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Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.
Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.
Natural History of Medullary Thyroid Cancer
Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 56,460 cancer diagnoses and 1,780 cancer deaths per year. Of these cancer diagnoses, 2% to 3% are medullary thyroid cancer (MTC).[2,3]
MTC arises from the parafollicular calcitonin-secreting cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by C-cell hyperplasia (CCH), although CCH is a relatively common abnormality in middle-aged adults.[4,5]
Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90% to 94% 5-year survival for papillary and follicular thyroid cancer).[3,6] Survival is correlated with stage at diagnosis, and decreased survival in MTC can be accounted for in part by a high proportion of late-stage diagnosis.[3,6,7]
In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic form, and diagnosis by biochemical screening (i.e., screening for calcitonin elevation) versus symptoms.[7,8,9,10]
A Surveillance, Epidemiology, and End Results (SEER) population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95.6% for disease confined to the thyroid gland to 40% for those with distant metastases.
Hereditary Medullary Thyroid Cancer
While the majority of MTC cases are sporadic, approximately 20% to 25% are hereditary because of mutations in the RET (REarranged during Transfection) proto-oncogene.[11,12,13] Mutations in the RET gene cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN 1) (OMIM) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN 2; however, the similar nomenclature for MEN 1 and MEN 2 may cause confusion. Of note, there is no increased risk for thyroid cancer for MEN 1.
Historically, MEN 2 has been classified into three subtypes based on the presence or absence of certain endocrine tumors in the individual or family:
All three subtypes impart a high risk for developing MTC. MEN 2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN 2B has an increased risk of pheochromocytoma and includes additional clinical features such as mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and an asthenic Marfanoid body habitus. FMTC has been defined as the presence of at least four individuals with MTC without any other signs or symptoms of pheochromocytoma or hyperparathyroidism in the proband or other family members.
Some families previously classified as FMTC will go on to develop one or more of the MEN 2A-related tumors, suggesting that FMTC is simply a milder variant of MEN 2A. Offspring of affected individuals have a 50% chance of inheriting the gene mutation.
The age of onset of MTC varies in different subtypes of MEN 2. MTC typically occurs in early childhood for MEN 2B, predominantly early adulthood for MEN 2A, and middle age for FMTC.
Germline deoxyribonucleic acid (DNA)-based testing of the RET gene (chromosomal region 10q11.2) identifies disease-causing mutations in more than 95% of individuals with MEN 2A and MEN 2B and in about 88% of individuals with FMTC.
The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN 2) are medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia (CCH); pheochromocytoma; and parathyroid adenomas and/or hyperplasia. MEN 2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH. In contrast, sporadic MTC is typically unilateral and/or unifocal. Since approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease. Metastatic spread of MTC to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites, such as the liver, is common in patients who present with a palpable thyroid mass or diarrhea.[2,3] Although pheochromocytomas rarely metastasize, they can be clinically significant in cases of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities in MEN 2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.
Historically, individuals and families with MEN 2 were classified into one of the following three clinical subtypes based on the presence or absence of certain endocrine tumors in the individual or family:
Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the mutation) and phenotype.
Clinical findings in the three MEN 2 subtypes are summarized in Table 1. All three subtypes confer a high risk of MTC; MEN 2A and MEN 2B confer an increased risk of pheochromocytoma, and MEN 2A has an increased risk of parathyroid hyperplasia and/or adenoma. Classifying a patient or family by MEN 2 subtype is useful in determining prognosis and management.
Medullary Thyroid Cancer and C-Cell Hyperplasia
MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland. MTC is diagnosed when nests of C-cells extend beyond the basement membrane and infiltrate and destroy thyroid follicles. CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells.[10,11] Individuals with RET (REarranged during Transfection) mutations and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal.[12,13] MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration.
A study of 10,864 patients with nodular thyroid disease found 44 (1 of every 250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test. CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population; therefore, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC and cannot always distinguish between carriers and noncarriers in an MEN 2 family.[12,13,15]
MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in the United States, although this figure may be an underrepresentation of true incidence because of changes in diagnostic techniques. The total number of new cases of MTC diagnosed annually in the United States is between 1,000 and 1,200, about 75% of which are sporadic (i.e., they occur in the absence of a family history of either MTC or other endocrine abnormalities seen in MEN 2). The peak incidence of the sporadic form is in the fifth and sixth decades of life.[2,17] A study in the United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year among a population of 55 million.
