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Gondaliya H, Aggarwal S, Khadilkar K, Kumbenahalli SS, Sooragonda B, Shetty AJ, Pillai V, Bhushan V, Shetty V, Dokhe Y, Lakshmikantha A, Kannan S. Clinical Utility of Next-Generation Sequencing-Based Molecular Panel in Thyroid Nodules. Indian J Endocrinol Metab 2025; 29:178-183. [PMID: 40416468 PMCID: PMC12101746 DOI: 10.4103/ijem.ijem_313_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 12/18/2024] [Accepted: 01/10/2025] [Indexed: 05/27/2025] Open
Abstract
Introduction The molecular testing of indeterminate thyroid nodules (ITNs) empowers clinicians to make informed treatment decisions. Despite being recommended by the ATA 2015 guidelines, the utility of molecular testing in India is hindered by challenges related to availability and cost-effectiveness, thereby limiting its widespread adoption. We aimed to evaluate the clinical utility of next-generation sequencing (NGS)-based molecular testing in Indian patients with ITNs. Methods The study included patients with Bethesda III and IV and selected Bethesda II nodules who underwent Thyrotrack NGS-based assay on fine needle aspirate (FNA) material. Surgery was recommended for patients with clinically significant mutations, while others were followed sonographically. Post-surgical histopathology results were compared with mutation variants to calculate the sensitivity, specificity, and negative predictive value of the NGS assay. Results Among 35 patients (mean age 37.7 ± 12.4 years, 80% female), 20 (57%) had clinically significant mutations. Surgery was performed on 11 patients. The most common mutation was RAS (detected in 15 patients), followed by BRAF, TSH-R, ETV6/NTRK3, and PAX8/PPARG. Post-surgical outcomes showed an overall sensitivity of 86% and a specificity of 74%, with a negative predictive value of 94%. Among the mutation-negative group, only one patient had a malignancy, and the rest were benign showing a high negative predictive value of the NGS-based testing. Conclusion NGS-based assays provide a reliable and cost-effective option for ruling out malignancy in ITNs in India, offering a high negative predictive value and complementing ACR-TIRADS and Bethesda cytology classifications.
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Affiliation(s)
- Hetashvi Gondaliya
- Department of Endocrinology and Metabolism, Narayana Health, Bengaluru, Karnataka, India
| | - Suruchi Aggarwal
- Department of Scientific Affairs, Oncology, Medgenome, Bengaluru, Karnataka, India
| | - Kranti Khadilkar
- Department of Endocrinology and Metabolism, Narayana Health, Bengaluru, Karnataka, India
| | | | - Basavaraj Sooragonda
- Department of Endocrinology and Metabolism, Narayana Health, Bengaluru, Karnataka, India
| | - Anirudh J. Shetty
- Department of Endocrinology and Metabolism, Narayana Health, Bengaluru, Karnataka, India
| | - Vijay Pillai
- Department of Head and Neck Oncology, Narayana Health, Bengaluru, Karnataka, India
| | - Vidhya Bhushan
- Department of Head and Neck Oncology, Narayana Health, Bengaluru, Karnataka, India
| | - Vivek Shetty
- Department of Head and Neck Oncology, Narayana Health, Bengaluru, Karnataka, India
| | - Yogesh Dokhe
- Department of Endocrinology and Metabolism, Narayana Health, Bengaluru, Karnataka, India
| | | | - Subramanian Kannan
- Department of Endocrinology and Metabolism, Narayana Health, Bengaluru, Karnataka, India
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Riccio I, Laforteza A, Landau MB, Hussein MH, Linhuber J, Staav J, Issa PP, Toraih EA, Kandil E. Decoding RAS mutations in thyroid cancer: A meta-analysis unveils specific links to distant metastasis and increased mortality. Am J Otolaryngol 2025; 46:104570. [PMID: 39708591 DOI: 10.1016/j.amjoto.2024.104570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 12/15/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND/OBJECTIVES RAS mutations are common in thyroid cancer, but their impact on clinical outcomes remains controversial. This study aimed to evaluate the prevalence of RAS mutations in thyroid cancer and their association with various clinical and pathological features. METHODS We conducted a systematic review and meta-analysis of studies reporting on RAS mutations in thyroid cancer. Both one-arm and pairwise meta-analyses were performed to compare outcomes between RAS-mutated (RAS+) and wild-type (RAS-) thyroid cancers. RESULTS Our analysis included 2552 thyroid cancer patients from 17 studies. The overall prevalence of RAS mutations was 35.4 % (95 % CI: 22.7 %-50.7 %). NRAS mutations were most common (69.47 %, 95 % CI: 66.15 %-72.66 %), followed by HRAS (25.83 %, 95 % CI: 22.77 %-29.14 %) and KRAS (6.92 %, 95 % CI: 5.27 %-9.04 %). No statistically significant differences were found between RAS+ and RAS- cases in rates of T1/2 tumors, lymph node metastasis, extrathyroidal extension, or recurrence. The risk of distant metastasis was significantly higher in RAS+ cases (15 %, 95 % CI: 6 %-34 %) compared to RAS- cases (4 %, 95 % CI: 1 %-12 %), with a relative risk of 3.23 (95 % CI: 1.49-7.02). Notably, RAS+ cases showed a significantly higher mortality rate (8 %, 95 % CI: 3 %-18 %) compared to RAS- cases (2 %, 95 % CI: 1 %-5 %), with a relative risk of 4.36 (95 % CI: 1.23-15.50, p = 0.03). CONCLUSION While RAS mutations are prevalent in thyroid cancer, they do not significantly impact most clinical and pathological features. However, the presence of RAS mutations is associated with a significantly higher risk of distant metastasis and mortality, suggesting their potential role as a prognostic marker in thyroid cancer. These findings underscore the importance of RAS mutation testing in risk stratification and treatment planning for thyroid cancer patients.
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Affiliation(s)
- Isabel Riccio
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | | | | | - Mohammad H Hussein
- Ochsner Clinic Foundation, New Orleans, LA, USA; Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Joshua Linhuber
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Jonathan Staav
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Peter P Issa
- School of Medicine, LSU Health Sciences Center School of Medicine, New Orleans, LA, USA
| | - Eman A Toraih
- Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA; Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
| | - Emad Kandil
- Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
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Storozuk T, Biernacka A, Lastra R, Mueller J, Olivas A, Reeves W, Yassan L, Antic T. Fate of nondiagnostic thyroid fine needle aspirations. Diagn Cytopathol 2024; 52:709-714. [PMID: 39051543 DOI: 10.1002/dc.25386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/12/2024] [Accepted: 07/15/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND Thyroid nodules may be detected during the workup of thyroid hormone abnormalities and as incidental findings during unrelated imaging studies. The diagnosis of a thyroid nodule is mainly established by performing fine needle aspiration (FNA) under ultrasound guidance. Thyroid nodules are classified as nondiagnostic, defined in the Bethesda System for Reporting Thyroid Cytopathology as samples with excess blood, cyst fluid only, and lack of thyroid follicular cells. The current study evaluates a series of nondiagnostic FNAs to assess whether repeat sampling improves yield and what patient management, and outcomes are after a nondiagnostic FNA. METHODS Thyroid FNAs from 2016 to 2023 were retrieved from our institution archives. All cases were performed under ultrasound guidance and with rapid on-site evaluation. Cases were assigned the Bethesda System Category. Nondiagnostic FNAs were further reviewed for repeat FNA procedures, potential molecular testing, or diagnostic resections. RESULTS In total 3104 thyroid FNAs were reviewed, with 153 (4.9%) being nondiagnostic. Of the 154 FNAs, there were 129 patients with an average age of 60 and a male-to-female ratio of 1:3.2. Of the 130 patients, there were 50 patients who underwent 55 repeat FNAs. Thirty-seven (67%) of the repeats were benign, 13 (24%) were nondiagnostic again, and 5 (9%) were atypia of undetermined significance (AUS). Molecular testing was performed on repeat FNAs diagnosed AUS. Four cases showed no mutations and had a high likelihood of being benign. One case did have an NRAS Q61R mutation, and resection revealed a noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Seventeen (13% of all cases) with nondiagnostic FNA were resected. Twelve (71%) thyroidectomies showed benign adenomatous nodules. The remainder showed incidental papillary thyroid microcarcinoma (0.1 cm), an infarcted follicular adenoma, a noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and metastatic renal cell carcinoma (2×). CONCLUSION Thyroid nodules with nondiagnostic cytology are reassuring of being highly likely a benign nodule. Only 5 of the 55 (9%) repeat FNAs yielded abnormalities, with only one of those being truly a follicular neoplasm (confirmed by molecular testing and resection). No primary thyroid malignancies have been identified in follow-up (repeat FNA or surgery). Clinical and ultrasound follow-up may be more appropriate management for nondiagnostic thyroid FNAs.
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Affiliation(s)
- Tanner Storozuk
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Anna Biernacka
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Ricardo Lastra
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Jeffrey Mueller
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Andrea Olivas
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Ward Reeves
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Lindsay Yassan
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Tatjana Antic
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
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Wang Q, Dai L, Lin S, Zhang S, Wen J, Chen E, Li Q, You J, Qu J, Ni C, Cai Y. Combining radiomics and molecular biomarkers: a novel economic tool to improve diagnostic ability in papillary thyroid cancer. Front Endocrinol (Lausanne) 2024; 15:1378360. [PMID: 39205691 PMCID: PMC11349561 DOI: 10.3389/fendo.2024.1378360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/10/2024] [Indexed: 09/04/2024] Open
Abstract
Background A preoperative diagnosis to distinguish malignant from benign thyroid nodules accurately and sensitively is urgently important. However, existing clinical methods cannot solve this problem satisfactorily. The aim of this study is to establish a simple, economic approach for preoperative diagnosis in eastern population. Methods Our retrospective study included 86 patients with papillary thyroid cancer and 29 benign cases. The ITK-SNAP software was used to draw the outline of the area of interest (ROI), and Ultrosomics was used to extract radiomic features. Whole-transcriptome sequencing and bioinformatic analysis were used to identify candidate genes for thyroid nodule diagnosis. RT-qPCR was used to evaluate the expression levels of candidate genes. SVM diagnostic model was established based on the METLAB 2022 platform and LibSVM 3.2 language package. Results The radiomic model was first established. The accuracy is 73.0%, the sensitivity is 86.1%, the specificity is 17.6%, the PPV is 81.6%, and the NPV is 23.1%. Then, CLDN10, HMGA2, and LAMB3 were finally screened for model building. All three genes showed significant differential expressions between papillary thyroid cancer and normal tissue both in our cohort and TCGA cohort. The molecular model was established based on these genetic data and partial clinical information. The accuracy is 85.9%, the sensitivity is 86.1%, the specificity is 84.6%, the PPV is 96.9%, and the NPV is 52.4%. Considering that the above two models are not very effective, We integrated and optimized the two models to construct the final diagnostic model (C-thyroid model). In the training set, the accuracy is 96.7%, the sensitivity is 100%, the specificity is 93.8%, the PPV is 93.3%, and the NPV is 100%. In the validation set, the accuracy is 97.6%, the sensitivity remains 100%, the specificity is 84.6%, the PPV is 97.3%, and the NPV is 100%. Discussion A diagnostic panel is successfully established for eastern population through a simple, economic approach using only four genes and clinical data.
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Affiliation(s)
- Qingxuan Wang
- Department of Thyroid Surgery, National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Linghui Dai
- Division of thyroid Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Sisi Lin
- Department of Operating Room, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shuwei Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jing Wen
- Department of Thyroid Surgery, National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Endong Chen
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Quan Li
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jie You
- Department of Thyroid Surgery, National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jinmiao Qu
- Department of Thyroid Surgery, National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chunjue Ni
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yefeng Cai
- Department of Thyroid Surgery, National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for Malignant Tumor, Hangzhou, Zhejiang, China
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Liu Q, Jiang X, Tu W, Liu L, Huang Y, Xia Y, Xia X, Shi Y. Comparative efficiency of differential diagnostic methods for the identification of BRAF V600E gene mutation in papillary thyroid cancer (Review). Exp Ther Med 2024; 27:149. [PMID: 38476918 PMCID: PMC10928970 DOI: 10.3892/etm.2024.12437] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 02/02/2024] [Indexed: 03/14/2024] Open
Abstract
V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) encodes a serine-threonine kinase. The V600E point mutation in the BRAF gene is the most common mutation, predominantly occurring in melanoma, and colorectal, thyroid and non-small cell lung cancer. Particularly in the context of thyroid cancer research, it is routinely employed as a molecular biomarker to assist in diagnosing and predicting the prognosis of papillary thyroid cancer (PTC), and to formulate targeted therapeutic strategies. Currently, several methods are utilized in clinical settings to detect BRAF V600E mutations in patients with PTC. However, the sensitivity and specificity of various detection techniques vary significantly, resulting in diverse detection outcomes. The present review highlights the advantages and disadvantages of the methods currently employed in medical practice, with the aim of guiding clinicians and researchers in selecting the most suitable detection approach for its high sensitivity, reproducibility and potential to develop targeted therapeutic regimens for patients with BRAF gene mutation-associated PTC.
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Affiliation(s)
- Qian Liu
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Xue Jiang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Wenling Tu
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Lina Liu
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Ying Huang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Yuxiao Xia
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Xuliang Xia
- Department of General Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Yuhong Shi
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
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Riccio IR, LaForteza AC, Hussein MH, Linhuber JP, Issa PP, Staav J, Fawzy MS, Toraih EA, Kandil E. Diagnostic utility of RAS mutation testing for refining cytologically indeterminate thyroid nodules. EXCLI JOURNAL 2024; 23:283-299. [PMID: 38487090 PMCID: PMC10938255 DOI: 10.17179/excli2024-6975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 02/08/2024] [Indexed: 03/17/2024]
Abstract
RAS mutations are prevalent in indeterminate thyroid nodules, but their association with malignancy risk and utility for diagnosis remains unclear. We performed a systematic review and meta-analysis to establish the clinical value of RAS mutation testing for cytologically indeterminate thyroid nodules. PubMed and Embase were systematically searched for relevant studies. Thirty studies comprising 13,328 nodules met the inclusion criteria. Random effects meta-analysis synthesized pooled estimates of RAS mutation rates, risk of malignancy with RAS positivity, and histologic subtype outcomes. The pooled mutation rate was 31 % (95 % CI 19-44 %) among 5,307 indeterminate nodules. NRAS mutations predominated at 67 % compared to HRAS (24 %) and KRAS (12 %). The malignancy rate with RAS mutations was 58 % (95 %CI=48-68 %). RAS positivity increased malignancy risk 1.7-fold (RR 1.68, 95 %CI=1.21-2.34, p=0.002), with significant between-study heterogeneity (I2=89 %). Excluding one outlier study increased the relative risk to 1.75 (95 %CI=1.54-1.98) and I2 to 14 %. Funnel plot asymmetry and Egger's test (p=0.03) indicated potential publication bias. Among RAS-positive malignant nodules, 38.6 % were follicular variant papillary carcinoma, 34.1 % classical variant, and 23.2 % follicular carcinoma. No statistically significant difference in the odds of harboring RAS mutation was found between subtypes. In conclusion, RAS mutation testing demonstrates clinical utility for refining the diagnosis of cytologically indeterminate thyroid nodules. Positivity confers a 1.7-fold increased malignancy risk, supporting use for personalized decision-making regarding surgery vs. monitoring. Follicular variant papillary carcinoma constitutes the most common RAS-positive malignant histological subtype. See also the graphical abstract(Fig. 1).
