According to Surveillance, Epidemiology, and End Results (SEER) data, medullary thyroid carcinoma (MTC) accounts for 1–2% of thyroid cancers in the United States, which is a lower range than the 3-5% often cited, primarily because of the increased incidence of papillary thyroid carcinoma.  Thyroid cancer is traditionally seen as a largely curable disease: thyroidectomy, suppression of thyroid stimulating hormone (TSH), and administration of radioactive iodine confers overall survival rates of 71% at 10 years and 55% at 20 years. [2, 3, 4]
Yet these survival rates are only true for the 90% of differentiated thyroid cancers that originate in the follicular cells, comprising papillary, follicular, and Hürthle cell thyroid carcinomas. Medullary thyroid cancer (MTC), which represents approximately 4% of cases, tends to present at late stages and does not respond to TSH suppression or iodine, making it difficult to manage and conferring worse outcomes overall.
MTC originates from calcitonin-secreting neuroendocrine parafollicular or C cells of the thyroid. These cells lack TSH receptors and do not concentrate radioactive iodine. Approximately 50% of patients present with stage III/IV disease and 5-year survival rates range from 73% for patients with stage III disease to 40% for patients with stage IV disease. [2, 5, 6]
It is estimated that 20% of MTCs are associated with one of three inherited endocrine syndromes caused by germline mutations of the RET gene.  The remaining 80% of MTCs are sporadic, although somatic mutations in RET can be seen in 40% to 50% of sporadic cases. Each of the syndromes can be distinguished by a unique cluster of clinical findings.
Multiple endocrine neoplasia (MEN) 2A is associated with RET mutations in codons 609, 611, 618, and 620 in exon 10, as well as in codon 634 in exon 11. Patients with MEN2A typically have MTC, pheochromocytoma, and primary hyperparathyroidism (PHPT). 
MEN2B is associated with RET mutations in codons 918 in exon 16 (> 95% of cases) and codon 883 in exon 15. These patients present with the most aggressive type of MTC. They typically have pheochromocytoma but not PHPT, and, unlike in the other syndromes, also exhibit musculoskeletal abnormalities and other developmental defects.
Finally, familial medullary thyroid cancer (FMTC) is associated with mutations in codons 609, 611, 618, and 620 in exon 10, as well as codon 768 in exon 13 and codon 804 in exon 14. In these patients, MTC is often the only clinical finding, ie, patients do not necessarily have either pheochromocytoma or PHPT. The diagnosis of FMTC is therefore made after demonstrating MTC in at least 4 family members.
As in MEN2B, the most common mutation in patients with sporadic MTC is in codon 918 in exon 16. Patients with sporadic MTC typically have decreased survival compared with the inherited forms, and often demonstrate lymph node metastases at presentation. 
Table. Common Mutations in Sporadic MTC (Open Table in a new window)
|Most Common Mutation(s)||Typical Clinical Findings|
• Codons 609, 611, 618, and 620 in exon 10
• Codon 634 in exon 11
|• MTC, pheochromocytoma, and PHPT|
• Codon 918 in exon 16 (> 95% of cases)
• Codon 883 in exon 15
• Most aggressive MTC
• Pheochromocytoma, not PHPT
• Musculoskeletal abnormalities and developmental defects
• Codons 609, 611, 618, and 620 in exon 10
• Codon 768 in exon 13
• Codon 804 in exon 14
• MTC present in at least 4 family members
• Pheochromocytoma and PHPT not necessarily present
|Sporadic||• Codon 918 in exon 16||
• Decreased survival
• Lymph nodes metastases at presentation
The American Thyroid Association has published revised guidelines for medullary thyroid cancer, including the following  :
The recommended method of initial testing for MEN2A is either a single or multi-tiered analysis to detect RET mutations in exon 10 (codons 609, 611, 618, and 620), exon 11 (codons 630 and 634), and exons 8, 13, 14, 15, and 16.
Sequencing of the entire coding region should be reserved for situations in which no RET mutation is identified or there is a discrepancy between the MEN2 phenotype and the expected genotype.
Patients with the MEN2B phenotype should be tested for the RET codon M918T mutation (exon 16) and, if negative, the RET codon A883F mutation (exon 15). If there are no mutations identified in these 2 exons, the entire RET coding region should be sequenced.
Genetic counseling and genetic testing for RET germline mutations should be offered to first-degree relatives of patients with proven hereditary MTC; parents whose infants or young children have the classic phenotype of MEN2B; patients with CLA; and infants or young children with Hirschsprung disease (HD) and exon 10 RET germline mutations, and adults with MEN2A and exon 10 mutations who have symptoms suggestive of HD.
To see complete information, see the Medscape Reference article on Medullary Thyroid Cancer.
Few definitive clinical trials have been conducted in patients with MTC to determine the optimal treatment approach for each genetic and clinical syndrome. Rather, years of clinical experience combined with accumulated clinical trial data have led to a basic set of management guidelines.
Of note, because the presence of specific RET mutations predict which inherited syndrome the patient will develop, management guidelines also incorporate preventive strategies for patients who carry mutations known to cause the more aggressive forms of disease.
