Pediatric Papillary Thyroid Cancer Research Articles

Prognostic Value of Tumor Multifocality in Pediatric Papillary Thyroid Carcinoma: A Real-Life Multicentric Study.

To investigate the association of multifocality with clinical outcomes in pediatric papillary thyroid cancer. Multicenter retrospective study of prospectively collected data. Tertiary referral center. This study included patients 18 years or younger who underwent total thyroidectomy and radioiodine ablation for papillary thyroid carcinoma (PTC) between 2005 and 2020 at 3 tertiary adult and pediatric hospitals in China. For disease-free survival (DFS), events were defined as persistent and/or recurrent diseases. The primary outcome was the association of tumor multifocality and DFS, assessed using Cox proportional hazards regression models. One hundred and seventy-three patients (median age 16 years [range, 5-18 years]) were recruited. Multifocal diseases were seen in 59 patients (34.1%). After a median follow-up of 57 (range, 12-193 months) months, 63 (36.4%) patients had persistent diseases. There was a significant association between tumor multifocality and decreased DFS on univariable analysis (hazard ratio [HR] = 1.90, p = .01), yet it was nonsignificant after multivariate adjustment (HR = 1.20, p = .55). In a subgroup analysis of 132 pediatric patients with clinically M0 PTC, neither unadjusted HR (2.21, p = .06) nor adjusted HR (1.70, p = .27) of multifocal PTC was significantly higher in comparison to unifocal PTC. In this highly selective surgical pediatric patient cohort with PTC, tumor multifocality was not an independent risk factor for decreased DFS.

Prophylactic Central Neck Dissection to Improve Disease-Free Survival in Pediatric Papillary Thyroid Cancer.

BackgroundPediatric PTC is a rare disease. Although, the prognosis is excellent and the mortality rate is low, the role of prophylactic central neck dissection is still the subject of debate. The aim was to evaluate both the role and safety of prophylactic central neck dissection (CND) in managing pediatric papillary thyroid cancer (PTC), especially in respect of disease-free survival (DFS).Patients and MethodsIn this retrospective study, we collected 54 pediatric cN0 PTC patients (≤ 18 years of age) who were treated from January 2014 to January 2021 at a high-volume thyroid surgery center. Patients were divided into two groups based on the status of prophylactic CND. We analyzed the factors related to the clinicopathological features and recurrence of PTC in children.ResultsOf the 54 cN0 patients, 35 underwent prophylactic CND and 19 patients did not undergo prophylactic CND. The two groups were similar in clinical and pathologic features, such as age, gender, tumor size, multifocal status, and follow-up time. The average DFS was 84.4 ± 2.7 months. Log-rank tests on Kaplan-Meier curves revealed that age, gender, tumor size, multifocality, and extrathyroid extension did not relate to DFS time. Furthermore, DFS time was not affected by the extent of thyroidectomy (p=0.07) or RAI treatment (p=0.21). Prophylactic CND was found to increase DFS time for pediatric patients with cN0 PTC (p = 0.003). There was no statistically significant difference in complications such as transient hypocalcemia (p=0.15) and transient recurrent laryngeal nerve injury (p=0.37) between the prophylactic CND group and the no-prophylactic CND group.ConclusionProphylactic CND was found to be associated with increased DFS and not with increased rates of complications after surgery.

NTRK-fusions in pediatric thyroid tumors: Current state and future perspectives

Pediatric and adult papillary thyroid cancer (PTC) share many similar oncogenic drivers, but differ in the pathological features and outcomes of the disease. The most frequent genetic alterations in adult PTCs are mutually exclusive point mutations in BRAF or the RAS family. In pediatric PTC, fusion oncogenes involving chromosomal translocations in tyrosine kinase (TK) receptors, most commonly RET and NTRK, are the most common genetic alterations observed. This review of the literature describes the current state of translational research in pediatric NTRK-driven thyroid cancer and highlights opportunities to improve our understanding and current models of pediatric PTC.