In the absence of a positive family history, MEN 2 may be suspected when MTC occurs at an early age or is bilateral or multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germline RET mutations,[18,19] larger series indicate a prevalence range of 1% to 7%.[20,21] Based on these data, it is widely recommended that RETgene mutation testing be performed for all cases of MTC.[22,23,24,25]
Level of evidence (Screening): 3
Pheochromocytomas (OMIM) arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor and are suspected among patients with refractory hypertension or when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid) in 24-hour urine collections or plasma. In the past, measurement of urinary catecholamines was considered the preferred biochemical screening method. However, given that catecholamines are only released intermittently and are metabolized in the adrenal medulla into metanephrine and normetanephrine, the measurement of urine or plasma fractionated metanephrines has become the gold standard.[26,27,28,29,30,31] When biochemical screening in an individual who has or is at risk for MEN 2 suggests pheochromocytoma, localization studies such as magnetic resonance imaging (MRI) or computed tomography (CT) can be performed. Confirmation of the diagnosis can be made using I131 -metaiodobenzylguanidine (MIBG) scintigraphy or positron emission tomography (PET) imaging.[13,32,33,34]
A diagnosis of MEN 2 is often considered in individuals with bilateral pheochromocytoma, those with an early age of onset (age <35 years), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN 2 is not the only genetic disorder that includes a predisposition to pheochromocytoma. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL), and the hereditary paraganglioma syndromes. A large European consortium that included 271 patients from Germany, 314 patients from France, and 57 patients from Italy (total = 642) with apparently sporadic pheochromocytoma analyzed the known pheochromocytoma/functional paraganglioma susceptibility genes (NF1, RET, VHL, SDHB, and SDHD). The diagnosis of NF1 in this series was made clinically, while all other conditions were diagnosed based on the presence of a germline mutation in the causative gene. The disease was associated with a positive family history in 166 (25.9%) patients; germline mutations were detected in RET (n = 31), VHL (n = 56), NF1 (n = 14), SDHB (n = 34), or SDHD (n = 31). Rigorous clinical evaluation and pedigree analysis either before or after testing revealed that of those with a positive family history and/or a syndromic presentation, 58.4% carried a mutation, compared with 12.7% who were nonsyndromic and/or had no family history. Of the 31 individuals with a germline RET mutation, 28 (90.3%) had a positive family history and/or syndromic presentation, suggesting that most individuals with RET mutations and pheochromocytoma will have a positive family history or other manifestations of the disease.
These data indicate that a significant proportion of individuals presenting with apparently sporadic pheochromocytoma are carriers of germline genetic mutations. Studies have identified additional susceptibility genes that predispose to pheochromocytoma, including TMEM127, MAX, and SDHAF2.[40,41,42,43] Mutations in these genes are thought to account for a small proportion of all hereditary pheochromocytoma. Since testing for mutations in multiple genes in every patient may not be feasible or cost-effective, clinical and genetic screening algorithms have been proposed to assist clinicians in deciding which genes to test and in which order.[32,38,39,44,45,46]
Primary hyperparathyroidism (PHPT) is the third most common endocrine disorder in the general population. The incidence increases with age with the vast majority of cases occurring after the sixth decade of life. Approximately 80% of cases are the results of a single adenoma. PHPT can also be seen as a component tumor in several different hereditary syndromes, including the following:
Hereditary PHPT is typically multiglandular, presents earlier in life, and can have histologic evidence of both adenoma and glandular hyperplasia.
Incidence and Prevalence
The prevalence of MEN 2 has been estimated to be between 1 in 30,000 [51,52] and 1 in 35,000. The vast majority of MEN 2 cases are MEN 2A. In the United States, an estimated 423 cases of MEN 2-related MTC are diagnosed per year.
Clinical Diagnosis of MEN 2 Subtypes
The diagnosis of the three MEN 2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene (chromosomal region 10q11.2).
MEN 2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma and/or hyperplasia) in a single individual or in close relatives.
The MEN 2A subtype makes up about 60% to 90% of MEN 2 cases. The MEN 2A subtype was initially called Sipple syndrome. Since genetic testing for RET mutations has become available, it has become apparent that about 95% of individuals with MEN 2A will develop MTC; about 50% will develop pheochromocytoma; and about 15% to 30% will develop hyperparathyroidism.[13,56,57,58]
MTC is generally the first manifestation of MEN 2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC.[13,57] In families with MEN 2A, the biochemical manifestations of MTC generally appear between the ages of 5 and 25 years (mean 15 years). If presymptomatic screening is not performed, MTC typically presents as a neck mass or neck pain at about age 5 to 20 years. More than 50% of such patients have cervical lymph node metastases. Diarrhea, the most frequent systemic symptom, occurs in patients with a plasma calcitonin level of greater than 10 ng/mL and implies a poor prognosis. Up to 30% of patients with MTC present with diarrhea and advanced disease.
MEN 2-associated pheochromocytomas are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[60,61,62] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[60,63] MEN 2-associated pheochromocytomas usually present after MTC, typically with intractable hypertension.
Unlike the PHPT seen in MEN 1, hyperparathyroidism in individuals with MEN 2 is typically asymptomatic or associated with only mild elevations in calcium.[59,64] A series of 56 patients with MEN 2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group. The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN 2. This is in sharp contrast to MEN 1, in which the vast majority of patients (87%–99%) initially present with primary hyperparathyroidism.[65,66,67] Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid carcinoma in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, four double adenomas, and 25 hyperplastic glands.
A small number of families with MEN 2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC.[68,69]
Familial medullary thyroid carcinoma (FMTC)
The FMTC subtype makes up 5% to 35% of MEN 2 cases and is defined as families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. Families with two or three cases of MTC and incompletely documented screening for pheochromocytoma and parathyroid disease may actually represent MEN 2A; it has been suggested that these families should be considered unclassified.[7,70] Misclassification of families with MEN 2A as having FMTC (because of too-small family size or later onset of other manifestations of MEN 2A) may result in overlooking the risk of pheochromocytoma, a disease with significant morbidity and mortality. For this reason, there is debate about whether FMTC represents a separate entity or is a variation of MEN 2A in which there is a lack of or delay in the onset of the other (nonthyroidal) manifestations of the MEN 2A syndrome. Some authors recommended, therefore, that patients thought to have pure FMTC also be screened for pheochromocytoma and hyperparathyroidism. (Refer to the Screening of at-risk individuals for pheochromocytoma and Screening of at-risk individuals for hyperparathyroidism sections of this summary for more information.)
