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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. In a population-based study in Sweden, 26% of patients with MTC were familial.[3] A French national registry and a US clinical series both reported a higher proportion of familial cases (43% and 44% respectively).[2,4] Familial cases represent Multiple Endocrine Neoplasia Type 2 (MEN2), a group of autosomal dominant genetic disorders caused by inherited mutations in the RET oncogene.
In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial vs sporadic, and diagnosis by biochemical screening (that is, screening for calcitonin elevation) vs symptoms.[2-4]
The disorder is classified into 3 subtypes based on the presence of other clinical complications: MEN 2A, familial medullary thyroid carcinoma (FMTC), and MEN 2B. All 3 subtypes have a high risk of developing MTC; MEN 2A has an increased risk of pheochromocytoma and parathyroid adenoma and hyperplasia. MEN2B has an increased risk of pheochromocytoma and includes additional clinical features such as mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and an asthenic "Marfanoid" body habitus.
The age of onset of MTC varies in different subtypes of MEN2. MTC typically occurs in early childhood for MEN 2B, early adulthood for MEN 2A, and middle age for FMTC.
All MEN 2 subtypes are inherited in an autosomal dominant manner. Offspring of affected individuals have a 50% chance of inheriting the gene mutation.
DNA-based testing of the RET gene (chromosomal locus 10q11) identifies disease-causing mutations in 95% of individuals with MEN 2A and MEN 2B and in about 85% of individuals with FMTC.
Clinical findings in the 3 MEN 2 subtypes are summarized in Table 1. All 3 subtypes have a high risk of MTC; MEN 2A and MEN 2B have an increased risk of pheochromocytoma; and MEN 2A has an increased risk of parathyroid hyperplasia and adenoma. Classifying a patient or family by MEN 2 subtype is useful for determining prognosis and management.
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Table 1. Percent of Patients with Clinical Features of MEN 2 by Subtype
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Subtype Medullary Thyroid Pheochromocytoma Parathyroid
Carcinoma Disease
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MEN 2A 95% 50% 20%-30%
FMTC 100% 0% 0%
MEN 2B 100% 50% Uncommon
FMTC = familial medullary thyroid carcinoma
Percentages based on observations in referral populations.[4-6]
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MTC accounts for 3% to 4% of new cases of thyroid cancer diagnosed annually in the United States. The total number of new cases of MTC diagnosed annually is between 1000 and 1200, of which about 75% to 80% are sporadic; that is, 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.[2,9] In the absence of a positive family history, MEN 2 may be suspected when MTC occurs at an early age or is multifocal. Between 1% and 24% of individuals with sporadic MTC have been reported to carry inherited disease-causing mutations in the RET gene.[10-12] Some experts recommend RET gene mutation testing for all cases of MTC.[1,13]
MEN 2A is diagnosed clinically by the occurrence of 2 or more specific endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual or in close relatives.
The MEN 2A subtype makes up about 60%-90% of MEN 2 cases. The MEN 2A subtype was initially called Sipple syndrome.[17] Since genetic testing for RET mutations has become available, it has become apparent that 95% of individuals with MEN 2A will develop MTC, about 50% will develop pheochromocytoma, and about 20% to 30% will develop hyperparathyroidism.[18]
MTC is generally the first manifestation of MEN 2A. In asymptomatic young at-risk individuals, provocative testing may reveal elevated plasma calcitonin levels and the presence of C-cell hyperplasia or MTC. In families with MEN 2A, the biochemical manifestations of MTC generally appear between the ages of 5 and 25 years (mean 5 years).[8] If presymptomatic screening is not done, 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.[2] Diarrhea, the most frequent systemic symptom, occurs in patients with a plasma calcitonin level of more than 10ng/ml and implies a poor prognosis.[2] Up to 30% of patients with MTC present with diarrhea and advanced disease.[19]
Pheochromocytomas usually present after MTC, typically with intractable hypertension. They are often bilateral.[5] Sudden death from anesthesia-induced hypertensive crisis has been described in patients with MEN 2A and unsuspected pheochromocytoma.[2] Malignant transformation is uncommon and is estimated to occur in about 4% of familial cases.[20]
A small number of families with MEN 2A have pruritic cutaneous lichen amyloidosis, also known as cutaneous lichen amyloidosis. This is a lichenoid skin lesion located over the upper portion of the back and may appear before the onset of MTC.[21,22]
FMTC is diagnosed in families with 4 cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.[18] Families in which there are 2 or 3 cases of MTC and incompletely documented screening for pheochromocytoma and parathyroid disease may represent MEN 2A; it has been suggested that these families should be considered "unclassified."[6] Misclassification of families with MEN 2A as having FMTC (due to 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.
