Are we really at the dawn of understanding sporadic pediatric thyroid carcinoma?

in Endocrine-Related Cancer
Authors:
Maria Isabel C Vieira Cordioli Genetic Bases of Thyroid Tumors Laboratory, Division of Endocrinology, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, Pedro de Toledo 669, 11 andar, 04039‐032, São Paulo, SP, Brazil

Search for other papers by Maria Isabel C Vieira Cordioli in
Current site
Google Scholar
PubMed
Close
,
Lais Moraes Genetic Bases of Thyroid Tumors Laboratory, Division of Endocrinology, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, Pedro de Toledo 669, 11 andar, 04039‐032, São Paulo, SP, Brazil

Search for other papers by Lais Moraes in
Current site
Google Scholar
PubMed
Close
,
Adriano Namo Cury Genetic Bases of Thyroid Tumors Laboratory, Division of Endocrinology, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, Pedro de Toledo 669, 11 andar, 04039‐032, São Paulo, SP, Brazil

Search for other papers by Adriano Namo Cury in
Current site
Google Scholar
PubMed
Close
, and
Janete M Cerutti Genetic Bases of Thyroid Tumors Laboratory, Division of Endocrinology, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, Pedro de Toledo 669, 11 andar, 04039‐032, São Paulo, SP, Brazil

Search for other papers by Janete M Cerutti in
Current site
Google Scholar
PubMed
Close

Free access

Sign up for journal news

Data from the National Cancer Institute and from the literature have disclosed an increasing incidence of thyroid cancer in children, adolescents and adults. Although children and adolescents with thyroid cancer tend to present with more advanced disease than adults, their overall survival rate is excellent; however, there is no clear explanation for the differences observed in the clinicopathological outcomes in these age groups. There has been an ongoing debate regarding whether the clinicopathological differences may be due to the existence of distinct genetic alterations. Efforts have been made to identify these acquired genetic abnormalities that will determine the tumor's biological behavior and ultimately allow molecular prognostication. However, most of the studies have been performed in radiation-exposed pediatric thyroid carcinoma. Therefore, our understanding of the role of these driver mutations in sporadic pediatric differentiated thyroid cancer development is far from complete, and additionally, there is a strong need for studies in both children and adolescents. The aim of this review is to present an extensive literature review with emphasis on the molecular differences between pediatric sporadic and radiation-exposed differentiated thyroid carcinomas and adult population.

Abstract

Data from the National Cancer Institute and from the literature have disclosed an increasing incidence of thyroid cancer in children, adolescents and adults. Although children and adolescents with thyroid cancer tend to present with more advanced disease than adults, their overall survival rate is excellent; however, there is no clear explanation for the differences observed in the clinicopathological outcomes in these age groups. There has been an ongoing debate regarding whether the clinicopathological differences may be due to the existence of distinct genetic alterations. Efforts have been made to identify these acquired genetic abnormalities that will determine the tumor's biological behavior and ultimately allow molecular prognostication. However, most of the studies have been performed in radiation-exposed pediatric thyroid carcinoma. Therefore, our understanding of the role of these driver mutations in sporadic pediatric differentiated thyroid cancer development is far from complete, and additionally, there is a strong need for studies in both children and adolescents. The aim of this review is to present an extensive literature review with emphasis on the molecular differences between pediatric sporadic and radiation-exposed differentiated thyroid carcinomas and adult population.

Introduction

The incidence of thyroid cancer has increased worldwide over the last decades. Essentially, one of the largest annual increases from 2006 to 2010 was for thyroid cancer (Davies & Welch 2006, Lise et al. 2012, Siegel et al. 2014a). Differentiated thyroid cancer (DTC) is most frequently diagnosed among adults aged 45–54, with a mean age at diagnosis of 50 (SEER Stat Fact Sheets: thyroid cancer, available at http://seer.cancer.gov/statfacts/html/thyro.html accessed July 2015) and with a female predominance. Currently, it is the fifth most common cancer in women in the United States (Siegel et al. 2014a), and in Italy, it is the second most frequent cancer in women below age of 45 (Pellegriti et al. 2013). In São Paulo, Brazil, not only the thyroid cancer incidence rates were consistently higher than in the United States but also the female predominance was higher than that reported in SEER (Veiga et al. 2013).

Although rare in the young population, DTC rates are also increasing significantly in children and adolescents. Among DTC, papillary thyroid cancer (PTC) accounts for nearly 90% and follicular thyroid carcinoma (FTC) accounts for about 5–10% of all thyroid cancer that occurs in the pediatric population (Demidchik et al. 2007, Hogan et al. 2009). It has been suggested that FTC is very rare and occurs in a slightly older age group (Jarzab et al. 2005). Medullary thyroid carcinoma, poorly differentiated thyroid carcinoma and undifferentiated thyroid carcinoma are rare in young patients (Hogan et al. 2009) and are not the focus of this review.

Regardless the ethnicity, an increased trend in incidence rates of pediatric thyroid carcinomas was found in most regions of the United States in both genders (Vergamini et al. 2014). When stratified by age, the annual incidence rate of cancer in children and adolescents is 0.43 (5–9 years), 3.50 (10–14 years) and 15.16 per million (15–19 years) (Vergamini et al. 2014). Others have also demonstrated that the incidence rates increased with age (Hogan et al. 2009, Siegel et al. 2014b). In fact, among 15- to 19-year-old adolescents, thyroid is the eighth most common cancer diagnosed and the second most common cancer among girls (Wu et al. 2003, Ward et al. 2014). Similar to that observed in adults, there is a female predominance (Landau et al. 2000, Hogan et al. 2009, Lazar et al. 2009).

The reasons for increasing incidences rates of pediatric thyroid cancer are currently unknown. Previous studies suggested that the increasing incidence of thyroid cancer among adults was predominantly due to better access to medical care and increased diagnostic scrutiny (Davies & Welch 2006). It is possible that advances in ultrasound imaging technologies have improved diagnosis and, consequently, over time, may have contributed to detect small and asymptomatic pediatric thyroid cancers.

Although increased diagnostic scrutiny may account for some of the rise, the increased incidence across all tumor sizes in young patients argue in favor of a true increase (Vergamini et al. 2014). Besides, it has been suggested that some of this increase may be due to environmental factors and lifestyle changes (Boas et al. 2006). Finally, the increase in the incidence of PTC with no similar increase in the incidence of other histological types of thyroid cancer is an argument in favor that environmental factors may contribute to the increase (Mazzaferri 1993).

There are significant molecular, pathological and clinical differences in DTC among children, compared to the adult population. To indorse best practice standards for the diagnosis and management of thyroid cancer in the pediatric population, a task force appointed by the American Thyroid Association (ATA) recently provided the first recommendations specifically addressing the management of thyroid nodules and DTC in children and adolescents (Francis et al. 2015). The authors suggested applying these recommendations to patients up to 18 years old, when the majority of pediatric patients have completed growth and development.

The aim of this review is to present an extensive literature review with emphasis on the molecular differences between the pediatric and adult population. Although several studies of pediatric DTC included individuals up to 21 years of age, we mainly focused on studies that involved individual ≤18 years of age.

Clinical presentation

The thyroid cancer in children usually presents as a solitary nodule (Welch Dinauer et al. 1998, Grigsby et al. 2002). The occurrence of palpable cervical adenopathy at diagnosis is also a common finding in pediatric DTC (Grigsby et al. 2002). Previous studies reported significant differences in the clinical presentation and outcomes of DTC in pediatric patients compared to adults (Jarzab & Handkiewicz-Junak 2007).

Although thyroid nodules are uncommon in the pediatric population, there is a greater risk of malignancy in nodules diagnosed in children and adolescents than in adults (26% vs 5%) (Niedziela 2006, Gharib & Papini 2007, Romei & Elisei 2012). Moreover, pediatric cases are more likely to present a more advanced stage of the disease at diagnosis, often a more aggressive local disease and higher rates of distant metastases (Zimmerman et al. 1988, Chow et al. 2004, Kumagai et al. 2004, Jarzab et al. 2005, Alzahrani et al. 2015). Neck lymph node metastasis at diagnosis was reported in nearly 90% of pediatric cases, while they were detected in 35% of adults (Zimmerman et al. 1988). Other series reported lymph node involvement at diagnosis in 40–90% of pediatric cases (Newman et al. 1998, Landau et al. 2000, Dinauer et al. 2008, Lazar et al. 2009, O'Gorman et al. 2010), compared to 20–50% of adults (Zaydfudim et al. 2008, Ahn et al. 2015) (Table 1).

