Pediatric Differentiated Thyroid Cancer Research Articles

Radioiodine Therapy in Pediatric Differentiated Thyroid Cancer: Dosimetry, Clinical Care, and Future Challenges.

Thyroid cancer is very rare in children. 131 I therapy after thyroidectomy is established in pediatric differentiated thyroid cancer (DTC). Pediatric DTC guideline is silent on the optimum amount of 131 I that could be safely and effectively administered to children who are more radiosensitive. Like adult DTC, children are also given 131 I therapy empirically based either on age or body weight. Pediatric DTC guideline recommends that patient-specific dosimetry is important in children. Still, due to the low incidence rate and the practical difficulties of dosimetry, it has neither been established nor adopted in routine practice. This review article aims to discuss current approaches of 131 I therapy in children and young adult patients with DTC and dosimetric data obtained by several investigators. Efforts are required to simplify dosimetric procedures and precise results, especially in determining lesion size. We prefer 3-dimensional dosimetry over planar dosimetry, where lesion size could be measured accurately. 124 I PET/CT-based dosimetry is expected to give accurate dosimetric results. The most challenging aspect is that no randomized controlled trials are available to compare the empiric 131 I therapy results versus dosimetry-based treatment outcomes in children and young adults. Suppose dosimetry-based 131 I therapy could be shown to have better outcomes, namely, successful ablation rate, better disease-free survival, and lesser treatment-emergent adverse events than empirical 131 I treatment. In that case, one can argue in favor of the former. Unfortunately, no convincing study is currently available. Thus, there is a need for a randomized control trial to settle this issue.

Late Breaking Abstracts

Late Breaking Abstracts

Progressive diastolic dysfunction in survivors of pediatric differentiated thyroid carcinoma.

Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding. This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e' mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers. Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8-60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2-48.8). Between the first and second evaluation, the e' mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e' mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e' mean (β coefficient: -0.169, 95% CI: -0.292; -0.047, P = 0.008 and β coefficient: -0.177, 95% CI: -0.240; -0.113, P < 0.001, respectively). In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

Strategies for Radioiodine Treatment: What’s New

Simple SummaryRadioactive iodine treatment is the oldest targeted therapy for differentiated thyroid cancer. It can be used for normal thyroid remnant ablation (in order to increase the sensitivity and the specificity of the serum marker thyroglobulin), as an adjuvant treatment (in order to improve recurrence-free survival), or to treat radioiodine avid residual disease. Thanks to the use of sensible diagnostic tools, reliable prognostic classifications, and molecular profiling, the indication and modalities of radioiodine treatment are shifting from a one-size-fits-all to a tailored approach. This review provides insights into the most recent and high-quality evidence relating to radioactive iodine treatment.Radioiodine treatment (RAI) represents the most widespread and effective therapy for differentiated thyroid cancer (DTC). RAI goals encompass ablative (destruction of thyroid remnants, to enhance thyroglobulin predictive value), adjuvant (destruction of microscopic disease to reduce recurrences), and therapeutic (in case of macroscopic iodine avid lesions) purposes, but its use has evolved over time. Randomized trial results have enabled the refinement of RAI indications, moving from a standardized practice to a tailored approach. In most cases, low-risk patients may safely avoid RAI, but where necessary, a simplified protocol, based on lower iodine activities and human recombinant TSH preparation, proved to be just as effective, reducing overtreatment or useless impairment of quality of life. In pediatric DTC, RAI treatments may allow tumor healing even at the advanced stages. Finally, new challenges have arisen with the advancement in redifferentiation protocols, through which RAI still represents a leading therapy, even in former iodine refractory cases. RAI therapy is usually well-tolerated at low activities rates, but some concerns exist concerning higher cumulative doses and long-term outcomes. Despite these achievements, several issues still need to be addressed in terms of RAI indications and protocols, heading toward the RAI strategy of the future.

Applicability of Adults 2015 American Thyroid Association Differentiated Thyroid Cancer Guidelines for Postoperative Risk Stratification and Postradioiodine Treatment Dynamic Risk Stratification in Pediatric Population.

