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Cancers
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Molecular Testing for Thyroid Nodules and Cancer
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Molecular Testing for Thyroid Nodules and Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 13213

Special Issue Editors

Dr. Marc P. Pusztaszeri

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Guest Editor
Department of Pathology, Jewish General Hospital, McGill University, Montréal, QC, Canada
Interests: thyroid cancer; papillary thyroid carcinoma; poorly differentiated thyroid carcinoma; anaplastic thyroid carcinoma; molecular pathology; cytology; fine needle aspiration; histopathology
Special Issues, Collections and Topics in MDPI journals
Dr. Richard J. Payne

E-Mail Website
Guest Editor
Department of Otolaryngology—Head and Neck Surgery, Jewish General Hospital, McGill University, Montréal, QC, Canada
Interests: surgery of the thyroid and parathyroid glands
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last decade, molecular testing for thyroid nodules and cancers has made significant progress and is able to identify thyroid-cancer-related molecular markers which can then be applied clinically for improved decision making in different settings, representing a powerful diagnostic, prognostic, and predictive tool when used judiciously in conjunction with clinical, pathological, and radiological data. The main application of molecular testing is for thyroid nodules with indeterminate cytology (Bethesda III or IV), which represent 10–30% of thyroid nodules. For these indeterminate thyroid nodules, molecular testing is increasingly used in North America to refine the probability of cancer and to help to guide management, including surveillance for nodules that are likely benign or surgery for nodules that are likely malignant. For the latter nodules, molecular testing may also inform the extent of surgical management (lobectomy vs. total thyroidectomy) by predicting the cancer type and risk of cancer recurrence. Similarly, molecular testing may also be considered for thyroid nodules that are suspicious or positive for malignancy on cytology (Bethesda V and VI) if the results are expected to impact the management, including the timing and optimal extent of surgery.  Finally, in patients with advanced thyroid cancer, including anaplastic thyroid carcinoma, molecular testing plays a critical role in identifying potential therapeutic targets allowing for the consideration of neoadjuvant targeted therapy and redefining the role and timing of surgical intervention.

On the other hand, the various molecular testing platforms for thyroid nodules are still costly and not widely available, and data demonstrating a significant clinical impact and supporting their routine use in various clinical settings are still limited.

This Special Issue will include original articles and reviews focusing on key genetic alterations in thyroid nodules and cancers and the application of molecular testing with different platforms in the various clinical settings highlighted above.

We look forward to receiving your contribution.

Dr. Marc Pusztaszeri
Dr. Richard Payne
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • thyroid nodules
  • thyroid cancer
  • molecular testing
  • cytology
  • fine needle aspiration
  • personalized medicine
  • mutations

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Published Papers (6 papers)

