Adult Papillary Thyroid Carcinoma Research Articles

8576 Genomic and Transcriptomic Characterization of Pediatric Thyroid Cancers

Abstract Disclosure: J.C. Ricarte-Filho: None. E.R. Reichenberger: None. K. Hinkle: None. A.R. Isaza: None. A.J. Bauer: None. A.T. Franco: None. Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in both pediatric and adult populations. Recent genomic profiling of papillary thyroid cancers, including that of the Cancer Genome Atlas, has uncovered the genetic alterations and molecular mechanisms driving thyroid cancer. However, these studies were primarily focused on adult patients. Despite their favorable prognosis, pediatric PTCs have higher rates of metastasis and recurrence than adult PTCs, but the molecular characterization of these tumors have been comparatively lacking. Methods: Here we explore the genomic and transcriptomic landscape of pediatric PTCs from 126 patients, including 107 primary tumors and 19 lymph node metastases (non-paired) using whole-exome sequencing and RNA sequencing. Thirteen primary tumors also had a paired lymph node metastasis analyzed. Results: We found driver alterations in 113 of 126 (90%) of the PTCs investigated, including the identification of a novel receptor tyrosine kinase (RTK) fusion not previously reported in thyroid cancer. Genetic drivers were predominantly kinase fusions (48%), most commonly fusions of RET (22%), NTRK3 (10%), ALK (5%) and NTRK1 (5%). The most common point mutations were BRAF p.V600E (21%), NRAS p.Q61R/K (9%) and hotspot mutations in DICER1 (4%). We found genetic alterations in 12 of the 13 paired lymph node metastasis. In all 12 cases the metastatic tissue harbored the same alterations found in the primary tumor. Eight out of 12 cases had fusions (3 RET, 3 NTRK3 and 2 NTRK1), and the additional 4 cases had point mutations (3 BRAFV600E and 1 TSHRM543T). Fourteen patients (11%) had widely invasive disease with lateral lymph node and distant metastases (N1bM1). Most of these N1bM1 tumors (13/14; 93%) were driven by RTK fusions (5 NTRK3, 3 RET, 3 NTRK1 and 2 ALK). The one case lacking a kinase fusion had a CHEK2 mutation. Conclusion: Our genomic and transcriptomic analysis allowed the detection of driver alterations in ∼90% of the cases, reducing the so-called “dark matter” in our cohort. Our data support that kinase fusions are associated with metastatic disease in pediatric PTC. Patients with RET/NTRK/ALK fusions have worse outcomes than those with BRAF p.V600E mutation and RAS-like alterations (NRAS, DICER1, non-V600 BRAF, PTEN). By using the transcriptional profiling generated in this study, we are currently investigating the molecular mechanisms underlying the metastatic behavior of pediatric PTCs harboring oncogenic fusions, including changes in MAPK transcriptional output, differentiation score and recruitment of signaling pathways potentially associated with the metastatic behavior of these tumors. Presentation: 6/3/2024

More aggressive biological behavior in pediatric than in adult papillary thyroid carcinoma

ObjectivePapillary thyroid carcinoma (PTC) remains a common malignancy of the endocrine system in children and adolescents. This study aimed to investigate the differences in clinical characteristics between children and adults with PTC. MethodsA total of 360 patients [ 308 adults (≥20 years) and 52 children and adolescents (<20 years)] with PTC who underwent thyroid surgery in our center from 2017 to 2022 were retrospectively analyzed. Statistical analysis and comparisons of the clinicopathological data and tumor characteristics between children and adults were performed. ResultsAmong all enrolled patients, the mean tumor diameter was 26.21 ± 12.72 mm in the pediatric group, while that in the adult group was 11.62 ± 10.21 mm, which was a significant difference (p < 0.001). Pediatric patients were more prone to central lymph node metastasis (90.38% vs. 49.35%, p<0.001), lateral lymph node metastasis (78.85% vs. 45.7%, p<0.001), capsular invasion (90.38% vs. 63.96%, p<0.001) and extrathyroidal extension (61.54% vs. 15.26%, p＜0.001) than adult patients. However, the pediatric group had a lower BRAFV600E mutation rate (54.76% vs. 87.7%, p < 0.001) and lower incidence of Hashimoto's thyroiditis (15.38% vs. 30.84%, p = 0.023) than the adult group. There were no significant differences in clinicopathological factors, such as sex, multifocality and hypothyroidism. ConclusionsPediatric patients were more likely to present with advanced disease at diagnosis, including larger tumor volume, more lymph node metastasis, more extensive local invasion, and lower rates of BRAF mutation and concomitant Hashimoto's thyroiditis. Therefore, appropriate surgical management and comprehensive treatment decisions are needed for pediatric patients with PTC.

Nomogram for predicting central lymph node metastasis in T1-T2 papillary thyroid cancer with no lateral lymph node metastasis.