Risk factors for lateral lymph node metastasis of papillary thyroid carcinoma in children

IntroductionLateral cervical lymph node metastases (LNM) for pediatric patients with papillary thyroid cancer (PTC) is a poor prognostic factor. We aimed to identify risk factors for lateral LNM. MethodsThis retrospective study had included 48 pediatric patients with papillary thyroid cancer underwent total thyroidectomy and central cervical lymphadenectomy at K hospital from 2016 to 2020. ResultsThe number of patients in each T stage was as follows: 24 (50.0%) in stage 1, 9 (18.7%) in Stage 2, 8 (16.7%) in Stage 3, and 7 (14.6%) in Stage 4. Most of the patients had LNM with N1a and N1b rates of 83.3% and 62.5%, respectively. Lung metastases were observed at presentation in three patients (6.3%). Univariate analysis revealed that age (p = 0.021), male (p = 0.011), tumor size > 10 mm (p = 0.002), multifocality (p < 0.001), extrathyroidal extension (p = 0.001) and central LNM (p < 0.001) were factors that increase the risk of metastasis to lateral LNM. ConclusionApproximately 62.5% of pediatric patients with PTC exhibited lateral LNM at the time of diagnosis. Our study confirmed that multifocality, maximum tumor diameter, extrathyroidal extension and central LNM were independent risk factors for lateral LNM in pediatric PTC. Level of EvidenceLevel IV.

The clinical aspect of NTRK-fusions in pediatric papillary thyroid cancer

Although adult and pediatric papillary thyroid cancer (PTC) share similar oncogenic drivers, they differ in the pathological features and outcomes of the disease. In adults with PTC, the most frequent genetic alterations are mutually exclusive point mutations in BRAFV600E or the RAS family with BRAFV600E commonly associated with invasive disease and decreased response to radioiodine therapy. In pediatric PTC, fusion oncogenes involving chromosomal translocations in tyrosine kinase (TK) receptors, most commonly RET and NTRK, are often found in patients with lateral neck and distant metastases. This brief report reviews clinical data from a single-institute's cohort of NTRK-driven pediatric PTC cases with an updated review of the literature and comparison to adult NTRK-driven PTC.

High Incidence of Distant Metastasis Is Associated With Histopathological Subtype of Pediatric Papillary Thyroid Cancer - a Retrospective Analysis Based on SEER.

ObjectiveChildren with papillary thyroid cancer (PTC) have a higher invasive rate and distant metastasis rate, but the mortality rate is lower with unknown reasons. The majority of PTC cases comprise classical papillary thyroid carcinoma (CPTC) and follicular variant papillary thyroid carcinoma (FVPTC). This study aimed to determine the relationship between histopathological subtype and rate of distant metastasis and investigate factors influencing distant metastasis in pediatric PTC.MethodsA total of 102,981 PTC patients were recruited from SEER registry, 2004-2015. Proportion of distant metastasis between children (≤18 years) and adults with different histopathological subtypes was compared by propensity score matching. The cut-off age for distant metastasis in children was calculated by receiver operating characteristic (ROC) curve, and the risk factors for distant metastasis in pediatric patients were analyzed by logistic regression models.ResultsAmong the 1,484 children and 101,497 adults included in the study, the incidence of CPTC patients with distant metastasis in children was higher than that in adults (p<0.001). The ROC curve was calculated, which yielded a cut-off age for distant metastasis in CPTC children as 16 years old. In CPTC, the proportion of young children (2-16 years) with distant metastasis was higher than that of adolescents (17-18 years) and adults (>18 years) (both p<0.001). While there was no such trend in FVPTC. In young children (2-16 years), the incidence of CPTC with distant metastasis was higher than FVPTC (p=0.006). There was no difference between the proportion of CPTC and FVPTC with distant metastasis in adolescents (17-18 years) and adults. Logistic regression models revealed that extrathyroidal extension, lymph node metastasis and CPTC histopathological subtype were risk factors for distant metastasis in young children aged 2 -16 years.ConclusionsIn CPTC, the incidence of distant metastasis in young children (2-16 years) was significantly higher than that in adolescents (17-18 years) and adults (>18 years). In patients with distant metastasis aged 2-16 years, the proportion of CPTC was higer than that of FVPTC. Extrathyroidal extension, lymph node metastasis, and CPTC histopathological subtype were risk factors for distant metastasis in young children aged 2-16 years.