Purpose This retrospective study aimed to study the applicability of 2015 adult American Thyroid Association (ATA) differentiated thyroid cancer (DTC) postoperative risk stratification and guidelines in the pediatric population for evaluating the number of metastatic lymph nodes in the postoperative risk stratification and postradioactive iodine (RAI) treatment dynamic risk stratification (DRS) using response to treatment (RTT) reclassification. In addition, the effect of pubertal status and gender was assessed on disease presentation and prognosis. Methods Data of 63 DTC patients aged 20 years or less, stratified into prepubertal, pubertal, and postpubertal age groups, was divided into low, intermediate, and high-risk groups using pediatric ATA recurrence risk stratification. Forty-seven patients were classified as responders (excellent and indeterminate responses) and incomplete responders (biochemical and structurally incomplete responses) by assessing the RTT at 1.5 years follow-up similar to recommendation of 2015 adult DTC ATA guidelines. Results Female-to-male ratio showed a trend of gradual increase with increasing age. Significantly more responders were observed in low- and intermediate-risk groups than in high-risk group ( p = 0.0013; p = 0.017, respectively), while prepubertal group had more extensive (N1b) disease. Using DRS at follow-up of 1.5 year, pubertal and postpubertal groups showed significantly better response to RAI. More female than male patients showed response and took significantly less time to respond to RAI ( p = 0.003). Conclusion RAI response in pediatric DTC depends on pubertal status, gender, and number of malignant nodes. DRS using RTT classification may be applicable early at 1.5 years after initial therapy in different pubertal age and risk groups.

The 2015 American Thyroid Association guidelines and trends in hemithyroidectomy utilization for pediatric thyroid cancer.

In 2015, the American Thyroid Association (ATA) released its inaugural recommendations for the management of thyroid cancer in children. We aim to evaluate whether there has been a change in hemithyroidectomy utilization for pediatric differentiated thyroid cancer, and the association between those changes and the release of the ATA guidelines. The National Cancer Database was queried and identified 4776 patients ≤18 years old with differentiated thyroid cancer. Causal impact time-series analysis and logistic analysis were utilized to assess factors associated with use of hemithyroidectomy. Post-2015 hemithyroidectomy rate was greater than predicted based on preguideline trends (predicted: 8.4%, actual: 12.6%, p=0.001). In logistic analysis of factors associated with hemithyroidectomy use, we find that Papillary histology, tumor size >1cm, nodal examination, and positive nodes were associated with lower rate of hemithyroidectomy (OR: 0.23, 0.51, 0.62, and 0.18, respectively). There has been a significant increase in hemithyroidectomy utilization for pediatric differentiated thyroid cancer.

Association Between Radioactive Iodine Treatment for Pediatric and Young Adulthood Differentiated Thyroid Cancer and Risk of Second Primary Malignancies.

PURPOSESince the 1980s, both the incidence of differentiated thyroid cancer (DTC) and use of radioactive iodine (RAI) treatment increased markedly. RAI has been associated with an increased risk of leukemia, but risks of second solid malignancies remain unclear. We aimed to quantify risks of second malignancies associated with RAI treatment for DTC in children and young adults, who are more susceptible than older adults to the late effects of radiation.METHODSUsing nine US SEER cancer registries (1975-2017), we estimated relative risks (RRs) for solid and hematologic malignancies associated with RAI (yes v no or unknown) using Poisson regression among ≥ 5- and ≥ 2-year survivors of nonmetastatic DTC diagnosed before age 45 years, respectively.RESULTSAmong 27,050 ≥ 5-year survivors (median follow-up = 15 years), RAI treatment (45%) was associated with increased risk of solid malignancies (RR = 1.23; 95% CI, 1.11 to 1.37). Risks were increased for uterine cancer (RR = 1.55; 95% CI, 1.03 to 2.32) and nonsignificantly for cancers of the salivary gland (RR = 2.15; 95% CI, 0.91 to 5.08), stomach (RR = 1.61; 95% CI, 0.70 to 3.69), lung (RR = 1.42; 95% CI, 0.97 to 2.08), and female breast (RR = 1.18; 95% CI, 0.99 to 1.40). Risks of total solid and female breast cancer, the most common cancer type, were highest among ≥ 20-year DTC survivors (RRsolid = 1.47; 95% CI, 1.24 to 1.74; RRbreast = 1.46; 95% CI, 1.10 to 1.95). Among 32,171 ≥ 2-year survivors, RAI was associated with increased risk of hematologic malignancies (RR = 1.51; 95% CI, 1.08 to 2.01), including leukemia (RR = 1.92; 95% CI, 1.04 to 3.56). We estimated that 6% of solid and 14% of hematologic malignancies in pediatric and young adult DTC survivors may be attributable to RAI.CONCLUSIONIn addition to leukemia, RAI treatment for childhood and young-adulthood DTC was associated with increased risks of several solid cancers, particularly more than 20 years after exposure, supporting the need for long-term surveillance of these patients.

Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers.

In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant (H-K-NRAS), BRAF-mutant (BRAF p.V600E), and RET/NTRK fusion (RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

Unique Molecular Signatures Are Associated with Aggressive Histology in Pediatric Differentiated Thyroid Cancer.

Background: Molecular testing (MT) enhances the diagnostic accuracy of thyroid fine-needle aspiration biopsy, reducing the need for diagnostic lobectomy in adult patients with indeterminate nodules (Bethesda class III/IV). However, little is known about genetic alterations in pediatric thyroid carcinoma (TC). Our aim was to analyze MT results of pediatric differentiated TC (DTC) cases to determine associations with histological and clinical features. Methods: A retrospective review identified all patients (aged <19 years) diagnosed with DTC from 2001 to 2017 at the University of Pittsburgh Medical Center. Histology was rereviewed to confirm diagnosis and identify tissue for MT using next-generation sequencing (ThyroSeq, version 3, TSv3). Correlation with histological and clinical features was analyzed using regression analysis. Results: Of 71 patients with MT results, 62 (87%) patients had papillary TC. All patients were alive at a median follow-up of 6 years (range 18 days to 18 years). Genetic alterations were identified in 65 (92%) patients. These alterations were grouped as BRAF-like point mutations or fusions (39, 55%), RAS-like mutations or fusions (21, 30%), or copy number alterations (5, 7%). On multiple regression analysis accounting for patient sex and tumor size in patients with papillary TC, increased tumor stage (β: 0.234, p < 0.001), multifocal disease (odds ratio [OR]: 3.60, p = 0.042), and lymph node metastases (OR: 6.13, p = 0.044) were associated with BRAF-like gene fusions. When considering individual mutations, ETV6/NTRK3 fusions were associated with increased tumor stage (β: 2.07, p = 0.023) and BRAF-like point mutations were associated with increased likelihood of surgery for recurrence over time (hazard ratio: 19.5, p = 0.004). Conclusions: Among our cohort of pediatric TC patients who underwent comprehensive MT, >90% had an identifiable genetic alteration. Aggressive features were primarily associated with BRAF-like gene fusions. Preoperative MT results may be useful in guiding the extent of the initial operation in pediatric patients (aged <19 years) with TC.

Cutoff Age Between Pediatric and Adult Thyroid Differentiated Cancer: Is 18 Years Old Appropriate?

