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From the Section of Endocrinology (MDR), Washington Hospital Center/MedStar Research Institute, Washington, DC; and the Division of Pediatric Endocrinology (MAL), Johns Hopkins University School of Medicine, Baltimore, Maryland.
Correspondence: Address correspondence to: Michael A. Levine, MD, Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, 211 Park Building, 600 N. Wolfe St., Baltimore, MD 21287; Fax: 410-955-9773; E-mail: mlevine{at}jhmi.edu
Follicular cell-derived thyroid cancer is far less common in children than adults and accounts for approximately 1% of all pediatric malignancies. Compared with adults, children and adolescents with differentiated papillary and follicular thyroid cancer are more likely to have advanced or multicentric disease and metastatic dissemination of cancer to regional lymph nodes and distant tissues at the time of initial diagnosis. Cancer recurrence is also more common in children with differentiated thyroid cancer (DTC) than in adults. On the other hand, despite the advanced stage of their cancers, children and adolescents with DTC have an excellent prognosis and enjoy very low mortality rates. This striking dissonance suggests that late diagnosis rather than aggressive behavior may account for the more extensive disease at presentation. Still, there may be fundamental differences in the biology of childhood and adult thyroid cancer that have potentially important clinical implications. For example, the juvenile thyroid gland exhibits enhanced sensitivity to radiation-induced genetic change and neoplasia, which could relate to the increased propensity to multicentric disease. Nikiforov et al.1 demonstrated that approximately 70% of pediatric papillary thyroid cancers contained RET/PTC oncogene rearrangements regardless of a history of radiation exposure. By contrast, only 20% of sporadic adult papillary cancers contain a RET/PTC rearrangement.2 Regardless of patient age, management of DTC generally includes surgery, total thyroidectomy if the tumors are larger than 1.5 cm or metastases are detected, and resection of enlarged cervical lymph nodes. Surgery is generally followed by administration of radioactive iodine to eradicate any remaining normal and malignant thyroid tissue. After this initial ablative therapy, patients are treated with supra-physiological doses of L-thyroxine to suppress pituitary secretion of thyrotropin, a trophic hormone that can promote growth of thyroid cancer cells. Patients are subsequently monitored to detect any evidence of recurrence or progression of thyroid cancer, most commonly by whole body iodine-131 (131I) scintigraphy and measurement of serum levels of thyroglobulin after administration of recombinant thyrotropin or after induction of hypothyroidism via withdrawal of L-thyroxine therapy. In selected patients additional tests might include ultrasound examination of the neck or magnetic resonance imaging, computed tomography, and positron emission tomography scans. Recurrent or persistent cancer is then treated with additional surgery, radioactive iodine, or external beam radiation, either alone or in combination.
Do the available data support aggressive initial surgery in the management of childhood DTC? Are the benefits worth the risks of permanent hypothyroidism and laryngeal nerve dysfunction? Exchange scalpel for sword, and the exploits of Pyrrhus, the courageous if imprudent warrior king of the Hellenistic kingdom of Epirus, come to mind. In 281 BC, Pyrrhus assembled an army of 25,000 men and 20 elephants to march against Rome and establish a kingdom of Sicily and lower Italy. Although successful, his many battles were so costly that he was forced to withdraw from Italy, remarking, "Another such victory and I shall be ruined." By analogy, clinicians must ask whether our surgical victories over thyroid cancer come at too great a morbidity. A conclusive answer is not yet available, and the impact of initial surgical therapy on outcome in patients with DTC continues to be a very controversial topic. Management of adult patients with DTC is based on the results of large, long-term, prospective and retrospective studies, and treatment protocols for postpubertal adolescents are routinely derived from extrapolation of therapeutic practices in adults. By contrast, treatment algorithms for younger children have been derived from single-institution clinical cohorts, reports of extensive personal experience, and secondary reviews of published literature.3 Most studies in adults have demonstrated that total thyroidectomy for large, aggressive thyroid cancers is associated with reduced tumor recurrence rates over time compared with unilateral surgery.4 However, for small, early-stage tumors, the rationale for total thyroidectomy is less certain because most patients will do well for many years regardless of initial surgical choice. In a recent review from the Mayo Clinic of the influence of surgical management on outcome in patients with stage 1 or 2 papillary thyroid cancer, Hay et al.5 reported a significant reduction in local recurrence over 30 years in patients treated with total thyroidectomy (4%) as compared with patients treated with subtotal thyroidectomy (17%). These patients were not treated with 131I ablation, and there was no survival advantage for the total thyroidectomy group. Similarly, Mazzaferri et al.6 also noted an advantage for adults with either follicular or papillary treated with a bilateral, rather than a unilateral operation with respect to tumor recurrence.
Because thyroid tumors tend to be associated with multicentric disease and early nodal metastases in children, it has been suggested that total (or near total) thyroidectomy with regional node dissection may be the best initial surgery. This approach, although aggressive, is designed to remove all malignant and benign thyroid tissue to facilitate postoperative radioiodine therapy and monitoring. This more extensive surgical procedure, however, may be associated with a higher rate of hypoparathyroidism and recurrent laryngeal nerve damage. On the other hand, less surgery may increase the dosage requirements of postoperative radioiodine treatment, which may also carry significant risk for children due to their enhanced sensitivity to the oncogenic potential of radioiodine. These conundrums emphasize the need for careful risk-benefit assessment in children with DTC. But the overall excellent prognosis of thyroid cancer, and its infrequent occurrence in children, makes it unlikely that long-term prospective randomized studies will be performed to address the impact of initial therapy in children. Thus, clinicians may be compelled to seek guidance from small observational analyses and limited retrospective studies to determine the impact of initial surgery on outcome in pediatric thyroid cancer.
