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The sodium-iodide symporter (NIS, SLC5A5) is expressed at the basolateral membrane of the thyroid follicular cell, and facilitates the thyroidal iodide uptake required for thyroid hormone biosynthesis. Biallelic loss-of-function mutations in NIS are a rare cause of dyshormonogenic congenital hypothyroidism. Affected individuals typically exhibit a normally sited, often goitrous thyroid gland, with absent uptake of radioiodine in the thyroid and other NIS-expressing tissues. We report a novel homozygous NIS mutation (c.1067 C>T, p.S356F) in four siblings from a consanguineous Indian kindred, presenting with significant hypothyroidism. Functional characterization of the mutant protein demonstrated impaired plasma membrane localization and cellular iodide transport.

Thyroid carcinomas originating from follicular cells of the thyroid gland occur in both humans and dogs and they have highly similar histomorphologic patterns. In dogs, thyroid carcinomas have not been extensively investigated, especially concerning the familial origin of thyroid carcinomas. Here we report familial thyroid follicular cell carcinomas confirmed by histology in 54 Dutch origin German longhaired pointers. From the pedigree, 45 of 54 histopathologically confirmed cases are closely related to a pair of first-half cousins in the past, indicating a familial disease. In addition, genetics contributed more to the thyroid follicular cell carcinoma than other factors by an estimated heritability of 0.62 based on pedigree. The age of diagnosis ranged between 4.5 and 13.5 years, and 76% of cases were diagnosed before 10 years of age, implying an early onset of disease. We observed a significant higher pedigree-based inbreeding coefficient in the affected dogs (mean F 0.23) compared to unaffected dogs (mean F 0.14), suggesting the contribution of inbreeding to tumour development. The unique occurrence of familial thyroid follicular cell carcinoma in this dog population and the large number of affected dogs make this population an important model to identify the genetic basis of familial thyroid follicular cell carcinoma in this breed and may contribute to the research into pathogenesis, prevention and treatment in humans. This article is protected by copyright. All rights reserved.

Background: The development of the thyroid follicular cell has been well characterized as it progresses from the original stem cell, either embryonic or adult, through a series of transitions to form a differentiated and functional thyroid cell. Summary: In this review, we briefly outline what is known about this transitional process with emphasis on characterizing the thyroid progenitor stem cell by using data obtained from both in vitro and in vivo studies and both mouse and human cells. It is of particular importance to note the influence of independent factors that guide the transcriptional control of the developing thyroid cell as it is subjected to extracellular signals, often working via epigenetic changes, and initiating intrinsic transcriptional changes leading to a functional cell. Conclusion: Thyroid stem cells fall into the category of dispositional stem cells and are greatly influenced by their environment.

Objective: To determine the malignancy in multinodular goiter by doing final histopathology of specimen. Study Design: This is an observational study. Setting: Study carried out in the department of ENT, Head & Neck Surgery of Khairpur Medical College Hospital Khairpur, from August 2016 to July 2019. Materials and Methods: All those patients with MNG with or without thyrotoxicosis were selected and advised for Thyroid function tests, ultrasound thyroid and serum calcium level. FNAC was performed only in cases with suspicious nodule. All the patients under went total/near total thyroidectomy after all base line routine investigations along with thyroid function tests. Histopathological evaluation was also conducted. Results: Out of total 70 patients with MNG, 17 (24.3%) cases were suspected of malignancy. Out of 17 suspicious cases, FNAc showed colloid goiter in 8 (47%), follicular in 7 (41%) cases and papillary in 2 (12%) cases. Final histopathology showed total 5 (29%) cases as malignant and remaining 12 (71%) cases were benign. Out of 5 malignant cases, 4 (80%) cases were papillary and 1 (20%) cases were Follicular cell carcinoma. While other 53 (75.7%) cases under went for near total thyroidectomy and specimens sent for histopathology, among these only 1 (2%) case found as Papillary cell Carcinoma. Total 6 cases were malignant out of which in which 5 cases were Papillary cell Carcinoma and one was Follicular cell Carcinoma. Conclusion: We conclude that multinodular goiter is the most prevalent thyroid disease found in female. Follicular thyroid carcinoma is the most frequent cancer seen in this study.

Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients’ clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC). Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals. DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028). S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients’ risk assessment.

Thyroid cancer cells have a high amino acid demand for proliferation, invasion, and metastasis. Amino acids are taken up by thyroid cancer cells, both thyroid follicular cell and thyroid parafollicular cells (commonly called “C-cells”), via amino acid transporters. Amino acid transporters up-regulate in many cancers, and their expression level associate with clinical aggressiveness and progno sis. This is the review to discuss the therapeutic potential of amino acid transporters and as molecular targets in thyroid cancer.