Background: The characteristics of pediatric differentiated thyroid cancer (DTC) are substantially different from those of adult DTC. This study investigated whether the cutoff age of 18 years, as recommended by the American Thyroid Association (ATA) management guidelines for pediatric DTC, is appropriate based on clinical characteristics and outcomes. Methods: The medical records of 288 patients aged <21 years with DTC, who underwent initial surgery between 1979 and 2014, were retrospectively reviewed. Disease-free survival (DFS) rates and distant metastasis-free survival (DMFS) rates were calculated using the Kaplan-Meier method. As per the International Incidence of Childhood Cancer Report and the ATA management guidelines, cutoff ages of 14 and 18 years were analyzed in this study. Results: The age distributions of the subjects were as follows: 53 patients were aged <15 years (18.4%), 118 patients were aged 15-18 years (41%), and 117 patients were aged 19-20 years (40.6%). The DMFS rates were significantly different between the two cutoff ages. The DMFS was also significantly different between patients aged >15 years and patients aged 15-18 years; however, no significant difference was observed between patients aged 15-18 and 19-20 years. Multivariate analyses showed that clinically apparent lymph node metastasis (cN1) and gross extrathyroidal extension were significant factors related to DFS and DMFS. Although age as a continuous variant was not a significant factor related to either DFS or DMFS, when the cutoff age was set as 14 years rather than 18 years, differences in patient characteristics related to DMFS and DFS stood out. Conclusions: This study found that age was not significantly related to clinical outcome. However, in the younger patient group, more patients had factors that related to DFS and DMFS. Due to the indolent biological behavior of DTC, age at presentation or thyroidectomy does not always represent the age at occurrence, but patients aged <15 years had distinct clinical manifestations. Age <15 years rather than <19 years may therefore be a more suitable cutoff age in pediatric DTC.

Chronic Lymphocytic Thyroiditis and Aggressiveness of Pediatric Differentiated Thyroid Cancer.

Hashimoto's Thyroiditis (HT) is a common cause of hypothyroidism. Among adults with differentiated thyroid cancer (DTC), HT appears to be associated with less severe disease burden. In the absence of information regarding HT and disease burden among children with DTC, we assessed the relationship between pediatric DTC severity and HT. Retrospective cohort. Charts from 90 pediatric patients who underwent surgical removal of DTC from 2002 to 2017 at tertiary-care children's hospital were reviewed. Demographic, clinical, surgical, pathology, and outcome details were compared between patients with and without HT. Consistency among diagnostic modalities of HT was also evaluated. Median age at presentation was 16.0 years (range 4.2-18.9 years). Twenty-two patients were male (24%). Forty-five patients (50%) had HT based on presence of thyroid autoantibodies and/or surgical pathology findings and 45 patients did not have HT. Patients with HT had increased odds of microcalcifications (odds ratio [OR]: 3.01, P=.031) and decreased odds of palpable nodules (OR: 0.212, P=.024) and T2 lesions (vs. T1) (OR: 0.261, P=.015) compared with non-HT. No significant differences in demographics and the incidence of multifocality, extrathyroidal extension, lymphovascular invasion, lymph node or pulmonary metastases, disease recurrence, or radioactive iodine treatment were found between the two groups. Thyroglobulin/thyroid peroxidase autoantibodies and surgical pathology indicative of HT were concordant in 82.4% (κ=0.635, P < .001). HT was present in 50% of children with DTC. Patients with DTC and HT presented with smaller tumors compared to non-HT patients. No significant differences in other markers of disease aggressiveness were found between the two groups. 3 Laryngoscope, 132:1668-1674, 2022.

Differentiated Thyroid Cancer in Children and Adolescents: Long Term Outcome and Risk Factors for Persistent Disease.

