scholarly journals Characterization of thyroid cancer driven by known and novel ALK fusions

2019 ◽  
Vol 26 (11) ◽  
pp. 803-814 ◽  
Author(s):  
Federica Panebianco ◽  
Alyaksandr V Nikitski ◽  
Marina N Nikiforova ◽  
Cihan Kaya ◽  
Linwah Yip ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Nodules ◽  
Thyroid Neoplasms ◽  
Thyroid Carcinomas ◽  
Fine Needle Aspirates ◽  
Target Spectrum ◽  
Radiation History ◽  
Rare Gene ◽  
Poorly Differentiated ◽  
Well Differentiated

ALK fusions are found in various tumors, including thyroid cancer, and serve as a diagnostic marker and therapeutic target. Spectrum and outcomes of ALK fusions found in thyroid nodules and cancer are not fully characterized. We report a series of 44 ALK-translocated thyroid neoplasms, including 31 identified preoperatively in thyroid fine-needle aspirates (FNA). The average patients’ age was 43 years (range, 8–76 years); only one with radiation history. All 19 resected thyroid nodules with ALK fusion identified preoperatively were malignant. Among nodules with known surgical pathology (n = 32), 84% were papillary thyroid carcinomas (PTCs) and 16% poorly differentiated thyroid carcinomas (PDTCs). PTCs showed infiltrative growth with follicular architecture seen exclusively (30%) or in combination with papillary and/or solid growth (37%). Tumor multifocality was seen in 10 (31%) PTC cases. Most PDTC had a well-differentiated PTC component. Lymph node metastases were identified in 10/18 (56%) patients with neck dissection. The most common ALK fusion partners were STRN (n = 22) and EML4 (n = 17). In five cases, novel ALK fusion partners were discovered. All five PDTCs carried STRN-ALK fusion. On follow-up, ten patients were free of disease at 2–108 months, whereas two patients with PDTC died of disease. In summary, ALK fusion-positive thyroid carcinomas are typically infiltrative PTC with common follicular growth, which may show tumor dedifferentiation associated with increased mortality. Compared to EML4-ALK, STRN-ALK may be more common in PDTC, and ~10% of ALK fusions occur to rare gene partners. When ALK fusion is detected preoperatively in FNA samples, malignancy should be expected.

scholarly journals Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment

2019 ◽  
Vol 20 (13) ◽  
pp. 3258 ◽  
Author(s):  
Livia Manzella ◽  
Michele Massimino ◽  
Stefania Stella ◽  
Elena Tirrò ◽  
Maria Stella Pennisi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Thyroid Neoplasms ◽  
Thyroid Carcinomas ◽  
Signaling Inhibitors ◽  
Poorly Differentiated ◽  
Biological Entities ◽  
Complex Signaling ◽  
Igf Signaling

The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)—comprising papillary (PTC) and follicular (FTC) tumors—respond to radioiodine therapy, while undifferentiated tumors—including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)—are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.

Thyroid cancer

2018 ◽  
Vol 11 (4) ◽  
pp. 212-217
Author(s):  
Jonathan Mills ◽  
William Dalleywater
Keyword(s):  
Thyroid Cancer ◽  
Mortality Rate ◽  
Poor Prognosis ◽  
Survival Rates ◽  
Thyroid Neoplasms ◽  
Thyroid Cells ◽  
Endocrine Differentiation ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
The Uk

Thyroid neoplasms represent the most-common endocrine tumour and constitute an extremely varied spectrum of disease. At the most severe end, they may have a very poor prognosis. Malignant thyroid tumours constitute around 1% of cancers and cancer-specific deaths in the UK, with just under 3000 new diagnoses each year and around 350 deaths annually in the UK alone. Although the incidence has doubled over the last 20 years, the mortality rate among men has not changed, although survival rates have improved in women. Thyroid cancer originates from follicular or parafollicular thyroid cells that can give rise to cancer that is well-differentiated to poorly differentiated. Most tumours retain endocrine differentiation, however, and may cause problematic symptoms from aberrant hormone levels.

The Accuracy of ACR TI-RADS Classification of Neck Ultrasound as a First-Line Diagnostic Approach for Thyroid Neoplasms in Pediatric Patients: A Retrospective Study

2018 ◽  
Vol 5 (1) ◽  
pp. 13-23
Author(s):  
Nikolai S. Grachev ◽  
Elena V. Feoktistova ◽  
Igor N. Vorozhtsov ◽  
Natalia V. Babaskina ◽  
Ekaterina Yu. Iaremenko ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Predictive Value ◽  
Thyroid Nodules ◽  
Pediatric Patients ◽  
Thyroid Neoplasms ◽  
Diagnostic Methods ◽  
Diagnostic Approach ◽  
First Line ◽  
Neck Ultrasound