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Affiliation(s)
- Isabel R. Riccio
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Alexandra C. LaForteza
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Mohammad H. Hussein
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | | | - Peter P. Issa
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Jonathan Staav
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Manal S. Fawzy
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Eman A. Toraih
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Emad Kandil
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
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Loberg MA, Tigue ML, Gallant JN, Wang H, Canberk S, Weiss VL. Evolving approaches in paediatric thyroid cytopathology: A review. Cytopathology 2024; 35:60-69. [PMID: 37759375 PMCID: PMC11027193 DOI: 10.1111/cyt.13311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/22/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023]
Abstract
The guidelines for the workup of thyroid nodules have been established in adult populations and secondarily applied to paediatric populations. In particular, The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is commonly applied to both adult and paediatric thyroid nodules. However, as paediatric nodules have distinct molecular drivers and behavioural trajectories, there is renewed interest in diagnostic and management strategies that are paediatric specific. Here, we review key differences between paediatric and adult thyroid cancer and recent literature evaluating the use of TBSRTC in paediatric populations.
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Affiliation(s)
- Matthew A Loberg
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Megan L Tigue
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jean-Nicolas Gallant
- Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Huiying Wang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sule Canberk
- i3S/ Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Vivian L Weiss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Abstract
Background: Very little was known about the molecular pathogenesis of thyroid cancer until the late 1980s. As part of the Centennial celebration of the American Thyroid Association, we review the historical discoveries that contributed to our current understanding of the genetic underpinnings of thyroid cancer. Summary: The pace of discovery was heavily dependent on scientific breakthroughs in nucleic acid sequencing technology, cancer biology, thyroid development, thyroid cell signaling, and growth regulation. Accordingly, we attempt to link the primary observations on thyroid cancer molecular genetics with the methodological and scientific advances that made them possible. Conclusions: The major genetic drivers of the common forms of thyroid cancer are now quite well established and contribute to a significant extent to how we diagnose and treat the disease. However, many challenges remain. Future work will need to unravel the complexity of thyroid cancer ecosystems, which is likely to be a major determinant of their biological behavior and on how they respond to therapy.
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Affiliation(s)
- James A. Fagin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Yuri E. Nikiforov
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Fumagalli C, Serio G. Molecular testing in indeterminate thyroid nodules: an additional tool for clinical decision-making. Pathologica 2023; 115:205-216. [PMID: 37711036 PMCID: PMC10688247 DOI: 10.32074/1591-951x-887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/12/2023] [Indexed: 09/16/2023] Open
Abstract
Thyroid nodules are commonly encountered in clinical practice, affecting up to 50% of the population. The large majority of thyroid lumps are benign incidental findings detected by imaging, while approximately 5-15% harbor malignancy. For a target patient's care, it is of paramount importance to identify and treat thyroid malignancy, while preventing unnecessary invasive surgery in patients with benign lesions. Although fine needle aspiration (FNA) associated with cytological examination provides malignant risk information, 20-30% of diagnoses fall into the "indeterminate thyroid nodule" (ITN) category. ITN clinical management remains a challenging issue for physicians since the ITN risk of malignancy varies from 5% to 40% and most thyroid nodules undergo overtreatment with surgery procedures. ITN molecular testing may better define malignant risk in the single nodule and is able to discriminate with accuracy benign from malignant nodules. Nowadays there are different technologies and different molecular panels, each with its own specificity, sensitivity and predictive values. In view of widespread introduction of molecular testing , some outstanding questions remain and are addressed in the present review such as the presence of molecular panels acting as "rule in" or "rule out" tools, the effective impact of testing results in the clinical decision-making process, and the prohibitive cost of commercial assays associated with the lack of test reimbursement in national health systems.
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Parpounas C, Constantinides V. Advances in Molecular Profiling and Their Potential Influence on the Extent of Surgery in Well-Differentiated Thyroid Carcinoma (WDTC). Life (Basel) 2023; 13:1382. [PMID: 37374164 DOI: 10.3390/life13061382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/02/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Thyroid cancer surgery has evolved dramatically with advances in our understanding of the biological behaviour of WDTC. Molecular profiling is shedding light on the subset that may behave aggressively. In an era when thyroid cancer management is becoming increasingly conservative, decision making regarding the extent of surgery must be objectively guided by molecular markers. The aim of the present article is to summarise the current published literature and provide possible practice recommendations. An online search for relevant published articles was performed using several databases. Title, abstract, and full-text screening, along with data extraction, was performed by two independent reviewers after the inclusion and exclusion criteria were defined. A total of 1241 articles were identified, and 82 relevant articles were extracted and scrutinised. BRAF V600E and TERT promoter mutations were found to be associated with an increased risk of disease recurrence and distant metastases. Several other mutations have been identified that enhance disease aggressiveness (such as RET/PTC, PTEN, and TP53). One of the most important determinants of the outcome in WDTC is the extent of surgical resection. The evolution of molecular testing has reached a stage of personalised incorporation into surgical practice. Guidelines for molecular testing and surgery in WDTC will need to be clearly defined, arguably representing the next chapter in the management of the disease.
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Affiliation(s)
- Constantinos Parpounas
- Department of Endocrine Surgery, Evangelistria Medical Centre, 1 Michael Giorgalla Street, 1095 Nicosia, Cyprus
| | - Vasilis Constantinides
- Department of Endocrine Surgery, Evangelistria Medical Centre, 1 Michael Giorgalla Street, 1095 Nicosia, Cyprus
- Medical School, University of Nicosia, 93 Ayiou Nikolaou Street, Engomi, 2408 Nicosia, Cyprus
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Zhang W, Yun X, Xu T, Wang X, Li Q, Zhang T, Xie L, Wang S, Li D, Wei X, Yu Y, Qian B. Integrated gene profiling of fine-needle aspiration sample improves lymph node metastasis risk stratification for thyroid cancer. Cancer Med 2023; 12:10385-10392. [PMID: 36916410 DOI: 10.1002/cam4.5770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 02/08/2023] [Accepted: 02/22/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Lymph node metastasis risk stratification is crucial for the surgical decision-making of thyroid cancer. This study investigated whether the integrated gene profiling (combining expression, SNV, fusion) of Fine-Needle Aspiration (FNA) samples can improve the prediction of lymph node metastasis in patients with papillary thyroid cancer. METHODS In this retrospective cohort study, patients with papillary thyroid cancer who went through thyroidectomy and central lymph node dissection were included. Multi-omics data of FNA samples were assessed by an integrated array. To predict lymph node metastasis, we built models using gene expressions or mutations (SNV and fusion) only and an Integrated Risk Stratification (IRS) model combining genetic and clinical information. Blinded histopathology served as the reference standard. ROC curve and decision curve analysis was applied to evaluate the predictive models. RESULTS One hundred and thirty two patients with pathologically confirmed papillary thyroid cancer were included between 2016-2017. The IRS model demonstrated greater performance [AUC = 0.87 (0.80-0.94)] than either expression classifier [AUC = 0.67 (0.61-0.74)], mutation classifier [AUC = 0.61 (0.55-0.67)] or TIRADS score [AUC = 0.68 (0.62-0.74)] with statistical significance (p < 0.001), and the IRS model had similar predictive performance in large nodule [>1 cm, AUC = 0.88 (0.79-0.97)] and small nodule [≤1 cm, AUC = 0.84 (0.74-0.93)] subgroups. The genetic risk factor showed independent predictive value (OR = 10.3, 95% CI:1.1-105.3) of lymph node metastasis in addition to the preoperative clinical information, including TIRADS grade, age, and nodule size. CONCLUSION The integrated gene profiling of FNA samples and the IRS model developed by the machine-learning method significantly improve the risk stratification of thyroid cancer, thus helping make wise decisions and reducing unnecessary extensive surgeries.
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Affiliation(s)
- Weituo Zhang
- Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinwei Yun
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
| | - Tianyu Xu
- Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Clinical Research Promotion and Development Center, Shanghai Hospital Development Center, Shanghai, China
| | - Xiaoqing Wang
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
| | - Qiang Li
- Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tiantian Zhang
- Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Xie
- Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Suna Wang
- Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dapeng Li
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
| | - Xi Wei
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
| | - Yang Yu
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
| | - Biyun Qian
- Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Clinical Research Promotion and Development Center, Shanghai Hospital Development Center, Shanghai, China
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12
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Hudson TJ, Pusztaszeri MP, Hier MP, Forest VI, Yang JW, Payne RJ. Does the likelihood of malignancy in thyroid nodules with RAS mutations increase in direct proportion with the allele frequency percentage? J Otolaryngol Head Neck Surg 2023; 52:12. [PMID: 36774522 PMCID: PMC9921308 DOI: 10.1186/s40463-022-00611-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 12/06/2022] [Indexed: 02/13/2023] Open
Abstract
BACKGROUND Genomic testing has enhanced pre-surgical decision making for cytologically indeterminate thyroid nodules, but there remains uncertainty regarding RAS mutations. The addition of extra genetic alterations to previous driver mutation panels has been shown to improve predictive value. This study aims to evaluate the relationship between the mutant allele frequency (AF) and likelihood of malignancy in thyroid nodules with RAS mutations. METHODS A retrospective cohort review was performed evaluating patients with indeterminate cytology (Bethesda categories III, IV and V) and ThyroSeq® v3 testing demonstrating a RAS mutation, who underwent surgery. Univariate and multivariate regression analyses were used to evaluate relationships between AF, other genetic alterations, and malignancy. RESULTS Thirty-nine patients met criteria, 77% of the thyroid nodules (30/39) were found to be malignant. None demonstrated aggressive pathology. On univariate regression, there was no relationship between AF and likelihood of malignancy. There was, however, a significant correlation between AF and the rate of an additional genetic alteration. Multivariate analysis found a trend between RAS, a second genetic alteration and malignancy, but it did not reach statistical significance. CONCLUSIONS There was no direct relationship between the level of allelic frequency in thyroid nodules expressing RAS mutations and the likelihood of malignancy. There was a statistically significant relationship between increasing AF and the presence of a second genetic abnormality, suggesting a possible progression from initial driver mutation and then a second genetic alteration prior to malignant transformation.
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Affiliation(s)
- Thomas J Hudson
- Department of Otolaryngology - Head and Neck Surgery, Jewish General Hospital, McGill University, 3755 Ch. de la Côte-Sainte-Catherine Rd., Montreal, QC, H3T 1E2, Canada.,nt of Otolaryngology - Head and Neck Surgery, McGill University Health Centre, Montreal, QC, Canada
| | | | - Michael P Hier
- Department of Otolaryngology - Head and Neck Surgery, Jewish General Hospital, McGill University, 3755 Ch. de la Côte-Sainte-Catherine Rd., Montreal, QC, H3T 1E2, Canada
| | - Veronique-Isabelle Forest
- Department of Otolaryngology - Head and Neck Surgery, Jewish General Hospital, McGill University, 3755 Ch. de la Côte-Sainte-Catherine Rd., Montreal, QC, H3T 1E2, Canada
| | - Ji-Wei Yang
- Division of Endocrinology, McGill University Health Centre, Montreal, QC, Canada
| | - Richard J Payne
- Department of Otolaryngology - Head and Neck Surgery, Jewish General Hospital, McGill University, 3755 Ch. de la Côte-Sainte-Catherine Rd., Montreal, QC, H3T 1E2, Canada. .,nt of Otolaryngology - Head and Neck Surgery, McGill University Health Centre, Montreal, QC, Canada.
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13
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Dutta S, Tarafdar S, Mukhopadhyay P, Bhattacharyya NP, Ghosh S. Detection of driver mutations in plasma cell-free nucleic acids in differentiated thyroid neoplasm. Eur J Endocrinol 2023; 188:6976051. [PMID: 36744987 DOI: 10.1093/ejendo/lvac018] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 12/15/2022] [Accepted: 12/27/2022] [Indexed: 01/11/2023]
Abstract
IMPORTANCE This proof-of-concept paper demonstrates that driver mutations can be detected in plasma in differentiated thyroid tumors, and we were able to detect mutations in upto 80% malignant thyroid nodules. Additionally, cancer subtypes could also be predicted using a 8-gene panel. In almost 90% follicular adenoma, rat sarcoma virus (RAS) mutations were detectable. There was a strong agreement between driver mutations found in plasma samples, FNAC materials, and histopathology samples. This has potential as a noninvasive, preoperative diagnostic tool (particularly of clinical importance in indeterminate nodules) and may help in detection of residual tumor after surgery. Future research is warranted to test the role of this tool to detect tumor recurrence. OBJECTIVE Ultrasonographic (USG) evaluation and fine-needle aspiration (FNA) are cornerstone for evaluation of thyroid neoplasm. Molecular technique including detection of driver mutation from FNA cytology (FNAC) material is an established modality. In this study, we explored the feasibility of using plasma cell-free nucleic acids to identify known driver mutations in differentiated thyroid neoplasm. DESIGN Patients presenting with thyroid nodules underwent USG with Thyroid Image Reporting and Data Systems scoring and FNAC (Bethesda classification). All patients in Bethesda 3, 4, 5, 6 underwent surgery and histopathological confirmation. Patients in Bethesda 2 (cosmetic concerns, compressive symptoms) underwent surgery, and rest were presumed benign on the basis of USG, FNAC features, and clinical followup.). SETTING Endocrinology clinic. PARTICIPANTS Subjects with thyroid nodule. INTERVENTION(S) OR EXPOSURE(S) None. MAIN OUTCOME(S) AND MEASURE(S) Plasma sample, FNA, and histopathology material were evaluated for driver mutations (8-gene panel comprising BRAF-V600E, RET/PTC3, RET/PTC1, TERT promoter, HRAS, NRAS, KRAS, and PAX8-PPARG). RESULTS A total of 223 subjects were recruited; of these 154 were benign and 69 had differentiated thyroid cancer. We were able to detect driver mutation from plasma in 55 subjects (79.71%) of all malignant patients, and 11 patients in benign category had RAS mutation (follicular adenoma). Rest of the benign nodules did not have any detectable driver mutations. CONCLUSIONS AND RELEVANCE Plasma might be a viable noninvasive alternative source for detection of driver mutations (8-gene panel) in subjects with differentiated thyroid tumors and may have significant clinical utility.
