Cancers

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Open AccessEditorial

What Is New in Thyroid Cancer: The Special Issue of the Journal Cancers

by Efisio Puxeddu, Giovanni Tallini and Roberta Vanni

Cancers 2020, 12(10), 3036; https://doi.org/10.3390/cancers12103036 - 19 Oct 2020

Cited by 5 | Viewed by 2615

Abstract

The incidence of thyroid cancer has increased over the past 3 to 4 decades. Nonetheless, the mortality from thyroid cancer has remained stable. The thyroid gland may develop nodules encompassing several types of cell proliferation, from frankly benign to very aggressive forms with [...] Read more.

The incidence of thyroid cancer has increased over the past 3 to 4 decades. Nonetheless, the mortality from thyroid cancer has remained stable. The thyroid gland may develop nodules encompassing several types of cell proliferation, from frankly benign to very aggressive forms with many intermediate challenging variants. For this reason, there is growing interest in evaluating thyroid nodules from many points of view, from the clinical to the molecular aspects, in the search for innovative diagnostic and prognostic parameters. The aim of this Special Issue was to provide an overview of recent developments in understanding the biology and molecular oncology of thyroid tumors of follicular cell derivation and their repercussions on the diagnosis, prognosis, and therapy. The contributions of many experts in the field made up a Special Issue of Cancers journal, that focusing on different aspects, including mechanistic and functional facets, gives the status of art of clinical and biological perspectives of thyroid cancer. Full article

(This article belongs to the Special Issue Thyroid Cancer)

Research

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15 pages, 1728 KiB

Open AccessArticle

BRAF Exon 15 Mutations in Papillary Carcinoma and Adjacent Thyroid Parenchyma: A Search for the Early Molecular Events Associated with Tumor Development

by Giorgia Acquaviva, Dario de Biase, Chiara Diquigiovanni, Chiara Maria Argento, Antonio De Leo, Elena Bonora, Kerry Jane Rhoden, Annalisa Pession and Giovanni Tallini

Cancers 2020, 12(2), 430; https://doi.org/10.3390/cancers12020430 - 12 Feb 2020

Cited by 11 | Viewed by 4518

Abstract

BRAF exon 15 mutations are the most common molecular alterations found in papillary thyroid carcinoma (PTC). To date, there is no information regarding BRAF alterations in the thyroid parenchyma surrounding the tumor. To explore the early events associated with the development of PTC, [...] Read more.

BRAF exon 15 mutations are the most common molecular alterations found in papillary thyroid carcinoma (PTC). To date, there is no information regarding BRAF alterations in the thyroid parenchyma surrounding the tumor. To explore the early events associated with the development of PTC, we used massively parallel sequencing to investigate BRAF exon 15 in 30 PTCs and in 100 samples from the thyroid parenchyma surrounding the tumor. BRAF p.V600E was identified in 19/30 PTCs (63.3%). BRAF p.V600E mutations were identified in the tissue adjacent the PTC only in samples containing psammoma bodies. The other samples were either BRAF wild type (WT) or carried BRAF non p.V600E mutations. Specifically, BRAF p.G593D, -p.A598T, -p.V600M, -p.R603Q, -p.S607F, and -p.S607P were identified in 4 of 36 (11.1%) samples with follicular cell atypia, in 2 of 16 (12.5%) with follicular cell hyperplasia, and in 1 of 33 (3.0%) histologically normal samples—Only in tissue surrounding BRAF p.V600E mutated PTCs. These mutations are predicted to affect protein function in silico but, in vitro, have kinase activity and BRAF phosphorylation levels similar to BRAF WT. No BRAF exon 15 mutations were identified in samples adjacent to PTCs that were BRAF WT. A mutagenic process affecting BRAF exon 15 occurs in a subset of thyroid glands that develop BRAF p.V600E mutated PTCs. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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18 pages, 4749 KiB

Open AccessArticle

Does the Site of Origin of the Microcarcinoma with Respect to the Thyroid Surface Matter? A Multicenter Pathologic and Clinical Study for Risk Stratification

by Giovanni Tallini, Antonio De Leo, Andrea Repaci, Dario de Biase, Maria Letizia Bacchi Reggiani, Doriana Di Nanni, Francesca Ambrosi, Cira Di Gioia, Giorgio Grani, Kerry Jane Rhoden, Erica Solaroli, Fabio Monari, Sebastiano Filetti and Cosimo Durante

Cancers 2020, 12(1), 246; https://doi.org/10.3390/cancers12010246 - 19 Jan 2020

Cited by 17 | Viewed by 3366

Abstract

It is unclear whether the site of origin of papillary thyroid microcarcinoma (mPTC) with respect to the thyroid surface has an influence on clinicopathologic parameters. The objectives of the study were to: (i) Accurately measure the mPTC distance from the thyroid surface; (ii) [...] Read more.

It is unclear whether the site of origin of papillary thyroid microcarcinoma (mPTC) with respect to the thyroid surface has an influence on clinicopathologic parameters. The objectives of the study were to: (i) Accurately measure the mPTC distance from the thyroid surface; (ii) analyze whether this distance correlates with relevant clinicopathologic parameters; and (iii) investigate the impact of the site of origin of the mPTC on risk stratification. Clinicopathologic features and BRAF mutational status were analyzed and correlated with the site of origin of the mPTC in a multicenter cohort of 298 mPTCs from six Italian medical institutions. Tumors arise at a median distance of 3.5 mm below the surface of the thyroid gland. Statistical analysis identified four distinct clusters. Group A, mPTC: size ≥ 5 mm and distance of the edge of the tumor from the thyroid capsule = 0 mm; group B, mPTC: size ≥ 5 mm and distance of the edge of the tumor from the thyroid capsule > 0 mm; group C, mPTC: size < 5 mm and distance of the edge of the tumor from the thyroid capsule = 0 mm; and group D, mPTC: size < 5 mm and distance of the edge of the tumor from the thyroid capsule > 0 mm. Univariate analysis demonstrates significant differences between the groups: Group A shows the most aggressive features, and group D the most indolent ones. By multivariate analysis, group A tumors are characterized by tall cell histotype, BRAF V600E mutation, tumor fibrosis, aggressive growth with invasive features, vascular invasion, lymph node metastases, and intermediate ATA risk. The mPTC clinicopathologic features vary according to the tumor size and distance from the thyroid surface. A four-group model may be useful for risk stratification and to refine the selection of nodules to be targeted for fine needle aspiration. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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18 pages, 4226 KiB

Open AccessArticle

The Long Non-Coding RNA Prader Willi/Angelman Region RNA5 (PAR5) Is Downregulated in Anaplastic Thyroid Carcinomas Where It Acts as a Tumor Suppressor by Reducing EZH2 Activity

by Simona Pellecchia, Romina Sepe, Myriam Decaussin-Petrucci, Cristina Ivan, Masayoshi Shimizu, Carmela Coppola, Domenico Testa, George Adrian Calin, Alfredo Fusco and Pierlorenzo Pallante

Cancers 2020, 12(1), 235; https://doi.org/10.3390/cancers12010235 - 17 Jan 2020

Cited by 37 | Viewed by 4041

Abstract

Anaplastic thyroid carcinoma (ATC) represents one the most aggressive neoplasias in humans, and, nowadays, limited advances have been made to extend the survival and reduce the mortality of ATC. Thus, the identification of molecular mechanism underlying its progression is needed. Here, we evaluated [...] Read more.

