Multiple Endocrine Neoplasia: Types 1 and 2
Deborah J. Marsha · Oliver Gimmb,c
ªHormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney E25, St. Leonards, N.S.W., Australia; bDepartment of Surgery and ‘Institute for Clinical and Experimental Medicine (IKE), University Hospital, Linköping, Sweden
Abstract
Multiple endocrine neoplasia type 1 (MEN 1) and type 2 (MEN 2) are autosomal-dominantly inherited syndromes where highly penetrant germline mutations predispose patients to the development of tumours in hormone- secreting cells. In the case of MEN 1, loss-of-function ger- mline mutations in the tumour suppressor gene MEN1 increase the risk of developing pituitary, parathyroid and pancreatic islet tumours, and less commonly thymic car- cinoids, lipomas and benign adrenocortical tumours. In the case of MEN 2, gain-of-function germline mutations clustered in specific codons of the RET proto-oncogene increase the risk of developing medullary thyroid car- cinoma (MTC), phaeochromocytoma and parathyroid tumours. Offering RET testing is best practice for the clinical management of patients at-risk of MEN 2, and MEN 2 has become a classic model for the integration of molecular medicine into patient care. Prophylactic thyroidectomy in an asymptomatic RET mutation carrier to address the risk of developing MTC can prevent or cure this malignancy. No similar preventative strategies can be employed to prevent or cure MEN 1-associated tumours. Genetic testing for MEN 1 is therefore both more complex due to a general lack of mutational hot- spots, and the benefit to patients is less straight for- ward. While a number of genotype-phenotype corre- lations exist in MEN 2, providing further rationale for performing genetic testing in this condition, these cor- relations are absent in MEN 1. This review summarises our current knowledge of these two syndromes with emphasis on those aspects with specific relevance to the otorhinolaryngologist.
Copyright @ 2011 S. Karger AG, Basel
Multiple endocrine neoplasia (MEN) types 1 and 2 are part of a group of rare familial endocrine neoplasia disorders characterised by the presence of tumours in hormone secreting cells along with other disorders including von Hippel-Lindau dis- ease, familial paraganglioma and phaeochromo- cytoma, Cowden syndrome, hyperparathyroid- ism jaw-tumour syndrome and Carney complex (reviewed in Marsh and Zori [1]). MEN 1 and MEN 2 fall at either end of the spectrum when considering both the ease of conducting genetic testing, and the ability to act on genetic informa- tion to prevent or cure a tumour.
Multiple Endocrine Neoplasia Type 1
Clinical Presentation/Phenotype
MEN 1 has been estimated to occur in between 1 in 10,000 to 1 in 100,000 people [2] and is char- acterised by neuroendocrine tumours of the gastro-enteric-pancreatic tract. These lesions in- clude parathyroid tumours causing primary hy- perparathyroidism (pHPT), pancreatic islet cell tumours, anterior pituitary tumours, and less commonly thymic carcinoids, lipomas, thyroid tumours, benign tumours of the adrenal cortex, and atypically generally benign tumours of the
| Organ | Type of tumour/disease | Biochemical investigation | Suggested age to commence screening, years |
|---|---|---|---|
| MEN 1 | |||
| Parathyroid | primary | (ionised) calcium, (intact) parathormone | 10 |
| hyperparathyroidism | |||
| Pancreas | insulinoma | insulin, fasting glucose | 5 |
| gastrinoma | (stimulated) gastrin | 20 | |
| other tumours | chromogranin A, pancreatic polypeptide, proinsulin, glucagon | 20 | |
| Pituitary | prolactinoma | prolactin | ? |
| Foregut | carcinoids | serotonin, 5-hydroxyindoleacetic acid (5-HIAA) | 20 |
| thymic carcinoids | serotonin | 20-25 | |
| MEN 2 | |||
| Thyroid | medullary thyroid carcinoma | calcitonin | MEN 2A: 5-10 MEN 2B: birth |
| Parathyroid | primary hyperparathyroidism | (ionised) calcium, (intact) parathormone | MEN 2A: 20-35 MEN 2B: never |
| Adrenal | phaeochromocytoma | catecholamines, metanephrines, vanillylmandelic acid (VMA), chromogranin A | 30-40 |
adrenal medulla (phaeochromocytoma); howev- er, presentation can vary markedly between two individuals (table 1).
