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Multiple endocrine neoplasia
ENDOCRINE CANCER
Multiple endocrine neoplasia syndromes, characteristic tumours and biochemical abnormalities
Multiple endocrine neoplasia
Type MEN1
Tumours Parathyroids
Rajesh V Thakker Pancreatic islets • Gastrinoma
Multiple endocrine neoplasia (MEN) is characterized by tumours involving two or more endocrine glands within a single patient. This disorder has previously been termed ‘multiple endocrine adenopathy’ and ‘pluriglandular syndrome’, but MEN is now the preferred term. There are two major forms of MEN, type 1 (MEN1, Wermer’s syndrome) and type 2 (MEN2, Sipple’s syndrome); each form is characterized by the development of tumours within specific endocrine glands (Figure 1). The clinical manifestations of the MEN syndromes are related to the sites of the tumours and to their products of secretion. The diagnosis and management of each tumour is similar to that in non-MEN patients. The MEN syndromes are uncommon, but because they are inherited as autosomal dominant disorders, the finding of MEN in a patient has important implications for other family members; firstdegree relatives have about a 50% risk of developing the disease. Occasionally, a MEN syndrome may arise sporadically (i.e. without a family history). It may be difficult to distinguish sporadic and familial forms; in some cases, there is no family history because the parent with the disease died before developing any manifestations. Thus, biochemical and genetic screening are important in all patients with MEN syndromes and their families.
• Insulinoma • Glucagonoma • VIPoma
• PPoma Pituitary (anterior) • Prolactinoma • GH-secreting • ACTH-secreting
• Non-functioning Associated tumours • Adrenal cortical
MEN2a
Multiple endocrine neoplasia type 1 MEN1 is characterized by the combined occurrence of tumours of the parathyroids, pancreatic islet cells and anterior pituitary. Parathyroid tumours occur in 95% of MEN1 patients, resulting in the hypercalcaemia of primary hyperparathyroidism. Parathyroid tumours detected by hypercalcaemia are the first manifestation of MEN1 in about 90% of patients. Pancreatic islet cell tumours occur in 40% of MEN1 patients. Gastrinomas are the most common type and insulinomas the second most common. Glucagonomas and VIPomas are rare, whereas pancreatic polypeptidomas are more common but remain asymptomatic. Gastrinomas, leading to Zollinger–Ellison syndrome, are the most important cause of morbidity and mortality in MEN1 patients. Anterior pituitary tumours occur in 30% of MEN1 patients. Most (60%) are prolactinomas; somatotrophinomas (growth hormone-secreting tumours) are the next most common (20%). Less than 15% are corticotrophinomas or non-functioning tumours. Associated tumours that occur in MEN1 include adrenal cortical tumours (5%), carcinoid tumours (4–10%), lipomas (1%), facial angiofibromas (88%) and collagenomas (72%).
MEN2b
↑Gastrin and ↑basal gastric acid output Hypoglycaemia and ↑insulin Glucose intolerance and ↑glucagon ↑Vasoactive intestinal peptide, and watery diarrhoea, hypokalaemia and achlorhydria ↑Pancreatic polypeptide Hyperprolactinaemia ↑Growth hormone Hypercortisolaemia and ↑adrenocorticotrophic hormone Nil or α-subunit Hypercortisolaemia or primary hyperaldosteronism ↑5-hydroxyindoleacetic acid Nil Hypercalcitoninaemia1 ↑Catecholamines Hypercalcaemia and ↑parathyroid hormone Hypercalcitoninaemia
Medullary thyroid carcinoma ↑Catecholamines Phaeochromocytoma Associated abnormalities • Mucosal neuromas • Marfanoid habitus • Medullated corneal nerve fibres • Megacolon
Autosomal dominant inheritance of MEN has been established In some patients, basal serum calcitonin concentrations are normal but exhibit an abnormal rise at 1 minute and 5 minutes after stimulation with pentagastrin, 0.5 µg/kg 1