Whether routine central lymph node dissection (CLND) is necessary for T1-T2 papillary thyroid carcinoma (PTC) patients without certain lateral lymph node metastases (LLNM) remains controversial. This study aims to construct a nomogram that predicts central lymph node metastasis (CLNM) for T1-T2 PTC patients without LLNM. We retrospectively reviewed adult T1-T2 PTC patients with no LLNM retrieved from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. We also collected data from patients treated at the First Hospital of China Medical University between February and April 2021 for external validation. Logistic regression model was used to construct a risk prediction model nomogram. The receiver-operating characteristic (ROC) curve, calibration plot, and decision curve analyses (DCA) were used for assessing the nomogram. 5,094 patients from the SEER database and 300 patients from our department were finally included in this study. Variables such as age, gender, race, tumor size, multifocality, and minimal extrathyroidal extension (mETE) were found to be associated with CLNM and were subsequently incorporated into our nomogram. The C-index of our constructed model was 0.704, while the internal and external validation C-indexes were 0.693 and 0.745, respectively. The nomogram was then evaluated using calibration and decision curve analyses. A visualized nomogram was successfully developed to predict CLNM in T1-T2 PTC patients without LLNM and assist clinicians in making personalized clinical decisions.

PAPILLARY THYROID CARCINOMA IN PEDIATRIC PATIENT- A CASE REPORT

Thyroid carcinoma is the most common endocrine malignant diseases, accounting for 06% of all pediatrics cancer. Papillar y thyroid carcinoma which accounts f or approximately 90% of pediatric thyroid cancer. However, pediatric papillary thyroid carcinoma is still a rare disease. Due to lack of clinical trials, treatment options remain controversial. Pediatric thyroid cancers typically present as neck masses with no associated symptoms and thus come to medical attention at widely varying stages of disease progression. In contrast to adult papillary thyroid carcinoma, pediatric papillary thyroid carcinoma tends to be more aggressive at presentation with higher incidence of multifocality, lymph node metastases and extracapsular extension

Radioiodine remnant ablation in stage I adult papillary thyroid carcinoma: does it improve postoperative outcome?

ObjectiveTo determine whether radioiodine remnant ablation (RRA) reduces cause-specific mortality (CSM) or tumor recurrence rates (TRR) after potentially curative bilateral thyroidectomy (BT) in low-risk adult papillary thyroid carcinoma (APTC) patients, we compared postoperative outcomes in 1836 pTNM stage I APTC patients having BT alone with 832 having BT+RRA during two consecutive 25-year periods.MethodsThe THEN cohort (consecutively managed during 1966–1990) comprised 809 patients (36% having BT+RRA) and the NOW cohort (1991–2015) comprised 1859 patients (29% BT+RRA). Analyses of differences in occurrence rates between BT alone and BT+RRA patients were performed with SAS software.ResultsDuring 1966–1990, when RRA rates rose ten-fold, 20-year CSM after BT alone was 0.6% and after BT+RRA was 1.2% (P = 0.66); during 1991–2015, when RRA rates progressively fell, no PTC deaths occurred in 1859 patients. In the THEN cohort, RRA did not significantly improve TRR at local, regional, or distant sites (P > 0.1), when compared to BT alone. RRA in NOW cohort was administered to 49% of node-positive (pN1) patients and 17% of node-negative (pN0/NX) patients (P < 0.0001); TRR therefore, were examined separately for pN0/NX and pN1 patients. In 1157 pN0/NX cases, 20-year locoregional TRR were 3.1% after BT and were higher (P = 0.049) at 8.6% after BT+RRA. In four pN1 groups, stratified by metastatic nodal burden, RRA did not significantly reduce the locoregional TRR observed after BT with curative intent (P > 0.5).ConclusionsIn a 5-decade experience, RRA administered postoperatively to stage I APTC patients did not reduce either CSM or TRR and should probably not be indicated when such patients undergo potentially curative BT.

Trends in the Management of Localized Papillary Thyroid Carcinoma in the United States (2000-2018).