Thyroid Lobectomy for T1 Papillary Thyroid Carcinoma in Pediatric Patients

The current recommendation for pediatric patients with papillary thyroid cancer (PTC) is a total thyroidectomy. This recommendation applies to all stages of PTC, including papillary thyroid microcarcinoma (≤1 cm, T1a) tumors. To evaluate the characteristics of American Joint Committee on Cancer T1 PTC tumors in a large pediatric population and to identify a subgroup of patients who may benefit from a thyroid lobectomy instead of a total thyroidectomy. This retrospective cohort study was conducted from January 1, 2009, to May 31, 2020. The study took place at a tertiary care medical center and included 102 patients who were surgically treated for T1 PTC: 52 with stage T1a (≤1 cm) tumors and 50 with stage T1b (>1 cm but ≤2 cm) tumors. Primary outcomes included the presence of bilateral disease and lymph node metastasis. A total of 102 patients (mean age, 15.3 years [range, 9.7-18.9 years]; 84 girls [82.4%]) were included in the analysis. Among 52 patients with T1a tumors, 10 (19.2%) had bilateral disease, and 15 (28.8%) had central neck lymph node (N1a) metastasis. Among 50 patients with T1b tumors, 10 (20%) had bilateral and 13 (26%) had N1a disease. Of those with T1a, unilateral multifocality was associated with bilateral disease (odds ratio [OR], 2.1; 95% CI, 1.3-3.4) and N1a disease (OR, 5.1; 95% CI, 1.5-17.6). Both N1a disease (OR, 20.0; 95% CI, 3.5-115.0) and ≥4 positive lymph nodes (OR, 8.6; 95% CI, 1.2-60.9) were associated with bilateral disease. In patients with no pathologic evidence of lymph node metastasis (N0), there was a 95% rate of unilateral PTC. In patients with T1b tumors, unilateral multifocality was also associated with bilateral disease (OR, 1.8; 95% CI, 1.3-2.7). Patients with T1b tumors had an increased risk of lateral (N1b) neck lymph node metastasis when compared with those with T1a tumors (OR, 3.7; 95% CI, 1.0-14.5). The findings of this cohort study suggest that, in patients with unifocal T1a PTC without clinically evident nodal disease on preoperative ultrasonography, a thyroid lobectomy and central neck dissection may be considered. If there is no evidence of unilateral multifocality or if there are fewer than 4 positive lymph nodes on postoperative pathology, then close observation may be considered. These findings have substantial clinical implications and may result in practice changes regarding the extent of thyroid surgery on low-stage pediatric PTC.

NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake.

BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Abstract 2425: Prevalence of NTRK fusions and clinico-pathological characteristics of Middle Eastern papillary thyroid cancer revealed enrichment in BRAF wild-type PTC

Abstract Fusions involving neurotrophic tyrosine receptor kinase (NTRK) are known oncogenic drivers in a broad range of tumor types. It recently gained attention as predictor of targeted therapy, since selective NTRK inhibitor are now approved in US and Europe for patients with solid tumor harboring gene fusions. However, estimation of NTRK gene fusion/alteration frequency and its clinico-pathological characteristics in papillary thyroid cancer (PTC) is limited, especially in a population with high incidence for PTC like Middle Eastern population. This study aims to characterize the NTRK gene fusion frequency using FISH analysis and investigate the utility of pan-Trk immunohistochemistry as predictor of NTRK fusion in a large cohort of Middle Eastern PTC. FISH analysis for NTRK gene fusions as well as immunohistochemical (IHC) staining was conducted on a cohort of 315 Middle Eastern PTC. Correlation of NTRK with clinico-pathological markers and patient outcome were determined. 6.0% (19/315) patients were identified with NTRK gene fusions and significantly associated with pediatric PTC, lymph node metastasis and BRAF wild-type. Pan-Trk IHC was positive in 9.2% (29/315) and significantly associated with NTRK gene fusion with a sensitivity of 73.7% and specificity of 94.9% in this cohort. In conclusion, this study confirms the presence of NTRK fusions in Middle Eastern PTC and mostly enriched in BRAF wild-type and pediatric age group and propose the usefulness of IHC to screen for PTC patients with NTRK fusion that might benefit from TRK inhibitors. Citation Format: Abdul K. Siraj, Rong Bu, Sandeep K. Parvathareddy, Yan Kong, Padmanaban Annaiyappanaidu, Saeeda O. Ahmed, Maha Al-Rasheed, Khawla S. Al-Kuraya. Prevalence of NTRK fusions and clinico-pathological characteristics of Middle Eastern papillary thyroid cancer revealed enrichment in BRAF wild-type PTC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2425.