1
Genetics: the gene causing MEN1 is on chromosome 11q13 and is a putative tumour suppressor gene. It comprises ten exons encoding a novel 610-amino acid protein (MENIN) that interacts with the activated protein 1 transcriptional factor JunD in the nucleus. MENIN acts by the transcriptional regulation pathway, suppressing JunDactivated transcription and thereby controlling cell proliferation. Most (> 80%) of the germline MEN1 mutations in MEN1 families
Rajesh V Thakker is May Professor of Medicine and Head of the Academic Endocrine Unit at the University of Oxford, UK. Conflicts of interest: none declared. MEDICINE 33:12
• Carcinoid • Lipoma Medullary thyroid carcinoma Phaeochromocytoma Parathyroid
Biochemical features Hypercalcaemia and ↑parathyroid hormone
44
© 2005 The Medicine Publishing Company Ltd
ENDOCRINE CANCER
Screening for multiple endocrine neoplasia type 1 and hypercalcaemia is the first manifestation in about 90% of MEN1 patients. Measurement of gastrointestinal hormones and specific endocrine function tests (Figure 1) should be reserved for individuals who have symptoms and signs of a MEN1-associated tumour. Genetic testing – mutational analysis of the coding region identifies the abnormality in about 95% of MEN1 patients. This may be used to identify family members who are at risk of developing tumours, enabling targeting of screening at these individuals. Relatives who do not have the mutation can be reassured and do not require regular screening. Begin annual screening (minimum of serum calcium and prolactin) at 5 years of age in MEN1-affected families, and 6-monthly screening for additional tumours (as above and Figure 1) in any patient known to have MEN1.
Who should be screened for MEN1? • Any patient with two or more MEN1-associated endocrine tumours • Any patient < 30 years of age with one MEN1-associated endocrine tumour • Any individual with a relative with MEN1 Screening Clinical history and examination are undertaken, looking for symptoms and signs of hypercalcaemia, nephrolithiasis, peptic ulcer disease, neuroglycopenia, hypopituitarism, galactorrhoea and amenorrhoea in women, acromegaly, Cushing’s disease, visual field loss, subcutaneous lipomas, facial angiofibromas and collagenomas. Biochemical screening of serum calcium and prolactin is required in all individuals – patients may be asymptomatic,
2
Multiple endocrine neoplasia type 2b. a Note the thyroidectomy scar, and the nodule on the left side of the neck representing metastases of medullary thyroid carcinoma. b Mucosal neuromas on the tongue and lips. c Bilateral lung metastases of medullary thyroid carcinoma. The patient had a history of diarrhoea and malabsorption as a result of multiple intestinal diverticulae (Figure 4).
a
b
c
3
MEN2a is the most common. Medullary thyroid carcinoma is associated with phaeochromocytoma (50% of patients), which may be bilateral, and parathyroid tumours (20%). MEN2b represents 5% of cases of MEN2. It is characterized by medullary thyroid carcinoma (Figure 3a) and phaeochromocytoma associated with a marfanoid habitus, mucosal neuromas (Figure 3b), medullated corneal fibres, and intestinal autonomic ganglion dysfunction leading to multiple diverticulae (Figure 4) and megacolon. Parathyroid tumours do not usually occur. MTC-only – in this variant, medullary thyroid carcinoma is the sole manifestation of the syndrome.
are inactivating, and each family generally has a unique mutation. Furthermore, there appears to be a lack of phenotype–genotype correlation, as found in MEN2 (see below). It is therefore difficult to implement MEN1 gene testing in the clinical setting, and genetic tests (Figure 2) are not yet routinely available.