Background: In response to evidence of overdiagnosis and overtreatment of papillary thyroid carcinoma (PTC), the 2009 and 2015 American Thyroid Association (ATA) adult guidelines recommended less extensive surgery (lobectomy vs. total thyroidectomy) and more restricted use of postsurgical radioactive iodine (RAI) in management of PTC at low risk of recurrence. In 2015, active surveillance was suggested as a viable option for some <1-cm PTCs, or microcarcinomas. The 2015 ATA pediatric guidelines similarly shifted toward more restricted use of RAI for low-risk PTCs. The impact of these recommendations on low-risk adult and pediatric PTC management remains unclear, particularly after 2015. Methods: Using data from 18 Surveillance, Epidemiology, and End Results (SEER) U.S. registries (2000-2018), we described time trends in reported first-course treatment (total thyroidectomy alone, total thyroidectomy+RAI, lobectomy, no surgery, and other/unknown) for 105,483 patients diagnosed with first primary localized PTC (without nodal/distant metastases), overall and by demographic and tumor characteristics. Results: The declining use of RAI represented the most pronounced change in management of PTCs <4 cm (44-18% during the period 2006-2018), including microcarcinomas (26-6% during the period 2007-2018). In parallel, an increasing proportion of PTCs were managed with total thyroidectomy alone (35-54% during the period 2000-2018), while more subtle changes were observed for lobectomy (declining from 23% to 17% during the period 2000-2006, stabilizing, and then rising from 17% to 24% during the period 2015-2018). Use of nonsurgical management did not meaningfully change over time, impacting <1% of microcarcinomas annually during the period 2000-2018. Similar treatment trends were observed by sex, age, race/ethnicity, metropolitan vs. nonmetropolitan residence, and insurance status. For pediatric patients (<20 years), use of RAI peaked in 2009 (59%), then decreased markedly to 11% (2018), while use of total thyroidectomy alone and, to a lesser extent, lobectomy increased. No changing treatment trends were observed for ≥4-cm PTCs. Conclusions: The declining use of RAI in management of low-risk adult and pediatric PTC is consistent with changing recommendations from the ATA practice guidelines. Post-2015 trends in use of lobectomy and nonsurgical management of low-risk PTCs, particularly microcarcinomas, were more subtle than expected; however, these trends may change as evidence regarding their safety continues to emerge.

Risk Factors for Central Lymph Node Metastases and Benefit of Prophylactic Central Lymph Node Dissection in Middle Eastern Patients With cN0 Papillary Thyroid Carcinoma.

BackgroundProphylactic central lymph node dissection (PCLND) for adult patients with papillary thyroid carcinoma (PTC) is still a matter of debate. Data on incidence, risk and benefits of PCLND in Middle Eastern patients is lacking. Therefore, we aimed to identify the incidence and predictive clinico-pathological and molecular marker of PCLND in adult patients with clinically node negative (cN0) Middle Eastern PTC.MethodsThis retrospective study included 942 adult Middle Eastern patients with cN0 PTC who underwent total thyroidectomy (TT) or TT+PCLND. Clinico-pathological associations of central lymph node metastasis (CLNM) were assessed. Multivariate analysis was performed using logistic regression and Cox proportional hazards model.Results213 patients underwent PCLND and 38.0% (81/213) had positive CLNM. Multivariate analysis demonstrated age ≤55 years (Odds Ratio (OR) = 7.38; 95% Confidence Interval (CI) = 1.59 – 34.31; p = 0.0108), tumor bilaterality (OR = 3.01; 95% CI = 1.01 – 9.21; p = 0.0483), lymphovascular invasion (OR = 2.92; 95% CI = 1.18 – 7.23; p = 0.0206) and BRAF mutation (OR = 3.24; 95% CI = 1.41 – 7.49; p = 0.0058) were independent predictors of CLNM in adult PTC. Furthermore, patients who underwent PCLND showed significant association with improved recurrence-free survival (RFS; p = 0.0379). Multivariate analysis demonstrated that PCLND was an independent predictor of improved recurrence-free survival.ConclusionscN0 Middle Eastern PTC patients treated with PCLND showed a significantly better prognosis. PCLND was effective in improving RFS in Middle Eastern PTC patients and should be encouraged for patients with potential risk factors for CLNM.

Does macroscopic extrathyroidal extension to the strap muscles alone affect survival in papillary thyroid carcinoma?

BackgroundMacroscopic extrathyroidal extension to structures adjacent to the thyroid gland is one of the most important predictors of survival in papillary thyroid carcinoma. However, the prognostic significance of macroscopic extrathyroidal extension to strap muscles alone is unknown. The aim of this study is to determine the impact on survival in patients with macroscopic extrathyroidal extension to strap muscles alone compared to those with no macroscopic extrathyroidal extension and macroscopic extrathyroidal extension involving other adjacent structures. MethodsAfter institutional review board approval, adult papillary thyroid carcinoma patients were identified from an institutional database of 6,259 patients undergoing initial surgery for well-differentiated thyroid carcinoma from 1986 to 2015. Patients were classified as having no macroscopic extrathyroidal extension, macroscopic extrathyroidal extension to strap muscles alone, or macroscopic extrathyroidal extension to other adjacent structures. Disease-specific survival was calculated using the Kaplan-Meier method and groups were compared using the log-rank test. A P value < .05 was considered statistically significant and significant factors were used in a Cox proportional hazard model to predict disease-specific survival. ResultsThere were 5,880 patients included in the analysis; 5,485 patients (93.3%) in the no macroscopic extrathyroidal extension group, 179 (3.0%) in the macroscopic extrathyroidal extension to strap muscles alone group and 216 (3.7%) in the macroscopic extrathyroidal extension involving other adjacent structures group. With a median follow-up of 64 months, the estimated 10-year disease-specific survival for patients with no macroscopic extrathyroidal extension, macroscopic extrathyroidal extension to strap muscles alone, and macroscopic extrathyroidal extension involving other adjacent structures were 98.9%, 95.7%, and 83.7%, respectively (P < .0001). In the ≥55-year-old cohort, the estimated 10-year disease-specific survival for patients with no macroscopic extrathyroidal extension, macroscopic extrathyroidal extension to strap muscles alone, and macroscopic extrathyroidal extension involving other adjacent structures were 97.6%, 89.3%, and 68.1%, respectively (P <.0001). After controlling for pathological nodal stage and distant metastasis stage, extent of extrathyroidal extension remained an independent predictor of disease-specific survival; patients with macroscopic extrathyroidal extension to strap muscles alone had a 3.3-fold increased likelihood of a disease-specific death compared to no macroscopic extrathyroidal extension patients (hazard ratio 3.294; 95% confidence interval 1.076–10.086, P < .0368). ConclusionIn our study, patients aged ≥55 years with papillary thyroid carcinoma and macroscopic extrathyroidal extension to strap muscles alone appear to have an increased likelihood of a disease-specific death compared to patients with no macroscopic extrathyroidal extension.

