Pediatric 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

Pediatric Papillary Thyroid Carcinoma: Outcomes After Surgery Without Adjuvant Radioactive Iodine.

Pediatric papillary thyroid carcinoma (PTC) is usually treated with total thyroidectomy followed by radioactive iodine (RAI). Recently, RAI is being used more selectively based on surgical pathology and postoperative dynamic risk stratification (DRS). To describe patients with pediatric PTC not initially treated with RAI and their disease outcomes. This was an ambispective study at a tertiary cancer center of patients < 19 years diagnosed from 1/1/1990 to 12/31/2021 with stage I PTC who intentionally were not treated with RAI within a year of diagnosis. We assessed clinical characteristics, management, and disease outcomes using DRS. Of 490 PTC patients, we identified 93 eligible patients (median age at diagnosis 16y; 87% female), including 46 (49%) with cervical lymph node metastases. Initial management included: total thyroidectomy ± neck dissection (n=69, 75%), lobectomy ± neck dissection (n=20, 21%), or a Sistrunk procedure for ectopic PTC (n=4, 4%). After a median follow-up of 5.5 years (range 1-26), most patients (85/93; 91%) remained disease-free with no further therapy. Persistent (n=5) or recurrent (n=3) disease was found in 9% of the entire cohort. Four patients ultimately received RAI, of which only one clearly benefited, and additional surgery was performed or planned in four patients, two of whom had an excellent response at last follow-up. Selected pediatric PTC patients, even those with lymph node metastases, may not require therapeutic 131I and can avoid the unnecessary risks of RAI while still benefitting from the excellent long-term outcomes that are well-described for this disease.

Genomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

Application value of multi-gene mutation detection in the clinical management of pediatric papillary thyroid carcinoma: a preliminary exploration.

Thyroid cancer rarely occurs in children and adolescents. Molecular markers such as BRAF, RAS, and RET/PTC have been widely used in adult PTC. It is currently unclear whether these molecular markers have equivalent potential for application in pediatric patients. This study aims to explore the potential utility of a multi-gene conjoint analysis based on next-generation targeted sequencing for pediatric papillary thyroid carcinoma (PTC). The patients diagnosed with PTC (aged 18 years or younger) in the pediatrics department of Lishui District Hospital of Traditional Chinese Medicine were retrospectively screened. A targeted enrichment and sequencing analysis of 116 genes associated with thyroid cancer was performed on paraffin-embedded tumor tissues and paired paracancerous tissue of fifteen children (average age 14.60) and nine adults (average age 49.33) PTC patients. Demographic information, clinical indicators, ultrasonic imaging information and pathological data were collected. The Kendall correlation test was used to establish a correlation between molecular variations and clinical characteristics in pediatric patients. A sample of 15 pediatric PTCs revealed a detection rate of 73.33% (11/15) for driver gene mutations BRAF V600E and RET fusion. Compared to adult PTCs, the genetic mutation landscape of pediatric PTCs was more complex. Six mutant genes overlap between the two groups, and an additional seventeen unique mutant genes were identified only in pediatric PTCs. There was only one unique mutant gene in adult PTCs. The tumor diameter of pediatric PTCs tended to be less than 4cm (p<0.001), and the number of lymph node metastases was more than five (p<0.001). Mutations in specific genes unique to pediatric PTCs may contribute to the onset and progression of the disease by adversely affecting hormone synthesis, secretion, and action mechanisms, as well as the functioning of thyroid hormone signaling pathways. But, additional experiments are required to validate this hypothesis. BRAF V600E mutation and RET fusion are involved in the occurrence and development of adolescent PTC. For pediatric thyroid nodules that cannot be determined as benign or malignant by fine needle aspiration biopsy, multiple gene combination testing can provide a reference for personalized diagnosis and treatment by clinical physicians.

