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2nd Edition: Molecular Testing for Thyroid Nodules and Cancer
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2nd Edition: 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: 31 August 2025 | Viewed by 4209

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 it 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 predict the probability of cancer and help 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 upon cytological examination (Bethesda V and VI) if the results are expected to impact patient 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 significant clinical impacts and supporting their routine use in various clinical settings are still limited.

This Special Issue will include original articles and reviews that focus 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.

You may choose our Joint Special Issue in Current Oncology.

We look forward to receiving your contribution.

Dr. Marc P. Pusztaszeri
Dr. Richard J. 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 (4 papers)

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Research

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15 pages, 1021 KiB  
Article
Single-Nucleotide Polymorphisms of BRCA1 and BRCA2 and Risk of Papillary Thyroid Carcinoma
by Chang Myeon Song, Yun Jin Kim, Hyun Sub Cheong, Yong Bae Ji and Kyung Tae
Cancers 2025, 17(9), 1456; https://doi.org/10.3390/cancers17091456 - 26 Apr 2025
Viewed by 316
Abstract
Background/Objectives: We sought to evaluate the association between the risk of papillary thyroid carcinoma (PTC) and single-nucleotide polymorphisms (SNPs) of breast cancer genes 1 (BRCA1) and 2 (BRCA2). Methods: We prospectively recruited 515 cases with PTC and [...] Read more.
Background/Objectives: We sought to evaluate the association between the risk of papillary thyroid carcinoma (PTC) and single-nucleotide polymorphisms (SNPs) of breast cancer genes 1 (BRCA1) and 2 (BRCA2). Methods: We prospectively recruited 515 cases with PTC and 296 controls without cancer. The genotypes of five BRCA1 SNPs (rs8176318, rs1799966, rs799917, rs16940, rs1799949) and three BRCA2 SNPs (rs15869, rs1799943, rs1799955) were determined using the TaqMan assay. We evaluated the association of haplotypes with the risk of PTC due to linkage disequilibrium (LD). Results: The five BRCA1 SNPs were significantly associated with the risk of PTC. The AC genotype of rs8176318 (OR = 0.69, p = 0.02) and the CT and CC genotypes of rs1799966 (OR = 0.70, p = 0.02 and OR = 0.67, p = 0.01, respectively) were associated with a decreased risk of PTC. The AG genotype of rs16940 (OR = 0.67, p = 0.01) and the AG genotypes of rs799917 and rs1799949 (both OR = 0.70, p = 0.02) decreased the risk of PTC. Haplotype 1 [rs8176318(C)-rs1799966(T)-rs799917(G)-rs16940(A)-rs1799949(G)] ± (OR = 0.69, p = 0.02) and haplotype 2 [rs8176318(A)-rs1799966(C)-rs799917(A)-rs16940(G)-rs1799949(A)] ± (OR = 0.71, p = 0.03) of BRCA1 reduced the risk of PTC. Conclusions: Our findings suggest that the polymorphisms of BRCA1 may contribute to the susceptibility to PTC in the Korean population. Full article
(This article belongs to the Special Issue 2nd Edition: Molecular Testing for Thyroid Nodules and Cancer)
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10 pages, 899 KiB  
Article
Clinical and Pathologic Characteristics of Cytologically Indeterminate Thyroid Nodules with Non-V600E BRAF Alterations
by Ryan Instrum, Christina E. Swartzwelder, Ronald A. Ghossein, Bin Xu, Babak Givi, Richard J. Wong, Brian R. Untch and Luc G. T. Morris
Cancers 2025, 17(5), 741; https://doi.org/10.3390/cancers17050741 - 22 Feb 2025
Viewed by 716
Abstract
Background: Molecular assays serve as a potential risk stratification tool for cytologically indeterminate thyroid nodules (ITNs). BRAF V600E mutations are nearly always associated with thyroid cancer. However, the malignancy risk for ITNs with other less common BRAF alterations is less well understood. In this [...] Read more.
Background: Molecular assays serve as a potential risk stratification tool for cytologically indeterminate thyroid nodules (ITNs). BRAF V600E mutations are nearly always associated with thyroid cancer. However, the malignancy risk for ITNs with other less common BRAF alterations is less well understood. In this retrospective cohort study, we examine the risk of malignancy (ROM), histopathologic diagnoses, and clinical outcomes for non-V600E BRAF-altered ITNs. Methods: Genomic profiling data obtained from 1034 pre-operative fine-needle aspiration samples from 955 patients were reviewed. Nodules harboring BRAF V600E were excluded. Clinical, radiographic, and histopathologic data were analyzed retrospectively from BRAF-altered ITNs managed surgically at one comprehensive cancer center (2014–2024). Diagnoses were subdivided based on American Thyroid Association (ATA) risk categories. Results: Thirty-seven patients (3.9%) with non-V600E BRAF-altered ITNs were identified (isolated BRAF mutation: n = 29 [78.4%], BRAF + other mutation: n = 3 [8.1%], BRAF fusion: n = 4 [10.8%], BRAF-like gene expression: n = 1 [2.7%]). All BRAF mutations identified in the cohort were class II (RAS-independent, intermediate to high kinase