Diverse Oncogenic Fusions and Distinct Gene Expression Patterns Define the Genomic Landscape of Pediatric Papillary Thyroid Carcinoma.

Pediatric papillary thyroid carcinoma (PPTC) is clinically distinct from adult-onset disease. Although there are higher rates of metastasis and recurrence in PPTC, prognosis remains highly favorable. Molecular characterization of PPTC has been lacking. Historically, only 40% to 50% of childhood papillary thyroid carcinoma (PTC) were known to be driven by genomic variants common to adult PTC; oncogenic drivers in the remainder were unknown. This contrasts with approximately 90% of adult PTC driven by a discrete number of variants. In this study, 52 PPTCs underwent candidate gene testing, followed in a subset by whole-exome and transcriptome sequencing. Within these samples, candidate gene testing identified variants in 31 (60%) tumors, while exome and transcriptome sequencing identified oncogenic variants in 19 of 21 (90%) remaining tumors. The latter were enriched for oncogenic fusions, with 11 nonrecurrent fusion transcripts, including two previously undescribed fusions, STRN-RET and TG-PBF. Most fusions were associated with 3' receptor tyrosine kinase (RTK) moieties: RET, MET, ALK, and NTRK3. For advanced (distally metastatic) tumors, a driver variant was described in 91%. Gene expression analysis defined three clusters that demonstrated distinct expression of genes involved in thyroid differentiation and MAPK signaling. Among RET-CCDC6-driven tumors, gene expression in pediatric tumors was distinguishable from that in adults. Collectively, these results show that the genomic landscape of pediatric PTC is different from adult PTC. Moreover, they identify genomic drivers in 98% of PPTCs, predominantly oncogenic fusion transcripts involving RTKs, with a pronounced impact on gene expression. Notably, most advanced tumors were driven by a variant for which targeted systemic therapy exists. SIGNIFICANCE: This study highlights important distinctions between the genomes and transcriptomes of pediatric and adult papillary thyroid carcinoma, with implications for understanding the biology, diagnosis, and treatment of advanced disease in children.

Clinical and Molecular Characterizations of Papillary Thyroid Cancer in Children and Young Adults: A Multicenter Retrospective Study.

Background: Papillary thyroid carcinoma (PTC) is a rare malignancy in children and young adults (CAYA). It often presents with aggressive disease patterns and advanced stages, which are clinically distinct from those in adult patients. In this study, we sought to characterize and better understand the clinical variants of PTC in CAYA and explore the underlying mechanisms. Methods: CAYA patients (age ≤18 years) diagnosed with PTC between June 2006 and June 2018 were retrospectively recruited from five hospitals. Demographic information, pathological data, and follow-up status were recorded. Tumor samples obtained from 20 children (mean age 15.15 years) and 10 adults (mean age 38.80 years) underwent comprehensive whole transcriptome sequencing. Differentially expressed genes (DEGs), mutational landscape, and immune infiltration were analyzed. Results: A total of 217 CAYA-PTC patients (162 females and 55 males) with an average age of 14.38 ± 3.53 years (range 2-18) were included. Lymph node metastasis (LNM) was observed in 85.71%, of which 57.60% were in the lateral cervical compartment. Disease recurred in 28 of 217 (12.90%) patients with a median follow-up of 4.76 years. Multivariate logistic regression analysis revealed that age, bilateral disease, extrathyroidal extension, and coexisting Hashimoto's thyroiditis (co-HT) were independent risk factors for LNM, while co-HT was the only risk factor for recurrence. Using whole transcriptome sequencing of PTC tissues, we identified 301 DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that differences in immune mediators played important roles, based on the distributions of mutation frequencies, types, and expression levels between CAYA and adult patients. Based on the integrated data sets, we identified significantly mutated immune genes, cluster of differentiation 24 (CD24), coagulation factor 12 (F12), coagulation factor 5 (F5), integrin subunit alpha 3 (ITGA3), and retinoic acid early transcript 1L (RAET1L), which were then verified by immunohistochemistry. Furthermore, resting mast cells, resting natural killer cells, plasma cells, and regulatory T cells were different in the CAYA-PTC group and correlated with the expression of immune checkpoints. Conclusions: There are considerable variabilities that may contribute to the different clinical presentations between CAYA and adult PTC patients, among which the decrease in protective immune cells may be a factor. Collectively, our results add to the possible biological mechanisms involved in CAYA-PTC.