An individualized protein-based prognostic model to stratify pediatric patients with papillary thyroid carcinoma

Pediatric papillary thyroid carcinomas (PPTCs) exhibit high inter-tumor heterogeneity and currently lack widely adopted recurrence risk stratification criteria. Hence, we propose a machine learning-based objective method to individually predict their recurrence risk. We retrospectively collect and evaluate the clinical factors and proteomes of 83 pediatric benign (PB), 85 pediatric malignant (PM) and 66 adult malignant (AM) nodules, and quantify 10,426 proteins by mass spectrometry. We find 243 and 121 significantly dysregulated proteins from PM vs. PB and PM vs. AM, respectively. Function and pathway analyses show the enhanced activation of the inflammatory and immune system in PM patients compared with the others. Nineteen proteins are selected to predict recurrence using a machine learning model with an accuracy of 88.24%. Our study generates a protein-based personalized prognostic prediction model that can stratify PPTC patients into high- or low-recurrence risk groups, providing a reference for clinical decision-making and individualized treatment.

Relationship between sonographic features, clinicopathological characteristics and lymph node metastasis of papillary thyroid carcinoma in children

Objective: This study aimed to evaluate the relationship between sonographic features, clinicopathological characteristics and lymph node metastasis (LNM) of papillary thyroid carcinoma (PTC) in children ( 18 years). S ≤ ubject and method: A total of 46 pediatric patients who were histopathologically diagnosed with PTC from January 2015 to March 2022 were included in this study. The preoperative ultrasonography, histological, and LNM features after surgery were retrospectively analyzed. Result: PTC in children accounted for 0.6% of all PTC, with a higher rate of females (67.4%), aged 15-18 years was 71.7%. The tumors weremostly classic type (87.0%), tumor size &gt; 10mm (76.1%), with high rates of central and lateral LNM (69.6% and 45.7%, respectively). Central LNM was significantly related to extrathyroidal extension (ETE). A significant relationship was observed between lateral LNM and tumor size, multifocality, ETE, intrathyroidal spread, microcalcification, and abnormal lymph nodes on ultrasound. Conclusion: Central and lateral LNM in pediatric PTC were common (69.6% and 45.7%, respectively). Several sonographic and clinicopathologic features had a significant relationship with LNM, especially lateral LNM. Patients with risk factors should undergo both clinical and neck ultrasound examinations in order to find evidence of LNM.

Sustained Response with Dose-reduced Selpercatinib in a Pediatric Patient with Metastatic NCOA4-RET Fusion Papillary Thyroid Carcinoma.

Understanding the molecular landscape of papillary thyroid carcinoma (PTC), the most common thyroid cancer in children, creates additional therapeutic approaches. RET gene rearrangements are observed in pediatric PTC, and selective inhibition of RET is now possible with specific tyrosine kinase inhibitors designed to target diverse RET -activating alterations. We present a 13-year-old female with metastatic PTC, clinically resistant to radioactive iodine, and found to harbor a NCOA4-RET fusion. She responded to selpercatinib treatment with the elimination of supplemental oxygen need, marked reduction in pulmonary nodules and mediastinal lymphadenopathy, and biomarker decline. The response was maintained despite 2 dose reductions for possibly related weight gain.

Single BRAFV600E mutation is not associated with aggressive biological behavior in adolescent and pediatric papillary thyroid carcinoma.

Papillary thyroid carcinoma is more likely to show aggressive biological behaviors in the majority of pediatric patients than in adult patients. The aim of this study was to investigate the mutation rate of the BRAFV600E gene in adolescents and children with papillary thyroid carcinoma and to analyze the association between BRAFV600E gene mutation and tumor-aggressive pathological factors. A total of 42 pediatric patients with papillary thyroid carcinoma who underwent thyroid surgery from 2017 to 2022 were studied retrospectively. Whether the BRAFV600E gene mutation in papillary thyroid carcinoma was related to aggressive biological behavior was analyzed. Among the 42 pediatric patients with papillary thyroid carcinoma, the median patient age was 15.71±2.51years (mean±SD) and the median tumor diameter was 24.95±12.29mm (mean±SD). Among all enrolled patients, the mutation rate of the BRAFV600E gene was 54.76% (23 of 42). There were 33 patients with classic papillary thyroid carcinoma, and 22 (66.67%) with classic subtypes were BRAFV600E positive. The BRAFV600E mutation was associated with lower distant metastasis (p=.013) and less Hashimoto's thyroiditis (p=.006). There was no significant difference in clinicopathological factors such as sex, age, tumor size, capsular invasion, multifocality, hypothyroidism, recurrence, lymph node metastasis, and extrathyroidal extension. The BRAFV600E mutation is not uncommon in pediatric papillary thyroid carcinoma but is not significantly associated with aggressive biological behavior. It is not possible to determine whether to adopt more active diagnosis and treatment measures on the basis of the mutation of a single BRAFV600E gene.