Simple SummaryDespite their excellent prognosis, pediatric differentiated thyroid cancers (P-DTC) often undergo aggressive treatment due to the advanced disease presentation. Reliable risk stratification tools to guide management are needed; unfortunately, the current American Thyroid Association (ATA) classification for P-DTC lacks an unequivocal definition of the three risk categories. In line with previous work, our data confirm a favorable long-term outcome in P-DTC including cases with distant metastases. We propose a modified ATA pediatric risk stratification using a cut-off of five lymph nodes as proposed by the 2015 ATA guidelines for adult DTC. The modified pediatric ATA risk class independently predicted short- and long-term outcome. The utility of applying dynamic risk classification was also confirmed as P-DTC with an excellent response seldom experiences relapse. Background: Pediatric differentiated thyroid cancer (P-DTC) frequently presents with advanced disease. The study aim was to evaluate the outcome of P-DTC and a modified 2015 American Thyroid Association risk classification (ATA-R). Methods: A retrospective study of consecutive P-DTC patients was performed. The ATA-R for P-DTC was used with a cut-off of ≤ 5 N1a for low-risk. The outcome could be excellent response (ER) (thyroglobulin < 1 ng/mL and no evidence of disease (EoD) at imaging), biochemical incomplete response (BIR) (thyroglobulin ≥ 1 ng/mL and no EoD at imaging) or structural incomplete response (SIR) (EoD at imaging). Results: We studied 260 P-DTC (70% females; median age at diagnosis 14 years; 93% total thyroidectomy and 82% lymph node dissection). The ATA-R was low in 30% cases, intermediate in 15% and high in 55%, including 31.5% with distant metastases. Radioiodine treatment was administered in 218 (83.8%), and further radioiodine and surgery was performed in 113 (52%) and 76 (29%) patients, respectively. After a median follow-up of 8.2 years, the outcome was ER in 193 (74.3%), BIR in 17 (6.5%) and SIR in 50 (19.2%). Independent predictors of SIR or BIR at first and last visits were ATA-R intermediate or high. Conclusion: P-DTC has an excellent prognosis. Modified ATA-R is a useful prognostic tool in P-DTC to guide management.

Incidence of Recurrent Differentiated Thyroid Carcinoma in Paediatrics and Adolescents after Thyroid Surgery: A Meta-Analysis Study of Last 20 Years

Abstract Background: Childhood onset differentiated thyroid cancer is distinct from the adult-onset disease being more aggressive at the time of initial evaluation with a higher risk category for disease recurrence; however, it is ultimately less lethal. Unfortunately, there is no consensus regarding the means of follow-up, timing and management strategy regarding pediatric differentiated thyroid cancer. For these reasons, unique man-agement for children and adolescents with thyroid tumors are needed. Aim of Study: To locate relevant studies comparing incidence of recurrent differentiated thyroid carcinoma in paediatrics and adolescents after thyroid surgery modalities most commonly used in childhood onset differentiated thyroid cancer that are published in the period from June 1999 to June 2019, revising all these studies, and designing meta-analysis study to assess the overall results and define which management may provide better outcome and fewer rate of complications. Patients and Methods: The search strategy above will be viewed,and articles that appear to fulfil the inclusion criteria will be retrieved in full. Each article identified will be reviewed and categorized into one of the following groups: Included or excluded. When there will be a doubt, a second reviewer will assess the article and a consensus will be reached. Results: Medline databases (PubMed, Medscape, Science Direct. EMF-Portal) and all materials available in the Internet till 2019. Conclusion: All children will require life-long surveillance after thyroid surgery, especially for thyroid cancer. Paediatric thyroid cancer is rare. (The incidence of differentiated thyroid cancer is 1 per 1,000,000 in children less than 10 years of age). It is a treatable disease with an excellent prognosis. Treatment with radioactive iodine is recommended for most children after total thyroidectomy for papillary and follicular cancer. Radioiodine ablation should be carried about 4 weeks after surgery, with a diagnostic scan 6 months later. Regular review should include neck palpation, serum thyroglobulin, and ultrasound with cytology if necessary. In case of a cancer, follow-up ultrasound and TSH-suppressed thyroglobulin (Tg) level assessment is performed 6 months after initial therapy and at least annually thereafter, although it may be preferable to observe patients every 6 months for at least 5 years after diagnosis of more advanced initial or metastatic cancer. Assessment of free T4, T3, and TSH levels is indicated every 6 months, and 1-2 months after dosage changes. Calcitonin is a marker of recurrent disease in medullary cancer. This suggests that an aggressive operative approach to lymph node resection may be safer (lower recurrence, lower complications) in experienced hands than a less complete resection in a lower volume center.

