Correspondence

Correction

Childhood Progression of Hereditary Medullary Thyroid Cancer

N Engl J Med 2007; 356:1583-1585April 12, 2007

Article

To the Editor:

Machens et al. (Oct. 16, 2003, issue)1 confirmed that medullary thyroid carcinoma develops very early in children carrying a germ-line mutation of the rearranged during transfection (RET) gene. However, an error in Figure 1 of their article may alter the message of this important article. According to Figure 1, the risk of medullary thyroid carcinoma for a child with a codon 634 RET mutation is approximately 10% at 5 years of age. This finding seems to be inconsistent with the data provided by Machens et al.: that 75% of children with a codon 634 RET mutation (12 of 16) who underwent prophylactic thyroidectomy before the age of 5 years had medullary thyroid carcinoma.

It appears to us that the cumulative risks presented in Figure 1 have been incorrectly calculated by dividing, at each age interval, the number of children with medullary thyroid carcinoma by the total number of children (130), rather than by the number who underwent surgery at each age interval (12 divided by 130 is nearly 10%).

An international consensus established in 1999 and published in 2001 stated that all children with a codon 634 RET mutation should undergo thyroidectomy before 5 years of age.2 Although feasible, this guideline is rarely implemented.3 Correction of Figure 1 might help the medical community understand the reasons 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@chu-grenoble.fr

3 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

3. 3

   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 | Web of Science | Medline

Author/Editor Response

We welcome the opportunity to illustrate the rationale behind the recommendation to perform total thyroidectomy in carriers of codon 634 RET mutations before the age of 5 years.1 In our article on the multicenter European Multiple Endocrine Neoplasia (EUROMEN) study, we presented the cumulative probability of detecting medullary thyroid carcinomas before a certain age among the 130 carriers of codon 634 mutations. As noted by Chabre and colleagues, the Kaplan–Meier curve in Figure 1 cannot be construed as reflecting an age-specific malignant progression of medullary thyroid carcinoma, since this would lead to an underestimation of the risk of cancer at younger ages.

We have reanalyzed our data in order to correct the errors in our original figure (Figure 1AFigure 1Original 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.), using logistic-regression analysis to enforce monotonicity of the curve2 and smoothing the estimates of cancer rates by modeling the log-prevalence odds as a linear function of age. The resultant age-related malignant progression of medullary thyroid carcinoma is shown in the corrected figure (Figure 1B). The model-based estimate of the prevalence of cancer was 52 to 66% before the age of 5 years for asymptomatic carriers of codon 634 mutations in the EUROMEN study. The corrected curve supports the need for early prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations.

We would like to join Chabre and colleagues in their plea for widespread adoption of early thyroidectomy before the age of 5 years in carriers of high-risk RET mutations, including those in codon 634, to accomplish complete translation of DNA-based information from the bench to the bedside.

Andreas Machens, M.D.
Martin-Luther-Universität Halle-Wittenberg, 06097 Halle (Saale), Germany
andreasmachens@aol.com

Josef Hoegel, Ph.D.
Universität Ulm, 89081 Ulm, Germany

Henning Dralle, M.D.
Martin-Luther-Universität Halle-Wittenberg, 06097 Halle (Saale), Germany

2 References

1. 1

   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
   CrossRef | Web of Science | Medline

2. 2

   Dinse GE, Lagakos SW. Regression analysis of tumor-prevalence data. J R Stat Soc [C] 1983;32:236-248
   Web of Science

Citing Articles (1)

Citing Articles

1. 1

   Steven G. Waguespack. (2009) A Perspective from Pediatric Endocrinology on the Hereditary Medullary Thyroid Carcinoma Syndromes. Thyroid 19:6, 543-546
   CrossRef