Is Multifocality a Predictor of Poor Outcome in Childhood and Adolescent Papillary Thyroid Carcinoma?

Total thyroidectomy in pediatric papillary thyroid carcinoma (PTC) is recommended in national guidelines because of the high incidence of multifocal disease (MFD). To determine the incidence of MFD in childhood and adolescent vs adult PTC and whether MFD is a predictor for poorer outcomes in childhood and adolescent PTC. We conducted an institutional review board-approved review of patients with PTC undergoing surgery (1986-2021) at Memorial Sloan Kettering Cancer Center. Clinical and pathological characteristics in patients with unifocal disease (UFD) and MFD were compared using Pearson's χ2 test. Survival outcomes were analyzed using the Kaplan-Meier method and log-rank test. Multivariate analysis assessed the impact of MFD on outcome. MFD was less common in childhood and adolescent patients with PTC (45%; 127/283) than in adults (54%; 3023/5564; P = .002). Childhood and adolescent patients with UFD and MFD had similar tumor stage and PTC subtype at presentation, with no significant difference in histopathologic features. Median follow-up was 68 months. There was no significant difference in 5-year recurrence-free probability and overall survival was 100% in both groups. There was no significant difference in 5-year contralateral lobe PTC-free probability between patients with UFD and MFD treated with lobectomy. Multivariate analysis showed MFD was not a predictor for recurrence. MFD was less common in childhood and adolescent patients with PTC than adults and was not a predictor of poor outcome on multivariate analysis, with excellent long-term outcomes in all patients with PTC. MFD does not appear to warrant completion thyroidectomy in childhood and adolescent patients selected for lobectomy.

Thyroid Nodules and Follicular Cell-Derived Thyroid Carcinomas in Children.

Although pediatric thyroid tumors have many similarities to those occurring in adults, significant differences are also recognized. For example, although thyroid nodules in children are much less common than in adults, a higher percentage is malignant. Moreover, while pediatric papillary thyroid carcinoma (PTC) is associated with more advanced disease, death due to disease in children and adolescents is very rare, even when distant metastases are present. Some subtypes of thyroid carcinoma, like diffuse sclerosing variant, are especially common in children and adolescents. Moreover, certain histologic findings, such as a tall cell morphology or increased mitotic activity, may not carry the same prognostic significance in children as in adults. Recent studies exploring the molecular underpinnings of pediatric thyroid carcinoma indicate that while driver alterations of thyroid tumorigenesis in children and adults are essentially the same, they occur at very different frequencies, with translocation-associated tumors (most commonly harboring RET and NTRK fusions) comprising a sizable and distinct group of pediatric PTC. DICER1 mutations, an infrequent mutation in adult thyroid tumors, are relatively frequent in pediatric encapsulated follicular-patterned thyroid tumors (with or without invasion or nuclear features of PTC). Additionally, tumor predisposition syndromes (most notably DICER1 syndrome and PTEN hamartoma tumor syndromes such as Cowden syndrome) should be considered in children with thyroid tumors, especially follicular-patterned thyroid tumors and poorly differentiated thyroid carcinoma. This review will explore the current state of knowledge of thyroid nodules and carcinomas in children and adolescents.

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

Prepubertal Children with Papillary Thyroid Carcinoma Present with More Invasive Disease Than Adolescents and Young Adults.