Anaplastic thyroid carcinoma (ATC) represents one the most aggressive neoplasias in humans, and, nowadays, limited advances have been made to extend the survival and reduce the mortality of ATC. Thus, the identification of molecular mechanism underlying its progression is needed. Here, we evaluated the long non-coding RNA (lncRNA) expression profile of nine ATC in comparison with five normal thyroid tissues by a lncRNA microarray. By this analysis, we identified 19 upregulated and 28 downregulated lncRNAs with a fold change >1.1 or <−1.1 and p-value < 0.05, in ATC samples. Some of them were subsequently validated by qRT-PCR. Then, we investigated the role of the lncRNA Prader Willi/Angelman region RNA5 (PAR5), drastically and specifically downregulated in ATC. The restoration of PAR5 reduces proliferation and migration rates of ATC-derived cell lines indicating that its downregulation contributes to thyroid cancer progression. Our results suggest that PAR5 exerts its anti-oncogenic role by impairing Enhancer of Zeste Homolog 2 (EZH2) oncogenic activity since we demonstrated that PAR5 interacts with it in thyroid cancer cell lines, reducing EZH2 protein levels and its binding on the E-cadherin promoter, relieving E-cadherin from the negative regulation by EZH2. Consistently, EZH2 is overexpressed in ATC, but not in differentiated thyroid carcinomas. The results reported here define a tumor suppressor role for PAR5 in undifferentiated thyroid neoplasias, further highlighting the pivotal role of lncRNAs in thyroid carcinogenesis. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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20 pages, 11909 KiB

Open AccessArticle

The Aryl Hydrocarbon Receptor Is Expressed in Thyroid Carcinoma and Appears to Mediate Epithelial-Mesenchymal-Transition

by Sonia Moretti, Nicole Nucci, Elisa Menicali, Silvia Morelli, Vittorio Bini, Renato Colella, Martina Mandarano, Angelo Sidoni and Efisio Puxeddu

Cancers 2020, 12(1), 145; https://doi.org/10.3390/cancers12010145 - 7 Jan 2020

Cited by 33 | Viewed by 4568

Abstract

Aryl hydrocarbon receptor (AhR) is expected to promote initiation, progression and invasion of cancer cells regulating proliferation, differentiation, gene expression, inflammation, cell motility and migration. Furthermore, an immunosuppressant function of AhR has been recognized. This study evaluated AhR expression and its role in [...] Read more.

Aryl hydrocarbon receptor (AhR) is expected to promote initiation, progression and invasion of cancer cells regulating proliferation, differentiation, gene expression, inflammation, cell motility and migration. Furthermore, an immunosuppressant function of AhR has been recognized. This study evaluated AhR expression and its role in thyroid cancer progression. AhR expression was assessed by qPCR in 107 thyroid cancer samples (90 PTCs, 11 MTCs, 6 ATCs), and by immunohistochemistry in 41 PTCs. To estimate receptor activation, the expression of target genes CYP1A1 and CYP1B1 was measured. AhR functional effects were evaluated in kynurenine-stimulated FTC-133 and BcPap cell lines by analyzing the expression of genes involved in EMT and cell motility. AhR mRNA expression resulted significantly higher in all the analyzed thyroid cancer samples compared to normal thyroid and a statistically significant correlation with CYP1B1 was detected. Kynurenine-stimulated FTC-133 and BcPap showed the activation of a specific AhR-driven EMT program characterized by E-cadherin decrease and SLUG, N-cadherin and fibronectin increase, resulting in boost of cell motility and invasion. This study confirmed the importance of the IDO1-Kyn-AhR pathway in thyroid cancer tumorigenesis, suggesting an AhR pivotal role in mediating an immunosuppressive microenvironment and favoring the acquisition of a mesenchymal phenotype that could promote invasiveness and metastasis. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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17 pages, 5185 KiB

Open AccessArticle

Cancer Associated Fibroblasts and Senescent Thyroid Cells in the Invasive Front of Thyroid Carcinoma

by Emanuela Minna, Silvia Brich, Katia Todoerti, Silvana Pilotti, Paola Collini, Elisa Bonaldi, Paola Romeo, Loris De Cecco, Matteo Dugo, Federica Perrone, Adele Busico, Andrea Vingiani, Ilaria Bersani, Andrea Anichini, Roberta Mortarini, Antonino Neri, Giancarlo Pruneri, Angela Greco and Maria Grazia Borrello

Cancers 2020, 12(1), 112; https://doi.org/10.3390/cancers12010112 - 1 Jan 2020

Cited by 34 | Viewed by 4432

Abstract

Thyroid carcinoma (TC) comprises several histotypes with different aggressiveness, from well (papillary carcinoma, PTC) to less differentiated forms (poorly differentiated and anaplastic thyroid carcinoma, PDTC and ATC, respectively). Previous reports have suggested a functional role for cancer-associated fibroblasts (CAFs) or senescent TC cells [...] Read more.

Thyroid carcinoma (TC) comprises several histotypes with different aggressiveness, from well (papillary carcinoma, PTC) to less differentiated forms (poorly differentiated and anaplastic thyroid carcinoma, PDTC and ATC, respectively). Previous reports have suggested a functional role for cancer-associated fibroblasts (CAFs) or senescent TC cells in the progression of PTC. In this study, we investigated the presence of CAFs and senescent cells in proprietary human TCs including PTC, PDTC, and ATC. Screening for the driving lesions BRAFV600E and N/H/KRAS mutations, and gene fusions was also performed to correlate results with tumor genotype. In samples with unidentified drivers, transcriptomic profiles were used to establish a BRAF- or RAS-like molecular subtype based on a gene signature derived from The Cancer Genome Atlas. By using immunohistochemistry, we found co-occurrence of stromal CAFs and senescent TC cells at the tumor invasive front, where deposition of collagen (COL1A1) and expression of lysyl oxidase (LOX) enzyme were also detected, in association with features of local invasion. Concurrent high expression of CAFs and of the senescent TC cells markers, COL1A1 and LOX was confirmed in different TC histotypes in proprietary and public gene sets derived from Gene Expression Omnibus (GEO) repository, and especially in BRAF mutated or BRAF-like tumors. In this study, we show that CAFs and senescent TC cells co-occur in various histotypes of BRAF-driven thyroid tumors and localize at the tumor invasive front. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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14 pages, 1002 KiB