Molecular pathogenesis of pediatric thyroid carcinoma.

ABSTRACTThere has been little understanding of the molecular pathogenesis of pediatric thyroid cancers. Most of them are histologically classified as papillary thyroid carcinoma (PTC). Ionizing radiation is the most important environmental factor to induce PTC, especially in children. Particularly, radiation-related pediatric PTCs after the Chernobyl accident provided invaluable information. In addition, the recent accumulation of sporadic pediatric PTC cases, partly due to advances in diagnostic imaging, has also provided insight into their general pathogenesis. In PTC development, basically two types of genetic alterations, fusion oncogenes, mainly RET/PTC, and a point mutation, mainly BRAFV600E, are thought to play a key role as driver oncogenes. Their frequencies vary depending on patient age. The younger the age, the more prevalent the fusion oncogenes are. Higher incidence of fusion oncogenes was also observed in cases exposed to radiation. In short, fusion oncogenes are associated with both age and radiation and are not evidence of radiation exposure. The type of driver oncogene is shifted toward BRAFV600E during adolescence in sporadic PTCs. However, until about this age, fusion oncogenes seem to still confer dominant growth advantages, which may lead to the higher discovery rate of the fusion oncogenes. It has been postulated that RET/PTC in radiation-induced PTC is generated by ionizing radiation; however, there is an interesting hypothesis that thyroid follicular cell clones with pre-existing RET/PTC were already present, and radiation may play a role as a promoter/progressor but not initiator. Telomerase reverse transcriptase gene (TERT) promoter mutations, which are the strongest marker of tumor aggressiveness in adult PTC cases, have not been detected in pediatric cases; however, TERT expression without the mutations may play a role in tumor aggressiveness. In this paper, the recent information regarding molecular findings in sporadic and radiation-associated pediatric PTCs is summarized.

Noncoding RNAs in Papillary Thyroid Cancer: Interaction with Cancer-Associated Fibroblasts (CAFs) in the Tumor Microenvironment (TME) and Regulators of Differentiation and Lymph Node Metastasis.

A large majority of all thyroid cancers are papillary thyroid carcinomas (PTC), named for the specific papillary architecture observed histologically. Despite the high rate of success with modern diagnostic and therapeutic algorithms, there are significant areas where the management of PTC can be improved. Aggressive PTC subtypes that are refractory to radioactive iodine (RAI) therapy carry a more severe prognosis and account for most of PTC-related deaths. As lymph node metastasis is present in roughly 40% of all adult PTC cases, higher specificity in these tests is a clinical need, especially since lymph node metastases are associated with reduced survival and higher recurrence rates. Additionally, this cancer can progress to more dedifferentiated and aggressive variants, such as poorly differentiated papillary thyroid cancer (PDPTC) and anaplastic thyroid cancer (ATC). Therefore, development of more sensitive and specific detection methods that allow unnecessary surgeries to be avoided is of the utmost importance. The body of large-scale, unbiased gene expression analysis in PTC has focused on the coding transcriptome, specifically mRNAs and microRNAs. However, there have been implications for the potential use of long noncoding RNAs (lncRNAs) in PTC diagnosis, prognosis, and treatment via the utilization of genome-wide studies of patient samples. lncRNAs have diverse regulatory potential in gene expression, alternative splicing, posttranscriptional mRNA modification, and epigenomic alterations. Many lncRNAs have tissue-specific expression and are demonstrated to play key roles in cancer progression and prognosis. However, lncRNAs are not being exploited as biomarkers or therapeutic targets currently, despite their elucidated effects on oncogenesis. These potent biomarkers would be revolutionary in detection at early stages, as this significantly increases the chances of survival. Their aberrant expression in cancer and correlation with steps in tumorigenesis as well as their role in differentiation would allow for a promising role as a prognostic and diagnostic biomarker in thyroid cancer. This would help prevent the more aggressive ATC that derives from dedifferentiation of the less aggressive PTC and FTC. The targeting of the specific lncRNAs could also pose a valuable treatment option via preventing or reversing this dedifferentiation process and making this usually refractory form of thyroid cancer more responsive to standard treatment options.

Genetic Landscape of Papillary Thyroid Carcinoma and Nuclear Architecture: An Overview Comparing Pediatric and Adult Populations.