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Affiliation(s)
- Susmita Dutta
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Soham Tarafdar
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Pradip Mukhopadhyay
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Nitai P Bhattacharyya
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Sujoy Ghosh
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
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14
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Hsiao V, Massoud E, Jensen C, Zhang Y, Hanlon BM, Hitchcock M, Arroyo N, Chiu AS, Fernandes-Taylor S, Alagoz O, Sundling K, LiVolsi V, Francis DO. Diagnostic Accuracy of Fine-Needle Biopsy in the Detection of Thyroid Malignancy: A Systematic Review and Meta-analysis. JAMA Surg 2022; 157:1105-1113. [PMID: 36223097 PMCID: PMC9558056 DOI: 10.1001/jamasurg.2022.4989] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/16/2022] [Indexed: 01/22/2023]
Abstract
Importance Fine-needle biopsy (FNB) became a critical part of thyroid nodule evaluation in the 1970s. It is not clear how diagnostic accuracy of FNB has changed over time. Objective To conduct a systematic review and meta-analysis estimating the accuracy of thyroid FNB for diagnosis of malignancy in adults with a newly diagnosed thyroid nodule and to characterize changes in accuracy over time. Data Sources PubMed, SCOPUS, and Cochrane Central Register of Controlled Trials were searched from 1975 to 2020 using search terms related to FNB accuracy in the thyroid. Study Selection English-language reports of cohort studies or randomized trials of adult patients undergoing thyroid FNB with sample size of 20 or greater and using a reference standard of surgical histopathology or clinical follow-up were included. Articles that examined only patients with known thyroid disease or focused on accuracy of novel adjuncts, such as molecular tests, were excluded. Two investigators screened each article and resolved conflicts by consensus. A total of 36 of 1023 studies met selection criteria. Data Extraction and Synthesis The MOOSE guidelines were used for data abstraction and assessing data quality and validity. Two investigators abstracted data using a standard form. Studies were grouped into epochs by median data collection year (1975 to 1990, 1990 to 2000, 2000 to 2010, and 2010 to 2020). Data were pooled using a bivariate mixed-effects model. Main Outcomes and Measures The primary outcome was accuracy of FNB for diagnosis of malignancy. Accuracy was hypothesized to increase in later time periods, a hypothesis formulated prior to data collection. Results Of 16 597 included patients, 12 974 (79.2%) were female, and the mean (SD) age was 47.3 (12.9) years. The sensitivity of FNB was 85.6% (95% CI, 79.9-89.5), the specificity was 71.4% (95% CI, 61.1-79.8), the positive likelihood ratio was 3.0 (95% CI, 2.3-4.1), and the negative likelihood ratio was 0.2 (95% CI, 0.2-0.3). The area under the receiver operating characteristic curve was 86.1%. Epoch was not significantly associated with accuracy. None of the available covariates could explain observed heterogeneity. Conclusions and Relevance Accuracy of thyroid FNB has not significantly changed over time. Important developments in technique, preparation, and interpretation may have occurred too heterogeneously to capture a consistent uptrend over time. FNB remains a reliable test for thyroid cancer diagnosis.
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Affiliation(s)
- Vivian Hsiao
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Surgery, University of Wisconsin–Madison, Madison
| | - Elian Massoud
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Surgery, University of Wisconsin–Madison, Madison
| | - Catherine Jensen
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Surgery, University of Wisconsin–Madison, Madison
| | - Yanchen Zhang
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Otolaryngology, University of Wisconsin–Madison, Madison
| | - Bret M. Hanlon
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison
| | - Mary Hitchcock
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Ebling Library for the Health Sciences, University of Wisconsin–Madison
| | - Natalia Arroyo
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Surgery, University of Wisconsin–Madison, Madison
| | - Alexander S. Chiu
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Surgery, University of Wisconsin–Madison, Madison
- Division of Endocrine Surgery, University of Wisconsin–Madison, Madison
| | - Sara Fernandes-Taylor
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Surgery, University of Wisconsin–Madison, Madison
| | - Oguzhan Alagoz
- Department of Industrial and Systems Engineering, University of Wisconsin–Madison, Madison
| | - Kaitlin Sundling
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Pathology, University of Wisconsin–Madison, Madison
- Wisconsin State Laboratory of Hygiene, University of Wisconsin–Madison, Madison
| | - Virginia LiVolsi
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia
| | - David O. Francis
- University of Wisconsin–Madison School of Medicine and Public Health, Madison
- Department of Surgery, University of Wisconsin–Madison, Madison
- Department of Otolaryngology, University of Wisconsin–Madison, Madison
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15
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Makazlieva T, Stoilovska Rizova B, Stojanoski S, Manevska N, Vaskova O, Velikj Stefanovska V, Miladinova D. Ultrasound features and preoperative accuracy of the fine needle aspiration biopsy in detection of thyroid carcinomas. JOURNAL OF CLINICAL ULTRASOUND : JCU 2022; 50:1338-1344. [PMID: 36129366 DOI: 10.1002/jcu.23302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 05/22/2022] [Accepted: 05/25/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To analyze the ultrasound (US) characteristics and fine needle biopsy (FNAB) of thyroid carcinomas (TCs) prior to surgery and compare with postoperative histopathology and to determine FNAB sensitivity and specificity. MATERIAL AND METHODS Retrospective analysis of the US data during 1999-2015 was performed, as well as analysis of FNAB results and using histopathology report as "gold standard" the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of this method was evaluated. RESULTS Data revealed that tumors >51 mm were declining by 50% in the period 2011-2015 compared to 2005-2010 or by 18% 2011-2015 compared to 1999-2004 and significant increase was detected in diagnosis of multicentric tumors. The analysis revealed that FNAB has sensitivity = 65.7% CI (0.59% - 0.71%) and specificity = 50% CI (0.43%-0.56%), PPV = 56.9% and NPV = 59.2%. CONCLUSION We found increasing detection of smaller TCs, as well as more frequent detection of multicentricity of the neoplastic foci. FNAB results in our study revealed low sensitivity and specificity. Major limitation of the study was inability to exactly separate US guided from non US guided FNAB in evaluation of the sensitivity and specificity, due to retrospective nature of the analysis. Further studies evaluating only US guided FNAB should be performed.
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Affiliation(s)
- Tanja Makazlieva
- Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, University Ss Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Bojana Stoilovska Rizova
- Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, University Ss Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Sinisa Stojanoski
- Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, University Ss Cyril and Methodius, Skopje, Republic of North Macedonia
- Medical Faculty, Lazarski University, Warsaw, Poland
| | - Nevena Manevska
- Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, University Ss Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Olivija Vaskova
- Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, University Ss Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Vesna Velikj Stefanovska
- Institute of Epidemiology and Biostatistics with Medical Informatics, Medical Faculty, University Ss Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Daniela Miladinova
- Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, University Ss Cyril and Methodius, Skopje, Republic of North Macedonia
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16
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Vinod A, Ramachandran R, Pillai AV, Padmanabhan DS, Ravindran GC, Babu MJC, Jacob P, Nair GC. Serum TSH Level as a Simple Efficient Tool to Assess the Risk of Thyroid Malignancy in Euthyroid Patients with Indeterminate Cytology - A Cohort Study. Indian J Endocrinol Metab 2022; 26:446-452. [PMID: 36618514 PMCID: PMC9815193 DOI: 10.4103/ijem.ijem_75_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 07/06/2022] [Accepted: 08/26/2022] [Indexed: 11/19/2022] Open
Abstract
Context A significant number of fine-needle aspiration cytology (FNAC) for thyroid nodules is reported as indeterminate. Expensive molecular testing can give a clue to the possibility of malignancy in this group. The effectiveness of serum thyroid-stimulating hormone (TSH) levels as a diagnostic tool in euthyroid patients with indeterminate cytology has not been previously studied, especially in the Indian population. Aims This study was conducted to evaluate the predictive efficacy of serum TSH in the early diagnosis and treatment of malignancy. Settings and Design This is a retrospective cross-sectional study on a cohort of patients who presented to our department with complaints of thyroid swelling and underwent thyroidectomy. Methods and Material Euthyroid patients who underwent thyroid surgery for newly diagnosed thyroid nodules with FNAC reported as indeterminate cytology were included in our study. Based on the histopathological report, the patients were divided into two groups and into quartiles based on TSH values. Statistical Analysis Used The mean difference in the numerical variables between groups was compared using the independent two-sample 't' test for parametric data and Mann-Whitney 'u' test for non-parametric data. A logistic regression analysis was done with age, sex, TSH level and nodule size as dependant variables and malignancy as the independent variable. Results There were 211 patients in group A and 93 in group B. Patients with malignancy confirmed on final histopathology showed higher serum TSH levels compared to benign nodules (2.93 ± 1.067 vs 1.73 ± 1.051, P = <0.001). The mean TSH levels of all types of malignant nodules correlated with our test model (>2.185 mIU/L). Conclusions Serum TSH above 2.185 mIU/mL is a good predictor of malignancy in indeterminate nodules. It is an inexpensive, safe and reliable diagnostic screening test for the risk of malignancy in an indeterminate nodule.
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Affiliation(s)
- Ashwin Vinod
- Department of Surgery, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - Riju Ramachandran
- Department of Surgery, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | | | | | - Greeshma C. Ravindran
- Department of Biostatistics, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - Misha J. C. Babu
- Department of Surgery, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - Pradeep Jacob
- Department of Surgery, Amrita Institute of Medical Sciences, Kochi, Kerala, India
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17
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PAPPA Expression in Indeterminate Thyroid Nodules as Screening Test to Select Patients for Molecular Testing. Int J Mol Sci 2022; 23:ijms23094648. [PMID: 35563038 PMCID: PMC9099529 DOI: 10.3390/ijms23094648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 11/16/2022] Open
Abstract
Pregnancy-associated plasma protein A (PAPPA) acts as an oncogene, and its expression is increased in multiple malignancies, including thyroid cancer. Molecular tests represent a useful tool in the management of indeterminate thyroid nodules; however, they are not conducted in all centers, and they contribute to increase the per-patient cost of nodule evaluation. In this study, we examined whether PAPPA expression could represent a promising new screening test in the management of indeterminate thyroid nodules. Toward this aim, PAPPA expression was evaluated in 107 fine needle aspiration cytologies (FNAC) belonging to Bethesda III–IV categories that had been sent to molecular biology to discriminate the nature of the nodules. We found that the PAPPA expression increased and showed an elevated sensitivity (97.14%) and negative predictive value (98%) in indeterminate cytological samples positive for mutations. The enhanced expression was not linked to a specific oncogene. Our findings demonstrated that assessing the PAPPA expression in indeterminate thyroid cytologies could represent a useful screening tool to select all patients that effectively need to be sent to molecular testing, thereby, leading to a potential cost reduction in the management of patients.
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18
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Marzocchi C, Capezzone M, Sagnella A, Cartocci A, Caroli Costantini M, Brindisi L, Mancini V, Cantara S, Castagna MG. Pregnancy-associated plasma protein A mRNA expression as a marker for differentiated thyroid cancer: results from a "surgical" and a "cytological" series. J Endocrinol Invest 2022; 45:369-378. [PMID: 34350538 PMCID: PMC8783868 DOI: 10.1007/s40618-021-01655-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 07/29/2021] [Indexed: 01/21/2023]
Abstract
PURPOSE Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase initially described for its role during pregnancy. PAPPA regulates IGF ligands 1 (IGF1) bioavailability through the degradation of IGF-binding protein 4 (IGFBP4). After the cleavage of IGFBP4, free IGF1 is able to bind IGF1 receptors (IGF1R) triggering the downstream signaling. Recently, PAPPA expression has been linked with development of several cancers. No data have been published on thyroid cancer, yet. METHODS We evaluated PAPPA, insulin-like growth factor (IGF1), IGF1 receptors (IGF1R) and IGF-binding protein 4 (IGFBP4) mRNA expression levels in a "Surgical series" of 94 thyroid nodules (64 cancers, 16 follicular adenomas and 14 hyperplastic nodules) and in a "Cytological series" of 80 nodules from 74 patients underwent to fine-needle aspiration cytology (FNAC). In tissues, PAPPA was also evaluated by western blot. RESULTS We found that PAPPA expression was increased in thyroid cancer specimen at mRNA and protein levels and that, adenomas and hyperplastic nodules had an expression similar to normal tissues. When applied on thyroid cytologies, PAPPA expression was able to discriminate benign from malignant nodules contributing to pre-surgical classification of the nodules. We calculated a cut-off with a good specificity (91%) which reached 100% when combined with molecular biology. CONCLUSION These results show that PAPPA could represent a promising diagnostic marker for differentiated thyroid cancer.
