Management of Differentiated Thyroid Cancer in Children: Focus on the American Thyroid Association Pediatric Guidelines

https://doi.org/10.1053/j.semnuclmed.2015.10.006Get rights and content

First introduced in 1946, radioactive iodine (I-131) produces short-range beta radiation with a half-life of 8 days. The physical properties of I-131 combined with the high degree of uptake in the differentiated thyroid cancers (DTCs) led to the use of I-131 as a therapeutic agent for DTC in adults. There are two indications for the potential use of I-131 therapy in pediatric thyroid disorders: nonsurgical treatment of hyperthyroidism owing to Graves’ disease and the treatment of children with intermediate- and high-risk DTC. However, children are not just miniature adults. Not only are children and the pediatric thyroid gland more sensitive to radiation than adults but also the biologic behavior of DTC differs between children and adults as well. As opposed to adults, children with DTC typically present with advanced disease at diagnosis; yet, they respond rapidly to therapy and have an excellent prognosis that is significantly better than that in adult counterparts with advanced disease. Unfortunately, there are also higher rates of local and distant disease recurrence in children with DTC compared with adults, mandating lifelong surveillance. Further, children have a longer life expectancy during which the adverse effects of I-131 therapy may become manifest. Recognizing the differences between adults and children with DTC, the American Thyroid Association commissioned a task force of experts who developed and recently published a guideline to address the unique issues related to the management of thyroid nodules and DTC in children. This article reviews the epidemiology, diagnosis, staging, treatment, therapy-related effects, and suggestions for surveillance in children with DTC, focusing not only on the differences between adults and children with this disease but also on the latest recommendations from the inaugural pediatric management guidelines of the American Thyroid Association.

Introduction

Guidelines for the evaluation, treatment, and follow-up of thyroid nodules and differentiated thyroid cancer (DTC) in adults have been published by various groups.1, 2, 3 Traditionally, the evaluation, management, and follow-up of children with thyroid cancers mirrored that of the adult guidelines. Recognizing the differences in physiology, clinical presentation, and long-term outcomes of children as compared with adults regarding DTC, the American Thyroid Association (ATA) commissioned a multidisciplinary task force consisting of an international group of endocrinologists, surgeons, nuclear medicine specialists, radiologists, as well as a molecular geneticist, to develop separate guidelines for the management of thyroid nodules and DTC in children. Acknowledging the paucity of randomized, double-blind controlled clinical trials in children with DTC as well as the relatively short length of follow-up in most reported retrospective series, this task force produced 61 graded recommendations in 34 key areas of evaluation and treatment based on available scientific evidence and expert opinion in their document titled “Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer.”4, 5 As the pathophysiology, epidemiology, clinical presentation, approach to diagnosis, treatment, and surveillance of children with DTC are discussed in this article, key recommendations from these guidelines would be incorporated into the review.

There are four histologic types of thyroid carcinoma: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC) including Hurthle cell, medullary thyroid carcinoma (MTC), and anaplastic. Papillary and follicular carcinomas, commonly referred to as the well-differentiated thyroid carcinomas (DTCs), arise from follicular cells, the cells that are involved in thyroid hormone production. The well-differentiated thyroid carcinomas are typically iodine avid.

PTC is the most common type of thyroid carcinoma in both adults and children. In adults, the papillary subtype comprises 80% of all thyroid cancers.6 Mean age of presentation occurs in the third decade of life; peak incidence occurs at age 40 years and beyond, with an earlier peak in women than in men. Cervical lymph node metastases occur in 30%-40%; distant metastases are present in 2%-14%. Multifocal disease is common with incidences ranging from 30%-85% depending on whether routine or thin histologic sectioning has been performed. Bilateral disease is present in 33%. Overall survival in adults with PTC is 90% at 20 years.

Medullary carcinomas arise in parafollicular or C-cells of the thyroid that manufacture calcitonin. As these cancers arise in cells that are not involved in thyroid hormone production, MTCs are not iodine avid and consequently, radioiodine does not play a role in either the diagnosis or the management of these patients.6, 7

Anaplastic thyroid carcinomas, comprising 4%-10% of thyroid cancers, are highly aggressive tumor types associated with a poor prognosis.6 These poorly differentiated carcinomas are rarely iodine avid; thus, aggressive chemotherapy and external-beam radiation, and not radioiodine usage comprise the treatment regimen for patients with these tumors.

