Dataset Information

Evaluation of the Molecular Landscape of Pediatric Thyroid Nodules and Use of a Multigene Genomic Classifier in Children.

ABSTRACT:

Importance

Definitive diagnosis of a thyroid nodule in a child is obtained through diagnostic surgery. This is problematic because pediatric thyroid surgery is associated with higher rates of complications. In adults, preoperative molecular testing improves the management of thyroid nodules, but this has not been validated in children.

Objective

To determine whether the molecular landscape of pediatric thyroid nodules is amenable to detection by a multigene genomic classifier (GC) test (ThyroSeq v3; Sonic Healthcare USA).

Design, setting, and participants

This was a retrospective consecutive case series and GC testing of fine-needle aspiration (FNA) and formalin-fixed paraffin-embedded (FFPE) tissues from sequential pediatric thyroidectomies performed between January 2003 and December 2019 at a single tertiary academic medical center. The study included 95 patients (median [range] age, 16.3 [4.8 to 21.1] years; 75 [79%] female) who underwent surgery for a thyroid nodule.

Interventions

A total of 118 thyroid nodule samples (95 FFPE, 23 companion FNAs) yielded informative next-generation sequencing data and multigene GC.

Main outcomes and measures

The primary outcome was the determination of the pediatric thyroid molecular landscape. The secondary outcome was the diagnostic accuracy of the GC test for pediatric thyroid nodules.

Results

Of the 95 patients, 75 (79%) were female, and the median (IQR) age was 16.3 (14.0-17.3) years. Next-generation sequencing confirmed the unique molecular landscape of malignant pediatric thyroid nodules (compared with adults), which is dominated by gene fusions (most commonly RET and NTRK), rare BRAF/RAS alterations, and no TP53 or TERT promoter pathogenic variants. Several poorly differentiated thyroid cancers harbored DICER1 variants. Benign nodules appeared to be almost exclusively associated with TSHR and DICER1 alterations. The test demonstrated a 96% sensitivity (95% CI, 87%-99%) and 78% specificity (95% CI, 64%-88%). The negative predictive value was 95% (95% CI, 88%-98%) and the positive predictive value was 83% (95% CI, 74-89%). The concordance of GC between 23 pairs of matched FFPE and FNA tissues was 96%.

Conclusions and relevance

The study results of this retrospective consecutive case series suggest that the molecular landscape of pediatric nodules is unique but remains amenable to molecular classification. The multigene GC test, with high sensitivity and reasonably high specificity, represents a potential addition to the diagnostic workup of children with thyroid nodules and may decrease the use of diagnostic surgery.

SUBMITTER: Gallant JN

PROVIDER: S-EPMC9185516 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Evaluation of the Molecular Landscape of Pediatric Thyroid Nodules and Use of a Multigene Genomic Classifier in Children.

Gallant Jean-Nicolas JN Chen Sheau-Chiann SC Ortega Carlos A CA Rohde Sarah L SL Belcher Ryan H RH Netterville James L JL Baregamian Naira N Wang Huiying H Liang Jiancong J Ye Fei F Nikiforov Yuri E YE Nikiforova Marina N MN Weiss Vivian L VL

JAMA oncology 20220901 9

<h4>Importance</h4>Definitive diagnosis of a thyroid nodule in a child is obtained through diagnostic surgery. This is problematic because pediatric thyroid surgery is associated with higher rates of complications. In adults, preoperative molecular testing improves the management of thyroid nodules, but this has not been validated in children.<h4>Objective</h4>To determine whether the molecular landscape of pediatric thyroid nodules is amenable to detection by a multigene genomic classifier (GC) ...[more]