Table 1

Clinical features of pediatric thyroid carcinomas

AuthorCases (n)RI exposure (%)Mean age/(range years)Gender (female) (%)Multifocality (%)Bilateral (%)ET (%)Cervical meta (%)Distant meta (%)Recurrence (%)Survival (%)
Zimmerman et al. (1988)58No<1769NANA249073076
Newman et al. (1998)3291315.2 (0.4–20.8)76NANA3274253299
Welch Dinauer et al. (1998)137519 (3–21)7630.7NANA3962099
Fenton et al. (2000)33No18 (6–21)7148NANANANA15100
Alessandri et al. (2000)382112.6 (4.5–16.8)74NDNA4260545100
Landau et al. (2000)30No<167723NANA57104070
Grigsby et al. (2002)56No15.8 (4–20)7757303673133498
Kumagai et al. (2004)29No11.3 (<15)77NANA236823NDNA
Lazar et al. (2009)27712.8 (6.1–17)7888.9NA52674118100
Hogan et al. (2009)1753NA15.9 (1–19)81NANANA468NANA
O'Gorman et al. (2010)54913 (F); 13.4 (M)6775.928NA4615NANA
Ito et al. (2012)110No17 (7–19)89NANA84172498
Sassolas et al. (2012)28NA8–19NANANA32507NANA
Givens et al. (2014)19No13.6 (2.8–18)NANANA42682611NA
Henke et al. (2014)27No18.6 (5.8–21.2)79NA223763437100
Alzahrani et al. (2015)97No17 (8–20)8143NA53781634100

NA, not available.

Distant metastasis was found in virtually 7–30% of pediatric patients compared to 2–9% of adults (Zimmerman et al. 1988, Newman et al. 1998, La Quaglia et al. 2000, Chow et al. 2004, Handkiewicz-Junak et al. 2007, Dinauer et al. 2008, Hogan et al. 2009, O'Gorman et al. 2010). Mostly pediatric patients present distant metastasis in the lungs, but few cases have been also reported in the brain, soft tissue or bone (Newman et al. 1998, Jarzab & Handkiewicz-Junak 2007) (Table 1).

Nevertheless, a marked heterogeneity within the pediatric group has been reported. Pediatric cases tend to be more symptomatic in the prepubertal group (Jarzab et al. 2005). Children present with more aggressive local disease and are more likely to have lymph node metastases at diagnosis. In fact, it was demonstrated that prepubertal children had a greater degree of extrathyroid extension and lymph node involvement than adolescents (Alessandri et al. 2000, Lazar et al. 2009). Additionally, they are more prone to develop subsequent distant metastases (Jarzab et al. 2005, Dinauer et al. 2008, Lazar et al. 2009, O'Gorman et al. 2010, Rivkees et al. 2011), and they also experience recurrence more frequently and earlier than adolescents (Alessandri et al. 2000). The biological hypothesis for greater differentiation and responsiveness to treatment is discussed below.

The mean tumor size tends to be larger in pediatric patients. Comparison between 58 pediatric (<17 years old) and 981 adult consecutive PTC patients treated at the Mayo Clinic revealed that the mean tumor size was greater in pediatric cases (3.1 cm; ±1.7) than in adults (2.1 cm; ±1.7). The authors also showed that tumors larger than 4 cm were more prevalent in pediatric cases (36%) than in adults (15%) (Zimmerman et al. 1988). Furthermore, papillary microcarcinomas (≤1 cm) are rarely reported in pediatric cases (3% of cases), whereas microcarcinomas comprise about 30% of all thyroid carcinomas diagnosed in adults (Chow et al. 2004). It is likely that in populations undergoing extensive screening, small pediatric PTC will be detected. Excluding the screening programs conducted in the Belarus area after the Chernobyl accident in 1986 (Ashizawa et al. 1997) and the screening of children from different Japanese prefectures after the Fukushima Daiichi Nuclear Power Plant accident in 2011 (Ashizawa et al. 1997, Yasumura et al. 2012, Hayashida et al. 2013), studies reporting the prevalence of small thyroid nodules in the pediatric population are scarce. Ultrasound examination in children from Fukushima, Aomori, Yamanashi and Nagasaki prefectures revealed that between 35 and 51% of children who underwent thyroid ultrasound examination showed thyroid cysts and nearly 1% showed thyroid nodules ≤0.5 cm (Hayashida et al. 2013, Yamashita & Suzuki 2013).

Another difference between pediatric and adult DTC is the higher rates of bilateral and multifocal disease in childhood. Pediatric patients present bilateral disease in about 30% of cases (Grigsby et al. 2002, Lazar et al. 2009) and multifocal disease in 30–80% of cases (Welch Dinauer et al. 1998, Grigsby et al. 2002, Gorman et al. 2010). This higher rate of bilateral and multifocal disease is one of the arguments used to recommend for a more comprehensive thyroid surgery in pediatric patients (Francis et al. 2015).

PTC variants, such as follicular variant of PTC (FVPTC) and diffuse sclerosing PTC (DSPTC), are more frequently found in pediatric patients than in adults (Neiva et al. 2012). Although there is no consensus on the prognosis of a different histological type, it was recently demonstrated that DSPTC is frequently associated with bilateral disease, extrathyroidal extension, lymph node involvement, lung metastasis and lower rates of recurrence-free survival than that of non-DSPTC (Koo et al. 2009).

Treatment and prognosis

Because pediatric DTC is an uncommon malignancy, randomized trials have not been applied to test best-care options in this group of patients (Rivkees et al. 2011). Therefore, the optimal initial and long-term treatment and follow-up remain controversial.

Despite a more advanced disease at presentation and a higher risk of recurrence, the prognosis of childhood DTC is generally fairly good. The reported mortality rate is low or even zero in some series (Newman et al. 1998, Alessandri et al. 2000, Henke et al. 2014). For this reason, the ATA guideline for children with thyroid nodules and DTC developed recommendations based on the available scientific evidence and expert opinion (Francis et al. 2015). The authors suggested reconsidering the former recommendation that all children with DTC should be similarly treated with a more extensive surgery and routine RAI therapy (Rivkees et al. 2011). A more comprehensive surgical approach raises the risk of important clinical complications, mainly transient or permanent hypoparathyroidism and recurrent laryngeal nerve damage. The RAI therapy is associated with an increase in the risk of second primary malignancy, especially salivary cancer (Marti et al. 2015).

The ideal surgical approach for the majority of patients is total thyroidectomy (TT) (Francis et al. 2015). However, in patients with a small unilateral tumor and without extrathyroidal extension, a near-TT can be considered to lower the risk of injury to either the recurrent laryngeal nerve or parathyroid glands (Rivkees et al. 2011, Francis et al. 2015). Previous studies that assessed the outcomes of a less comprehensive surgical approach in pediatric patients have shown a higher risk of relapse rates with lobectomy vs TT (Hay et al. 2010, Handkiewicz-Junak et al. 2007). Despite the high rate of cervical metastasis in pediatric DTC, routine central lymph node dissection is no longer recommended. The central neck dissection should be performed when there is evidence of central and/or lateral neck metastasis or gross extrathyroidal invasion (Francis et al. 2015)

Regarding RAI indications, the current recommendation in pediatric DTC is for treatment of nodal or other locoregional disease that is not amenable to surgery as well as distant metastases that are iodine-avid. Moreover, the RAI therapy can also be consider in children with T3 tumors or extensive regional nodal involvement (Francis et al. 2015). Similar to adults, there is no evidence of benefit of RAI remnant ablation in pediatric patients with intra-thyroidal disease and no lymph node disease (Lamartina et al. 2015).

Risk factors

The link between ionizing radiation during childhood and thyroid cancer has been known since 1950. The first sharp rise in the incidence of thyroid cancer was reported in epidemiological studies after external radiation to treat common childhood conditions such as acne, tinea capitis and enlarged tonsils or thymus gland. A pool analysis of seven studies demonstrated a high risk of thyroid cancer in subjects irradiated at a young age, even for radiation doses as low as 0.10 Gy. Although the risk of developing thyroid cancer is still present more than 40 years after exposure, it is higher between 15 and 30 years. The risk decreased significantly with increasing age at exposure, with very little risk after age 20 (Ron et al. 1995).

The second peak of thyroid cancer was observed in 1996, 10 years after the Chernobyl nuclear power station accident, when over 1018 Bq of radioactivity was released into the atmosphere, mainly 131I and 137Cs. The highest levels of contamination occurred in Belarus, Ukraine and western Russia. Children and adults have been exposed to a relatively high dose of 131I. Predominantly, through ingestion of contaminated food and drink, their thyroid has accumulated a high dose of 131I. As childhood thyroid is very radiosensitive, one would expect a high prevalence of thyroid disease in those subjects exposed to radiation at a young age. In fact, the incidence rate of childhood thyroid carcinoma in the heavily contaminated region of Belarus reached 40 per million, while an annual incidence of 1 per million was reported in this area before the accident. The highest risk group was those patients aged 0–4 years at the time of exposure. After 1996, the incidence declined progressively, and after 2001, only sporadic cases (not exposed to radiation) were reported in pediatric patients (<15 years old) (Demidchik et al. 2007, Williams 2008, Tuttle et al. 2011).

