Cytomorphological and molecular genetic findings in pediatric thyroid fine-needle aspiration

Authors


  • Presented in part at the United States and Canadian Academy of Pathology (USCAP) Annual Meeting; March 17-23, 2012; Vancouver, BC, Canada.

Abstract

BACKGROUND:

The Bethesda System for Reporting Thyroid Cytopathology is largely based on data from adult studies. Although thyroid nodules in children are rare, the rate of malignancy is high. The authors' aim was to analyze the cytomorphology and mutational profiles in pediatric thyroid fine-needle aspirations (FNAs).

METHODS:

Thyroid FNAs from patients 21 years old or younger were identified from the authors' pathology archive, categorized using the Bethesda System for Reporting Thyroid Cytopathology, and correlated with histological and molecular follow-up.

RESULTS:

A total of 179 samples from 142 patients were identified, including 96 cases (54%) with histological follow-up and 66 cases (37%) with molecular data. The diagnoses included 21 (12%) unsatisfactory, 82 (46%) negative, 43 (24%) atypia or follicular lesion of undetermined significance, 19 (11%) suspicious for follicular neoplasm, 6 (3%) suspicious for malignancy, and 8 (4%) positive for malignancy. The rate of malignancy in each category was 0%, 7%, 28%, 58%, 100%, and 100%, respectively. Of the 66 FNAs with molecular data, there were 11 (17%) positive for mutations. All mutation-positive FNAs were papillary thyroid carcinomas (PTCs) on resection. The overall sensitivity and specificity in this population were 80% and 100%, respectively.

CONCLUSIONS:

This study demonstrates that thyroid FNA in children is a sensitive and highly specific tool. There was a 17% positivity rate for a genetic mutation, which correlated with malignancy in all cases. In comparison to adults, there was a higher prevalence of RET/PTC mutations and lower prevalence of BRAF mutations, which may in part explain the less aggressive nature of PTCs reported in children. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.

INTRODUCTION

Although thyroid nodules are uncommon in children, with an incidence of 0.5% to 2%,1-3 thyroid carcinomas are the most common endocrine tumors in children, and the risk of malignancy in pediatric thyroid nodules is reportedly higher than that in adults.1-10 Of these malignancies, papillary thyroid carcinoma (PTC) is the most common type and comprises the majority of these malignancies.5, 11

Thyroid fine-needle aspiration (FNA) in children has been a useful diagnostic modality and has been shown to have a sensitivity of approximately 70% to 100% and a specificity of approximately 80% to 95%, with the highest sensitivities and specificities reported in more recent studies using ultrasound-guided FNA.12-17 Because of its success as a preoperative diagnostic tool, FNA has been the screening test of choice for thyroid nodules and has significantly decreased surgery for benign nodules.14

In 2007, the National Cancer Institute Thyroid FNA State of the Science Conference convened. The meeting resulted in a proposed uniform classification system, known as the Bethesda System for Reporting Thyroid Cytopathology, with 6 diagnostic categories and suggested management guidelines.18, 19 This reporting system was largely based on data from adult populations, and there were no distinct guidelines specified for the evaluation of thyroid FNAs in the pediatric population. Furthermore, no studies to date have explored the use of molecular analysis and the new Bethesda classification in thyroid FNAs performed in children.

In prior studies looking at pediatric thyroid FNAs, a 4-tier system (nondiagnostic, benign, atypical, malignant) has been used.6, 7, 13 However, given the recent classification scheme suggested by the Bethesda System for Reporting Thyroid Cytopathology, our aim was to look at the utility of the 6-tier Bethesda system and the molecular genetic findings from our institution's experience with pediatric thyroid FNAs.

MATERIALS AND METHODS

During a period of 4 and a half years from January 2007 to July 2011, a total of 179 cases of thyroid FNAs in children (aged 21 years old or younger) were retrieved from the pathology files at the University of Pittsburgh Medical Center. The cytopathological diagnoses, ancillary studies (including molecular genetic studies), available clinical information, and histological follow-up were retrospectively reviewed. This study was reviewed and approved by the institutional review board at the University of Pittsburgh Medical Center.