PMID: 35679040

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Project description:Background: Molecular testing is increasingly used to refine the probability of cancer and assess recurrence risk in thyroid nodules with Bethesda III/IV fine needle aspiration (FNA) cytology. However, limited data exist for Bethesda V (suspicious for malignancy [SFM]) samples. This study evaluated the performance of ThyroSeq v3 (TSv3) in thyroid nodules with SFM cytology. Methods: In this single-institution retrospective cohort study, consecutive thyroid FNA samples diagnosed as SFM with TSv3 testing and known surgical outcome were identified. Clinical, pathology, and molecular findings were reviewed. The TSv3 Cancer Risk Classifier was used to determine molecular risk groups (MRGs). For test-negative cases diagnosed as cancer/noninvasive follicular thyroid neoplasm with papillary-like nuclear features, TSv3 was performed on the resected tumors. Results: Among 128 SFM samples studied, 100 (78.1%) were TSv3 positive, and 28 (21.9%) were negative. The cancer prevalence on surgery was 82.8%. Among test-positive samples, 95% were malignant and 5% benign. Among test-negative samples, 17 (60.7%) were benign and 11 (39.3%) malignant. Overall, TSv3 had a sensitivity of 89.6% (confidence interval; CI 82.4-94.1) and a specificity of 77.3% (CI 56.6-89.9). For a cancer prevalence of 50-75% expected in SFM cytology by the Bethesda system, the negative predictive value was expected to range from 71.2% to 88.1% and the positive predictive value from 79.8% to 92.2%. Among test-positive nodules, 20% were MRG-Low (mostly RAS-like alterations), 66% MRG-Intermediate (mostly BRAF-like alterations), and 14% MRG-High. Among patients with cancer, 65 (61.3%) were American Thyroid Association low risk, 25 (23.6%) intermediate risk, and 6 (5.7%) high risk. During the mean follow-up of 51.2 months (range: <1 to 470 months), 12 (13.0%) patients had disease recurrence, which was more common in MRG-High (54.6%) compared with MRG-Intermediate (9.5%) and MRG-Low (0%) cancers (p < 0.001). Upon reexamining tumors with false-negative results, half of evaluable cases had alterations likely missed due to limiting FNA sampling, and the remainder represented low-risk tumors. Potentially targetable alterations were identified in 10 samples. Conclusions: In this large series of SFM thyroid nodules, TSv3 further improved cancer prediction and detected RAS-like, BRAF-like, high-risk, and potentially targetable alterations, all of which may inform more optimal patient management. MRGs were associated with recurrence-free survival, offering potential preoperative cancer risk stratification.

Project description:ImportanceApproximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery.ObjectiveTo determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules.Design, setting, and participantsProspective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules.InterventionsA total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3).Main outcomes and measuresThe primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules.ResultsOf the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%.Conclusions and relevanceIn this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.

Project description:ImportanceUse of next-generation sequencing of RNA and machine learning algorithms can classify the risk of malignancy in cytologically indeterminate thyroid nodules to limit unnecessary diagnostic surgery.ObjectiveTo measure the performance of a genomic sequencing classifier for cytologically indeterminate thyroid nodules.Design, setting, and participantsA blinded validation study was conducted on a set of cytologically indeterminate thyroid nodules collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the United States. All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. There were 210 potentially eligible thyroid biopsy samples with Bethesda III or IV indeterminate cytopathology that constituted a cohort previously used to validate the gene expression classifier. Of these, 191 samples (91.0%) had adequate residual RNA for validation of the genomic sequencing classifier. Algorithm development and independent validation occurred between August 2016 and May 2017.ExposuresThyroid nodule surgical histopathology diagnosis by an expert panel blinded to all genomic data.Main outcomes and measuresThe primary end point was measurement of genomic sequencing classifier sensitivity, specificity, and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary end point was measurement of classifier performance in biopsies from Bethesda II, V, and VI nodules.ResultsOf the 183 included patients, 142 (77.6%) were women, and the mean (range) age was 51.7 (22.0-85.0) years. The genomic sequencing classifier had a sensitivity of 91% (95% CI, 79-98) and a specificity of 68% (95% CI, 60-76). At 24% cancer prevalence, the negative predictive value was 96% (95% CI, 90-99) and the positive predictive value was 47% (95% CI, 36-58).Conclusions and relevanceThe genomic sequencing classifier demonstrates high sensitivity and accuracy for identifying benign nodules. Its 36% increase in specificity compared with the gene expression classifier potentially increases the number of patients with benign nodules who can safely avoid unnecessary diagnostic surgery.