Open AccessArticle

Microfluidic Droplet Digital PCR Is a Powerful Tool for Detection of BRAF and TERT Mutations in Papillary Thyroid Carcinomas

by Dorina Ylli, Aneeta Patel, Kirk Jensen, Zhao-Zhang Li, Maria Cecilia Mendonca-Torres, John Costello, Cristiane Jeyce Gomes-Lima, Leonard Wartofsky, Kenneth Dale Burman and Vasyl V. Vasko

Cancers 2019, 11(12), 1916; https://doi.org/10.3390/cancers11121916 - 2 Dec 2019

Cited by 18 | Viewed by 3920

Abstract

We examined the utility of microfluidic digital PCR (dPCR) for detection of BRAF and TERT mutations in thyroid tumors. DNA extracted from 100 thyroid tumors (10 follicular adenomas, 10 follicular cancers, 5 medullary cancers, and 75 papillary thyroid cancer (PTC) were used for [...] Read more.

We examined the utility of microfluidic digital PCR (dPCR) for detection of BRAF and TERT mutations in thyroid tumors. DNA extracted from 100 thyroid tumors (10 follicular adenomas, 10 follicular cancers, 5 medullary cancers, and 75 papillary thyroid cancer (PTC) were used for detection of BRAF and TERT mutations. Digital PCRs were performed using rare mutation SNP genotyping assays on QuantStudio 3D platform. In PTCs, BRAFV600E was detected by dPCR and Sanger sequencing in 42/75 (56%) and in 37/75 (49%), respectively. BRAFV600E was not detected in other tumors. The ratio of mutant/total BRAF alleles varied from 4.7% to 47.5%. These ratios were higher in classical PTCs (27.1%) as compared to follicular variant PTCs (9.4%) p = 0.001. In PTCs with and without metastases, the ratios of mutant/total BRAF alleles were 27.6% and 18.4%, respectively, (p = 0.03). In metastatic lesions percentages of mutant/total BRAF alleles were similar to those detected in primary tumors. TERTC228T and TERTC250T were found in two and one cases, respectively, and these tumors concomitantly harbored BRAFV600E. These tumors exhibited gross extra-thyroidal extension, metastases to lymph nodes, and pulmonary metastases (one case). Our results showed that dPCR allows quantitative assessment of druggable targets in PTCs and could be helpful in a molecular-based stratification of prognosis in patients with thyroid cancer. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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18 pages, 295 KiB

Open AccessArticle

Coexisting Germline CHEK2 and Somatic BRAF^V600E Mutations in Papillary Thyroid Cancer and Their Association with Clinicopathological Features and Disease Course

by Danuta Gąsior-Perczak, Artur Kowalik, Agnieszka Walczyk, Monika Siołek, Krzysztof Gruszczyński, Iwona Pałyga, Estera Mikina, Tomasz Trybek, Janusz Kopczyński, Ryszard Mężyk, Stanisław Góźdź and Aldona Kowalska

Cancers 2019, 11(11), 1744; https://doi.org/10.3390/cancers11111744 - 7 Nov 2019

Cited by 15 | Viewed by 3078

Abstract

BRAF^V600E is the most common somatic mutation in papillary thyroid carcinoma (PTC) and the majority of evidence indicates that it is associated with an aggressive clinical course. Germline mutations of the CHEK2 gene impair the DNA damage repair process and increase the [...] Read more.

BRAF^V600E is the most common somatic mutation in papillary thyroid carcinoma (PTC) and the majority of evidence indicates that it is associated with an aggressive clinical course. Germline mutations of the CHEK2 gene impair the DNA damage repair process and increase the risk of PTC. Coexistence of both mutations is expected to be associated with poorer clinical course. We evaluated the prevalence of concomitant CHEK2 and BRAF^V600E mutations and their associations with clinicopathological features, treatment response, and disease course in PTC patients. The study included 427 unselected PTC patients (377 women and 50 men) from one center. Relationships among clinicopathological features, mutation status, treatment response, and disease outcomes were assessed. Mean follow-up was 10 years. CHEK2 mutations were detected in 15.2% and BRAF^V600E mutations in 64.2% patients. Neither mutation was present in 31.4% cases and both BRAF^V600E and CHEK2 mutations coexisted in 10.8% patients. No significant differences in clinicopathological features, initial risk, treatment response, or disease outcome were detected among these patient groups. CHEK2 mutations were significantly associated with older age, while BRAF^V600E was significantly associated with older age and extrathyroidal extension. The coexistence of both mutations was not associated with more aggressive clinicopathological features of PTC, poorer treatment response, or disease outcome. Full article

(This article belongs to the Special Issue Thyroid Cancer)

12 pages, 1457 KiB

Open AccessArticle

Epidemiology of Simultaneous Medullary and Papillary Thyroid Carcinomas (MTC/PTC): An Italian Multicenter Study

by Marialuisa Appetecchia, Rosa Lauretta, Agnese Barnabei, Letizia Pieruzzi, Irene Terrenato, Elisabetta Cavedon, Caterina Mian, Maria Grazia Castagna and Rossella Elisei

Cancers 2019, 11(10), 1516; https://doi.org/10.3390/cancers11101516 - 9 Oct 2019

Cited by 24 | Viewed by 3467

Abstract

Background: The concomitant presence of papillary thyroid cancer (PTC) and medullary TC (MTC) is rare. In this multicentric study, we documented the epidemiological characteristics, disease conditions and clinical outcome of patients with simultaneous MTC/PTC. Methods: We collected data of patients with concomitant [...] Read more.