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Affiliation(s)
- C Marzocchi
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 16, 53100, Siena, Italy
| | - M Capezzone
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 16, 53100, Siena, Italy
| | - A Sagnella
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 16, 53100, Siena, Italy
| | - A Cartocci
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - M Caroli Costantini
- Department of Oncology and Pathological Anatomy, Azienda Ospedaliera, Universitario Senese, Siena, Italy
| | - L Brindisi
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 16, 53100, Siena, Italy
| | - V Mancini
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - S Cantara
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 16, 53100, Siena, Italy.
| | - M G Castagna
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 16, 53100, Siena, Italy
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19
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Tolaba N, Spedalletti Y, Bazzoni P, Galindez M, Cerioni V, Santillan C, Richter G, Herrera C, Sanchez L, Van Cawulaert L, Toscano MA, Nallar M, Monteros Alvi M, Moya CM. Testing of mutations on thyroid nodules with indeterminate cytology: A prospective study of 112 patients in Argentina. ENDOCRINOL DIAB NUTR 2022; 69:122-130. [PMID: 35256055 DOI: 10.1016/j.endien.2022.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 02/21/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND The study of genetic mutations in thyroid nodules makes it possible to improve the preoperative diagnosis of and reduce unnecessary surgeries on benign nodules. In this study, we analysed the impact of implementing a 7-gene mutation panel that enables mutations to be detected in BRAF and RAS (H/N/K) and the gene fusions PAX8/PPARG, RET/PTC1 and RET/PTC2, in a population in northern Argentina. METHODS We performed a prospective analysis of 112 fine needle aspirations diagnosed as having indeterminate cytology according to the Bethesda classification system. These include the Bethesda III or atypia of unknown significance/follicular lesion of unknown significance and Bethesda IV or follicular neoplasm/suspicious for follicular neoplasm categories. The mutations of the 7-gene panel were analysed and this information was linked to the available histology and ultrasound monitoring. RESULTS The BRAF V600E and RET/PTC1 mutations were associated with carcinoma in 100% of cases (n = 8), whereas only 37.5% (n = 3) of the nodules with RAS and 17% (n = 1) with PAX8/PPARG mutations were associated with carcinoma. From the histological diagnosis and ultrasound monitoring of patients, we can estimate that this panel has a sensitivity of 86% in detecting malignant carcinoma, a specificity of 77%, a positive predictive value (PPV) of 54% and a negative predictive value (NPV) of 94%. In this study, it was possible to reduce the number of surgeries by 48% in the patients analysed. CONCLUSION The implementation of the mutation panel allowed the appropriate surgical strategy to be selected for each patient, the number of two-step surgeries to be reduced, and active follow-up to be established in low-risk patients.
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Affiliation(s)
- Norma Tolaba
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina.
| | - Yamila Spedalletti
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Paola Bazzoni
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Macarena Galindez
- Programa de Endocrinología, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Valeria Cerioni
- Programa de Endocrinología, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Cecilia Santillan
- Programa de Endocrinología, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Gilda Richter
- Área de Cirugía Percutánea, Técnicas Cardíacas e Imágenes. Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Cecilia Herrera
- Área de Cirugía Percutánea, Técnicas Cardíacas e Imágenes. Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Laura Sanchez
- Área de Cirugía Percutánea, Técnicas Cardíacas e Imágenes. Hospital Dr. Arturo Oñativia, Salta, Argentina
| | | | - Marta A Toscano
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Marcelo Nallar
- Área de Cirugía Percutánea, Técnicas Cardíacas e Imágenes. Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Marcelo Monteros Alvi
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina.
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20
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Cancela E Penna G, Costa CT, Pires MC, Nunes TA. Are the anatomical, clinical, and ultrasound characteristics of thyroid nodules with Bethesda III or IV cytology and ACR TI-RADS 3, 4, or 5 able to refine the indications for molecular diagnostic tests? ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:625-631. [PMID: 34591407 PMCID: PMC10528568 DOI: 10.20945/2359-3997000000402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/29/2021] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To analyze the association of clinical, anatomical, and ultrasound (US) characteristics of malignancies in Bethesda III or IV (III-B or IV-B) thyroid nodules. METHODS The association between malignancies and the following variables were analyzed: III-B or IV-B, age < 55 years and ≥ 55 years, sex, family history of thyroid cancer, history of irradiation, nodule size, and ACR TI-RADS classification in 62 participants who underwent thyroidectomy. RESULTS Of the 62 participants, 87.1% (54/62) were women, 74.2% were < 55 years old, 95.2% had no family history of thyroid cancer, 56.5% had nodules < 2 cm in size, 62.9% were IV-B, and 69.4% were ACR TI-RADS 4. Thirty-two patients had thyroid carcinoma, and 30 had benign histology. Among all factors associated with malignancy, only ACR TI-RADS 5 classification on US was found to be statistically significant (p = 0.014), while III-B with architectural atypia cytological classification was the only one significantly associated with benign status (p = 0.004). CONCLUSION Only a high risk of malignancy as assessed using US was able to refine the indication for molecular tests in a group of patients with indeterminate nodules. We found 85% (53/62) of III-B or IV-B thyroid nodules would benefit from available molecular diagnostic tests.
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Affiliation(s)
- Gustavo Cancela E Penna
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil,
| | - Camila Teixeira Costa
- Programa de Pós-Graduação em Ciências Aplicadas à Cirurgia e à Oftalmologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Magda Carvalho Pires
- Departamento de Estatística, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Tarcizo Afonso Nunes
- Programa de Pós-Graduação em Ciências Aplicadas à Cirurgia e à Oftalmologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
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21
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Marotta V, Bifulco M, Vitale M. Significance of RAS Mutations in Thyroid Benign Nodules and Non-Medullary Thyroid Cancer. Cancers (Basel) 2021; 13:cancers13153785. [PMID: 34359686 PMCID: PMC8345070 DOI: 10.3390/cancers13153785] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Only about 4% of thyroid nodules are carcinomas and require surgery. Fine-needle aspiration cytology is the most accurate tool to distinguish benign from malignant thyroid nodules, however it yields an indeterminate result in about 30% of the cases, posing diagnostic and prognostic dilemmas. Testing for genetic mutations, including those of RAS, has been proposed for indeterminate cytology to solve these dilemmas and support the clinician decision making process. A passionate debate is ongoing on the biological and clinical significance of RAS mutations, calling into question the utility of RAS as tumor marker. Recently, the description of a new entity of non-invasive follicular thyroid neoplasm and the accurate review of more recent analyses demonstrate that RAS mutations have limited utility in both the diagnostic and prognostic setting of thyroid nodular disease. Abstract Thyroid nodules are detected in up to 60% of people by ultrasound examination. Most of them are benign nodules requiring only follow up, while about 4% are carcinomas and require surgery. Malignant nodules can be diagnosed by the fine-needle aspiration cytology (FNAC), which however yields an indeterminate result in about 30% of the cases. Testing for RAS mutations has been proposed to refine indeterminate cytology. However, the new entity of non-invasive follicular thyroid neoplasm, considered as having a benign evolution and frequently carrying RAS mutations, is expected to lower the specificity of this mutation. The aggressive behavior of thyroid cancer with RAS mutations, initially reported, has been overturned by the recent finding of the cooperative role of TERT mutations. Although some animal models support the carcinogenic role of RAS mutations in the thyroid, evidence that adenomas harboring these mutations evolve in carcinomas is lacking. Their poor specificity and sensitivity make the clinical impact of RAS mutations on the management of thyroid nodules with indeterminate cytology unsatisfactory. Evidence suggests that RAS mutation-positive benign nodules demand a conservative treatment. To have a clinical impact, RAS mutations in thyroid malignancies need not to be considered alone but rather together with other genetic abnormalities in a more general context.
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Affiliation(s)
- Vincenzo Marotta
- UOC Clinica Endocrinologica e Diabetologica, AOU S. Giovanni di Dio e Ruggi D’Aragona, 84131 Salerno, Italy;
| | - Maurizio Bifulco
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80100 Naples, Italy;
| | - Mario Vitale
- Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
- Correspondence: ; Tel.: +39-089-672-753
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22
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Patel SG, Carty SE, Lee AJ. Molecular Testing for Thyroid Nodules Including Its Interpretation and Use in Clinical Practice. Ann Surg Oncol 2021; 28:8884-8891. [PMID: 34275048 DOI: 10.1245/s10434-021-10307-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 05/31/2021] [Indexed: 01/09/2023]
Abstract
Despite advances in imaging and biopsy techniques, the management of thyroid nodules often remains a diagnostic and clinical challenge. In particular, patients with cytologically indeterminate nodules often undergo diagnostic thyroidectomy although only a minority of patients are found to have thyroid malignancy on final pathology. More recently, several molecular testing platforms have been developed to improve the stratification of cancer risk for patients with cytologically indeterminate thyroid nodules. Based on numerous studies demonstrating its accuracy, molecular testing has been incorporated as an important diagnostic adjunct in the management of indeterminate thyroid nodules in the National Comprehensive Cancer Network Guidelines as well as in the American Thyroid Association (ATA) and American Association of Endocrine Surgeons (AAES) guidelines. This overview describes the currently available molecular testing platforms and highlights the published data to date on the clinical validity and utility of molecular testing in the contemporary management of thyroid nodules.
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Affiliation(s)
- Snehal G Patel
- Department of Surgery, Division of General Surgery, Emory University, Atlanta, GA, USA
| | - Sally E Carty
- Department of Surgery, Division of Endocrine Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Andrew J Lee
- Department of Surgery, Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
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23
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Tolaba N, Spedaletti Y, Bazzoni P, Galindez M, Cerioni V, Santillan C, Richter G, Herrera C, Sanchez L, Van Cauwlaert L, Toscano MA, Nallar M, Monteros Alvi M, Moya CM. Testing of mutations on thyroid nodules with indeterminate cytology: A prospective study of 112 patients in Argentina. ENDOCRINOL DIAB NUTR 2021; 69:S2530-0164(21)00143-9. [PMID: 34172433 DOI: 10.1016/j.endinu.2021.02.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 02/17/2021] [Accepted: 02/21/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND The study of genetic mutations in thyroid nodules makes it possible to improve the preoperative diagnosis of and reduce unnecessary surgeries on benign nodules. In this study, we analysed the impact of implementing a 7-gene mutation panel that enables mutations to be detected in BRAF and RAS (H/N/K) and the gene fusions PAX8/PPARG, RET/PTC1 and RET/PTC2, in a population in northern Argentina. METHOD We performed a prospective analysis of 112 fine needle aspirations diagnosed as having indeterminate cytology according to the Bethesda classification system. These include the Bethesda III or atypia of unknown significance/follicular lesion of unknown significance and Bethesda IV or follicular neoplasm/suspicious for follicular neoplasm categories. The mutations of the 7-gene panel were analysed and this information was linked to the available histology and ultrasound monitoring. RESULTS The BRAF V600E and RET/PTC1 mutations were associated with carcinoma in 100% of cases (n=8), whereas only 37.5% (n=3) of the nodules with RAS and 17% (n=1) with PAX8/PPARG mutations were associated with carcinoma. From the histological diagnosis and ultrasound monitoring of patients, we can estimate that this panel has a sensitivity of 86% in detecting malignant carcinoma, a specificity of 77%, a positive predictive value (PPV) of 54% and a negative predictive value (NPV) of 94%. In this study, it was possible to reduce the number of surgeries by 48% in the patients analysed. CONCLUSION The implementation of the mutation panel allowed the appropriate surgical strategy to be selected for each patient, the number of two-step surgeries to be reduced, and active follow-up to be established in low-risk patients.
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Affiliation(s)
- Norma Tolaba
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina.
| | - Yamila Spedaletti
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Paola Bazzoni
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Macarena Galindez
- Programa de Endocrinología, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Valeria Cerioni
- Programa de Endocrinología, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Cecilia Santillan
- Programa de Endocrinología, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Gilda Richter
- Área de Cirugía Percutánea, Técnicas Cardíacas e Imágenes. Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Cecilia Herrera
- Área de Cirugía Percutánea, Técnicas Cardíacas e Imágenes. Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Laura Sanchez
- Área de Cirugía Percutánea, Técnicas Cardíacas e Imágenes. Hospital Dr. Arturo Oñativia, Salta, Argentina
| | | | - Marta A Toscano
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Marcelo Nallar
- Área de Cirugía Percutánea, Técnicas Cardíacas e Imágenes. Hospital Dr. Arturo Oñativia, Salta, Argentina
| | - Marcelo Monteros Alvi
- Programa de Anatomía Patológica y Genética, Hospital Dr. Arturo Oñativia, Salta, Argentina.
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Rossi D, Belotti A, di Tonno C, Midolo V, Maffini FA, Nicosia L, De Fiori E, Mauri G. Changes in thyroid fine needle aspiration practice during the COVID-19 pandemic. Cytopathology 2021; 32:732-737. [PMID: 34137099 PMCID: PMC8597111 DOI: 10.1111/cyt.13020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 06/03/2021] [Accepted: 06/06/2021] [Indexed: 12/30/2022]
Abstract
Purpose To investigate the diagnostic accuracy of a different sample preparation protocol for fine needle aspiration cytology (FNAC) of thyroid nodules established during the COVID‐19 pandemic. Methods From April 2020, conventional smears during FNAC were ceased according to World Health Organization recommendations due to the increased infection risk for operators, and a new protocol using only liquid‐based cytology (LBC) was adopted. FNACs performed between April and July 2020 (COVID‐19 group) were retrospectively compared with those from December 2019 through March 2020 (Pre‐COVID‐19 group). The distribution of diagnoses based on SIAPEC‐IAP categories and the concordance between cytological and histological results were compared using the chi‐squared test. Results Categories based on FNAC for 90 and 82 thyroid nodules in the Pre‐COVID‐19 and COVID‐19 groups showed no significant difference in distribution (P = .081), with the following respective cases (and percentages): TIR1, 7 (8%) and 8 (10%); TIR1C, 0 (0%) and 6 (7%); TIR2, 59 (66%) and 55 (67%); TIR3A, 8 (9%) and 5 (6%); TIR3B, 1 (1%) and 2 (3%); TIR4, 5 (6%) and 1 (1%); and TIR5, 10 (12%) and 5 (7%). Among patients with potentially malignant lesions, surgery was performed for 12/16 (75%) nodules in the Pre‐COVID‐19 and 7/8 (88%) nodules in the COVID‐19 groups, with no significant differences between cytological and histological diagnoses (P = .931). Conclusion The new LBC‐only protocol provided similar diagnostic accuracy in comparison with conventional smears, and can be effectively applied during a viral pandemic improving operator safety.