Multiple endocrine neoplasia type 2 MEN2 is the association of medullary thyroid carcinoma and phaeochromocytoma. Three variants are recognized – MEN2a, MEN2b and MTC-only. MEDICINE 33:12
45
© 2005 The Medicine Publishing Company Ltd
ENDOCRINE CANCER
Screening for multiple endocrine neoplasia type 2 Who should be screened for MEN2? • Any patient with medullary thyroid carcinoma, or two or more MEN2-associated endocrine tumours • Any patient < 30 years of age with one MEN2-associated endocrine tumour • Any patient with mucosal neuromas or somatic features of MEN2b • Any individual with a relative with MEN2 or a history of goitre, hypertension, stroke or sudden death Screening Mutational analysis of the c-ret gene codons 609, 611, 618, 634, 768, 804 and 918 is currently available via regional genetics laboratories. The c-ret mutation is initially identified for the proband, and the family members (usually first-degree relatives) are tested for this; further clinical and biochemical screening is restricted to members who have inherited the mutation. Clinical and biochemical screening is performed every 3–6 months in known MEN2 patients to identify development of additional tumours, and every 6–12 months in unaffected carriers; look for symptoms and signs of: • medullary thyroid carcinoma (e.g. lumps in the neck), diarrhoea (30% of patients) or dysphagia (16%) • phaeochromocytoma (e.g. hypertension, headaches, palpitations, sweating) • hypercalcaemia caused by parathyroid tumours • MEN2b-related neuromas and features. Biochemical tests include serum calcitonin (basal and post-pentagastrin stimulation), urinary catecholamines and/or metanephrines, and serum calcium and parathyroid hormone.
4 Radiograph of barium meal and follow-through in a patient with multiple endocrine neoplasia type 2b (Figure 3). Note the presence of multiple intestinal diverticulae, which are secondary to autonomic ganglion dysfunction.
Genetics: the gene causing MEN2 is on chromosome 10cen–10q11.2, a region containing the c-ret proto-oncogene, which encodes a tyrosine kinase receptor with cadherin-like and cysteine-rich extracellular domains and a tyrosine kinase intracellular domain. Specific mutations of c-ret have been identified for each of the three MEN2 variants. • In 95% of patients, MEN2a is associated with mutations of the cysteine-rich extracellular domain. Mutations in codon 634 account for 85% of MEN2a mutations. • MTC-only is associated with mutations in the cysteine-rich extracellular domain. Most mutations are in codon 618. • MEN2b is associated with mutations in codon 918 of the intracellular tyrosine kinase domain in 95% of patients. The c-ret proto-oncogene is also involved in the aetiology of papillary thyroid carcinomas and Hirschsprung’s disease. Genetic testing – mutational analysis of c-ret to detect mutations in codons 609, 611, 618, 634, 768 and 804 in MEN2a and MTConly, and codon 918 in MEN2b, has been used in the diagnosis and management of patients and families with these disorders. Such testing quickly and reliably identifies the 50% of family members who do not have the mutation and who therefore do not have to undergo further screening (Figure 5). For family members who have inherited the mutation and are at high risk of developing tumours, there are two clinical approaches. • In one approach, continued testing of calcitonin release following pentagastrin stimulation is recommended; total thyroidectomy is reserved until an abnormal pentagastrin test is observed. This usually delays total thyroidectomy until 10–13 years of age. • In the alternative approach, total thyroidectomy is recommended, on the sole basis of the abnormal genetic test, at the age of 5 years; this is the earliest age at which metastasis in MEN2a has been identified. In MEN2b, metastasis at 2 years of age has been reported, and total thyroidectomy at an earlier age has been recommended. The advantages of this approach are that pentagastrin testing is avoided, and that it is more likely that a cure will be achieved before micrometastases develop. MEDICINE 33:12
5
Management of affected families is complex, requiring careful coordination between the medical team (endocrinologist, geneticist, surgeon and general practitioner) and the family.
