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13 pages, 625 KiB

Open AccessArticle

Validation of Ultrasound Risk Stratification Systems for Cervical Lymph Node Metastasis in Patients with Thyroid Cancer

by Ji Ye Lee, Roh-Eul Yoo, Jung Hyo Rhim, Kyung Hoon Lee, Kyu Sung Choi, Inpyeong Hwang, Koung Mi Kang and Ji-hoon Kim

Cancers 2022, 14(9), 2106; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092106 - 23 Apr 2022

Cited by 8 | Viewed by 2243

Abstract

A malignancy risk stratification system (RSS) for cervical lymph nodes (LNs) has not been fully established. This study aimed to validate the current RSS for the diagnosis of cervical LN metastasis in thyroid cancer. In total, 346 LNs from 282 consecutive patients between [...] Read more.

A malignancy risk stratification system (RSS) for cervical lymph nodes (LNs) has not been fully established. This study aimed to validate the current RSS for the diagnosis of cervical LN metastasis in thyroid cancer. In total, 346 LNs from 282 consecutive patients between December 2006 and June 2015 were included. We determined the malignancy risk of each ultrasound (US) feature and performed univariable and multivariable logistic regression analyses. Each risk category from the Korean Society of Thyroid Radiology (KSThR) and the European Thyroid Association (ETA) was applied to calculate malignancy risks. The effects of size, number of suspicious features, and primary tumor characteristics were analyzed to refine the current RSS. Suspicious features including echogenic foci, cystic change, hyperechogenicity, and abnormal vascularity were independently predictive of malignancy (p ≤ 0.045). The malignancy risks of probably benign, indeterminate, and suspicious categories were 2.2–2.5%, 26.8–29.0%, and 85.8–87.4%, respectively, according to the KSThR and ETA criteria. According to the ETA criteria, 15.1% of LNs were unclassifiable. In indeterminate LNs, multiplicity of the primary tumor was significantly associated with malignancy (odds ratio, 6.53; p = 0.004). We refined the KSThR system and proposed a US RSS for LNs in patients with thyroid cancer. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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18 pages, 4611 KiB

Open AccessArticle

Comprehensive Analysis of the Prognosis and Drug Sensitivity of Differentiation-Related lncRNAs in Papillary Thyroid Cancer

by Wenlong Wang, Ning Bai and Xinying Li

Cancers 2022, 14(5), 1353; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051353 - 07 Mar 2022

Cited by 7 | Viewed by 2629

Abstract

Dedifferentiation is the main concern associated with radioactive iodine (RAI) refractoriness in patients with papillary thyroid cancer (PTC), and the underlying mechanisms of PTC dedifferentiation remain unclear. The present work aimed to identify a useful signature to indicate dedifferentiation and further explore its [...] Read more.

Dedifferentiation is the main concern associated with radioactive iodine (RAI) refractoriness in patients with papillary thyroid cancer (PTC), and the underlying mechanisms of PTC dedifferentiation remain unclear. The present work aimed to identify a useful signature to indicate dedifferentiation and further explore its role in prognosis and susceptibility to chemotherapy drugs. A total of five prognostic-related DR-lncRNAs were selected to establish a prognostic-predicting model, and corresponding risk scores were closely associated with the infiltration of immune cells and immune checkpoint blockade. Moreover, we built an integrated nomogram based on DR-lncRNAs and age that showed a strong ability to predict the 3- and 5-year overall survival. Interestingly, drug sensitivity analysis revealed that the low-risk group was more sensitive to Bendamustine and TAS-6417 than the high-risk group. In addition, knockdown of DR-lncRNAs (DPH6-DT) strongly promoted cell proliferation, invasion, and migration via PI3K-AKT signal pathway in vitro. Furthermore, DPH6-DT downregulation also increased the expression of vimentin and N-cadherin during epithelial-mesenchymal transition. This study firstly confirms that DR-lncRNAs play a vital role in the prognosis and immune cells infiltration in patients with PTC, as well as a predictor of the drugs’ chemosensitivity. Based on our results, DR-lncRNAs can serve as a promising prognostic biomarkers and treatment targets. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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17 pages, 1280 KiB

Open AccessArticle

The BRAF^V600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age

by Liudmyla Zurnadzhy, Tetiana Bogdanova, Tatiana I. Rogounovitch, Masahiro Ito, Mykola Tronko, Shunichi Yamashita, Norisato Mitsutake, Serhii Chernyshov, Sergii Masiuk and Vladimir A. Saenko

Cancers 2021, 13(23), 6038; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236038 - 30 Nov 2021

Cited by 12 | Viewed by 2364

Abstract

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAF^V600E-positive PTCs, whose proportion is growing with time, are not well described yet. We [...] Read more.

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAF^V600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAF^V600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAF^V600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAF^V600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAF^V600E-negative tumors. Comparison of the BRAF^V600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAF^V600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAF^V600E-negative sporadic tumors. Thus, BRAF^V600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAF^V600E-negative tumors. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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16 pages, 52894 KiB

Open AccessArticle

PPARγ Targets-Derived Diagnostic and Prognostic Index for Papillary Thyroid Cancer

by Jaehyung Kim, Soo Young Kim, Shi-Xun Ma, Seok-Mo Kim, Su-Jin Shin, Yong Sang Lee, Hojin Chang, Hang-Seok Chang, Cheong Soo Park and Su Bin Lim

Cancers 2021, 13(20), 5110; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205110 - 12 Oct 2021

Cited by 1 | Viewed by 2445

Abstract

In most cases, papillary thyroid cancer (PTC) is highly curable and associated with an excellent prognosis. Yet, there are several clinicopathological features that lead to a poor prognosis, underscoring the need for a better genomic strategy to refine prognostication and patient management. We [...] Read more.

In most cases, papillary thyroid cancer (PTC) is highly curable and associated with an excellent prognosis. Yet, there are several clinicopathological features that lead to a poor prognosis, underscoring the need for a better genomic strategy to refine prognostication and patient management. We hypothesized that PPARγ targets could be potential markers for better diagnosis and prognosis due to the variants found in PPARG in three pairs of monozygotic twins with PTC. Here, we developed a 10-gene personalized prognostic index, designated PPARGi, based on gene expression of 10 PPARγ targets. Through scRNA-seq data analysis of PTC tissues derived from patients, we found that PPARGi genes were predominantly expressed in macrophages and epithelial cells. Machine learning algorithms showed a near-perfect performance of PPARGi in deciding the presence of the disease and in selecting a small subset of patients with poor disease-specific survival in TCGA-THCA and newly developed merged microarray data (MMD) consisting exclusively of thyroid cancers and normal tissues. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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10 pages, 1163 KiB

Open AccessArticle

Prognostic Role of Pre-Treatment [¹⁸F]FDG PET/CT in Patients with Anaplastic Thyroid Cancer

by Hyun Jeong Kim, Hang-Seok Chang and Young Hoon Ryu

Cancers 2021, 13(16), 4228; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164228 - 23 Aug 2021

Cited by 6 | Viewed by 2568

Abstract

Anaplastic thyroid carcinoma (ATC) is a rare but highly lethal disease. Therefore, its diagnosis at an early stage and a rapid and accurate establishment of a proper treatment strategy is warranted. Tumor glycolysis assessed by ¹⁸fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography [...] Read more.

