Genetics of Medullary Thyroid Cancer (PDQ®): Genetics - Health Professional Information [NCI]

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Genetics of Medullary Thyroid Cancer

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of medullary thyroid cancer. This summary is reviewed regularly and updated as necessary by the Cancer Genetics Editorial Board.

The following information is included in this summary:

  • Family history and other risk factors for medullary thyroid cancer
  • Major genes associated with medullary thyroid cancer risk
  • Genetic testing, screening and risk modification for hereditary medullary thyroid cancer
  • Psychosocial issues associated with hereditary medullary thyroid cancer and genetic testing

The summary also contains level-of-evidence designations. These designations are intended to help readers assess the strength of the evidence in relation to specific studies or strategies. A description of how level-of-evidence designations are made is described in detail in the PDQ summary Cancer Genetics Overview.

This summary is intended to provide clinicians a framework for discussing genetic testing, screening, and risk modification options with individuals at risk for medullary thyroid cancer, as well as for making referrals to cancer risk counseling services. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

Medullary Thyroid Cancer

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.

Thyroid cancer represents approximately 2% of malignancies occurring in the United States, accounting for an estimated 37,200 cancer diagnoses and 1,630 cancer deaths per year.[1] Of these cancers, 2% to 3% are medullary thyroid cancer (MTC).[2,3] Average survival for MTC is lower than that for more common thyroid cancers, e.g., 83% 5-year survival for MTC compared to 90% to 94% 5-year survival for papillary and follicular thyroid cancer.[3,4] 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 diagnoses.[3,4,5] A Surveillance, Epidemiology, and End Results (SEER) population-based study of 1,252 medullary thyroid cancer 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.[6]

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), though CCH is a relatively common abnormality in middle-aged adults. In a population-based study in Sweden, 26% of patients with MTC had the familial form.[7] A French national registry and a U.S. clinical series both reported a higher proportion of familial cases (43% and 44%, respectively).[5,8] Familial cases often indicate the presence of multiple endocrine neoplasia type 2, a group of autosomal dominant genetic disorders caused by inherited mutations in the RET proto-oncogene (OMIM).

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.[5,6,7,8]

References:

1. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
2. Incidence: Thyroid Cancer. Bethesda, Md: National Cancer Institute, SEER, 2004. Available online. Last accessed March 7, 2007.
3. Hundahl SA, Fleming ID, Fremgen AM, et al.: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments] Cancer 83 (12): 2638-48, 1998.
4. Bhattacharyya N: A population-based analysis of survival factors in differentiated and medullary thyroid carcinoma. Otolaryngol Head Neck Surg 128 (1): 115-23, 2003.
5. Modigliani E, Vasen HM, Raue K, et al.: Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med 238 (4): 363-7, 1995.
6. Roman S, Lin R, Sosa JA: Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 107 (9): 2134-42, 2006.
7. Bergholm U, Bergström R, Ekbom A: Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79 (1): 132-8, 1997.
8. Kebebew E, Ituarte PH, Siperstein AE, et al.: Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88 (5): 1139-48, 2000.

Multiple Endocrine Neoplasia Type 2

Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disorder associated with a high lifetime risk of medullary thyroid cancer (MTC). It is caused by germlinemutations in the RET proto-oncogene.

The disorder is classified into 3 subtypes based on the presence of other clinical complications: MEN 2A (OMIM), familial medullary thyroid carcinoma (FMTC) (OMIM), and MEN 2B (OMIM). All 3 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 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 MEN 2. 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.

Deoxyribonucleic acid (DNA)-based testing of the RET gene (chromosomal region 10q11) identifies disease-causing mutations in more than 95% of individuals with MEN 2A and MEN 2B and in about 85% of individuals with FMTC.