The radiation-associated risk of thyroid cancer to the exposed children and residents after the Fukushima Daiichi Nuclear Power Plant accident on March 2011 is still unclear. The RAI measured after the accident was one-tenth or less that measured after the Chernobyl accident, and the radiation exposure dose measured in children from neighboring regions after the accident was at a near negligible level. The Fukushima prefecture started the Fukushima Health Management Survey Project aimed at long-term health care administration and early medical diagnosis/treatment for prefectural residents. As the first round of screening, a thyroid ultrasound examination was conducted from October 2011 to March 2014 in nearly 300 000 individuals aged <18 years. From a total of 108 (0.8%) children with suspicious nodules, 84 had thyroid carcinoma, most (96%) were PTC (Yamashita & Takamura 2015). Although a not significant increase in the prevalence of thyroid cancer has been reported after the Fukushima Daiichi Nuclear Power Plant accident (Iwaku et al. 2014), a sharp increase in the incidence of thyroid cancer was observed 4–5 years after the Chernobyl accident, and, therefore, it was preceded by a latency phase. Only a long-term follow-up will clarify whether a third peak of thyroid cancer might occur after the Fukushima Daiichi Nuclear Power Plant accident.

These findings recognized the extreme sensitivity of children's thyroid to radiation, compared to adults. Many epidemiologic studies have explored whether the exposure to radiation during medical diagnostic and therapeutic procedures represent a risk factor for pediatric thyroid cancer. It has been demonstrated that the thyroid exposure to X-rays due to dental radiographic procedures (Memon et al. 2010) or primary beam during computed tomography scan of the neck during childhood is associated with a low but not negligible risk of cancer (Mazonakis et al. 2007, Pellegriti et al. 2013). Regarding therapeutic procedures, it is well known that survivors of pediatric cancer may suffer from late sequelae of treatment, including secondary malignant neoplasia in the irradiated region. Secondary thyroid carcinoma after radiotherapy to the neck has been reported in many publications. Interestingly, the risk of a subsequent thyroid cancer after a first tumor in childhood rose with an increasing radiation dose (greatest risk 20–29 Gy) but doses higher than 30 Gy is consistent with a cell-killing effect (Sigurdson et al. 2005). As an example, the cumulative incidence for patients with up to 30 years of follow-up after the diagnosis of Hodgkin's lymphoma (HL) was 4.4% for thyroid carcinoma and the mean interval after HL diagnosis was 13.2 years (range 4.0–29.2 years). The most frequent thyroid carcinoma identified in these patients is PTC (Dorffel et al. 2000, Levy et al. 2012, Marti et al. 2012).

This pediatric thyroid cancer peak incidence and a ‘latency phase’ reinforce that a long-term follow-up of patients should be undertaken for survivors of both the Fukushima Daiichi Nuclear Power Plant accident and any cancer during childhood involving radiotherapy to the thorax or head and neck region.

Hints from cancer biology

Recently, the Cancer Genome Atlas (TCGA) Research Network, using next-generation DNA and RNA-sequencing, copy-number variation, miRNA, methylomic, transcriptomic and proteomic profiles, combined with clinic-pathological data, characterizes the landscape of nearly 500 PTCs of adults. The study confirmed that PTC is associated with mutations in genes that code for proteins involved in the MAPK pathway such as RET, BRAF and RAS. The TCGA also identified new cancer-causing gene mutations that occur in PTC (EIF1AX, CHEK2, PM1D), as well as new fusion transcripts and somatic copy number alteration (recurrent 22q deletion and 1p amplification) that reduced the so-called ‘dark matter’ of the PTC. The large collection of genetic alterations, combined with a comprehensive transcriptomic and proteomic analysis, revealed fundamental biological differences between PTCs. This increased knowledge helped stratify PTC into subgroups, which ultimately will refine preoperative diagnosis of thyroid nodules and prognosis and treatment of adult PTC (The Cancer Genome Atlas Research Network 2014).

Several studies have suggested that the spectrum of mutations may differ between tumors of pediatric patients and tumors of adults (Bongarzone et al. 1996). Moreover, few studies have indicated that radiation-exposed and sporadic pediatric thyroid carcinomas are different biological types of cancer with the same histology (Nikiforov et al. 1997).

To obtain a whole picture of the genomic landscape of the radiation-exposed pediatric thyroid carcinomas, a research team performed RNA-sequencing in five patients with thyroid carcinoma from the regions of Ukraine and who were younger than 10 years at the time of the Chernobyl nuclear accident. They selected patients who were negative for known BRAF mutations and known fusion transcripts (RET/PTC, TPR-NTRK1, PAX8-PPARG and AKA9-BRAF). Moreover, the research group performed low-pass whole-genome sequencing of five radiation-exposed and five patients with sporadic pediatric thyroid carcinoma who were from the same geographical regions (Ricarte-Filho et al. 2013). The authors identified new kinase fusion oncogenes in radiation-exposed thyroid carcinomas. First, this study ratifies that the MAPK pathway plays a critical role in pediatric PTC development (Ricarte-Filho et al. 2013). Second, the prevalence of fusion oncogenes in radiation-induced tumors (84%) was much higher than the prevalence in sporadic cases (33%). This finding supports the concept that ionizing radiation induces chromosomal rearrangement but contests the notion that the prevalence of fusion oncogenes is similar in both sporadic and radiation-induced pediatric PTC. Last, it reinforces the idea that spectrum of mutations in pediatric tumors differ from adults.

The hints from molecular biology suggest that the clinical and pathological differences observed between pediatric and adults might be fundamentally due to their biological differences. Therefore, the therapy that may be recommended for an adult may not be appropriate for a child, which validates the development of unique pediatric guidelines (Francis et al. 2015).

The major known somatic events associated with radiation-exposed and sporadic pediatric thyroid carcinomas reported in the literature are summarized below (Fig. 1, Supplementary Tables 1 and 2, see section on supplementary data given at the end of this article.).

Figure 1
Figure 1

Overall prevalence of point mutations and rearrangements identified in sporadic pediatric and radiation-exposed pediatric papillary thyroid carcinomas. Other fusion groups include PAX8-PPARG, AKAP9-BRAF, AGK-BRAF, NTRK1, CREB3L2-PPARG. The other somatic mutation groups include BRAF V600_K601E and TSHR S425I. The prevalence of RET/PTC isoforms is show in detail in the bottom panel. The prevalence and categories of mutations are detailed in Supplementary Tables 1 and 2.

Citation: Endocrine-Related Cancer 22, 6; 10.1530/ERC-15-0381

RET/PTC fusions transcripts

The RET (rearranged during transfection) gene, located in the chromosome 10q11.2, encodes for a cell membrane receptor tyrosine kinase (TK). RET rearrangement was initially described in an irradiated PTC (Fusco et al. 1987). Through chromosome rearrangement, RET was fused to the NH2 terminus of a heterologous gene denominated CCD6 (formerly named H4). RET gene is not expressed in normal follicular thyroid cells. However, the fusion product expresses intrinsic and constitutive TK activity. This not only was the first example of oncogene activation in solid tumors but also was the first RET rearrangement described in PTC and, hence, named RET/PTC1 (Fusco & Santoro 2007).

In the subsequent years, other RET/PTC isoforms were identified in sporadic and radiation-exposed PTC. Currently, nearly 20 types of RET/PTC rearrangements were identified (Fusco & Santoro 2007, Romei et al. 2008, Ricarte-Filho et al. 2013, The Cancer Genome Atlas Research Network 2014). In all isoforms the TK domain of RET is conserved and fused to other genes. Although RET/PTC rearrangement was described in benign lesions, in most series it was specifically found in PTC. An elegant work that was performed by the Nikiforova group shows that this thyroid specificity is likely due to nuclear architecture of thyroid cells, i.e., spatial proximity between partners and RET may influence their participation in the RET/PTC rearrangements in the human thyroid cell (Nikiforova et al. 2000).

While in most series RET/PTC fusion is the second most common genetic event in PTC of adults (Romei & Elisei 2012), it is the main genetic event found in both sporadic and radiation-induced pediatric PTC (Figs 1 and 2).

Figure 2
Figure 2

The worldwide prevalence of RET/PTC and BRAF V600E in sporadic and radiation-exposed pediatric PTC is shown. Studies from the same country were groups and the prevalence calculated.

Citation: Endocrine-Related Cancer 22, 6; 10.1530/ERC-15-0381

In this systematic review of literature, we estimate the overall prevalence of RET/PTC in pediatric sporadic and radiation-exposed PTC. The overall prevalence of RET/PTC differs between sporadic and radiation-exposed pediatric PTC carcinomas (41% vs 58% respectively) (Fig. 1) (Student's t-test; P=0.034). The reported prevalence of RET/PTC in sporadic PTC varies from 22% (France/Italy) to 65% (USA), while its prevalence in radiation-exposed varies from 33% (Belarus) to 76% (Belarus) (Fig. 2, Supplementary Tables 1 and 2). The highest incidence was found in post-Chernobyl pediatric PTC patients. As radiation exposure induces DNA double-strand breaks and RET gene and their partners are juxtaposed in the nuclei of thyroid cells, it facilitates chromosome recombination. Few studies reported PTC with concomitant RET/PTC in sporadic (Fenton et al. 2000, Penko et al. 2005) and radiation-induced PTC (Elisei et al. 2001). The reported prevalence of concomitant RET/PTC rearrangements in sporadic cases was 2% and radiation-exposed was 1% (Fig. 1).