A Search for Causes of Rising Incidence of Differentiated Thyroid Cancer in Children and Adolescents after Chernobyl and Fukushima: Comparison of the Clinical Features and Their Relevance for Treatment and Prognosis

The incidence of differentiated thyroid cancer (DTC) is steadily increasing globally. Epidemiologists usually explain this global upsurge as the result of new diagnostic modalities, screening and overdiagnosis as well as results of lifestyle changes including obesity and comorbidity. However, there is evidence that there is a real increase of DTC incidence worldwide in all age groups. Here, we review studies on pediatric DTC after nuclear accidents in Belarus after Chernobyl and Japan after Fukushima as compared to cohorts without radiation exposure of those two countries. According to the Chernobyl data, radiation-induced DTC may be characterized by a lag time of 4–5 years until detection, a higher incidence in boys, in children of youngest age, extrathyroidal extension and distant metastases. Radiation doses to the thyroid were considerably lower by appr. two orders of magnitude in children and adolescents exposed to Fukushima as compared to Chernobyl. In DTC patients detected after Fukushima by population-based screening, most of those characteristics were not reported, which can be taken as proof against the hypothesis, that radiation is the (main) cause of those tumors. However, roughly 80% of the Fukushima cases presented with tumor stages higher than microcarcinomas pT1a and 80% with lymph node metastases pN1. Mortality rates in pediatric DTC patients are generally very low, even at higher tumor stages. However, those cases considered to be clinically relevant should be followed-up carefully after treatment because of the risk of recurrencies which is expected to be not negligible. Considering that thyroid doses from the Fukushima accident were quite small, it makes sense to assess the role of other environmental and lifestyle-related factors in thyroid carcinogenesis. Well-designed studies with assessment of radiation doses from medical procedures and exposure to confounders/modifiers from the environment as e.g., nitrate are required to quantify their combined effect on thyroid cancer risk.

Factors Influencing Cervical Lymph Node Metastasis in Pediatric Differentiated Thyroid Cancers.

Lymph node metastasis is a considerable variable influencing postoperative American Thyroid Association (ATA) risk stratification in pediatric differentiated thyroid cancer (DTC). The primary aim of this study was to ascertain the factors predicting nodal metastasis and describe the outcomes in relation to the ATA risk. Patients 18years or younger operated between December 2005 and December 2019 were analyzed. Demographic, clinicopathological, treatment, and outcome data were recorded. Factors associated with nodal metastasis were assessed by univariate and multivariate regression analysis. Patients were stratified into low-, intermediate-, and high-risk as per the pediatric ATA guidelines. A total of 86 patients (43% male; median [IQR] age, 12 (10-14) years) underwent surgery during the study period. Lymph node metastases were present in 70 (82.4%) patients involving the lateral (8%) and central compartment (4.7%) alone and both (88.6%) compartments. Extrathyroid extension (ETE) was present in 65%; 35%, minimal; and 30%, extensive. On univariate analysis, nodal metastasis was more frequent in male patients, multifocal tumor, lymphovascular invasion, and ETE. On multivariate analysis, only ETE was predictive of nodal disease with an odds ratio of 8. Minimal and extensive ETEs were both significantly associated with lymph node metastases when compared to the absence of ETE. The 5-year disease-free survival was 100%, 95.7%, and 66% in the low-, intermediate-, and high-risk groups respectively (p < 0.0001). Pediatric DTCs have an exceptionally high incidence of lymph node metastasis. ETE is the single most important predictor of nodal disease. The ATA pediatric risk stratification is useful in predicting clinical outcomes.

Surgical treatment for pediatric differentiated thyroid cancer

Surgical treatment for pediatric differentiated thyroid cancer

Distant Metastasis in Pediatric and Adolescent Differentiated Thyroid Cancer: Clinical Outcomes and Risk Factor Analyses