MEN 2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic Marfanoid body habitus, and MTC.[72,73,74]
The MEN 2B subtype makes up about 5% of MEN 2 cases. The MEN 2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome. MEN 2B is characterized by the early development of an aggressive form of MTC in all patients.[75,76] Patients with MEN 2B who do not undergo thyroidectomy at an early age (at approximately age 1 year) are likely to develop metastatic MTC at an early age. Before intervention with early risk-reducing thyroidectomy, the average age at death in patients with MEN 2B was 21 years. Pheochromocytomas occur in about 50% of MEN 2B cases; about half are multiple and often bilateral. Clinically apparent parathyroid disease is very uncommon.[5,56,77] Patients with MEN 2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.
About 40% of patients have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distension, megacolon, constipation, and diarrhea. About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.[73,74]
Genetically Related Disorder
Hirschsprung disease (HSCR)
HSCR (OMIM), a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, is observed in a small number of individuals with MEN 2A, FMTC, or very rarely, MEN 2B. Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline mutations in the RET proto-oncogene and are designated HSCR1.[79,80] Some of these RET mutations are located in codons that lead to the development of MEN 2A or FMTC (i.e., codons 609, 618, and 620).[78,81]
In a study of 44 families, seven families (16%) had cosegregation of MEN 2A and HSCR1. The probability that individuals in a family with MEN 2A and an exon 10 Cys mutation would manifest HSCR1 was estimated to be 6% in one series. Furthermore, in a multicenter international RET mutation consortium study, 6 of a total of 62 kindreds carrying either the C618R or C620R mutation also had HSCR.
A novel analytic approach employing family-based association studies coupled with comparative and functional genomic analysis revealed that a common RET variant within a conserved enhancer-like sequence in intron 1 makes a 20-fold greater contribution to HSCR compared with all known RET mutations. This mutation has low penetrance and different genetic effects in males and females. Transmission to sons and daughters leads to a 5.7-fold and 2.1-fold increase in susceptibility, respectively. This finding is consistent with the greater incidence of HSCR in males. Demonstrating this strong relationship between a common noncoding mutation in RET and the risk of HSCR also accounts for previous failures to detect coding mutations in RET-linked families.
Molecular Genetics of MEN 2
MEN 2 syndromes are the result of inherited mutations in the RET gene, located on chromosome region 10q11.2.[83,84,85] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[86,87]
RET encodes a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. Details of RET receptor and ligand interaction in this signaling pathway have been reviewed. Briefly, the extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region that interacts with one of four ligands identified to date. These ligands, e.g., glial-derived neurotropic factor (GDNF), neurturin (NTN), persephin (PSF), and artemin (ATF), also interact with one of four coreceptors in the GFR-alpha family. The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules. Normal tissues contain transcripts of several lengths.[89,90,91]
MEN 2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of the management for at-risk family members. It meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology in its most recent genetic testing policy statement. At-risk individuals are defined as first-degree relatives (parents, siblings, and children) of a person known to have MEN 2. Testing allows the identification of people with asymptomatic MEN 2 who can be offered risk-reducing thyroidectomy and biochemical screening as preventive measures. A negative mutation analysis in at-risk relatives, however, is informative only after a disease-causing mutation has been identified in an affected relative. (Refer to the PDQ summary Cancer Genetics Risk Assessment and Counseling for more information.) Because early detection of at-risk individuals affects medical management, testing of children who have no symptoms is considered beneficial.[92,93] (Refer to the Genotype-Phenotype Correlations and Risk Stratification section of this summary for more information about clinical management of at-risk individuals.)
Germline DNA testing for RET mutations is generally recommended to all individuals with a diagnosis of MTC, regardless of whether there is a personal or family history suggestive of MEN 2.[23,94] Approximately 95% of patients with MEN 2A or MEN 2B will have an identifiable germline RET mutation. For FMTC the detection rate is slightly lower at 88%. Importantly, 1% to 7% of apparently sporadic cases of MTC will carry a germline RET mutation, underscoring the importance of testing all cases.[18,19,20,21]
There is no evidence for the involvement of other genetic loci, and all mutation-negative families analyzed to date have demonstrated linkage to the RET gene. For families that do not have a detectable mutation, clinical recommendations can be based on the clinical features in the affected individual and in the family.
There is considerable diversity in the techniques used and the approach to RET mutation testing among the various laboratories that perform this procedure. Methods used to detect mutations in RET include polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis, single-stranded conformation polymorphism (SSCP) analysis, denaturing high-performance liquid chromatography (DHPLC), and DNA sequencing.[95,96,97,98] Most testing laboratories, at a minimum, offer testing using a targeted exon approach; that is, the laboratories look for mutations in the exons that are most commonly found to carry mutations (exons 10, 11, 13, 14, 15 and 16). Other laboratories offer testing for all exons. If targeted exon testing in a family with a high clinical suspicion for MEN 2 is normal, sequencing of the remaining exons can then be performed.
These differences in mutation detection method and targeted versus full gene testing represent important considerations for selecting a laboratory to perform a test and in interpreting the test result. (Refer to the PDQ summary Cancer Genetics Risk Assessment and Counseling for more information on clinical validity.)