FURTHER READING Gagel R F. Multiple endocrine neoplasia type 2. In: DeGroot L J, Jameson J L, eds. Endocrinology. 4th ed. Philadelphia: Saunders, 2001: 2518–32. Gagel R F, Cotes G J. Ret protooncogene mutations in multiple endocrine neoplasia type 2. In: Bilezikian J P, Raisz L G, Rodan G A, eds. Principles of bone biology. San Diego: Academic Press,1996: 799–807. Thakker R V. Multiple endocrine neoplasia type 1. In: DeGroot L J, Jameson J L, eds. Endocrinology. 4th ed. Philadelphia: Saunders, 2001: 2503–17. 46
© 2005 The Medicine Publishing Company Ltd
Multiple endocrine neoplasia syndromes, characteristic tumours and biochemical abnormalities
Multiple endocrine neoplasia
Type MEN1
Tumours Parathyroids
Rajesh V Thakker Pancreatic islets • Gastrinoma
Multiple endocrine neoplasia (MEN) is characterized by tumours involving two or more endocrine glands within a single patient. This disorder has previously been termed ‘multiple endocrine adenopathy’ and ‘pluriglandular syndrome’, but MEN is now the preferred term. There are two major forms of MEN, type 1 (MEN1, Wermer’s syndrome) and type 2 (MEN2, Sipple’s syndrome); each form is characterized by the development of tumours within specific endocrine glands (Figure 1). The clinical manifestations of the MEN syndromes are related to the sites of the tumours and to their products of secretion. The diagnosis and management of each tumour is similar to that in non-MEN patients. The MEN syndromes are uncommon, but because they are inherited as autosomal dominant disorders, the finding of MEN in a patient has important implications for other family members; firstdegree relatives have about a 50% risk of developing the disease. Occasionally, a MEN syndrome may arise sporadically (i.e. without a family history). It may be difficult to distinguish sporadic and familial forms; in some cases, there is no family history because the parent with the disease died before developing any manifestations. Thus, biochemical and genetic screening are important in all patients with MEN syndromes and their families.
• Insulinoma • Glucagonoma • VIPoma
• PPoma Pituitary (anterior) • Prolactinoma • GH-secreting • ACTH-secreting
• Non-functioning Associated tumours • Adrenal cortical
MEN2a
Multiple endocrine neoplasia type 1 MEN1 is characterized by the combined occurrence of tumours of the parathyroids, pancreatic islet cells and anterior pituitary. Parathyroid tumours occur in 95% of MEN1 patients, resulting in the hypercalcaemia of primary hyperparathyroidism. Parathyroid tumours detected by hypercalcaemia are the first manifestation of MEN1 in about 90% of patients. Pancreatic islet cell tumours occur in 40% of MEN1 patients. Gastrinomas are the most common type and insulinomas the second most common. Glucagonomas and VIPomas are rare, whereas pancreatic polypeptidomas are more common but remain asymptomatic. Gastrinomas, leading to Zollinger–Ellison syndrome, are the most important cause of morbidity and mortality in MEN1 patients. Anterior pituitary tumours occur in 30% of MEN1 patients. Most (60%) are prolactinomas; somatotrophinomas (growth hormone-secreting tumours) are the next most common (20%). Less than 15% are corticotrophinomas or non-functioning tumours. Associated tumours that occur in MEN1 include adrenal cortical tumours (5%), carcinoid tumours (4–10%), lipomas (1%), facial angiofibromas (88%) and collagenomas (72%).
MEN2b
↑Gastrin and ↑basal gastric acid output Hypoglycaemia and ↑insulin Glucose intolerance and ↑glucagon ↑Vasoactive intestinal peptide, and watery diarrhoea, hypokalaemia and achlorhydria ↑Pancreatic polypeptide Hyperprolactinaemia ↑Growth hormone Hypercortisolaemia and ↑adrenocorticotrophic hormone Nil or α-subunit Hypercortisolaemia or primary hyperaldosteronism ↑5-hydroxyindoleacetic acid Nil Hypercalcitoninaemia1 ↑Catecholamines Hypercalcaemia and ↑parathyroid hormone Hypercalcitoninaemia
Medullary thyroid carcinoma ↑Catecholamines Phaeochromocytoma Associated abnormalities • Mucosal neuromas • Marfanoid habitus • Medullated corneal nerve fibres • Megacolon