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Research

Jump to: Review

11 pages, 653 KiB  
Article
The Difference in Clinical Behavior of Gene Fusions Involving RET/PTC Fusions and THADA/IGF2BP3 Fusions in Thyroid Nodules
by George Tali, Alexandra E. Payne, Thomas J. Hudson, Sabrina Daniela da Silva, Marc Pusztaszeri, Michael Tamilia and Véronique-Isabelle Forest
Cancers 2023, 15(13), 3394; https://doi.org/10.3390/cancers15133394 - 28 Jun 2023
Cited by 2 | Viewed by 1848
Abstract
Background: Molecular testing has been used as an adjunct to morphological evaluation in the workup of thyroid nodules. This study investigated the impact of two gene fusions, RET/PTC and THADA/IGF2BP3, that have been described as oncogenic events in thyroid neoplasms. Methods: We [...] Read more.
Background: Molecular testing has been used as an adjunct to morphological evaluation in the workup of thyroid nodules. This study investigated the impact of two gene fusions, RET/PTC and THADA/IGF2BP3, that have been described as oncogenic events in thyroid neoplasms. Methods: We performed a retrospective, single-centered study at a McGill University teaching hospital in Montreal, Canada, from January 2016 to August 2021. We included patients who underwent surgery for thyroid nodules that pre-operatively underwent molecular testing showing either RET/PTC or THADA/IGF2BP3 gene fusion. Results: This study included 697 consecutive operated thyroid nodules assessed using molecular testing, of which five had the RET/PTC fusion and seven had the THADA/IGF2BP3 fusion. Of the five nodules in the RET/PTC group, 100% were malignant and presented as Bethesda V/VI. Eighty percent (4/5) were found to have lymph node metastasis. Twenty percent (1/5) had extrathyroidal extensions. Sixty percent (3/5) were a diffuse sclerosing variant of papillary thyroid carcinoma, and the rest were the classical variant. Of the seven THADA/IGF2BP3 nodules, all presented as Bethesda III/IV and 71.4% (5/7) were malignant based on the final pathology analysis, and 28.6% (2/7) were NIFTP. All the THADA/IGF2BP3 fusion malignancies were a follicular variant of papillary thyroid carcinoma. None had lymph node metastasis or displayed extrathyroidal extensions. Conclusions: RET/PTC nodules presented as Bethesda V/VI and potentially had more aggressive features, whereas THADA/IGF2BP3 nodules presented as Bethesda III/IV and had more indolent behavior. This understanding may allow clinicians to develop more targeted treatment plans, such as the extent of surgery and adjuvant radioactive iodine treatment. Full article
(This article belongs to the Special Issue Molecular Testing for Thyroid Nodules and Cancer)
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10 pages, 1057 KiB  
Article
Characteristics of PTEN Mutation in Thyroid Tumours: A Retrospective Chart Review
by Saruchi Bandargal, Mohannad Rajab, Véronique-Isabelle Forest, Marc Philippe Pusztaszeri, Michael P. Hier, Sabrina Daniela da Silva and Richard J. Payne
Cancers 2023, 15(5), 1575; https://doi.org/10.3390/cancers15051575 - 3 Mar 2023
Cited by 9 | Viewed by 2343
Abstract
While some studies suggest that PTEN mutations correlate with a low-risk phenotype in pediatric thyroid nodules, the relationship between the mutation and malignancy in the adult populations is abstruse. This study investigated whether PTEN mutations result in thyroid malignancy, and whether these malignancies [...] Read more.
While some studies suggest that PTEN mutations correlate with a low-risk phenotype in pediatric thyroid nodules, the relationship between the mutation and malignancy in the adult populations is abstruse. This study investigated whether PTEN mutations result in thyroid malignancy, and whether these malignancies are aggressive. This multicenter study involved 316 patients who underwent preoperative molecular testing, and subsequent lobectomy or total thyroidectomy at two quaternary care hospitals. A four-year retrospective review was performed on the 16 charts of patients that opted for surgery following a positive PTEN mutation on molecular testing results from January 2018 to December 2021. Of the total 16 patients, 37.5% (n = 6) had malignant tumours, 18.75% (n = 3) had non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), and 43.75% (n = 7) had benign disease. Aggressive features were detected in 33.33% of the malignant tumours. Malignant tumours were found to have a statistically significant higher allele frequency (AF). The aggressive nodules were all poorly differentiated thyroid carcinomas (PDTCs) with copy number alterations (CNAs) and the highest AFs. Full article
(This article belongs to the Special Issue Molecular Testing for Thyroid Nodules and Cancer)
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10 pages, 1499 KiB  
Article
Is There a Role for Molecular Testing for Low-Risk Differentiated Thyroid Cancer? A Cost-Effectiveness Analysis
by Idit Tessler, Moshe Leshno, Gilad Feinmesser, Eran E. Alon and Galit Avior
Cancers 2023, 15(3), 786; https://doi.org/10.3390/cancers15030786 - 27 Jan 2023
Cited by 2 | Viewed by 1958
Abstract
Molecular testing for thyroid nodules has been rapidly developed in recent years, aiming to predict the presence of malignancy and aggressive features. While commonly utilized to predict malignancy, its role in guiding the management approach is still developing. The high cost of genetic [...] Read more.