Background: The concomitant presence of papillary thyroid cancer (PTC) and medullary TC (MTC) is rare. In this multicentric study, we documented the epidemiological characteristics, disease conditions and clinical outcome of patients with simultaneous MTC/PTC. Methods: We collected data of patients with concomitant MTC/PTC at 14 Italian referral centers. Results: In total, 183 patients were enrolled. Diagnosis was mostly based on cytological examination (n = 58, 32%). At diagnosis, in the majority of cases, both PTC (n = 142, 78%) and MTC (n = 100, 54%) were at stage I. However, more cases of stage II–IV were reported with MTC (stage IV: n = 27, 15%) compared with PTC (n = 9, 5%). Information on survival was available for 165 patients: 109 patients (66%) were disease-free for both PTC and MTC at the last follow-up. Six patients died from MTC. Median time to progression was 123 months (95% confidence interval (CI): 89.3–156.7 months). Overall, 45% of patients were disease-free after >10 years from diagnosis (125 months); this figure was 72.5% for PTC and 51.1% for MTC. Conclusions: When MTC and PTC are concurrent, the priority should be given to the management of MTC since this entity appears associated with the most severe impact on prognosis. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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16 pages, 678 KiB

Open AccessArticle

Thyroid Cancer after Exposure to Radioiodine in Childhood and Adolescence: ¹³¹I-Related Risk and the Role of Selected Host and Environmental Factors

by Ljubica Zupunski, Evgenia Ostroumova, Vladimir Drozdovitch, Ilya Veyalkin, Viktor Ivanov, Shunichi Yamashita, Elisabeth Cardis and Ausrele Kesminiene

Cancers 2019, 11(10), 1481; https://doi.org/10.3390/cancers11101481 - 2 Oct 2019

Cited by 14 | Viewed by 5087

Abstract

In this study, we expanded on a previously published population-based case-control study on subjects exposed to iodine-131 (¹³¹I) from Chernobyl fallout at age ≤18 years using improved individual ¹³¹I absorbed thyroid doses. We further studied the impact of iodine deficiency [...] Read more.

In this study, we expanded on a previously published population-based case-control study on subjects exposed to iodine-131 (¹³¹I) from Chernobyl fallout at age ≤18 years using improved individual ¹³¹I absorbed thyroid doses. We further studied the impact of iodine deficiency and other selected host risk factors on ¹³¹I-related thyroid cancer risk after childhood exposure. We included 298 thyroid cancer cases and 1934 matched controls from the most contaminated regions of Belarus and the Russian Federation. We performed statistical analysis using conditional logistic regression models. We found a statistically significant linear quadratic dose-effect association between thyroid cancer and ¹³¹I thyroid dose in the range up to 5 grays (Gy). Self-reported personal history of benign nodules, any thyroid disease except thyroid cancer, family history of thyroid cancer, increased body mass index, and deficient stable iodine status at the time of the accident were statistically significant risk factors (p < 0.05 for each factor) for thyroid cancer after adjustment for thyroid ¹³¹I dose effect. Subjects who received stable iodine supplementation in the years after the accident had a significantly lower ¹³¹I-related risk of thyroid cancer. Our findings are important for thyroid cancer prevention, and for further improvement of medical surveillance in the affected populations. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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11 pages, 1576 KiB

Open AccessArticle

MALDI-MSI as a Complementary Diagnostic Tool in Cytopathology: A Pilot Study for the Characterization of Thyroid Nodules

by Giulia Capitoli, Isabella Piga, Stefania Galimberti, Davide Leni, Angela Ida Pincelli, Mattia Garancini, Francesca Clerici, Allia Mahajneh, Virginia Brambilla, Andrew Smith, Fulvio Magni and Fabio Pagni

Cancers 2019, 11(9), 1377; https://doi.org/10.3390/cancers11091377 - 16 Sep 2019

Cited by 26 | Viewed by 4967

Abstract

The present study applies for the first time as Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) on real thyroid Fine Needle Aspirations (FNAs) to test its possible complementary role in routine cytology in the diagnosis of thyroid nodules. The primary aim is [...] Read more.

The present study applies for the first time as Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) on real thyroid Fine Needle Aspirations (FNAs) to test its possible complementary role in routine cytology in the diagnosis of thyroid nodules. The primary aim is to evaluate the potential employment of MALDI-MSI in cytopathology, using challenging samples such as needle washes. Firstly, we designed a statistical model based on the analysis of Regions of Interest (ROIs), according to the morphological triage performed by the pathologist. Successively, the capability of the model to predict the classification of the FNAs was validated in a different group of patients on ROI and pixel-by-pixel approach. Results are very promising and highlight the possibility to introduce MALDI-MSI as a complementary tool for the diagnostic characterization of thyroid nodules. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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13 pages, 464 KiB

Open AccessArticle

Predictive Factors of Recurrence in Patients with Differentiated Thyroid Carcinoma: A Retrospective Analysis on 579 Patients

by Fabio Medas, Gian Luigi Canu, Francesco Boi, Maria Letizia Lai, Enrico Erdas and Pietro Giorgio Calò

Cancers 2019, 11(9), 1230; https://doi.org/10.3390/cancers11091230 - 22 Aug 2019

Cited by 36 | Viewed by 5301

Abstract

Differentiated thyroid carcinoma (DTC) is usually associated with a favorable prognosis. Nevertheless, up to 30% of patients present a local or distant recurrence. The aim of this study was to assess the incidence of recurrence after surgery for DTC and to identify predictive [...] Read more.

Differentiated thyroid carcinoma (DTC) is usually associated with a favorable prognosis. Nevertheless, up to 30% of patients present a local or distant recurrence. The aim of this study was to assess the incidence of recurrence after surgery for DTC and to identify predictive factors of recurrence. We included in this retrospective study 579 consecutive patients who underwent thyroidectomy for DTC from 2011 to 2016 at our institution. We observed biochemical or structural recurrent disease in 36 (6.2%) patients; five-year disease-free survival was 94.1%. On univariate analysis, male sex, histotype, lymph node yield, lymph node metastasis, extrathyroidal invasion and multicentricity were associated with significantly higher risk of recurrence, while microcarcinoma was correlated with significantly lower risk of recurrence. On multivariate analysis, only lymph node metastases (OR 4.724, p = 0.012) and microcarcinoma (OR 0.328, p = 0.034) were detected as independent predictive factors of recurrence. Postoperative management should be individualized and commensurate with the risk of recurrence: Patients with high-risk carcinoma should undergo strict follow-up and aggressive treatment. Furthermore, assessment of the risk should be repeated over time, considering individual response to therapy. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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13 pages, 1103 KiB

Open AccessArticle

Anaplastic Thyroid Cancer: Clinical Picture of the Last Two Decades at a Single Oncology Referral Centre and Novel Therapeutic Options

by Joana Simões-Pereira, Ricardo Capitão, Edward Limbert and Valeriano Leite

Cancers 2019, 11(8), 1188; https://doi.org/10.3390/cancers11081188 - 15 Aug 2019

Cited by 21 | Viewed by 4189

Abstract

Anaplastic thyroid cancer (ATC) is a rare tumour but also one of the most lethal malignancies. Therapeutic modalities have usually been limited, but clinical trials with new drugs are now being implemented. The aims of this study were to analyse the clinical presentation, [...] Read more.

