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Molecular Profiling of 50,734 Bethesda III-VI Thyroid Nodules by ThyroSeq v3: Implications for Personalized Management

Chiosea, Simion; Hodak, Steven P; Yip, Linwah; Abraham, Devaprabu; Baldwin, Chelsey; Baloch, Zubair; Gulec, Seza A; Hannoush, Zeina C; Haugen, Bryan R; Joseph, Lija; Kargi, Atil Y; Khanafshar, Elham; Livhits, Masha J; McIver, Bryan; Patel, Kepal; Patel, Snehal G; Randolph, Gregory W; Shaha, Ashok R; Sharma, Jyotirmay; Stathatos, Nikolaos; van Zante, Annemieke; Carty, Sally E; Nikiforov, Yuri E; Nikiforova, Marina N
CONTEXT/BACKGROUND:Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine-needle aspiration (FNA) samples has not been reported. OBJECTIVE:To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. DESIGN/METHODS:Retrospective analysis of FNA samples tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier. SETTING/METHODS:UPMC MGP laboratory. PARTICIPANTS/METHODS:A total of 50,734 BCIII-VI nodules from 48,225 patients. INTERVENTION/METHODS:None. MAIN OUTCOME MEASURES/METHODS:Prevalence of diagnostic, prognostic, and targetable genetic alterations. RESULTS:Among 50,734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alteration. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.2% of cases. CONCLUSIONS:In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutationsand targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.
PMID: 37071871
ISSN: 1945-7197
CID: 5466102

General Principles for the Safe Performance, Training, and Adoption of Ablation Techniques for Benign Thyroid Nodules: An American Thyroid Association Statement

Sinclair, Catherine F; Baek, Jung Hwan; Hands, Kathleen E; Hodak, Steven P; Huber, Timothy C; Hussain, Iram; Lang, Brian Hung-Hin; Noel, Julia E; Papaleontiou, Maria; Patel, Kepal N; Russ, Gilles; Russell, Jonathon; Spiezia, Stefano; Kuo, Jennifer H
PMID: 37642289
ISSN: 1557-9077
CID: 5609202

Molecular Profiles of Noninvasive, Minimally Invasive, and Invasive Follicular Patterned Thyroid Neoplasms with Papillary Nuclear Features

Brandler, Tamar C; Zhou, Fang; Liu, Cheng Z; Serrano, Antonio; Sun, Wei; Nikiforov, Yuri E; Hodak, Steven P
PMID: 37014083
ISSN: 1557-9077
CID: 5540792

DICER1 Mutation in Bethesda III Thyroid Nodules [Meeting Abstract]

Karimkhan, Afreen; Xia, Rong; Hindi, Issa; Belovarac, Brendan; Shafizadeh, Negin; Sun, Wei; Patel, Kepal; Givi, Babak; Hodak, Steven; Simsir, Aylin; Brandler, Tamar
ISSN: 0023-6837
CID: 5525462

Do ACR TI-RADS scores demonstrate unique thyroid molecular profiles?

Xia, Rong; Sun, Wei; Yee, Joseph; Sheth, Sheila; Slywotzky, Chrystia; Hodak, Steven; Brandler, Tamar C
PURPOSE/OBJECTIVE:The present study aimed to examine the molecular profiles of cytologically indeterminate thyroid nodules stratified by American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) categories and to determine whether certain ultrasonographic features display particular molecular alterations. METHODS:A retrospective review was conducted of cases from January 1, 2016 to April 1, 2018. Cases with in-house ultrasonography, fine-needle aspiration Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) diagnoses, molecular testing, and surgery were included. All cases were diagnosed as TBSRTC indeterminate categories. The ultrasound studies were retrospectively reviewed and assigned TI-RADS scores (TR1-TR5) by board-certified radiologists. The final diagnoses were determined based on the surgical resection pathology. Binary logistic regression analysis was used to study whether demographic characteristics, TI-RADS levels, and TBSRTC diagnoses were associated with ThyroSeq molecular results. RESULTS:Eighty-one cases met the inclusion criteria. RAS mutations were the most common alteration across all TI-RADS categories (TR2 2/2; TR3 10/19, TR4 13/44, and TR5 8/16), and did not stratify with any particular TI-RADS category. Only TR4 and TR5 categories displayed more aggressive mutations such as BRAFV600E and TERT. ThyroSeq results were positively correlated with thyroid malignancy when non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was categorized in the malignant category (odds ratio [OR], 6.859; P<0.01), but not when NIFTP was removed from the malignancy category. Echogenicity scores were found to be negatively correlated with ThyroSeq results in thyroid nodules (OR, 0.162; P<0.01). CONCLUSION/CONCLUSIONS:Higher-risk molecular alterations tended to stratify with the higher TI-RADS categories.
PMID: 35189676
ISSN: 2288-5919
CID: 5175032