The FNAs were primarily performed under ultrasound guidance (175 cases, 98%) by a radiologist or endocrinologist, whereas only 4 were performed by pathologists using palpation (4 cases, 2%). A 23- to 27-gauge needle was used, and approximately 3 to 5 passes were performed for each targeted site, depending on the ability to obtain adequate material and the ability of the procedure to be tolerated. The aspirated material was used to make air-dried direct smears stained with Diff-Quik (Protocol Hema 3; Fisher Scientific, Kalamazoo, Mich) and direct smears fixed in 95% alcohol for Papanicolaou staining. A small portion of the residual aspirated material was placed in 400 μL of an RNA/DNA Stabilization Reagent (Roche Applied Science, Indianapolis, Ind; Cat. # 1934317) for molecular testing, and the remainder was submitted for Thin Prep processing and/or cell block preparation. The material collected in the nucleic acid preservative solution was frozen at −20°C and transported to the laboratory to be stored at the same temperature until testing was requested, based on the final cytological diagnosis. Diagnoses were made by pathologists specializing in cytopathology and/or pediatric pathology, and the diagnoses were established before the molecular testing results.

On retrospective review, cases were categorized based on the diagnostic categories from the Bethesda System for Reporting Thyroid Cytopathology, the findings were correlated with the available histological follow-up and molecular analysis performed on the targeted nodule. Because our institution implemented the Bethesda System for Reporting Thyroid Cytopathology in September 2008, all cases before this time were reviewed and reclassified according to the Bethesda system. Sensitivity and specificity calculations were performed using those cases with histopathological follow-up and a definitive FNA diagnosis (negative/benign and positive/malignant).

Thyroid FNA cases were sent for mutational analysis starting in April 2007 at our institution for all cytological final diagnoses, except negative for malignant cells (benign) and unsatisfactory/nondiagnostic diagnoses. The adequacy of samples for molecular testing was based on the quantity and quality of isolated nucleic acids and the proportion of epithelial cells in the sample. Mutational analysis was performed for BRAF (V600E), NRAS codon 61, HRAS codon 61, and KRAS codons 12 and 13 using real time polymerase chain reaction (PCR) and post-PCR fluorescence melting curve analysis on the LightCycler (Roche Applied Science). A pair of primers flanking each mutation site and 2 fluorescent probes were used, as previously described.20 Amplification was performed using 5 to 50 ng of DNA, 40 pmol of each primer, and 2 pmol of each hybridization probe, and a LightCycler FastStart DNA Master HybProbe Kit (Roche Applied Science). The reaction mixture was subjected to 40 cycles of PCR amplification consisting of denaturation at 95°C for 5 seconds, annealing at 54°C for 20 seconds, and extension at 72°C for 12 seconds. Postamplification fluorescence melting curve analysis was performed by gradual heating of samples at a rate of 0.1°C/s from 45°C to 95°C. Samples that were positive for a mutation on fluorescence melting curve analysis were confirmed by Sanger sequencing. The RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements were detected by real time reverse transcriptase PCR with primers designed to flank the respective fusion point on ABI 7500 (Applied Biosystems, Foster City, Calif), as previously described.20, 21 Two controls (GAPDH and KRT7) were used to assess quality and quantity of sample as previously published.20, 21

RESULTS

Clinicopathological Features

A total of 179 cases from 142 patients were identified, with a mean age of 16.5 years (range, 4-20 years). There were 115 (81%) females and 27 (19%) males. The targeted lesions were located on the right (93 cases; 52%), left (62 cases; 35%), or isthmus (12 cases; 7%) of the thyroid gland in the 167 cases with available information. A total of 96 cases (54%) had histological follow-up available in our records, and 66 cases (37%) had molecular data. Of the 96 cases with histological follow-up, 44 cases (46%) cases were benign, 39 cases (41%) cases were malignant (37 PTC, 2 follicular carcinoma), and 13 cases (14%) cases had other neoplasms (12 follicular or oncocytic adenoma, 1 granular cell tumor). The papillary thyroid carcinomas included classical PTC (21 cases, 56.5%), follicular variant PTC (15 cases, 41%), and 1 cribriform-morular variant PTC (1 case, 2.5%).