Clinical Description

The endocrine disorders observed in MEN 2 are MTC, its precursor C-cell hyperplasia (CCH), pheochromocytoma, and parathyroid adenomas and/or hyperplasia. Bilateral or multifocal areas of MTC and CCH are usually observed at the time of thyroidectomy in patients undergoing risk-reducing thyroidectomy.[1] 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 and often has occurred in patients who present with a palpable thyroid mass or diarrhea.[2,3] Although pheochromocytomas rarely metastasize, they can be lethal because of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities can range from benign parathyroid adenomas to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

Clinical findings in the 3 MEN 2 subtypes are summarized in Table 1. All 3 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 adenoma. Classifying a patient or family by MEN 2 subtype is useful for determining prognosis and management.

Table 1. Percentage of Patients with Clinical Features of MEN 2 by Subtype

FMTC = familial medullary thyroid carcinoma
Percentages based on observations in referral populations.[4,5,6]
Subtype Medullary Thyroid Carcinoma (%) Pheochromocytoma (%) Parathyroid Disease (%)
MEN 2A 95 50 20-30
FMTC ~100 0 0
MEN 2B 100 50 Uncommon

Prevalence

The prevalence of MEN 2 has been estimated to be 1 in 30,000. 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.[6]

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. C-cell hyperplasia (CCH) is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells. Individuals with RET mutations and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal.[7,8] MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration. In provocative testing, plasma calcitonin concentration is measured before (basal level) and at 2 and 5 minutes after intravenous administration of calcium (stimulated level). A positive test has a peak stimulated level that is more than 3 times the basal level or exceeds 300 picograms per milliliter.[8] 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.[7,8]

MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in the United States,[9] though this figure may be an underrepresentation of true incidence due to changes in diagnostic techniques. 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.[10] The total number of new cases of MTC diagnosed annually 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.[2,11] In the absence of a positive family history, MEN 2 may be suspected when MTC occurs at an early age or is multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germline RET mutations,[12,13] the 2 largest series indicate a prevalence range of 1.5% to 12.5%.[14,15] It is widely recommended that RET gene mutation testing be performed for all cases of MTC.[1,16,17]

Pheochromocytoma

Pheochromocytoma (OMIM) is 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. Abdominal magnetic resonance imaging (MRI) is usually performed when a pheochromocytoma is suspected clinically or when urinary catecholamine values are increased. It is unusual for an individual with pheochromocytoma and no family history of endocrine tumors to have MEN 2A or a disease-causing mutation in the RET gene.[18,19,20] When pheochromocytoma is diagnosed in a person suspected of having MEN 2, I131 -metaiodobenzylguanidine (MIBG) scintigraphy or positron emission tomography (PET) imaging may be used for further evaluation because of the high frequency of multiple tumors.[8,21,22]

MEN 2 is not the only genetic disorder that includes a predisposition to pheochromocytoma. Other disorders include neurofibromatosis 1 (NF1), von Hippel-Lindau disease (VHL),[23] and the hereditary paraganglioma syndromes.[24] A large European consortium that included 271 patients from Germany,[25] 314 patients from France,[26] and 57 patients from Italy (total = 642) with apparently sporadic pheochromocytoma analyzed the known pheochromocytoma/functional paraganglioma susceptibility genes (NF1No molecular testing was performed. Diagnosis was made by clinical evaluation only using known clinical diagnostic criteria., RET, VHL, SDHB and SDHD).[27] In 166 (25.9%) patients the disease was, in fact, associated with a positive family history; 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. Since testing for mutations in five different 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.[26,27,28]

Clinical Diagnosis of MEN 2 Subtypes

The diagnosis of the 3 MEN 2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene (chromosomal region 10q11).