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Affiliation(s)
- Duccio Rossi
- Postgraduate School of Radiodiagnostics, Università Degli Studi di Milano, Milan, Italy
| | - Alessia Belotti
- Postgraduate School of Pathology, Università Degli Studi di Milano, Milan, Italy
| | - Clementina di Tonno
- Division of Cytopathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Valeria Midolo
- Division of Cytopathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | | | - Luca Nicosia
- Department of Breast Radiology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Elvio De Fiori
- Department of Radiology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Giovanni Mauri
- Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy.,Division of Interventional Radiology, IEO, European Institute of Oncology IRCCS, Milan, Italy
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Yousefi E, Sura GH, Somma J. The gray zone of thyroid nodules: Using a nomogram to provide malignancy risk assessment and guide patient management. Cancer Med 2021; 10:2723-2731. [PMID: 33763983 PMCID: PMC8026948 DOI: 10.1002/cam4.3866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/04/2021] [Accepted: 03/13/2021] [Indexed: 01/21/2023] Open
Abstract
Background Thyroid nodules have a low prevalence of malignancy and most proven cancers do not behave aggressively. Thus, risk‐stratification of nodules is a critical step to avoid surgical overtreatment. We hypothesized that a risk management system superior to those currently in use could be created to reduce the number of clinically indeterminate nodules (i.e., the “gray zone”) by concurrently considering the malignancy risks conferred by clinical, ultrasonographic, and cytologic variables. Methods Thyroidectomy cases were reviewed from three institutions. Their benign versus malignant outcome was used to evaluate the variables for correlation. A binary logistic regression model was trained and, using indeterminate nodules with Bethesda III and IV results, validated. A scoring nomogram was designed to demonstrate the application of the model in clinical practice. Results One hundred thirty thyroidectomies (28% malignant) met inclusion criteria. The final logistic regression model included difficulty in swallowing, hypothyroidism, echogenicity, hypervascularity, margins, calcification, and cytology diagnosis as input parameters. The model was highly successful in determining the outcome (p value: 0.001) with a R2(Nagelkerke) score of 0.93. The area under the curve as determined by receiver operating characteristics was 0.91. The accuracy of the model on the training dataset was 93% (sensitivity and specificity 92% and 96%, respectively) and, on the validation dataset, 80% (sensitivity and specificity 91% and 67%, respectively). Conclusions We report a model for risk assessment of thyroid nodules that has the potential to significantly reduce indeterminates and surgical overtreatment. We illustrate its application via a straightforward nomogram, which integrates clinical, ultrasonographic, and cytologic data, and can be used to create clear, evidence‐based management plans for patients.
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Affiliation(s)
- Elham Yousefi
- Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | - Gloria H Sura
- Department of Pathology, LSU Health Sciences Center, New Orleans, LA, USA
| | - Jonathan Somma
- Department of Pathology, LSU Health Sciences Center, New Orleans, LA, USA
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26
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Capezzone M, Cantara S, Di Santo A, Sagnella A, Pilli T, Brilli L, Ciuoli C, Maino F, Forleo R, Cartocci A, Castagna MG. The Combination of Sonographic Features and the Seven-Gene Panel May be Useful in the Management of Thyroid Nodules With Indeterminate Cytology. Front Endocrinol (Lausanne) 2021; 12:613727. [PMID: 33716969 PMCID: PMC7943869 DOI: 10.3389/fendo.2021.613727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 01/14/2021] [Indexed: 12/24/2022] Open
Abstract
Introduction The management of patients with indeterminate thyroid nodules, which account for 10-25% of thyroid fine needle aspiration biopsies (FNABs), is still very challenging. Aim To verify the utility of the seven-gene panel in combination with ultrasound features in the clinical management of indeterminate thyroid nodules. Results The study group included 188 indeterminate thyroid nodules, divided into TIR3A (56.4%) and TIR3B (43.6%). A significant correlation between US categories and both cytological and molecular results was observed. In detail, TIR3B cytology was more frequent in EU-TIRADS 4 and 5 nodules (54.7 and 50%, respectively) than in EU-TIRADS 2 and 3 nodules (31%, p = 0.04). Similarly, the rate of a nodule with a mutation increased with the increase of US risk class (6.0% in EU-TIRADS 2 and 3, 9.3% in EUTIRADS-4 and 27.8% in EUTIRAD-5, p = 0.01). Among thyroid nodules submitted to surgery, final histology was benign in 61.4% nodules, while malignancy was diagnosed in 38.6% nodules. Using US score as tool for decision-making in TIR3A subgroup, we correctly classified 64.5% of thyroid nodules. The second tool (seven-gene panel test) was used in the subgroup of US high-risk nodules. By multiple tests with a series approach (US in all cases and US plus seven-gene panel in US high risk nodules) 84% of cases were correctly classified. In TIR3B nodules, using only seven-gene panel as tool for decision making, we correctly classified 61.9% of indeterminate nodules. By multiple tests with series approach (seven-gene panel in all cases and seven-gene panel plus US score in non-mutated nodules) only a slight improvement of thyroid nodule classification (66.6%) was observed. Conclusions US score seems able to correctly discriminate between TIR3A nodules in which a conservative approach may be used, and those in which additional test, such as molecular test, may be indicated. On the contrary, in TIR3B nodules both US risk stratification and seven-gene panel seem to be of little use, because the risk of thyroid cancer remains high regardless of US score and mutational status.
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Affiliation(s)
- Marco Capezzone
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Silvia Cantara
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | | | - Alfonso Sagnella
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Tania Pilli
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Lucia Brilli
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Cristina Ciuoli
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Fabio Maino
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Raffaella Forleo
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | | | - Maria Grazia Castagna
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
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Bardet S, Goardon N, Lequesne J, Vaur D, Ciappuccini R, Leconte A, Monpeyssen H, Saguet-Rysanek V, Clarisse B, Lasne-Cardon A, Ménégaux F, Leenhardt L, Buffet C. Diagnostic and prognostic value of a 7-panel mutation testing in thyroid nodules with indeterminate cytology: the SWEETMAC study. Endocrine 2021; 71:407-417. [PMID: 32638211 PMCID: PMC7881964 DOI: 10.1007/s12020-020-02411-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE The aim of this prospective study (ClinicalTrials.gov: NCT01880203) was to evaluate the diagnostic and prognostic value of a 7-panel mutation testing in the aspirates of thyroid nodules with indeterminate cytology (IC). METHODS Eligible patients had a thyroid nodule ≥15 mm with IC (Bethesda III-V) for which surgery had been recommended. Detection of BRAF and RAS mutations was performed using pyrosequencing and RET/PTC and PAX8/PPARγ rearrangements using Real-Time quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS Among 131 nodules with IC, 21 (16%) were malignant including 20 differentiated cancers and one thyroid lymphoma. Molecular abnormalities were identified in 15 nodules with IC corresponding to 10 malignant and 5 benign tumours. BRAF mutation was detected in 4 nodules all corresponding to classic PTC, and PAX8/PPARγ rearrangement in 2 HCC. In contrast, RAS mutation was identified in eight nodules, of which four were malignant, and one RET/PTC3 rearrangement in a follicular adenoma. This data resulted in an accuracy of 88%, sensitivity of 48%, specificity of 95%, positive-predictive value of 67%, and negative-predictive value of 91%. After a 56 month's follow-up, the proportion of excellent response was similar in patients with molecular alterations (67%) and those without (60%). CONCLUSIONS By increasing the overall risk of cancer from 16 to 67% in mutated nodules and by diminishing it to 9% in wild-type, this study confirms the relevance of the 7-panel mutation testing in the diagnostic of nodules with IC. Genetic testing, however, did not predict outcome in the cancer patient subgroup.
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Affiliation(s)
- Stéphane Bardet
- Department of Nuclear Medicine and Thyroid Unit, Centre François Baclesse, Caen, France.
| | - Nicolas Goardon
- Department of Molecular Biology, Centre François Baclesse, Caen, France
| | - Justine Lequesne
- Department of Clinical Research, Centre François Baclesse, Caen, France
| | - Dominique Vaur
- Department of Molecular Biology, Centre François Baclesse, Caen, France
| | - Renaud Ciappuccini
- Department of Nuclear Medicine and Thyroid Unit, Centre François Baclesse, Caen, France
| | - Alexandra Leconte
- Department of Clinical Research, Centre François Baclesse, Caen, France
| | | | | | | | | | - Fabrice Ménégaux
- Department of Endocrine Surgery, Pitié Salpêtrière Hospital, IUC, University Paris VI, Paris, France
| | - Laurence Leenhardt
- Thyroid and Endocrine Tumors Unit, Institute of Endocrinology, Pitié Salpêtrière Hospital, IUC Sorbonne University, Paris, France
| | - Camille Buffet
- Thyroid and Endocrine Tumors Unit, Institute of Endocrinology, Pitié Salpêtrière Hospital, IUC Sorbonne University, Paris, France
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28
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Liu M, Chen P, Hu HY, Ou-Yang DJ, Khushbu RA, Tan HL, Huang P, Chang S. Kinase gene fusions: roles and therapeutic value in progressive and refractory papillary thyroid cancer. J Cancer Res Clin Oncol 2021; 147:323-337. [PMID: 33387037 DOI: 10.1007/s00432-020-03491-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/02/2020] [Indexed: 12/19/2022]
Abstract
The incidence of papillary thyroid cancer (PTC), the major type of thyroid cancer, is increasing rapidly around the world, and its pathogenesis is still unclear. There is poor prognosis for PTC involved in rapidly progressive tumors and resistance to radioiodine therapy. Kinase gene fusions have been discovered to be present in a wide variety of malignant tumors, and an increasing number of novel types have been detected in PTC, especially progressive tumors. As a tumor-driving event, kinase fusions are constitutively activated or overexpress their kinase function, conferring oncogenic potential, and their frequency is second only to BRAFV600E mutation in PTC. Diverse forms of kinase fusions have been observed and are associated with specific pathological features of PTC (usually at an advanced stage), and clinical trials of therapeutic strategies targeting kinase gene fusions are feasible for radioiodine-resistant PTC. This review summarizes the roles of kinase gene fusions in PTC and the value of clinical therapy of targeting fusions in progressive or refractory PTC, and discusses the future perspectives and challenges related to kinase gene fusions in PTC patients.
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Affiliation(s)
- Mian Liu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Pei Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Hui-Yu Hu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Deng-Jie Ou-Yang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Rooh-Afza Khushbu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Hai-Long Tan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Peng Huang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Shi Chang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Romanelli K, Wells J, Patel A, Mendonca Torres M, Costello J, Jensen K, Vasko V. Clinical and molecular characterization of thyroid cancer when seen as a second malignant neoplasm. Ther Adv Endocrinol Metab 2021; 12:20420188211058327. [PMID: 35154635 PMCID: PMC8832328 DOI: 10.1177/20420188211058327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 10/19/2021] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Second malignant neoplasms (SMN) are among the most serious long-term adverse health conditions in cancer survivors. The aim of this study was to characterize clinical findings of patients who developed thyroid cancers as SMN, and to examine genomic alterations in thyroid cancer tissue. METHODS Retrospective analysis of medical records from patients seen for management of thyroid cancer over 10-year period was performed. Clinical and pathologic data were retrieved from their medical charts. Tumor DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and subjected to next-generation sequencing (NGS) using Ion Torrent Oncomine Focus Assay. Microfluidic digital polymerase chain reactions (PCRs) were performed using QIAcuity Digital PCR System to identify BRAF V600E mutations and RET/PTC fusions. RESULTS Sixteen of 620 patients operated for thyroid cancer had history of previously diagnosed malignancy. Eight patients were male and eight patients were female, with a median age at diagnosis of 58.5 years (range, 4-78). Four patients had history of pediatric malignancy (PedCa), and 12 patients had a history of prior malignancy as an adult (AdCa). The latency periods for development of SMN in PedCa and AdCa patients were 10.8 (±5.2) years and 9.5 (±5.2) years, respectively. Histopathology revealed papillary thyroid cancers in 15 cases, and follicular thyroid cancer in 1 case. All tumors were classified as T1 or T2, and there were no patients presenting with metastases at the time of surgery. Genomic alterations were detected in 13/16 (81.2%) tumors including eight gene mutations (BRAF V600E (N = 4), RAS (N = 2), PI3CA (N = 2) and five gene fusions (RET/PTC1 (N = 4) and STRN/ALK (N = 1). In patients with PedCa and AdCa, mutations were detected in 1/4 (25%) and 7/12 (58.3%), respectively, p = 0.56; and fusions were detected in 3/4 (75%) and 2/12 (16.6%), respectively, p = 0.06. In patients with and without history of therapeutic irradiation, mutations were detected with the same frequencies (5/10 (50%), and 3/6 (50%), respectively, p = 1.0). Gene fusions were detected in patients with and without history of irradiation in 5/10 (55.5%) and 0/6 (0%), respectively, p = 0.09. CONCLUSIONS Monitoring of cancer survivors for thyroid disorders allowed diagnosis of second thyroid cancers at early stages. Second thyroid cancers harbor genomic alterations that are typical for sporadic as well as for radio-induced thyroid cancers.
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Affiliation(s)
- Kristen Romanelli
- Department of Pediatric, Hematology/Oncology,
Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Justin Wells
- Department of Pathology, Walter Reed National
Military Medical Center, Bethesda, MD, USA
| | - Aneeta Patel
- Department of Pediatrics, Uniformed Services
University of Health Sciences, Bethesda, MD, USA
| | - Maria Mendonca Torres
- Department of Pediatrics, Uniformed Services
University of Health Sciences, Bethesda, MD, USA
| | - John Costello
- Department of Pediatrics, Uniformed Services
University of Health Sciences, Bethesda, MD, USA
| | - Kirk Jensen
- Department of Pediatrics, Uniformed Services
University of Health Sciences, Bethesda, MD, USA
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Gupta O, Gautam U, Chandrasekhar M, Rajwanshi A, Radotra BD, Verma R, Srinivasan R. Molecular Testing for BRAFV600E and RAS Mutations from Cytoscrapes of Thyroid Fine Needle Aspirates: A Single-Center Pilot Study. J Cytol 2020; 37:174-181. [PMID: 33776257 PMCID: PMC7984513 DOI: 10.4103/joc.joc_45_20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 09/17/2020] [Accepted: 09/23/2020] [Indexed: 12/31/2022] Open
Abstract
Context and Aim: Molecular testing of thyroid FNA has been advocated in the indeterminate categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) 2018. The utility of cytoscrapes of thyroid FNA samples for BRAF V600E and RAS mutations was evaluated in this pilot study. Methods and Materials: Thyroid FNA samples between 2015 and 2018 from TBSRTC categories 3–6 were included. DNA was extracted from one to two representative smears (cytoscrape). Real-time PCR for BRAF V600E and RAS (KRAS, NRAS, and HRAS) gene mutations was performed. Histopathology correlation was available in 44 cases. Statistical Methods: Chi-square test and calculation of sensitivity, specificity, and positive/negative predictive values were performed. Results: A total of 73 thyroid FNA cases and 11 nodal metastases of papillary thyroid carcinoma (PTC) were evaluated. The DNA yield ranged from 1.9 to 666 ng/μl (mean 128 ng/μl) in 80 cases and was insufficient in four cases. Overall, mutations were seen in 45 (56.25%) cases with BRAF V600E, NRAS, HRAS, and KRAS in 21 (46.7%), 19 (42.2%), 4, and 1 cases, respectively. BRAF V600E mutation was seen in PTC (11/18, 61%), nodal PTC metastases (5/10, 50%), and occasionally in TBSRTC category 3 (1/18, 5.5%). NRAS mutations were seen across all categories and were maximum in the AUS/FLUS group (6/18, 33%). BRAF V600E /RAS testing had an overall sensitivity, specificity, and positive and negative predictive values of 61.7%, 80%, 91.3%, and 38%, respectively, for the detection of malignancy. In indeterminate thyroid nodules, the sensitivity, specificity, PPV, and NPV were 56.2%, 80%, 81.8%, and 53.3%, respectively. Conclusion: BRAF V600E/RAS mutation testing from cytoscrapes are useful as a rule-in test for indeterminate thyroid nodules and provide molecular confirmation in nodal metastases of PTC.