Even if part of these differences can be attributed to geographic variability, the major differences in the prevalence of RET/PTC have been reported in radiation-exposed cases from the Belarus area (Klugbauer et al. 1995, Nikiforov et al. 1997, Thomas et al. 1999, Pisarchik et al. 1998, Rabes et al. 2000, Elisei et al. 2001, Kumagai et al. 2004, Nikiforova et al. 2004, Ricarte-Filho et al. 2013) (Fig. 2). It has been suggested that other factors, probably influenced by ethnic or genetic background, may act independently from or in cooperation with radiations to trigger RET rearrangement (Elisei et al. 2001). It has also been suggested that tumor heterogeneity and the use of different detection methods may contribute to the variability in the reported prevalence of RET/PTC (Zhu et al. 2006, Nikiforov & Nikiforova 2011).

Others have reinforced that tumor latency changes the prevalence and the type of RET/PTC rearrangement. Higher prevalence of RET/PTC3 rearrangements was found in faster developing tumors and in the most heavily contaminated areas (Rabes et al. 2000). Others have also found that RET/PTC3 is preferentially found in radiation-associated pediatric PTC with a short latency period, whereas RET/PTC1 is mainly found in later occurring PTC (Smida et al. 1999).

Regarding the prevalence of different RET/PTC isoforms, RET/PTC1 and RET/PTC3 are by far the most prevalent isoforms identified in tumors from two groups (Fig. 1, Supplementary Tables 1 and 2). RET/PTC1 was found at comparable prevalence in sporadic (20%) and radiation-induced pediatric PTC (18%), while the prevalence of RET/PTC3 was higher in radiation-exposed (33%) than in sporadic (10%) pediatric PTC (Fisher exact test; P=0.01). Although very few studies have examined the prevalence of RET/PTC2, this isoform was more prevalent in the sporadic group (Nikiforov et al. 1997, Fenton et al. 2000).

In the radiation-induced group, RET/PTC3 fusion oncogene was associated with more aggressive variants such as solid variant and DSPTC, whereas RET/PTC1 was mainly found in classical and FVPTC (Rabes et al. 2000, Elisei et al. 2001).

Even though it was described in a radiation-exposed PTC 28 years ago, it is still not clear whether RET/PTC rearrangement correlated with age or a more aggressive phenotype and histological subtype in sporadic pediatric PTC.

BRAF V600E mutation

The BRAF V600E, the T1799A nucleotide transversion that leads to a substitution of valine to glutamic acid, is the most common and specific genetic alteration found in PTC of adults (Kimura et al. 2003, Xing 2005, Frasca et al. 2008, Oler & Cerutti 2009, The Cancer Genome Atlas Research Network 2014).

This review of the literature and appraisal of the overall prevalence of BRAF V600E in the pediatric population shows that the prevalence of BRAF V600E is lower in radiation-exposed tumors (3%) than in sporadic cases (13%), although the observed differences did not reach statistical significance. In the sporadic group, the prevalence ranges from 0% to 37%, while in the radiation-exposed group, the prevalence ranges from 0% to 8% (Fig. 2).

Though patient age was not specified in all series, none of the patients with BRAF mutation were younger than 10 years (Lima et al. 2004, Sassolas et al. 2012, Ricarte-Filho et al. 2013, Givens et al. 2014). The lack of the BRAF V600E mutation in children and a lower prevalence of mutation in adolescents suggest that the prevalence of BRAF V600E increases with age and that BRAF V600E may not play a major role in pediatric tumors.

Recently, a group reported a high prevalence (63%) of BRAF V600E mutation in pediatric PTC (Henke et al. 2014). The median age of patients enrolled in this study was 18.6 years and the number of patients younger than 10 years old and their BRAF mutation status were not mentioned. As the methodology used to detected BRAF V600E was PCR-RFLP, instead of PCR-sequencing, this study was not included in overall analysis.

All together, the prevalence of BRAF V600E is significantly lower than RET/PTC in both sporadic and radiation-exposed pediatric groups (Fisher exact test; P=0.0055).

RAS point mutations

Activating mutation in codons 12, 13 or 61 of RAS genes (NRAS, KRAS and HRAS) has also been described in PTC. According to the catalogue of somatic mutations in cancer (http://sanger.ac.uk/cosmic), NRAS is the most frequently mutated RAS isoform in PTC. The highest rates of mutation were found in exon 2 of NRAS (13%). The Q61K mutation results in substitution from a glutamine (Q) to a lysine (K), at position 61. Recently, NRAS was also reported as the second most common mutation found in PTC by the TCGA study (The Cancer Genome Atlas Research Network 2014).

A strong association has been found between the presence of RAS mutations and histology in PTC of adults, with RAS mutations characterizing FVPTC (Zhu et al. 2003, Adeniran et al. 2006, Rivera et al. 2010, Park et al. 2013, The Cancer Genome Atlas Research Network 2014). High prevalence of mutations in the RAS gene has been described in FTC (18–57%) and follicular thyroid adenoma (FTA) (24–53%) (Fukahori et al. 2012). This mutation is also found in poorly differentiated and anaplastic carcinomas (18–31%) (Pita et al. 2014).

Relatively few studies have evaluated the occurrence of RAS point mutation in pediatric DTC and the incidence rates range from 0% to 7% in sporadic tumors (Kumagai et al. 2004, Sassolas et al. 2012, Ricarte-Filho et al. 2013) and 0% in radiation-exposed tumors (Suchy et al. 1998, Kumagai et al. 2004, Ricarte-Filho et al. 2013). In these studies only mutations at codon Q61 of NRAS were described. Although Suchy et al. (1998) found mutations at codons 14 and 15 of HRAS, these were silent mutations or did not interfere with GTPase activity or protein binding capacity, respectively. Thus, different from adults, RAS mutations exert a minor role in the pathogenesis of pediatric PTC.

ETV6-NTRK3 fusions transcripts

The ETV6-NTRK3 is a new fusion oncogene recently described in 7% of pediatric radiation-exposed PTC (Ricarte-Filho et al. 2013). The ETV6-NTRK3 fusion results from an interchromosomal translocation, which juxtaposes exons 1–4 of ETV6 to exons 12–18 of NTRK3. The chimeric transcript is able to activate MAPK and PI3K signaling pathways and promotes cell growth of NIH-3T3 cells as well as colony formation in soft agar (Ricarte-Filho et al. 2013). Further validation analysis showed that 7% of sporadic pediatric PTC from the Ukraine area had ETV6-NTRK3 fusion (Ricarte-Filho et al. 2013). The authors found that pathological characteristic of both radiation-exposed tumors and sporadic cases appeared to correlate with the nature of underlying drive mutations, i.e., ETV6-NTRK3 was mainly found in FVPTC. Finally, all tumors with ETV6-NTRK3 fusion were from patients older than 13 years of age at surgery.

ETV6-NTRK3 was later detected in 14.5% post-Chernobyl PTCs (age range from 14 to 32 years) and in 2% of sporadic (age range from 15 to 97 years) (Leeman-Neill et al. 2014). ETV6-NTRK3 was the second most common rearrangement, after RET/PTC, in radiation-induced PTCs. One of the tumors with ETV6-NTRK3 was from a patient who was aged 1 year at the time of the Chernobyl accident and another tumor was from a patient who was aged 10 years at the time of exposure. All radiation-induced PTCs in which ETV6-NTRK3 fusion was identified had some component of a solid growth pattern and most were classified as FVPTC (Leeman-Neill et al. 2014). Importantly, the authors demonstrated that the presence of ETV6-NTRK3 rearrangement, as well as RET/PTC and PAX8-PPARγ positive tumors, was significantly more common in tumors associated with higher dose exposure to 131I than tumors that had point mutations (NRAS, HRAS and BRAF).

The prevalence of ETV6-NTRK3 in pediatric sporadic PTC, its prognosis significance and whether in pediatric cases it is associated with older age (>10–18 years old) remains uncertain.

Other fusions transcripts

Other less prevalent fusion transcripts have been described in pediatric radiation-exposed PTC. The overall prevalence of these other fusion transcripts was 6% in a pediatric radiation-exposed PTC range from 3% to 19% (Ciampi et al. 2005, Sassolas et al. 2012, Ricarte-Filho et al. 2013) and 0% in sporadic (Ricarte-Filho et al. 2013).

The PAX8-PPARG and CREB3L2-PPARG fusions were previously identified in follicular thyroid cancer (Kroll et al. 2000, Lui et al. 2008). PAX8-PPARG rearrangement is predominantly identified in FTC and less often in FVPTC (Placzkowski et al. 2008). In adults, the PAX8-PPARG rearrangement occurs in up to 45–55% of FTC (Sahin et al. 2005, Castro et al. 2006), whereas the occurrence in follicular variant of PTC ranges from 0% to 35% (Zhu et al. 2003, Castro et al. 2006). In pediatric patients, the occurrence of PAX8-PPARG rearrangement was assessed only in one cohort of sporadic and radiation-exposed PTC patients. The authors did not find PAX8-PPAG in the sporadic group, whereas its prevalence was nearly 4% in the radiation-exposed group (Ricarte-Filho et al. 2013).