Management of localized disease
Prophylactic thyroidectomy is recommended for all patients under age 5 years known to carry any RET mutation EXCEPT those in codons 768, 790, 791, 804, and 891, which are considered least likely to cause aggressive disease. [2, 10, 11] Surgery can be delayed past age 5 if annual thyroid ultrasounds show no abnormalities, if annual calcitonin levels are normal, and if the patient has a family history of less aggressive disease.
The potential benefits of extensive node dissection in all patients are somewhat unclear; dissection is therefore typically reserved for cases that predict for more aggressive disease. For example, a calcitonin level > 40 mg/mL predicts for a higher risk of lymph node metastases, and would therefore warrant extensive node dissection.  Similarly, extensive node dissection would be warranted in MEN2B patients whose tumor is >0.5 cm and in MEN2A/FMTC patients whose tumor is >1 cm. In both situations, the larger tumor size predicts for a more aggressive tumor and potentially a worse outcome. 
Unlike in other tumor types, adjuvant therapy is not considered a mainstay of treatment. Guidelines recommend adjuvant radiotherapy in patients with T4 disease to prevent local recurrence, but also note that there are too few data to definitively demonstrate a benefit with this treatment modality. [2, 10]
As noted above, MTC cells do not concentrate radioactive iodine. Adjuvant radioactive iodine, which is commonly used in differentiated thyroid cancers, is not recommended in patients with MTC. [2, 10]
Management of persistent or recurrent disease
The multitarget tyrosine kinase inhibitors vandetanib and cabozantinib have been approved by the US Food and Drug Administration (FDA) for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease. These agents target various tyrosine kinases including MET, RET, and VEGFR-2. [10, 12, 13, 14, 15, 16, 17, 4, 18]
In a phase III clinical trial, 331 patients randomized to vandetanib demonstrated significantly improved progression-free survival, with an estimated benefit of approximately 11 months compared with those receiving placebo. Objective response rate, disease control rate, and biochemical response were also significantly improved with vandetanib compared with placebo. Final analysis of overall survival data is not yet available, but analysis at 24 months’ follow-up showed no difference between the groups. [12, 13]
Of note, a 55% response rate to vandetanib was found in patients with sporadic MTC who had a RET mutation in codon 918, compared with a 31% response rate in sporadic, mutation-negative patients randomized to vandetanib. However, the number of patients with known mutation status was small, so although these data potentially underscore the benefit of targeting RET mutations, whether the higher response rate will translate into improved outcomes is unknown. [12, 13]
The approved dosage regimen is 300 mg PO daily with or without food, continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs.
Twelve percent of patients discontinued vandetanib because of toxicity and 8% showed grade 3 QT prolongation, prompting the FDA to include a boxed warning on the potential cardiotoxicity risks with vandetanib. The FDA also mandated that the drug be distributed with a risk evaluation and mitigation strategy with prescriber education focused on patient selection, monitoring, and awareness of drug interactions with other drugs that may prolong the QT interval. 
The most common adverse events in vandetanib-treated patients are diarrhea, rash, folliculitis, nausea, QTc prolongation, hypertension, and fatigue. 
Approval for cabozantinib was based on the EXAM clinical trial, an international, multicenter, randomized study that included 330 patients with progressive, metastatic medullary thyroid carcinoma. A statistically significant prolongation in progression-free survival was seen with cabozantinib compared with placebo (11.2 vs 4 mo; P < .0001). Partial responses were observed only among patients in the in the active treatment arm (27% vs 0%; P < .0001), and more patients in the cabozantinib group than in the placebo group were alive and free of disease progression at 1 year (47.3% vs 7.2%). Median duration of response was 14.7 months. 
The approved dosage regimen is 140 mg PO daily without food, continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs. Dosage adjustment is needed if coadministered with strong CYP3A4 inhibitors or inducers or if toxicity occurs.
Despite the approval of vandetanib and cabozantinib, guidelines recommend considering a clinical trial of an investigational agent for all patients with progressive disease. Cabozatinib is a good treatment option for unresectable locally advanced or metastatic MTC.  Phase I/II trials of the RET and/or VEGF-targeting axitinib, motesanib, sorafenib, and sunitinib have all shown at least some clinical benefit in patients with persistent or recurrent MTC. [19, 20, 21, 12, 13, 22, 16, 17]
However, in many of these trials, patients demonstrated high stable disease rates and low rates of objective response, and the clinical significance of these findings remains unknown. There are, as yet, no phase III trial data demonstrating a survival benefit with these agents, and there are also no data demonstrating response according to specific RET mutations, leaving open the question of whether these agents might be used in tailoring therapy toward patients with specific RET mutations and clinical findings.
Testing for the Genetic Mutation
All patients with a personal medical history of primary C cell hyperplasia, MTC, or MEN2A/B should be offered germline RET testing. In addition, individuals with a family history consistent with MEN2A/B or FMTC who are at risk for autosomal dominant inheritance of the syndrome should be offered RET testing. For MEN2B, testing should be done shortly after birth; for MEN2A and FMTC, testing should be done before 5 years of age. 
Most laboratories test for RET mutations in the five most commonly mutated codons in exons 10 and 11 (634, 609, 611, 618, and 620). Some will also test for mutations in exons 13, 14, 15, and/or 16, but only a few will include exon 8.
Full sequencing of the RET gene is recommended only in patients with MEN2B if tests are negative for mutations in codons 918 and 883 in exons 16 and 15, respectively.  Testing laboratories can be found at genetests.org