a less virulent form of MTC than do MEN2B patients.
- Parathyroid hyperplasia - MEN2A patients may have parathyroid hyperplasia, which is rare in MEN2B patients.
A third subtype of MEN2 is familial MTC only.
- Patients may present with symptoms related to MTC, hyperparathyroidism, or phaeochromocytoma. Patients may present with features of phaeochromocytoma or hyperparathyroidism but MEN2 has a very high lifetime risk of developing MTC (more than 95% in untreated patients).
- MTC may present as early as 2 months old.
- 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.
- Around 40% of patients with MEN2 develop phaeochromocytoma.
- Cutaneous lichen amyloidosis in 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.
- MTC occurs in nearly all MEN2A patients and is generally the first manifestation of MEN2A, whereas phaeochromocytoma occurs in 30-50% and hyperparathyroidism occurs in about 20% of MEN2A patients.
- Parathyroid hyperplasia occurs in up to 80% of patients with MEN2A but only about 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.
- Nephrolithiasis, nephrocalcinosis or chronic kidney disease 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
- MEN2B is characterised by early development of aggressive MTC. Multiple and bilateral phaeochromocytoma occur in 50% of patients.
- Patients tend to present much earlier than MEN2A. 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.
- 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:
- 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
See also separate Thyroid Cancer article.
In 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 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 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) and fine-needle aspiration, and DNA testing for familial cases. Adverse prognostic indicators include older age, higher-grade lesions and incomplete surgical resection of the lesion.
See also separate Phaeochromocytoma article.
- Phaeochromocytoma occurs in 50% of MEN2. Phaeochromocytomas in patients with MEN2 are usually found in the adrenals after presentation of MTC.
- About 70% are bilateral, almost all are benign and they are rarely extra-adrenal.
- They produce excessive adrenaline (epinephrine) 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 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 phaeochromocytomas.
- 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 two and five 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:
- 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 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.
In 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 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.
- 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.
- 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.
- In patients with the genetic mutation for MEN2B, early prophylactic total thyroidectomy is recommended.
- 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 CEA.
Patients with MEN2B tend to do worse than those with MEN2A, as the MTC is more aggressive. The prognosis is particularly poor in individuals with MEN2B who present with clinically apparent MTC, when death from metastatic disease in the mid-twenties is common.
Other syndromes associated with endocrine neoplasia
There are other syndromes which overlap with the MEN syndromes, including:
- 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.This 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 MTC.
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