BRAF fusions have also been described in post-Chernobyl thyroid cancer, suggesting that this is a new mechanism of BRAF activation in human cancers (Ciampi et al. 2005, Ricarte-Filho et al. 2013). As far as we known, AGK-BRAF fusion was described in a tumor from one radiation-exposed PTC case who was 13 years old at surgery (Ricarte-Filho et al. 2013), while AKAP9-BRAF was identified in three tumors from radiation-exposed patients. Fuctional analyses revealed that both fusion oncogenes are able to activate the MAPK pathway. None of the pediatric sporadic PTC evaluated presented the AGK-BRAF fusion transcript (Ricarte-Filho et al. 2013).

Is the expression of iodine uptake and metabolism proteins higher in pediatric DTC than in adults?

It is well known that iodine uptake is a result of an active transport mechanism mediated by the sodium iodide symporter (NIS) protein, which is found in the basolateral membrane of thyroid follicular cells. It has served as an effective means for therapeutic doses of radioiodine to target and destroy cancer cells in which endogenous NIS is functionally expressed (Dadachova & Carrasco 2004). However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function (Liu et al. 2012, Xing 2013).

An important difference between pediatric and adult DTC is the high prevalence of functional metastases and the greater differentiation and radioiodine responsiveness in pediatric DTC. Accordingly, it has been suggested that the expression of NIS, as well as other proteins involved in iodine uptake and metabolism in pediatric patients, is higher than their expression in adults (Patel et al. 2002, Faggiano et al. 2004, Espadinha et al. 2009). Nonetheless, in some series, there is a higher prevalence of extrathyroidal extension, regional lymph node involvement and distant metastases in younger children than in adolescents (Alessandri et al. 2000, Jarzab et al. 2005, Dinauer et al. 2008, Lazar et al. 2009, O'Gorman et al. 2010, Rivkees et al. 2011, Vaisman et al. 2011, Francis et al. 2015). Therefore, one could postulate that the expression of NIS in children is lower than its expression in adolescents and, therefore, treatment of pediatric DTC should be stratified into more than one group.

In fact, the hypothesis that DTC from pediatric patients usually has a higher expression of iodine-metabolizing genes than DTC from adults and older patients has little support in the available literature, especially for young children (<0 years old). Either younger children were commonly underrepresented and/or patients over the age of 18 years at diagnosis were also included into the pediatric group. Moreover, only two studies specifically addressed the expression of iodine-metabolizing genes in pediatric patients (Patel et al. 2002, Espadinha et al. 2009). The former study assessed the expression of NIS in the malignant tumor and compared to benign lesions as a substitute of normal thyroid. The authors did not find a significant difference between benign and malignant thyroid lesions (Patel et al. 2002). Because the overall recurrence risk was increased for those tumors that had undetectable NIS expression, the authors suggested that NIS expression is a favorable prognostic indicator for DTC in children and adolescents (Patel et al. 2002). Additionally, the authors studied patients up to 21 years of age and only two cases under the age of 10. No comparison was made between children and adolescents. The subsequent study suggested that the expression of PDS, TPO and TSHR mRNA is higher in the pediatric group compared to adult (22–59 years) and elderly patients (>60 years). Nevertheless, among the 15 pediatric patients, only three cases were under 10 years of age, and there was no specific information regarding the expression of iodine-metabolizing genes in these patients (Espadinha et al. 2009).

Finally, it has been suggested that overactivation of the MAPK pathway, mainly through BRAF V600E mutation, leads to tumor dedifferentiation and, hence, reduced expression of proteins involved in iodine uptake and metabolism in PTC of adults (Romei et al. 2008, The Cancer Genome Atlas Research Network 2014, Zhang et al. 2014). However, it is becoming clear that the BRAF V600E-mutated group consists of distinct subgroups with variable degrees of thyroid differentiation (The Cancer Genome Atlas Research Network 2014), which suggests that additional genetic events may be associated with dedifferentiation status of the thyroid.

Of note the prevalence of BRAF V600E mutation in pediatric PTC is much lower than the prevalence observed in adults (Figs 1 and 2). Whether other genetic alteration that activates the MAPK pathway may modulate the expression of NIS in pediatric groups is still uncertain.

Therefore, the data are unclear as to whether younger age indicates a greater risk for extensive disease or recurrence, and the hypothesis of a greater expression of genes such as NIS, TPO and other proteins associated with iodine metabolism in pediatric patients would be associated with greater radioiodine responsiveness and overactivation of the MAPK pathways needs further evaluation.

Future plans

After the identification of new driver genes that are altered in radiation-exposed pediatric PTC cases lacking known genetic events (RET/PTC, RAS, BRAF mutations, AKAP9-BRAF, TPR-NTRK1 and PAX8-PPARG), significantly reduced the so-called dark matter. Nearly 84% had fusion, most oncoproteins activate MAPK pathways, suggesting that pediatric PTC are also MAPK-driver cancer. Conversely, the prevalence of drive fusion oncogenes in sporadic pediatric PTC was much lower. Nearly 30% of cases are negative for the fusion events and/or point mutations found in radiation-induced pediatric cohort (Ricarte-Filho et al. 2013). As the risk factor to the development of sporadic pediatric thyroid carcinoma is not known and the landscape of sporadic pediatric cancer likely differs significantly from the landscape of the radiation-exposed pediatric cases, it is expected that sporadic cases might have higher prevalence of point mutations than radiation-induced pediatric thyroid carcinomas. Further in-depth genome analysis of sporadic pediatric thyroid carcinoma is necessary to address and clarify this issue. Furthermore, such analysis may also help define whether pediatric tumors from children and adolescents represent different molecular subgroups.

The use of molecular diagnostic testing in thyroid nodules became a reality and aims to improve the accurate diagnosis in cytologically indeterminate thyroid nodules and, consequently, to avoid unnecessary surgical procedures. Although the evaluation and treatment of thyroid nodules in children should be the same as in adults (Francis et al. 2015), the molecular tests that are available for indeterminate thyroid nodules have not been validated in the pediatric patients. Although two studies have suggested a molecular test might improve the diagnosis of an indeterminate cytology in pediatric patients (Monaco et al. 2012, Buryk et al. 2013), it is still uncertain its usefulness. Although positive results may be associated with malignancy, the insufficient data associated with the fact that the ‘dark matter’ of sporadic pediatric thyroid carcinomas has not yet been well characterized suggest that is too early to rely on negative genetic tests to exclude malignancy. The in-depth genome analysis of the sporadic pediatric cases that had no known driver mutations will help define a panel of mutations/fusions that may be better applied to the diagnosis of pediatric thyroid nodules.

In conclusion, most of the efforts to determine the landscape of pediatric cases have been focused in radiation-exposed pediatric thyroid cancer, while most routine cases of thyroid nodules/cancer are indeed sporadic cases. As PTC is the most prevalent histological type of pediatric thyroid carcinoma, further efforts should be undertaken to define the genomic landscape of pediatric sporadic PTC.

Regarding treatment, although children with DTC have high rates of regional lymph node involvement and distant metastasis, the overall survival is good. Therefore, the extent of surgery and proper dose of 131I should be better defined based on the risk of recurrence. Whether molecular classification will help better classify pediatric thyroid carcinomas into subgroups and, therefore, refine diagnosis, prognosis and treatment, it is still a ‘dark matter.’

Supplementary data

This is linked to the online version of the paper at http://dx.doi.org/10.1530/ERC-15-0381.

Declaration of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by research grants 2012/02902-9 and 2013/03867-5 from the São Paulo State Research Foundation (FAPESP) and 470441/2013-5 from the Brazilian Research Council (CNPq). L Moraes is a FAPESP scholar. J M Cerutti is a CNPq investigator.