Anaplastic thyroid carcinoma (ATC) is a rare but highly lethal disease. Therefore, its diagnosis at an early stage and a rapid and accurate establishment of a proper treatment strategy is warranted. Tumor glycolysis assessed by ¹⁸fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET)/computed tomography (CT) is predictive of many cancers despite its limited proven applicability to ATC. We investigated the prognostic capability of [¹⁸F]FDG PET/CT in patients with ATC. Forty patients with ATC were subjected to [¹⁸F]FDG PET/CT for pre-treatment evaluation. The tumor size and stage, overall survival (OS), and PET parameters, including the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were analyzed. The 1-year OS rate was 17.5% with a mean life expectancy of 7.1 months. Distant metastasis was detected solely using PET/CT in 37.5% of cases. High SUVmax, MTV, and TLG were significantly associated with poor prognosis (p < 0.001, p = 0.002, and p < 0.001, respectively). A significant difference (p < 0.001) was observed in OS between patients with a high and low tumor SUVmax. Glucose metabolism assessed by [¹⁸F]FDG PET/CT was significantly associated with the OS of patients with ATC. PET-derived parameters such as SUVmax, MTV, and TLG are useful prognostic biomarkers for ATC. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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18 pages, 2688 KiB

Open AccessArticle

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

by Tatiana I. Rogounovitch, Svetlana V. Mankovskaya, Mikhail V. Fridman, Tatiana A. Leonova, Victor A. Kondratovitch, Natalya E. Konoplya, Shunichi Yamashita, Norisato Mitsutake and Vladimir A. Saenko

Cancers 2021, 13(13), 3374; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133374 - 05 Jul 2021

Cited by 7 | Viewed by 2862

Abstract

Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics [...] Read more.

Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAF^V600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAF^K601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAF^V600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAF^V600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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14 pages, 3181 KiB

Open AccessArticle

Simultaneous Expression of Long Non-Coding RNA FAL1 and Extracellular Matrix Protein 1 Defines Tumour Behaviour in Young Patients with Papillary Thyroid Cancer

by Seonhyang Jeong, Seul-Gi Lee, Hyunji Kim, Gibbeum Lee, Sunmi Park, In-Kyu Kim, Jandee Lee and Young-Suk Jo

Cancers 2021, 13(13), 3223; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133223 - 28 Jun 2021

Cited by 5 | Viewed by 1970

Abstract

We investigated the regulatory mechanism of FAL1 and unravelled the molecular biological features of FAL1 upregulation in papillary thyroid cancer (PTC). Correlation analyses of FAL1 and neighbouring genes adjacent to chromosome 1q21.3 were performed. Focal amplification was performed using data from copy number [...] Read more.

We investigated the regulatory mechanism of FAL1 and unravelled the molecular biological features of FAL1 upregulation in papillary thyroid cancer (PTC). Correlation analyses of FAL1 and neighbouring genes adjacent to chromosome 1q21.3 were performed. Focal amplification was performed using data from copy number alterations in The Cancer Genome Atlas (TCGA) database. To identify putative transcriptional factors, PROMO and the Encyclopaedia of DNA Elements (ENCODE) were used. To validate c-JUN and JUND as master transcription factors for FAL1 and ECM1, gene set enrichment analysis was performed according to FAL1 and ECM1 expression. Statistical analyses of the molecular biological features of FAL1- and ECM1-upregulated PTCs were conducted. FAL1 expression significantly correlated with that of neighbouring genes. Focal amplification of chromosome 1q21.3 was observed in ovarian cancer but not in thyroid carcinoma. However, PROMO suggested 53 transcription factors as putative common transcriptional factors for FAL1 and ECM1 simultaneously. Among them, we selected c-JUN and JUND as the best candidates based on ENCODE results. The expression of target genes of JUND simultaneously increased in FAL1- and ECM1-upregulated PTCs, especially in young patients. The molecular biological features represented RAS-driven PTC and simultaneously enriched immune-related gene sets. FAL1 and ECM1 expression frequently increased simultaneously and could be operated by JUND. The simultaneous upregulation might be a potential diagnostic and therapeutic target for RAS-driven PTC. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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14 pages, 1660 KiB

Open AccessArticle

Quercetin Induces Anticancer Activity by Upregulating Pro-NAG-1/GDF15 in Differentiated Thyroid Cancer Cells

by Yukyung Hong, Jaehak Lee, Hyunjin Moon, Chang H. Ryu, Jungirl Seok, Yuh-Seog Jung, Junsun Ryu and Seung J. Baek

Cancers 2021, 13(12), 3022; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123022 - 16 Jun 2021

Cited by 25 | Viewed by 3845

Abstract

Although the treatment of thyroid cancer has improved, unnecessary surgeries are performed due to a lack of specific diagnostic and prognostic markers. Therefore, the identification of novel biomarkers should be considered in the diagnosis and treatment of thyroid cancer. In this study, antibody [...] Read more.

Although the treatment of thyroid cancer has improved, unnecessary surgeries are performed due to a lack of specific diagnostic and prognostic markers. Therefore, the identification of novel biomarkers should be considered in the diagnosis and treatment of thyroid cancer. In this study, antibody arrays were performed using tumor and adjacent normal tissues of patients with papillary thyroid cancer, and several potential biomarkers were identified. Among the candidate proteins chosen based on the antibody array data, mature NAG-1 exhibited increased expression in tumor tissues compared to adjacent normal tissues. In contrast, pro-NAG-1 expression increased in normal tissues, as assessed by western blot analysis. Furthermore, pro-NAG-1 expression was increased when the thyroid cancer cells were treated with phytochemicals and nonsteroidal anti-inflammatory drugs in a dose-dependent manner. In particular, quercetin highly induced the expression of pro-NAG-1 but not that of mature NAG-1, with enhanced anticancer activity, including apoptosis induction and cell cycle arrest. Examination of the NAG-1 promoter activity showed that p53, C/EBPα, or C/EBPδ played a role in quercetin-induced NAG-1 expression. Overall, our study indicated that NAG-1 may serve as a novel biomarker for thyroid cancer prognosis and may be used as a therapeutic target for thyroid cancers. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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11 pages, 1709 KiB

Open AccessArticle

Proposal of a New Prognostic Model for Differentiated Thyroid Cancer with TERT Promoter Mutations

by Jun Park, Sungjoo Lee, Jiyun Park, Hyunju Park, Chang-Seok Ki, Young-Lyun Oh, Jung-Hee Shin, Jee-Soo Kim, Sun-Wook Kim, Jae-Hoon Chung, Kyunga Kim and Tae-Hyuk Kim

Cancers 2021, 13(12), 2943; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122943 - 11 Jun 2021

Cited by 8 | Viewed by 2626

Abstract

The role of telomerase reverse transcriptase (TERT) promoter mutations as an independent poor prognostic factor in differentiated thyroid cancer (DTC) patients is well known, but there is no prognostic system that combines the TERT promoter mutation status with tumor-node-metastasis (TNM) stage [...] Read more.