activity). Nodules had a median pre-operative diameter of 1.8 cm (interquartile range [IQR] 1.4–2.5). Patients presented with nodal metastases in 2.7% (n = 1) of cases, and local invasion was not identified in any patients in the cohort. Approximately half of patients (54.1%) were initially treated with a partial thyroidectomy (lobectomy: n = 17 [45.9%], isthmusectomy: n = 3 [8.1%]), and the remaining patients underwent total thyroidectomy (n = 17 [45.9%]). Median post-operative follow-up was 28 months (IQR 17.8–45.5). ROM for BRAF alterations was 73% (95%CI 59–87%; ATA low risk: 64.9%/ATA int risk: 5.4%/ATA high risk: 2.7%). There were no high-risk cancers identified in patients with isolated BRAF mutation (benign: n = 10 [34.5%], ATA low risk: n = 19 [65.5%]), and the most common isolated mutation was K601E (n = 17, 45.9%) which had a 58.8% ROM (all ATA low risk). Patients with isolated BRAF mutations had a significantly lower rate of ATA intermediate or high risk pathology when compared to all other BRAF alterations (0% vs. 37.5%, p = 0.0072). Only three patients were treated with radioactive iodine post-operatively (8.1%), and no completion thyroidectomy procedures were performed in those who did not initially undergo total thyroidectomy. No patients in the cohort were found to have distant metastatic disease or recurrence, and there were no deaths during the follow-up interval. Conclusions: ITNs harboring non-V600E BRAF alterations were rare (3.9% of patients) and typically malignant (73%). Nearly all nodules were benign or ATA low-risk cancers. Only 8% of such nodules were ATA intermediate or high risk cancers. In ITNs with isolated non-V600E BRAF and no other genetic alterations, one-third were non-malignant, and all cancers were ATA low risk. In the appropriate clinical context, thyroid lobectomy or active surveillance can be considered for initial management of non-V600E BRAF-altered ITNs. Full article
(This article belongs to the Special Issue 2nd Edition: Molecular Testing for Thyroid Nodules and Cancer)
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10 pages, 692 KiB  
Article
The Impact of BRAF V600E Mutation Allele Frequency on the Histopathological Characteristics of Thyroid Cancer
by Mawaddah Abdulhaleem, Saruchi Bandargal, Marc Philippe Pusztaszeri, Mohannad Rajab, Hannah Greenspoon, Joshua Ross Krasner, Sabrina Daniela Da Silva, Véronique-Isabelle Forest and Richard J. Payne
Cancers 2024, 16(1), 113; https://doi.org/10.3390/cancers16010113 - 25 Dec 2023
Cited by 9 | Viewed by 2049
Abstract
Background: A BRAF V600E mutation in papillary thyroid cancer (PTC) has been shown to be associated with aggressive behavior. Nevertheless, not all BRAF V600E PTCs behave aggressively. Allele frequency (AF) is the number of mutated molecules divided by the total number of wild-type [...] Read more.
Background: A BRAF V600E mutation in papillary thyroid cancer (PTC) has been shown to be associated with aggressive behavior. Nevertheless, not all BRAF V600E PTCs behave aggressively. Allele frequency (AF) is the number of mutated molecules divided by the total number of wild-type molecules at a specific location in the genome. The relationship between BRAF V600E AF and the histopathological features of thyroid malignancies is not well understood. We hypothesized that the BRAF V600E AF will correlate directly with aggressive histopathological behavior. The aim of this study was to examine this relationship. Methods: A retrospective chart review was performed for patients treated for BRAF V600E thyroid malignancies from 2019 to 2022 at McGill University tertiary care hospitals (n = 317). Patients with BRAF V600E-positive malignancies that included information on AF were included (n = 44). The correlation between AF and tumor histopathological features was analyzed. Results: Out of the 44 nodules with a BRAF V600E mutation, those with aggressive features of PTC had a mean AF of 25.8%, which was significantly higher than the non-aggressive group with a mean AF of 10.25% (p = 0.020). Additionally, there was a statistically significant difference in mean AF between patients with a positive sentinel LN (29%) and those with a negative sentinel LN (17.8%) (p = 0.021). Classical PTC was present in 29.5% (13/44) of nodules, with a mean AF of 15.6%. The tall cell subtype was found in 64% (28/44) of nodules, with a mean AF of 23%. Solid and hobnail subtypes were less common in this study, and there was no statistically significant relationship between AF and histopathological subtypes (p = 0.107). Nodules smaller than 1cm had a mean AF of 13.3%, while nodules ranging from 1 2cm had a mean AF of 20.6%, and those larger than 2cm had a mean AF of 27.7%. However, no statistical difference was observed between AF and nodule size (p = 0.160). Conclusion: In this study, BRAF V600E mutations in conjunction with AF help to determine whether thyroid malignancies will display aggressive behavior. This pre-operative finding can help thyroid specialists to determine the extent of thyroidectomy and whether lymph node dissection is required. Full article
(This article belongs to the Special Issue 2nd Edition: Molecular Testing for Thyroid Nodules and Cancer)
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Review