Minimally Invasive Techniques for the Management of Thyroid Nodules

Baldwin, Chelsey K; Natter, Michael B; Patel, Kepal N; Hodak, Steven P
Image-guided interventional techniques have emerged as promising treatments for thyroid disease. Percutaneous ethanol ablation, radiofrequency ablation, laser ablation, high intensity focused ultrasound, and microwave ablation have shown efficacy in treating benign thyroid disease. There is increasing evidence that these techniques may effectively treat papillary thyroid microcarcinomas, recurrent and metastatic disease, follicular neoplasms, and parathyroid lesions. They are performed in an outpatient setting, well-tolerated, with negligible risk for thyroid hormone supplementation, making them a popular alternative to surgical resection. In this comprehensive review, we discuss the devices, techniques, advantages, and disadvantages of each intervention, and summarize the published outcomes.
PMID: 35662444
ISSN: 1558-4410
CID: 5236282

Prognostic Significance of Singular RAS Mutations in Cytologically Indeterminate Thyroid Nodules [Meeting Abstract]

Dublin, J C; Papazian, M; Zan, E; Oweity, T; Sun, W; Hodak, S; Baldwin, C K; Patel, K N; Brandler, T C; Givi, B
Introduction: The prognostic significance of a singular RAS mutation in cytologically indeterminate thyroid nodules (ITN) is unclear. This study aimed to analyze the incidence of malignancy and clinical outcomes of ITNs diagnosed on fine needle aspiration (FNA) cytology with RAS mutations.
Method(s): All FNA ITNs that underwent ThyroSeq testing and thyroidectomy from 2014-2018 were reviewed. ITNs with RAS (N-, H-, or K-RAS) mutations identified on ThyroSeq testing were selected. Demographics, Bethesda classifications, genomic profiles, treatment, final pathology, and clinical outcomes were recorded.
Result(s): During the study period, 93 patients with cytologic diagnosis of ITN and RAS mutations were identified. The mean nodule size was 2.2 cm (range: 0.5-6.6 cm). Most nodules were classified as Bethesda III (77, 82.8%). NRAS mutations were the most common (53, 57%), followed by HRAS (24, 25.8%), and KRAS (16, 17.2%). The majority of patients were treated with thyroid lobectomy (67, 72%). On final pathology, 9 (10%) were diagnosed as malignant (follicular variant of papillary thyroid carcinoma [FVPTC]) and were distributed among all 3 RAS variants (NRAS: 4 [7.5%]; HRAS: 4 [16.7%]; KRAS: 1 [6.3%]; p=0.4). Most FVPTCs were encapsulated (8, 88.9%). With a median follow up of 19 months (interquartile range = 8-35), no recurrences or progression was seen.
Conclusion(s): The risk of malignancy in ITNs with singular RAS mutations is low. All malignancies were low-risk. Our findings demonstrate a low incidence of high-risk malignancy in ITNs with RAS mutations, suggesting that initial management with conservative approaches such as thyroid lobectomy may be justified.
ISSN: 1879-1190
CID: 5024622

Concordance of Initial and Repeat Molecular Analysis in Cytologically Indeterminate Thyroid Nodules [Meeting Abstract]

