Multiple Endocrine Neoplasia

The multiple endocrine neoplasia syndromes are genetic neoplastic conditions. Two types are recognised, classified as MEN 1 and MEN 2. Type 2 has three variants, classified as MEN2A, MEN2B and familial medullary carcinoma of thyroid.

Both are autosomal dominants with a high degree of penetrance. MEN 1 and MEN 2 have some clinical similarities but they are genetically different.

• The genetic abnormality of MEN 1 is on the long arm of chromosome 11 (11q13), and the gene cluster has been mapped precisely.¹
• The genetic defect in MEN 2, is on chromosome 10 (10q11.2) and has also been identified both for MEN2A² and MEN2B.³

The underlying problem for all the MEN syndromes is failure of a tumour suppressor gene.

It is also known as Wermer's syndrome.

Presentation (MEN1)

There is a combination of:

• Parathyroid hyperplasia
• Pancreatic endocrine tumours
• Pituitary adenomas.

The prevalence of MEN1 has been estimated at about 1 in 10,000 with an equal sex distribution. Many MEN 1 cases are sporadic mutations, and usually present between the 3rd and 5th decades, but familial cases can be identified earlier through screening.

• Parathyroid hyperplasia and adenomata. Hyperparathyroidism is the presenting feature of MEN 1 in the majority of patients, and occurs in almost all cases. Patients present either with asymptomatic hypercalcaemia on biochemical screening or with the features of sporadic hyperparathyroidism. All 4 glands are diffusely hyperplastic and there may be nodule formation.
• Pancreatic endocrine tumours occur in about 70% of patients with MEN 1 and usually present between the ages of 15 and 50 if not identified by screening. Over 60% of tumours are gastrinomas and produce the Zollinger-Ellison syndrome and about 30% are insulinomas. They account for most of the morbidity and mortality of the MEN 1 syndrome. They both occur in about 10% of cases. As well as peptic ulcer, gastrinoma produces oesophagitis and diarrhoea. VIPoma and PPoma have rarely been described and there are only isolated reports of glucagonoma, but non-functioning tumours may occur frequently. Diffuse hyperplasia of the pancreas is usually seen and is similar to the parathyroid. In the majority of cases there are multiple adenomata, most of which are less than 1cm in diameter. Duodenal microgastrinoma is very common and probably account for almost half of all MEN 1 associated gastrinomas. They are usually multiple, with up to 15 separate tumours.
• Pituitary adenoma is detected by screening in 30% of patients, but is found at autopsy in 50%. Unlike the pancreas and parathyroid, there does not appear to be diffuse pituitary hyperplasia. Prolactinoma producing hyperprolactinaemia is the commonest tumour, and occurs in about 30% of cases. They tend to be more aggressive than sporadic cases.⁴ Acromegaly, due to excessive production of growth hormone (HGH) occurs in about 30%. ACTH may produce Cushing's syndrome but other functioning tumours are rare. The clinical presentation of pituitary tumours is described in the article on the subject.
• Skin lesions are common and occur in nearly 90% of patients, but they can be easily overlooked because of their subtle appearance. Benign tumours include multiple angiofibromas⁵ that were previously considered pathognomonic for tuberous sclerosis, collagenomas, and lipomas. They should be sought because they can act as markers for this syndrome.
• Other lesions in other tissues have been reported, but their relationship to the syndrome remains controversial. Carcinoid tumours of the foregut, midgut, and thymus occur in about 10%, and are often found in the pancreas, but they are rarely symptomatic. Lipomata occur in a significant proportion of patients and act as a marker for affected individuals.

Diagnosis

Diagnosis of MEN1 depends on having a high level of suspicion in patients who present with one of the features such as hyperparathyroidism or increased gastric acid secretion.

Many people may also be diagnosed because of a proband in the family. This is discussed below under screening.

Management (MEN1)

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

• Diazoxide can be used to inhibit release of insulin, especially in tumours that are beyond surgery.
• High dose proton pump inhibitors are required for gastrin secreting tumours.
• After surgery to the pituitary, hormone replacement may be required.

The surgical approach to pancreatic endocrine tumours in MEN 1 is controversial.

• Surgical cure is best achieved by removing the pancreas and duodenum with adjacent lymph nodes. There is still a high rate of recurrence but the overall mortality remains low.⁶
• An alternative, potentially curative, approach is to perform a subtotal pancreatectomy with enucleation of palpable tumours in the head and careful exploration for duodenal lesions, which should also be resected.
• A more conservative strategy is to enucleate gross lesions to reduce the risk of developing metastatic disease and then control hormonal syndromes with appropriate medical therapy. The latter approach is probably appropriate for gastrinomas, because proton pump inhibitors are such an effective treatment, but for insulinomas medical therapy is often unsuccessful and symptoms usually recur after enucleation alone and more aggressive surgical management may be the best option.
• Treatment is the same as for sporadic pituitary tumours. This usually involves a transphenoidal operation to remove the tumour.
• Parathyroidectomy, subtotal or complete, is practiced for MEN1 but long-term follow-up reveals a high rate of recurrence in MEN 1 despite surgical intervention.⁷
• The treatment of metastatic disease is the same as in sporadic cases.