The role of telomerase reverse transcriptase (TERT) promoter mutations as an independent poor prognostic factor in differentiated thyroid cancer (DTC) patients is well known, but there is no prognostic system that combines the TERT promoter mutation status with tumor-node-metastasis (TNM) stage to predict cancer-specific survival (CSS). A total of 393 patients with pathologically confirmed DTC after thyroidectomy were enrolled. After incorporating wild-type TERT and mutant TERT with stages I, II, and III/IV of the AJCC TNM system 8th edition (TNM-8), we generated six combinations and calculated 10-year and 15-year CSS and adjusted hazard ratios (HRs) for cancer-related death using Cox regression. Then, a new mortality prediction model termed TNM-8T was derived based on the CSS and HR of each combination in the four groups. Of the 393 patients, there were 27 (6.9%) thyroid cancer-related deaths during a median follow-up of 14 years. Patients with a more advanced stage had a lower survival rate (10-year CSS for TNM-8T stage 1, 2, 3, and 4: 98.7%, 93.5%, 77.3%, and 63.0%, respectively; p < 0.001). TNM-8T showed a better spread of CSS (p < 0.001) than TNM-8 (p = 0.002) in the adjusted survival curves. The C-index for mortality risk predictability was 0.880 (95% CI, 0.665–0.957) in TNM-8T and 0.827 (95% CI, 0.622–0.930) in TNM-8 (p < 0.001). TNM-8T, a new prognostic system that incorporates the TERT mutational status into TNM-8, showed superior predictability to TNM-8 in the long-term survival of DTC patients. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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15 pages, 1124 KiB

Open AccessArticle

Comparison of Four Ultrasonography-Based Risk Stratification Systems in Thyroid Nodules with Nondiagnostic/Unsatisfactory Cytology: A Real-World Study

by You-Bin Lee, Young-Lyun Oh, Jung-Hee Shin, Sun-Wook Kim, Jae-Hoon Chung, Yong-Ki Min, Soo-Yeon Hahn and Tae-Hyuk Kim

Cancers 2021, 13(8), 1948; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081948 - 18 Apr 2021

Cited by 3 | Viewed by 1805

Abstract

We compared American Thyroid Association (ATA) guidelines, Korean (K)-Thyroid Imaging, Reporting and Data Systems (TIRADS), EU-TIRADS, and American College of Radiology (ACR) TIRADS in diagnosing malignancy for thyroid nodules with nondiagnostic/unsatisfactory cytology. Among 1143 nondiagnostic/unsatisfactory aspirations from April 2011 to March 2016, malignancy [...] Read more.

We compared American Thyroid Association (ATA) guidelines, Korean (K)-Thyroid Imaging, Reporting and Data Systems (TIRADS), EU-TIRADS, and American College of Radiology (ACR) TIRADS in diagnosing malignancy for thyroid nodules with nondiagnostic/unsatisfactory cytology. Among 1143 nondiagnostic/unsatisfactory aspirations from April 2011 to March 2016, malignancy was detected in 39 of 89 excised nodules. The minimum malignancy rate was 7.82% in EU-TIRADS 5 and 1.87–3.00% in EU-TIRADS 3–4. In the other systems, the minimum malignancy rate was 14.29–16.19% in category 5 and ≤3% in the remaining categories. Although the EU-TIRADS category ≥ 5 exhibited the highest positive likelihood ratio (LR) of only 2.214, category ≥ 5 in the other systems yielded the highest positive LR of >5. Receiver operating characteristic (ROC) curves of all systems to predict malignancy were located statistically above the diagonal nondiscrimination line (P for ROC curve: EU-TIRADS, 0.0022; all others, 0.0001). The areas under the ROC curve (AUCs) were not significantly different among the four systems. The ATA guidelines, K-TIRADS, and ACR TIRADS may be useful to guide management for nondiagnostic/unsatisfactory nodules. The EU-TIRADS, although also useful, exhibited inferior performance in predicting malignancy for nondiagnostic/unsatisfactory nodules in Korea, an iodine-sufficient area. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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13 pages, 2446 KiB

Open AccessArticle

NTRK Fusion Genes in Thyroid Carcinomas: Clinicopathological Characteristics and Their Impacts on Prognosis

by Barbora Pekova, Vlasta Sykorova, Karolina Mastnikova, Eliska Vaclavikova, Jitka Moravcova, Petr Vlcek, Petr Lastuvka, Milos Taudy, Rami Katra, Petr Bavor, Daniela Kodetova, Martin Chovanec, Jana Drozenova, Jaromir Astl, Petr Hrabal, Josef Vcelak and Bela Bendlova

Cancers 2021, 13(8), 1932; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081932 - 16 Apr 2021

Cited by 57 | Viewed by 4752

Abstract

Chromosomal rearrangements of NTRK genes are oncogenic driver mutations in thyroid cancer (TC). This study aimed to identify NTRK fusion-positive thyroid tumors and to correlate them with clinical and pathological data and determine their prognostic significance. The cohort consisted of 989 different TC [...] Read more.

Chromosomal rearrangements of NTRK genes are oncogenic driver mutations in thyroid cancer (TC). This study aimed to identify NTRK fusion-positive thyroid tumors and to correlate them with clinical and pathological data and determine their prognostic significance. The cohort consisted of 989 different TC samples. Based on the detected mutation, samples were triaged, and those that were positive for a BRAF, HRAS, KRAS, NRAS, RET, RET/PTC or PAX8/PPARγ mutation were excluded from further analyses. NTRK fusion gene testing was performed in 259 cases, including 126 cases using next-generation sequencing. NTRK fusion genes were detected in 57 of 846 (6.7%) papillary thyroid carcinomas and in 2 of 10 (20.0%) poorly differentiated thyroid carcinomas. A total of eight types of NTRK fusions were found, including ETV6/NTRK3, EML4/NTRK3, RBPMS/NTRK3, SQSTM1/NTRK3, TPM3/NTRK1, IRF2BP2/NTRK1, SQSTM1/NTRK1 and TPR/NTRK1.NTRK fusion-positive carcinomas were associated with the follicular growth pattern, chronic lymphocytic thyroiditis and lymph node metastases. NTRK1-rearranged carcinomas showed a higher frequency of multifocality and aggressivity than NTRK3-rearranged carcinomas. Tumor size, presence of metastases, positivity for the NTRK3 or NTRK1 fusion gene and a late mutation event (TERT or TP53 mutation) were determined as factors affecting patient prognosis. NTRK fusion genes are valuable diagnostic and prognostic markers. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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11 pages, 5845 KiB

Open AccessArticle

Prognostic Value of the Neutrophil-to-Lymphocyte Ratio before and after Radiotherapy for Anaplastic Thyroid Carcinoma

by Jiyun Park, Jun Park, Jung-Hee Shin, Young-Lyun Oh, Hyun-Ae Jung, Man-Ki Chung, Jun-Ho Choe, Yong-Chan Ahn, Sun-Wook Kim, Jae-Hoon Chung, Tae-Hyuk Kim and Jae-Myoung Noh

Cancers 2021, 13(8), 1913; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081913 - 15 Apr 2021

Cited by 9 | Viewed by 2183

Abstract

The neutrophil–lymphocyte ratio (NLR) is a marker of systemic inflammation, and its elevation has recently been associated with poor survival in many solid cancers. Leukocyte elevation and lymphocyte reduction are associated with a poor response to radiotherapy (RT). This study aimed to assess [...] Read more.