Anaplastic thyroid cancer (ATC) is a rare tumour but also one of the most lethal malignancies. Therapeutic modalities have usually been limited, but clinical trials with new drugs are now being implemented. The aims of this study were to analyse the clinical presentation, therapeutic modalities and independent prognostic factors for survival. We also reviewed the most recent literature on novel ATC therapies. We performed a retrospective analysis of 79 patients diagnosed between 2000 and 2018. Variables with impact on survival were identified using the Cox proportional-hazard regression model. At presentation, 6.3% had thyroid-confined disease, 30.4% evidenced extrathyroidal extension and 60.8% were already metastatic. Surgery was feasible in 41.8% and radiotherapy was applied to 35.4%, with those receiving >45 Gy having longer estimated survival (p = 0.020). Chemotherapy, either conventional or with tyrosine kinase inhibitors, was performed in 17.7% and 7.6%, respectively. Multimodality therapy with surgery, radiotherapy and chemotherapy/tyrosine kinase inhibitors (TKI) had the greatest impact on disease specific survival (DSS), providing a risk reduction of death of 96.9% (hazard ratio (HR) = 0.031, 0.005–0.210, p < 0.001). We concluded that most of these patients join reference centres at advanced stages of disease and multimodality treatment may offer the best chances for prolonging survival. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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18 pages, 5111 KiB

Open AccessArticle

Papillary Thyroid Carcinoma Variants are Characterized by Co-dysregulation of Immune and Cancer Associated Genes

by Jaideep Chakladar, Wei Tse Li, Michael Bouvet, Eric Y. Chang, Jessica Wang-Rodriguez and Weg M. Ongkeko

Cancers 2019, 11(8), 1179; https://doi.org/10.3390/cancers11081179 - 15 Aug 2019

Cited by 14 | Viewed by 4803

Abstract

Papillary thyroid carcinoma (PTC) variants exhibit different prognosis, but critical characteristics of PTC variants that contribute to differences in pathogenesis are not well-known. This study aims to characterize dysregulated immune-associated and cancer-associated genes in three PTC subtypes to explore how the interplay between [...] Read more.

Papillary thyroid carcinoma (PTC) variants exhibit different prognosis, but critical characteristics of PTC variants that contribute to differences in pathogenesis are not well-known. This study aims to characterize dysregulated immune-associated and cancer-associated genes in three PTC subtypes to explore how the interplay between cancer and immune processes causes differential prognosis. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to identify dysregulated genes in each variant. The dysregulation profiles of the subtypes were compared using functional pathways clustering and correlations to relevant clinical variables, genomic alterations, and microRNA regulation. We discovered that the dysregulation profiles of classical PTC (CPTC) and the tall cell variant (TCPTC) are similar and are distinct from that of the follicular variant (FVPTC). However, unique cancer or immune-associated genes are associated with clinical variables for each subtype. Cancer-related genes MUC1, FN1, and S100-family members were the most clinically relevant in CPTC, while APLN and IL16, both immune-related, were clinically relevant in FVPTC. RAET-family members, also immune-related, were clinically relevant in TCPTC. Collectively, our data suggest that dysregulation of both cancer and immune associated genes defines the gene expression landscapes of PTC variants, but different cancer or immune related genes may drive the phenotype of each variant. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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18 pages, 2280 KiB

Open AccessArticle

MiRNAs Are Involved in Tall Cell Morphology in Papillary Thyroid Carcinoma

by Laura A. Boos, Anja Schmitt, Holger Moch, Paul Komminoth, Cedric Simillion, Ilaria Marinoni, Yuri E. Nikiforov, Marina N. Nikiforova, Aurel Perren and Matthias S. Dettmer

Cancers 2019, 11(6), 885; https://doi.org/10.3390/cancers11060885 - 25 Jun 2019

Cited by 10 | Viewed by 3884

Abstract

Five percent of papillary thyroid carcinomas (PTC) show an adverse clinical outcome (ACO). The tall cell variant of papillary thyroid carcinomas (TCV) is a good predictor of an ACO, however, the identification of tall-cells is subjective. Micro RNAs are short non-coding ribonucleic acids [...] Read more.

Five percent of papillary thyroid carcinomas (PTC) show an adverse clinical outcome (ACO). The tall cell variant of papillary thyroid carcinomas (TCV) is a good predictor of an ACO, however, the identification of tall-cells is subjective. Micro RNAs are short non-coding ribonucleic acids (miRNA). Their expression in PTC could be a powerful, more objective predictor of prognosis. Methods: Forty-four PTC underwent miRNA profiling, twenty-four of them were TCV. The miRNA dataset was validated by analysis of expression of known target proteins (vascular endothelial growth factor (VEGF) and phosphatase and tensin homolog (PTEN)) in 125 patients including 48 TCV and 57 with an ACO. Results: One hundred and forty-nine miRNAs were significantly associated with an ACO, seventy-one of them with TC-morphology. Twenty-two miRNAs were identified as targets for VEGF and thirty-two as targets for PTEN. In univariate and multivariable analysis, reduced expression of PTEN and an increased expression of VEGF were associated with shorter relapse free survival. A classifier, including TC-morphology, pT-stage, VEGF, and PTEN, predicted relapse with an 80% accuracy. Conclusions: Some miRNAs predict outcome in PTC and are involved in TC-morphology in PTC. These miRNAs may serve as more objective indicators of an ACO than tall cell morphology. PTEN and VEGF protein expression are prognostically relevant and are at least partially regulated by miRNAs. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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13 pages, 1652 KiB

Open AccessArticle

Atypical Histiocytoid Cells and Multinucleated Giant Cells in Fine-Needle Aspiration Cytology of the Thyroid Predict Lymph Node Metastasis of Papillary Thyroid Carcinoma

by Ji Eun Choi, Ja Seong Bae, Dong-Jun Lim, So Lyung Jung and Chan Kwon Jung

Cancers 2019, 11(6), 816; https://doi.org/10.3390/cancers11060816 - 12 Jun 2019

Cited by 11 | Viewed by 6115

Abstract

Preoperative detection of cervical lymph node metastasis in papillary thyroid carcinoma (PTC) is crucial for determining the surgical strategy to prevent locoregional recurrence of the disease. We identified the cytological predictors of lymph node metastasis in 222 consecutive patients with PTC using fine-needle [...] Read more.