Clinical implications of TPO and AOX1 in pediatric papillary thyroid carcinoma.

BackgroundThyroid carcinoma is a common pediatric head and neck cancer, of which papillary thyroid cancer (PTC) is the most common type. Previously, we found that thyroid peroxidase (TPO) and aldehyde oxidase 1 (AOX1) were differentially expressed in PTC. This study explored the clinical importance of TPO and AOX1 in the diagnosis and prognosis of PTC in children.MethodsBoth TPO and AOX1 expression in PTC were analyzed using datasets from Gene Expression Omnibus (GEO). TPO and AOX1 protein levels in plasma from patients with PTC and non-tumor controls were detected via enzyme-linked immunosorbent assay (ELISA). The diagnostic accuracy of TPO and AOX1 was assessed using receiver operating characteristic (ROC) curve analysis. The association between gene expression levels and patient survival was explored using the Kaplan-Meier plotter online database.ResultsThe results revealed that TPO and AOX1 expression was significantly downregulated in four independent datasets (GSE33630, GSE27155, GSE3678, and GSE3467). TPO and AOX1 protein levels in blood plasma were significantly decreased in patients with PTC. Quantitative analysis demonstrated that TPO and AOX1 levels in plasma had satisfactory predictive performance and the ability to discriminate PTC from healthy samples. Prognostic analysis demonstrated that low levels of TPO and AOX1 were markedly associated with poor survival in patients with PTC.ConclusionsIn summary, these results implied that TPO and AOX1 could serve as novel biomarkers for the diagnosis and prognosis of pediatric PTC.

Trends and Outcomes of Surgical Management of Primary Papillary Carcinoma in the Pediatric Population

BackgroundChildhood papillary thyroid cancer is more aggressive than carcinomas in adults. Current American Thyroid Association pediatric guidelines recommend a total or near-total thyroidectomy for all pediatric patients without gross evidence of lymph node metastases. Our objective is to analyze trends in the surgical management of pediatric papillary thyroid cancer and assess how well the guidelines are implemented. MethodsA retrospective cohort study of pediatric patients (ages 19 y and under) who underwent a thyroidectomy was conducted using the Surveillance, Epidemiology, and End Results database 2006-2017. Procedure type was classified as lobectomy or less and subtotal or total thyroidectomy. Descriptive statistics to illustrate patient and tumor characteristics as well as chi-square analysis to evaluate frequency of treatment with total thyroidectomies versus lobectomy or less were performed. Logistic regression analysis controlling for age, sex, size of tumor, rural versus urban institutions, and surgery year was conducted to identify factors predictive of procedure type. ResultsA total of 2271 children underwent surgical management of papillary thyroid cancer between 2006 and 2017. Most patients received a subtotal or total thyroidectomy as surgical management (n = 2,085, 91.8%). One hundred eighty-six patients (8.2%) received a lobectomy or less. The number of lobectomies or less increased with time, with 41 (6.6%) patients between 2006 and 2009, 98 (8.0%) between 2009 and 2015, and 47 (11.1%) between 2016 and 2017 (P = 0.03). Mortality rates were low (n = 15, 0.7%). On logistic regression analysis, later stages, larger sizes, and earlier operative years were predictive of a near-total or total thyroidectomy. ConclusionsDespite the American Thyroid Association Guidelines recommending a total thyroidectomy for pediatric well-differentiated thyroid cancer, the results of this study demonstrate that thyroid lobectomies are being performed in increasing frequency for smaller tumors in earlier stages of disease. Further investigation of whether this trend actually affects the outcomes in this patient cohort is needed.

NTRK fusion analysis reveals enrichment in Middle Eastern BRAF wild-type PTC.