The FMTC subtype makes up about 5%-35% of MEN 2 cases. In this subtype of MEN 2, MTC is the only clinical manifestation.
MEN 2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic "Marfanoid" body habitus, and MTC.[23]
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.[24] MEN 2B is characterized by the early development of an aggressive form of MTC in all patients.[24,25] Patients with MEN 2B who do not undergo thyroidectomy at an early age (approximately 1 year) are likely to develop metastatic MTC at an early age. Before intervention with early prophylactic thyroidectomy, the average age of death in patients with MEN 2B was 21 years. Pheochromocytomas occur in 50% of MEN 2B cases; about half are multiple and often bilateral. Patients with undiagnosed pheochromocytoma may die from a cardiovascular crisis perioperatively. Parathyroid disease is very uncommon.[4,18,26]
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, or 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. On rare occasions, individuals with MEN 2B and the M918T mutation have been found to have Hirschsprung Disease (HSCR1); see discussion below.[27]
Other Subtypes
The International RET Mutation Consortium classified MEN 2 into 6 separate phenotypes for the purpose of correlating specific mutations with clinical expression.[11,18] They specified 3 forms of MEN 2A: MEN 2A(1), MEN 2A(2), MEN 2A(3), and single forms of MEN 2B, FMTC, and Other, which included families that did not conform to the other phenotypes. The clinical usefulness of these additional subtypes for MEN 2A has not been demonstrated.
Hirschsprung disease (HSCR), 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. About 20%-40% of all HSCR cases are caused by germline mutations in the RET proto-oncogene and are designated HSCR1.[28] Some of these RET mutations are located in codons that lead to the development of MEN 2A (i.e., codon 609 in exon 10 and codon 620 in exon 11).[27] Other mutations lie in codons that lead to the development of MTC (i.e., 618 and 620).
In a study, 7 of 44 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 1 series.[28]
Multiple Endocrine Neoplasia Type 1 (MEN 1)
This autosomal dominant endocrinopathy is genetically and clinically distinct from MEN 2; however, the similar nomenclature for MEN 1 and MEN 2 may cause confusion. MEN 1 is caused by mutations in the MEN 1 gene (chromosomal locus 11q13). MEN 1 is characterized by a triad of pituitary adenomas, pancreatic islet cell tumors, and parathyroid disease consisting of hyperplasia or adenoma. Patients can also have adrenal cortical tumors, carcinoid tumors, and lipomas.[29] Rarely, patients with MEN 1 have pituitary adenomas and pheochromocytomas, which has led to the hypothesis of an "overlap" syndrome with MEN 2.[30]
RET produces a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. The extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region. The extracellular domain interacts with at least 1 ligand identified to date, glial-derived neurotropic factor (GDNF), which promotes dimerization of the protein after interacting with a second protein called GDNFRa.[40] The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events with unidentified second messenger molecules. Normal tissues contain transcripts of several lengths.[41]
Mutation Analysis
Approximately 95% of families with MEN 2A have a RET mutation in exon 10 or 11.[10,37] Mutations of codon 634 Cys occur in about 85% of families; mutation of cysteine residues at codons 609, 611, 618, and 620 together account for the remainder of identifiable mutations in exons 10 and 11. Other rare mutations have been reported in single families.[8,42,43]
Approximately 85% of families with FMTC have an identifiable RET mutation.[10,37] These mutations occur at 1 of the 5 cysteine residues (codons 609, 611, 618, 620, and 634) with mutations of codons 618, 620, and 634 each accounting for 25% to 35% of mutations. Mutations in codons 631, 768, 790, 791, 804, 844, and 891 have also been identified in a small number of families.[44-47]