Summary Thyroid carcinomas are a common form of endocrine neoplasia in dogs. In the present study, we combined histopathology with immunohistochemistry (IHC) to search for the presence of oestrogen receptor alpha (ORα), Cox-2 and Ki67 in canine thyroid carcinomas. Forty-eight thyroid carcinomas were diagnosed throughout the study period. Thyroglobulin and calcitonin IHC distinguished between thyroid tumours with a follicular and medullary (C-cell) origin, respectively. IHC-based diagnosis showed that 42 (87.50%) of the cases were follicular cell carcinoma. In these cases, the follicular–compact pattern was the most frequent (n = 20/42; 47.62%) and six cases (12.5%) were medullary cell (C-cell) carcinomas. Both medullary (C-cell) and follicular carcinomas expressed Ki67 and Cox-2. No differences were observed between medullary and follicular carcinomas with respect to expression of Ki67 (P = 0.34) and Cox-2 (P = 0.9523) markers. A total of 4.17% (n = 2/48) of thyroid carcinomas showed positive nuclear labelling for ORα, suggesting that oestrogen does not directly participate in the pathogenesis of canine thyroid neoplasia.

This study was designed to investigate the effect of continuous treatment with the anti-thyroid drug, propylthiouracil (PTU), on renal and hepatic functions in rabbits as an experimental animal model. Animals were randomly divided into four different isolated groups (n = 10); Group I received normal saline. Group II, III, and IV were daily administrated with PTU in oral dosing of 50, 75, and 150 mg/kg, BWT, respectively, for three successive weeks. Serum T3 and T4 levels were measured in all groups. Increased serum creatinine and blood urea nitrogen levels (P

Human ovarian folliculogenesis is a highly regulated and complex process. Characterization of follicular cell signatures during this dynamic process is important to understand follicle fate (to grow, become dominant, or undergo atresia). The transcriptional signature of human oocytes and granulosa cells (GCs) in early-growing and ovulatory follicles have been previously described, however, that of oocytes with surrounding GCs in small antral follicles have not been studied yet. Here, we have generated a unique dataset of single-cell transcriptomics (SmartSeq2) consisting of the oocyte with surrounding GCs from several individual (non-dominant) small antral follicles isolated from adult human ovaries. We have identified two main types of (healthy) follicles, with a distinct oocyte and GC signature. Using the CellphoneDB algorithm, we then investigated the bi-directional ligand–receptor interactions regarding the transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP), wingless-type (MMTV)-integration site (WNT), NOTCH, and receptor tyrosine kinases (RTK) signaling pathways between oocyte and GCs within each antral follicle type. Our work not only revealed the diversity of small antral follicles, but also contributes to fill the gap in mapping the molecular landscape of human folliculogenesis and oogenesis.

Secretory carcinoma of the thyroid gland is histologically and genetically similar to its mammary and salivary gland counterparts. Unlike differentiated thyroid carcinomas of follicular cell origin, thyroid SC is not a thyroglobulin-producing tumor and would not be amenable to radioactive iodine therapy. Instead, these carcinomas may respond to targeted therapy with TRK inhibitors, which further emphasizes the importance of their recognition among morphologically similar thyroid entities. Based on eleven cases reported to date, most primary thyroid SC tend to present as locally advanced malignancies and are characterized by frequent recurrences and long-term survival. High-grade histologic features, increased mitotic count and necrosis have been described but their impact on clinical course and outcome remains unclear. We hereby report the case of a primary SC with high-grade features arising in the thyroid of a 49-year-old man, who was treated with Larotrectinib for his second recurrence. The patient achieved a durable response that lasted for 18 months but then he continued to progress and died of disease 181 months after the diagnosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12105-021-01386-6.

Familial thyroid cancer originating from follicular cells accounts for 5–15% of all the thyroid carcinoma cases in humans. Previously, we described thyroid follicular cell carcinomas in a large number of the Dutch German longhaired pointers (GLPs) with a likely autosomal recessive inheritance pattern. Here, we investigated the genetic causes of the disease using a combined approach of genome-wide association study and runs of homozygosity (ROH) analysis based on 170k SNP array genotype data and whole-genome sequences. A region 0–5 Mb on chromosome 17 was identified to be associated with the disease. Whole-genome sequencing revealed many mutations fitting the recessive inheritance pattern in this region including two deleterious mutations in the TPO gene, chr17:800788G&gt, A (686F&gt, V) and chr17:805276C&gt, T (845T&gt, M). These two SNP were subsequently genotyped in 186 GLPs (59 affected and 127 unaffected) and confirmed to be highly associated with the disease. The recessive genotypes had higher relative risks of 16.94 and 16.64 compared to homozygous genotypes for the reference alleles, respectively. This study provides novel insight into the genetic causes leading to the familial thyroid follicular cell carcinoma, and we were able to develop a genetic test to screen susceptible dogs.

Thyrotropin receptor (TSHR), sodium iodide symporter (NIS), pendrin, and thyroid peroxidase (TPO) are essential for the uptake of iodine by follicular thyroid cells. The aim of this study was to establish immunohistochemistry (IHC) protocols for TSHR, NIS, pendrin, and TPO in canine tissues and characterize their expression in organoids derived from canine follicular cell thyroid carcinoma (FTC) and in the respective primary tumors. This constitutes a fundamental step to establish organoids as a model to study the uptake of iodine in canine FTC. Commercially available antibodies directed against human proteins were selected. Antibody specificity was confirmed by western blot using lysates of the HTori-3 human thyroid cell line and healthy canine thyroid gland. IHC was validated using HTori-3 cells and a set of canine normal tissues including healthy thyroid gland. The expression of TSHR, NIS, pendrin, and TPO was evaluated in 3 organoid lines derived from FTC and respective primary tumors. All 4 antibodies produced specific bands by western blot and cytoplasmic labeling in follicular cells by IHC in both human HTori-3 cells and canine thyroid gland. NIS also showed basolateral membrane immunolabeling in follicular cells. All 4 proteins were highly expressed in organoids derived from FTC. The expression was similar or higher compared to the primary tumors. The results of this study characterize organoids derived from canine FTC as a suitable in vitro model to investigate iodine uptake, opening new research possibilities in the field of canine thyroid cancer therapy.