MEN 2A

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% to 90% of MEN 2 cases. The MEN 2A subtype was initially called Sipples syndrome.[29] 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 20% to 30% will develop hyperparathyroidism.[30]

MTC is generally the first manifestation of MEN 2A. In asymptomatic young and elderly at-risk individuals, provocative testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC.[8,31] In families with MEN 2A, the biochemical manifestations of MTC generally appear between the ages of 5 and 25 years (mean, 15 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 10 ng/mL and implies a poor prognosis.[2] Up to 30% of patients with MTC present with diarrhea and advanced disease.[32]

Pheochromocytomas usually present after MTC, typically with intractable hypertension, and 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.[33]

A series of 56 patients with MEN 2–related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[34] 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.[35,36,37] 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, 4 double adenomas, and 25 hyperplastic glands. Notably, other genetic causes of familial hyperparathyroidism have been identified, including the hyperparathyroidism–jaw tumor syndrome, MEN 1, and NF1.[38,39] Germline mutations in the HRPT2 tumor suppressor gene (OMIM) have been described in several families with familial isolated hyperparathyroidism.[38]

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.[40,41]

Familial medullary thyroid carcinoma

The FMTC subtype makes up from 5% to 35% of MEN 2 cases and is defined as families with 4 or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.[30] Families with 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.[6,42] 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.

MEN 2B

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.[43,44,45]

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.[46] MEN 2B is characterized by the early development of an aggressive form of MTC in all patients.[46,47] 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 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. Patients with undiagnosed pheochromocytoma may die from a cardiovascular crisis perioperatively. Clinically apparent parathyroid disease is very uncommon.[4,30,48]

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.[44,45]

Genetically Related Disorders

Hirschsprung disease

Hirschsprung disease (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.[49] 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.[50,51] Some of these RET mutations are located in codons that lead to the development of MEN 2A or FMTC (i.e., codons Cys609, Cys618, and Cys620).[49,52]

In a study of 44 families, 7 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.[50] 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.[30]

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.[53] 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.

Multiple endocrine neoplasia type 1

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. MEN 1 is caused by mutations in the MEN1 gene (chromosomal region 11q13) (OMIM). 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.[54] Rarely, patients with MEN 1 have pituitary adenomas and pheochromocytomas, which has led to the hypothesis of an overlap syndrome with MEN 2.[55]

Molecular Genetics of MEN 2

MEN 2 syndromes are due to inherited mutations in the RET gene, located on chromosome region 10q11.[56,57,58] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[59,60] A partial sequence was cloned in 1988.[61] Renumbering of the full-length sequence added 254 codons to the original assignments.[62] Early publications that described allelic variants utilized the codon numbering for the partial sequence. Neutral sequence variants that do not alter the risk of the disease have been described.[63,64]

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.[65] Briefly, the extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region that interacts with 1 of 4 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 4 coreceptors in the GDNFRa family.[65] 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.[66,67,68]

A significantly higher frequency of CCH has been found in peritumoral thyroid tissue of radiation-induced epithelial thyroid tumors than in the surrounding tissue of sporadic thyroid tumors or control thyroid tissue.[69] Further, the RET Gly691Ser polymorphism was present with a much higher frequency in radiation-induced epithelial tumors (55%) as compared to either sporadic thyroid tumors (20%) or control thyroid (15%). In those radiation-induced thyroid tumors that had CCH in the surrounding tissue, there was an 88% frequency of the polymorphism.

Mutation analysis

At least 95% of families with MEN 2A have a RET mutation in exon 10 or exon 11.[14,62,70] Mutations of codon Cys634 in exon 11 occur in about 85% of families; mutation of cysteine codons at amino acid positions 609, 611, 618, and 620 in exon 10 together account for the remainder of identifiable mutations.[14] Other rare mutations have been reported in single families,[71,72,73] including those at codons 635, 637, 790, 791, Val804 (specifically Val804Leu), and 891.