Approximately 95% of individuals with the MEN 2B phenotype have a single point mutation in the tyrosine kinase domain of the RET gene at codon 918 in exon 16, which substitutes a threonine for methionine (M918T).[48,49] A second mutation at codon 883 in exon 15 has recently been identified in 4 MEN 2B patients without a M918T mutation.[50,51]
Mutations involving the cysteine codons 609, 618, and 620 are associated with MEN 2A, FMTC, and HSCR1. Mutations in these codons are detected in about 10% of families with MEN 2A and 2 out of 3 of families with FMTC. Mutations in the codons are associated with low transforming activity of RET.[53] Any RET mutation at codon 634 in exon 11 results in a higher incidence of pheochromocytomas and hyperparathyroidism.[18] Among the mutations at codon 634, it has been reported that C634R significantly correlates with the presence of hyperparathyroidism,[37] but other studies do not confirm this correlation.[55,56] Some mutations, such as those involving codons 618 and 620 in exon 10, may be associated with milder forms of the disease.[10,57]
In vitro assays demonstrate that the transforming activity of cysteine 634 mutations is 3-fold to 5-fold higher than that of codon 609, 611, 618, or 620 mutations.[53]
Possible correlation between the presence of mutations in codon 634 in the RET gene and the skin lesion cutaneous lichen amyloidosis needs to be confirmed by larger studies.[58]
RET germline M918T mutations are only associated with MEN 2B; however, somatic mutations at this codon are frequently observed in sporadic MTC.[59,60]
Mutations in codons 768 in exon 13 and 804 in exon 14 may only be associated with the development of MTC, since these mutations have been identified only in the FMTC subtype.[18,45,61,62]
Testing for the common mutations in exons 10, 11, and 16 is available at a number of clinical laboratories; some laboratories also include analysis of some of the rarer mutations. Methods used to detect mutations in RET include PCR with restriction enzyme digestion of PCR products, heteroduplex analysis, single-strand conformation polymorphism analysis, and DNA sequencing.[38,65-67]
---------------------------------------------------------------------------- Table 2. Testing Used in the Molecular Diagnosis of MEN 2 ---------------------------------------------------------------------------- Disease Name Mutation Detection Rate Test Type ---------------------------------------------------------------------------- MEN 2A 95% DNA-based FMTC 85% DNA-based MEN 2B 95% DNA-based ----------------------------------------------------------------------------
Mutation analysis can only be used for testing of at-risk relatives if a disease-causing germline mutation has previously been identified in an affected family member.
A small number of families with MEN 2 have been described without detectable abnormalities in the RET coding sequence. There is no evidence, however, for involvement of other genetic loci, and all mutation-negative families analyzed to date have demonstrated linkage to the RET gene.
Linkage Analysis
When a disease-causing mutation in the RET gene cannot be identified, linkage analysis can be considered in families with more than 1 affected family member in 2 or more generations. Linkage studies are based on accurate clinical diagnosis of MTC and/or pheochromocytoma in the affected family members and accurate understanding of the genetic relationships in the family. Linkage analysis is dependent on the availability and willingness of all family members to be tested. The markers used for linkage are highly informative and very tightly linked to the RET gene; thus, they can be used in more than 95% of families with MEN2 with greater than 95% accuracy.[68]
Linkage testing is not possible in families in which there is a single affected individual.