Prognosis

• The prognosis is generally good if adequate treatment is provided for parathyroid, pancreatic, and pituitary tumours.
• Pancreatic endocrine tumours associated with MEN 1 are less malignant than sporadic tumours and carry a better prognosis, with a median survival of 15 years compared to 5 years for patients with sporadic tumours. This may reflect more indolent disease or earlier diagnosis.

Screening (MEN1)

• The screening of first and second degree relatives of patients with MEN 1 is aimed at early detection of parathyroid, pancreatic, or pituitary lesions in gene carriers, to reduce the associated morbidity.
• There is no evidence that screening reduces mortality, although the identification of affected individuals in "malignant kindred" with aggressive pancreatic disease may allow curative surgery which would be expected to prolong survival.
• Screening lowers the age of detection of the syndrome by about 20 years.
• The most useful screening investigations are serum calcium, fasting gastrin, and prolactin, although in practice a full gut hormone screen is usually performed. It has been suggested that the most sensitive markers of pancreatic disease are basal and test-meal stimulated pancreatic polypeptide and gastrin, and basal insulin and proinsulin, identifying lesions at least 3 years before imaging studies. As pancreatic tumours are the only life-threatening aspect of the syndrome, such a screening protocol has merit.
• The MEN 1 syndrome rarely develops before the age of 5 or after the age of 70, and so screening should be performed annually from 5 to 65, and at longer intervals thereafter. 80% of affected individuals will have been identified by the 5th decade. Screening of patients with apparently sporadic pancreatic endocrine tumours for evidence of MEN 1 is probably justified, especially in those with gastrinomas or insulinomas.
• There is little evidence to support screening in those with sporadic pituitary tumours.
• MEN 1 is present in 15% of all patients with hyperparathyroidism, but hypercalcaemia per se may be associated with elevated fasting gastrin and pancreatic polypeptide. In those at risk of MEN 1 this would be highly significant, but in those with sporadic hyperparathyroidism, this very rarely indicates pancreatic disease. Hence, screening of all patients with hypercalcaemia is not warranted.
• Routine germline MEN1 mutation testing of all cases of "classical" MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services and testing should be considered for patients under 30 years old with sporadic hyperparathyroidism and multigland hyperplasia.⁸
• Genetic linkage analysis has greater than 95% predictive accuracy, and in most families a haplotype associated with the mutant allele can be found. If three markers can be identified, the accuracy improves to greater than 99%.

This is the association of medullary cell carcinoma of the thyroid (MTC) and phaeochromocytoma. The clinical features depend on the type of tumour present. Almost all patients with MEN2 have medullary carcinoma of the thyroid.

• 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.
• MEN 2B has the characteristic features of mucosal neuromas and a habitus suggestive of Marfan's syndrome .
  • Patients present much earlier than MEN 2A due to their characteristic appearance with a habitus suggestive of Marfan's syndrome and mucosal neuromas. This allow earlys intervention, as these characteristics 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 MEN2, especially MEN2B, and they may require surgery.⁹
  • 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.
• Medullary cell carcinoma of the thyroid (MTC) may occur alone without other features.

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.

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 MEN2A.
• Familial MTC alone (without the other features) is the most benign form of MTC.¹⁰ 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.

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.

Diagnosis of MEN 2

• 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.¹¹
• Parathyroid abnormalities are diagnosed when there are simultaneously elevated serum calcium and parathyroid hormone (PTH) levels with an elevated urinary calcium to creatinine ratio.

Screening for MEN2

In 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 2.¹²
• 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.

In 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.

In MTC:
There is familial medullary carcinoma of thyroid, without other associated malignancies. Screening for MTC is described above.

Management (MEN2)

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.¹³

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.¹⁴

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 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.

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.
• The role of prophylactic thyroidectomy in children carrying a MEN2 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.¹⁵
• 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).¹⁶

Counselling of patients with MEN is important so that they know what to expect and why continued follow-up is so important.¹⁷ Leaflets and various sources of information for patients are very valuable.

Prognosis (MEN2)

• Patients with MEN2B tend to do worse than those with MEN2A 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
• von Hippel-Lindau syndrome¹⁸ 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.
• Phaeochromocytoma may be associated with prolactinoma as a mixed MEN syndrome.