Approximately 85% of families with FMTC have an identifiable RET mutation.[62,70] These mutations typically affect 1 of the 5 cysteine residues (codons 609, 611, 618, 620, and 634), with mutations of the first 3 each accounting for 25% to 35% of all mutations. The 634 mutations in FMTC are rarely, if ever, Cys634Arg.[14] Mutations in the extracellular domain of RET, at codons 532, 533, Cys630, and in the intracellular domain, at codons Glu768, Leu790, Tyr791, Val804 (specifically Val804Met), Ser891, and 912 have also been identified.[74,75,76,77,78] Mutations at codons 532, 533, 768, 844, and 912 have only been seen in families with FMTC.[74,76,79,80,81,82]

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 Met918 in exon 16, which substitutes a threonine for methionine (Met918Thr).[83,84] A second mutation at codon Ala883 in exon 15 has been identified in several MEN 2B patients without a Met918Thr mutation.[83,85,86,87] MEN 2B has also been described in a compound heterozygote who carried Val804Met and Tyr806Cys mutations in the same allele.[88]

Functional Effects of RET Mutations and Genotype-Phenotype Correlations

Mutations in codons in the cysteine-rich extracellular domain (609, 611, 618, 620, and 634) cause ligand-independent RET dimerization, leading to constitutive activation (i.e., gain of function) of tyrosine kinase.[89,90] The disease-causing point mutation in codon Met918 that causes 95% of the MEN 2B phenotype lies within the catalytic core of the tyrosine kinase and causes an alteration in substrate specificity of the normal RET.[89,90,91] Mutations in cysteine codons 609, 618, and 620 are associated with lower transforming activity of RET when compared with codons Cys634 and Met918.[89,90] In contrast to the activating mutations in MEN 2, mutations that cause HSCR result in loss of function.[92]

The following genotype-phenotype correlations have been suggested for RET mutations:

  • RET germline Met918Thr and Ala883Phe mutations are associated only with MEN 2B. Somatic mutations in these codons are frequently observed in sporadic MTC.[84,93,94]
  • Mutations involving the cysteine codons 609, 618, and 620 are associated with either MEN 2A, FMTC, or HSCR1. Mutations in these codons are detected in about 10% of families with MEN 2A and 65% of families with FMTC.[30]
  • Mutations in codons Glu768 in exon 13 and Val804 in exon 14 may only be associated with the development of MTC, since these mutations have been identified primarily in the FMTC subtype.[14,30,75,95,96,97]
  • Any RET mutation at codon Cys634 in exon 11 results in higher incidence of pheochromocytomas and hyperparathyroidism.[30,62]
  • Among the mutations at codon Cys634, it has been reported that Cys634Arg significantly correlates with the presence of hyperparathyroidism,[30,62] but other studies do not confirm this correlation.[98,99] This discrepancy may be explained by differences in study methodology and by the fact that hyperparathyroidism has an age-related penetrance, increasing with age.[100]
  • Some mutations, such as those involving cysteine codons 609, 620 in exon 10, 768, 790, 791, Val804 in exon 14, and 891 may be associated with milder forms of the disease.[30,70,101,102,103]
  • Possible correlation between the presence of mutations in codon Cys634 in the RET gene and the cutaneous lichen amyloidosis skin lesion has been noted.[30,104,105]

Genetic Variants in RET with Unknown Functional Effect

Many polymorphisms in both coding and noncoding sequences have been identified in the RET gene and have been evaluated with respect to disorders associated with RET gene mutations. Of these, a C?T change resulting in a silent polymorphism, Ser836Ser, has been found to be more frequent in sporadic, nonfamilial German patients with MTC.[106,107] Substantially more information will be required to determine whether this variant is truly an MTC risk factor.

Genetic Testing

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.[108] 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.[109,110]

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

Testing for the common mutations in exons 10, 11, 13, 14, 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 polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis, single-strand conformation polymorphism analysis, and DNA sequencing.[63,111,112,113]

A small number of families with MEN 2 have been described without detectable abnormalities in the RET coding sequence. There is considerable diversity in the approach to RET mutation testing among the various laboratories that perform this procedure. These range from selective testing of those exons most likely to harbor MEN 2 mutations to full sequencing of the entire gene. These differences 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.) 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.

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 informative families with MEN 2 with greater than 95% accuracy.[114]

Linkage testing is not possible in families in which there is a single affected individual.