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Affiliation(s)
- Ojas Gupta
- Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Upasana Gautam
- Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Muralidaran Chandrasekhar
- Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Arvind Rajwanshi
- Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Bishan Dass Radotra
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Roshan Verma
- Department of Otorhinolaryngology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Radhika Srinivasan
- Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Abstract
INTRODUCTION Fine-needle aspiration (FNA) is an important diagnostic tool for the evaluation of thyroid nodules. However, in almost ¼ of all nodules submitted to FNA cytology is indeterminate. Since the majority of genetic alterations in thyroid cancer have been identified, the use of molecular testing platforms has been endorsed by American Thyroid Association for management of indeterminate nodules. EVIDENCE ACQUISITION Several commercial tests were based on mRNA expression of FNA samples (Afirma®, Veracyte, South San Francisco, CA, USA) while others detect DNA alterations (ThyroSeq, UPMC, Pittsburgh, PA, USA). Noncommercial tests detect limited number of point mutations or re-arrangements (gene panels). Literature study included a Pubmed research for adult original studies from 2003 to 2020, focusing on terms such as "molecular tests," "nodules with indeterminate AUS/FLUS and FN/SFN cytology." EVIDENCE SYNTHESIS Gene expression profile tests serve as "rule out" tests due to their high negative predictive value and perform better in a setting of low cancer pretest probability. Genetic alteration platforms display high positive predictive value and serve as rather "rule in" tests but their diagnostic accuracy is hampered either because a small proportion of nodules does not harbor any of these alterations targeted (gene panels) or because commonly identified RAS mutations can also be found in benign nodules. CONCLUSIONS Next generation sequencing development and incorporation of other genetic markers such as miRNA can improve diagnostic accuracy of molecular tests.
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Affiliation(s)
- Olga Karapanou
- 401Hellenic Army General Military Hospital of Athens, Athens, Greece -
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Fazeli SR, Zehr B, Amraei R, Toraldo G, Guan H, Kindelberger D, Lee S, Cerda S. ThyroSeq v2 Testing: Impact on Cytologic Diagnosis, Management, and Cost of Care in Patients with Thyroid Nodule. Thyroid 2020; 30:1528-1534. [PMID: 32349630 DOI: 10.1089/thy.2019.0191] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Background: Novel molecular tests (MTs), such as ThyroSeq, may improve the management of thyroid nodules with indeterminate cytologic diagnoses; however, the impact of these tests on cost and outcome of management is unknown. Here, we evaluated the impact of ThyroSeq testing on the cytopathologic diagnosis, management, and cost of care in patients with thyroid nodules. Methods: In a retrospective study, using actual patient cohorts, the outcome and cost of management of patients with thyroid nodules seen before the introduction of ThyroSeq v2 at our institution (standard of care [StC] cohort) were compared with those seen after the introduction of this test (MT cohort). Results: A total of 773 consecutive patients entered the study (393 StC, 380 MT). The incidence of cytologically benign nodules decreased from 71.0% (StC) to 53.2% (MT) and those of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) and follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) increased from 8.9% (StC) to 21.3% (MT) and from 3.1% (StC) to 6.3% (MT), respectively. The overall rate of surgery did not change significantly (23.4% in StC vs. 23.2% in MT). Among patients who underwent surgery, the rate of overtreatment (surgeries performed on histologic benign nodules without clinical indication: compressive symptoms, hyperthyroidism resistant to medication, and nodule size >4 cm) slightly decreased from 18.8% (StC) to 16.7% (MT). The rate of malignancy decreased from 45.5% (StC) to 37.9% (MT) in AUS/FLUS and increased from 40.0% to 53.8% in FN/SFN. However, the overall rate of malignancy remained equal (47.8% in StC vs. 47.7% in MT). The average cost of care per patient in the AUS/FLUS and FN/SFN categories increased from $6,566 (StC) to $8,444 (MT) and from $9,313 (StC) to $10,253 (MT), respectively. Similarly, the overall average cost of care of a patient who underwent thyroid fine-needle aspiration increased from $3,088 (StC) to $4,282 (MT). Finally, the average cost per thyroid cancer detected increased from $26,312 (StC) to $38,746 (MT). Conclusions: Introduction of ThyroSeq v2 resulted in a shift toward indeterminate cytology results. The institutional rate of surgery, overtreatment, and malignancy did not change significantly. Lack of decrease in the rate of surgery along with the additional cost of ThyroSeq v2 increased the overall cost of care of patients including those with indeterminate cytology results.
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Affiliation(s)
- Shoreh R Fazeli
- Department of Pathology & Laboratory Medicine at Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts, USA
| | - Bradley Zehr
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Razie Amraei
- Department of Pathology & Laboratory Medicine at Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts, USA
| | - Gianluca Toraldo
- Lahey Hospital and Medical Center Endocrinology, Burlington, Massachusetts, USA
| | - Haixia Guan
- Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University Medical Center, Boston, Massachusetts, USA
| | - David Kindelberger
- Department of Pathology, Harvard Vanguard Medical Associates Atrius Health, Boston, Massachusetts, USA
| | - Stephanie Lee
- Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University Medical Center, Boston, Massachusetts, USA
| | - Sandra Cerda
- Department of Pathology & Laboratory Medicine at Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts, USA
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Abdelhakam DA, Mojica RE, Huenerberg KA, Nassar A. Impact of a genomic classifier on indeterminate thyroid nodules: an institutional experience. J Am Soc Cytopathol 2020; 10:155-163. [PMID: 33067175 DOI: 10.1016/j.jasc.2020.09.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/03/2020] [Accepted: 09/15/2020] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Indeterminate thyroid cytology (ITC) occurs in 20% to 25% of cases, and the associated risk of malignancy ranges from 5% to 30%. The genomic classifier ThyroSeq (CBLPath/UPMC, Rye Brook, NY), a targeted next-generation sequencing technology, could classify ITC nodules as malignant and nonmalignant. We sought to characterize our institutional experience with ThyroSeq testing. MATERIALS AND METHODS We retrospectively identified all patients seen from January 2015 through November 2019 who had ITC nodules analyzed with ThyroSeq. Relevant clinical, pathologic, and resection data were reviewed. RESULTS Of the 133 cases identified, diagnostic categories included atypia (or follicular lesion) of undetermined significance) (n = 65 [48.9%]), suspicious for follicular neoplasm (SFN) (n = 48 [36.1%]), and suspicious for Hürthle cell neoplasm (n = 20 [15.0%]). About half of the papillary thyroid carcinoma (PTC) cases (n = 9 [56.3%]) and more than one-third of the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) cases (n = 3/8 [37.5%]) were classified as SFN. Most patients (n = 87 [65.4%]) did not undergo resection; of these, 73 (83.9%) were negative for all molecular alterations. Of the 54 cases with molecular alterations, isolated RAS or RAS-like variants were most common (n = 35 [64.8%]); 9 (25.7%) were identified in PTC and 8 (22.9%) in NIFTP. NRAS was the most common alteration (n = 20 [37.0%]), followed by HRAS (n = 6 [11.1%]), which was mostly detected in NIFTP cases (n = 4 of 6 [66.7%]). CONCLUSION Resection was avoided in 73 patients (54.9%) because of negative ThyroSeq results. ThyroSeq v2 and v3 offered a more accurate categorization of ITC nodules, improved patient management, and reduced unnecessary surgical procedures.
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Affiliation(s)
- Dina A Abdelhakam
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Department of Pathology and Laboratory Medicine, Mayo Clinic, Jacksonville, Florida
| | - Rafael E Mojica
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Jacksonville, Florida; Edward Via College of Osteopathic Medicine, Spartanburg, South Carolina
| | | | - Aziza Nassar
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida
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Valerio E, Pastorello RG, Calsavara V, Porfírio MM, Engelman GG, Francisco Dalcin J, Bovolim G, Domingos T, De Brot L, Saieg M. Should we wait 3 months for a repeat aspiration in non-diagnostic/indeterminate thyroid nodules? A cancer centre experience. Cytopathology 2020; 31:525-532. [PMID: 32656878 DOI: 10.1111/cyt.12887] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 06/15/2020] [Accepted: 07/08/2020] [Indexed: 01/21/2023]
Abstract
INTRODUCTION The Bethesda System recommends repeat fine needle aspiration (rFNA) as a management option for nodules classified under the non-diagnostic (ND) and atypia of undetermined significance (AUS/FLUS) categories. We evaluated the impact of an rFNA in diagnostic resolution and the role of early (≤3 months) vs delayed (more than 3 months) rFNA of nodules initially diagnosed as ND and AUS/FLUS. METHODS We retrospectively collected all thyroid FNA performed in a 4-year period with repeat aspiration. For cases initially signed out as ND or AUS/FLUS, diagnostic resolution was defined as a change to a Bethesda System category other than these two on rFNA. Comparison and regression models were fitted to identify the impact of time of rFNA on diagnostic resolution. RESULTS In total, 184 cases were initially assigned as ND and 143 as AUS/FLUS, with overall diagnostic resolution rates for the reassessment of these nodules calculated at 70.1% and 62.9%, respectively. For ND cases, time of rFNA was not significantly associated with diagnostic resolution (P > .05). For AUS/FLUS nodules, however, repeat aspiration performed in more than 3 months after the initial diagnosis was 2.5 times more likely to achieve a resolution in diagnosis than early rFNA (P = .024). CONCLUSIONS Repeat aspiration of ND and AUS/FLUS nodules helped define diagnosis for the majority of cases, being highly effective in determining correct patient management. For AUS/FLUS nodules, repeat aspiration performed more than 3 months after the initial diagnosis was associated with a higher diagnostic resolution.
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Affiliation(s)
- Ediel Valerio
- Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil
| | | | - Vinicius Calsavara
- Department of Epidemiology and Statistics, A.C. Camargo Cancer Center, São Paulo, Brazil
| | | | | | | | - Graziele Bovolim
- Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil
| | - Tábata Domingos
- Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil
| | - Louise De Brot
- Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil
| | - Mauro Saieg
- Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil.,Department of Pathology, Santa Casa Medical School, São Paulo, Brazil.,Department of Pathology, Fleury Laboratories, São Paulo, Brazil
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Cho YY, Park SY, Shin JH, Oh YL, Choe JH, Kim JH, Kim JS, Yim HS, Kim YL, Ki CS, Kim TH, Chung JH, Kim SW. Highly Sensitive and Specific Molecular Test for Mutations in the Diagnosis of Thyroid Nodules: A Prospective Study of BRAF-Prevalent Population. Int J Mol Sci 2020; 21:ijms21165629. [PMID: 32781560 PMCID: PMC7460614 DOI: 10.3390/ijms21165629] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/31/2020] [Accepted: 08/04/2020] [Indexed: 12/26/2022] Open
Abstract
Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70–80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.
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Affiliation(s)
- Yoon Young Cho
- Division of Endocrinology and Metabolism, Department of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, Korea;
| | - So Young Park
- Division of Endocrinology and Metabolism, Department of Medicine, Korea University Ansan Hospital, Ansan 15355, Korea;
| | - Jung Hee Shin
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 06351, Korea;
| | - Young Lyun Oh
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 06351, Korea;
| | - Jun-Ho Choe
- Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 06351, Korea; (J.-H.C.); (J.-H.K.); (J.S.K.)
| | - Jung-Han Kim
- Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 06351, Korea; (J.-H.C.); (J.-H.K.); (J.S.K.)
| | - Jee Soo Kim
- Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 06351, Korea; (J.-H.C.); (J.-H.K.); (J.S.K.)
| | - Hyun Sook Yim
- BioSewoom Inc., Sungdong-gu, Seoul 04783, Korea; (H.S.Y.); (Y.-L.K.)
| | - Yoo-Li Kim
- BioSewoom Inc., Sungdong-gu, Seoul 04783, Korea; (H.S.Y.); (Y.-L.K.)
| | | | - Tae Hyuk Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 06351, Korea; (T.H.K.); (J.H.C.)
| | - Jae Hoon Chung
- Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 06351, Korea; (T.H.K.); (J.H.C.)
| | - Sun Wook Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 06351, Korea; (T.H.K.); (J.H.C.)