Inherited thyroid tumours are an important group which need clarification. This is partly because of the common use of the term Familial Non-Medullary Thyroid Cancer when some of the specific entities included under this heading really represent inherited benign tumours with a risk of progression to malignancy. The subject is briefly reviewed, and one syndromic and one non-syndromic type of inherited thyroid tumours of follicular cell origin discussed in more detail to emphasise the point that each of these groups need to be treated as separate entities.

Objective: Angioimmunoblastic T cell lymphoma (AITL) is an aggressive form of non-Hodgkin lymphoma derived from matureT cells. However, the underlying pathogenesis of AITL remains unresolved. We aimed to explore the role of FOXO1-mediatedsignaling in the tumorigenesis and progression of AITL. Methods: FOXO1 expression was assessed using immunohistochemistry on a total of 46 AITL tissue samples. Retrovirusesencoding FOXO1 shRNA were used to knockdown FOXO1 expression in CD4+ T cells. Flow cytometric assays analyzed theproliferation and survival of FOXO1 knockdown CD4+ T cells. Furthermore, we performed adoptive T-cell transfer experimentsto identify whether inactivation of FOXO1 induced neoplastic follicular-helper T (Tfh) cell polarization and function. Results: Patients with low FOXO1 protein levels were prone to have an advanced tumor stage (P = 0.049), higher ECOG ps (P =0.024), the presence of bone marrow invasion (P = 0.000), and higher IPI (P = 0.035). Additionally, the survival rates of patients inthe FOXO1 high-expression group were significantly better than those in the FOXO1 low-expression group (χ2 = 5.346, P =0.021). We also observed that inactivation of FOXO1 increased CD4+ T cell proliferation and altered the survival and cell-cycleprogression of CD4+ T cells. Finally, we confirmed that inactivation of FOXO1 induces Tfh cell programing and function. Conclusions: Inactivation of FOXO1 in AITL plays a key role in the tumorigenesis and progression of AITL. We propose thatFOXO1 expression could be a useful prognostic marker in AITL patients to predict poor survival, and to design appropriatetherapeutic strategies. Cite this article as: Xu M, Wang F, Chen H, Liu L, Liu W, Yang Y, et al.Inactivation of FOXO1 induces T follicular cell polarization and involvesangioimmunoblastic T cell lymphoma. Cancer Biol Med. 2019; 16: 743-55.doi: 10.20892/j.issn.2095-3941.2019.0115

Manipulation of oocytes enclosed in preantral follicles (MOEPF) allows for analyzing follicular development and use of this biotechnology in the pre-analysis of the beneficial or toxic effects of bio-products on granulosa cells and oocytes at different developmental stages. In this study, there was evaluation of the effects of gossypol by culturing granulosa cells and oocytes in ewe ovarian tissues. Ovarian tissues were cultured with gossypol at 37 °C, in humidified air and 5% CO2. Variables that were evaluated were morphology, morphometry, ultrastructure and abundance of estradiol receptor α (α-ER). There were no differences in developmental characteristics when there was treatment with any of the gossypol doses that were evaluated. Immunostaining indicated that when the gossypol dose increases, the abundance of α-ER also increases in the cytoplasm, nucleus, and granulosa cells. Findings with the ultrastructural analysis indicated that for granulosa cells there was fewer cells and greater disorganization and a lack of structural integrity of follicular cell layers as a result of all gossypol treatments. The culture of oocytes in preantral ovarian follicles in presence of gossypol did not affect the morphological-metric structure at the doses evaluated. The findings with evaluation of ultrastructural and immunohistochemical structures indicated granulosa cells and α-ER were affected by the treatments with gossypol indicating there were effects of this compound on ovarian function in sheep. This study indicated there is a toxic action of gossypol when using the biotechnology, MOEPF. Thus, gossypol negatively affects granulosa cell development and structural integrity of preantral follicles in sheep.

It has been a subject of much debate whether thyroid follicular cells originate from the ultimobranchial body, in addition to median thyroid primordium. Ultimobranchial remnants are detected in normal dogs, rats, mice, cattle, bison and humans and also in mutant mice such as Eya1 homozygotes, Hox3 paralogs homozygotes, Nkx2.1 heterozygotes and FRS2α2F/2F. Besides C cells, follicular cell lineages immunoreactive for thyroglobulin are located within these ultimobranchial remnants. In dogs, the C cell complexes, i.e., large cell clusters consisting of C cells and undifferentiated cells, are present together with parathyroid IV and thymus IV in or close to the thyroid lobe. In addition, follicular cells in various stages of differentiation, including follicular cell groups and primitive and minute follicles storing colloid, are intermingled with C cells in some complexes. This review elaborates the transcription factors and signaling molecules involved in folliculogenesis and it is supposed why the follicular cells in the ultimobranchial remnants are sustained in immature stages. Pax8, a transcription factor crucial for the development of follicular cells, is expressed in the fourth pharyngeal pouch and the ultimobranchial body in human embryos. Pax8 expression is also detected in the ultimobranchial remnants of Eya1 and Hes1 null mutant mice. To determine whether the C cells and follicular cells in the ultimobranchial remnants consist of dual lineage cells or are derived from the common precursor, the changes of undifferentiated cells in dog C cell complexes are examined after chronically induced hypercalcemia or antithyroid drug treatment.