Interventions

Risk-reducing thyroidectomy

Risk-reducing thyroidectomy and parathyroidectomy with reimplantation of 1 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.[3] Current recommendations are based on clinical experience and vary for different MEN 2 subtypes, as noted below. The general approach to MEN 2 management employed in Germany and the Netherlands has been reviewed.[103,115]

In a study of biochemical screening in a large family with MEN 2A done 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.[116]

Two case series provide data supporting early risk-reducing thyroidectomy following testing for RET mutations.[117,118] 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, whereas the other study reported 21 patients seen at a referral center.[117,118] 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.[117] No studies have compared the outcome of thyroidectomy based on mutation testing to thyroidectomy based on biochemical screening.

In the most comprehensive literature review published to date, 260 MEN 2A subjects aged 0 to 20 years were identified as having undergone either an early total thyroidectomy (ages 1-5, n = 42), or late thyroidectomy (ages 6-20, n = 218).[119] There was a significantly lower rate of invasive or metastatic MTC among those operated on at an early age (57%) compared with those operated on late (76%). Follow-up information was available on only 28% of the cohort, due to 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 prior to age 6 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 the Cys634 mutation were much more likely to present with invasive or metastatic MTC, and more likely to develop persistent or recurrent disease, than were those with the Cys804, Cys618, or Cys620 mutations.

A study of young, clinically asymptomatic individuals with MEN 2A sought to determine if early thyroidectomy could prevent or cure MTC.[120] This study included 50 consecutively identified RET mutation carriers who underwent thyroidectomy at age 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.

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.[8,46] Therefore, though 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 parathyroid glands need thyroid hormone replacement therapy and monitoring for possible hypoparathyroidism.

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 in 2 siblings with MEN 2A.[121] Conversely, another case report documents onset of cancer in midlife or later in some families with FMTC, as well as in elderly relatives who carry the FMTC genotype but have not developed cancer.[122] The possibility that certain specific mutations (e.g., Cys634) might convey a significantly worse prognosis, if confirmed, may permit tailoring intervention based on knowing the specific RET mutation.[119] 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.

As noted above, there is controversy about the age at which to perform risk-reducing thyroidectomy, in part because outcome data are limited to uncontrolled studies or relatively small populations. Observational studies of the genotype-phenotype correlations suggest significant differences in biological aggressiveness of the medullary thyroid cancers that occur in MEN 2A, MEN 2B, and FMTC.[16,105] As a result of these observations, several consortia have recommended stratifying RET mutations into three groups based on the aggressiveness of MTC. Patients with mutations in risk level 1 (codons 609, 768, 790, 791, 804, and 891) have the lowest risk of developing MTC and tend to have an older age of onset. Patients with level 2 mutations (codons 611, 618, 620, and 634) have an intermediate risk, and patients with level 3 mutations (codons 883, 918) have the highest risk for aggressive MTC and a very early age of onset.[16,103] Patients with level 3 mutations, and perhaps those with level 2 mutations, could be considered for early thyroidectomy; however, this approach has not been prospectively validated as a basis for clinical decision-making.

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) compared 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.[123] Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery.[16] A summary of current practice in referral centers suggests the following:[124]

MEN 2A: In most centers, thyroidectomy is performed in patients by the age of 5 years or when a mutation is identified.[16,17]

FMTC: Some centers recommend management similar to that for MEN 2A. Others recommend that for carriers of certain low-risk mutations (codons 609, 768, 790, 791, 804, 891) thyroidectomy should be performed only after an abnormal stimulated plasma calcitonin level is detected.[17,115]

MEN 2B: In most centers, surgery is performed within the first 6 months of life, preferably within the first month, because of the very early age of MTC onset and the particularly aggressive biologic behavior of MTC in the patients.[16]

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. In addition, annual biochemical screening is recommended, followed by MRI only if the biochemical results are abnormal.[33,124] Studies have suggested that measurement of catecholamine metabolites, specifically plasma-free metanephrines and/or urinary fractionated metanephrines, provides a higher diagnostic sensitivity than urinary catecholamines, due to the episodic nature of catecholamine excretion.[28,125,126,127,128,129,130,131] Other screening studies, such as abdominal ultrasound examination or CT scan, may be warranted in some patients. Several reviews provide a succinct summary of the biochemical diagnosis, localization, and management of pheochromocytoma.[28,132] 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. Typical surveillance recommendations are as follows:

MEN 2A: Annual biochemical screening.