Introduction: Pediatric papillary thyroid carcinomas (PTCs) are more invasive than adult PTCs. No large, contemporary cohort study has been conducted to determine whether younger children are at higher risk for advanced disease at presentation compared to adolescents. We aimed to describe pediatric PTC and contextualize its characteristics with a young adult comparison cohort. Methods: The National Cancer Database was interrogated for pediatric and young adult PTCs diagnosed between 2004 and 2017. Clinical variables were compared between prepubertal (≤10 years old), adolescent (11-18 years old), and young adult (19-39 years old) groups. Multivariable logistic regression modeling for independent predictors of metastases was conducted. A subanalysis of microcarcinomas (size ≤10 mm) was performed. Results: A total of 4860 pediatric (prepubertal n = 274, adolescents n = 4586) and 101,159 young adult patients were included. Prepubertal patients presented with more extensive burden of disease, including significantly larger primary tumors, higher prevalence of nodal and distant metastases, and increased frequency of features such as lymphovascular invasion, and extrathyroidal extension (ETE). Prepubertal age was an independent predictor of positive regional nodes (adjusted odds ratio [AOR] = 1.36 [95% confidence interval {CI} 1.01-1.84], p = 0.04) and distant metastatic disease (AOR = 3.12 [CI 1.96-4.96], p < 0.001). However, there was no difference in survival between groups (p = 0.32). Prepubertal age independently predicted lymph node metastases for microcarcinomas (AOR = 2.19 [CI 1.10-4.36], p = 0.03). Prepubertal (n = 41) versus adolescent (n = 937) patient age was associated with gross ETE (p = 0.004), even with primary tumors ≤1 cm in size. Conclusions: Patients aged <11 years old present with more advanced disease than adolescents, with a higher likelihood of nodal and distant metastatic disease at time of diagnosis, although survival is high. Prepubertal children undergo more extensive treatment, likely reflective of more invasive disease at the outset, even in the setting of a subcentimeter primary tumor.

Analysis of surgical strategy for pediatric papillary thyroid carcinoma with low-intermediate risk

Objective: To explore the feasibility and rationality of lobectomy in the treatment of pediatric thyroid papillary carcinoma (PTC) with low-intermediate risk. Methods: The clinicopathological features and follow-up data of pediatric PTC with low-intermediate risk were reviewed from March 2000 to December 2018 in Cancer Hospital of Chinese Academy of Medical Sciences. The correlations between different surgical procedures and prognoses were evaluated. Propensity score matching(PSM) was used to adjust for risk factors, and the difference in prognoses between the total thyroidectomy (TT) group and the lobectomy (LT) group was compared. Results: A total of 140 patients were included in the study, including 36 males and 104 females. The age range was from 6-year-old to 18-year-old. There were 43 low-risk patients and 97 intermediate-risk patients. The median follow-up time was 87.5 months, ranging from 8 to 241 months, and 20 patients (14.3%) showed recurrence during the follow-up period. Univariate analysis showed that N1b, extrathyroidal extension, the number of lymph node metastasis>5, the ratio of lymph node metastasis≥0.19, and radioactive iodine treatment were risk factors for recurrence (all P value below 0.05), but multivariate analysis showed that only the ratio of lymph node metastasis≥0.19 (HR=8.69, 95%CI=1.08-70.21, P=0.043) was an independent risk factor for recurrence. There was no significant difference in the 5-year recurrence free survival rates between TT group and LT group before propensity score matching (82.8% vs. 86.5%, χ2=0.219, P=0.640) and after propensity score matching (89.6% vs. 90.4%, χ2=0.099, P=0.753). Conclusion: There is no significant difference in recurrence-free survival between TT group and LT group. Lobectomy is feasible for selective pediatric PTC with low-intermediate risk.

DICER1 Mutations Occur in More Than One-Third of Follicular-Patterned Pediatric Papillary Thyroid Carcinomas and Correlate with a Low-Risk Disease and Female Gender Predilection.