Simple SummaryPapillary thyroid carcinoma (PTC) represents 80–90% of all differentiated thyroid carcinomas. PTC has a high rate of gene fusions and mutations, which can influence clinical and biological behavior in both children and adults. In this review, we focus on the comparison between pediatric and adult PTC, highlighting genetic alterations, telomere-related genomic instability and changes in nuclear organization as novel biomarkers for thyroid cancers.Thyroid cancer is a rare malignancy in the pediatric population that is highly associated with disease aggressiveness and advanced disease stages when compared to adult population. The biological and molecular features underlying pediatric and adult thyroid cancer pathogenesis could be responsible for differences in the clinical presentation and prognosis. Despite this, the clinical assessment and treatments used in pediatric thyroid cancer are the same as those implemented for adults and specific personalized target treatments are not used in clinical practice. In this review, we focus on papillary thyroid carcinoma (PTC), which represents 80–90% of all differentiated thyroid carcinomas. PTC has a high rate of gene fusions and mutations, which can influence the histologic subtypes in both children and adults. This review also highlights telomere-related genomic instability and changes in nuclear organization as novel biomarkers for thyroid cancers.

BRAF V600E and TERT promoter mutations in paediatric and young adult papillary thyroid cancer and clinicopathological correlation.

Objectives The primary objective of this study was to determine the prevalence of BRAF V600E and TERTpromoter mutations in paediatric and young adult patients with papillary thyroid carcinoma (PTC) and the secondary objective, to assess their association with clinicopathological features. Methods Patients≤20 years who underwent surgery for differentiated thyroid cancer (DTC) from 2005 to 2018 were consecutively enrolled for BRAF V600E and TERTpromoter mutations analysis and records analysed for the association of aggressive features. Univariate analysis and multivariate logistic regression were used to identify the independent predictors of BRAF V600E mutations. Results Among 100 patients with DTC, 68 patients were≤18 years and the remaining 30 patients were >18 years of age with a median age of 17 years (IQR 14-19 years) 98 patients had PTC and 2 had FTC. BRAF V600E mutation was present in 14/98 (14.3%) PTC and TERTpromoter mutation noted in none. Multivariate analysis identified RAI refractoriness (OR:10.57, 95% CI: 2.6 to 41.6, P-0.0008) as an independent factor associated with BRAF V600E mutation. 17 patients with distant metastases were negative forboth BRAF V600E or TERTpromoter mutation. No significant association was observed between age, gender, PTC variants, extra-thyroidal extension, lymphovascular invasion, multifocality, RAI administration and event rate with BRAF V600E mutation. Irrespective of BRAF V600E mutation, radioiodine refractory status (p-0.0001) had a reduced EFS probability. Conclusion In paediatric & young adult PTC, TERTpromoter mutation is absent and BRAFV600E mutation is not associated with distant metastasis. The prevalence rate of the BRAF V600E mutation is much lower compared to adult PTC patients.

Is a Prophylactic Central Compartment Neck Dissection Required in Papillary Thyroid Carcinoma Patients with Clinically Involved Lateral Compartment Lymph Nodes?

The 2015 American Thyroid Association guidelines state that a prophylactic central compartment neck dissection (PCND) should be considered for patients with papillary thyroid carcinoma (PTC) and clinically involved lateral neck lymph nodes (cN1b). The purpose of our study was to determine the rate of central neck recurrence in select cN1b patients, with no evidence of clinically involved central compartment lymph nodes, treated without a PCND. After institutional review board approval, adult PTC patients with cN1b disease who were treated with a total thyroidectomy and lateral neck dissection were identified from an institutional database of 6259 patients who underwent initial surgery for well-differentiated thyroid carcinoma from 1986 to 2015. Patients with gross extrathyroidal extension, distant metastases, or no preoperative imaging were excluded. Patients with evidence of clinically involved central compartment lymph nodes, on preoperative imaging or intraoperative evaluation, also were excluded. A total of 152 cN1b patients were included and categorized into non-PCND and PCND groups. Central neck recurrence-free probability (CNRFP) was calculated using the Kaplan-Meier method and log-rank tests. One hundred three patients (67.8%) did not have a PCND. With a median follow-up of 65months, the 5- and 10-year CNRFP was 98.4% in the non-PCND group and 93.6% in the PCND group (p = 0.133). Select PTC patients with cN1b disease but no evidence of clinically involved central compartment lymph nodes, on preoperative imaging and intraoperative evaluation, appear to have a low rate of central neck recurrence. These patients may not require or benefit from a PCND.