The neutrophil–lymphocyte ratio (NLR) is a marker of systemic inflammation, and its elevation has recently been associated with poor survival in many solid cancers. Leukocyte elevation and lymphocyte reduction are associated with a poor response to radiotherapy (RT). This study aimed to assess the prognostic value of NLR before and after RT for anaplastic thyroid carcinoma (ATC). This retrospective study analyzed 40 patients with ATC who received RT with available complete blood cell count data from November 1995 through May 2020 at Samsung Medical Center (Seoul, Korea). Patients were classified into two groups according to the NLR before and after RT. The median overall survival (OS) was 8.9 months (range, 3.5–18.2) in the low NLR group (<3.47) and 5.2 months (range, 2.7–7.5) months in the high NLR group (≥3.47). The association between NLR and OS was also observed in multivariable Cox regression analysis (hazard ratio, 3.18; 95% confidence interval, 1.15–8.85; p = 0.026). The OS curves differed significantly according to post-RT NLR (p = 0.036). A high NLR before and after RT may be significantly associated with poor OS in patients with ATC who receive RT. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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13 pages, 2600 KiB

Open AccessArticle

Serum CYFRA 21.1 Level Predicts Disease Course in Thyroid Cancer with Distant Metastasis

by Chaiho Jeong, Jeongmin Lee, Hyukjin Yoon, Jeonghoon Ha, Min-Hee Kim, Ja-Seong Bae, Chan-Kwon Jung, Jeong-Soo Kim, Moo-Il Kang and Dong-Jun Lim

Cancers 2021, 13(4), 811; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040811 - 15 Feb 2021

Cited by 4 | Viewed by 2581

Abstract

Background: Serum Cyfra 21.1, the soluble fragment of CK19, has been used as a prognostic tumor marker in various cancers, indicating poor tumor differentiation and increased metastasis. Methods: We analyzed the serum Cyfra 21.1 level in 51 consecutive patients with thyroid cancer manifesting [...] Read more.

Background: Serum Cyfra 21.1, the soluble fragment of CK19, has been used as a prognostic tumor marker in various cancers, indicating poor tumor differentiation and increased metastasis. Methods: We analyzed the serum Cyfra 21.1 level in 51 consecutive patients with thyroid cancer manifesting distant metastasis treated with prior total thyroidectomy. Serum Cyfra 21.1 levels of 26 thyroid cancer patients without metastasis and 50 healthy individuals were used for comparison. Results: Higher serum Cyfra 21.1 levels were detected in thyroid cancer patients with distant metastasis compared with healthy subjects and thyroid cancer patients without metastasis (p = 0.012). Serum Cyfra 21.1 levels were significantly increased in patients with positive BRAF V600E mutation (p = 0.019), undergoing Tyrosine Kinase Inhibitor (TKI) therapy (p = 0.008), with radioiodine-refractory status (p = 0.047), and in disease progression compared with those manifesting stable disease (p = 0.007). In progressive disease with undetectable or unmonitored thyroglobulin because of thyroglobulin antibody, serum Cyfra 21.1 was useful as a biomarker for follow-up of disease course. Conclusion: Serum Cyfra 21.1 in thyroid cancer patients might represent an alternative biomarker predicting tumor progression, especially in cases not associated with serum Tg levels. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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19 pages, 3347 KiB

Open AccessFeature PaperArticle

MicroRNA Profile for Diagnostic and Prognostic Biomarkers in Thyroid Cancer

by Jong-Lyul Park, Seon-Kyu Kim, Sora Jeon, Chan-Kwon Jung and Yong-Sung Kim

Cancers 2021, 13(4), 632; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040632 - 05 Feb 2021

Cited by 11 | Viewed by 2559

Abstract

The challenge in managing thyroid nodules is to accurately diagnose the minority of those with malignancy. We aimed to identify diagnostic and prognostic miRNA markers for thyroid nodules. In a discovery cohort, we identified 20 candidate miRNAs to differentiate between noninvasive follicular thyroid [...] Read more.

The challenge in managing thyroid nodules is to accurately diagnose the minority of those with malignancy. We aimed to identify diagnostic and prognostic miRNA markers for thyroid nodules. In a discovery cohort, we identified 20 candidate miRNAs to differentiate between noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and papillary thyroid carcinomas (PTC) by using the high-throughput small RNA sequencing method. We then selected three miRNAs (miR-136, miR-21, and miR-127) that were differentially expressed between the PTC follicular variant and other variants in The Cancer Genome Atlas data. High expression of three miRNAs differentiated thyroid cancer from nonmalignant tumors, with an area under curve (AUC) of 0.76–0.81 in an independent cohort. In patients with differentiated thyroid cancer, the high-level expression of the three miRNAs was an independent indicator for both distant metastases and recurrent or persistent disease. In patients with PTC, a high expression of miRNAs was associated with an aggressive histologic variant, extrathyroidal extension, distant metastasis, or recurrent or persistent disease. Three miRNAs may be used as diagnostic markers for differentiating thyroid cancers from benign tumors and tumors with extremely low malignant potential (NIFTP), as well as prognostic markers for predicting the risk of recurrent/persistent disease for differentiated thyroid cancer. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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17 pages, 2438 KiB

Open AccessArticle

Preoperative Typing of Thyroid and Parathyroid Tumors with a Combined Molecular Classifier

by Sergei E. Titov, Evgeniya S. Kozorezova, Pavel S. Demenkov, Yulia A. Veryaskina, Irina V. Kuznetsova, Sergey L. Vorobyev, Roman A. Chernikov, Ilya V. Sleptsov, Nataliya I. Timofeeva and Mikhail K. Ivanov

Cancers 2021, 13(2), 237; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13020237 - 11 Jan 2021

Cited by 7 | Viewed by 2307

Abstract

In previous studies, we described a method for detecting and typing malignant tumors of the thyroid gland in fine-needle aspiration biopsy samples via analysis of a molecular marker panel (normalized HMGA2 mRNA level; normalized microRNA-146b, -221, and -375 levels; mitochondrial-to-nuclear DNA ratio; and [...] Read more.

In previous studies, we described a method for detecting and typing malignant tumors of the thyroid gland in fine-needle aspiration biopsy samples via analysis of a molecular marker panel (normalized HMGA2 mRNA level; normalized microRNA-146b, -221, and -375 levels; mitochondrial-to-nuclear DNA ratio; and BRAF^V600E mutation) in cytological preparations by quantitative PCR. In the present study, we aimed to estimate the specificity of the typing of different thyroid tumors by the proposed method. Fine-needle aspiration cytological preparations from 278 patients were used. The histological diagnosis was known for each sample. The positive and negative predictive values of the method assessed in this study were, respectively, 100% and 98% for papillary thyroid carcinoma (n = 63), 100% and 100% for medullary thyroid carcinoma (n = 19), 43.5% and 98% for follicular carcinoma (n = 15), and 86% and 100% for Hürthle cell carcinoma (n = 6). Thus, we demonstrate that the diagnostic panel, including the analysis of microRNA expression, mRNA expression, the BRAF^V600E mutation, and the mitochondrial-to-nuclear DNA ratio, allows the highly accurate identification of papillary thyroid carcinoma, medullary thyroid carcinoma, and Hürthle cell carcinoma but not malignant follicular tumors (positive predictive value was below 50%). Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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9 pages, 686 KiB

Open AccessArticle

Hürthle Cells on Fine-Needle Aspiration Cytology Are Important for Risk Assessment of Focally PET/CT FDG Avid Thyroid Nodules

by David N. Poller, Hakim Megadmi, Matthew J. A. Ward and Pierpaolo Trimboli

Cancers 2020, 12(12), 3544; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123544 - 27 Nov 2020

Cited by 6 | Viewed by 2046

Abstract

This study assesses the role of [¹⁸F] FDG PET/CT, fine needle aspiration (FNA) cytology and ultrasound in the 1–2% of patients with focally positive thyroid nodules on FDG PET/CT. All FDG PET/CT scans with focally increased thyroid FDG PET/CT uptake performed [...] Read more.