Autosomal dominant inheritance of MEN has been established In some patients, basal serum calcitonin concentrations are normal but exhibit an abnormal rise at 1 minute and 5 minutes after stimulation with pentagastrin, 0.5 µg/kg 1
1
Genetics: the gene causing MEN1 is on chromosome 11q13 and is a putative tumour suppressor gene. It comprises ten exons encoding a novel 610-amino acid protein (MENIN) that interacts with the activated protein 1 transcriptional factor JunD in the nucleus. MENIN acts by the transcriptional regulation pathway, suppressing JunDactivated transcription and thereby controlling cell proliferation. Most (> 80%) of the germline MEN1 mutations in MEN1 families
Rajesh V Thakker is May Professor of Medicine and Head of the Academic Endocrine Unit at the University of Oxford, UK. Conflicts of interest: none declared. MEDICINE 33:12
• Carcinoid • Lipoma Medullary thyroid carcinoma Phaeochromocytoma Parathyroid
Biochemical features Hypercalcaemia and ↑parathyroid hormone
44
© 2005 The Medicine Publishing Company Ltd
ENDOCRINE CANCER
Screening for multiple endocrine neoplasia type 1 and hypercalcaemia is the first manifestation in about 90% of MEN1 patients. Measurement of gastrointestinal hormones and specific endocrine function tests (Figure 1) should be reserved for individuals who have symptoms and signs of a MEN1-associated tumour. Genetic testing – mutational analysis of the coding region identifies the abnormality in about 95% of MEN1 patients. This may be used to identify family members who are at risk of developing tumours, enabling targeting of screening at these individuals. Relatives who do not have the mutation can be reassured and do not require regular screening. Begin annual screening (minimum of serum calcium and prolactin) at 5 years of age in MEN1-affected families, and 6-monthly screening for additional tumours (as above and Figure 1) in any patient known to have MEN1.
Who should be screened for MEN1? • Any patient with two or more MEN1-associated endocrine tumours • Any patient < 30 years of age with one MEN1-associated endocrine tumour • Any individual with a relative with MEN1 Screening Clinical history and examination are undertaken, looking for symptoms and signs of hypercalcaemia, nephrolithiasis, peptic ulcer disease, neuroglycopenia, hypopituitarism, galactorrhoea and amenorrhoea in women, acromegaly, Cushing’s disease, visual field loss, subcutaneous lipomas, facial angiofibromas and collagenomas. Biochemical screening of serum calcium and prolactin is required in all individuals – patients may be asymptomatic,
2
Multiple endocrine neoplasia type 2b. a Note the thyroidectomy scar, and the nodule on the left side of the neck representing metastases of medullary thyroid carcinoma. b Mucosal neuromas on the tongue and lips. c Bilateral lung metastases of medullary thyroid carcinoma. The patient had a history of diarrhoea and malabsorption as a result of multiple intestinal diverticulae (Figure 4).
a
b
c
3
MEN2a is the most common. Medullary thyroid carcinoma is associated with phaeochromocytoma (50% of patients), which may be bilateral, and parathyroid tumours (20%). MEN2b represents 5% of cases of MEN2. It is characterized by medullary thyroid carcinoma (Figure 3a) and phaeochromocytoma associated with a marfanoid habitus, mucosal neuromas (Figure 3b), medullated corneal fibres, and intestinal autonomic ganglion dysfunction leading to multiple diverticulae (Figure 4) and megacolon. Parathyroid tumours do not usually occur. MTC-only – in this variant, medullary thyroid carcinoma is the sole manifestation of the syndrome.
are inactivating, and each family generally has a unique mutation. Furthermore, there appears to be a lack of phenotype–genotype correlation, as found in MEN2 (see below). It is therefore difficult to implement MEN1 gene testing in the clinical setting, and genetic tests (Figure 2) are not yet routinely available.