Prophylactic thyroidectomy with reimplantation of the parathyroid glands into the neck or forearm is a preventive option for all subtypes of MEN 2. In order to implement this management strategy, biochemical screening to identify CCH or genetic testing to identify persons who carry causative RET mutations is needed to identify candidates for prophylactic surgery (see below). The optimal timing of surgery, however, is controversial.[3] Current recommendations are based on clinical experience and vary for different MEN2 subtypes, as noted below.
In a study of biochemical screening in a large family with MEN2A done before genotyping 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 postoperative calcitonin levels.[69]
Two case series provide data supporting early prophylactic thyroidectomy following testing for RET mutations.[70,71] Cases reported in both series could reflect selection biases; 1 study reported 71 patients from a national registry who had been treated with thyroidectomy, but did not specify how these patients were selected; while the other study reported 21 patients seen at a referral center.[70,71] In both, a series of children from families with MEN2 or FMTC who were found to have RET mutations were screened for C-cell hyperplasia and treated with prophylactic thyroidectomy. These studies documented MTC in 93% and 77% of patients respectively. 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.[70] No studies have compared the outcome of thyroidectomy based on mutations testing with thyroidectomy based on biochemical screening.
In these and other studies, thyroid glands removed from individuals with a disease-causing mutation who had normal plasma calcitonin levels have been found to contain MTC.[8,24] Therefore, although thyroidectomy prior to biochemical evidence of disease may reduce the risk of recurrent disease, continued monitoring for residual or recurrent MTC is still recommended.[3] All individuals who have undergone thyroidectomy and autotransplantation of the parathyroids need thyroid hormone replacement therapy and monitoring for possible hypoparathyroidism.
Questions remain concerning the natural history of MEN2. 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 in 2 siblings with MEN2A.[72] Conversely, another case report documents onset of cancer in mid-life or later in some families with FMTC, as well as in elderly relatives who carry the FMTC genotype but have not developed cancer.[73] These clinical observations suggest that the natural history of the MEN2 syndromes is variable and could be subject to modifying effects related to specific RET mutations, other genes, behavioral factors, or environmental exposures.
As noted above, there is controversy about the age at which to perform prophylactic thyroidectomy in part because outcome data are limited to uncontrolled studies or relatively small populations. The genotype/phenotype correlations suggest significant differences in biological aggressiveness of the medullary thyroid cancers that occur in MEN 2A, MEN 2B, and FMTC.[13] Some authors suggest basing decisions on the timing of prophylactic thyroidectomy and the extent of surgery on these differences.[13] A summary of current practice in referral centers suggests the following:[74]
MEN 2A: In some centers, thyroidectomy is performed in patients as young as 5 years.
FMTC: Some centers recommend management similar to that for MEN 2A.
MEN 2B: In some centers, surgery is performed before age 1 (perhaps as early as 6 months) because of the very early age of MTC onset and the particularly aggressive biologic behavior of MTC in the patients.
Level of evidence: 5
Screening 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. In addition, annual biochemical screening is recommended, followed by MRI only if the biochemical results are abnormal.[20,74] Other screening studies, such as abdominal ultrasound examination or CT scan, may be warranted in some patients. Typical screening recommendations are as follows:
MEN 2A: Annual biochemical screening until age 35 years.
FMTC: Screening as for MEN 2A because not all families classified as FMTC are MTC-only.[57]
MEN 2B: Same as MEN 2A.[74]
Unclassified: Same as MEN 2A.
Level of evidence: 5
Screening for Parathyroid Adenoma or Hyperplasia
Annual biochemical screening is recommended for those patients who have not had parathyroidectomy and autotransplantation, as follows:
MEN 2A: Starting at the time of diagnosis.[74]
FMTC: Screening as for MEN2A because not all families classified as FMTC are MTC-only.[57]
MEN 2B: Same as MEN 2A.[74]
Unclassified: Same as MEN 2A.