This study assesses the role of [¹⁸F] FDG PET/CT, fine needle aspiration (FNA) cytology and ultrasound in the 1–2% of patients with focally positive thyroid nodules on FDG PET/CT. All FDG PET/CT scans with focally increased thyroid FDG PET/CT uptake performed over 37 months in one institution were matched to patients undergoing thyroid FNA. Diffuse FDG PET/CT uptake patients were excluded. A total of 47 patients showed focally increased thyroid uptake. Consistent with previous studies, 18 (38.2%) patients had malignancy—12 primary thyroid carcinoma, 1 parathyroid carcinoma, 3 metastatic carcinoma to the thyroid and 2 lymphoma. A total of 15 (31.9%) lesions categorized as non-malignant contained Hürthle cells/oncocytes. A total of 14 lesions (29.8%) had focally increased FDG PET/CT uptake with no specific cytological or histopathological cause identified. No focally PET avid Hürthle cell/oncocytic lesions were found to be malignant. Exclusion of oncocytic lesions increased the calculated risk of malignancy (ROM) of focally PET avid nodules from 38% to 68%. It may be useful to exclude focally FDG PET/CT avid Hürthle cell/oncocytic lesions, typically reported as follicular neoplasm or suspicious for a follicular neoplasm, Hürthle cell type (Oncocytic) type, RCPath Thy 3F: Bethesda IV or sometimes Thy 3a: Bethesda III FNAs) from ROM calculations. Oncocytic focally PET/CT FDG avid lesions appear of comparatively lower risk of malignancy and require investigation or operation but these lesions should be readily identified by FNA cytology on diagnostic work up of focally PET avid thyroid nodules. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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19 pages, 3697 KiB

Open AccessArticle

CD73 Overexpression Promotes Progression and Recurrence of Papillary Thyroid Carcinoma

by Young Mun Jeong, Haejin Cho, Tae-Min Kim, Yourha Kim, Sora Jeon, Andrey Bychkov and Chan Kwon Jung

Cancers 2020, 12(10), 3042; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12103042 - 19 Oct 2020

Cited by 19 | Viewed by 3761

Abstract

CD73 is involved in tumor immune escape and promotes the growth and progression of cancer cells. The functional role of CD73 expression in papillary thyroid carcinoma (PTC) has not yet been established. In 511 patients with PTC, immunohistochemistry for CD73 on tissue microarrays [...] Read more.

CD73 is involved in tumor immune escape and promotes the growth and progression of cancer cells. The functional role of CD73 expression in papillary thyroid carcinoma (PTC) has not yet been established. In 511 patients with PTC, immunohistochemistry for CD73 on tissue microarrays showed that the high expression of CD73 was associated with an aggressive histologic variant (p = 0.002), extrathyroidal extension (p < 0.001), lymph node metastasis (p < 0.001), and BRAF^V600E mutation (p = 0.015). Survival analysis results showed that patients with high CD73 expression had worse recurrence-free survival (p = 0.023). CD73 inhibitors induced G1 cell cycle arrest and apoptosis, inhibited the migration and invasion of PTC cells, and suppressed tumor growth in PTC xenograft nude mice. High expression of CD73 (NT5E) mRNA was associated with unfavorable clinicopathologic characteristics, the abundance of Tregs and dendritic cells, depletion of natural killer (NK) cells, and high expression of immune checkpoint genes and epithelial-to-mesenchymal transition-related genes in The Cancer Genome Atlas (TCGA) dataset. Taken together, CD73 expression promotes tumor progression and predicts low recurrence-free survival. Targeting the CD73–adenosine axis in the tumor microenvironment offers an attractive pathway for therapeutic strategies aimed at advanced PTC. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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13 pages, 636 KiB

Open AccessArticle

Preoperative Serum Calcitonin and Its Correlation with Extent of Lymph Node Metastasis in Medullary Thyroid Carcinoma

by Hyunju Park, Jun Park, Min Sun Choi, Jinyoung Kim, Hosu Kim, Jung Hee Shin, Jung-Han Kim, Jee Soo Kim, Sun Wook Kim, Jae Hoon Chung and Tae Hyuk Kim

Cancers 2020, 12(10), 2894; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102894 - 09 Oct 2020

Cited by 19 | Viewed by 2749

Abstract

The optimal initial surgical extent for medullary thyroid carcinoma (MTC) remains controversial. Previous studies on serum calcitonin are limited to reporting the calcitonin threshold according to anatomical disease burden. Here, we evaluated whether preoperative calcitonin levels can be used to predict optimal surgical [...] Read more.

The optimal initial surgical extent for medullary thyroid carcinoma (MTC) remains controversial. Previous studies on serum calcitonin are limited to reporting the calcitonin threshold according to anatomical disease burden. Here, we evaluated whether preoperative calcitonin levels can be used to predict optimal surgical extent. We retrospectively reviewed the 170 patients with MTC at a tertiary Korean hospital from 1994 to 2019. We extracted data on preoperative calcitonin level, primary tumor size and the number and location of lymph node metastases (LNMs). To evaluate disease extent, we divided the patients into five groups: no LNM, central LNM, ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis. We calculated the positive and negative likelihood ratios (LRs) for multiple categories of preoperative calcitonin levels. Preoperative calcitonin level positively correlated with primary tumor size (rho = 0.744, p < 0.001) and LNM number (rho = 0.537, p < 0.001). Preoperative calcitonin thresholds of 20, 200, and 500 pg/mL were associated with the presence of ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis, respectively. The negative LRs were 0.1 at a preoperative calcitonin cut-off of 100 pg/mL in the central LNM, 0.18 at a cut-off of 300 pg/mL in the ipsilateral lateral LNM, and 0 at a cut-off of 300 pg/mL in the contralateral lateral LNM. The preoperative calcitonin level correlates with disease extent and has diagnostic value for predicting LNM extent. Our results suggest that the preoperative calcitonin level can be used to determine optimal initial surgical extent. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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12 pages, 2486 KiB

Open AccessArticle

The Value of Microvascular Imaging for Triaging Indeterminate Cervical Lymph Nodes in Patients with Papillary Thyroid Carcinoma

by Seongyong Lee, Ji Ye Lee, Ra Gyoung Yoon, Ji-hoon Kim and Hyun Sook Hong

Cancers 2020, 12(10), 2839; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102839 - 01 Oct 2020

Cited by 14 | Viewed by 4086

Abstract

Assessment of lymph node (LN) status in patients with papillary thyroid carcinoma (PTC) is often troublesome because of cervical LNs with indeterminate US (ultrasound) features. We aimed to explore whether Superb Microvascular Imaging (SMI) could be helpful for distinguishing metastasis from indeterminate LNs [...] Read more.