FMTC: Screening as for MEN 2A because not all families classified as FMTC are MTC-only.[101]

MEN 2B: Same as MEN 2A.[124]

Unclassified: Same as MEN 2A.

Level of evidence: 5

Screening of at-risk individuals for parathyroid hyperplasia or adenoma

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.[34] 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.[124]

FMTC: Screening as for MEN 2A because not all families classified as FMTC are MTC-only.[101]

MEN 2B: Same as MEN 2A, though clinically apparent hyperparathyroidism is seldom observed in MEN 2B.[124]

Unclassified: Same as MEN 2A.

Level of evidence: 5

Screening of at-risk individuals in kindreds without an identifiable RET mutation

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.[7,8,133] In addition, there is significant risk of false-negative test results in patients younger than 15 years.[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. 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,[3,134,135] although phase I and II clinical trials are ongoing at selected centers (NCI's PDQ Cancer Clinical Trials Registry).

Level of evidence: 5

Treatment for those with pheochromocytoma

Pheochromocytoma may be either unilateral or bilateral in patients with MEN 2. Laparoscopic adrenalectomy is recommended by some authorities for the treatment of unilateral pheochromocytoma.[16] It is unclear whether bilateral adrenalectomy should be performed routinely in patients with MEN 2-related pheochromocytoma in the absence of bilateral pheochromocytomas.

In 1 series, 23 patients with a unilateral pheochromocytoma and a macroscopically normal contralateral adrenal gland were treated initially with unilateral adrenalectomy.[136] 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 1 episode of acute adrenal insufficiency; 1 of these patients died. Unilateral adrenalectomy appears to represent a reasonable management strategy for unilateral pheochromocytoma in patients with MEN 2,[137,138] when coupled with periodic surveillance (serum or urinary catecholamine measurements) for the development of disease in the contralateral adrenal gland.

Cortical-sparing adrenalectomy represents an additional approach to disease management in patients with bilateral pheochromocytomas.[139] Fourteen (93%) of 15 patients undergoing laparotomy for bilateral pheochromocytomas were treated with a procedure that spared as much normal-appearing adrenal cortex as possible. Thirteen 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).[140] Adrenal cortex-sparing surgery may also be accomplished laparoscopically, with intraoperative ultrasound guidance.[141] These approaches require long-term patient follow-up, as recurrence may develop many years after the initial operation.

Level of evidence: 5

Treatment for those with parathyroid hyperplasia or adenoma

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.[16] In general, fewer than 4 of the parathyroid glands are involved at the time of detected abnormalities in calcium metabolism. Uncertainty exists regarding the criteria that would indicate parathyroidectomy and the role of parathyroid autotransplantation in the management of these patients.

Cure of hyperparathyroidism was achieved surgically in 89% of 1 large series of patients;[34] 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 thyroidectomy, 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.[142]

Genetic Counseling

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.[143]

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.[144,145] The majority of de novo mutations are paternal in origin, but cases of maternal origin have been reported.[146]

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.

Psychosocial issues

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.[147,148] Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[149,150,151,152] 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 of age, single, and had a history of responding to distressful situations with anxiety.[153] 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."[154]

A small qualitative study (N = 21) evaluated how patients with MEN 2A and family members conceptualized participation in lifelong high-risk surveillance.[155] 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 medullary thyroid carcinoma undergoing lifelong surveillance.[156]

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