Genotype-Phenotype Correlations and Risk Stratification
Genotype-phenotype correlations in MEN 2 are well-established and have long been used to guide clinicians in making medical management recommendations. Several groups have developed mutation-stratification tables based on clinical phenotype, age of onset, and aggressiveness of MTC.[23,25,70] This classification strategy was first put forth after the Seventh International Workshop on MEN in 2001, which provided guidelines for the age of genetic testing and prophylactic thyroidectomy. This stratification was revised by the American Thyroid Association (ATA). The original classification scheme provided three levels of risk based on the genetic mutation of an individual. The new guidelines by the ATA added a fourth category for codon 634 mutations, in recognition of their aggressive clinical course. The specific mutations and their ATA classification are summarized in Table 2 and Table 3 below. The ATA's classification scheme has not been prospectively validated as a basis for clinical decision-making.
ATA-level D mutations are the most aggressive and carry the highest risk of developing MTC. These mutations, which are typically seen in MEN 2B, are associated with the youngest age at disease onset and the highest risk of mortality. ATA-level C mutations (codon 634) are associated with a slightly lower risk, yet the MTC in patients with these mutations is still quite aggressive and may present at an early age. ATA-level A and level B mutations are associated with a lower risk of aggressive MTC relative to the risk seen in level C and level D mutation carriers. However, the risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.
A European multicenter study of 207 RET mutation carriers supported previous suggestions that some mutations are associated with early-onset disease. For example, this study found that individuals with the C634Y mutation developed MTC at a significantly younger age (mean 3.2 years; 95% confidence interval [CI], 1.2–5.4) than individuals with the C634R mutation (mean 6.9 years; 95% CI, 4.9–8.8). In the former group of patients, risk-reducing thyroidectomy warrants consideration before the age of 5 years. Although limited by small numbers, the same study did not support a need for risk-reducing thyroidectomy in asymptomatic carriers of mutations in codons 609, 630, 768, 790, 791, 804, or 891 before the age of 10 years or for central lymph node dissection before the age of 20 years. Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery. Others have advocated using basal and stimulated calcitonin levels as a basis for determining the appropriate timing of thyroidectomy.
Mutations 883 and 918 have only been seen in MEN 2B and are associated with the earliest age of onset and the most aggressive form of MTC.[101,102,103,104,105] Approximately 95% of individuals with MEN 2B will have the M918T mutation.[101,102,103,106] As discussed above, 50% of individuals with MEN 2B will develop pheochromocytoma but PHPT is rare. In addition to mutations at codons 883 and 918, some individuals with a MEN 2B-like phenotype have been found to carry two germline mutations.[107,108,109,110,111] It is likely that as testing for RET becomes more common in clinical practice, additional double mutation phenotypes will be described.
Mutations at codon 634 (ATA-level C) are by far the most frequent finding in families with MEN 2A. One study of 477 RET carriers showed that 52.1% had the C634R mutation, 26.0% carried the C634Y mutation, and 9.1% had the C634G mutation. In general, mutations at codon 634 are associated with pheochromocytomas and PHPT.[56,112] Until recently, MEN 2A with cutaneous lichen amyloidosis (CLA) had been seen almost exclusively in patients with mutations at codon 634.[56,58,113] However, a recent report described MTC and CLA in an individual previously thought to have FMTC due to a codon 804 mutation. Codon 634 mutations have also been described in FMTC but are almost exclusively C634Y.
In summary, ATA-level D and level C mutations confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of pheochromocytoma (up to 50%).[56,115] Individuals with codon 634 mutations (but not codon 883 or 918 mutations) also have an increased risk of PHPT.
ATA-level B mutations, located in exon 10 of the RET gene, include mutations at codons 609, 611, 618, 620, and 630. These mutations involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN 2A and those with MTC only (FMTC).[20,56,70,116,117,118,119,120] The risk of MTC in individuals with ATA-level B mutations is approximately 95% to 100%; the risk of pheochromocytoma and hyperparathyroidism is lower than that seen in ATA-level A mutations. In a large series of 518 probands with MTC undergoing RET testing, most individuals with codon 609, 611, 618, 620, or 630 mutations had only MTC and no other features suggestive of MEN 2. The authors attributed this to the relatively short follow-up time, incomplete screening of family members, or the method of ascertainment (population-based). Another large study of 390 exon 10 mutation carriers showed an age-related risk of pheochromocytoma for individuals carrying any exon 10 mutation of 23.1% by age 50 years and 33% by age 60 years. Overall prevalence of pheochromocytoma was 17%. This study reported a 3.9% risk of developing hyperparathyroidism by age 60 years.
Individuals with ATA-level A mutations have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these mutations tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with ATA-level A mutations who developed MTC before age 20 years.[56,123,124,125,126,127] Although pheochromocytoma and PHPT are not commonly associated with level A mutations, they have been described.
In addition to the mutations categorized in Table 2, a number of rare or novel RET mutations have been described. Some of these represent mutations that lead to an FMTC or MEN 2 phenotype. Others may represent low penetrance alleles or modifying alleles that confer only a modest risk of developing MTC. Still others may be benign polymorphisms of no clinical significance. A variety of approaches, including segregation analyses, in silico analyses, association studies, and functional assays, can be employed to determine the functional and clinical significance of a given genetic variant. A publicly available RET mutation online database repository was recently developed and includes a complete list of mutations and their associated pathogenicity, phenotype, and other associated clinical information and literature references.