Multiple endocrine neoplasia type 2 MEN2 is the association of medullary thyroid carcinoma and phaeochromocytoma. Three variants are recognized – MEN2a, MEN2b and MTC-only. MEDICINE 33:12
45
© 2005 The Medicine Publishing Company Ltd
ENDOCRINE CANCER
Screening for multiple endocrine neoplasia type 2 Who should be screened for MEN2? • Any patient with medullary thyroid carcinoma, or two or more MEN2-associated endocrine tumours • Any patient < 30 years of age with one MEN2-associated endocrine tumour • Any patient with mucosal neuromas or somatic features of MEN2b • Any individual with a relative with MEN2 or a history of goitre, hypertension, stroke or sudden death Screening Mutational analysis of the c-ret gene codons 609, 611, 618, 634, 768, 804 and 918 is currently available via regional genetics laboratories. The c-ret mutation is initially identified for the proband, and the family members (usually first-degree relatives) are tested for this; further clinical and biochemical screening is restricted to members who have inherited the mutation. Clinical and biochemical screening is performed every 3–6 months in known MEN2 patients to identify development of additional tumours, and every 6–12 months in unaffected carriers; look for symptoms and signs of: • medullary thyroid carcinoma (e.g. lumps in the neck), diarrhoea (30% of patients) or dysphagia (16%) • phaeochromocytoma (e.g. hypertension, headaches, palpitations, sweating) • hypercalcaemia caused by parathyroid tumours • MEN2b-related neuromas and features. Biochemical tests include serum calcitonin (basal and post-pentagastrin stimulation), urinary catecholamines and/or metanephrines, and serum calcium and parathyroid hormone.
4 Radiograph of barium meal and follow-through in a patient with multiple endocrine neoplasia type 2b (Figure 3). Note the presence of multiple intestinal diverticulae, which are secondary to autonomic ganglion dysfunction.
Genetics: the gene causing MEN2 is on chromosome 10cen–10q11.2, a region containing the c-ret proto-oncogene, which encodes a tyrosine kinase receptor with cadherin-like and cysteine-rich extracellular domains and a tyrosine kinase intracellular domain. Specific mutations of c-ret have been identified for each of the three MEN2 variants. • In 95% of patients, MEN2a is associated with mutations of the cysteine-rich extracellular domain. Mutations in codon 634 account for 85% of MEN2a mutations. • MTC-only is associated with mutations in the cysteine-rich extracellular domain. Most mutations are in codon 618. • MEN2b is associated with mutations in codon 918 of the intracellular tyrosine kinase domain in 95% of patients. The c-ret proto-oncogene is also involved in the aetiology of papillary thyroid carcinomas and Hirschsprung’s disease. Genetic testing – mutational analysis of c-ret to detect mutations in codons 609, 611, 618, 634, 768 and 804 in MEN2a and MTConly, and codon 918 in MEN2b, has been used in the diagnosis and management of patients and families with these disorders. Such testing quickly and reliably identifies the 50% of family members who do not have the mutation and who therefore do not have to undergo further screening (Figure 5). For family members who have inherited the mutation and are at high risk of developing tumours, there are two clinical approaches. • In one approach, continued testing of calcitonin release following pentagastrin stimulation is recommended; total thyroidectomy is reserved until an abnormal pentagastrin test is observed. This usually delays total thyroidectomy until 10–13 years of age. • In the alternative approach, total thyroidectomy is recommended, on the sole basis of the abnormal genetic test, at the age of 5 years; this is the earliest age at which metastasis in MEN2a has been identified. In MEN2b, metastasis at 2 years of age has been reported, and total thyroidectomy at an earlier age has been recommended. The advantages of this approach are that pentagastrin testing is avoided, and that it is more likely that a cure will be achieved before micrometastases develop. MEDICINE 33:12
5
Management of affected families is complex, requiring careful coordination between the medical team (endocrinologist, geneticist, surgeon and general practitioner) and the family.
FURTHER READING Gagel R F. Multiple endocrine neoplasia type 2. In: DeGroot L J, Jameson J L, eds. Endocrinology. 4th ed. Philadelphia: Saunders, 2001: 2518–32. Gagel R F, Cotes G J. Ret protooncogene mutations in multiple endocrine neoplasia type 2. In: Bilezikian J P, Raisz L G, Rodan G A, eds. Principles of bone biology. San Diego: Academic Press,1996: 799–807. Thakker R V. Multiple endocrine neoplasia type 1. In: DeGroot L J, Jameson J L, eds. Endocrinology. 4th ed. Philadelphia: Saunders, 2001: 2503–17. 46
© 2005 The Medicine Publishing Company Ltd