Iodine is a crucial component of thyroid hormones; therefore, a key requirement for thyroid hormone biosynthesis is that iodide (I2) be actively accumulated in the thyroid follicular cell. The ability of the thyroid epithelia to concentrate I2 is ultimately dependent on functional Na+/ I2 symporter (NIS) expression at the plasma membrane. Underscoring the significance of NIS for thyroid physiology, loss-of-function mutations in the NIS-coding SLC5A5 gene cause an I2 transport defect, resulting in dyshormonogenic congenital hypothyroidism. Moreover, I2 accumulation in the thyroid cell constitutes the cornerstone for radioiodide ablation therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit reduced (or even undetectable) I2 transport compared with normal thyroid tissue, and they are diagnosed as cold nodules on thyroid scintigraphy. Paradoxically, immunohistochemistry analysis revealed that cold thyroid nodules do not express NIS or express normal, or even higher NIS levels compared with adjacent normal tissue, but NIS is frequently intracellularly retained, suggesting the presence of posttranslational abnormalities in the transport of the protein to the plasma membrane. Ultimately, a thorough comprehension of the mechanisms that regulate NIS transport to the plasma membrane would have multiple implications for radioiodide therapy, opening the possibility to identify new molecular targets to treat radioiodide-refractory thyroid tumors. Therefore, in this review, we discuss the current knowledge regarding posttranslational mechanisms that regulate NIS transport to the plasma membrane under physiological and pathological conditions affecting the thyroid follicular cell, a topic of great interest in the thyroid cancer field. Fil: Martín, Mariano. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Geysels, Romina Celeste. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina Fil: Peyret, Victoria. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bernal Barquero, Carlos Eduardo. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina Fil: Masini-Repiso, Ana María. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina Fil: Nicola, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina

Malignant thyroid lesions are the most common malignancy of the endocrine glands with increasing rates in the last two decades. Papillary thyroid cancer is the most common thyroid malignancy. In our study, we aimed to quantitatively evaluate the levels of DNA repair proteins MSH2, MLH1, MGMT, which are representative blocks of patients diagnosed with papillary carcinoma, chronic thyroiditis, or colloidal goiter. Total or subtotal thyroidectomy material of 90 patients diagnosed with papillary carcinoma, nodular colloidal goiter, or chronic thyroiditis between 2009 and 2012 were retrospectively evaluated. Tissue samples obtained from paraffin blocks were stained with MGMT, MSH2, MLH1 proteins and their immunohistochemistry was evaluated. Prepared sections were examined qualitatively by an impartial pathologist and a clinician, taking into account the staining method under the trinocular light microscope. Although there was no statistically significant difference in MGMT, MSH2, MLH1, follicular cell positivity, staining intensity, and immunoreactivity values, papillary carcinoma cases showed a higher rate of follicular cell positivity, and this difference was more pronounced between papillary carcinoma and colloidal goiter. In the MSH2 follicular cell positivity evaluation, the difference between chronic thyroiditis and colloidal goiter was significant (p = 0.023). The difference between chronic thyroiditis and colloidal goiter was significant in the MSH2 staining intensity evaluation (p = 0.001). The difference between chronic thyroiditis and colloidal goiter was significant in MLH1 immunoreactivity evaluation (p = 0.012). Papillary carcinoma cases were demonstrated by nuclear staining only for MSH2 and MLH1 proteins as opposed to hyperplastic nodules. The higher levels of expression of DNA repair genes in malignant tumors compared to benign tumors are attributed to the functional activation of DNA repair genes. Further studies are needed for DNA repair proteins to be a potential test in the development and progression of thyroid cancer.

Thyroid carcinomas originating from follicular cells of the thyroid gland occur in both humans and dogs and they have highly similar histomorphologic patterns. In dogs, thyroid carcinomas have not been extensively investigated, especially concerning the familial origin of thyroid carcinomas. Here we report familial thyroid follicular cell carcinomas confirmed by histology in 54 Dutch origin German longhaired pointers. From the pedigree, 45 of 54 histopathologically confirmed cases are closely related to a pair of first-half cousins in the past, indicating a familial disease. In addition, genetics contributed more to the thyroid follicular cell carcinoma than other factors by an estimated heritability of 0.62 based on pedigree. The age of diagnosis ranged between 4.5 and 13.5 years, and 76% of cases were diagnosed before 10 years of age, implying an early onset of disease. We observed a significant higher pedigree-based inbreeding coefficient in the affected dogs (mean F 0.23) compared to unaffected dogs (mean F 0.14), suggesting the contribution of inbreeding to tumour development. The unique occurrence of familial thyroid follicular cell carcinoma in this dog population and the large number of affected dogs make this population an important model to identify the genetic basis of familial thyroid follicular cell carcinoma in this breed and may contribute to the research into pathogenesis, prevention and treatment in humans.