Fusions involving neurotrophic tyrosine receptor kinase (NTRK) are known oncogenic drivers in a broad range of tumor types. It recently gained attention as a predictor of targeted therapy since selective NTRK inhibitors are now approved in the US and Europe for patients with solid tumors harboring gene fusions. However, estimation of NTRK gene fusion/alteration frequency and its clinicopathological characteristics in papillary thyroid cancer (PTC) is limited, especially in a population with high incidence for PTC like Middle Eastern population. This study aims to characterize the NTRK gene fusion frequency and investigate the utility of pan-Trk immunohistochemistry (IHC) as predictor of NTRK fusion in a large cohort of Middle Eastern PTC. FISH analysis for NTRK gene fusions and pan-Trk IHC was performed on 315 Middle Eastern PTCs. Correlation of NTRK gene fusion and protein expression with clinicopathological markers and patient outcome were determined. In our cohort, 6.0% (19/315) patients showed NTRK gene fusions and were significantly associated with pediatric PTC (P = 0.0143), lymph node metastasis (P = 0.0428) and BRAF WT tumors (P < 0.0001). Pan-Trk IHC was positive in 9.2% (29/315) of cases and significantly associated with NTRK fusions, with a sensitivity of 73.7% and specificity of 94.9% in this cohort. This study confirms the presence of NTRK fusions in Middle Eastern PTC which is significantly enriched in BRAF WT as well as pediatric age group and proposes the usefulness of IHC to screen for PTC patients with NTRK fusion that might benefit from TRK inhibitors.

Association between clinical and tumor features with postoperative thyroglobulin in pediatric papillary thyroid cancer

BackgroundWhy certain patients after total thyroidectomy for thyroid cancer who do not have distant metastasis have increased serum stimulated thyroglobulin (s-Tg) is unknown. The aim of our study was to systematically investigate the associations of preablation s-Tg with clinical and tumor characteristics in children and young adults less than 20 years old after total thyroidectomy for papillary thyroid cancer. MethodsWe performed a retrospective analysis of 93 children and young adults younger than 20 years old who had undergone total thyroidectomy and were without known distant metastases who underwent remnant ablation. Before any remnant preablation, we assessed the association of s-Tg after thyroid hormone withdrawal with the clinical and histopathologic characteristics according to the American Thyroid Association pediatric initial risk classification system. ResultsThe median age was 18 years, and the majority of patients were female (80%). The preablation s-Tg ranged from 0.02 to 902.00 ng/mL, with a median of 9.2 ng/mL. Forty-five (48%) patients had an increased preablation s-Tg >10 ng/mL. In multivariate analyses of clinical and tumor characteristics, high-risk stratification and high neck uptake (>2%) were the independent predictive factors for the presence of an increased preablation s-Tg. ConclusionChildren and young adults younger than 20 years old with high-risk stratification and high neck uptake are likely to present a high level of preablation s-Tg after total thyroidectomy for papillary thyroid cancer. Continued long-term surveillance is necessary in this cohort of patients to confirm the role of preablation s-Tg as a biomarker for monitoring postoperative residual disease.

EV PD-L1 is Correlated With Clinical Features and Contributes to T Cell Suppression in Pediatric Thyroid Cancer.

The contribution of blood extracellular vesicular (EV) programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) in papillary thyroid cancer (PTC) is uncertain. We sought to determine the relationship of EV PD-L1/PD-1 with the clinical features of pediatric PTC and the role of EV PD-L1 in immunosuppression. Plasma levels of EV and soluble PD-L1 and PD-1 and levels of plasma cytokines in children with PTC and controls were determined by enzyme-linked immunosorbent assay. Levels of tumor PD-L1 and the tumor-infiltrating lymphocyte (TIL) score were determined by immunohistochemistry. Correlations of the plasma PD-L1/PD-1 level with clinicopathological characteristics, levels of plasma cytokines, tumor PD-L1 expression, and TIL score were analyzed. T-cell suppression by EVs from PTC patients was determined by incubation of PD-L1high or PD-L1low EVs with activated CD8+ T cells. Changes in CD69 and PD-1 expression and changes in tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) secretion were measured by flow cytometry. The levels of plasma PD-L1/PD-1 were significantly higher in children with PTC than in controls. The levels of plasma EV PD-L1 significantly correlated with tumor T stage, tumor PD-L1 expression, TIL score, and plasma cytokine content. Levels of plasma soluble PD-1 significantly correlated with patient age, plasma EV PD-L1, and IFNα concentration. PD-L1high EVs significantly inhibited the activation of CD8+ T cells. Plasma levels of EV PD-L1, but not soluble PD-L1, were associated with tumor T stage in children with PTC. Plasma EV PD-L1 emerges as a useful metric for assessing tumor T stage and T cell suppression in PTC.