Project description:ObjectiveThyroid cancer is the third most prevalent cancer among females. Genetic testing based on next-generation sequencing may provide an auxiliary diagnosis to reduce cytologically diagnostic uncertainty. However, commercial multigene tests are not widely available and are not well-tested in the Chinese population.MethodsIn this study, we designed a multigene testing panel and evaluated its performance in 529 cytologically indeterminate thyroid nodules (Bethesda III, IV and V). The molecular data of the DNA mutations and RNA fusions of fine needle aspiration samples were reviewed in conjunction with a clinical diagnosis, pathological reports, and definitive surgery for retrospective analysis. Then, the molecular risk stratification was investigated for its accuracy in malignant risk prediction.ResultsThe overall combined consistency revealed substantial agreement (Kappa = 0.726) with the sensitivity, specificity, positive predictive value, and negative predictive values of 97.80%, 82.14%, 98.99%, and 67.65%, respectively. The most common aberration was BRAFV600E (82.59%), followed by NRAS mutants (4.07%), RET fusions (3.70%), and KRAS mutants (3.15%). Two cases (0.44%) were categorized into a high-risk group, 426 cases (94.67%) were categorized into a BRAF-like group with totally histopathologic papillary patterned tumors, and 22 cases (4.89%) were categorized into a RAS-like group with 14 papillary and eight follicular patterned tumors when the cohort concurrent aberrations were excluded. Potentially aggressive features may be related to concurrent molecular alterations of BRAFV600E with TERTQ302R, and AKT1L52R, NRASG12C, NRASQ61R, and CCDC6-RET fusions.ConclusionsThis study provided a multigene panel for identifying benign nodules from cytologically indeterminate thyroid nodules to avoid unnecessary surgery. We provide further evidence for using molecular risk stratification as a promising predictor of disease outcomes. The results of this study may be limited by the extremely high prevalence of cancer in the cohort for clinical reference.

Project description:BackgroundThyroid nodules are highly prevalent, with fine-needle aspiration (FNA) commonly used as the standard preoperative tool for their diagnosis. However, the method classifies some of the samples as indeterminate, leading to unnecessary surgery. In this study, we evaluated the value of next-generation sequencing (NGS) for cancer diagnosis in indeterminate thyroid nodules.Materials and methodsWe performed a prospective, blinded cohort study on 189 patients, with 196 Bethesda III/IV nodules. Specifically, we analyzed DNA mutations and RNA fusions across the FNA samples using NGS, then reviewed follow-up reports from 84 nodules following definitive surgery, to determine the assay performance.ResultsEnough DNA and RNA were obtained in 188 nodules, revealing mutations or fusions in 34.6% of them. The most frequently mutated genes were RAS, followed by BRAF V600E. Based on surgical pathology, 39% (33/84) and 4.8% (4/84) of the nodules were malignant and intermediate, respectively. According to the risk stratification criteria, 28 cases were categorized High-Risk group, all of the resected nodules (n = 20) were malignant. Twenty-four thyroid nodules were in the Low-Risk group, 28.6% (4/14) surgically removed nodules were malignant. In the Benign-Like category, 18.0% (9/50) were malignant. Five out of 13 nodules with benign mutations were resected, including SPOP, EZH1, and ZNF148, all of them were benign. If genetic alterations annotated with High-Risk or Low-Risk was considered as positive, and negative if Benign-Like. Multigene testing revealed sensitivity, specificity, positive predictive values (PPV), and negative predictive value (NPV) of 73%, 80%, 71%, and 82%, respectively. In addition, if four intermediate nodules were counted as malignant, the PPV and NPV were 71% and 74%.ConclusionOur results allow for further stratification of Bethesda III/IV thyroid nodules based on the risk of their malignancy. SPOP, EZH1, and ZNF148 mutations may be used as benign markers.

Dataset Information

Evaluation of the Molecular Landscape of Pediatric Thyroid Nodules and Use of a Multigene Genomic Classifier in Children.

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Publications

Evaluation of the Molecular Landscape of Pediatric Thyroid Nodules and Use of a Multigene Genomic Classifier in Children.

Similar Datasets

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