Some pediatric papillary thyroid carcinoma (PPTC) cohorts have suggested a preliminary correlation with respect to DICER1 mutation status and histomorphology in both benign and malignant follicular cell-derived nodules; however, the data regarding correlates of DICER1-related sporadic PPTCs subtyped based on the 2022 WHO classification criteria are largely unavailable. The current study investigated the status of hotspot DICER1 mutations with clinical, histological and outcome features in a series of 56 patients with PPTCs with no clinical or family history of DICER1-related syndromic manifestation. Fifteen (27%) PPTCs harbored BRAF p.V600E. Eight (14%) cases ofPPTCs harbored DICER1 mutations with no associated BRAF p.V600E. DICER1 mutations were identified in exons 26 and 27. A novel D1810del (c.5428_5430delGAT) mutation was also detected. We also confirmed the absence of hotspot DICER1 mutations in the matched non-tumor tissue DNA in all 8 DICER1-related PPTCs. The mean age of DICER1-harboring PPTCs was 15.1 (range: 9-18) years whereas the rest of this cohort had a mean age of 14.8 (range 6-18) years. With the exception of one PPTC, all DICER1-related PPTCs were seen in females (female-to-male ratio: 7). The female to male ratio was 3.8 in 48 DICER1-wild type PPTCs. In terms of histological correlates, 5 of 8 (63%) DICER1-mutant PPTCs were invasive encapsulated follicular variant papillary thyroid carcinomas (FVPTCs) including 4 minimally invasive FVPTCs and 1 encapsulated angioinvasive FVPTC, whereas the remaining 3 PPTCs were infiltrative classic papillary thyroid carcinomas (p < 0.05). The incidence of DICER1 mutations was 19.5% in BRAF p.V600E-wild type PPTCs. Sixty-three percent ofDICER1 hotspot mutations occurred in invasive encapsulated FVPTCs, and this figure represents 38% of invasive encapsulated FVPTCs. Only one (12%) patient with DICER1-related disease showed a single lymph node with micro-metastasis. Unlike DICER1-wild type patients, no distant metastasis is identified in patients with DICER1-related PPTCs. The current series expands on the surgical epidemiology of somatic DICER1-related PPTCs by correlating the mutation status with the clinicopathological variables. Our findings underscore that female gender predilection and enrichment in low-risk follicular-patterned PTCs are characteristics of DICER1-related PPTCs.

The clinical significance of BRAFV600E mutations in pediatric papillary thyroid carcinomas

This study aimed to review the clinical significance of BRAFV600E mutations in pediatric papillary thyroid carcinoma (PTC). From 2018 to 2021, 392 pediatric thyroid operations were performed in the first affiliated Hospital of Zhengzhou University. Of these, 169 patients underwent their first operation in our hospital and were histopathologically diagnosed as papillary thyroid carcinoma. BRAFV600E gene mutation detection was performed in these 169 pediatric patients to investigate the correlation between BRAF gene mutations and clinicopathological features. Ninety-seven of our 169 patients had a BRAFV600E mutation, with a mutation rate of 57.4%. The incidence of BRAFV600E was higher in boys than in girls, and in the 13–18-year age group as compared with the 6–12-year age group (P < 0.05). The positivity rate of BRAFV600E in unilateral PTC (67.7%) was significantly higher than the ones in bilateral PTC (28.9%). The occurrence of diffuse microcalcification of the thyroid negatively correlated with the presence of BRAFV600E mutations. BRAFV600E mutations were found more frequently in patients with smaller tumor size, a lack of multifocality, lower TSH levels and central lymph node metastasis. During the follow-up time, 70 patients were treated with iodine-131. Eight patients required a second surgery (All had cervical lymph node recurrence). BRAFV600E mutations do not suggest a more aggressive course in papillary thyroid carcinoma in pediatric patients in the short term.

Optimal value of lymph node ratio and metastatic lymph node size to predict risk of recurrence in pediatric thyroid cancer with lateral neck metastasis