Assessment of lymph node (LN) status in patients with papillary thyroid carcinoma (PTC) is often troublesome because of cervical LNs with indeterminate US (ultrasound) features. We aimed to explore whether Superb Microvascular Imaging (SMI) could be helpful for distinguishing metastasis from indeterminate LNs when combined with power Doppler US (PDUS). From 353 consecutive patients with PTC, LNs characterized as indeterminate by PDUS were evaluated by SMI to distinguish them from metastasis. Indeterminate LNs were reclassified according to the SMI, the malignancy risk of each category was assessed, and the diagnostic performance of suspicious findings on SMI was calculated. The incidence of US-indeterminate LNs was 26.9%. Eighty PDUS-indeterminate LNs (39 proven as benign, 41 proven as malignant) were reclassified into probably benign (n = 26), indeterminate (n = 20), and suspicious (n = 34) categories according to SMI, with malignancy risks of 19.2%, 20.0%, and 94.1%, respectively. After combining SMI with PDUS, 80.8% (21/26) of probably benign LNs and 94.1% (32/34) of suspicious LNs could be correctly diagnosed as benign and metastatic, respectively. The diagnostic sensitivity, specificity, and accuracy of categorizing LNs as suspicious based on SMI were 78.1%, 94.9%, and 86.3%, respectively. In conclusion, the combination of SMI with PDUS was helpful for the accurate stratification of indeterminate LNs based on US in patients with PTC. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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10 pages, 1114 KiB

Open AccessArticle

The Impact of BRAF Mutation on the Recurrence of Papillary Thyroid Carcinoma: A Meta-Analysis

by Xin Li and Hyungju Kwon

Cancers 2020, 12(8), 2056; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082056 - 25 Jul 2020

Cited by 18 | Viewed by 2573

Abstract

Previous meta-analyses indicated that the BRAF V600E mutation was associated with an increased recurrence rate of papillary thyroid carcinoma (PTC). However, with recent publications of large cohort studies, the need for an updated meta-analysis increases. Therefore, we conducted a comprehensive meta-analysis to assess [...] Read more.

Previous meta-analyses indicated that the BRAF V600E mutation was associated with an increased recurrence rate of papillary thyroid carcinoma (PTC). However, with recent publications of large cohort studies, the need for an updated meta-analysis increases. Therefore, we conducted a comprehensive meta-analysis to assess the impact of the BRAF V600E mutation on PTC recurrences. We performed a literature search using PubMed, SCOPUS, the Cochrane Database of Systematic Reviews, and the Web of Science Core Collection, from their inception to May 31, 2020. The relevant studies compared recurrence rates using the hazard ratio (HR) of BRAF mutations; 11 studies comprising 4674 patients were identified and included. Recurrence rates in patients with the BRAF V600E mutation were comparable with BRAF wild-type patients (HR 1.16, 95% CI 0.78–1.71), after adjustment for possible confounders. In subgroup analysis, both geographical region (HRs for America, Asia, and Europe were 2.16, 1.31 and 0.66, respectively) and tumor stage (HRs for stage I and II were 1.51 and 4.45, respectively) can affect the HRs of the BRAF mutation for recurrence. In conclusion, the BRAF mutation does not increase the risk of recurrences in patients with PTC. Differences in the geographical region or tumor stage should be considered when interpreting the impact of a BRAF mutation on recurrence. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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13 pages, 1893 KiB

Open AccessArticle

Characterization of Driver Mutations in Anaplastic Thyroid Carcinoma Identifies RAS and PIK3CA Mutations as Negative Survival Predictors

by Wei-An Lai, Chih-Yi Liu, Shih-Yao Lin, Chien-Chin Chen and Jen-Fan Hang

Cancers 2020, 12(7), 1973; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071973 - 20 Jul 2020

Cited by 16 | Viewed by 3669

Abstract

Anaplastic thyroid carcinoma (ATC) is rare but highly aggressive. We investigated the association of selected driver mutations, including BRAF, RAS, PIK3CA, TERT promoter, TP53, POLE, and mismatch repair deficiency (MMR-D) with the clinicopathological features of ATC to identify prognostic [...] Read more.

Anaplastic thyroid carcinoma (ATC) is rare but highly aggressive. We investigated the association of selected driver mutations, including BRAF, RAS, PIK3CA, TERT promoter, TP53, POLE, and mismatch repair deficiency (MMR-D) with the clinicopathological features of ATC to identify prognostic and predictive biomarkers. Thirty-nine retrospective cases from pathology archives were enrolled for clinicopathology analysis and immunohistochemistry, and 27 cases had sufficient specimens for further molecular testing using targeted next-generation sequencing and mass spectrometry. BRAF^V600E and RAS mutations were identified in 25.9% and 40.7% of ATC, respectively. BRAF^V600E mutation was significantly associated with coexisting papillary thyroid carcinoma (p = 0.009) and RAS mutations with female gender (p = 0.012). In univariant analysis, the non-BRAF/RAS tumors were significantly associated with the presence of a sarcomatoid pattern (p = 0.045). PIK3CA, TERT promoter, and TP53 mutations were identified in 14.8%, 81.5%, and 70.4% of cases, respectively. No MMR-D or POLE mutations were detected. In survival analyses, RAS and PIK3CA mutations were significantly associated with inferior outcomes (p = 0.03 and p = 0.006, respectively). In conclusion, driver mutations in ATC are associated with distinct clinicopathological features. RAS and PIK3CA mutations were negative predictors for patient survival. Emerging therapeutic agents targeting BRAF, RAS, and PI3 kinase may benefit a substantial proportion of ATC patients. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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17 pages, 35666 KiB

Open AccessArticle

Prognostic Implications of CD10 and CD15 Expression in Papillary Thyroid Carcinoma

by Eun Ji Oh, Andrey Bychkov, Haejin Cho, Tae-Min Kim, Ja Seong Bae, Dong-Jun Lim and Chan Kwon Jung

Cancers 2020, 12(6), 1413; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061413 - 30 May 2020

Cited by 7 | Viewed by 3013

Abstract

Patients with papillary thyroid carcinoma (PTC) have excellent survival, but recurrence remains a major problem in the management of PTC. We aimed to determine the prognostic impact of the expression of CD10 and CD15 in patients with PTC. Immunohistochemistry for CD10 and CD15 [...] Read more.

Patients with papillary thyroid carcinoma (PTC) have excellent survival, but recurrence remains a major problem in the management of PTC. We aimed to determine the prognostic impact of the expression of CD10 and CD15 in patients with PTC. Immunohistochemistry for CD10 and CD15 was performed on the tissue microarrays of 515 patients with PTC. The expression of CD10 and CD15 was detected in 201 (39.0%) and 295 (57.3%) of 515 PTC cases, respectively, but not in the adjacent benign thyroid tissue. Recurrence was inversely correlated with CD15 expression (p = 0.034) but not with CD10 expression. In 467 PTC patients treated with radioiodine remnant ablation, the CD15 expression had an adjusted hazard ratio of 0.500 (p = 0.024) for recurrence-free survival and an adjusted odds ratio of 2.678 (p = 0.015) for predicting long-term excellent therapeutic response. CD10 expression was not associated with clinical outcomes. In the Cancer Genome Atlas dataset, the expression level of FUT4 (CD15) mRNA was higher in the low/intermediate-risk group for recurrence than in the high-risk group and exhibited positive correlation with SLC5A5 (NIS) mRNA expression (p = 0.003). Taken together, CD15 expression was identified as an independent prognostic marker for improved prognosis in PTC patients. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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15 pages, 1843 KiB

Open AccessArticle

Genomic and Transcriptomic Characteristics According to Size of Papillary Thyroid Microcarcinoma

by Young Shin Song, Byung-Hee Kang, Seungbok Lee, Seong-Keun Yoo, Young Sik Choi, Jungsun Park, Dong Yoon Park, Kyu Eun Lee, Jeong-Sun Seo and Young Joo Park

Cancers 2020, 12(5), 1345; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051345 - 25 May 2020

Cited by 11 | Viewed by 3431

Abstract

It is controversial as to whether papillary thyroid microcarcinoma (PTMC) has some genomic and transcriptomic characteristics that differentiate between an early-stage lesion that would eventually evolve into the larger papillary thyroid cancer (PTC), and an occult indolent cancer in itself. To investigate this, [...] Read more.