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.

AIMS Metastasis to the thyroid gland is a rare occurrence that may pose a diagnostic challenge. In this study, we aimed to report the clinicopathological features, immunoprofile, molecular alterations and outcome of 30 patients treated at our centre from 2003 to 2019. METHODS AND RESULTS The most common site of the primary tumour was the kidney, followed by the lung, lower gastrointestinal tract and breast. In seven (23%) patients, the thyroid metastases were resected prior to the diagnosis of the primary tumours. Six patients (20%) had thyroid as the sole metastatic site. Three (10%) patients harboured tumour-to-tumour metastasis; 71% had a unilateral unifocal thyroid mass, which might be mistaken for a primary thyroid tumour. Among the 13 cases that were initially diagnosed at an outside hospital, four (31%) were misinterpreted as a thyroid primary. An immunohistochemical panel of thyroid follicular cell markers was most useful to differentiate primary thyroid tumours from metastasis. Molecularly, the metastasis showed alterations characteristic of the primary tumour, which may be helpful in establishing the diagnosis and primary site. Although the prognosis was poor, with a 5-year disease specific survival of 58%, a long-term cure was possible in cases with oligometastasis successfully treated with surgery. CONCLUSIONS Metastasis to the thyroid gland is an uncommon phenomenon, with an incidence of 0.36% in all thyroid malignancies. It may present as a solitary thyroid mass before the discovery of the primary tumour, posing a diagnostic challenge. Although the overall prognosis is poor, a subset of patients with oligometastasis can be managed surgically.

Over the last few years, incidental thyroid nodules are being diagnosed with increasing frequency with the use of highly sensitive imaging techniques. The ultrasound thyroid gland examination, followed by the fine-needle aspiration cytology is the standard diagnostic approach. However, in cases of the follicular nature of nodules, cytological diagnosis is not enough. Analysis of miRNAs in the biopsy presents a promising approach. Increasing our knowledge of miRNA&rsquo, s role in follicular carcinogenesis, and development of the appropriate the miRNA analytical technologies are required to implement miRNA-based tests in clinical practice. We used material from follicular thyroid nodes (n.84), grouped in accordance with their invasive properties. The invasion-associated miRNAs expression alterations were assayed. Expression data were confirmed by highly sensitive two-tailed RT-qPCR. Reciprocally dysregulated miRNAs pair concentration ratios were explored as a diagnostic parameter using receiver operation curve (ROC) analysis. A new bioinformatics method (MiRImpact) was applied to evaluate the biological significance of the observed expression alterations. Coupled experimental and computational approaches identified reciprocal dysregulation of miR-146b and miR-451 as important attributes of follicular cell malignant transformation and follicular thyroid cancer progression. Thus, evaluation of combined dysregulation of miRNAs relevant to invasion and metastasis can help to distinguish truly malignant follicular thyroid cancer from indolent follicular adenoma.

Poorly differentiated thyroid carcinomas (PDTCs) are a rare subtype of thyroid carcinomas that are biologically situated between well-differentiated papillary/follicular thyroid carcinomas and anaplastic thyroid carcinomas (ATCs).The diagnosis of conventional as well as oncocytic poorly differentiated thyroid carcinoma is difficult and often missed in daily routine. The current WHO criteria to allow the diagnosis of PDTCs are based on the results of a consensus meeting held in Turin in 2006. Even a minor poorly differentiated component of only 10%of a given carcinoma significantly affects patient prognosis and the oncocytic subtype may even have a worse outcome. Immunohistochemistry is not much help and is mostly used to exclude a medullary thyroid carcinoma with calcitonin and to establish a follicular cell of origin via thyroglobulin staining.Due to the concept of stepwise dedifferentiation, there is a vast overlap of different molecular alterations like BRAF, RAS, CTNNB1, TP53 and others between different thyroid carcinoma subtypes. A distinctive molecular tumor profile is therefore currently not available.PDTCs have a unique miRNA signature, which separates them from other thyroid carcinomas. The average relapse free survival is less than one year and about 50% of patients die of the disease. Modern tyrosine kinase inhibitors offer in conjunction with powerful molecular diagnostic new chances in these difficult to treat carcinomas.

The mammalian ovary is a highly dynamic organ, in which proliferation and differentiation occur constantly during the entire life span, particularly in camels that are characterized by a follicular wave pattern and induced ovulation. Granulosa cells are the main cells of mature follicles. Two distinct cell types, namely, the mural and cumulus granulosa cells are distinguished on the basis of antral fluid increase. The multipotency of follicular fluid and the luteinizing cell were recently demonstrated. However, reports regarding the plasticity of cumulus cells are lacking. We obtained cumulus cells from cumulus-oocyte complexes and showed that camel cumulus cells expressed stem cell mRNA transcripts (POU5A1, KLF4, SOX2, and MYC) and were able to differentiate into other non-ovarian follicular cell types in vitro, such as neurons, osteoblasts, and adipocytes. In contrast, removal of the ooplasm (oocytectemy) showed no effect on cumulus cell proliferation and differentiation. This is the first report to identify an invaluable source of multipotent stem cells, which is routinely discarded during in vitro embryo production. The plasticity and transdifferentiation capability of camel cumulus cells definitely requires attention as it provides a cheap biological experimental model for basic research in stem cells and for understanding ovarian differentiation, both of which are relevant for use in regenerative medicine and tissue engineering in humans and animals.