Diagnostic criteria for MEN 1 specifies that an individual must have abnormalities in at least two of the more commonly affected endocrine glands, as well as a first-degree relative with at least one MEN 1-related lesion or a known MEN1 mutation [3]. Almost 50% of MEN 1 patients will succumb to MEN 1-related disease, most frequently associ- ated with pancreatic islet cell tumours [4]. Almost all patients with MEN 1 develop pHPT that can lead to hypercalcemia throughout their lifetime, and although this is almost always benign, its
recurring nature can make surgical management difficult. In comparison to sporadic pHPT, these patients typically present between 20 and 25 years of age, approximately 30 years earlier than their sporadic counterparts [5]. Biochemical screening is recommended from the age of 10 years. The un- derlying genetic cause implies that all parathyroid glands can be affected. In fact, by the time of diag- nosis, most patients already present with multiple parathyroid gland enlargement classified as either parathyroid hyperplasia or multiple adenomas. In MEN 1 patients, the diagnosis of pHPT is made if both parathyroid hormone (PTH) and ionised calcium levels are elevated [6].
Genetic Background/Genotype
Germline mutations in the tumour suppressor gene MEN1 were first identified in 1997 in pa- tients with MEN 1 [7, 8]. MEN1 mutations are also found rarely in the related condition Familial Isolated Hyperparathyroidism (FIH). MEN1 con- sists of 10 exons, where exon 1 is not translated. It encodes the 610 amino acid (67 kDa) ubiquitous- ly expressed and predominantly nuclear protein menin that has roles in the regulation of transcrip- tion, controlling genome stability, the regulation of cell division and cell cycle control. Up to 90% of MEN 1 patients will have a MEN1 mutation, with approximately 10% of these mutations appearing to be de novo, i.e. identified in patients with ap- parently sporadic parathyroid adenomas [9].
Mutations are predicted to be loss of function and include small (and less frequently large) dele- tions, small insertions, insertion-deletions, as well as nonsense and missense point mutations and splicing mutations, with the majority predicted to prematurely truncate menin [10, 11]. There are over 570 mutation entries for MEN1 in The Human Genome Mutation Database, Cardiff, UK (http:// www.hgmd.cf.ac.uk/ac/index.php), and well over 1,000 mutations reported in total [11], with mu- tations covering the entirety of the gene. There is some indication of potential mutational hot-spots at codons 83-84, 516 and 210-211 accounting for approximately 12% of all mutations [11]; howev- er, in general, lack of frequent mutational clusters complicates genetic screening for this disorder. Of note, in MEN 1 patients without MEN1 mutation, germline mutations in one of the cyclin-dependent kinase inhibitor genes have been reported; how- ever, these would appear to be rare [12].
Genotype-Phenotype Correlations
No appreciable genotype-phenotype correlations have been identified in MEN 1 [11, 13, 14].
Genetic Screening
Knowledge of a patient’s MEN1 mutation carrier status is useful for clinical management strategies
and life-planning decisions, but cannot avoid or cure the malignancies associated with this condi- tion [3]. This is largely because there are no op- tions for prophylactic surgery for MEN 1 patients, who are generally not treated until their condition first manifests. Biochemical screening to search for early disease in asymptomatic mutation carri- ers is recommended. If a member of a family tests negative for a MEN1 mutation that is present in affected family members, this removes them from the lifelong burden of biochemical and radiologi- cal screening for associated tumours. Guidelines have been published outlining recommended di- agnostic tests and therapy for MEN1 mutation carriers [5, 10].
Surgery and Experimental Therapies
The indication to operate is given in any MEN 1 patient with the diagnosis of pHPT. Prior to pri- mary surgery, sophisticated imaging techniques are generally not recommended since their sen- sitivity is low in MEN 1-associated pHPT [15]. Due to the fact that MEN 1-associated pHPT is a multiglandular disease, an attempt must be made to identify all parathyroid glands intraoperative- ly. This implies routine removal of the thyrothy- mic ligament where parathyroid glands can be found in up to 20% of patients. Once all para- thyroid glands are localised, the smallest gland should be identified. A remnant about half the size of a normal gland should either be left in situ (referred to as subtotal parathyroidectomy) or be autotransplanted (referred to as total para- thyroidectomy and autotransplantation). The other parathyroid glands shall be removed com- pletely. As recurrence of the preserved tissue is common, if subtotal parathyroidectomy is per- formed the remnant should be marked with a non-absorbable suture or clip in order to facili- tate reoperation [15].
Calcimimetics, calcium-sensing receptor ago- nists, show promise for the treatment of sporad- ic pHPT and may have a role in treating elevated PTH in the context of MEN 1 [5, 16, 17]. Depot
long-acting octreotide has also been used to treat MEN 1-associated pHPT [18]. Multicentre, ran- domised clinical trials still need to be conducted in order to assess the efficacy of these experimen- tal therapies.