Abstract A36: Integrated sequencing of pediatric thyroid carcinoma reveals frequent targetable alterations

Abstract Background: Papillary thyroid carcinomas (PTC) comprise 90% of thyroid cancers in children. Pediatric PTC is known to be clinically and biologically different than adult PTC, with pediatric tumors more likely to present with metastases and less likely to have the typical alterations found in adult tumors, including BRAF V600E mutations and RET alterations. While the prognosis for pediatric PTC is generally good, some patients with metastatic and/or refractory disease have poorer outcomes and novel treatment approaches are needed. Given the relative lack of genomic information available for pediatric PTC, we sought to perform integrated DNA and RNA-based sequencing of a cohort of clinically annotated tumors in order to identify genetic alterations that might inform improved diagnostic and therapeutic approaches for these patients. Methods: Potential cases were identified through review of the Texas Children’s Hospital Pathology archives for the years 2005-2016. Clinical review of each patient chart was performed, with metastatic and treatment-refractory tumors prioritized for analysis. Nucleic acids (DNA/RNA) were extracted from FFPE tumor samples with sufficient tissue available. Tumor DNA was captured using a custom-designed next-generation mutation panel that includes the entire coding regions and select noncoding regions of 124 genes implicated in pediatric solid tumors. Tumor RNA was assessed for fusions using a commercially available multiplex gene fusion panel (Archer Oncology Research panel) targeting 75 pediatric solid tumor genes. Sequencing was performed on an Illumina MiSeq. After completion of DNA/RNA mutation panel testing in all available cases, more comprehensive analyses (exome sequencing, capture transcriptome sequencing) will be performed on cases in which driver alterations are not identified. Putative driver alterations will be confirmed by targeted DNA/RNA testing. Results: A total of 41 pediatric PTC cases were prioritized for analysis. Of those, 40 were from patients of age 8-18 years, with a single sample from a 23-year-old. The majority of patients were metastatic to cervical lymph nodes (31/40, 77.5%), and just over one third of those patients were found to have additional pulmonary metastases (11/31, 35.5%). The male-to-female ratio was 1:3. Relapsed or refractory disease occurred in 18 patients (18/41, 44%). Nucleic acid extractions have been completed for 29 cases. DNA sequencing has been performed for 11 cases, revealing potentially targetable mutations in 6 tumors (54%): BRAF p.V600E x 4, PIK3R1 p.Y29fs, and PTPN11 p.S502T. RNA samples have been successfully sequenced for 16 cases, identifying potentially targetable fusions in 8 tumors (50%): NTRK3 x 4 (both known and novel fusions), BRAF x 2, and RET x 2. All driver alterations detected in cases successfully subjected to both DNA and RNA sequencing to date are mutually exclusive, with a single alteration per tumor. Conclusions: Frequent alterations were identified in known cancer genes in pediatric PTC cases, many of which are currently targetable with FDA-approved or investigational agents (e.g., MAPK pathway inhibitors; PI3K pathway inhibitors, other kinase inhibitors). Use of both DNA and RNA panel sequencing targeting genes known to be altered in pediatric solid tumors has the potential to identify alterations of clinical relevance in a majority of pediatric PTC patients. Citation Format: Samara L. Potter, Jacquelyn Reuther, Ilavarasi Gandhi, Faith Hollingsworth, Hadi Sayeed, Horatiu Voicu, Nipun Kakkar, Koel Sen Baksi, Stephen F. Sarabia, Monica E. Lopez, Daniel C. Chelius, Ioanna D. Athanassaki, Rajkumar Venkatramani, Norma M. Quintanilla, Dolores Lopez-Terrada, Angshumoy Roy, Donald Williams Parsons. Integrated sequencing of pediatric thyroid carcinoma reveals frequent targetable alterations [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A36.

DICER1 Mutations Are Frequent in Adolescent-Onset Papillary Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC) is a common malignancy in adolescence and is molecularly and clinically distinct from adult PTC. Mutations in the DICER1 gene are associated with thyroid abnormalities, including multinodular goiter and differentiated thyroid carcinoma. In this study, we sought to characterize the prevalence of DICER1 variants in pediatric PTC, specifically in tumors without conventional PTC oncogenic alterations. Patients (N = 40) who underwent partial or total thyroidectomy and who were <18 years of age at the time of surgery were selected. The 40 consecutive thyroidectomy specimens (30 malignant, 10 benign) underwent genotyping for 17 PTC-associated variants, as well as full sequencing of the exons and exon-intron boundaries of DICER1. Conventional alterations were found in 12 of 30 (40%) PTCs (five BRAFV600E, three RET/PTC1, four RET/PTC3). Pathogenic DICER1 variants were identified in 3 of 30 (10%) PTCs and in 2 of 10 (20%) benign nodules, all of which lacked conventional alterations and did not recur during follow-up. DICER1 alterations thus constituted 3 of 18 (16.7%) PTCs without conventional alterations. The three DICER1-mutated carcinomas each had two somatic DICER1 alterations, whereas two follicular-nodular lesions arose in those with germline DICER1 mutations and harbored characteristic second somatic RNase IIIb "hotspot" mutations. DICER1 is a driver of pediatric thyroid nodules, and DICER1-mutated PTC may represent a distinct class of low-risk malignancies. Given the prevalence of variants in children, we advocate for inclusion of DICER1 sequencing and gene dosage determination in molecular analysis of pediatric thyroid specimens.