Molecular testing for thyroid nodules has been rapidly developed in recent years, aiming to predict the presence of malignancy and aggressive features. While commonly utilized to predict malignancy, its role in guiding the management approach is still developing. The high cost of genetic tests and long-term sequences of thyroid cancer is limiting to real-life studies. Objective: To evaluate the cost effectiveness of molecular testing for low-risk differentiated thyroid cancer (lrDTC). Methods: We developed a Markovian decision tree model of a simulated lrDTC cohort, comparing two management strategies: (I) Conducting genetic tests (GT)—patients are stratified into three risk groups for distant metastasis by the identified molecular markers: low-, intermediate- and high-risk molecular profile; followed by management accordingly: patients with low-risk will undergo hemithyroidectomy (HT), patients with intermediate-risk will undergo total thyroidectomy (TT), and high-risk patients will undergo TT with central neck dissection; (II) Without genetic tests (wGT)—all patients will undergo HT according to the ATA recommendations for lrDTC. Outcomes were measured as quality-adjusted life years (QALYs) and costs of each strategy. Results: GT was found as cost effective, leading to a gain of 1.7 QALYs with an additional cost of $327 per patient compared to wGT strategy. This yielded an incremental cost-effectiveness ratio of $190 per QALY. Sensitivity analysis demonstrated robust results across the variables’ ranges. The most impactful variable was the benefit from performing TT rather than HT for intermediate to high-risk patients. Conclusions: Our model found that molecular testing for lrDTC is cost-effective, allowing tailored management according to the patient’s personal risk level reflected in the genetic profile, hence improving outcomes. Full article
(This article belongs to the Special Issue Molecular Testing for Thyroid Nodules and Cancer)
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11 pages, 531 KiB  
Article
Effect of Having Concurrent Mutations on the Degree of Aggressiveness in Patients with Thyroid Cancer Positive for TERT Promoter Mutations
by Sama Alohali, Alexandra E. Payne, Marc Pusztaszeri, Mohannad Rajab, Véronique-Isabelle Forest, Michael P. Hier, Michael Tamilia and Richard J. Payne
Cancers 2023, 15(2), 413; https://doi.org/10.3390/cancers15020413 - 8 Jan 2023
Cited by 7 | Viewed by 1653
Abstract
This study aimed to examine whether concurrent mutations with a TERT promoter mutation are associated with a greater likelihood of more aggressive disease than a TERT promoter mutation alone. The medical records of 1477 patients who underwent thyroid surgery at two tertiary hospitals [...] Read more.
This study aimed to examine whether concurrent mutations with a TERT promoter mutation are associated with a greater likelihood of more aggressive disease than a TERT promoter mutation alone. The medical records of 1477 patients who underwent thyroid surgery at two tertiary hospitals between 2017 and 2022 were reviewed. Twenty-four patients had TERT promoter mutations based on molecular profile testing. Clinicodemographic data, mutational profiles, and histopathological features were assessed. Descriptive analysis, Fisher’s exact test, and binary logistic regression were performed. Seven patients had single-gene TERT promoter mutations, and 17 had concurrent mutations, including BRAF V600E, HRAS, NRAS, PIK3CA, and EIF1AX. The overall prevalence of malignancy was 95.8%, of which 78.3% were aggressive thyroid cancers. There was a statistically significant association between concurrent mutations and disease aggressiveness. The odds of having aggressive disease were 10 times higher in patients with a TERT promoter mutation and a concurrent molecular alteration than in those with a TERT promoter mutation alone. This is an important finding for thyroid specialists to consider when counseling patients concerning risk stratification and management options. Full article
(This article belongs to the Special Issue Molecular Testing for Thyroid Nodules and Cancer)
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10 pages, 269 KiB  
Article
Surgical Outcomes of Thyroid Nodules Positive for Gene Expression Alterations Using ThyroSeq V3 Genomic Classifier
by Samer Salameh, Mohannad Rajab, Veronique-Isabelle Forest, Marc Pusztaszeri and Richard J. Payne
Cancers 2023, 15(1), 49; https://doi.org/10.3390/cancers15010049 - 22 Dec 2022
Cited by 3 | Viewed by 2139
Abstract
ThyroSeq V3 (TsV3) tests for various genetic alterations, including gene expression alterations (GEAs), to improve diagnostic accuracy and clinical decision-making for indeterminate thyroid nodules. This study aimed to clarify the clinico-pathological features and outcomes of GEA-positive thyroid nodules, which have not yet been [...] Read more.
ThyroSeq V3 (TsV3) tests for various genetic alterations, including gene expression alterations (GEAs), to improve diagnostic accuracy and clinical decision-making for indeterminate thyroid nodules. This study aimed to clarify the clinico-pathological features and outcomes of GEA-positive thyroid nodules, which have not yet been well-described in the literature. A retrospective chart review was performed whereby patients were included if they underwent thyroid surgery between January 2018 and May 2022 at two McGill University teaching hospitals and their surgery was preceded by pre-operative molecular TsV3 testing. In total, 75 of the 328 patients with thyroid nodules (22.9%) who underwent molecular testing and surgery were GEA-positive. On surgical pathology, GEA-positive nodules showed a significantly higher malignancy rate compared to their GEA-negative counterparts (90.7% vs. 77.7%, respectively, p = 0.011). Among those that were malignant, 48.5% had at least one aggressive pathological feature, including histological subtype, extra-thyroidal extension, or lymph node metastasis. BRAF V600E mutation had a significantly greater association with aggressive malignant GEA-positive nodules compared to non-aggressive ones (p < 0.001). This study demonstrates that GEA may be an effective diagnostic and prognostic tool for thyroid nodule management. However, further investigation is needed to characterize the clinico-pathological features of GEA in isolation and in association with other gene alterations. Full article
(This article belongs to the Special Issue Molecular Testing for Thyroid Nodules and Cancer)