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21 pages, 714 KiB  
Review
Paediatric Thyroid Carcinoma: The Genetic Revolution and Its Implications for Therapy and Outcomes
by Joel A. Vanderniet, Noemi A. Fuentes-Bolanos, Yoon Hi Cho, Katherine M. Tucker, Antoinette Anazodo, Andrew J. Bauer and Paul Z. Benitez-Aguirre
Cancers 2025, 17(9), 1549; https://doi.org/10.3390/cancers17091549 - 2 May 2025
Viewed by 396
Abstract
Background: The understanding of the molecular basis of paediatric thyroid carcinoma has expanded rapidly in the last decade. Most carcinomas are associated with de novo somatic gene alterations that confer distinct clinicopathological characteristics. In comparison to adults, paediatric carcinomas are less commonly [...] Read more.
Background: The understanding of the molecular basis of paediatric thyroid carcinoma has expanded rapidly in the last decade. Most carcinomas are associated with de novo somatic gene alterations that confer distinct clinicopathological characteristics. In comparison to adults, paediatric carcinomas are less commonly associated with point mutations and more commonly with gene fusions, which are characterised by more-invasive disease. Cancer predisposition genes play an important role in a small percentage of tumours, and the family history and the recognition of other syndromic features are key to identifying these patients. Molecular testing platforms for clinical use have been developed and validated in adults, and their use is becoming established in the management of indeterminate thyroid nodules, where they significantly reduce the rates of diagnostic lobectomy. Paediatric data are more limited than adult data, and the role of molecular testing in paediatric thyroid carcinoma management is evolving. Methods: This review describes the current knowledge of molecular alterations in paediatric thyroid carcinomas, evidence supporting molecular testing in clinical practice, and future directions for research. Results and Conclusions: A molecular diagnosis enables the use of molecularly targeted therapies for children and adolescents with advanced or radioiodine-refractory disease. There is also great potential for molecular testing to improve the accuracy of the risk-stratification of paediatric thyroid nodules, reducing surgical intervention and complications without negatively impacting outcomes, and data to support such an approach are emerging. Full article
(This article belongs to the Special Issue 2nd Edition: Molecular Testing for Thyroid Nodules and Cancer)
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