It is controversial as to whether papillary thyroid microcarcinoma (PTMC) has some genomic and transcriptomic characteristics that differentiate between an early-stage lesion that would eventually evolve into the larger papillary thyroid cancer (PTC), and an occult indolent cancer in itself. To investigate this, we comprehensively elucidated the genomic and transcriptomic landscapes of PTMCs of different sizes, using a large-scaled database. This study included 3435 PTCs, 1985 of which were PTMCs. We performed targeted next-generation sequencing for 221 PTCs and integrated these data with the data including The Cancer Genome Atlas (TCGA) project. The frequency of v-raf murine sarcoma viral oncogene homolog B (BRAF)^V600E mutation was higher in PTMCs >0.5 cm than that in very small PTMCs (≤0.5 cm) and decreased again in PTCs >2 cm. Among PTMCs, the prevalence of mutations in rat sarcoma (RAS) and telomerase reverse transcriptase (TERT) promoter was not significantly different according to their size, but lower than in large PTCs. There was no change in the tumor mutational burden, the number of driver mutations, and transcriptomic profiles with tumor size, among PTMCs and all PTCs. Although a few genes with differential expression and TERT promoter mutations were found in a few PTMCs, our findings showed that there were no useful genomic or transcriptomic characteristics for the prediction of the future progression of PTMC. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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12 pages, 2622 KiB

Open AccessFeature PaperArticle

Added Value of Computed Tomography to Ultrasonography for Assessing LN Metastasis in Preoperative Patients with Thyroid Cancer: Node-by-Node Correlation

by Roh-Eul Yoo, Ji-hoon Kim, Inpyeong Hwang, Koung Mi Kang, Tae Jin Yun, Seung Hong Choi, Chul-Ho Sohn and Sun-Won Park

Cancers 2020, 12(5), 1190; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051190 - 08 May 2020

Cited by 12 | Viewed by 2628

Abstract

Diagnostic accuracy of US in the evaluation of lymph node (LN) metastasis for thyroid cancer patients is limited. We investigated the value of CT added to US for characterizing LNs in preoperative thyroid cancer patients by node-by-node correlation. A total of 225 primary [...] Read more.

Diagnostic accuracy of US in the evaluation of lymph node (LN) metastasis for thyroid cancer patients is limited. We investigated the value of CT added to US for characterizing LNs in preoperative thyroid cancer patients by node-by-node correlation. A total of 225 primary thyroid cancer patients who underwent LN biopsy were included. Based on node-by-node correlation, 274 LNs were classified into probably benign, indeterminate, and suspicious categories on US, CT, and combined US/CT. Malignancy risks were calculated for each category and were compared between US/CT concordant and discordant cases. On US, CT, and combined US/CT, malignancy risks were 1.7%, 8.7%, and 0% in the probably benign category, 22.4%, 5.9%, and 8.0% in the indeterminate category, and 77.2%, 82.0%, and 75.6% in the suspicious category, respectively. Malignancy risk of the concordant suspicious category was higher than that of the discordant suspicious category (84.7% vs. 43.2%, p < 0.001). The addition of CT helped correctly detect additional metastasis in 16.4% of the US indeterminate LNs and in 1.7% of the US probably benign LNs. CT may complement US for LN characterization in thyroid cancer patients by suggesting the diagnostic confidence level for the suspicious category and helping correctly detect metastasis in US indeterminate LNs. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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11 pages, 1073 KiB

Open AccessArticle

Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer

by Naveen Ravi, Minjun Yang, Nektaria Mylona, Johan Wennerberg and Kajsa Paulsson

Cancers 2020, 12(3), 680; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030680 - 13 Mar 2020

Cited by 17 | Viewed by 3548

Abstract

Anaplastic thyroid cancer (ATC) is one of the most malignant tumors, with a median survival of only a few months. The tumorigenic processes of this disease have not yet been completely unraveled. Here, we report an mRNA expression and DNA methylation analysis of [...] Read more.

Anaplastic thyroid cancer (ATC) is one of the most malignant tumors, with a median survival of only a few months. The tumorigenic processes of this disease have not yet been completely unraveled. Here, we report an mRNA expression and DNA methylation analysis of fourteen primary ATCs. ATCs clustered separately from normal thyroid tissue in unsupervised analyses, both by RNA expression and by DNA methylation. In expression analysis, enrichment of cell-cycle-related genes as well as downregulation of genes related to thyroid function were seen. Furthermore, ATC displayed a global hypomethylation of the genome but with hypermethylation of CpG islands. Notably, several cancer-related genes displayed a correlation between RNA expression and DNA methylation status, including MTOR, NOTCH1, and MAGI1. Furthermore, TSHR and SLC26A7, encoding the thyroid-stimulating hormone receptor and an iodine receptor highly expressed in normal thyroid, respectively, displayed low expression as well as aberrant gene body DNA methylation. This study is the largest investigation of global DNA methylation in ATC to date. It shows that aberrant DNA methylation is common in ATC and likely contributes to tumorigenesis in this disease. Future explorations of novel treatments should take this into consideration. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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10 pages, 761 KiB

Open AccessArticle

Preoperative Serum Thyroglobulin and Its Correlation with the Burden and Extent of Differentiated Thyroid Cancer

by Hosu Kim, So Young Park, Jun-Ho Choe, Jee Soo Kim, Soo Yeon Hahn, Sun Wook Kim, Jae Hoon Chung, Jaehoon Jung and Tae Hyuk Kim

Cancers 2020, 12(3), 625; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030625 - 08 Mar 2020

Cited by 26 | Viewed by 6209

Abstract

Lymph node metastasis (LNM) in differentiated thyroid cancer (DTC) is usually detected with preoperative ultrasonography; however, this has limited sensitivity for small metastases, and there is currently no predictive biomarker that can help to inform the extent of surgery required. We evaluated whether [...] Read more.

Lymph node metastasis (LNM) in differentiated thyroid cancer (DTC) is usually detected with preoperative ultrasonography; however, this has limited sensitivity for small metastases, and there is currently no predictive biomarker that can help to inform the extent of surgery required. We evaluated whether preoperative serum thyroglobulin levels can predict tumor burden and extent. We retrospectively reviewed the clinical records of 4029 DTC cases diagnosed and treated at a Samsung Medical Center between 1994 and 2016. We reviewed primary tumor size, number and location of LNM, and presence of distant metastases to reveal relationships between tumor burden and extent and preoperative serum thyroglobulin levels. We found a linear association between increasing preoperative thyroglobulin levels, the size of the primary tumor, and the number of LNM (r = 0.34, p < 0.001, r = 0.20, p < 0.001, respectively). Tumor extent also increased with each decile of increasing preoperative thyroglobulin level (r = 0.18, p < 0.001). Preoperative thyroglobulin levels of 13.15 ng/mL, 30.05 ng/mL, and 62.9 ng/mL were associated with the presence of ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis, respectively. Our results suggest that preoperative measurement of serum thyroglobulin may help to predict LNM and help to tailor surgery. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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13 pages, 2983 KiB

Open AccessArticle

VE1 Immunohistochemistry Improves the Limit of Genotyping for Detecting BRAF^V600E Mutation in Papillary Thyroid Cancer

by Sonam Choden, Somboon Keelawat, Chan Kwon Jung and Andrey Bychkov

Cancers 2020, 12(3), 596; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030596 - 05 Mar 2020

Cited by 20 | Viewed by 4173

Abstract

Detection of BRAF^V600E is useful for making diagnosis and risk stratification of papillary thyroid carcinoma (PTC). Molecular testing, however, is not always available for routine clinical use. To assess the clinical utility and reliability of VE1 immunohistochemistry (IHC) for detecting BRAF^V600E [...] Read more.