- Correspondence: ; Tel.: +82-2-3410-1653; Fax: +82-2-3410-3849
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Muzza M, Colombo C, Pogliaghi G, Karapanou O, Fugazzola L. Molecular markers for the classification of cytologically indeterminate thyroid nodules. J Endocrinol Invest 2020; 43:703-716. [PMID: 31853887 DOI: 10.1007/s40618-019-01164-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 12/11/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND The diagnosis of indeterminate lesions of the thyroid is a challenge in cytopathology practice. Indeed, up to 30% of cases lack the morphological features needed to provide definitive classification. Molecular tests have been developed to assist in the diagnosis of these indeterminate cases. The first studies dealing with the preoperative molecular evaluation of FNA samples focused on the analysis of BRAFV600E or on the combined evaluation of two or three genetic alterations. The sensitivity of molecular testing was then improved through the introduction of gene panels, which became available for clinical use in the late 2000s. Two different categories of molecular tests have been developed, the 'rule-out' methods, which aim to reduce the avoidable treatment of benign nodules, and the 'rule-in' tests that have the purpose to optimize surgical management. The genetic evaluation of indeterminate thyroid nodules is predicted to improve patient care, particularly if molecular tests are used appropriately and with the awareness of their advantages and weaknesses. The main disadvantage of these tests is the cost, which makes them rarely used in Europe. To overcome this limitation, customized panels have been set up, which are able to detect the most frequent genetic alterations of thyroid cancer. CONCLUSIONS In the present review, the most recent available versions of commercial molecular tests and of custom, non-commercial panels are described. Their characteristics and accuracy in the differential diagnosis of indeterminate nodules, namely Bethesda classes III (Atypical follicular lesion of undetermined significance, AUS/FLUS) and IV (Suspicious for follicular neoplasm, FN/SFN) are fully analyzed and discussed.
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Affiliation(s)
- M Muzza
- Division of Endocrine and Metabolic Diseases, IRCCS IstitutoAuxologicoItaliano, 20149, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, P.le Brescia 20, 20149, Milano, Italy
| | - C Colombo
- Division of Endocrine and Metabolic Diseases, IRCCS IstitutoAuxologicoItaliano, 20149, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, P.le Brescia 20, 20149, Milano, Italy
| | - G Pogliaghi
- Division of Endocrine and Metabolic Diseases, IRCCS IstitutoAuxologicoItaliano, 20149, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, P.le Brescia 20, 20149, Milano, Italy
| | - O Karapanou
- Department of Endocrinology, 401 Military Hospital, 11525, Athens, Greece
| | - L Fugazzola
- Division of Endocrine and Metabolic Diseases, IRCCS IstitutoAuxologicoItaliano, 20149, Milan, Italy.
- Department of Pathophysiology and Transplantation, University of Milan, P.le Brescia 20, 20149, Milano, Italy.
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Rao SN, Bernet V. Indeterminate thyroid nodules in the era of molecular genomics. Mol Genet Genomic Med 2020; 8:e1288. [PMID: 32436637 PMCID: PMC7503096 DOI: 10.1002/mgg3.1288] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 03/02/2020] [Indexed: 01/21/2023] Open
Abstract
Background Indeterminate thyroid nodules are diagnosed in up to 30% of fine‐needle aspirations and the risk of malignancy in these cases are highly variable. Consequently, managing these nodules has been a challenge. While a diagnostic thyroidectomy would help clarify the pathology, there is the risk of developing surgical‐related complications for a procedure that may not have been necessary and associated high costs. Genomic testing of indeterminate thyroid nodules may help better guide management. Methods We present an unbiased comprehensive review of available molecular testing for classifying indeterminate thyroid nodules, as well as their strengths and limitations, with the objective to allow practitioners to choose the best testing modality for their patients. Results Molecular testing of these nodules provided a platform to help distinguish benign versus malignant nodules, providing more confidence to rule in or rule out the likelihood of thyroid cancer in indeterminate nodules. Conclusion Genomic testing has evolved to more comprehensive panels to better stratify indeterminate nodules, including Hürthle cell neoplasms and noninvasive follicular neoplasm with papillary‐like nuclear features. Understanding the methodology of each available test improves patient care and reduces unnecessary costs.
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Affiliation(s)
- Sarika N Rao
- Division of Endocrinology, Mayo Clinic, Jacksonville, FL, USA
| | - Victor Bernet
- Division of Endocrinology, Mayo Clinic, Jacksonville, FL, USA
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The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults. Ann Surg 2020; 271:e21-e93. [PMID: 32079830 DOI: 10.1097/sla.0000000000003580] [Citation(s) in RCA: 281] [Impact Index Per Article: 56.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy. BACKGROUND Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US. METHODS The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches to Thyroidectomy, Laryngology, Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSIONS Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.
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Castagna MG, Pilli T, Maino F, Marzocchi C, Cairano GD, Cantara S. EIF1AX c.338-2A>T splice site mutation in a patient with trabecular adenoma and cytological indeterminate lesion. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2020; 64:185-189. [PMID: 32236306 PMCID: PMC10118949 DOI: 10.20945/2359-3997000000208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 09/16/2019] [Indexed: 11/23/2022]
Abstract
The EIF1AX gene mutations have been recently associated with papillary thyroid carcinoma and anaplastic thyroid cancer. According with these reports, the gene as been considered as a drive gene for thyroid cancer development. However, the occurrence of these alterations in benign thyroid lesions is not known and is still under investigation. Some authors have already reported the presence of EIF1AX variants in follicular adenomas and hyperplastic nodules. Here, we describe for the first time a case of a man with the EIF1AX c.338-2A>T splice site mutation in an indeterminate FNA lesion with trabecular adenoma at final histology in the absence of other pathogenetic mutations, demonstrating that further studies are required to better understand EIF1AX role in the tumorigenesis of thyroid carcinoma.
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Affiliation(s)
- Maria Grazia Castagna
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Tania Pilli
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Fabio Maino
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Carlotta Marzocchi
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Giovanni Di Cairano
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Silvia Cantara
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
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Asban A, Patel AJ, Reddy S, Wang T, Balentine CJ, Chen H. Cancer of the Endocrine System. ABELOFF'S CLINICAL ONCOLOGY 2020:1074-1107.e11. [DOI: 10.1016/b978-0-323-47674-4.00068-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Jianming L, Jibin L, Linxue Q. Suspicious ultrasound characteristics correlate with multiple factors that predict central lymph node metastasis of papillary thyroid carcinoma: Significant role of HBME-1. Eur J Radiol 2019; 123:108801. [PMID: 31918249 DOI: 10.1016/j.ejrad.2019.108801] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 09/04/2019] [Accepted: 12/15/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE Papillary thyroid carcinoma (PTC) is frequently associated with central lymph node metastasis (CLNM). In the present study, we aimed to identify possible risk factors for CLNM in PTC, including suspicious ultrasound (US) features coexisting with thyroid diseases, immunohistochemical markers, and BRAFV600E. These were used to establish a model to predict the risk of CLNM. METHODS From January 2016 to March 2018, we identified a cohort of patients with classic PTC who underwent cervical US and were diagnosed by postoperative pathology. Fine-needle aspiration biopsies were analyzed for the presence ofBRAFV600E, and immunohistochemistry was used to detect tumor markers. US imaging was performed in accordance with a standardized protocol. A model to determine the risk of CLNM was established using the outcomes of univariate and multivariate analyses. RESULTS Age of ≥45 years, male sex, mean tumor diameter of ≥1.0 cm, taller-than-wide tumor shape, multiple PTCs, capsule contact, and HBME-1 expression were significant independent risk predictors of CLNM. Hashimoto's thyroiditis, nodular goiter, andBRAFV600E were not significantly associated with CLNM. The cutoff value (area under the curve = 0.760) for predicting risk was determined from receiver operating characteristic curves (sensitivity, 75.6 %; specificity, 60.7 %). CONCLUSIONS Male sex, age of ≥45 years, mean tumor diameter of ≥1.0 cm, taller-than-wide shape, multiple tumors, capsule contact, and HBME-1 expression were independent predictors of the risk of CLNM in patients with PTC. The risk model may be useful for evaluating patients' prognoses and selecting optimal surgical strategies.
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Affiliation(s)
- Li Jianming
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Liu Jibin
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA.
| | - Qian Linxue
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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Steward DL, Carty SE, Sippel RS, Yang SP, Sosa JA, Sipos JA, Figge JJ, Mandel S, Haugen BR, Burman KD, Baloch ZW, Lloyd RV, Seethala RR, Gooding WE, Chiosea SI, Gomes-Lima C, Ferris RL, Folek JM, Khawaja RA, Kundra P, Loh KS, Marshall CB, Mayson S, McCoy KL, Nga ME, Ngiam KY, Nikiforova MN, Poehls JL, Ringel MD, Yang H, Yip L, Nikiforov YE. Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study. JAMA Oncol 2019; 5:204-212. [PMID: 30419129 PMCID: PMC6439562 DOI: 10.1001/jamaoncol.2018.4616] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Question Can the diagnosis of benign disease or cancer in thyroid nodules with indeterminate cytology be established by molecular testing instead of diagnostic surgery? Findings This prospective, blinded, multicenter cohort study of a multigene genomic classifier (ThyroSeq v3) test included 257 indeterminate cytology thyroid nodules with informative test results. It demonstrated a high sensitivity (94%) and reasonably high specificity (82%), with 61% of the nodules yielding a negative test result and only 3% residual cancer risk in these nodules. Meanings Up to 61% of patients with indeterminate cytology thyroid nodules may avoid diagnostic surgery by undergoing multigene genomic classifier testing. Importance Approximately 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. Objective To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules. Design, Setting, and Participants Prospective, 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. Interventions A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3). Main Outcomes and Measures The 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. Results Of 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 Relevance In 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.
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Affiliation(s)
- David L Steward
- Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio
| | - Sally E Carty
- Division of Endocrine Surgery, University of Pittsburgh, Pittsburgh, Pennslyvania
| | | | - Samantha Peiling Yang
- Endocrinology Division, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Julie A Sosa
- Section of Endocrine Surgery, Department of Surgery, Duke Cancer Institute and Duke Clinical Research Institute, Duke University, Durham, North Carolina.,Department of Surgery, University of California, San Francisco
| | - Jennifer A Sipos
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University School of Medicine, Columbus
| | - James J Figge
- Diabetes & Endocrine Care, St Peter's Health Partners, Rensselaer, New York
| | - Susan Mandel
- Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Bryan R Haugen
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora
| | - Kenneth D Burman
- Department of Medicine, Endocrinology Section, MedStar Washington Hospital Center, Washington, DC
| | - Zubair W Baloch
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Ricardo V Lloyd
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison
| | - Raja R Seethala
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - William E Gooding
- Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Simion I Chiosea
- Department of Medicine, Endocrinology Section, MedStar Washington Hospital Center, Washington, DC
| | - Cristiane Gomes-Lima
- Department of Medicine, Endocrinology Section, MedStar Washington Hospital Center, Washington, DC
| | - Robert L Ferris
- Departments of Otolaryngology and Immunology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Jessica M Folek
- Diabetes & Endocrine Care, St Peter's Health Partners, Rensselaer, New York
| | - Raheela A Khawaja
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University School of Medicine, Columbus
| | - Priya Kundra
- Department of Medicine, Endocrinology Section, MedStar Washington Hospital Center, Washington, DC
| | - Kwok Seng Loh
- Department of Otolaryngology-Head and Neck Surgery, National University Hospital, Singapore
| | - Carrie B Marshall
- Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado
| | - Sarah Mayson
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora
| | - Kelly L McCoy
- Division of Endocrine Surgery, University of Pittsburgh, Pittsburgh, Pennslyvania
| | - Min En Nga
- Department of Pathology, National University Hospital, Singapore
| | - Kee Yuan Ngiam
- Department of General Surgery, University Surgical Cluster, National University Hospital, Singapore
| | | | - Jennifer L Poehls
- Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin, Madison
| | - Matthew D Ringel
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University School of Medicine, Columbus
| | - Huaitao Yang
- Department Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio
| | - Linwah Yip
- Division of Endocrine Surgery, University of Pittsburgh, Pittsburgh, Pennslyvania
| | - Yuri E Nikiforov
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Li X, Li E, Du J, Wang J, Zheng B. BRAF mutation analysis by ARMS-PCR refines thyroid nodule management. Clin Endocrinol (Oxf) 2019; 91:834-841. [PMID: 31441082 DOI: 10.1111/cen.14079] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/19/2019] [Accepted: 08/19/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Fine-needle aspiration (FNA) of thyroid nodules leads to nearly 25% indeterminate nodules, while BRAFV600E mutation helps to predicting papillary thyroid carcinoma (PTC). However, the clinical validity and utility of the BRAFV600E mutation detected using preoperative FNA samples in a large cohort were rarely reported. AIM To explore the clinical significance of the BRAFV600E mutation on preoperative diagnosis and decision-making in a large FNA cohort in China. DESIGN This was a prospective study of BRAFV600E mutation analysis using an amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in FNA samples. PATIENTS The study involved 2640 samples from 2307 patients undergoing FNA procedures in a Chinese medical centre. RESULTS A high mutation rate of 86.7% was found in the PTC population. For indeterminate thyroid nodules, the malignant rate of BRAFV600E+ and BRAFV600E- was 87.8% and 39.5% in the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) III, and 88.2% and 31.8% in the BSRTC IV, respectively. A cost-effective diagnostic model combining both BSRTC grading and BRAFV600E mutation status showed the highest sensitivity of 82.9% and specificity of 85.4%. Central lymph node metastasis (CLNM) was independent of the BRAF mutation status and accounted for 34.2% of the patients with PTC. CT values of BRAFV600E of patients with PTMC were significantly lower in young patients and patients with CLNM. CONCLUSIONS The combined analysis of cytological results and BRAFV600E mutation is highly recommended in BRAFV600E high-prevalence regions, including China. Prophylactic central neck dissection should be performed in selected patients without regard to the BRAF mutation status.