Cytomorphological Findings and Histological Correlation

Overall, there were a total of 21 cases (12%) with insufficient material for diagnosis, and 8 (38%) of these cases had histological follow-up with no evidence of malignancy. Of the remaining 158 cases (88%), 88 cases (56%) had histological follow-up, with malignancy identified in 39 cases (44%). A total of 82 FNA cases (46%) were negative for malignant cells, and of the cases with available follow-up, 2 were diagnosed as the encapsulated follicular variant of PTC on follow-up. These negative cases were retrospectively reviewed and did not show evidence of PTC in the FNA specimen, suggesting that these discrepancies were related to sampling errors. Of the atypia or follicular lesion of undetermined significance (AUS/FLUS) cases, there were 7 targeted nodules (28%) found to be malignant on follow-up, including 4 follicular variant PTC, 2 classical PTC, and 1 follicular carcinoma. The remaining 18 cases with follow-up included 13 benign/nodular hyperplasia cases and 5 follicular or oncocytic adenomas. Figure 1 shows the cytomorphology, follow-up histology, and molecular results in an AUS/FLUS case. Of the cases with a diagnosis of suspicious for follicular neoplasm, 10 of the 13 cases (77%) were malignant on histological follow-up, including PTC follicular variant (9 cases) and follicular carcinoma (1 case; Fig. 2). The other cases had diagnoses of follicular adenoma (1 case) and nodular hyperplasia (2 cases). Of the cases with a diagnosis of suspicious for oncocytic neoplasm, 1 of the 6 cases (17%) was a PTC follicular variant on histological follow-up. The remaining nonmalignant diagnoses in this category included oncocytic adenoma (2 cases), nodular hyperplasia (2 cases), and granular cell tumor (1 case). All of the FNAs with a diagnosis of suspicious or positive for malignant cells were found to be malignant on follow-up (Figs. 3 and 4). These findings are presented in Table 1. The overall sensitivity of thyroid FNA in this population was 80%, and the specificity was 100%.

Figure 1.

Pediatric thyroid fine-needle aspiration (FNA) with atypia or follicular lesion of undetermined significance diagnosis and positive molecular testing is shown. (A, B) The FNA slides were limited by scant cellularity and showed a few crowded cell groups trapped within blood clot (Diff-Quik; original magnification, ×400). (C) Reflex molecular testing revealed an HRAS mutation. (D) On resection, there was an encapsulated follicular variant of papillary thyroid carcinoma with capsular invasion (H & E; original magnification, ×400).

Figure 2.

Pediatric thyroid FNA diagnosed as suspicious for follicular neoplasm and positive for PAX8/PPARγ rearrangement is shown. The aspirates are cellular and show follicular cells in clusters with microfollicle formation and scant colloid. (A) The cells show occasional nucleoli, but no definitive intranuclear cytoplasmic inclusions were identified (Diff-Quik; original magnification, ×400). (B) Follow-up molecular testing was positive for the PAX8/PPARγ rearrangement, and (C) the histological follow-up revealed a follicular variant of papillary thyroid carcinoma (H & E; original magnification, ×400).

Figure 3.

Pediatric thyroid fine-needle aspiration with a diagnosis of suspicious for malignant cells and positive for RET/PTC rearrangement. (A, B) The aspirates showed cells with crowding, occasional grooves, and small nucleoli, but no definitive intranuclear cytoplasmic inclusions were identified; thus, the case was categorized as suspicious for papillary thyroid carcinoma (A: Diff-Quik; original magnification, ×400; B: Papanicolaou; original magnification, ×400). (C) Follow-up molecular testing was positive for the RET/PTC rearrangement.

Figure 4.

Papillary thyroid carcinoma in a child diagnosed by thyroid fine-needle aspiration with positive BRAF testing is shown. (A, B) The aspirates were cellular, with clusters of cells showing cleared out chromatin, grooves, and small peripherally placed nucleoli, against a background of scant dense colloid. In addition, intranuclear inclusions were easily identified (arrow; A: Diff-Quik; original magnification, ×400; B: Papanicolaou, original magnification, ×400). (C) Mutational testing was positive for the BRAF mutation. (D) The histological follow-up revealed a conventional papillary thyroid carcinoma (H & E; original magnification, ×400).

Table 1. Correlation of Pediatric Thyroid Fine-Needle Aspiration Diagnoses With Histopathological Results
DiagnosisCases, No. (%)Total With Follow-up, No. (%)Malignant on Follow-up, No. (%)
    
  1. Abbreviations: AUS/FLUS, atypia or follicular lesion of undetermined significance; TBSRTC, the Bethesda System for Reporting Thyroid Cytopathology.