Detection of BRAF^V600E is useful for making diagnosis and risk stratification of papillary thyroid carcinoma (PTC). Molecular testing, however, is not always available for routine clinical use. To assess the clinical utility and reliability of VE1 immunohistochemistry (IHC) for detecting BRAF^V600E mutation in PTC, VE1 IHC was performed on the tissue microarrays of 514 patients with PTC and was compared with Sanger sequencing results. Of 514 PTC cases, 433 (84.2%) were positive for VE1 expression. Among 6 discordant cases between VE1 IHC and Sanger sequencing, 3 initial VE1-false negative cases turned out to be true false negative on repeat testing, and 3 VE1-false positive cases showed BRAF^V600E mutation using digital PCR analysis. PTCs with low variant allele fraction were positive for VE1 IHC but were not detected using sequencing. VE1 IHC showed 99.3% sensitivity, 100% specificity, 100% positive predictive value, and 96.4% negative predictive value. The BRAF^V600E mutation was significantly associated with older age, multifocality, extrathyroidal extension, lymph node metastasis, and advanced tumor stage. In conclusion, VE1 IHC is a reliable method for detecting BRAF^V600E mutation in PTC specimens. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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11 pages, 1150 KiB

Open AccessArticle

Optimization of Predictive Performance for the Therapeutic Response Using Iodine Scan-Corrected Serum Thyroglobulin in Patients with Differentiated Thyroid Carcinoma

by Su Woong Yoo, Md. Sunny Anam Chowdhury, Subin Jeon, Sae-Ryung Kang, Sang-Geon Cho, Jahae Kim, Changho Lee, Young Jae Ryu, Ho-Chun Song, Hee-Seung Bom, Jung-Joon Min and Seong Young Kwon

Cancers 2020, 12(2), 262; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020262 - 22 Jan 2020

Viewed by 2396

Abstract

We investigated whether the performance of serum thyroglobulin (Tg) for response prediction could be improved based on the iodine uptake pattern on the post-therapeutic I-131 whole body scan (RxWBS) and the degree of thyroid tissue damage with radioactive iodine (RAI) therapy. A total [...] Read more.

We investigated whether the performance of serum thyroglobulin (Tg) for response prediction could be improved based on the iodine uptake pattern on the post-therapeutic I-131 whole body scan (RxWBS) and the degree of thyroid tissue damage with radioactive iodine (RAI) therapy. A total of 319 patients with differentiated thyroid carcinoma who underwent total thyroidectomy and RAI therapy were included. Based on the presence/absence of focal uptake at the anterior midline of the neck above the thyroidectomy bed on RxWBS, patients were classified into positive and negative uptake groups. Serum Tg was measured immediately before (D0Tg) and 7 days after RAI therapy (D7Tg). Patients were further categorized into favorable and unfavorable Tg groups based on the prediction of excellent response (ER) using scan-corrected Tg developed through the stepwise combination of D0Tg with ratio Tg (D7Tg/D0Tg). We investigated whether the predictive performance for ER improved with the application of scan-corrected Tg compared to the single Tg cutoff. The combined approach using scan-corrected Tg showed better predictive performance for ER than the single cutoff of D0Tg alone (p < 0.001). Therefore, scan-corrected Tg can be a promising biomarker to predict the therapeutic responses after RAI therapy. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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Review

Jump to: Research

31 pages, 3508 KiB

Open AccessFeature PaperReview

Emerging Biomarkers in Thyroid Practice and Research

by Shipra Agarwal, Andrey Bychkov and Chan-Kwon Jung

Cancers 2022, 14(1), 204; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010204 - 31 Dec 2021

Cited by 30 | Viewed by 8476

Abstract

Thyroid cancer is the most common endocrine malignancy. Recent developments in molecular biological techniques have led to a better understanding of the pathogenesis and clinical behavior of thyroid neoplasms. This has culminated in the updating of thyroid tumor classification, including the re-categorization of [...] Read more.

Thyroid cancer is the most common endocrine malignancy. Recent developments in molecular biological techniques have led to a better understanding of the pathogenesis and clinical behavior of thyroid neoplasms. This has culminated in the updating of thyroid tumor classification, including the re-categorization of existing and introduction of new entities. In this review, we discuss various molecular biomarkers possessing diagnostic, prognostic, predictive and therapeutic roles in thyroid cancer. A comprehensive account of epigenetic dysregulation, including DNA methylation, the function of various microRNAs and long non-coding RNAs, germline mutations determining familial occurrence of medullary and non-medullary thyroid carcinoma, and single nucleotide polymorphisms predisposed to thyroid tumorigenesis has been provided. In addition to novel immunohistochemical markers, including those for neuroendocrine differentiation, and next-generation immunohistochemistry (BRAF V600E, RAS, TRK, and ALK), the relevance of well-established markers, such as Ki-67, in current clinical practice has also been discussed. A tumor microenvironment (PD-L1, CD markers) and its influence in predicting responses to immunotherapy in thyroid cancer and the expanding arena of techniques, including liquid biopsy based on circulating nucleic acids and plasma-derived exosomes as a non-invasive technique for patient management, are also summarized. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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16 pages, 281 KiB

Open AccessReview

Advances in Biomarker-Driven Targeted Therapies in Thyroid Cancer

by Prachi Mishra, Dipranjan Laha, Robert Grant and Naris Nilubol

Cancers 2021, 13(24), 6194; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246194 - 09 Dec 2021

Cited by 6 | Viewed by 1927

Abstract

Thyroid cancer is the most common type of endocrine malignancy comprising 2–3% of all cancers, with a constant rise in the incidence rate. The standard first-line treatments for thyroid cancer include surgery and radioactive iodine ablation, and a majority of patients show a [...] Read more.

Thyroid cancer is the most common type of endocrine malignancy comprising 2–3% of all cancers, with a constant rise in the incidence rate. The standard first-line treatments for thyroid cancer include surgery and radioactive iodine ablation, and a majority of patients show a good response to these therapies. Despite a better response and outcome, approximately twenty percent of patients develop disease recurrence and distant metastasis. With improved knowledge of molecular dysregulation and biological characteristics of thyroid cancer, the development of new treatment strategies comprising novel targets has accelerated. Biomarker-driven targeted therapies have now emerged as a trend for personalized treatments in patients with advanced cancers, and several multiple receptor kinase inhibitors have entered clinical trials (phase I/II/III) to evaluate their safety and efficacy. Most extensively investigated and clinically approved targeted therapies in thyroid cancer include the tyrosine receptor kinase inhibitors that target antiangiogenic markers, BRAF mutation, PI3K/AKT, and MAPK pathway components. In this review, we focus on the current advances in targeted mono- and combination therapies for various types of thyroid cancer. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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