Papazian, M; Dublin, J C; Zan, E; Oweity, T; Baldwin, C; Jacobson, A S; Hodak, S; Patel, K N; Brandler, T C; Givi, B
Introduction: Molecular tests such as ThyroSeq are recommended in the workup of cytologically indeterminate thyroid nodules (ITN). While repeat molecular testing is often performed after repeat fine needle aspiration (FNA) yields persistently indeterminate cytology, ThyroSeq's inter-test reliability is unclear. We assessed consistency of initial and repeat ThyroSeq analyses performed on samples from the same thyroid nodules.
Method(s): All thyroid nodules diagnosed as ITN on consecutive FNAs that received ThyroSeq with both biopsies from 2014-2018 at our institution, were reviewed. Initial analysis was ThyroSeq v2 while repeat was v2 or v3. Nodules with gene mutations, fusions, or copy number alterations (CNA) were considered ThyroSeq-positive.
Result(s): During the study period, 30 patients underwent ThyroSeq analysis on initial and repeat FNA samples (median interval=21 months). On initial testing, 27 (90%) nodules were ThyroSeq-negative and 3 (10%) low-risk mutations (RAS, EIF1AX, TSHR) were identified. Repeat ThyroSeq re-identified these 3 nodules and also interpreted 9 initially ThyroSeq-negative nodules as positive (kappa=0.286). All 9 molecular alterations were low-risk, most were identified on v3 (7, 77.8%), and CNA was the most common change (6, 66.7%). Of 12 patients with ThyroSeq-positive nodules, 8 underwent lobectomy. Final pathology identified low-risk malignancy in 3 nodules; the remainder were benign.
Conclusion(s): New findings on repeat ThyroSeq are possible. Whether these findings were detected by expanded panel or are the result of de-novo changes is unknown. The risk of missing high-risk changes appears to be low. More studies are needed to characterize the concordance of ThyroSeq analyses and natural evolution of ITNs.
ISSN: 1879-1190
CID: 5024612

The need for completion thyroidectomy and radioactive iodine therapy in the treatment of indeterminate thyroid nodules [Meeting Abstract]

Dublin, J; Papazian, M; Brandler, T; Zan, E; Oweity, T; Baldwin, C; Jacobson, A; Hodak, S; Patel, K; Givi, B
The majority of malignancies identified in indeterminate thyroid nodules (ITN) are low risk. Therefore, the need for total thyroidectomy or adjuvant treatment such as completion thyroidectomy or radioactive iodine (RAI) therapy in the treatment of ITNs is uncertain. This study aimed to analyze the likelihood of a need for total thyroidectomy and RAI therapy in the management of ITNs. All ITNs diagnosed on FNA cytology from 2014-2018 at NYU Langone Health were reviewed. ITNs managed with surgery were selected. Demographics, nodule characteristics, final pathology, treatment detail, and clinical outcomes were recorded. During the study period, 218 patients with surgically excised ITNs were identified. One hundred forty-two (65.1%) patients underwent thyroid lobectomy (TL), and 76 (34.9%) had total thyroidectomy (TT) upfront. In the lobectomy group, 26 (18.3%) had a malignant nodule on final surgical pathology, 8 (5.6%) underwent completion thyroidectomy, and 5 (3.5%) received RAI. In the total thyroidectomy group, 26 (34.2%) were diagnosed as malignant, and 14 (18.4%) received RAI. Follicular variant of papillary thyroid carcinoma (FVPTC) was the most common malignant diagnosis in both groups (TL: 20, 76.9%; TT: 12, 46.2%). Adenomatous nodule was the most common benign diagnosis (TL: 55, 72.5%; TT: 15, 51.2%). NIFTP accounted for 28.2% (40) of nodules treated with lobectomy and 27.6% (21) of nodules treated with upfront total thyroidectomy. In the entire cohort, only two (1%) patients had significant pathology in the contralateral lobe (1 [0.5%] with papillary thyroid carcinoma [PTC] and 1 [0.5%] with multifocal micro-PTC). Of all 218 ITNs, only 19 patients (8.7%) received RAI. With a median follow-up of 31.5 months (interquartile range = 21-39.5), no recurrences or progression was seen. The need for completion thyroidectomy or adjuvant RAI therapy in the treatment of ITN was low in our series. These data suggest that initial management of ITNs with lobectomy might be sufficient in the majority of cases
ISSN: 1557-9077
CID: 5179432

The American Association of Endocrine Surgeons (AAES) Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults

Hodak, Steven P; Duh, Quan-Yang
PMID: 32390572
ISSN: 1557-9077
CID: 4437952