Adequacy   
 Adequate158 (88)88 (56)34 (39)
 Inadequate21 (12)8 (38)0 (0)
TBSRTC diagnostic categories   
 Nondiagnostic21 (12)8 (38)0 (0)
 Negative for malignant cells/benign82 (46)30 (37)2 (7)
 AUS/FLUS43 (24)25 (58)7 (28)
 Suspicious for follicular or oncocytic neoplasm19 (11)19 (100)11 (58)
 Suspicious for malignant cells6 (3)6 (100)6 (100)
 Positive for malignant cells8 (4)8 (100)8 (100)
Total17996 (54)34 (35)

Results of Molecular Testing

Of the 66 samples (37%) with molecular analysis, there were 47 (71%) negative, 8 (12%) indeterminate, and 11 (17%) positive for mutations. The FNA samples with molecular testing positive for any mutation were all PTCs on resection, including follicular variant PTC (6 cases) and conventional PTC (5 cases). The molecular findings in these FNA cases included 4 RAS mutations (36%; 1 HRAS, 2 NRAS, and 1 with HRAS and NRAS), 3 RET/PTC rearrangements (27%), 2 BRAF mutations (18%), and 2 PAX8/PPARγ rearrangements (18%), as shown in Table 2. The FNA diagnoses (shown in Table 3) in these positive cases included AUS/FLUS (2 cases), suspicious for follicular or oncocytic neoplasm (5 cases), suspicious for malignancy (1 case), and positive for malignancy (3 cases). The 2 samples that tested positive for BRAF mutations were 2 separate nodules of conventional PTC in an 18-year-old woman. The final histological diagnosis in the 4 samples with RAS mutations was follicular variant of PTC. The 3 samples testing positive for RET/PTC rearrangements were conventional PTCs on final histology. The 2 samples with PAX8/PPARγ rearrangements were follicular variant of PTC on final histology. Of the 47 nodules that were negative for all the mutations tested, 33 nodules had histological follow-up, and 16 (48.5%) were malignant on histological follow-up. Of the 8 indeterminate cases by molecular testing, 1 case (12.5%) was found to be malignant on follow-up. Three nondiagnostic and 2 negative cases had molecular results, because these cases were reclassified upon review for the study. Overall, the rate of malignancy in the cases with molecular testing and available histological follow-up results was 54%. Figures 1 through 4 show illustrative cases in different diagnostic categories according to the Bethesda System for Reporting Thyroid Cytopathology with follow-up molecular results and histology.4

Table 2. Correlation of Pediatric Thyroid Fine-Needle Aspiration Diagnoses With Molecular Genetic Data (n = 66 Cases With Molecular Testing)
Molecular Genetic TestPositive Cases, No. (%)Cases With Molecular Testing, %Overall Cases, %
HRAS611 (9.0)1.60.6
NRAS612 (18.2)3.01.1
HRAS61 AND NRAS611 (9.0)1.60.6
BRAF V600E2 (18.2)3.01.1
RET/PTC1 rearrangement3 (27.3)4.51.7
PAX8/PPARg2 (18.2)3.01.1
Total1116.76.2
Table 3. Thyroid Fine-Needle Aspiration Diagnoses in Cases With Molecular Genetic Mutations Detected (n = 66 Cases With Molecular Testing)
TBSRTC CategoryPositive Molecular Cases, No. (%)Positive Molecular Cases of the Overall Cases in the Diagnostic Category, No. (%)
  1. Abbreviations: AUS/FLUS, atypia or follicular lesion of undetermined significance; TBSRTC, the Bethesda System for Reporting Thyroid Cytopathology.

AUS/FLUS2 (18)2 of 43 (5)
Suspicious for follicular or oncocytic neoplasm5 (45)5 of 19 (25)
   
Suspicious for malignant cells1 (9)1 of 6 (17)
Positive for malignant cells3 (27)3 of 8 (38)
Total11 (17)11 of 179 (6)
Table 4. Correlation of Molecular Testing Results With TBSRTC Categories and Follow-up
TBSRTC Diagnostic CategoriesCases, No. (%)Molecular Testing, No. (%)Molecular Cases With Surgical Follow-up, No. (%)Malignant on Surgical Follow-up, No. (%)
     
  1. Abbreviations: AUS/FLUS, atypia or follicular lesion of undetermined significance; FN/ON, follicular neoplasm or oncocytic neoplasm; TBSRTC, the Bethesda System for Reporting Thyroid Cytopathology.