Multiple Endocrine Neoplasia Type 2
Clinical Presentation/Phenotype
MEN 2 is believed to occur in 1 in 200,000 live births [19]. The clinical presentation of MEN 2 may vary significantly between two individuals and includes pHPT, medullary thyroid carcino- ma (MTC; a malignant tumour of parafollicular thyroid C cells that secrete calcitonin) and phae- ochromocytoma (phaeo; tumour of the adrenal medulla) (table 1). If two or more of these tu- mours are present in 1 patient or in a close rela- tive, a diagnosis of MEN 2 should be considered. Around two thirds of people harbouring a RET mutation will develop one or more of these tu- mours by 70 years of age [20].
Clinically and genetically, two major types can be distinguished, namely MEN 2A and MEN 2B. In contrast to MEN 2A, patients with MEN 2B present with a Marfanoid habitus, mucosal neu- romas (which often cause the lips to appear large and patulous) and ganglioneuromatosis of the gastrointestinal tract that are clues for this clini- cal diagnosis. A third form that is also part of the clinical and genetic MEN 2 spectrum is famil- ial medullary thyroid carcinoma (FMTC) where MTC is the only phenotype, and often displays a later age of onset [5].
From the otorhinolaryngological point of view, MTC and pHPT are the two MEN 2-associated diseases that may need surgical treatment. Approximately 25% of all MTCs occur as part of MEN 2, with patients presenting at a younger age compared to their sporadic counterparts, particu- larly when identified as part of a family screening program. If not identified during family screening procedures, patients usually present with either
a thyroid tumour and/or cervical lymph node metastases.
MEN 2-associated pHPT is seen in up to 30% of patients with MEN 2A, and may include hy- perplasia or adenoma. pHPT is not reported in MEN 2B patients. Patients with MEN 2A- associated pHPT in general present with a very mild form of pHPT that is often asymptomatic. Severe manifestations are occasionally reported and, as is the case for MEN 1, MEN 2-associated parathyroid carcinoma is exceedingly rare. While the underlying genetic cause implies that all para- thyroid glands may be affected in MEN 2, often only one gland is enlarged. Both Hirschsprung disease, a lack of enteric ganglia in the hindgut, and the skin disorder cutaneous lichen amyloido- sis have been reported in MEN 2A/FMTC fami- lies [5].
Genetic Background/Genotype
Gain-of-function mutations in the proto- oncogene RET were first identified in the ger- mline of patients with MEN 2A in 1993, making MEN 2 the first inherited endocrine neopla- sia to be clarified at the molecular level [21]. Identification of RET mutations associated with MEN 2B and FMTC followed shortly thereafter (reviewed in Marsh et al. [22]). In the spectrum of familial cancer syndromes, activating mutations in a proto-oncogene are rare, with the vast major- ity of inherited cancer syndromes being caused by loss of function of a tumour-suppressor gene such as is seen in MEN 1 (reviewed in Marsh and Zori [1]). The RET gene codes for a transmem- brane receptor tyrosine kinase with roles in pro- liferation, migration and differentiation of neural crest-derived tissue.
Although RET has 21 coding exons, MEN 2-associated germline mutations are essentially confined to 7 of these exons (exons 8, 10, 11, 13, 14, 15 and 16) and are almost exclusively mis- sense mutations. Activating germline mutations in cysteines in RET exon 10 codons 609, 611, 618 or 620, and exon 11 codons 630 or 634 would
appear to account for over 95% of MEN 2A fami- lies. Mutations are also found less frequently in non-cysteine residues, 768, 790, 791, 804 and 891, and predominantly in families with FMTC. Specific RET mutations account for MEN 2B; most commonly M918T in exon 16, and less fre- quently A883F in exon 15 (reviewed in Marsh et al. [22]). More than 50% of these MEN 2B muta- tions appear to be de novo.
Genotype-Phenotype Correlations
Genotype-phenotype correlations have been iden- tified in MEN 2 by international multi-centre stud- ies considering the family as a unit. These studies have indicated that the presence of a codon 634 mutation confers a higher risk of pHPT and phaeo [23, 24]. Specifically, presence of the C634R muta- tion has been reported to confer an even greater risk of pHPT than other mutations in the same codon [23], although this has not been shown for all studies. Furthermore, the C634R mutation has been reported to be associated with a higher inci- dence of metastases at diagnosis, while mutations at codon 634 have been associated with cutane- ous lichen amyloidosis (reviewed in Wiesner and Snow-Bailey [25]). Families in which MEN 2A or FMTC co-segregate with Hirschsprung’s disease tend to have germline RET mutations in codons 618 and 620 (reviewed in Eng [19]). Despite all of these correlations, it is important to observe that individuals within a single family who carry the same RET mutation can still display a highly vari- able phenotype.