Preoperative detection of cervical lymph node metastasis in papillary thyroid carcinoma (PTC) is crucial for determining the surgical strategy to prevent locoregional recurrence of the disease. We identified the cytological predictors of lymph node metastasis in 222 consecutive patients with PTC using fine-needle aspiration cytology (FNAC) of the thyroid. Cervical lymph node metastases occurred in 99 (44.6%) of 222 PTC patients. Lymph node metastasis was significantly associated with tumor multifocality (p = 0.003), and high cellularity (p = 0.021), atypical histiocytoid cells (p < 0.001), and multinucleated giant cells (p < 0.001) in thyroid FNAC. The BRAF V600E mutation was marginally associated with lymph node metastasis (p = 0.054). Multivariate analysis revealed that atypical histiocytoid cells (odds ratio = 2.717; p = 0.001) and multinucleated giant cells (odds ratio = 3.070; p = 0.031) were independent predictors of lymph node metastasis in patients with PTC. In a subgroup analysis of 164 patients with microcarcinomas, atypical histiocytoid cells (odds ratio = 2.761; p = 0.005) was an independent predictor of lymph node metastasis. Cytological detection of atypical histiocytoid cells and multinucleated giant cells on thyroid FNAC can be used to preoperatively predict cervical lymph node metastasis in patients with PTC. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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20 pages, 8661 KiB

Open AccessArticle

AXL Is a Novel Predictive Factor and Therapeutic Target for Radioactive Iodine Refractory Thyroid Cancer

by Francesca Collina, Lucia La Sala, Federica Liotti, Nella Prevete, Elvira La Mantia, Maria Grazia Chiofalo, Gabriella Aquino, Laura Arenare, Monica Cantile, Giuseppina Liguori, Francesca Di Gennaro, Luciano Pezzullo, Nunzia Simona Losito, Giancarlo Vecchio, Gerardo Botti, Rosa Marina Melillo and Renato Franco

Cancers 2019, 11(6), 785; https://doi.org/10.3390/cancers11060785 - 7 Jun 2019

Cited by 25 | Viewed by 4790

Abstract

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the [...] Read more.

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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13 pages, 832 KiB

Open AccessArticle

Identification of Targetable Lesions in Anaplastic Thyroid Cancer by Genome Profiling

by Naveen Ravi, Minjun Yang, Sigurdur Gretarsson, Caroline Jansson, Nektaria Mylona, Saskia R. Sydow, Eleanor L. Woodward, Lars Ekblad, Johan Wennerberg and Kajsa Paulsson

Cancers 2019, 11(3), 402; https://doi.org/10.3390/cancers11030402 - 22 Mar 2019

Cited by 33 | Viewed by 5397

Abstract

Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed whole exome sequencing and the RNA-sequencing of fourteen cases of ATC [...] Read more.

Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed whole exome sequencing and the RNA-sequencing of fourteen cases of ATC to delineate copy number changes, fusion gene events, and somatic mutations. A high frequency of genomic amplifications was seen, including 29% of cases having amplification of CCNE1 and 9% of CDK6; these events may be targetable by cyclin dependent kinase (CDK) inhibition. Furthermore, 9% harbored amplification of TWIST1, which is also a potentially targetable lesion. A total of 21 fusion genes in five cases were seen, none of which were recurrent. Frequent mutations included TP53 (55%), the TERT promoter (36%), and ATM (27%). Analyses of mutational signatures showed an involvement of processes that are associated with normal aging, defective DNA mismatch repair, activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity, failure of DNA double-strand break repair, and tobacco exposure. Taken together, our results shed new light on the tumorigenesis of ATC and show that a relatively large proportion (36%) of ATCs harbor genetic events that make them candidates for novel therapeutic approaches. When considering that ATC today has a mortality rate of close to 100%, this is highly relevant from a clinical perspective. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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13 pages, 233 KiB

Open AccessArticle

Long-Term Outcome after Hemithyroidectomy for Papillary Thyroid Cancer: A Comparative Study and Review of the Literature

by Yossi Geron, Carlos Benbassat, Miriam Shteinshneider, Shlomit Koren, Keren Or, Efrat Markus, Dania Hirsch and Limor Muallem Kalmovich

Cancers 2019, 11(1), 26; https://doi.org/10.3390/cancers11010026 - 27 Dec 2018

Cited by 17 | Viewed by 4379

Abstract

Background: The extent of surgery for differentiated thyroid cancer (DTC) remains a controversial issue. Since a less aggressive approach is becoming more predominant, we aim here to study the short- and long-term outcomes of DTC patients after hemithyroidectomy. Methods: From a total of [...] Read more.

Background: The extent of surgery for differentiated thyroid cancer (DTC) remains a controversial issue. Since a less aggressive approach is becoming more predominant, we aim here to study the short- and long-term outcomes of DTC patients after hemithyroidectomy. Methods: From a total of 1252 consecutive papillary thyroid cancer (PTC) patients, 109 treated with hemithyroidectomy and 50 with total thyroidectomy but no I¹³¹ were included. Persistent or recurrent disease was defined based on histopathology, imaging studies, and thyroglobulin levels. Results: Our hemithyroidectomy cohort included females (84.4%), microcarcinomas (81.9%), TNM stage I (95.4%), and a low American Thyroid Association (ATA) recurrence risk (94.5%). At one-year post-treatment, 3.7% had persistent disease (all female, median age 55 years, tumor size 7.5 mm). Recurrent disease was detected in 7.5% of those with excellent response at 1-year. With a follow-up of 8.6 years (1–48), all 109 patients were disease free at last visit, including the 11 patients (10.1%) who received additional treatment. Also, when comparing the hemi- and total thyroidectomy groups no significant differences were found in the rate of persistent and recurrent disease, overall mortality, and disease status at last visit. Conclusions: For properly selected low-risk PTC patients, hemithyroidectomy is a safe treatment option with a favorable long-term outcome. Full article

(This article belongs to the Special Issue Thyroid Cancer)

18 pages, 2415 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Immune Gene Signature Delineates a Subclass of Papillary Thyroid Cancer with Unfavorable Clinical Outcomes

by Kyuryung Kim, Sora Jeon, Tae-Min Kim and Chan Kwon Jung

Cancers 2018, 10(12), 494; https://doi.org/10.3390/cancers10120494 - 5 Dec 2018

Cited by 50 | Viewed by 6469

Abstract

Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) [...] Read more.

Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) consortium. Among three metagene signatures identified, two signatures were enriched in canonical BRAF-like and RAS-like thyroid cancers with up-regulation of genes involved in oxidative phosphorylation and cell adhesions, respectively. The third metagene signature representing up-regulation of immune-related genes further segregated BRAF-like and RAS-like PTCs into their respective subgroups of immunoreactive (IR) and immunodeficient (ID), respectively. BRAF-IR PTCs showed enrichment of tumor infiltrating immune cells, tall cell variant PTC, and shorter recurrence-free survival compared to BRAF-ID PTCs. RAS-IR and RAS-ID PTC subtypes included majority of normal thyroid tissues and follicular variant PTC, respectively. Immunopathological features of PTC subtypes such as immune cell fraction, repertoire of T cell receptors, cytolytic activity, and expression level of immune checkpoints such as and PD-L1 and CTLA-4 were consistently observed in two different cohorts. Taken together, an immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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19 pages, 3560 KiB

Open AccessArticle

CCND1 Splice Variant as A Novel Diagnostic and Predictive Biomarker for Thyroid Cancer

by Sora Jeon, Yourha Kim, Young Mun Jeong, Ja Seong Bae and Chan Kwon Jung

Cancers 2018, 10(11), 437; https://doi.org/10.3390/cancers10110437 - 13 Nov 2018

Cited by 34 | Viewed by 6580

Abstract

Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and [...] Read more.

Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and protein levels in 286 thyroid tumors. Genotype AA of rs9344 was associated with high expression of CCND1b mRNA and was more frequently found in thyroid cancer than in benign tumors. The mRNA expression levels of CCND1b were higher in papillary thyroid carcinoma (PTC) than in benign or other malignant tumors. However, the expression of CCND1a mRNA showed no association with the parameters. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was distinguished from PTC by low expression of CCND1b at mRNA and protein levels. We further observed that cyclin D1b immunostaining helped to avoid the misdiagnosis of classic PTC with predominant follicular pattern as NIFTP in a separate cohort. Nuclear cyclin D1b expression was associated with aggressive clinicopathologic features in PTC. These findings suggest that cyclin D1b overexpression can be used as a diagnostic and predictive biomarker in thyroid tumors and may be functionally involved in the development and progression of the disease. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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15 pages, 754 KiB

Open AccessReview

Intratumoral Genetic Heterogeneity in Papillary Thyroid Cancer: Occurrence and Clinical Significance

by Laura Fugazzola, Marina Muzza, Gabriele Pogliaghi and Mario Vitale

Cancers 2020, 12(2), 383; https://doi.org/10.3390/cancers12020383 - 7 Feb 2020

Cited by 29 | Viewed by 4005

Abstract

Intratumoral heterogeneity (ITH) refers to a subclonal genetic diversity observed within a tumor. ITH is the consequence of genetic instability and accumulation of genetic alterations, two mechanisms involved in the progression from an early tumor stage to a more aggressive cancer. While this [...] Read more.

Intratumoral heterogeneity (ITH) refers to a subclonal genetic diversity observed within a tumor. ITH is the consequence of genetic instability and accumulation of genetic alterations, two mechanisms involved in the progression from an early tumor stage to a more aggressive cancer. While this process is widely accepted, the ITH of early stage papillary thyroid carcinoma (PTC) is debated. By different genetic analysis, several authors reported the frequent occurrence of PTCs composed of both tumor cells with and without RET/PTC or BRAF^V600E genetic alterations. While these data, and the report of discrepancies in the genetic pattern between metastases and the primary tumor, demonstrate the existence of ITH in PTC, its extension and biological significance is debated. The ITH takes on a great significance when involves oncogenes, such as RET rearrangements and BRAF^V600E as it calls into question their role of driver genes. ITH is also predicted to play a major clinical role as it could have a significant impact on prognosis and on the response to targeted therapy. In this review, we analyzed several data indicating that ITH is not a marginal event, occurring in PTC at any step of development, and suggesting the existence of unknown genetic or epigenetic alterations that still need to be identified. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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27 pages, 669 KiB

Open AccessReview

Multi-omics Signatures and Translational Potential to Improve Thyroid Cancer Patient Outcome

by Myriem Boufraqech and Naris Nilubol

Cancers 2019, 11(12), 1988; https://doi.org/10.3390/cancers11121988 - 10 Dec 2019

Cited by 18 | Viewed by 5985

Abstract

Recent advances in high-throughput molecular and multi-omics technologies have improved our understanding of the molecular changes associated with thyroid cancer initiation and progression. The translation into clinical use based on molecular profiling of thyroid tumors has allowed a significant improvement in patient risk [...] Read more.

Recent advances in high-throughput molecular and multi-omics technologies have improved our understanding of the molecular changes associated with thyroid cancer initiation and progression. The translation into clinical use based on molecular profiling of thyroid tumors has allowed a significant improvement in patient risk stratification and in the identification of targeted therapies, and thereby better personalized disease management and outcome. This review compiles the following: (1) the major molecular alterations of the genome, epigenome, transcriptome, proteome, and metabolome found in all subtypes of thyroid cancer, thus demonstrating the complexity of these tumors and (2) the great translational potential of multi-omics studies to improve patient outcome. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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21 pages, 474 KiB

Open AccessReview

Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

by Anna Maria Malfitano, Sarah Di Somma, Nella Prevete and Giuseppe Portella

Cancers 2019, 11(10), 1532; https://doi.org/10.3390/cancers11101532 - 10 Oct 2019

Cited by 19 | Viewed by 3720

Abstract

Virotherapy is a novel cancer treatment based on oncolytic viruses (OVs), which selectively infect and lyse cancer cells, without harming normal cells or tissues. Several viruses, either naturally occurring or developed through genetic engineering, are currently under investigation in clinical studies. Emerging reports [...] Read more.

Virotherapy is a novel cancer treatment based on oncolytic viruses (OVs), which selectively infect and lyse cancer cells, without harming normal cells or tissues. Several viruses, either naturally occurring or developed through genetic engineering, are currently under investigation in clinical studies. Emerging reports suggesting the immune-stimulatory property of OVs against tumor cells further support the clinical use of OVs for the treatment of lesions lacking effective therapies. Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), have a poor prognosis and limited treatment options. Therefore, several groups investigated the therapeutic potential of OVs in PDTC/ATC models producing experimental data sustaining the potential clinical efficacy of OVs in these cancer models. Moreover, the presence of an immunosuppressive microenvironment further supports the potential use of OVs in ATC. In this review, we present the results of the studies evaluating the efficacy of OVs alone or in combination with other treatment options. In particular, their potential therapeutic combination with multiple kinases inhibitors (MKIs) or immune checkpoint inhibitors are discussed. Full article

(This article belongs to the Special Issue Thyroid Cancer)

14 pages, 262 KiB

Open AccessReview

BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives

by Fabiana Crispo, Tiziana Notarangelo, Michele Pietrafesa, Giacomo Lettini, Giovanni Storto, Alessandro Sgambato, Francesca Maddalena and Matteo Landriscina

Cancers 2019, 11(9), 1388; https://doi.org/10.3390/cancers11091388 - 18 Sep 2019

Cited by 77 | Viewed by 6126

Abstract

The Kirsten rat sarcoma viral oncogene homolog (RAS)/v-raf-1 murine leukemia viral oncogene homolog 1 (RAF)/mitogen-activated protein kinase 1 (MAPK) signaling cascade is the most important oncogenic pathway in human cancers. Tumors leading mutations in the gene encoding for v-raf murine sarcoma viral oncogene [...] Read more.