Risk-reducing thyroidectomy and parathyroidectomy with reimplantation of one or more parathyroid glands into the neck or nondominant forearm is a preventive option for all subtypes of MEN 2. To implement this management strategy, biochemical screening to identify CCH and/or genetic testing to identify persons who carry causative RET mutations is needed to identify candidates for risk-reducing surgery (see below). The optimal timing of surgery, however, is controversial. Current recommendations are based on clinical experience and vary for different MEN 2 subtypes, as noted in Table 3.
In contrast, a prospective analysis of 84 carriers of the RET gene mutation found that basal and pentagastrin-stimulated calcitonin levels could be used to determine the timing of total thyroidectomy. When the basal or stimulated calcitonin was greater than 10 pg/mL, total thyroidectomy and central neck dissection were strongly recommended. In this series, a basal calcitonin level lower than 60 pg/mL was always associated with an intrathyroidal MTC; none of the 56 patients who went to surgery had metastatic involvement. These findings suggest that surgery can be safely delayed in gene carriers of a RET mutation until basal or stimulated calcitonin is above 10 pg/mL, while still maintaining the ability to achieve a disease-free state (i.e., an undetectable basal and stimulated calcitonin 6–12 months after surgery). The benefits of this approach are particularly noteworthy in the younger population of gene carriers, as a delay in surgery until the patient is older may reduce the risk of surgical complications. While this approach is promising, pentagastrin is currently not available in the United States for stimulation testing. Although calcium may be used as a substitute for pentagastrin, it has not been widely validated.
In a study of biochemical screening in a large family with MEN 2A performed before mutation analysis became available, 22 family members without evidence of clinical disease had elevated calcitonin and underwent thyroidectomy. During a mean follow-up period of 11 years, all remained free of clinical disease, and 3 out of 22 had transient elevation of postoperative calcitonin levels. The use of biochemical screening is limited, however, by the lack of data on age-specific calcitonin levels in children under 3 years of age; caution should be used when interpreting these values in this age group.
A study of 93 patients with MEN 2 from a Dutch tumor registry documented the importance of early prophylactic thyroidectomy. This group of patients represented all known Dutch patients with hereditary MTC; the majority of cases (67%) were codon 634 mutations; only 6% were MEN 2B cases. Patients in this series were screened with either biochemical testing (pre-RET era) or RET mutation analysis. In both groups, patients who underwent surgery at a later age than recommended by current guidelines (see Table 3), but the percentage from the pre-RET era was significantly higher (96% vs. 69%, P = .004). Older age at prophylactic thyroidectomy was significantly associated with a higher risk of postoperative persistent/recurrent disease. Although there is concern that young age at total thyroidectomy is associated with higher risk of surgical complications, this study found no such evidence.
Two additional case series provide further data supporting early risk-reducing thyroidectomy following testing for RET mutations.[187,188] Cases reported in both series could reflect selection biases: one study reported 71 patients from a national registry who had been treated with thyroidectomy but did not specify how these patients were selected, whereas the other study reported 21 patients seen at a referral center.[187,188] In both studies, a series of children from families with MEN 2 or FMTC who were found to have RET mutations were screened for CCH and treated with risk-reducing thyroidectomy. These studies documented MTC in 93% of patients with MEN 2 and 77% of patients with FMTC. The larger study found a correlation between age and larger tumor size, nodal metastases, postoperative recurrence of disease, and mean basal calcitonin levels. Surgical complications were rare. No studies have compared the outcome of thyroidectomy based on mutation testing with thyroidectomy based on biochemical screening.
In one large series, 260 MEN 2A subjects aged 0 to 20 years were identified as having undergone either an early total thyroidectomy (ages 1–5 years, n = 42), or late thyroidectomy (ages 6–20 years, n = 218). There was a significantly lower rate of invasive or metastatic MTC among those who underwent surgery at an early age (57%) than among those who underwent surgery at a late age (76%). Follow-up information was available on only 28% of the cohort, as a result of the limitations of study design, with a median follow-up of only 2 years for this nonsystematically selected subgroup. Persistent or recurrent disease was reported among 0 of 9 early-surgery subjects, versus 21 of 65 late-surgery subjects. Both findings are consistent with the hypothesis that patients undergoing surgery before age 6 years have a more favorable outcome, but the nature of the data prevents this from being a definitive conclusion. Finally, there was evidence to suggest that subjects carrying codon 634 mutations were much more likely to present with invasive or metastatic MTC and to develop persistent or recurrent disease compared with those harboring mutations in codons 804, 618, or 620.
A study of young, clinically asymptomatic individuals with MEN 2A sought to determine if early thyroidectomy could prevent or cure MTC. This study included 50 consecutively identified RET mutation carriers who underwent thyroidectomy at 19 years or younger. Preoperative screening for CCH included basal and stimulated calcitonin levels and postoperative follow-up consisted of annual physical exam and intermittent basal and stimulated calcitonin measurements. All 50 individuals had at least 5 years of follow-up. Although MTC was identified in 33 of 50 patients at the time of surgery, in 44 of 50 (88%) there was no evidence of persistent or recurrent disease at a mean of 7 years follow-up. Six patients had basal or stimulated calcitonin abnormalities thought to represent residual MTC. None of the 22 patients operated on prior to age 8 years had any evidence of MTC. The data suggested that there was a lower incidence of persistent or recurrent disease in patients who had thyroidectomy earlier in life (defined as younger than 8 years) and who had no evidence of lymph node metastases.
