Multiple endocrine neoplasia

Published on 01/03/2015 by admin

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Multiple endocrine neoplasia

Multiple endocrine neoplasias (MEN) are inherited tumour predisposition syndromes, characterized by tumours in two or more endocrine glands. Clinical manifestations of these syndromes result either from hormone overproduction by the tumours or from other adverse effects of tumour growth. Inheritance is autosomal dominant.

MEN 1

A clinical diagnosis of MEN 1 can be made if the patient has at least two of the following:

parathyroid adenoma

pancreatic endocrine tumour

pituitary adenoma

adrenal cortex adenoma

carcinoid tumour.

The approximate frequencies of these tumours in MEN 1 are shown in Figure 71.1.

Fig 71.1 Tumours associated with MEN syndromes. Percentages are approximate.

The inactivated gene in MEN 1 is a tumour suppressor gene, the protein product of which (menin) normally inhibits genes involved in cell proliferation. MEN 1 gene mutations invariably lead to endocrine tumours, but family members carrying the same MEN 1 gene mutation can have completely different clinical manifestations of the syndrome. Genetic testing for MEN 1 allows earlier recognition and surgical removal of tumours. In the past patients with MEN 1 died from, e.g. peptic ulceration due to gastrinoma, or nephrolithiasis resulting from hyperparathyroidism.

Pituitary tumours in MEN 1 most often overproduce prolactin, but sometimes produce ACTH or growth hormone, resulting in Cushing’s disease or acromegaly respectively. The pancreatic tumours can produce gastrin, insulin, vasoactive intestinal polypeptide (VIP), glucagon or somatostatin, resulting in characteristic clinical features. The adrenocortical tumours seen in MEN 1 are often non-functional.

MEN 2

In MEN 2 the RET (REarrranged during Transfection) gene encodes a tyrosine kinase receptor for a family of growth factors. Unlike MEN 1, different mutations of this gene are associated with specific tumours or tumour combinations. Clinically, MEN 2 presents as several distinct phenotypes.

MEN 2A

Medullary carcinoma of the thyroid (MCT) is present, often with phaeochromocytoma or hyperparathyroidism (Fig 71.1). Phaeochromocytoma is bilateral in about 50% of affected cases.

MEN 2B

MCT is again present, along with phaeochromocytomas, but parathyroid adenomas are rare. Additional features specific to MEN 2B include mucosal ganglioneuromas in the gastrointestinal tract and a Marfanoid habitus. MEN 2B presents at an earlier age than MEN 2A, and carries a worse prognosis.

Familial medullary carcinoma of the thyroid

This shares many of the genetic and clinical features of MEN 2, but phaeochromocytomas and parathyroid adenomas occur less frequently.

Screening and treatment

Some of the endocrine tumours associated with MEN, e.g. parathyroid and pituitary adenomas, are common, and only rarely part of a wider syndrome. MEN should be suspected where these tumours present early (<35 years), or where there is a family history of a MEN-associated tumour. By contrast, pancreatic endocrine tumours are rare and their diagnosis should prompt routine biochemical screening for, e.g. hyperparathyroidism or prolactinoma. In cases where MEN is diagnosed, all family members should be screened.

All carriers of MEN mutations will develop one or other of the associated endocrine tumours. Periodic biochemical screening has an important role to play in the follow-up of identified carriers. However, definitive confirmation or exclusion of an individual’s MEN predisposition requires genetic testing. In some cases provocation tests may be necessary (Fig 71.2).

Fig 71.2 Calcium and pentagastrin provocation test of calcitonin secretion. There is an exaggerated response to combined calcium and pentagastrin provocation in a patient with medullary carcinoma of the thyroid.

Prophylactic surgical removal of the predisposed gland(s) may be indicated where the certainty of early cancer presentation is high. In particular, thyroidectomy is recommended for pre-school children who carry the RET mutations with the worst prognosis.

The APUD concept

Carcinoid and pancreatic islet cell tumours are seen in MEN syndromes but also occur sporadically. They arise from specialized neuroendocrine cells that have the capacity for amine precursor uptake and decarboxylation (APUD). Some of the peptides and amines secreted by these cells act like classical hormones, being delivered through the bloodstream, while others are local paracrine regulators or neurotransmitters (Table 71.1). Overproduction of peptides or amines by tumours gives rise to associated tumour syndromes.

Table 71.1

Selected molecules which regulate gastrointestinal function

Substance	Type of regulator	Major action
Gastrin	Hormone	Gastric acid and pepsin secretion
Cholecystokinin (CCK)	Hormone	Pancreatic enzyme secretion
Secretin	Hormone	Pancreatic bicarbonate secretion
Gastric inhibitory polypeptide (GIP)	Hormone	Enhances glucose mediated insulin release, inhibits gastric acid secretion
Vasoactive intestinal polypeptide (VIP)	Neurotransmitter	Smooth muscle relaxation. Stimulates pancreatic bicarbonate secretion
Motilin	Hormone	Initiates interdigestive intestinal motility
Somatostatin	Hormone	Numerous inhibitory effects
	Neurotransmitter
	Paracrine
Pancreatic polypeptide (PP)	Hormone
	Paracrine	Inhibits pancreatic bicarbonate and protein secretion
Enkephalins	Neurotransmitter	Opiate-like actions
Substance P	Neurotransmitter	Contraction of smooth muscle
	Paracrine

Carcinoid tumours

These most commonly arise in the appendix and ileocaecal region where the fore- and mid-gut meet. Carcinoid tumours may convert as much as half of the dietary intake of tryptophan into serotonin, secretion of which causes distinctive clinical effects, known as the carcinoid syndrome. This is characterized by flushing, diarrhoea and sometimes valvular heart disease. Intestinal carcinoid tumours only produce carcinoid syndrome if they have metastasized to the liver, whereas extra-intestinal carcinoids, e.g. bronchial, which do not drain into the portal circulation, may cause it even in the absence of metastasis. Serotonin may be measured directly in plasma or platelets, but the diagnosis is more often made by measurement in urine of its metabolite, 5-hydroxyindoleacetic acid (Fig 71.3).

Fig 71.3 Serotonin and its urinary metabolite 5-hydroxyindoleacetic acid. Certain foodstuffs, such as bananas and tomatoes, contain 5-hydroxyindoleacetic acid and may interfere with the urinary determination.

Insulinomas

These are the commonest pancreatic endocrine tumours.

Others

Gastrinomas, VIPomas, glucagonomas and somatostatinomas are all either rare or very rare.

Clinical note

Proton pump inhibitors (PPIs), such as omeprazole, are widely used to treat peptic ulcers. They may cause an increase in plasma gastrin concentrations to values that might suggest the presence of a gastrinoma. These drugs should be stopped before samples are taken for gastrin measurements.

Case history 57

A 50-year-old man, was referred to a neurologist after complaining of a 6-month history of severe headache. He was found to be slightly hypertensive. U & Es and LFTs were unremarkable. The only abnormality initially noted was a serum adjusted calcium concentration of 2.80 mmol/L.

• What further investigations are required in this patient?

Comment on page 170.

Multiple endocrine neoplasia

Multiple endocrine neoplasias are inherited cancer predisposition syndromes.

Diagnosis of MEN should prompt screening of family members.

Prophylactic surgical removal of endocrine glands may be appropriate.

The carcinoid syndrome is related to overproduction of serotonin.

Pancreatic islet cell tumours are rare.

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