Multiple endocrine neoplasia type 2

What is multiple endocrine neoplasia type 2?

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 35,000.³

There is an association between medullary thyroid cancer (MTC) and phaeochromocytoma. MEN2 is further divided into MEN2A and MEN2B, with the following distinctions:⁴

• MEN2A:

  • Nearly all patients with MEN2A have either C-cell hyperplasia or medullary thyroid cancer, 50% have pheochromocytoma, and 20-30% hyperparathyroidism, but incidence of these manifestations is dependent on the underlying RET mutation.

  • MEN2A patients have a less virulent form of MTC than do MEN2B patients.

  • MEN2A patients do not have the phenotypical abnormalities of mucosal neuromas and Marfanoid habitus found in MEN2B patients.

• MEN2B:

  • 100% incidence of C-cell hyperplasia or medullary thyroid cancer, pheochromocytoma in 30-50%, mucosal neuromas, and rarely hyperparathyroidism.

A third subtype of MEN2 is familial MTC only.⁵

Symptoms of multiple endocrine neoplasia type 2 (presentation)⁴

• 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).⁶

• MTC may present as early as 2 months old.⁷

• 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.⁸

• Cutaneous lichen amyloidosis in MEN2A presents with multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back.

MEN type 2A⁹

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.³

• 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:¹⁰
  

  • 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.

Phaeochromocytoma^{11 12}

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 complex¹³

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

The diagnosis of MEN2 is established when a RET pathological variant is detected by molecular genetic testing.⁴

• 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.

See also the separate articles on Thyroid Cancers, Phaeochromocytoma and Hyperparathyroidism.

Screening for multiple endocrine neoplasia type 2⁴

Genetic screening can identify gene carriers with high accuracy (98%). If initial sequence analysis is negative, and the clinical suspicion of a genetic syndrome remains high based on family history, physical characteristics, young age at diagnosis, or pathological findings in the thyroid such as extensive C-cell hyperplasia or bilateral MTC, then whole gene sequencing should be considered.

Patients who present with MTC, even with a negative family history need to be screened for RET mutations, as up to about 25% will be found to have a hereditary syndrome. A negative family history is not reliable in excluding patients from genetic testing, since about 40% of MEN2A gene carriers do not develop clinically apparent disease. De novo mutations are rare in MEN2A (up to 10%), in contrast to MEN2B, where de novo mutations are more frequent (45% of A883F carriers and 84% M918T carriers).

All patients of reproductive age carrying RET mutations, particularly those with mutations in codon 634 and 918, should be offered genetic counselling and be informed on the benefits and the potential risks of reproductive options, such as prenatal diagnosis and preimplantation diagnostic testing. The option of genetic testing in offspring should be discussed with future parents, where testing either directly after birth or at an older age could be discussed, based on the specific mutation in the family as well as individual preferences of the parents.

Patients at risk or with MTC, where genetic testing is not possible, should be under surveillance for MTC, phaeochromocytoma and hyperparathyroidism.

Management of multiple endocrine neoplasia type 2

General principles

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.¹⁴

If the condition is confirmed then genetic counselling is required.¹⁵ 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.

• 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.

MEN2B

• In patients with the genetic mutation for MEN2B, early prophylactic total thyroidectomy is recommended.¹⁶

• 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.¹⁷

Prognosis⁴

MTC is the major cause of death in MEN2. Phaeochromocytoma does not seem to have an association with shorter survival. Together with the presence of certain RET mutations, serum calcitonin, and number of lymph node metastases, these parameters are important factors influencing prognosis. The 10-year overall survival for patients with MTC was 64% in population based study from Denmark.

Disease stage is one of the most important prognostic factors: 10-year disease specific survival for patients with MTC is 98%, 93%, 87%, and 53% for disease stage I-IV, respectively. In children with MTC, higher disease stage also indicates a worse prognosis.

10-year survival rate in MEN2A patients (97%) is better than in patients with MEN2B (76%) which might be influenced by an earlier onset of disease and delay in diagnosis of MTC in (de novo) MEN2B patients.

Other syndromes associated with endocrine neoplasia

There are other syndromes which overlap with the MEN syndromes, including:¹⁸

• 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.¹⁹ 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.