Normal preoperative basal calcitonin does not exclude the possibility of the patient having MTC. In one study of 80 RET mutation carriers, 14 carriers had normal calcitonin tests and eight of these patients had small foci of MTC discovered at thyroidectomy. Another study confirmed these findings, as 14 children had total thyroidectomy based on positive genetic testing for MEN 2; MTC was present in 11 and only four had elevated stimulated calcitonin levels prior to surgery. Although basal calcitonin levels may not be able to identify all patients with MTC preoperatively, this test has utility as a predictor of postoperative remission, lymph node metastases, and distant metastases. In one study of 224 patients from a single institution, preoperative basal calcitonin levels greater than 500 pg/mL predicted failure to achieve biochemical remission. The authors of this study found that nodal metastases started appearing at basal calcitonin levels of 40 pg/mL (normal, <10 pg/mL). In node-positive patients, distant metastases emerged at basal calcitonin levels of 150 pg/mL to 400 pg/mL. Using current sensitive calcitonin assays, a study of 308 RET carriers found that a normal basal preoperative calcitonin excluded the presence of lymph node metastases (100% negative predictive value). Therefore, the preoperative basal calcitonin level is a useful prognostic indicator and may help guide the surgical approach.
While thyroidectomy prior to biochemical evidence of disease (normal preoperative calcitonin) may reduce the risk of recurrent disease, continued monitoring for residual or recurrent MTC is still recommended.[25,193] One study found that 10% of patients with MEN 2A undergoing thyroidectomy developed recurrent disease, based on an initially undetectable basal and stimulated calcitonin (<2 pg/mL) that became positive 5 to 10 years after surgery. Only 2% of patients had residual disease after prophylactic surgery as assessed by a persistently elevated basal or stimulated calcitonin.
Questions remain concerning the natural history of MEN 2. As more information is acquired, recommendations regarding the optimal age for thyroidectomy and the potential role for genetics and biochemical screening may change. For example, a case report documents MTC before age 5 years in two siblings with MEN 2A. Conversely, another case report documents onset of cancer in midlife or later in some families with FMTC and in elderly relatives who carry the FMTC genotype but have not developed cancer. The possibility that certain mutations (e.g., Cys634) might convey a significantly worse prognosis, if confirmed, may permit tailoring intervention based on knowing the specific RET mutation. These clinical observations suggest that the natural history of the MEN 2 syndromes is variable and could be subject to modifying effects related to specific RET mutations, other genes, behavioral factors, or environmental exposures.
Level of evidence: 5
Screening of at-risk individuals for pheochromocytoma
The presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening before thyroidectomy in any patient with MEN 2A or MEN 2B. However, childhood pheochromocytomas are rare in MEN 2. The ATA has recommended that annual screening for pheochromocytoma be considered after the age of 8 years in patients with RET mutations in codons 630 and 634 and in patients with RET mutations associated with MEN 2B. In carriers of other MEN 2A RET mutations, ATA recommends that annual screening begin by age 20 years. Patients with RET mutations associated only with FMTC should have periodic screening for pheochromocytoma beginning at age 20 years. MRI or other imaging tests should be ordered only if the biochemical results are abnormal.[196,197] Studies of individuals with sporadic or hereditary pheochromocytoma (including, but not limited to, individuals with MEN 2) have suggested that measurement of catecholamine metabolites, specifically plasma-free metanephrines and/or urinary fractionated metanephrines, provides a higher diagnostic sensitivity than urinary catecholamines because of the episodic nature of catecholamine excretion.[26,27,28,29,30,31,32,198] Several reviews provide a succinct summary of the biochemical diagnosis, localization, and management of pheochromocytoma.[32,199] In addition to surgery, there are other clinical situations in which patients with catecholamine excess face special risk. An example is the healthy at-risk female patient who becomes pregnant. Pregnancy, labor, or delivery may precipitate a hypertensive crisis in persons who carry an unrecognized pheochromocytoma. Pregnant patients who are found to have catecholamine excess require appropriate pharmacotherapy before delivery.
Screening of at-risk individuals for hyperparathyroidism
MEN 2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in the natural history of the disease, which, if left untreated, may become symptomatic. Childhood hyperparathyroidism is rare in MEN 2. Three studies found the median age at diagnosis was about 38 years.[64,200,201] The ATA provides recommendations for annual screening for hyperparathyroidism. Annual screening should begin at age 8 years in carriers of mutations in codons 630 and 634 and at age 20 years for carriers of other MEN 2A RET mutations. Patients with mutations associated only with FMTC should have periodic testing after the age of 20 years. Testing should include albumin-corrected calcium or ionized serum calcium with or without intact PTH measurement.
Screening of at-risk individuals in kindreds without an identifiableRETmutation
MEN 2A: Risk-reducing thyroidectomy is not routinely offered to at-risk individuals if the disorder is unconfirmed. The screening protocol for MTC is an annual calcitonin stimulation test; however, caution must be used in interpreting test results because CCH that is not a precursor to MTC occurs in about 5% of the population.[12,13,202] In addition, there is significant risk of false-negative test results in patients younger than 15 years. Screening for pheochromocytoma and parathyroid disease is the same as described above.
FMTC: Annual screening for MTC, as for MEN 2A.