Medullary thyroid carcinoma (MTC) accounts for 3%-5% of all thyroid malignancies. Most MTC can be diagnosed by their typical cytologic and histologic morphology and immunohistochemical features. However, some rare variants of MTC may pose diagnostic difficulties on both cytology and histology. Paraganglioma-like MTC (PLMTC) is a rare, but widely recognized variant of MTC. PLMTC is known to share morphological and architectural similarities with paraganglioma, hyalinizing trabecular tumor, and carcinomas of thyroid follicular cell origin, such as follicular carcinoma and follicular variant of papillary thyroid carcinoma. The combination of clinicopathologic features and a battery of immunohistochemical markers is essential for making a correct diagnosis. Herein, we report one case of PLMTC with both cytologic and histologic features and review the clinicopathologic features of previously reported cases.

Thyroid carcinomas originating from follicular cells have the prognosis of heterogeneous diseases, but pathologists classify them all as malignant disease. Epidemiologists have issued a stern warning regarding over-diagnosis and overtreatment of patients with indolent thyroid tumors that cause no harm to the patients. Review of the literature revealed that there were several proposals of borderline/precursor tumors to some indolent thyroid carcinomas. Thyroid tumor of uncertain malignant potential (UMP) was first proposed by Williams for encapsulated follicular pattern thyroid tumors to solve problems due to observer variation. Rosai et al. proposed to rename papillary microcarcinoma (PMC) to papillary micro-tumor as the overwhelming majority of them are of no clinical significance. Liu et al. proposed well-differentiated tumor with uncertain behavior (WDT-UB) which covered WDT of UMP (WDT-UMP) and non-invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). The EFVPTC without invasion was renamed as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) by an international panel of pathologists. A new prognostic classification of thyroid tumors was proposed by Kakudo et al., in which extremely low risk tumors were grouped in a borderline tumors category. The borderline/precursor thyroid tumors included encapsulated tumors [capsular invasion only follicular carcinoma, encapsulated papillary carcinoma without invasion, WDT-UMP and follicular tumor of UMP (FT-UMP)] and non-encapsulated tumors (PMC). The UMP and NIFTP were incorporated in the 4th edition WHO classification of thyroid tumors as a new tumor entity in chapter 2-2A: other encapsulated follicular patterned thyroid tumors. Their behavior codes were decided to be 1 (borderline or uncertain behavior), and not 0 (benign), 2 (in situ carcinoma) or 3 (malignant). These borderline/precursor thyroid tumors are indolent tumors biologically and should be treated more conservatively than as previously recommended for thyroid follicular cell carcinomas [total thyroidectomy (TTX) followed by radio-active iodine (RAI) treatment] by western clinical guidelines.

Perfluorooctane sulfonic acid (PFOS), as a potential endocrine disrupting chemical, is widely detected in the environment, wildlife and human. Currently few studies have documented the effects of chronic PFOS exposure on thyroid in aquatic organisms and the underlying mechanisms are largely unknown. The present study assessed the effect of chronic PFOS exposure on thyroid structure and function using zebrafish model. Zebrafish at 8 h post fertilization (hpf) were exposed to PFOS (250 µg/l) until 120 d post fertilization (dpf). Thyroid hormone (T3 and T4) level, thyroid morphology and thyroid function related gene expression were evaluated in zebrafish at 120 dpf. Our findings demonstrated that chronic PFOS exposure altered thyroid hormone level, thyroid follicular cell structure and thyroid hormone related gene expression, suggesting the validity of zebrafish as an alternative model for PFOS chronic toxicity screening.

The vast majority of low grade follicular cell derived thyroid carcinomas follows an indolent clinical course and is associated with very low mortality. Risk stratification using multiple clinical and pathologic characteristics has become the standard of care to guide appropriate management and avoid overtreatment. Over the past few decades, the field of thyroid pathology has witnessed several major changes that significantly impacted upon patients' care. These are: 1) The reclassification of non-invasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features; 2) the diagnosis of Hurthle cell carcinoma based on the presence of capsular and vascular invasion; 3) a detailed definition of poorly differentiated thyroid carcinoma, taking into consideration mitosis and necrosis; and 4) the emphasis on a detailed pathologic analysis such as the extent of vascular invasion and extrathyroidal extension. This review describes these histological concepts and details the history, rationale, and clinical impacts of such changes. These shifts in the classification and characterization of thyroid carcinoma provided a platform supporting therapy de-escalation. In addition several lessons were learned from these changes especially from the misclassification of the non-invasive encapsulated follicular variant of papillary thyroid carcinoma. We hope that the lessons learned will help better classify tumors in the future whether arising in the thyroid or other organs.