Level of evidence: 5
Screening At-risk Individuals in Kindreds Without an Identifiable RET Mutation
MEN 2A: Prophylactic thyroidectomy is not offered routinely to at-risk individuals who have not been confirmed to have the disorder. The screening protocol for MTC is an annual calcitonin stimulation test; however, caution needs to be used in interpreting test results because C-cell hyperplasia that is not a precursor to MTC occurs in about 5% of the population.[7,8] Screening for pheochromocytoma and parathyroid disease is the same as described above.
FMTC: Annual screening for MTC, as for MEN 2A.
Level of evidence: 5
Treatment for Those with MTC
Standard treatment for MTC is surgical removal of the entire thyroid gland, including the posterior capsule and central lymph node dissection. Chemotherapy and radiation are less effective against this type of cancer.[3,75,76]
Level of evidence: 5
Treatment for Those with Pheochromocytoma
Laparoscopic adrenalectomy is recommended by some authorities for the treatment of unilateral pheochromocytoma.[13]
Level of evidence: 5
All of the MEN 2 subtypes are inherited in an autosomal dominant manner. For a child of a person with MEN 2, the risk of inheriting the MEN 2 mutation is 50%. Some individuals with MEN 2, however, carry a de novo 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.[77]
FMTC: Multiple family members are affected, and thus all affected individuals have inherited the mutant gene from a parent.
MEN 2B: About 50% of affected individuals have de novo gene mutations, and 50% have inherited the mutation from a parent.[78,79] The majority of de novo mutations are paternal in origin, but cases of maternal origin have been reported.[80]
Sibs of a proband: The risk to sibs 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 needs to be considered, even though such an occurrence has not yet been reported.
Psychosocial Issues
The psychosocial impact of genetic testing for MEN2 is not extensively studied. Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[81-83] The medical value of early screening and prophylactic 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. Identification as the carrier of a deleterious mutation may affect self-esteem and family relationships. Misconceptions about genetic disease may stir blame and guilt within families. Medicalization of a developing child and social stigmatization may occur. Difficulty maintaining confidentiality and privacy, as well as potential conflict between cultural and family values and adoption of genetic counseling and testing are additional problem areas. One case report details the development of a serious psychosomatic condition, trichotillomania, following genetic testing and prophylactic thyroidectomy in a 13-year-old girl from a family with MEN2A.[84]
A Dutch study reports on a cohort of adults (N=87) applying to be tested for MEN2 and their partners and another cohort of parents applying for the genetic testing of their children (N=36).[85] Utilizing quantitative and qualitative measures, the researchers found that knowledge gaps remained after genetic counseling. Unanticipated shock was seen in carriers following disclosure, typically followed by rapid progression toward surgery. Two weeks after disclosure, half of the carriers reported continuing psychosomatic complaints with complaints dropping to 20% of the carriers by 1 year after diagnosis. Family communication and contact improved among carriers within most extended families, sometimes at the expense of the noncarriers, who felt excluded.
Among the noncarriers who were spared further physiological testing on the basis of their genetic test result, anxiety and psychosomatic complaints nonetheless remained high at 2 weeks after disclosure. Some emptiness and isolation were reported by family members testing negative soon after disclosure, with distress at normal levels by 12 months. Family members who felt coerced to undergo genetic testing were more likely to have adverse emotional reactions following disclosure. Parents who had surgery for MEN during adolescence were sometimes reluctant to allow their children to have surgery before adolescence. Communication within and beyond the family contributed to strain; friends were often not told about the condition. Little adverse effect was seen on job application, work situation, or insurance coverage.
In a related report, mean psychological distress of those applying for genetic testing was not above population norms, although about 9% had psychological morbidity, including high anxiety and somatic complaints. Prominent in this troubled group were applicants who were younger (ages 15-20 years), single, and at high risk of being mutation carriers.[86] A general predisposition to anxiety or distress enhanced the likelihood of high test-related anxiety. Nearly half of the parents believed that they would want continued clinical screening for their children, regardless of the DNA result. The need for attention to the potential psychological vulnerability of young individuals undergoing genetic testing for conditions with potentially favorable medical outcomes is highlighted.
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