These apprehensions notwithstanding, total (near total) thyroidectomy is in general remarkably successful, and in experienced hands, reasonably safe. In the current issue of the Annals of Surgical Oncology, Haveman et al.7 report their experience in 21 children treated for well-differentiated thyroid cancer at one institution. In this series, all patients had tumors >1 cm in size; 11 of 21 underwent ipsilateral node dissection to remove lymph node metastases. Transient complications occurred in 6 of 21 patients, but none had apparent permanent vocal cord paralysis or hypoparathyroidism, although two patients are reported to have required recurrent laryngeal nerve resection. Six of 21 patients had multifocal tumors and 8 of 21 demonstrated extrathyroidal extension. On subsequent radioiodine scanning, 3 of 21 disclosed pulmonary metastases. All patients were treated with at least one dose of radioactive iodine, and all patients, including two individuals with tumor recurrence, were free of disease at the end of the follow-up period. The authors conclude that total thyroidectomy, with lymph node dissection in selected cases, followed by radioiodine therapy is the treatment of choice for children with thyroid cancer and is associated with a low morbidity and an excellent prognosis.
The present study by Haveman et al.7 seems to confirm other recent retrospective analyses. Welch-Dinauer et al.8 reported an overall excellent long-term prognosis for children with thyroid cancer and an improved duration of disease-free survival in patients treated with total rather than unilateral thyroidectomy. The improved outcome was most significant for children over the age of 10 but was associated with a higher incidence of surgical complications. Vassilopoulou-Sellin et al.9 have noted a 100% survival 10 years after diagnosis of thyroid cancer but found a 7% death rate from thyroid cancer and a 7% incidence of radioiodine-related secondary malignancies over the following decade. Newman et al.10 reported a progression-free rate of 67% over 10 years in children treated aggressively with thyroid cancer but also reported a high rate of surgical complications from thyroidectomy in children less than 4 years of age. More recently, Arici et al.11 described the favorable long-term outcome of 15 patients between the ages of 15 and 21 years who were treated for DTC with either total or subtotal thyroidectomy (plus in many cases radioiodine ablation) and concluded that total (or near total) thyroidectomy was the appropriate initial surgical procedure.
In light of the absence of controlled clinical trials for the initial therapy of thyroid cancer, how does the clinician interpret these data? It is important to remember that even in children and adolescents, DTC can be a lethal neoplasm. Several reports document the eventual death of children either because of progressive disease12–15 or radiation-induced pulmonary fibrosis.16 Moreover, recent work shows that multicentric papillary thyroid cancers, which are more common in children and adolescents, frequently have distinct RET/PTC oncogene rearrangements, suggesting that these tumors arise independently in a background of genetic or environment susceptibility.17 In this context, it seems clear, based on the data of Haveman et al.7 and others, that children treated with aggressive surgery have an excellent outcome from thyroid cancer, thus supporting the growing consensus that total (or near total) thyroidectomy is the preferred surgical therapy for children with thyroid cancer. Certainly this form of surgery will increase the efficiency of subsequent 131I radioablation and seems to reduce tumor recurrence and increase disease-free survival. Moreover, it has been suggested, but not proven, that total thyroidectomy may improve overall survival in adults and children with DTC. As with all surgical procedures, selection of an experienced operator will be key to maximize the clinical benefit and to minimize the risk for treatment-related morbidity.
The data also support the responsiveness of pediatric thyroid cancers to radioiodine, making one wonder whether less surgery with more reliance on radioiodine may also be effective. However, the experience of Welch Dinauer et al.8 does not support this conservative approach, as multivariate analysis demonstrated an association between lower tumor recurrence and extent of surgery, even when nearly all patients were treated with adjuvant radioiodine. Finally, it appears that younger children may differ from older children with regard to risk of surgical complications and their potential to develop complications from radioiodine therapy. Thus, it seems that most children with DTC cancer, even those with advanced disease, have a very good outcome from thyroid cancer for at least 20 years. With the growing, albeit retrospective, data supporting the use of routine bilateral thyroid surgery in children to reduce tumor recurrence, it appears that bilateral surgery with node removal in selected cases is reasonable for the initial management of thyroid cancer in children. Younger children should be approached with care, as they may be particularly at risk for complications of surgery and radioiodine therapy. Further multicenter studies evaluating the prognosis of adults with a history of childhood thyroid cancer are needed to better clarify the impact of initial therapy. Although all questions regarding the optimal treatment of DTC are not yet answered, the present surgical strategy offers the expectation of long-term survival at a very low complication rate. No small accomplishment, and certainly no "Pyrrhic" victory.
Footnotes
This is a report of a single-center experience and review of the literature in children with well-differentiated thyroid carcinoma. An aggressive approach is associated with fewer recurrences and a lower complication rate.
Received for publication November 1, 2002. Accepted for publication November 8, 2002.
REFERENCES
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