Identification of Three Novel Fusion Oncogenes, SQSTM1/NTRK3, AFAP1L2/RET, and PPFIBP2/RET, in Thyroid Cancers of Young Patients in Fukushima.

The BRAFV600E mutation is the most frequent genetic abnormality in adult papillary thyroid carcinomas (PTCs). On the other hand, various chromosomal rearrangements are more prevalent in childhood and adolescent PTCs. The aim of the present study was to identify novel rearrangements in PTCs from young patients. Among 63 postoperative specimens of childhood and adolescent PTCs, which had been discovered by the thyroid ultrasound screening program in Fukushima, nine samples without prevalent known oncogenes, BRAFV600E, RAS, RET/PTC1, RET/PTC3, and ETV6/NTRK3, were analyzed in the current study by quantitative real-time reverse transcription polymerase chain reaction to screen for novel fusion genes by comparing transcript expression between extracellular and kinase domains of ALK, NTRK1, NTRK3, and RET. Of the above nine samples, five samples were suspected to harbor a fusion, and using subsequent 5' rapid amplification of cDNA end (RACE), two already reported fusion oncogenes, STRN/ALK and TPR/NTRK1, and three novel fusions, SQSTM1/NTRK3, AFAP1L2/RET, and PPFIBP2/RET, were identified. Functional analyses of these three chimeric genes were performed, and their transforming abilities were confirmed through the activation of mitogen-activated protein kinase (MAPK). Three novel fusion oncogenes have been identified in young PTC patients in Fukushima, suggesting that rare fusions may be present among the cases negative for known oncogenes in this age group and that such rearrangements can play a significant role in thyroid carcinogenesis.

Fusion Oncogenes Are the Main Genetic Events Found in Sporadic Papillary Thyroid Carcinomas from Children.

Previous studies reported significant differences in the clinical presentation and outcomes of papillary thyroid carcinoma (PTC) in pediatric patients compared with adults. Previous studies have suggested that the clinicopathological differences observed between pediatric and adult PTCs may be due the existence of distinct genetic alterations. However, the knowledge of genetic events in pediatric PTCs is based primarily on studies in radiation-exposed PTCs or in the few studies that enrolled predominantly adolescent patients. The aim of this study was to characterize the known oncogenic alterations of the MAPK pathway found in adult and radiation-exposed PTCs in a cohort of predominantly sporadic pediatric PTC patients. Thirty-five pediatric PTCs were screened for the most prevalent fusions (RET/PTC1, RET/PTC2, RET/PTC3, ETV6-NTRK3, and AGK-BRAF) and point mutations (BRAFV600E and NRASQ61) described in sporadic pediatric PTCs. The mutational status was correlated with clinicopathological data. Mutations were found in 20 out of 35 (57%) PTC cases. Fusion oncogenes were the main genetic alterations found. RET/PTC1-3 rearrangements were found in 13 (37%), ETV6-NTRK3 in 3 (9%), AGK-BRAF in 4 (11%), and BRAFV600E in 3 (9%). No mutation was found in NRASQ61. BRAFV600E was associated with older age and larger tumor size (p < 0.05), and RET/PTC3 was associated with a larger tumor size and multifocality (p < 0.05). The genetic signature in this cohort was remarkably different than that observed in adults. Although observed at a lower prevalence, the spectrum of mutations was quite similar to that described in radiation-exposed pediatric PTCs. As mutations were unidentifiable in over 40% of the PTC cases, more comprehensive studies conducted in these patients will help to decipher the genetic landscape of sporadic pediatric PTCs.

Characteristics of young adults of Belarus with post-Chernobyl papillary thyroid carcinoma: a long-term follow-up of patients with early exposure to radiation at the 30th anniversary of the accident.

Studies of thyroid cancer related to the Chernobyl accident have focused on children as they are the most vulnerable group with the highest risk of developing radiation-associated cancer. In contrast, our research aimed to look at the clinical and pathological features of patients with post-Chernobyl papillary thyroid carcinoma that were 2 years old or less at the time of the Chernobyl accident. The study subjects were patients (n = 359) aged 0 to 2 at the time of the Chernobyl accident and aged ≥19 years at presentation/surgery who were treated in Belarus for papillary thyroid carcinoma during the period 2003-2013. In conventional or oncocytic variant of papillary thyroid carcinoma, the prevalence of extra-thyroidal extension, nodal disease, infiltrative growth or lymphatic vessel invasion was above 50%. These features were less pronounced when compared to tall cell or diffuse sclerosing variants of papillary thyroid carcinoma. The highest frequency of central lymph node metastases was found in patients aged 1-2 years at exposure (P = 0·004). Subjects exposed in utero were characterized by absent/insignificant lymphocytic infiltration around the carcinoma (P = 0·025), predominance of conventional papillary architecture and an association with lymphocytic thyroiditis. A number of features were associated with this group of patients that were very young at the time of radiation exposure. In addition, the incidence and basic characteristics of adult papillary thyroid carcinoma varied depending on the types of exposure conditions.