The specific characteristics of pediatric and adolescent differentiated thyroid cancer (DTC) is the more frequent occurrence of distant metastasis (DM) compared with adult DTC. To investigate the clinical outcomes of DM in this population and analyze risk factors related to DM. Medical records of 171 patients with DTC < 19 years old, who underwent initial surgery between 1979 and 2014 were retrospectively reviewed. Clinical responses to radioiodine (RAI) therapy evaluated by the American Thyroid Association (ATA) guidelines for adult DTC and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Risk factors related to distant-metastasis-free survival (DMFS). DM was observed in 29 patients, and all were lung metastases. The pattern of lung metastasis was classified into 3 categories: macronodular, micronodular, and no apparent nodule (detected only by RAI scintigraphy). Patients with excellent responses according to the ATA guideline criteria or complete remission of the RECIST criteria were most frequently observed in those with no apparent nodule. Significant factors related to DMFS were sex, clinical lymph node metastasis (LNM), extrathyroidal extension, and number of LNM. Subjects were divided into 3 groups according to the number of risk factors: low risk (no risk factors); intermediate risk (1 risk factor); and high risk (≥2 risk factors). Twenty-year DMFS rates in the low-, intermediate-, and high-risk groups were 99.0%, 71.7%, and 28.6%, respectively. To achieve the full efficacy of RAI therapy, early diagnosis of DM before apparent metastases appear is desirable. The selective approach would be preferable for pediatric and adolescent DTC.

Breast Cancer After Treatment of Differentiated Thyroid Cancer With Radioiodine in Young Females: What We Know and How to Investigate Open Questions. Review of the Literature and Results of a Multi-Registry Survey.

Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case–control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial “misdiagnosis.”

Genetic Alterations in Pediatric Thyroid Cancer Using a Comprehensive Childhood Cancer Gene Panel.

Pediatric differentiated thyroid cancer (DTC) differs from adult DTC in its underlying genetics and clinicopathological features. In this report, we studied these aspects in 48 cases of pediatric DTC. We used the comprehensive Oncomine Childhood Cancer Gene panel on Ion Torrent next-generation sequencing platform. We included 48 patients (37 girls and 11 boys) with pediatric DTC (median age 17 years; range, 5-18 years) and studied the association between these genetic alterations and the clinicopathological features and outcome. Of 48 tumors, 33 (69%) had somatic genetic alterations that were mutually exclusive except in one tumor. BRAFV600E and RET-PTC1 were the most common, occurring in 9 different tumors (19%) each. RET-PTC3 and ETV6-NTRK3 were the next most common, with each occurring in 4 different tumors (8%). Other genetic alterations including EML4-NTRK1, EML4-ALK, NRAS, KRAS, PTEN, and CREBBP occurred once each. There were no differences between those who had mutations and those without mutations with respect to age, sex, tumor multifocality, extrathyroidal extension, vascular invasion, lymph node or distant metastasis, and American Thyroid Association response to therapy status at the last follow-up visits. Similarly, none of these factors was different between those with fusion genes vs single-point mutations vs no mutations. In pediatric DTC, fusion genes are more common than single-point mutations. The most common genetic alterations are RET-PTC1, BRAFV600E, RET-PTC3, and ETV6-NTRK3. Other alterations occur rarely. Genetic alterations do not correlate with the clinicopathological features or the outcome.

Risk of structural persistent disease in pediatric patients with low or intermediate risk differentiated thyroid cancer.

In pediatric patients with differentiated thyroid cancer (DTC), the risk of recurrence is high and the indication for postoperative 131I administration is still debated. The aim of this study was to assess the outcome in low and intermediate risk pediatric DTC patients. We retrospectively evaluated 45 pediatric patients with low or intermediate risk DTC, treated with surgery and 131I between 1992 and 2002 and with no detectable antithyroglobulin (Tg) antibodies. Follow-up was performed every 6-12 months with Tg blood level determination and imaging procedures. During follow-up (64 ± 53 months), 15 events occurred (33% cumulative event rate, with an annual event rate of 5% person years). Five of these patients were submitted to additional surgery and all these 15 patients underwent a second 131I treatment course. All patients were alive at the end of the follow-up. Structural persistent disease occurred more frequently in patients at intermediate risk (p < 0.01) and in those with Tg values after thyroid hormone withdrawal >10 ng/ml before 131I therapy (p < 0.01). At multivariate analysis, only a postoperative thyroid stimulating hormone-stimulated Tg level >10 ng/ml was an independent predictor of persistent disease. In pediatric patients with DTC, postoperative high stimulated Tg values (>10 ng/ml) should be taken into account for deciding the extent of both initial treatment and follow-up.