The Kirsten rat sarcoma viral oncogene homolog (RAS)/v-raf-1 murine leukemia viral oncogene homolog 1 (RAF)/mitogen-activated protein kinase 1 (MAPK) signaling cascade is the most important oncogenic pathway in human cancers. Tumors leading mutations in the gene encoding for v-raf murine sarcoma viral oncogene homolog B (BRAF) serine-threonine kinase are reliant on the MAPK signaling pathway for their growth and survival. Indeed, the constitutive activation of MAPK pathway results in continuous stimulation of cell proliferation, enhancement of the apoptotic threshold and induction of a migratory and metastatic phenotype. In a clinical perspective, this scenario opens to the possibility of targeting BRAF pathway for therapy. Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 29–83% of human thyroid malignancies and, differently from melanomas, are less sensitive to BRAF inhibitors and develop primary or acquired resistance due to mutational events or activation of alternative signaling pathways able to reactivate ERK signaling. In this review, we provide an overview on the current knowledge concerning the mechanisms leading to resistance to BRAF inhibitors in human thyroid carcinomas and discuss the potential therapeutic strategies, including combinations of BRAF inhibitors with other targeted agents, which might be employed to overcome drug resistance and potentiate the activity of single agent BRAF inhibitors. Full article

(This article belongs to the Special Issue Thyroid Cancer)

15 pages, 834 KiB

Open AccessReview

Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies

by Mohamed Aashiq, Deborah A. Silverman, Shorook Na’ara, Hideaki Takahashi and Moran Amit

Cancers 2019, 11(9), 1382; https://doi.org/10.3390/cancers11091382 - 17 Sep 2019

Cited by 104 | Viewed by 11380

Abstract

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory [...] Read more.

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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12 pages, 432 KiB

Open AccessReview

Radiation-Induced Thyroid Cancers: Overview of Molecular Signatures

by Keiji Suzuki, Vladimir Saenko, Shunichi Yamashita and Norisato Mitsutake

Cancers 2019, 11(9), 1290; https://doi.org/10.3390/cancers11091290 - 2 Sep 2019

Cited by 21 | Viewed by 5006

Abstract

Enormous amounts of childhood thyroid cancers, mostly childhood papillary thyroid carcinomas (PTCs), after the Chernobyl nuclear power plant accident have revealed a mutual relationship between the radiation exposure and thyroid cancer development. While the internal exposure to radioactive ¹³¹I is involved in [...] Read more.

Enormous amounts of childhood thyroid cancers, mostly childhood papillary thyroid carcinomas (PTCs), after the Chernobyl nuclear power plant accident have revealed a mutual relationship between the radiation exposure and thyroid cancer development. While the internal exposure to radioactive ¹³¹I is involved in the childhood thyroid cancers after the Chernobyl accident, people exposed to the external radiation, such as atomic-bomb (A-bomb) survivors, and the patients who received radiation therapy, have also been epidemiologically demonstrated to develop thyroid cancers. In order to elucidate the mechanisms of radiation-induced carcinogenesis, studies have aimed at defining the molecular changes associated with the thyroid cancer development. Here, we overview the literatures towards the identification of oncogenic alterations, particularly gene rearrangements, and discuss the existence of radiation signatures associated with radiation-induced thyroid cancers. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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12 pages, 1212 KiB

Open AccessReview

Critical Prognostic Parameters in the Anatomic Pathology Reporting of Differentiated Follicular Cell-Derived Thyroid Carcinoma

by Bin Xu and Ronald Ghossein

Cancers 2019, 11(8), 1100; https://doi.org/10.3390/cancers11081100 - 2 Aug 2019

Cited by 10 | Viewed by 14799

Abstract

In the past decades, pathology reporting on thyroid carcinoma has evolved from a narrative approach to structured synoptic reports. Many histologic variables are present in the current synoptic reports that are crucial elements for initial risk stratification and clinical management. In this review, [...] Read more.

In the past decades, pathology reporting on thyroid carcinoma has evolved from a narrative approach to structured synoptic reports. Many histologic variables are present in the current synoptic reports that are crucial elements for initial risk stratification and clinical management. In this review, we compare and summarize the key prognostic pathologic characteristics utilized by the most influential clinical and pathologic guidelines from the American Thyroid Association (ATA), the National Comprehensive Cancer Network (NCCN), the current World Health Organization (WHO) classification of endocrine tumors (fourth edition), the current American Joint Committee on Cancer (AJCC) staging system (eighth edition), the College of American Pathologists (CAP) protocol, and the International Collaboration on Cancer Reporting (ICCR) dataset. The aim is to provide a comprehensive review focused on the definitions and prognostic impacts of these crucial pathologic parameters. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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17 pages, 908 KiB

Open AccessReview

A Systematic Review of Phase II Targeted Therapy Clinical Trials in Anaplastic Thyroid Cancer

by Josip Ljubas, Therese Ovesen and Maria Rusan

Cancers 2019, 11(7), 943; https://doi.org/10.3390/cancers11070943 - 4 Jul 2019

Cited by 30 | Viewed by 6893

Abstract

Anaplastic thyroid carcinoma (ATC) is a rare, but devastating disease. Despite multimodal approaches combining surgery, chemotherapy and radiation therapy, ATC is associated with a dire prognosis, with a median overall survival of only three to ten months. Novel treatments are thus urgently needed. [...] Read more.

Anaplastic thyroid carcinoma (ATC) is a rare, but devastating disease. Despite multimodal approaches combining surgery, chemotherapy and radiation therapy, ATC is associated with a dire prognosis, with a median overall survival of only three to ten months. Novel treatments are thus urgently needed. Recent efforts towards the characterization of the molecular landscape of ATC have led to the identification of pro-oncogenic targetable alterations, lending promise for novel targeted therapeutic approaches. This systematic review summarizes the results of phase II clinical trials of targeted therapy in ATC, providing an overview of efficacy and safety profiles. The majority of trials to date have consisted of small single-arm studies and have presented modest results. However, only a minority of trials have selected or stratified patients by molecular alterations. In the setting of BRAF V600E mutated ATC, dabrafenib/trametinib combination therapy and vemurafenib monotherapy have both demonstrated efficacy. Everolimus has furthermore shown promising results in patients with PI3K/mTOR/AKT pathway alterations. These studies underscore the importance of molecular profiling of tumors for appropriate patient selection and determination of genomic correlates of response. Clinical trials are underway testing additional targeted therapies as monotherapy, or as a part of multimodal treatment, and in combination with immunotherapy. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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1 pages, 177 KiB

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Reply to Comment on “Malfitano, A.M. et al. Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer” Cancers 2019, 11, 1532

by Anna Maria Malfitano, Sarah Di Somma, Nella Prevete and Giuseppe Portella

Cancers 2020, 12(2), 281; https://doi.org/10.3390/cancers12020281 - 23 Jan 2020

Cited by 2 | Viewed by 1656

Abstract

Our work is focused on the future clinical use of oncolytic viruses (OVs) for the treatment of aggressive thyroid carcinomas [...] Full article

(This article belongs to the Special Issue Thyroid Cancer)

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