Recurrence and Complications in Pediatric and Adolescent Papillary Thyroid Cancer in a High-Volume Practice

BackgroundTreatment approaches for pediatric papillary thyroid cancer (PTC) are historically extrapolated from adult experience. However, pediatric PTC demonstrates a greater propensity for lymph node involvement, early metastases, and recurrence, highlighting the need for pediatric-specific treatment paradigms. Materials and methodsA retrospective review included patients with PTC aged ≤21 y, with ≥18 mo of follow-up, treated between 2002 and 2015. Fisher's exact test and Cox proportional hazard were used to estimate the effect of risk factors on disease recurrence. ResultsSeventy-two cases of PTC were identified with median age of 17.0 y and median follow-up of 64.1 mo. Disease recurred at a median of 24.6 mo (range 7.8-78.1) in 7 of 51 (13.7%) of patients with disease limited to the thyroid or central neck, 7 of 18 (39%) patients with lateral neck disease at presentation who underwent a compartment-based resection, and three of three patients (100%) with lateral neck disease who sought care after non–compartment-based resection. There were no deaths from disease. Univariate predictors of recurrence included tumor size >2 cm (P = 0.005), lateral neck disease (P = 0.004), lymphovascular invasion (P = 0.017), extracapsular invasion (P < 0.0001), multifocality (P = 0.03), and non-Caucasian race (P = 0.05). Multivariate analysis identified race (P = 0.05) as an independent predictor of recurrence. In patients without lateral neck disease, there was a trend toward lower recurrence in patients undergoing thyroidectomy with central neck dissection compared with thyroidectomy alone (P = 0.07). ConclusionsPediatric PTC is associated with excellent survival, although recurrence is common in patients with lateral node involvement. Predictors of recurrence are multifactorial and may be influenced by extent of disease, patient or tumor biology, and aggressiveness of resection. Level of evidencePrognosis study, level IV, retrospective case series.

Somatic genetic alterations in a large cohort of pediatric thyroid nodules.

There is a rise in the incidence of thyroid nodules in pediatric patients. Most of them are benign tissues, but part of them can cause papillary thyroid cancer (PTC). The aim of this study was to detect the mutations in commonly investigated genes as well as in novel PTC-causing genes in thyroid nodules and to correlate the found mutations with clinical and pathological data. The cohort of 113 pediatric samples consisted of 30 benign lesions and 83 PTCs. DNA from samples was used for next-generation sequencing to identify mutations in the following genes: HRAS, KRAS, NRAS, BRAF, IDH1, CHEK2, PPM1D, EIF1AX, EZH1 and for capillary sequencing in case of the TERT promoter. RNA was used for real-time PCR to detect RET/PTC1 and RET/PTC3 rearrangements. Total detection rate of mutations was 5/30 in benign tissues and 35/83 in PTCs. Mutations in RAS genes (HRAS G13R, KRAS G12D, KRAS Q61R, NRAS Q61R) were detected in benign lesions and HRAS Q61R and NRAS Q61K mutations in PTCs. The RET/PTC rearrangement was identified in 18/83 of PTCs and was significantly associated with higher frequency of local and distant metastases. The BRAF V600E mutation was identified in 15/83 of PTCs and significantly correlated with higher age of patients and classical variant of PTC. Germline variants in the genes IDH1, CHEK2 and PPM1D were found. In conclusion, RET/PTC rearrangements and BRAF mutations were associated with different clinical and histopathological features of pediatric PTC. RAS mutations were detected with high frequency in patients with benign nodules; thus, our results suggest that these patients should be followed up intensively.

