Multiple Endocrine Neoplasia Type 2 (MEN 2)
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. The use of biochemical screening is limited, however, by the lack of data on age-specific calcitonin levels in children under 3 years of age; caution should be used when interpreting these values in this age group.
A study of 93 patients with MEN 2 from a Dutch tumor registry documents the importance of early prophylactic thyroidectomy. This group of patients represents all known Dutch patients with hereditary MTC; the majority of cases (67%) were codon 634 mutations; only 6% were MEN 2B cases. Patients in this series were screened with either biochemical testing (pre-RET era) or RET mutation analysis. In both groups, patients were operated on at a later age than recommended by current guidelines (see Table 2), but the percentage from the pre-RET era was significantly higher (96% vs. 69%, P = .004). Older age at prophylactic thyroidectomy was significantly associated with a higher risk of postoperative persistent/recurrent disease. Although there is concern that young age at total thyroidectomy is associated with higher risk of surgical complications, this study found no such evidence.
Two additional case series provide further data supporting early risk-reducing thyroidectomy following testing for RET mutations.[121,122] Cases reported in both series could reflect selection biases: one 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.[121,122] 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. No studies have compared the outcome of thyroidectomy based on mutation testing with thyroidectomy based on biochemical screening.
In one large series, 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). 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, as a result of 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 codon 634 mutations were much more likely to present with invasive or metastatic MTC and to develop persistent or recurrent disease compared with those harboring mutations in codons 804, 618, or 620.