References

  • Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW & Nikiforov YE 2006 Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. American Journal of Surgical Pathology 30 216222. (doi:10.1097/01.pas.0000176432.73455.1b).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ahn BH, Kim JR, Jeong HC, Lee JS, Chang ES & Kim YH 2015 Predictive factors of central lymph node metastasis in papillary thyroid carcinoma. Annals of Surgical Treatment and Research 88 6368. (doi:10.4174/astr.2015.88.2.63).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alessandri AJ, Goddard KJ, Blair GK, Fryer CJ & Schultz KR 2000 Age is the major determinant of recurrence in pediatric differentiated thyroid carcinoma. Medical and Pediatric Oncology 35 4146. (doi:10.1002/1096-911X(200007)35:1<41::AID-MPO7>3.0.CO;2-7).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alzahrani AS, Alkhafaji D, Tuli M, Al-Hindi H & Bin Sadiq B Comparison of differentiated thyroid cancer in children and adolescents (</=20 years) with young adults Clinical Endocrinology 2015 [in press] doi:10.1111/cen.12845).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ashizawa K, Shibata Y, Yamashita S, Namba H, Hoshi M, Yokoyama N, Izumi M & Nagataki S 1997 Prevalence of goiter and urinary iodine excretion levels in children around Chernobyl. Journal of Clinical Endocrinology and Metabolism 82 34303433. (doi:10.1210/jcem.82.10.4285).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boas M, Feldt-Rasmussen U, Skakkebaek NE & Main KM 2006 Environmental chemicals and thyroid function. European Journal of Endocrinology 154 599611. (doi:10.1530/eje.1.02128).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bongarzone I, Fugazzola L, Vigneri P, Mariani L, Mondellini P, Pacini F, Basolo F, Pinchera A, Pilotti S & Pierotti MA 1996 Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 81 20062009. (doi:10.1210/jcem.81.5.8626874).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Buryk MA, Monaco SE, Witchel SF, Mehta DK, Gurtunca N, Nikiforov YE & Simons JP 2013 Preoperative cytology with molecular analysis to help guide surgery for pediatric thyroid nodules. International Journal of Pediatric Otorhinolaryngology 77 16971700. (doi:10.1016/j.ijporl.2013.07.029).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Castro P, Rebocho AP, Soares RJ, Magalhaes J, Roque L, Trovisco V, ieiradeCastro I, Cardoso-de-Oliveira M, Fonseca E & Soares P et al. 2006 PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 91 213220. (doi:10.1210/jc.2005-1336).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chow SM, Law SC, Mendenhall WM, Au SK, Yau S, Mang O & Lau WH 2004 Differentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine. Pediatric Blood & Cancer 42 176183. (doi:10.1002/pbc.10410).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, Rabes HM, Fagin JA & Nikiforov YE 2005 Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. Journal of Clinical Investigation 115 94101. (doi:10.1172/JCI23237).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dadachova E & Carrasco N 2004 The Na/I symporter (NIS): imaging and therapeutic applications. Seminars in Nuclear Medicine 34 2331. (doi:10.1053/j.semnuclmed.2003.09.004).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Davies L & Welch HG 2006 Increasing incidence of thyroid cancer in the United States, 1973-2002. Journal of the American Medical Association 295 21642167. (doi:10.1001/jama.295.18.2164).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Demidchik YE, Saenko VA & Yamashita S 2007 Childhood thyroid cancer in Belarus, Russia, and Ukraine after Chernobyl and at present. Arquivos Brasileiros de Endocrinologia e Metabologia 51 748762. (doi:10.1590/S0004-27302007000500012).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dinauer CA, Breuer C & Rivkees SA 2008 Differentiated thyroid cancer in children: diagnosis and management. Current Opinion in Oncology 20 5965. (doi:10.1097/CCO.0b013e3282f30220).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dorffel WV, Reitzig P, Dorffel Y & Possinger K 2000 Secondary malignant neoplasms in patients with breast cancer. Zentralblatt fur Gynakologie 122 419427. (doi:10.1055/s-2000-10604).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Elisei R, Romei C, Vorontsova T, Cosci B, Veremeychik V, Kuchinskaya E, Basolo F, Demidchik EP, Miccoli P & Pinchera A et al. 2001 RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. Journal of Clinical Endocrinology and Metabolism 86 32113216. (doi:10.1210/jcem.86.7.7678).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Espadinha C, Santos JR, Sobrinho LG & Bugalho MJ 2009 Expression of iodine metabolism genes in human thyroid tissues: evidence for age and BRAFV600E mutation dependency. Clinical Endocrinology 70 629635. (doi:10.1111/j.1365-2265.2008.03376.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Faggiano A, Coulot J, Bellon N, Talbot M, Caillou B, Ricard M, Bidart JM & Schlumberger M 2004 Age-dependent variation of follicular size and expression of iodine transporters in human thyroid tissue Journal of nuclear medicine: official publication. Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine 45 232237.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fenton CL, Lukes Y, Nicholson D, Dinauer CA, Francis GL & Tuttle RM 2000 The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. Journal of Clinical Endocrinology and Metabolism 85 11701175. (doi:10.1210/jcem.85.3.6472).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Francis G, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti J, Dinauer CA, Hamilton JK, Hay ID & Luster M 2015 Management guidelines for children with thyroid nodules and differentiated thyroid cancer. The American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer. Thyroid 25 716759. (doi:10.1089/thy.2014.0460).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Frasca F, Nucera C, Pellegriti G, Gangemi P, Attard M, Stella M, Loda M, Vella V, Giordano C & Trimarchi F et al. 2008 BRAF(V600E) mutation and the biology of papillary thyroid cancer. Endocrine-Related Cancer 15 191205. (doi:10.1677/ERC-07-0212).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fukahori M, Yoshida A, Hayashi H, Yoshihara M, Matsukuma S, Sakuma Y, Koizume S, Okamoto N, Kondo T & Masuda M et al. 2012 The associations between RAS mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort. Thyroid : Official Journal of the American Thyroid Association 22 683689. (doi:10.1089/thy.2011.0261).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fusco A & Santoro M 2007 20 years of RET/PTC in thyroid cancer: clinico-pathological correlations. Arquivos Brasileiros de Endocrinologia e Metabologia 51 731735. (doi:10.1590/S0004-27302007000500010).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA, Della Porta G & Vecchio G 1987 A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 328 170172. (doi:10.1038/328170a0).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gharib H & Papini E 2007 Thyroid nodules: clinical importance, assessment, and treatment. Endocrinology and Metabolism Clinics of North America 36 707735, vi. (doi:10.1016/j.ecl.2007.04.009).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Givens DJ, Buchmann LO, Agarwal AM, Grimmer JF & Hunt JP 2014 BRAF V600E does not predict aggressive features of pediatric papillary thyroid carcinoma. Laryngoscope 124 E389E393. (doi:10.1002/lary.24668).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gorman MF, Ji L, Ko RH, Barnette P, Bostrom B, Hutchinson R, Raetz E, Seibel NL, Twist CJ & Eckroth E et al. 2010 Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): a Therapeutic Advances in Childhood Leukemia (TACL) Consortium study. Pediatric Blood & Cancer 55 421429. (doi:10.1002/pbc.22612).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Grigsby PW, Gal-or A, Michalski JM & Doherty GM 2002 Childhood and adolescent thyroid carcinoma. Cancer 95 724729. (doi:10.1002/cncr.10725).

  • Handkiewicz-Junak D, Wloch J, Roskosz J, Krajewska J, Kropinska A, Pomorski L, Kukulska A, Prokurat A, Wygoda Z & Jarzab B 2007 Total thyroidectomy and adjuvant radioiodine treatment independently decrease locoregional recurrence risk in childhood and adolescent differentiated thyroid cancer. Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine 48 879888.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hay ID, Gonzalez-Losada T, Reinalda MS, Honetschlager JA, Richards ML & Thompson GB 1940 Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. World Journal of Surgery 34 11921202. (doi:10.1007/s00268-009-0364-0).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hayashida N, Imaizumi M, Shimura H, Okubo N, Asari Y, Nigawara T, Midorikawa S, Kotani K, Nakaji S & Otsuru A et al. 2013 Thyroid ultrasound findings in children from three Japanese prefectures: Aomori. PLoS ONE 8 e83220. (doi:10.1371/journal.pone.0083220).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henke LE, Perkins SM, Pfeifer JD, Ma C, Chen Y, DeWees T & Grigsby PW 2014 BRAF V600E mutational status in pediatric thyroid cancer. Pediatric Blood & Cancer 61 11681172. (doi:10.1002/pbc.24935).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI & Sola JE 2009 Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. Journal of Surgical Research 156 167172. (doi:10.1016/j.jss.2009.03.098).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Iwaku K, Noh JY, Sasaki E, Suzuki N, Kameda T, Kobayashi S, Yoshihara A, Ohye H, Watanabe N & Suzuki M et al. 2014 Changes in pediatric thyroid sonograms in or nearby the Kanto region before and after the accident at the Fukushima Daiichi nuclear power plant. Endocrine Journal 61 875881. (doi:10.1507/endocrj.EJ14-0032).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ito Y, Kihara M, Takamura Y, Kobayashi K, Miya A, Hirokawa M & Miyauchi A 2012 Prognosis and prognostic factors of papillary thyroid carcinoma in patients under 20 years. Endocrine Journal 59 539545. (doi:10.1507/endocrj.EJ12-0086).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jarzab B & Handkiewicz-Junak D 2007 Differentiated thyroid cancer in children and adults: same or distinct disease? Hormones 6 200209.