BackgroundNo specific guideline exists for risk stratification based on lymph node (LN) status in pediatric thyroid cancer. The purpose of our study is to identify optimal values of lymph node ratio (LNR) and largest metastatic LN size for predicting recurrent/persistent disease, especially in children with lateral neck metastasis (N1b). MethodsWe conducted a retrospective study from January 1997 to June 2018 at Samsung Medical Center. A total of 50 papillary thyroid carcinoma (PTC) patients who underwent total thyroidectomy + both central neck dissection (CND) + modified radical neck dissection (MRND) (unilateral or bilateral) was enrolled. ResultsThe median follow-up duration was 60.8 months (range, 6.2–247 months). The mean age was 14.6 years, and the mean tumor size was 2.9 cm. Mean size of the largest metastatic LN was 1.5 cm. Mean value of central LNR was 0.6, and mean value of lateral LNR was 0.3. Largest metastatic LN size [HR = 2.0 (95% CI 1.0–4.0), p = 0.040] and lateral LNR [HR = 43.6 (95% CI 2.2–871.0), p = 0.014] were significant prognostic factors for recurrence. The optimal combination of lateral LNR and largest metastatic LN size to predict recurrence were 0.3 and 2.5 cm, respectively, with the largest AUC (AUC at 60 months = 77.4) and significant p-value (p = 0.009 and p = 0.021) (Table 3). Kaplan-Meier curves showed significant differences in recurrence-free survival (RFS) rates among four groups (Fig. 2A,2B). ConclusionsIn pediatric PTC patients with N1b, lateral LNR and largest metastatic LN size are significant predictors for recurrence. Children with lateral LNR > 0.3 or any metastatic lymph node > 2.5 cm in the largest dimension have higher risk for recurrence. Children are classified as extensive N1b if lateral LNR > 0.3 or pathologic N1 with largest LN size > 2.5 cm, and vice versa.

Abstract 980: Genomic characterization of lymph node metastases in papillary thyroid carcinoma following the Chernobyl accident reveals an expression profile specific to metastatic process

Abstract Following the Chernobyl nuclear power plant explosion in Ukraine in 1986, increased childhood exposure to radioactive iodine (131I), which occurred primarily through contaminated food sources, has been consistently associated with increased risk of developing papillary thyroid carcinoma (PTC). Increased frequency of cervical lymph node metastases (LNM) is well recognized in pediatric PTC, including pediatric cases following the Chernobyl accident. We recently leveraged the collection of fresh-frozen tumor tissues from the Chernobyl Tissue Bank to conduct a genomic landscape analysis of 440 cases of PTC that provided new insights into radiation-related molecular characteristics of PTC occurring after the accident (Morton et al., Science 2021). Here, we extend that study to conduct a genomic landscape analysis of LNMs for a subset of 48 PTC cases to investigate the specific genomic alterations occurring in LNM. The analysis set comprised 144 samples, including fresh-frozen treatment-naïve primary and LNM PTC tumor samples as well as matched normal tissue or blood. Overall, the mutational load was highly concordant between primary and metastatic PTC. On average, 50% of somatic single nucleotide variants and 97% structural variants were shared between primary and metastatic PTCs. In contrast, the burden of somatic copy number alterations (SCNA) between primary tumor and LNM pairs was less concordant, particularly for copy number gains, whereas most of the copy number loss was found to be shared between matched pairs. PTC is usually driven by one driver mutation, most often involving the mitogen-activated protein kinase (MAPK) pathway. All driver mutations were shared between primary and metastatic PTC and were clonal; thus, no additional driver mutations were detected in metastatic PTC. Notably, however, the matched pairs in this study disproportionately had fusion drivers (77%), whereas only 23% of the drivers were BRAF V600E and none were RAS mutations. Transcriptome analysis revealed differentially expressed genes (DEGs) in metastatic PTC compared to primary PTC; three-quarters of the DEGs were overexpressed in metastatic PTC. Half of the LNM overexpressed DEGs were members of the HOXC family, which has been linked with epithelial-mesenchymal transition in cancer progression. There was also reduced expression in LNM for the DLX family, which relates to TGF-beta signaling. Our findings did not reveal a relationship between radiation dose and expression profiles in the LNM, comparable to our findings for the primary PTCs. We still observe that the efficiency of the radiation-induced PTC is paramount and subsequent events are directly related to the drivers in the MAPK pathway. For the cervical LNMs, we observed expression profiles not observed in the primary PTC that could give new insights into PTC local metastases. Citation Format: Olivia W. Lee, Danielle M. Karyadi, Chip Stewart, Tetiana I. Bogdanova, Jieqiong Dai, Stephen W. Hartley, Sara J. Schonfeld, Vidushi Kapoor, Marko Krznaric, Meredith Yeager, Amy Hutchinson, Belynda D. Hicks, Casey L. Dagnall, Julie M. Gastier-Foster, Jay Bowen, Mitchell J. Machiela, Elizabeth K. Cahoon, Kiyohiko Mabuchi, Vladimir Drozdovitch, Sergii Masiuk, Mykola Chepurny, Liudmyla Y. Zurnadzhy, Amy Berrington de González, Gad Getz, Gerry A. Thomas, Mykola D. Tronko, Lindsay M. Morton, Stephen J. Chanock. Genomic characterization of lymph node metastases in papillary thyroid carcinoma following the Chernobyl accident reveals an expression profile specific to metastatic process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 980.