Treatment for those with MTC
Standard treatment for adults with MTC is surgical removal of the entire thyroid gland, including the posterior capsule, and central lymph node dissection. Children with MEN 2B having prophylactic thyroidectomy within the first year of life may not require central neck dissection unless there is radiological evidence of nodal disease. Likewise, children with MEN 2A or FMTC having prophylactic thyroidectomy before 3 to 5 years of age should not have a central neck dissection in the absence of radiological evidence of metastatic lymph node involvement. The ATA also recommends that MEN 2A and FMTC patients older than 5 years or asymptomatic MEN 2B patients older than 1 year have a preoperative basal calcitonin test and neck ultrasound. A basal calcitonin level over 40 pg/mL or thyroid nodules greater than or equal to 5 mm requires further evaluation, as the patient may have more extensive disease requiring nodal dissection. If an MEN 2B patient older than 1 year has nodules smaller than 5 mm or basal calcitonin lower than 40 pg/mL, then total thyroidectomy may be sufficient therapy, but the ATA task force favors prophylactic central neck dissection without lateral compartment dissection in the absence of radiographic evidence of metastatic involvement (level C recommendation). See Table 4 for complete details.
The ATA recommends lymph node dissection for patients meeting any one of the following criteria:
Patients who have had total thyroidectomy will require lifelong thyroid hormone replacement therapy. The dosing of medication is age-dependent and treatment should be initiated based on ideal body weight. For healthy adults 60 years and younger with no cardiac disease, a reasonable starting dose is 1.6 to 1.8 µg/kg given once daily. Older patients may require 20% to 30% less thyroid hormone. Children clear T4 more rapidly than adults and consequently require relatively higher replacement by body weight. Depending on the age of the child, replacement should be between 2 to 6 µg/kg. It is important to note, however, that patients should be given replacement, rather than suppressive therapy. Since C-cell tumors are not TSH-dependent for growth, the T4 therapy for MTC patients therefore should be adjusted to maintain a TSH within the normal reference range.
There is no difference in survival between familial and sporadic forms of MTC when adjusted for clinicopathologic factors. Chemotherapy and radiation are not effective against this type of cancer,[3,206,207] although clinical trials (phases I-III) of various targeted molecular therapies are ongoing at selected centers. Some of these compounds have shown partial responses in a small percentage of patients, but most studies have demonstrated disease stability as the most favorable response.[208,209,210,211] The use of vandetanib is approved by the FDA for use in adult patients with progressive metastatic MTC who are ineligible for surgery. A phase III study found that progression-free survival was longer in patients who received the study drug than in those who received placebo. There was no demonstration of improved overall survival, however. Future studies will likely focus on the development of new targeted therapies and the use of combination therapy in medullary thyroid cancer. (Refer to NCI's List of Clinical Trials for more information about these trials. Refer to the PDQ summary on Thyroid Cancer Treatment for more information about the treatment of thyroid cancer.)
Treatment for those with pheochromocytoma
Pheochromocytoma may be either unilateral or bilateral in patients with MEN 2. Laparoscopic adrenalectomy is the recommended approach by some authorities for the treatment of unilateral pheochromocytoma.[23,25] Two studies examined the value of a posterior retroperitoneoscopic adrenalectomy and found that it was safe and effective, with zero mortality, associated with a low rate of minor complications, and required conversion to open or laparoscopic lateral surgery in only 1.7%.[213,214] This approach appears to be a feasible and safe alternative to open or laparoscopic surgery, but extensive experience is needed.
In one series, 23 patients with a unilateral pheochromocytoma and a macroscopically normal contralateral adrenal gland were treated initially with unilateral adrenalectomy. A pheochromocytoma developed within the retained gland in 12 (52%) of these subjects, occurring a mean of 11.9 years after initial surgery. During follow-up subsequent to unilateral adrenalectomy, no patient experienced a hypertensive crisis or other problems attributable to an undiagnosed pheochromocytoma. In contrast, 10 (23%) of 43 patients treated with bilateral adrenalectomy experienced at least one episode of acute adrenal insufficiency; one of these patients died. Unilateral adrenalectomy appears to represent a reasonable management strategy for unilateral pheochromocytoma in patients with MEN 2,[216,217,218] when coupled with periodic surveillance (serum or urinary catecholamine measurements) for the development of disease in the contralateral adrenal gland.
Cortical-sparing adrenalectomy is an option for patients with bilateral pheochromocytomas or for those with only one viable adrenal gland to minimize the risk of adrenal insufficiency. Fourteen (93%) of 15 patients undergoing laparotomy for bilateral pheochromocytomas were treated with cortical-sparing adrenalectomy; 13 patients did not require postoperative steroid hormone supplementation, and none experienced acute adrenal insufficiency. Three patients developed recurrent pheochromocytomas at 10 to 27 years after surgery. Similar results were obtained in a series of 26 patients undergoing cortex-sparing surgery for hereditary pheochromocytoma (including MEN 2). This type of surgery may also be accomplished laparoscopically, with intraoperative ultrasound guidance; however, these approaches require long-term follow-up, as recurrence may develop many years after the initial operation.
Treatment for those with hyperparathyroidism
Most patients with MEN2-related parathyroid disease are either asymptomatic or diagnosed incidentally at the time of thyroidectomy. Typically, the hypercalcemia (when present) is mild, although it may be associated with increased urinary excretion of calcium and nephrolithiasis. As a consequence, the indications for surgical intervention are generally similar to those recommended for patients with sporadic, primary hyperparathyroidism. In general, fewer than four of the parathyroid glands are involved at the time of detected abnormalities in calcium metabolism.