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Affiliation(s)
- Xinyang Li
- Department of Head and Neck Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Enling Li
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jing Du
- Department of Ultrasonography, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiadong Wang
- Department of Head and Neck Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Bing Zheng
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Barros-Filho MC, Dos Reis MB, Beltrami CM, de Mello JBH, Marchi FA, Kuasne H, Drigo SA, de Andrade VP, Saieg MA, Pinto CAL, Kowalski LP, Rogatto SR. DNA Methylation-Based Method to Differentiate Malignant from Benign Thyroid Lesions. Thyroid 2019; 29:1244-1254. [PMID: 31328658 DOI: 10.1089/thy.2018.0458] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background: The differential diagnosis of thyroid nodules using fine-needle aspiration biopsy (FNAB) is challenging due to the inherent limitation of the cytology tests. The use of molecular markers has potential to complement the FNAB-based diagnosis and avoid unnecessary surgeries. In this study, we aimed to identify DNA methylation biomarkers and to develop a diagnostic tool useful for thyroid lesions. Methods: Genome-wide DNA methylation profiles (Illumina 450K) of papillary thyroid carcinoma (PTC = 60) and follicular thyroid carcinoma (FTC = 10) were compared with non-neoplastic thyroid tissue samples (NT = 50) and benign thyroid lesions (BTL = 17). The results were confirmed in publicly available databases from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) using the same DNA methylation platform. Two classifiers were trained to discriminate FTC and PTC from BTL. To increase the applicability of the method, six differentially methylated CpGs were selected and evaluated in 161 thyroid tumors and 69 BTL postsurgical specimens and 55 prospectively collected FNAB using bisulfite-pyrosequencing. Results: DNA methylation analysis revealed 2130 and 19 differentially methylated CpGs in PTC and FTC, respectively. The CpGs confirmed by GEO and TCGA databases showing high areas under the receiver operating characteristic curve in all sample sets were used to train our diagnostic classifier. The model based on six CpGs was able to differentiate benign from malignant thyroid lesions with 94.3% sensitivity and 82.4% specificity. A similar performance was found applying the algorithm to TCGA and GEO external data sets (91.3-97.4% sensitivity and 87.5% specificity). We successfully evaluated the classifiers using a bisulfite-pyrosequencing technique, achieving 90.7% sensitivity and 75.4% specificity in surgical specimens (five of six CpGs). The study comprising FNAB cytology materials corroborated the applicability and performance of the methodology, demonstrating 86.7% sensitivity and 89.5% specificity in confirmed malignant tumors, and 100% sensitivity and 89% specificity in cases with indeterminate cytology. Conclusions: A novel diagnostic tool with potential application in preoperative screening of thyroid nodules is reported here. The proposed protocol has the potential to avoid unnecessary thyroidectomies.
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Affiliation(s)
| | - Mariana Bisarro Dos Reis
- International Research Center - CIPE-A.C.Camargo Cancer Center, São Paulo, Brazil
- Faculty of Medicine, University of Sao Paulo State-UNESP, Botucatu, Brazil
| | | | | | | | - Hellen Kuasne
- International Research Center - CIPE-A.C.Camargo Cancer Center, São Paulo, Brazil
| | | | | | - Mauro Ajaj Saieg
- Department of Pathology, A.C.Camargo Cancer Center, São Paulo, Brazil
| | | | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Silvia Regina Rogatto
- Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark
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Wu H, Zhang B, Cai G, Li J, Gu X. American College of Radiology thyroid imaging report and data system combined with K-RAS mutation improves the management of cytologically indeterminate thyroid nodules. PLoS One 2019; 14:e0219383. [PMID: 31295281 PMCID: PMC6622496 DOI: 10.1371/journal.pone.0219383] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 06/22/2019] [Indexed: 12/24/2022] Open
Abstract
We investigated whether use of American College of Radiology thyroid imaging report and data system (ACR TIRADS) in combination with K-RAS mutation status may facilitate risk stratification of patients with cytological Bethesda Category III and IV thyroid nodules. Ultrasonographic, cytological, and histopathological diagnoses were retrospectively correlated with K-RAS mutation status in a series of 43 cytologically indeterminate thyroid nodules (CITNs) that were referred for surgical excision. K-RAS mutations were detected in 8/43 (18.6%) fine-needle aspiration (FNA) samples as against 11/43 (25.6%) surgical specimens. ACR TIRADS level (TR) TR3 lesions had a malignancy risk of 40%; the K-RAS mutation rate in FNA samples and surgical specimens of category TR3 lesions was 40% and 60%, respectively. K-RAS mutation-positive malignancy was significantly more frequently detected in follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) lesions than that in atypia or follicular lesion of undetermined significance (AUS/FLUS) (P<0.01). Combined use of ACR TIRADS (TR5 as the diagnostic threshold) and K-RAS mutation status helped identify 83.3% (10/12) malignant nodules (58.6% specificity, 45.5% positive predictive value, 89.5% negative predictive value, and 65.9% accuracy). CITNs with ACR TIRADS category TR3 showed an unexpectedly high risk of malignancy. K-RAS mutation-positive FN/SFN nodules have a 50% risk of malignancy and surgery should be recommended. Combined use of ACR TIRADS and K-RAS mutation may facilitate risk-stratification of patients with CITNs. The high negative predictive value (NPV) for malignancy seems sufficient to allow conservative management of patients with active surveillance.
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Affiliation(s)
- Hongxun Wu
- Department of Ultrasound, Jiangyuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine (Key Laboratory of Nuclear Medicine, Ministry of Health/Jiangsu Key Laboratory of Molecular Nuclear Medicine), Wuxi, Jiangsu, China
- * E-mail:
| | - Bingjie Zhang
- Department of Ultrasound, Jiangyuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine (Key Laboratory of Nuclear Medicine, Ministry of Health/Jiangsu Key Laboratory of Molecular Nuclear Medicine), Wuxi, Jiangsu, China
| | - Gangming Cai
- Clinical Molecular Biology Laboratory, Jiangyuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine (Key Laboratory of Nuclear Medicine, Ministry of Health/Jiangsu Key Laboratory of Molecular Nuclear Medicine), Wuxi, Jiangsu, China
| | - Jie Li
- Department of Ultrasound, Jiangyuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine (Key Laboratory of Nuclear Medicine, Ministry of Health/Jiangsu Key Laboratory of Molecular Nuclear Medicine), Wuxi, Jiangsu, China
| | - Xiaobo Gu
- Clinical Molecular Biology Laboratory, Jiangyuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine (Key Laboratory of Nuclear Medicine, Ministry of Health/Jiangsu Key Laboratory of Molecular Nuclear Medicine), Wuxi, Jiangsu, China
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Lin P, Yao Z, Sun Y, Li W, Liu Y, Liang K, Liu Y, Qin J, Hou X, Chen L. Deciphering novel biomarkers of lymph node metastasis of thyroid papillary microcarcinoma using proteomic analysis of ultrasound-guided fine-needle aspiration biopsy samples. J Proteomics 2019; 204:103414. [PMID: 31195151 DOI: 10.1016/j.jprot.2019.103414] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 05/31/2019] [Accepted: 06/05/2019] [Indexed: 01/10/2023]
Abstract
Thyroid papillary microcarcinoma is now a common clinical problem. Cervical lymph node metastasis is the main metastasis mode of PTMC. However, before operation, it is still difficult to determine exactly whether PTMC patient is suffering with cervical lymph node metastasis. To resolve this dilemma, for better selection of optimum treatment plans, it is necessary to investigate the overall changes in proteomes of PTMC, and evaluate the potential of biomarkers to predict lymph node metastasis. Tandem mass tags combined with multidimensional liquid chromatography and mass spectrometry analyses were used aiming to screen the proteomic profiles of fine-needle aspiration biopsy samples. Quantitative proteomic analysis, significant pathway and functional categories were investigated. In total, 3391 proteins of the 3793 protein groups identified were quantified. Bioinformatics analysis indicated that differentially expressed proteins were involved in multiple biological functions, metastasis-related pathways. Moreover, IFN-stimulated gene 15 proteins were found to be well distinguished between patients with lymph node metastatic and patients with nonmetastatic PTMC. Knocking down ISG15 with shRNA inhibited the xenografted tumor growth. This study provided a reference proteome map for lymph node metastatic PTMC. ISG15 probably is a prognosis marker of thyroid papillary microcarcinoma patients with lymph node metastasis. SIGNIFICANCE: Nowadays, thyroid cancer has become a widespread epidemic. The rate of thyroid cancer incidence has been faster than any other cancers, reported by the American Cancer Society. Papillary thyroid microcarcinoma (PTMC) is a subset of PTC defined as PTC measuring≤1 cm in size, which comprises nearly one-half of all the cases of PTCs. Actually, the rapidly increasing global incidence of PTC is mainly attributed to the corresponding increase in the diagnosis of PTMC. Scholars have figuratively compared the increase of PTMC to the "tsunami". The treatment scheme for PTMC is still not uniform, and the controversy is mainly focused on the necessity of surgery treatment. PTMCs often have an indolent course in the absence of evidence of metastatic cervical lymph nodes, distant metastases and extrathyroidal extension. Therefore, it is important for us to reliably differentiate the small number of PTMC patients developing significant metastases progression from the larger population of patients that harbor indolent PTMCs. The present study aimed to investigate the overall changes in proteomes of PTMC, and evaluate the potential of biomarkers to predict lymph node metastasis. Tandem mass tags (TMT) combined with multidimensional liquid chromatography and mass spectrometry analyses were used aiming to screen the proteomic profiles of fine-needle aspiration biopsy (FNAB) samples. Quantitative proteomic analysis, significant pathway and functional categories were investigated. Our results showed that some differential expression proteins were likely to be important resources for finding new diagnostic biomarkers.
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Affiliation(s)
- Peng Lin
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China
| | - Zhina Yao
- Hospital for Reproductive Medicine Affiliated to Shandong University, Ji'nan 250012, Shandong, PR China
| | - Yu Sun
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China
| | - Wenjuan Li
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China
| | - Yan Liu
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China
| | - Kai Liang
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China
| | - Yuan Liu
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China
| | - Jun Qin
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China
| | - Xinguo Hou
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China
| | - Li Chen
- Department of Endocrine, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China.
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Straccia P, Brunelli C, Rossi ED, Lanza P, Martini M, Musarra T, Lombardi CP, Pontecorvi A, Fadda G. The immunocytochemical expression of
VE
‐1 (
BRAF
V600E‐related) antibody identifies the aggressive variants of papillary thyroid carcinoma on liquid‐based cytology. Cytopathology 2019; 30:460-467. [DOI: 10.1111/cyt.12690] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/14/2019] [Accepted: 03/06/2019] [Indexed: 01/04/2023]
Affiliation(s)
- Patrizia Straccia
- Division of Anatomic Pathology and Histology Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
| | - Chiara Brunelli
- Division of Anatomic Pathology and Histology Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
| | - Esther D. Rossi
- Division of Anatomic Pathology and Histology Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
| | - Paola Lanza
- Division of Anatomic Pathology and Histology Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
| | - Maurizio Martini
- Division of Anatomic Pathology and Histology Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
| | - Teresa Musarra
- Division of Anatomic Pathology and Histology Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
| | - Celestino Pio Lombardi
- Division of Endocrine Surgery Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
| | - Alfredo Pontecorvi
- Division of Endocrinology Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
| | - Guido Fadda
- Division of Anatomic Pathology and Histology Catholic University of Sacred Heart Foundation “Agostino Gemelli” University Hospital Rome Italy
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Abstract
The historical management approach for many patients with indeterminate thyroid nodule fine needle aspiration cytology is a diagnostic lobectomy or thyroidectomy. However, the majority of patients undergo surgery unnecessarily, because most are proven to have benign disease on histology. Molecular testing is a diagnostic tool that can be used to help guide the clinical management of thyroid nodules with indeterminate cytology results. Testing has evolved substantially over the last decade with significant advances in testing methodology and improvements in our understanding of the genetic basis of thyroid cancer.
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Affiliation(s)
- Sarah E Mayson
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, MS 8106, 12801 East 17th Avenue, Aurora, CO 80045, USA.
| | - Bryan R Haugen
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, MS 8106, 12801 East 17th Avenue, Aurora, CO 80045, USA
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Pfeifer A, Rusinek D, Żebracka-Gala J, Czarniecka A, Chmielik E, Zembala-Nożyńska E, Wojtaś B, Gielniewski B, Szpak-Ulczok S, Oczko-Wojciechowska M, Krajewska J, Polańska J, Jarząb B. Novel TG-FGFR1 and TRIM33-NTRK1 transcript fusions in papillary thyroid carcinoma. Genes Chromosomes Cancer 2019; 58:558-566. [PMID: 30664823 PMCID: PMC6594006 DOI: 10.1002/gcc.22737] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 01/14/2019] [Accepted: 01/15/2019] [Indexed: 02/06/2023] Open
Abstract
Papillary thyroid carcinoma (PTC) is most common among all thyroid cancers. Multiple genomic alterations occur in PTC, and gene rearrangements are one of them. Here we screened 14 tumors for novel fusion transcripts by RNA‐Seq. Two samples harboring RET/PTC1 and RET/PTC3 rearrangements were positive controls whereas the remaining ones were negative regarding the common PTC alterations. We used Sanger sequencing to validate potential fusions. We detected 2 novel potentially oncogenic transcript fusions: TG‐FGFR1 and TRIM33‐NTRK1. We detected 4 novel fusion transcripts of unknown significance accompanying the TRIM33‐NTRK1 fusion: ZSWIM5‐TP53BP2, TAF4B‐WDR1, ABI2‐MTA3, and ARID1B‐PSMA1. Apart from confirming the presence of RET/PTC1 and RET/PTC3 in positive control samples, we also detected known oncogenic fusion transcripts in remaining samples: TFG‐NTRK1, ETV6‐NTRK3, MKRN1‐BRAF, EML4‐ALK, and novel isoform of CCDC6‐RET.
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Affiliation(s)
- Aleksandra Pfeifer
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Dagmara Rusinek
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Jadwiga Żebracka-Gala
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Agnieszka Czarniecka
- Department of Oncological and Reconstructive Surgery, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Ewa Chmielik
- Tumor Pathology Department, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Ewa Zembala-Nożyńska
- Tumor Pathology Department, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Bartosz Wojtaś
- Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Bartłomiej Gielniewski
- Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Sylwia Szpak-Ulczok
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Małgorzata Oczko-Wojciechowska
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Jolanta Krajewska
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
| | - Joanna Polańska
- Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Gliwice, Poland
| | - Barbara Jarząb
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute - Oncology Center Gliwice Branch, Gliwice, Poland
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Abstract
Genomic, clinical, and pathologic studies have prompted a more risk-stratified approach to the management of patients with thyroid nodules. The recent nomenclature change concerning noninvasive follicular thyroid neoplasm with papillary-like nuclear features reflects the clinical trend toward conservative treatment choices for carefully selected low-risk thyroid neoplasms. These developments have occurred in parallel with a growing array of molecular tests intended to improve clinical triage for patients with indeterminate fine needle aspiration diagnoses. This review discusses the implications of the nomenclature revision on the interpretation of thyroid fine needle aspiration and updates available ancillary molecular tests for thyroid fine needle aspirations.
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Affiliation(s)
- Michiya Nishino
- Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
| | - Jeffrey F Krane
- Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Amory 3, Boston, MA 02115, USA
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