Background.Ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the gold standard in diagnosing the pathological nature of undetermined thyroid nodules. However, in some instances limitations and shortcomings arise, making it insufficient for determining a specific diagnosis.Objective.Our aim was to evaluate the effectiveness of ACR TI-RADS classification of neck ultrasound as a first-line diagnostic approach for thyroid neoplasms in pediatric patients.Methods.A retrospective analysis was made of FNA and US protocols in 70 patients who underwent the examination and treatment at Dmitry Rogachev National Research Center between January 2012 and August 2017. In the retrospective series 70% (49/70) of patients undergone FNA and 43% (30/70) of them undergone repeated FNA. All US protocols were interpreted according to ACR TI-RADS system by the two independent experts. The clinical judgment was assessed using the concordance test and the reliability of preoperative diagnostic methods was analized.Results.According to histologic examination protocols, benign nodules reported greater multimorbidity 29% (20/70), compared with thyroid cancer 17% (12/70), complicating FNA procedure. A statistically significant predictor of thyroid cancer with a tumor size ACR TI-RADS showed a significant advantage of ACR TI-RADS due to higher sensitivity (97.6 vs 60%), specificity (78.6 vs 53.8%), positive predictive value (87.2 vs 71.4%), and negative predictive value (95.7 vs 41.2%). Concordance on the interpreted US protocols according to ACR TI-RADS classification between two experts was high, excluding accidental coincidence.Conclusion.The data support the feasibility of US corresponding to the ACR TI-RADS classification as a first-line diagnostic approach for thyroid neoplasm reducing the number of unnecessary biopsies for thyroid nodules.

scholarly journals What is New on Thyroid Cancer Biomarkers

2008 ◽  
Vol 3 ◽  
pp. BMI.S669 ◽  
Author(s):  
Rosaria M. Ruggeri ◽  
Alfredo Campennì ◽  
Sergio Baldari ◽  
Francesco Trimarchi ◽  
Maria Trovato
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Nodules ◽  
Needle Aspiration ◽  
Follicular Epithelium ◽  
Routine Practice ◽  
Appropriate Treatment ◽  
Follicular Lesions ◽  
Needle Aspiration Cytology ◽  
Well Differentiated

Thyroid cancer harbours in about 5% of thyroid nodules. The majority of them are well-differentiated cancers originating from the follicular epithelium, and are subdivided into papillary and follicular carcinomas. Undifferentiated carcinomas and medullary thyroid carcinomas arising from C cells are less common. Although most thyroid nodules are benign, distinguishing thyroid cancer from benign lesions is crucial for an appropriate treatment and follow-up. The fine needle aspiration cytology (FNAC) allows the diagnosis of nature of thyroid nodules in the majority of cases. However, FNAC has some limitations, particularly in the presence of follicular lesions which can appear dubious in rare instances even at histology. In an effort to improve diagnostic accuracy and offer new prognostic criteria, several immunohistochemical and molecular markers have been proposed. However, most of them have to be validated on large series before being used in routine practice.

scholarly journals Role of biomarkers in predicting the occurrence of thyroid neoplasms in radiation-exposed children

2018 ◽  
Vol 25 (4) ◽  
pp. 481-491
Author(s):  
Joseph M Shulan ◽  
Leonid Vydro ◽  
Arthur B Schneider ◽  
Dan V Mihailescu
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Nodules ◽  
Subsequent Development ◽  
Thyroid Neoplasms ◽  
Childhood Cancer Survivors ◽  
Malignant Neoplasms ◽  
Increased Risk ◽  
Need To Evaluate

With increasing numbers of childhood cancer survivors who were treated with radiation, there is a need to evaluate potential biomarkers that could signal an increased risk of developing thyroid cancer. We aimed to examine the relationships between thyrotropin and thyroglobulin levels and the risk of developing thyroid nodules and cancer in a cohort of radiation-exposed children. 764 subjects who were irradiated in the neck area as children were examined and followed for up to 25 years. All subjects underwent a clinical examination, measurements of thyrotropin, thyroglobulin levels and thyroid imaging. At baseline, 216 subjects had thyroid nodules and 548 did not. Of those with nodules, 176 underwent surgery with 55 confirmed thyroid cancers. During the follow-up, 147 subjects developed thyroid nodules including 22 with thyroid cancer. Thyroglobulin levels were higher in subjects with prevalent thyroid nodules (26.1 ng/mL vs 9.37 ng/mL; P < 0.001) and in those who had an initial normal examination but later developed thyroid nodules (11.2 ng/mL vs 8.87 ng/mL; P = 0.017). There was no relationship between baseline thyrotropin levels and the prevalent presence or absence of thyroid nodules, whether a prevalent neoplasm was benign or malignant, subsequent development of thyroid nodules during follow-up or whether an incident nodule was benign or malignant. In conclusion, in radiation-exposed children, higher thyroglobulin levels indicated an increased risk of developing thyroid nodules but did not differentiate between benign and malignant neoplasms. There was no association between the baseline TSH level and the risk of developing thyroid nodules or cancer.

