To the Editor: Machens et al. (Oct. 16, 2003, issue)1 confirmedthat medullary thyroid carcinoma develops very early in childrencarrying a germ-line mutation of the rearranged during transfection(RET) gene. However, an error in Figure 1 of their article mayalter the message of this important article. According to Figure1, the risk of medullary thyroid carcinoma for a child witha codon 634 RET mutation is approximately 10% at 5 years ofage. This finding seems to be inconsistent with the data providedby Machens et al.: that 75% of children with a codon 634 RETmutation (12 of 16) who underwent prophylactic thyroidectomybefore the age of 5 years had medullary thyroid carcinoma.
It appears to us that the cumulative risks presented in Figure1 have been incorrectly calculated by dividing, at each ageinterval, the number of children with medullary thyroid carcinomaby the total number of children (130), rather than by the numberwho underwent surgery at each age interval (12 divided by 130is nearly 10%).
An international consensus established in 1999 and publishedin 2001 stated that all children with a codon 634 RET mutationshould undergo thyroidectomy before 5 years of age.2 Althoughfeasible, this guideline is rarely implemented.3 Correctionof Figure 1 might help the medical community understand thereasons behind the guidelines.
Olivier Chabre, M.D., Ph.D. Christian Piolat, M.D. Jean-Francois Dyon, M.D. University Hospital of Grenoble 38043 Grenoble, France olivierchabre{at}chu-grenoble.fr
References
Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003;349:1517-1525. [Free Full Text]
Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-5671. [Free Full Text]
Piolat C, Dyon J-F, Sturm N, et al. Very early prophylactic thyroid surgery for infants with a mutation of the RET proto-oncogene at codon 634: evaluation of the implementation of international guidelines for MEN type 2 in a single centre. Clin Endocrinol (Oxf) 2006;65:118-124. [CrossRef][Medline]
The authors reply: We welcome the opportunity to illustratethe rationale behind the recommendation to perform total thyroidectomyin carriers of codon 634 RET mutations before the age of 5 years.1In our article on the multicenter European Multiple EndocrineNeoplasia (EUROMEN) study, we presented the cumulative probabilityof detecting medullary thyroid carcinomas before a certain ageamong the 130 carriers of codon 634 mutations. As noted by Chabreand colleagues, the Kaplan–Meier curve in Figure 1 cannotbe construed as reflecting an age-specific malignant progressionof medullary thyroid carcinoma, since this would lead to anunderestimation of the risk of cancer at younger ages.
We have reanalyzed our data in order to correct the errors inour original figure (Figure 1A), using logistic-regression analysisto enforce monotonicity of the curve2 and smoothing the estimatesof cancer rates by modeling the log-prevalence odds as a linearfunction of age. The resultant age-related malignant progressionof medullary thyroid carcinoma is shown in the corrected figure(Figure 1B). The model-based estimate of the prevalence of cancerwas 52 to 66% before the age of 5 years for asymptomatic carriersof codon 634 mutations in the EUROMEN study. The corrected curvesupports the need for early prophylactic thyroidectomy in asymptomaticcarriers of RET gene mutations.
Figure 1. Original Curves (Panel A) and Corrected Curves (Panel B) for the Cumulative Risk of Medullary Thyroid Carcinoma among Carriers of Codon 634 Germ-Line RET Mutations, According to the Presence or Absence of Nodal Metastases and Age.
We would like to join Chabre and colleagues in their plea forwidespread adoption of early thyroidectomy before the age of5 years in carriers of high-risk RET mutations, including thosein codon 634, to accomplish complete translation of DNA-basedinformation from the bench to the bedside.
Andreas Machens, M.D. Martin-Luther-Universität Halle-Wittenberg 06097 Halle (Saale), Germany andreasmachens{at}aol.com
Josef Hoegel, Ph.D. Universität Ulm 89081 Ulm, Germany
Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-5671. [Free Full Text]
Dinse GE, Lagakos SW. Regression analysis of tumor-prevalence data. J R Stat Soc [C] 1983;32:236-48.
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