Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Genetics - Health Professional Information [NCI] - Multiple Endocrine Neoplasia Type 2
Table 4. Genotype-Phenotype Correlations and American Thyroid Association (ATA) Risk Levelsa,b continued...
Risk-reducing thyroidectomy and parathyroidectomy with reimplantation of one or more parathyroid glands into the neck or nondominant forearm is a preventive option for all subtypes of MEN2. To implement this management strategy, biochemical screening to identify CCH and/or genetic testing to identify persons who carry causative RET mutations is needed to identify candidates for risk-reducing surgery (see below). The optimal timing of surgery, however, is controversial. Current recommendations are based on clinical experience and vary for different MEN2 subtypes, as noted in Table 5.
In contrast, a prospective analysis of 84 carriers of the RET gene mutation found that basal and pentagastrin-stimulated calcitonin levels could be used to determine the timing of total thyroidectomy. When the basal or stimulated calcitonin was greater than 10 pg/mL, total thyroidectomy and central neck dissection were strongly recommended. In this series, a basal calcitonin level lower than 60 pg/mL was always associated with an intrathyroidal MTC; none of the 56 patients who went to surgery had metastatic involvement. These findings suggest that surgery can be safely delayed in gene carriers of a RET mutation until basal or stimulated calcitonin is above 10 pg/mL, while still maintaining the ability to achieve a disease-free state (i.e., an undetectable basal and stimulated calcitonin 6–12 months after surgery). The benefits of this approach are particularly noteworthy in the younger population of gene carriers, as a delay in surgery until the patient is older may reduce the risk of surgical complications. While this approach is promising, pentagastrin is currently not available in the United States for stimulation testing. Although calcium may be used as a substitute for pentagastrin, it has not been widely validated.
Table 5. American Thyroid Association Medullary Thyroid Cancer Risk Stratification and Management Guidelinesa
|Risk level||Mutated Codon(s)||Age ofRETTesting||Timing of Prophylactic Thyroidectomy|
|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.|
|D||883, 918, and compound heterozygotes V804M+E805K, V804M+Y806C, and V804M+S904C||ASAP and within the first y of life||ASAP and within the first y of life.|
|C||634||<3–5 y||Before age 5 y.|
|B||609b, 611, 618, 620, 630b, and compound heterozygote V804M+V778I||<3–5 y||Consider surgery before age 5 y. May delay surgery after age 5 y if criteria are met.c|
|A||768, 790, 791, 804, 891||<3–5 y||May delay surgery after age 5 y if criteria are met.c|