Columnar cell variant of papillary thyroid carcinoma (CCV-PTC) is an unusual neoplasm, the clinical behavior of which mainly depends on the encapsulation or infiltration. Patients with extensive extrathyroidal extension usually have an aggressive biological behavior. This study confirmed that beta-human chorionic gonadotropin (β-hCG) secreting invasive CCV-PTC has good prognosis comparing with a cohort of follicular cell differentiated thyroid carcinoma. On the contrary, positive immunoreaction with β-hCG was proved in three anaplastic thyroid carcinoma patients showing aggressive clinical courses. The clinicopathologic characteristics of CCV-PTC and the paraneoplastic syndromes in follicular cell differentiated thyroid carcinoma were further summarized using literature review.

Objectives Experimental models of Graves hyperthyroid disease accompanied by Graves orbitopathy (GO) can be efficiently induced in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. The interrelated pathological findings in the thyroid glands of Graves disease (GD) that explain the core changes classically include diffuse follicular hyperplasia and multifocal mild lymphocytic infiltrate. However, the relative contributions of different thyroid tissue components (colloid, follicular cells, and stroma) have not been previously evaluated. In this study, we characterize the thyroid gland of an experimental mouse model of autoimmune GD. Our objective was to define the relative contribution of the different thyroid tissue components to the pathology of glands in the experimental model. Methods Mice were immunized with human TSHR A-subunit plasmid. Antibodies induced to human TSHR were pathogenic in vivo due to their cross-reactivity to mouse TSHR. Results Autoimmune thyroid disease in the model was characterized by histopathology of hyperplastic glands with large follicular cells. Further examination of thyroid glands of immunized animals revealed a significantly increased follicular area and follicle/stroma ratio, morphometrically correlated with a noninflammatory follicular hyperplasia/hypertrophy. The increased follicle/stroma ratio was the most relevant morphometrically variable summarizing the pathological changes for screening purposes. Conclusion GD thyroid glands are enlarged and characterized by a noninflammatory diffuse follicular cell hyperplasia/hypertrophy and a significant increase in the follicles with an increased follicle/stroma ratio. Overall, this mouse model is a faithful model of an early hyperthyroid status of GD (diffuse glandular involvement and follicular expansion).

Follicular cell-derived thyroid carcinomas, including thyroid squamous cell carcinomas (SCCs) and anaplastic carcinomas, are immunoreactive for paired-box gene 8 (PAX8), while non-follicular cell-derived thyroid carcinomas stain negative for the PAX8 antibody. Intrathyroid thymic carcinoma (ITTC) arising from the intrathyroidal ectopic thymus exhibits moderate-to-strong nuclear reactivity for polyclonal PAX8. This is difficult to understand given that PAX8 is not associated with embryonic thymic development. We aimed to determine the diagnostic significance of monoclonal PAX8 antibody in distinguishing ITTCs from follicular cell-derived thyroid carcinomas. Ten ITTCs, 14 poorly differentiated thyroid carcinomas (PDTCs), 14 thyroid SCCs, 7 thymic tissue specimens, 7 thymomas, and 1 thymic carcinoma were analyzed using antibodies against polyclonal and monoclonal PAX8, thyroid transcription factor-1, p63, and CD5. Four ITTCs (40.0%) stained positive for polyclonal PAX8; none stained positive for monoclonal PAX8. All PDTCs and 92.9% of SCCs were immunoreactive for both polyclonal and monoclonal PAX8. All PDTCs, 46.2% of SCCs, and none of the ITTCs were immunoreactive for thyroid transcription factor-1. Eight ITTCs (80.0%), but none of the PDTCs and SCCs, were immunoreactive for CD5. We are the first to show that ITTCs stain negative for monoclonal PAX8. Monoclonal PAX8 is a more reliable marker than polyclonal PAX8 for determining follicular cell origin. We conclude that monoclonal PAX8 is a useful marker for distinguishing ITTCs from PDTCs and SCCs. Monoclonal PAX8 negativity is additional evidence in support of ITTCs not being follicular cell-derived thyroid carcinomas, but having a thymic origin.

"Noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) is a recent reclassification of the encapsulated follicular variant of papillary thyroid carcinoma, which is supposed to reflect its indolent clinical behavior and to prevent overtreatment of patients with this neoplasm. The diagnosis of NIFTP can only be made histologically on the surgical specimen according to specific inclusion and exclusion criteria, which requires the examination of the whole nodule and its capsule. Spindle cell proliferations, especially of follicular cell origin, arising within thyroid follicular neoplasms are very rare and may cause diagnostic difficulties. Few reports described spindle cell proliferations arising in follicular thyroid adenoma and papillary thyroid carcinoma. To the best of our knowledge, only one case has been reported in NIFTP so far. In this article, we report a unique case of NIFTP associated with a spindle cell proliferation that was characterized immunohistochemically. Specific issues related to this case are discussed.