Thyroid cancer occurs in all age groups. An increase in overall incidence rates of DTC has been reported in both adults and children in the United States.8 The incidence of thyroid cancer increases with age. Thyroid cancer is rare in those less than 10 years of age with an annual incidence of less than one case per million. Thyroid cancer is more common in older children and adolescents with incidence rates of 3.5 cases per million per year in those between the ages of 10 and 14 years compared with 15.4 cases per million per year in those aged 15-19 years. In those aged 25-29 years, the incidence of thyroid cancer is 60.8 cases per million per year.9, 10, 11

In addition to age-related differences in incidence, there are differences in the frequency of the pathologic types of thyroid cancer between children and adults. PTC is more common in children, accounting for 95% of cases of thyroid cancer, as opposed to adults, where it comprises approximately 80% of the subtypes. FTCs occur in approximately 5% in both adults and children. Anaplastic thyroid carcinoma and Hurthle cell pathologies are rare in children.12, 13

Section snippets

DTC in Children

Carcinomas comprise approximately 9.2% of cancers in children less than 20 years of age; the most common pediatric carcinomas (35%) are thyroid carcinomas.9, 10, 11 Thyroid cancer accounts for less than 1% of cancers in those younger than 10 years, 3.6 % of cancers in those aged 10-14 years, and 7.8% of cancers in those aged 15-19 years. As in adults, DTCs are the most commonly encountered thyroid cancers, representing more than 90% of pediatric thyroid carcinomas. PTC accounts for 95% and FTC

Pathogenesis and Predisposing Factors

Most thyroid cancers have no genetic basis and arise sporadically. Ongoing research has begun to identify biologic factors underlying the behavior of thyroid cancer. As in other cancers, activation of growth-stimulating molecular pathways seems to be an important component in many thyroid cancers, particularly those with aggressive or resistant behaviors. Chromosomal rearrangements of the RET proto-oncogene have been associated with the development of PTC. In these cases, the linking of the

Clinical Presentations

Differentiated thyroid carcinoma in children typically presents as an asymptomatic mass.16, 17, 19 Although only 1%-5% of children have thyroid nodules compared with 4%-7% of young adults and more than 50% of persons aged 60 years or older, children with a solitary nodule are more likely to harbor a malignancy that do their adult counterparts.51, 52, 53, 54, 55 Although the overall prevalence of thyroid carcinoma in a thyroid nodule is 5% in adults, the incidence of cancer in surgically removed

Diagnosis

In both children and adults, the diagnosis of DTC is based on physical examination, patient history, laboratory and imaging studies, and biopsy, preferably employing fine-needle aspiration (FNA) as opposed to excisional biopsy, as the latter often entails a lobectomy and may require a second surgery if the diagnosis of cancer cannot be made intraoperatively. When a painless thyroid nodule is first identified in a child or adolescent, serum triiodothyronine (T3), thyroxine (LT4), and TSH levels

Treatment

The goals of primary treatment of DTC are to eradicate disease and extend disease-free survival.3 Unfortunately, all cancer treatments—whether surgery, chemotherapy, or radiation—are associated with toxicities, both short term and long term, which can range from mild to debilitating, and which can affect all organ systems. The 10-year survival rate for adults with DTC exceeds 90%,6 it approaches nearly 100% in children.8 Although death from PTC is low, recent studies with long-term follow-up

Surgery

Total or near-total thyroidectomy (as opposed to lobectomy) is recommended for children with DTC as there is an increased risk of bilateral (30%) and multifocal (65%) disease as well as an increased risk of recurrence, which would necessitate a second surgery if a total or near-total thyroidectomy had not been performed initially.5, 21, 79, 80, 81 Surgical reintervention for recurrent disease in children initially treated with lobectomy alone has been associated with a higher complication rate.

Postoperative Staging

The purpose of radioiodine scanning, the mainstay of postoperative staging for DTC, is to assess for persistent locoregional disease and to identify patients likely to benefit from further treatment, either I-131 radiotherapy or additional surgery.

The presence of substantial thyroid tissue at the time of scanning limits identification of sites of disease. Thus, whole-body thyroid cancer surveys are possible only after near-total thyroidectomy. The initial staging study is typically performed

Risks of RAI

There are both short- and long-term risks associated with therapeutic I-131 administration. Short-term risks occur during or shortly after therapy and include toxicity for tissues that retain iodine. Mild nausea or emesis from radiation gastritis occur in as many as 50% of patients;101, 102, 119, 120, 121 acute sialadenitis is seen in up to 30%. Despite the use of preventative measures such as sour candies or lemon juice commencing 24 hours following I-131 dosing in conjunction with vigorous

Surveillance and Long-Term Follow-Up of DTC

Long-term follow-up in children with DTC includes periodic physical examinations and disease surveillance based on laboratory testing and neck US. It is important to verify that TSH is suppressed and to monitor serum thyroglobulin levels, the most important biochemical test to detect disease recurrence. At the same degree of TSH suppression, the Tg level on LT4 is considered to be the best predictor of changes in tumor mass,95, 150 although a negative-result Tg on LT4 does not predict a

Conclusions

Despite the aggressive nature of pediatric DTC compared with adults, overall survival is excellent. However late recurrences occur, often decades after treatment, mandating lifelong surveillance. Additionally, recent data with long-term follow-up spanning decades reveal an increase in all-cause mortality for survivors of childhood DTC, predominantly due to the development of secondary malignancies in those treated with I-131 radiotherapy. These issues complicate the management of children with

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