Cure of hyperparathyroidism was achieved surgically in 89% of one large series of patients; however, 22% of resected patients in this study developed postoperative hypoparathyroidism. Five patients (9%) had recurrent hyperparathyroidism. This series employed various surgical techniques, including total parathyroidectomy with autotransplantation to the nondominant forearm, subtotal parathyroidectomy, and resection only of glands that were macroscopically enlarged. Postoperative hypoparathyroidism developed in 4 (36%) of 11 patients, 6 (50%) of 12 patients, and 3 (10%) of 29 patients, respectively. These data indicate that excision of only those parathyroid glands that are enlarged appears to be sufficient in most cases.
Some investigators have suggested using the MEN 2 subtype to decide where to place the parathyroid glands that are identified at the time of thyroid surgery. For patients with MEN 2B in whom the risk of parathyroid disease is quite low, the parathyroid glands may be left in the neck. For patients with MEN 2A and FMTC, it is suggested that the glands be implanted in the nondominant forearm to minimize the need for further surgery on the neck after risk-reducing thyroidectomy and a central lymph node dissection.
All patients who have undergone parathyroid surgery with autotransplantation of parathyroid tissue should be monitored for hypoparathyroidism.[25,223,224]
Medical therapy of hyperparathyroidism has gained popularity with the advent of calcimimetics, agents that sensitize the calcium-sensing receptors on the parathyroid glands to circulating calcium levels and thereby reduce circulating PTH levels. In a randomized, double-blind, placebo-controlled trial, cinacalcet hydrochloride was shown to induce sustained reduction in circulating calcium and PTH levels in patients with primary hyperparathyroidism. In patients who are high-risk surgical candidates, those with recurrent hyperparathyroidism, or those in whom life expectancy is limited, medical therapy may be a viable alternative to a surgical approach.
Mode of inheritance
All of the MEN 2 subtypes are inherited in an autosomal dominant manner. For the child of someone with MEN 2, the risk of inheriting the MEN 2 mutation is 50%. Some individuals with MEN 2, however, carry a de novo gene mutation; that is, they carry a new mutation that was not present in previous generations of their family and thus do not have an affected parent. The proportion of individuals with MEN 2 who have an affected parent varies by subtype.
MEN 2A: About 95% of affected individuals have an affected parent. It is appropriate to evaluate the parents of an individual with MEN 2A for manifestations of the disorder. In the 5% of cases that are not familial, either de novo gene mutations or incomplete penetrance of the mutant allele is possible.
FMTC: Multiple family members are affected; therefore, all affected individuals inherited the mutant gene from a parent.
MEN 2B: About 50% of affected individuals have de novo RET gene mutations, and 50% have inherited the mutation from a parent.[227,228] The majority of de novo mutations are paternal in origin, but cases of maternal origin have been reported.
Siblings of a proband: The risk to siblings depends on the genetic status of the parent, which can be clarified by pedigree analysis and/or DNA-based testing. In situations of apparent de novo gene mutations, germline mosaicism in an apparently unaffected parent must be considered, even though such an occurrence has not yet been reported.
The psychosocial impact of genetic testing for MEN 2 has not been extensively studied. Published studies have had limitations such as small sample size and heterogeneous populations; thus, the clinical relevance of these findings should be interpreted with caution. Identification as the carrier of a deleterious mutation may affect self-esteem, family relationships, and quality of life. In addition, misconceptions about genetic disease may result in familial blame and guilt.[230,231] Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[232,233,234,235] The medical value of early screening and risk-reducing treatment are contrasted with the loss of decision-making autonomy for the individual. Lack of agreement between parents about the value and timing of genetic testing and surgery may spur the development of emotional problems within the family.
One study examined levels of psychological distress in the interval between submitting a blood sample and receiving genetic test results. Those individuals who experienced the highest level of distress were younger than 25 years, single, and had a history of responding to distressful situations with anxiety. Mutation-positive parents whose children received negative test results did not seem to be reassured, questioned the reliability of the DNA test, and were eager to continue screening of their noncarrier children.
A small qualitative study (N = 21) evaluated how patients with MEN 2A and family members conceptualized participation in lifelong high-risk surveillance. Ongoing surveillance was viewed as a reminder of a health threat. Acceptance and incorporation of lifelong surveillance into routine health care was essential for coping with the implications of this condition. Concern about genetic predisposition to cancer was peripheral to concerns about surveillance. Supportive interventions, such as Internet discussion forums, can serve as an ongoing means of addressing informational and support needs of patients with MTC undergoing lifelong surveillance.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Multiple Endocrine Neoplasia Type 2
Added level of evidence (Screening): 3 for RET gene mutation testing for individuals with medullary thyroid cancer.
Revised text to state that the prevalence of multiple endocrine neoplasia type 2 has been estimated to be between 1 in 30,000 and 1 in 35,000 (cited Mulligan et al. and Donis-Keller et al. as references 51 and 52, respectively).
Added text to state that pentagastrin is currently not available in the United States for stimulation testing; although calcium may be used as a substitute for pentagastrin, it has not been widely validated.
Added Scholten et al. as reference 218.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of medullary thyroid cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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National Cancer Institute: PDQ® Genetics of Medullary Thyroid Cancer. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/genetics/medullarythyroid/HealthProfessional. Accessed <MM/DD/YYYY>.
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