  • Jarzab B, Handkiewicz-Junak D & Wloch J 2005 Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review. Endocrine-Related Cancer 12 773803. (doi:10.1677/erc.1.00880).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE & Fagin JA 2003 High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Research 63 14541457.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klugbauer S, Lengfelder E, Demidchik EP & Rabes HM 1995 High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. Oncogene 11 24592467.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Koo JS, Hong S & Park CS 2009 Diffuse sclerosing variant is a major subtype of papillary thyroid carcinoma in the young. Thyroid : Official Journal of the American Thyroid Association 19 12251231. (doi:10.1089/thy.2009.0073).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM & Fletcher JA 2000 PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289 13571360. (doi:10.1126/science.289.5483.1357).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kumagai A, Namba H, Saenko VA, Ashizawa K, Ohtsuru A, Ito M, Ishikawa N, Sugino K, Ito K & Jeremiah S et al. 2004 Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 89 42804284. (doi:10.1210/jc.2004-0172).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lamartina L, Durante C, Filetti S & Cooper DS 2015 Low-risk differentiated thyroid cancer and radioiodine remnant ablation: a systematic review of the literature. Journal of Clinical Endocrinology and Metabolism 100 17481761. (doi:10.1210/jc.2014-3882).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Landau D, Vini L, A'Hern R & Harmer C 2000 Thyroid cancer in children: the Royal Marsden Hospital experience. European Journal of Cancer 36 214220. (doi:10.1016/S0959-8049(99)00281-6).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • La Quaglia MP, Black T, Holcomb GW III, Sklar C, Azizkhan RG, Haase GM & Newman KD 2000 Differentiated thyroid cancer: clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases. A report from the Surgical Discipline Committee of the Children's Cancer Group. Journal of Pediatric Surgery 35 955959.discussion 960 (doi:10.1053/jpsu.2000.6935).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lazar L, Lebenthal Y, Steinmetz A, Yackobovitch-Gavan M & Phillip M 2009 Differentiated thyroid carcinoma in pediatric patients: comparison of presentation and course between pre-pubertal children and adolescents. Journal of Pediatrics 154 708714. (doi:10.1016/j.jpeds.2008.11.059).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, Evdokimova VN, Hatch M, Zurnadzy LY & Nikiforova MN et al. 2014 ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer 120 799807. (doi:10.1002/cncr.28484).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Levy GH, Marti JL, Cai G, Kayne RD, Udelsman R, Hammers LW, Kowalski DP & Prasad ML 2012 Pleomorphic adenoma arising in an incidental midline isthmic thyroid nodule: a case report and review of the literature. Human Pathology 43 134137. (doi:10.1016/j.humpath.2011.02.025).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lima J, Trovisco V, Soares P, Maximo V, Magalhaes J, Salvatore G, Santoro M, Bogdanova T, Tronko M & Abrosimov A et al. 2004 BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 89 42674271. (doi:10.1210/jc.2003-032224).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lise M, Franceschi S, Buzzoni C, Zambon P, Falcini F, Crocetti E, Serraino D, Iachetta F, Zanetti R & Vercelli M et al. 2012 Changes in the incidence of thyroid cancer between 1991 and 2005 in Italy: a geographical analysis. Thyroid : Official Journal of the American Thyroid Association 22 2734. (doi:10.1089/thy.2011.0038).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu YY, Zhang X, Ringel MD & Jhiang SM 2012 Modulation of sodium iodide symporter expression and function by LY294002. Akti-1/2 and Rapamycin in thyroid cells. Endocrine-Related Cancer 19 291304. (doi:10.1530/ERC-11-0288).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lui WO, Zeng L, Rehrmann V, Deshpande S, Tretiakova M, Kaplan EL, Leibiger I, Leibiger B, Enberg U & Hoog A et al. 2008 CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis. Cancer Research 68 71567164. (doi:10.1158/0008-5472.CAN-08-1085).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Marti JL, Clark VE, Harper H, Chhieng DC, Sosa JA & Roman SA 2012 Optimal surgical management of well-differentiated thyroid cancer arising in struma ovarii: a series of 4 patients and a review of 53 reported cases. Thyroid : Official Journal of the American Thyroid Association 22 400406. (doi:10.1089/thy.2011.0162).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Marti JL, Jain KS & Morris LG 2015 Increased risk of second primary malignancy in pediatric and young adult patients treated with radioactive iodine for differentiated thyroid cancer. Thyroid : Official Journal of the American Thyroid Association 25 681687. (doi:10.1089/thy.2015.0067).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mazonakis M, Tzedakis A, Damilakis J & Gourtsoyiannis N 2007 Thyroid dose from common head and neck CT examinations in children: is there an excess risk for thyroid cancer induction? European Radiology 17 13521357. (doi:10.1007/s00330-006-0417-9).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mazzaferri EL 1993 Management of a solitary thyroid nodule. New England Journal of Medicine 328 553559. (doi:10.1056/NEJM199302253280807).

  • Memon A, Godward S, Williams D, Siddique I & Al-Saleh K 2010 Dental x-rays and the risk of thyroid cancer: a case-control study. Acta Oncologica 49 447453. (doi:10.3109/02841861003705778).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Monaco SE, Pantanowitz L, Khalbuss WE, Benkovich VA, Ozolek J, Nikiforova MN, Simons JP & Nikiforov YE 2012 Cytomorphological and molecular genetic findings in pediatric thyroid fine-needle aspiration. Cancer Cytopathology 120 342350. (doi:10.1002/cncy.21199).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Neiva F, Mesquita J, PacoLima S, Matos MJ, Costa C, Castro-Correia C, Fontoura M & Martins S 2012 Thyroid carcinoma in children and adolescents: a retrospective review. Endocrinologia y Nutricion: Organo de la Sociedad Espanola de Endocrinologia y Nutricion 59 105108. (doi:10.1016/j.endonu.2011.11.003).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Newman KD, Black T, Heller G, Azizkhan RG, Holcomb GW III, Sklar C, Vlamis V, Haase GM & LaQuaglia MP 1998 Differentiated thyroid cancer: determinants of disease progression in patients <21 years of age at diagnosis: a report from the Surgical Discipline Committee of the Children's Cancer Group. Annals of Surgery 227 533541. (doi:10.1097/00000658-199804000-00014).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Niedziela M 2006 Pathogenesis, diagnosis and management of thyroid nodules in children. Endocrine-Related Cancer 13 427453. (doi:10.1677/erc.1.00882).

  • Nikiforov YE & Nikiforova MN 2011 Molecular genetics and diagnosis of thyroid cancer Nature reviews. Endocrinology 7 569580. (doi:10.1038/nrendo.2011.142).

  • Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H & Fagin JA 1997 Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Research 57 16901694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA & Nikiforov YE 2000 Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290 138141. (doi:10.1126/science.290.5489.138).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nikiforova MN, Ciampi R, Salvatore G, Santoro M, Gandhi M, Knauf JA, Thomas GA, Jeremiah S, Bogdanova TI & Tronko MD et al. 2004 Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Letters 209 16. (doi:10.1016/j.canlet.2003.12.004).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • O'Gorman CS, Hamilton J, Rachmiel M, Gupta A, Ngan BY & Daneman D 2010 Thyroid cancer in childhood: a retrospective review of childhood course. Thyroid : Official Journal of the American Thyroid Association 20 375380. (doi:10.1089/thy.2009.0386).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oler G & Cerutti JM 2009 High prevalence of BRAF mutation in a Brazilian cohort of patients with sporadic papillary thyroid carcinomas: correlation with more aggressive phenotype and decreased expression of iodide-metabolizing genes. Cancer 115 972980. (doi:10.1002/cncr.24118).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Park JY, Kim WY, Hwang TS, Lee SS, Kim H, Han HS, Lim SD, Kim WS, Yoo YB & Park KS 2013 BRAF and RAS mutations in follicular variants of papillary thyroid carcinoma. Endocrine Pathology 24 6976. (doi:10.1007/s12022-013-9244-0).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Patel A, Jhiang S, Dogra S, Terrell R, Powers PA, Fenton C, Dinauer CA, Tuttle RM & Francis GL 2002 Differentiated thyroid carcinoma that express sodium-iodide symporter have a lower risk of recurrence for children and adolescents. Pediatric Research 52 737744. (doi:10.1203/00006450-200211000-00021).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pellegriti G, Frasca F, Regalbuto C, Squatrito S & Vigneri R 2013 Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. Journal of Cancer Epidemiology 2013 965212. (doi:10.1155/2013/965212).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Penko K, Livezey J, Fenton C, Patel A, Nicholson D, Flora M, Oakley K, Tuttle RM & Francis G 2005 BRAF mutations are uncommon in papillary thyroid cancer of young patients. Thyroid : Official Journal of the American Thyroid Association 15 320325. (doi:10.1089/thy.2005.15.320).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pisarchik AV, Ermak G, Fomicheva V, Kartel NA & Figge J 1998 The ret/PTC1 rearrangement is a common feature of Chernobyl-associated papillary thyroid carcinomas from Belarus. Thyroid : Official Journal of the American Thyroid Association 8 133139. (doi:10.1089/thy.1998.8.133).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pita JM, Figueiredo IF, Moura MM, Leite V & Cavaco BM 2014 Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 99 E497E507. (doi:10.1210/jc.2013-1512).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Placzkowski KA, Reddi HV, Grebe SK, Eberhardt NL & McIver B 2008 The role of the PAX8/PPARgamma fusion oncogene in thyroid cancer. PPAR Research 2008 672829. (doi:10.1155/2008/672829).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D & Klugbauer S 2000 Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clinical Cancer Research 6 10931103.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ricarte-Filho JC, Li S, Garcia-Rendueles ME, Montero-Conde C, Voza F, Knauf JA, Heguy A, Viale A, Bogdanova T & Thomas GA et al. 2013 Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. Journal of Clinical Investigation 123 49354944. (doi:10.1172/JCI69766).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rivera M, Ricarte-Filho J, Knauf J, Shaha A, Tuttle M, Fagin JA & Ghossein RA 2010 Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Modern Pathology 23 11911200. (doi:10.1038/modpathol.2010.112).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rivkees SA, Mazzaferri EL, Verburg FA, Reiners C, Luster M, Breuer CK, Dinauer CA & Udelsman R 2011 The treatment of differentiated thyroid cancer in children: emphasis on surgical approach and radioactive iodine therapy. Endocrine Review 32 798826. (doi:10.1210/er.2011-0011).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Romei C & Elisei R 2012 RET/PTC translocations and clinico-pathological features in human papillary thyroid carcinoma. Frontiers in Endocrinology 3 54. (doi:10.3389/fendo.2012.00054).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Romei C, Ciampi R, Faviana P, Agate L, Molinaro E, Bottici V, Basolo F, Miccoli P, Pacini F & Pinchera A et al. 2008 BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer. Endocrine-Related Cancer 15 511520. (doi:10.1677/ERC-07-0130).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ron E, Lubin JH, Shore RE, Mabuchi K, Modan B, Pottern LM, Schneider AB, Tucker MA & Boice JD Jr 1995 Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiation Research 141 259277. (doi:10.2307/3579003).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sahin M, Allard BL, Yates M, Powell JG, Wang XL, Hay ID, Zhao Y, Goellner JR, Sebo TJ & Grebe SK et al. 2005 PPARgamma staining as a surrogate for PAX8/PPARgamma fusion oncogene expression in follicular neoplasms: clinicopathological correlation and histopathological diagnostic value. Journal of Clinical Endocrinology and Metabolism 90 463468. (doi:10.1210/jc.2004-1203).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sassolas G, Hafdi-Nejjari Z, Ferraro A, Decaussin-Petrucci M, Rousset B, Borson-Chazot F, Borbone E, Berger N & Fusco A 2012 Oncogenic alterations in papillary thyroid cancers of young patients. Thyroid : Official Journal of the American Thyroid Association 22 1726. (doi:10.1089/thy.2011.0215).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Siegel R, Ma J, Zou Z & Jemal A 2014a Cancer statistics, 2014. CA: A Cancer Journal for Clinicians 64 929. (doi:10.3322/caac.21208).