Nondiagnostic21 (12)3 (14)2 (67)0 (0)
 Nondiagnostic with positive molecular 00 (0)0 (0)
 Nondiagnostic with negative molecular 21 (50)0 (0)
 Nondiagnostic with indeterminate molecular 11 (100)0 (0)
Negative/benign82 (46)2 (2)2 (100)0 (0)
 Negative/benign with positive molecular 00 (0)0 (0)
 Negative/benign with negative molecular 00 (0)0 (0)
 Negative/benign with indeterminate molecular 22 (100)0 (0)
AUS/FLUS43 (24)34 (79)15 (44)7 (28)
 AUS/FLUS with positive molecular 1 (HRAS)1 (100)1 (100)
 AUS/FLUS with negative molecular 2912 (41)2 (17)
 AUS/FLUS with indeterminate molecular 42 (50)0 (0)
Suspicious for FN/ON19 (11)14 (74)14 (100)9 (64)
 Suspicious for FN/ON with positive molecular 5 (HRAS, NRAS, PAX8/PPARg)5 (100)5 (100)
 Suspicious for FN/ON with negative molecular 99 (100)4 (67)
 Suspicious for FN/ON with indeterminate molecular 00 (0)0 (0)
Suspicious for malignant cells6 (3)6 (100)6 (100)6 (100)
 Suspicious for malignant cells with positive molecular 2 (RET/PTC1)2 (100)2 (100)
 Suspicious for malignant cells with negative molecular 33 (100)3 (100)
 Suspicious for malignant cells with indeterminate molecular 11 (100)1 (100)
Positive for malignant cells8 (4)7 (88)7 (100)7 (100)
 Positive for malignant cells with positive molecular 3 (1 RET/PTC1, 2 BRAF)3 (100)3 (100)
 Positive for malignant cells with negative molecular 44 (100)4 (100)
 Positive for malignant cells with indeterminate molecular 00 (0)0 (0)
Total179 (100)66 (37)46 (70)34 (74)

DISCUSSION

Thyroid nodules in children are uncommon, but have an increased risk of malignancy when compared with thyroid nodules in adults.2-10 Studies have shown that thyroid FNA is an effective screening tool in these young patients,11-17 but no prior studies have applied the new Bethesda System for Reporting Thyroid Cytopathology to pediatric thyroid FNAs and investigated the utility of reflex molecular genetic studies in children.

This study shows that the 6-tier system of the Bethesda System for Reporting Thyroid Cytopathology can be applied to children with a rate of malignancy that increases in an incremental fashion from nondiagnostic or negative to positive, including a lower rate of malignancy in the AUS/FLUS cases than in the suspicious categories. The proportion of cases in each category illustrates that 24% of the pediatric FNAs were classified in the AUS/FLUS category by the Bethesda System for Reporting Thyroid Cytopathology, and only 46% of cases were in the benign category. The greater proportion of cases in the AUS/FLUS category may be related to the smaller proportion of cases classified as negative for malignant cells, the presence of compromised cases with scant cellularity, or the high proportion of cases with the follicular variant of PTC on follow-up. The findings may also be related to the legitimate concern of missing a thyroid malignancy in young patients, with a greater chance of malignancy than adults.

Within the AUS/FLUS category, 28% of the FNAs with available histological follow-up were malignant, with the majority of cases were diagnosed as the follicular variant of PTC. This rate of malignancy is greater than the 5% to 10% chance of malignancy reported by the Bethesda System for Reporting Thyroid Cytopathology for the AUS/FLUS category18; however, it is similar to the malignancy rate reported in other studies examining malignancy in indeterminate pediatric thyroid FNAs.6, 7, 11, 13 The increased proportion of AUS/FLUS cases and the higher malignancy rate in this category may be related to the finding that the majority of the malignancies identified were the follicular variant of PTC, which is known to be difficult to diagnose based on the cytomorphology given the subtle nuclear features.18, 19 Given that the rate of malignancy in the AUS/FLUS group approximates the reported risk of malignancy in the suspicious for follicular or oncocytic neoplasm (20%-40%) category in the guidelines established by the Bethesda System for Reporting Thyroid Cytopathology, the findings suggest that the management guidelines established in the Bethesda system may not be directly applicable to pediatric patients.18 Young patients with an AUS/FLUS diagnosis may benefit more from having surgical treatment (partial thyroidectomy; as suggested by the Bethesda System for Reporting Thyroid Cytopathology for FNAs suspicious for a follicular or oncocytic neoplasm), as opposed to a repeat FNA, which has been described in other studies.13, 22