Long-Term Oncological Outcomes of Papillary Thyroid Cancer and Follicular Thyroid Cancer in Children: A Nationwide Population-Based Study

IntroductionPediatric thyroid carcinoma is a rare malignancy and data on long-term oncological outcomes are sparse. The aim of this study was to describe the long-term oncological outcomes of pediatric papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) in a national cohort, and to identify risk factors for recurrence.MethodsWe conducted a nationwide, retrospective cohort study, in which we combined two national databases. Patients aged <18 years, diagnosed with PTC or FTC in the Netherlands between 2000 and 2016, were included. pT-stage, pN-stage, multifocality and angioinvasion were included in a Cox-regression analysis for the identification of risk factors for recurrence.Results133 patients were included: 110 with PTC and 23 with FTC. Patients with PTC most often presented with pT2 tumors (24%) and pN1b (45%). During a median follow-up of 11.3 years, 21 patients with PTC developed a recurrence (19%). Nineteen recurrences were regional (91%) and 2 were pulmonary (9%). No risk factors for recurrence could be determined. One patient who developed pulmonary recurrence died two years later. Cause of death was not captured. Patients with FTC most often presented with pT2 tumors (57%). One patient presented with pN1b (4%). In 70%, no lymph nodes were collected. None of the patients with FTC developed a recurrence or died.ConclusionPediatric PTC and FTC are two distinct diseases. Recurrence in pediatric PTC is common, but in FTC it is not. Survival for both pediatric PTC and FTC is very good.

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.

Change in Antithyroglobulin Antibody Levels is a Good Predictor of Responses to Therapy in Antithyroglobulin Antibody-Positive Pediatric Papillary Thyroid Carcinoma Patients.

Objective Antithyroglobulin antibodies (TgAbs) could be used as a surrogate tumor marker of TgAb-positive-differentiated thyroid carcinoma. This study aims to determine whether the change in TgAb levels over time could be used as a predictor of responses to therapy in pediatric papillary thyroid carcinoma (PTC) patients. Methods We retrospectively analyzed the records of 48 pediatric PTC patients with TgAb levels ≥50 IU/ml 6 months after initial 131I treatment. Suppressed thyroglobulin (Tg) levels 6 months after initial 131I treatment were used to divide the patients into positive Tg (P-Tg, Tg ≥ 0.2 ng/ml) and negative Tg (N-Tg, Tg < 0.2 ng/ml) groups. Responses to therapy were classified as the acceptable response (AR) group and the not acceptable response (NAR) group. Results Of 48 enrolled patients with 58 months (range, 24–143 months) of follow-up, 28 patients had NAR and 20 patients had AR. TgAb levels were decreasing ≥50% in 28 patients, decreasing <50% in 8 patients, and increasing in 12 patients. Multivariate analysis showed that high initial risk stratification and TgAb levels decreasing <50% or increasing were significantly associated with NAR (p < 0.05). Changes in Tg levels were also associated with NAR in the P-Tg group (p < 0.05). Conclusion Changes in TgAb levels over time could be used as a predictor of responses to therapy in TgAb-positive pediatric PTC patients. Changes in Tg levels over time are also associated with NAR to therapy in both TgAb-positive and Tg-positive pediatric PTC patients.