Review

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18 pages, 14960 KiB  
Review
Expanding Our Knowledge of DICER1 Gene Alterations and Their Role in Thyroid Diseases
by Maria Cristina Riascos, Anh Huynh, William C. Faquin and Vania Nosé
Cancers 2024, 16(2), 347; https://doi.org/10.3390/cancers16020347 - 13 Jan 2024
Cited by 4 | Viewed by 2304
Abstract
Mutations in DICER1, a gene involved in RNA interference, have been associated with a wide range of multi-organ neoplastic and non-neoplastic conditions. Historically known for its association with pleuropulmonary blastoma, DICER1 syndrome has received more attention due to the association with newly [...] Read more.
Mutations in DICER1, a gene involved in RNA interference, have been associated with a wide range of multi-organ neoplastic and non-neoplastic conditions. Historically known for its association with pleuropulmonary blastoma, DICER1 syndrome has received more attention due to the association with newly discovered diseases and tumors. Recent studies evaluating DICER1 mutations and DICER1-driven thyroid disease in both pediatric and adult thyroid nodules revealed thyroid disease as the most common manifestation of DICER1 mutations. This study undertakes a comprehensive investigation into DICER1 mutations, focusing on their role in thyroid diseases. Specific attention was given to thyroid follicular nodular disease and differentiated thyroid carcinomas in infancy as highly indicative of germline DICER1 mutation or DICER1 syndrome. Additionally, poorly differentiated thyroid carcinoma and thyroblastoma were identified as potential indicators of somatic DICER1 mutations. Recognizing these manifestations should prompt clinicians to expedite genetic evaluation for this neoplastic syndrome and classify these patients as high risk for additional multi-organ malignancies. This study comprehensively synthesizes the current knowledge surrounding this genetically associated entity, providing intricate details on histologic findings to facilitate its diagnosis. Full article
(This article belongs to the Special Issue Molecular Testing for Thyroid Nodules and Cancer)
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