Data based upon molecular testing for the panel of mutations selected in our pediatric thyroid FNA samples show that approximately 17% of tested samples were positive for mutations or rearrangements. The presence of any mutation in this study correlated with malignancy in 100% of cases, including nodules with indeterminate cytology. The incidence of mutations and the malignancy rate in mutation-positive cases are higher than those reported in the adult population by our institution, where approximately 7% of tested samples were positive for a mutation, and 87% to 97% of mutation-positive adult nodules were positive for malignancy.20, 21 Of the positive cases, the more prevalent abnormalities were RAS mutations (6.2%) and RET/PTC rearrangements (4.5%). The increased prevalence of RET/PTC rearrangements in pediatric populations and their association with a favorable prognosis and low likelihood of progression to a more aggressive tumor are well known.23-26 The less common abnormalities in this young population were BRAF mutations (3%) and PAX8/PPARγ rearrangements (3%). The higher prevalence of RET/PTC mutations and lower prevalence of BRAF mutations in pediatric PTCs, as compared with adult populations, has been reported before,23, 25-28 and correlates with the less aggressive nature of PTC that has been reported in young individuals.23-26 However, the proportion of cases with PAX8/PPARγ rearrangements was higher than that seen in adult-predominant populations,20, 21 and this finding has not been well described in pediatric thyroid nodules. Furthermore, mutation-negative thyroid nodules in this young population had a malignancy rate of 48.5%, which is higher than the 14% rate of malignancy reported in mutation-negative thyroid nodules in adult-predominant populations.20, 21 This stresses the importance of cytological evaluation by FNA to identify those nodules requiring surgery.

The use of molecular testing may also be helpful in young patients with an indeterminate cytological diagnosis of AUS/FLUS or suspicious for follicular/oncocytic neoplasm, given that detection of a molecular genetic abnormality correlated with malignancy in all cases, and would change the management of the patient from that suggested by the Bethesda System for Reporting Thyroid Cytopathology. For example, positivity for a mutation would enable these young patients to go directly to thyroidectomy, without the need for a repeat FNA under anesthesia or a staged surgical approach (partial thyroidectomy followed by completion thyroidectomy).21 In our study, the molecular studies would change the management in 5% of the AUS/FLUS cases and 25% of the suspicious for follicular or oncocytic neoplasm cases, thereby expediting surgery and decreasing the need for unnecessary procedures (ie, repeat FNA with sedation or anesthesia or staged thyroidectomy) in these young patients. Although one could argue that this approach would increase the number of children being referred for surgery and the potential risk of complications, studies examining thyroid surgery in children by experienced surgeons have reported a low complication rate.22 Furthermore, molecular testing can help in suspicious and positive FNA cases, because the presence of a BRAF mutation has been associated with a greater chance of lymph node metastases, and therefore helps with preoperative management planning and risk stratification.29, 30

In our pediatric population, the overall rate of thyroid malignancy was 35%, and the vast majority of these malignancies were PTC (95%). This rate of malignancy is comparable to the range of malignancy (20%-50%) reported by other studies examining surgically resected pediatric and adult thyroid nodules,2, 5, 22, 30, 31 and likely overestimates the true risk of malignancy because of selection bias. Prior studies reporting lower malignancy rates (6.6%-18%) in pediatric thyroid nodules included smaller sample sizes and younger patients (13.1-14.6 vs 16.5 years of age).6, 9 Given that the risk of thyroid cancer is linked to age, with a much greater risk in children between the ages 15 and 19 years,32, 33 the different rates of malignancy in these studies may reflect the age of the study population.

Overall, in this study, thyroid FNA was a sensitive (80% sensitivity) and highly specific (100% specificity) diagnostic modality in children. Furthermore, the findings in this study demonstrate that the 6-tier classification system suggested by the Bethesda System for Reporting Thyroid Cytopathology can be applied, correlating with an incremental risk of malignancy. However, these pediatric patients differ in that there was a higher rate of malignancy in the AUS/FLUS group and a higher rate of molecular abnormalities detected, in comparison to adult populations. These findings raise the possibility that the management guidelines and risk of malignancy in pediatric patients may differ from those suggested in the Bethesda System for Reporting Thyroid Cytopathology. Furthermore, molecular genetic findings may help in a subset of pediatric patients to identify cancerous nodules that could go directly to the appropriate surgery without repeat aspiration or staged surgery. The higher prevalence of RET/PTC mutations and lower prevalence of BRAF mutations in this young population may in part explain the less aggressive nature of PTCs reported in children.

FUNDING SOURCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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