  • Siegel DA, King J, Tai E, Buchanan N, Ajani UA & Li J 2014b Cancer incidence rates and trends among children and adolescents in the United States, 2001–2009. Pediatrics 134 e945e955. (doi:10.1542/peds.2013-3926).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sigurdson AJ, Ronckers CM, Mertens AC, Stovall M, Smith SA, Liu Y, Berkow RL, Hammond S, Neglia JP & Meadows AT et al. 2005 Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 365 20142023. (doi:10.1016/S0140-6736(05)66695-0).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Smida J, Salassidis K, Hieber L, Zitzelsberger H, Kellerer AM, Demidchik EP, Negele T, Spelsberg F, Lengfelder E & Werner M et al. 1999 Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus International journal of cancer. International Journal of Cancer. Journal International du Cancer 80 3238. (doi:10.1002/(SICI)1097-0215(19990105)80:1<32::AID-IJC7>3.0.CO;2-L).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Suchy B, Waldmann V, Klugbauer S & Rabes HM 1998 Absence of RAS and p53 mutations in thyroid carcinomas of children after Chernobyl in contrast to adult thyroid tumours. British Journal of Cancer 77 952955. (doi:10.1038/bjc.1998.157).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • The Cancer Genome Atlas Research Network 2014 Integrated genomic characterization of papillary thyroid carcinoma. Cell 159 676690. (doi:10.1016/j.cell.2014.09.050).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, Cherstvoy ED, Tronko ND, Bogdanova TI, Chiappetta G & Viglietto G et al. 1999 High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. Journal of Clinical Endocrinology and Metabolism 84 42324238. (doi:10.1210/jcem.84.11.6129).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tuttle RM, Vaisman F & Tronko MD 2011 Clinical presentation and clinical outcomes in Chernobyl-related paediatric thyroid cancers: what do we know now? What can we expect in the future? Clinical Oncology 23 268275. (doi:10.1016/j.clon.2011.01.178).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vaisman F, Corbo R & Vaisman M 2011 Thyroid carcinoma in children and adolescents – systematic review of the literature. Journal of Thyroid Research 2011 845362. (doi:10.4061/2011/845362).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Veiga LH, Neta G, Aschebrook-Kilfoy B, Ron E & Devesa SS 2013 Thyroid cancer incidence patterns in Sao Paulo, Brazil, and the U.S. SEER program, 1997–2008. Thyroid : Official Journal of the American Thyroid Association 23 748757. (doi:10.1089/thy.2012.0532).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vergamini LB, Frazier AL, Abrantes FL, Ribeiro KB & Rodriguez-Galindo C 2014 Increase in the incidence of differentiated thyroid carcinoma in children, adolescents, and young adults: a population-based study. Journal of Pediatrics 164 14811485. (doi:10.1016/j.jpeds.2014.01.059).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ward E, DeSantis C, Robbins A, Kohler B & Jemal A 2014 Childhood and adolescent cancer statistics, 2014. CA: A Cancer Journal for Clinicians 64 83103. (doi:10.3322/caac.21219).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Welch Dinauer CA, Tuttle RM, Robie DK, McClellan DR, Svec RL, Adair C & Francis GL 1998 Clinical features associated with metastasis and recurrence of differentiated thyroid cancer in children, adolescents and young adults. Clinical Endocrinology 49 619628. (doi:10.1046/j.1365-2265.1998.00584.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Williams D 2008 Radiation carcinogenesis: lessons from Chernobyl. Oncogene 27 (Suppl 2) S918. (doi:10.1038/onc.2009.349).

  • Wu XC, Chen VW, Steele B, Roffers S, Klotz JB, Correa CN & Carozza SE 2003 Cancer incidence in adolescents and young adults in the United States, 1992–1997. Journal of Adolescent Health 32 405415. (doi:10.1016/S1054-139X(03)00057-0).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xing M 2005 BRAF mutation in thyroid cancer. Endocrine-Related Cancer 12 245262. (doi:10.1677/erc.1.0978).

  • Xing M 2013 Molecular pathogenesis and mechanisms of thyroid cancer. Nature Reviews. Cancer 13 184199. (doi:10.1038/nrc3431).

  • Yamashita S & Suzuki S 2013 Risk of thyroid cancer after the Fukushima nuclear power plant accident. Respiratory Investigation 51 128133. (doi:10.1016/j.resinv.2013.05.007).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yamashita S & Takamura N 2012 Post-crisis efforts towards recovery and resilience after the Fukushima Daiichi Nuclear Power Plant accident. Japanese Journal of Clinical Oncology 45 700707. (doi:10.1093/jjco/hyv076).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yasumura S, Hosoya M, Yamashita S, Kamiya K, Abe M, Akashi M, Kodama K & Ozasa K 2012 Study protocol for the Fukushima Health Management Survey. Journal of Epidemiology 22 375383. (doi:10.2188/jea.JE20120105).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zaydfudim V, Feurer ID, Griffin MR & Phay JE 2008 The impact of lymph node involvement on survival in patients with papillary and follicular thyroid carcinoma. Surgery 144 10701077; discussion 1077–1078. (doi:10.1016/j.surg.2008.08.034).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang Z, Liu D, Murugan AK, Liu Z & Xing M 2014 Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer. Endocrine-Related Cancer 21 161173. (doi:10.1530/ERC-13-0399).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhu Z, Gandhi M, Nikiforova MN, Fischer AH & Nikiforov YE 2003 Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. American Journal of Clinical Pathology 120 7177. (doi:10.1309/ND8D9LAJTRCTG6QD).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhu Z, Ciampi R, Nikiforova MN, Gandhi M & Nikiforov YE 2006 Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. Journal of Clinical Endocrinology and Metabolism 91 36033610. (doi:10.1210/jc.2006-1006).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zimmerman D, Hay ID, Gough IR, Goellner JR, Ryan JJ, Grant CS & McConahey WM 1988 Papillary thyroid carcinoma in children and adults: long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery 104 11571166.

    • PubMed
    • Search Google Scholar
    • Export Citation

 

  • Collapse
  • Expand
  • Overall prevalence of point mutations and rearrangements identified in sporadic pediatric and radiation-exposed pediatric papillary thyroid carcinomas. Other fusion groups include PAX8-PPARG, AKAP9-BRAF, AGK-BRAF, NTRK1, CREB3L2-PPARG. The other somatic mutation groups include BRAF V600_K601E and TSHR S425I. The prevalence of RET/PTC isoforms is show in detail in the bottom panel. The prevalence and categories of mutations are detailed in Supplementary Tables 1 and 2.

  • The worldwide prevalence of RET/PTC and BRAF V600E in sporadic and radiation-exposed pediatric PTC is shown. Studies from the same country were groups and the prevalence calculated.