Circulating Cytokeratin 19 Fragments in Patients with benign Nodules and Carcinomas of the Thyroid Gland

2008 ◽  
Vol 23 (1) ◽  
pp. 54-57 ◽  
Author(s):  
L. Giovanella ◽  
L. Ceriani ◽  
A. Ghelfo ◽  
M. Maffioli
Keyword(s):  
Thyroid Carcinoma ◽  
Thyroid Nodules ◽  
Differentiated Thyroid Carcinoma ◽  
Cytokeratin 19 ◽  
Thyroid Carcinomas ◽  
Poorly Differentiated ◽  
Benign Nodules ◽  
Thyroid Malignancies ◽  
Benign Thyroid Nodules ◽  
Benign Thyroid

Cytokeratin 19 (CK19) is an acidic protein of 40 kDa that is part of the cytoskeleton of epithelial cells and is highly expressed by differentiated thyroid carcinomas, mainly of the papillary subtype. The soluble fragments of CK19 (Cyfra 21.1) can be measured by immunometric assays employing specific monoclonal antibodies. The present study was planned to assess the serum expression of Cyfra 21.1 in patients with benign thyroid nodules and thyroid malignancies. We enrolled 135 patients with histologically proven benign thyroid nodules (n=79) and thyroid carcinomas (n=56). No differences were found in serum Cyfra 21.1 levels between patients with benign nodules and patients with carcinomas. When thyroid malignancies were subdivided according to tumor histology, serum Cyfra 21.1 increased significantly from classical differentiated thyroid carcinomas (papillary or follicular) to less differentiated or undifferentiated carcinomas (poorly differentiated or anaplastic). CK19 release into the bloodstream is strongly related to the apoptotic pathway, and particularly to hyperproliferation-related apoptosis. These pathways characterized anaplastic and poorly differentiated thyroid carcinoma but not classical forms of differentiated thyroid carcinoma. Consequently, Cyfra 21.1 may be regarded as a circulating marker of poorly differentiated and anaplastic thyroid carcinoma. Additionally, a role of Cyfra 21.1 as a dedifferentiation marker in patients with classical differentiated thyroid carcinomas may be postulated and should be explored by further focused studies.

Genetic profile of advanced thyroid cancers in relation to distant metastasis

2020 ◽  
Vol 27 (5) ◽  
pp. 285-293 ◽  
Author(s):  
Eyun Song ◽  
Dong Eun Song ◽  
Jonghwa Ahn ◽  
Tae Yong Kim ◽  
Won Bae Kim ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Distant Metastasis ◽  
Distant Metastases ◽  
Thyroid Tumors ◽  
Primary Tumors ◽  
Thyroid Cancers ◽  
Histone Methyltransferases ◽  
Thyroid Carcinomas ◽  
Poorly Differentiated

Major clinical challenges exist with differentiated thyroid cancers with distant metastases or rare but aggressive types, such as poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. The precise characterization of the mutational profile in these advanced thyroid cancers is crucial. Samples were collected from primary tumors and distant metastases of 64 patients with distant metastases from differentiated thyroid cancer, poorly differentiated thyroid carcinoma, or anaplastic thyroid carcinoma. Targeted next-generation sequencing was performed with 50 known thyroid-cancer-related genes. Of the 82 tissues, 63 were from primary tumors and 19 from distant metastases. The most prevalent mutation observed from the primary tumors was TERT promoter mutation (56%), followed by BRAF (41%) and RAS (24%) mutations. TP3 was altered by 11%. Mutations in histone methyltransferases, SWI/SNF subunit–related genes, and PI3K/AKT/mTOR pathway-related genes were present in 42%, 12%, and 22%, respectively. When the mutational status was analyzed in 15 matched pairs of thyroid tumors and their matched distant metastases and one pair of distant metastases with two distinct sites, the concordance was high. A similar frequency of mutations in TERT promoter (58%) and BRAF (42%) as well as histone methyltransferases (37%), SWI/SNF subunits (10%), and PI3K/AKT/mTOR pathway (26%) were noted. The same main, early and late mutations were practically always present in individual primary tumor–metastasis pairs. Enrichment of TERT promoter, BRAF, and RAS mutations were detected in highly advanced thyroid cancers with distant metastasis. The genetic profiles of primary thyroid tumors and their corresponding distant metastases showed a high concordance.

Well-differentiated Thyroid Cancer With a Minor Poorly Differentiated Component

2015 ◽  
Vol 23 (3) ◽  
pp. 196-201 ◽  
Author(s):  
Esther D. Rossi ◽  
Maurizio Martini ◽  
Sara Capodimonti ◽  
Patrizia Straccia ◽  
Luca Revelli ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
A Minor

scholarly journals Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation

2012 ◽  
Vol 19 (2) ◽  
pp. 167-179 ◽  
Author(s):  
Xiulong Xu ◽  
Helen Ding ◽  
Geetha Rao ◽  
Shalini Arora ◽  
Constantine P Saclarides ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Tumor Cell ◽  
Sonic Hedgehog ◽  
Thyroid Neoplasms ◽  
Thyroid Tumor ◽  
Tumor Cell Proliferation ◽  
Thyroid Carcinomas ◽  
Shh Pathway ◽  
Genes Encoding

The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status ofBRAFgene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown ofSHHandGLIexpression by miRNA constructs that targetSHHorGLImRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment.

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