Lymph node ratio predicts recurrence in pediatric papillary thyroid cancer

BackgroundRegional lymph node (LN) metastasis at the time of presentation plays a significant role in predicting recurrence in patients with papillary thyroid cancer (PTC). Multiple studies in the adult population have demonstrated that the lymph node ratio (LNR) in both the central and lateral neck can improve the accuracy of recurrence prediction, but this ratio has not been studied in the pediatric population. In this study, we sought to investigate the LNR in the central and lateral compartments as a prognostic predictor for recurrence in pediatric patients with PTC. MethodsA retrospective analysis of pediatric patients (≤21 years old) at a single institution between 2002 and 2014 who underwent total thyroidectomy with prophylactic central neck dissection (TTpCND) with at least 3 sampled nodes or total thyroidectomy with unilateral modified radical neck dissection (TTMRND) with at least 10 sampled nodes, and on whom at least 24 months of follow up data were available was performed. The LNR was defined as the ratio of metastatic LNs to total number of investigated LNs. Recurrence after TTpCND and TTMRND was examined separately as a function of LNR, using the value of 0.45 as a cutoff. ResultsForty-eight patients met inclusion criteria. Thirty-two underwent TTpCND, and sixteen underwent TTMRND. Median age at time of operation was 17 years (range 6–20), and median duration of follow-up was 53.5 months (range 24–183). In the TTpCND, LNR ranged from 0 to 1.0. There were two recurrences among the eight patients (25%) undergoing TTpCND in patients with LNRs >0.45 and a single recurrence among the 24 patients (4.2%) undergoing TTpCND with an LNR ≤0.45. In the TTMRND, LNR ranged from 0.1 to 1.0. There were 3 recurrences in 12 patients with LNR ≤0.45 (30.8%%) and 4 recurrences in 4 patients with LNR >0.45 (100%) (p = 0.03). ConclusionsAlthough limited by small sample size, LNR may be a useful predictor to stratify the likelihood of recurrence in pediatric patients undergoing TTpCND or TTMRND for pathologic N1a or N1b PTC. Type of studyPrognosis study / retrospective case series. Level of evidenceLevel IV.

Up-regulated lipocalin-2 in pediatric thyroid cancer correlated with poor clinical characteristics.

The incidence of thyroid cancer is fast increasing in both adults and children. The pediatric thyroid cancer had often already progressed to a more advanced stage of the disease at diagnosis. Early detection of pediatric thyroid cancer has been a problem for many years. Lipocalin-2 (Lcn2) has been reported to be over-expressed in cancers of diverse histological origin and it facilitates tumorigenesis by promoting survival, growth, and metastasis. The plasma Lcn2 concentration of 28 Chinese papillary thyroid cancer (PTC) children and 24 healthy controls was measured. Immunostaining for Ki-67 of tumor tissue from PTC children was performed. The expression levels of Lcn2 and NFκB in PTC tissue and peri-carcinoma tissue of PTC children were measured through Western blot. The plasma concentration of Lcn2 was significantly elevated in pediatric PTC patients compared with healthy controls. Besides, the plasma Lcn2 concentration significantly correlated with clinical characteristics, NFκB level, and Ki-67 positive rate of nucleus in tissue of PTC. This is the first study to evaluate the plasma Lcn2 in pediatric PTC patients. It is possible that the plasma Lcn2 may be a new biomarker of pediatric thyroid cancer. Further studies are needed to explore the definite role and mechanism of Lcn2 in thyroid cancer, which will help to explore novel diagnostic or therapeutic strategies.

Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers.

Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer (ATC) and identify genetic alterations of potential diagnostic, prognostic, and therapeutic significance.Experimental Design: The genetic profiles of 583 advanced differentiated and 196 ATCs generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed.Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared with other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated thyroid cancers and ATCs. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT, and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2, and JAK2, and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT, and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro Three genetically distinct types of ATCs are proposed.Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed. Clin Cancer Res; 24(13); 3059-68. ©2018 AACR.

Use of Ultrasound for Prognostication and Surgical Decision-making in Pediatric Papillary Thyroid Cancer*

Use of Ultrasound for Prognostication and Surgical Decision-making in Pediatric Papillary Thyroid Cancer*