Genetic Screening
Screening for RET mutations in patients either with MEN 2 or who are at-risk of developing this disease is recommended and suggested to be su- perior to the biochemical screening method for this disease that relies on the measurement of elevated calcitonin levels to detect the presence of MTC. As MTC can occur in very young chil- dren, it is suggested that RET testing should be performed at or before 5 years of age in at-risk
children [5]. Given the clustering of mutations in certain codons, the development of screening pro- grams that might involve methods such as direct sequencing, denaturing high-performance liquid chromatography, high resolution melt analysis, etc., is relatively straight forward. The benefits of genetic screening for MEN 2 are clear, in that prophylactic thyroidectomy can be performed in children with the ability to prevent or cure MTC. Knowledge of the exact RET mutation will give clues as to the likely aggressiveness of disease as indicated above, and can influence the age at which surgery is performed and perhaps even the extent of surgery.
Guidelines suggest that given the link between pHPT and codon 634 mutations, patients who harbour these mutations, and especially those with a C634R mutation, should be screened an- nually for pHPT by serum calcium and PTH test- ing [5].
Surgery and Experimental Therapies
In contrast to the sporadic form, MEN 2-associ- ated MTC is a multifocal disease and thyroid tis- sue left in situ is prone to develop MTC. Thus, total thyroidectomy should be performed and thyroid hormone replacement therapy instigated. Due to the high prevalence of often small lymph node metastases (LNM), a central cervical lymph node dissection should be included in index pa- tients, i.e. patients with clinically overt MTC, even if no LNM are found pre- or intraoperatively. In patients identified through RET mutation analy- sis, no central lymph node dissection is necessary if the calcitonin level is normal [26]. The onset of MTC in patients with MEN 2B is much ear- lier as compared to MEN 2A (table 1) and pa- tients should be treated as soon as the diagnosis is made.
MEN 2A-associated pHPT is rarely evident before the patient undergoes surgery for MTC where the opportunity exists to assess all para- thyroid glands for enlargement. Prior to surgery sophisticated imaging techniques for pHPT are
generally not recommended. Despite the fact that MEN 2A-associated pHPT has an underly- ing genetic cause, multiglandular disease is rarely seen. Still, an attempt should be made to identify all parathyroid glands intraoperatively. Once all parathyroid glands are localised, only glands that are enlarged need be removed [6]. Routine auto- transplantation of parathyroid tissue is not neces- sary. However, a normal parathyroid gland identi- fied during surgery for MTC that appears to have compromised vascularity (darkening of its sur- face) should be autotransplanted and marked as described for MEN 1.
Molecular target drugs that inhibit tyrosine ki- nase activity and angiogenesis are being investi- gated as therapies for MEN 2, predominantly as a treatment for advanced or metastatic MTC. One such drug, vandetanib (ZD6474) that is an inhibi- tor of RET and epidermal growth factor receptor (also a tyrosine kinase) activity, as well as vascular endothelial growth factor receptor shows promise [27]. As we enter the era of personalised medi- cine based on the presence of specific mutations and other molecular events in patients, it is ex- pected that additional options will arise for the treatment of MTC, pHPT and other manifesta- tions of MEN 2.
Conclusions
In summary, genetic testing is recommended for at-risk individuals in both MEN 1 and MEN 2 families; however, the ability to surgically prevent or cure an inherited malignancy based on this molecular knowledge is currently only possible in MEN 2. Clinical cancer geneticists and genetic counsellors should be part of a multidisciplinary team in addition to endocrinologists, endocrine surgeons, and where relevant, endocrine paedia- tricians managing MEN patients and their fam- ilies. As new molecular target drugs are discov- ered, knowledge of a patient’s mutation status, and likely the precise mutation, will become increas- ingly more important. The call for patients to par- ticipate in multicentre, randomised clinical trials to assess the efficacy of these experimental thera- pies will likely increase in coming years. For fur- ther reading, recent reviews and reports are rec- ommended that cover in more detail a number of topics raised in this chapter [10, 19, 22, 25].
Acknowledgements
D.J.M. is a Cancer Institute NSW Fellow (Australia).
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Deborah J. Marsh, PhD Hormones and Cancer Group, Kolling Institute of Medical Research University of Sydney, E25, Royal North Shore Hospital St. Leonards NSW 2065 (Australia) Tel. +61 2 99264500, Fax +61 2 99268484, E-Mail deborah.marsh@sydney.edu.au