Table 2. American Thyroid Association Medullary Thyroid Cancer Risk Stratification and Management Guidelinesa
a Adapted from Kloos et al.
b These mutations had not been reported at the time of the 7th International Workshop.
c Criteria include a normal annual basal and/or stimulated serum count, normal annual neck ultrasound, less aggressive medullary thyroid cancer family history, and family preference.
|Risk level||Mutated codon(s)||Age of RET testing||Timing of prophylactic thyroidectomy|
|D||883 and 918 as well as compound heterozygotes: V804M+E805K; V804M+Y806C; and V804M+S904C ||ASAP and within the 1st year of life||ASAP and within the 1st year of life|
|C||634||< 3-5 y||Before age 5|
|B||609b, 611, 618, 620, 630b, compound heterozygote: V804M+V778I ||< 3-5 y||Consider surgery before age 5. May delay surgery after age 5 if criteria are met.c|
|A||768, 790, 791, 804, 891||< 3-5 y||May delay surgery after age 5 if criteria are met.c|
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. Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery.
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.[93,94,95,96,97] Approximately 95% of individuals with MEN 2B will have the M918T mutation.[93,94,95,98] 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.[99,100,101,102,103] 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.[49,104] Until recently, MEN 2A with cutaneous lichen amyloidosis (CLA) had been seen almost exclusively in patients with mutations at codon 634.[49,51,105] 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.