Deficiency in Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) in humans is associated with the development of congenital hypothyroidism. However, the functions of GLIS3 in the thyroid gland and the mechanism by which GLIS3 dysfunction causes hypothyroidism are unknown. In the current study, we demonstrate that GLIS3 acts downstream of thyroid-stimulating hormone (TSH) and TSH receptor (TSHR) and is indispensable for TSH/TSHR-mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone. Using ChIP-Seq and promoter analysis, we demonstrate that GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, both of which showed enhanced GLIS3 binding at their promoters. The repression of cell proliferation of GLIS3-deficient thyroid follicular cells was due to the inhibition of TSH-mediated activation of the mTOR complex 1/ribosomal protein S6 (mTORC1/RPS6) pathway as well as the reduced expression of several cell division–related genes regulated directly by GLIS3. Consequently, GLIS3 deficiency in a murine model prevented the development of goiter as well as the induction of inflammatory and fibrotic genes during chronic elevation of circulating TSH. Our study identifies GLIS3 as a key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells and uncovers a mechanism by which GLIS3 deficiency causes neonatal hypothyroidism and prevents goiter development.

The goal of this in situ hybridization and image analysis technique is to study the effects of new pharmacological/chemical entities on the thyroid and pituitary gland in rats, reveal the pathogenesis of thyroid follicular cell hypertrophy and to retrospectively exclude the risk of thyroid tumor development in humans. In the present study, we describe the increase of thyroid-stimulating hormone- (TSH-) beta subunit mRNA in the pars distalis of the pituitary gland and the quantitative measurement of TSH mRNA positive cells from rats of three 4-week toxicity studies treated with three different test compounds inducing thyroid follicular cell and hepatocellular hypertrophy in rats. Compared to immunohistochemistry (IHC), in situ hybridization (ISH) for TSH was found to be more sensitive. With this technique we are able to exclude a direct effect of the test compound on the thyroid gland by showing the activation of thyrotrope cells from the pituitary gland and therefore this technique retrospectively enables us to exclude a possible risk for humans at an early stage of drug development. Also in case blood serum samples for evaluation of TSH are not available anymore or hepatocellular hypertrophy is not present (close metabolic relationship between thyroid gland and liver in rodents), the described method allows retrospective investigations on thyroid follicular cell hypertrophy or hyperplasia. This can be of high relevance in human safety assessment for certain drugs in order to exclude a primary effect on the thyroid gland especially when it comes to thyroid neoplasia in rodents as previously described.

Background Some poorly differentiated thyroid carcinomas (PDTC) arise from pre-existing, well-differentiated carcinomas of follicular cell origin; however, others most likely arise de novo. The case of a PDTC adjacent to a pre-existing nodular goiter is very rare. Case presentation A patient had a PDTC, a widely invasive, cellular tumor with cells that lacked the nuclear features of a papillary thyroid carcinoma. Carcinoma cells were arranged in trabecular, solid, and microfollicular histological patterns and displayed high mitotic activity. A nodule partially encapsulated in a thick fibrous capsule was found adjacent to the PDTC. The nodule was composed of small or dilated follicles, without papillary carcinoma-like nuclear features, that were consistent with a nodular goiter. The PDTC showed a high Ki-67 labeling index and an NRAS gene mutation (codon 61, Q61K). Conclusion These results support our diagnosis of a PDTC, probably arising from a nodular goiter.

The histometric and histologic standard techniques were used to provide comprehensive information on the morphological changes in the thyroid gland of West African Dwarf goat during the foetal and postnatal development stages. The foetal age was determined using crown rump length and the pre-pubertal and pubertal age of animals was determined by dentition. The early foetal thyroid, surrounded by a thin capsule of dense irregular connective tissue, was continuous with well vascularised loose connective tissue septa. The parenchyma was composed of solid cell clusters of follicular epithelial cells surrounding small lumina. Follicular arrangement was indistinct in foetal thyroid by 50-70 days of gestational age and many follicles of different sizes were present by 95-125 days onwards. Significant variations in the mean follicular diameter, mean capsule thickness and mean epithelial cell height of the thyroids were observed in all stages of development. The mean large follicular diameter in the foetal, pre-pubertal and pubertal ages were 17.70 ± 0.09 µm, 54.41 ± 0.28 µm,142.77 ± 0.51 µm respectively. The follicular cells were of low cuboidal shape in foetuses, assumed high cuboidal or columnar form in pre-pubertal group and squamous in older pubertal age. Ultimobranchial follicles were encountered in early foetal goat thyroids, while focal areas of follicular cell hyperplasia were frequently seen in the older pubertal thyroids. The strong PAS-positive reaction increased strikingly from the 95-125 days foetal age, and by pubertal age all follicles were fully distended with colloid. Colloid vacuolation (colloid droplets) were encountered frequently by the age of 95-125 days, indicating the ability to synthesize hormones towards the last trimester of gestation. Parafollicular cells were distinguished by its pale cytoplasm and large nucleus at 75-90 days onwards. They were located basally and as clusters in the interfollicular tissue. This finding suggested possible high prenatal function for the thyroids of goats in the synthesis of thyroid hormones.

Selenium (Se) is an essential micronutrient modulating several physiopathological processes in the human body. The aim of the study is to characterize the molecular effects determined by Se-supplementation in thyroid follicular cells, using as model the well-differentiated rat thyroid follicular cell line FRTL5. Experiments have been performed to evaluate the effects of Se on cell growth, mortality and proliferation and on modulation of pro- and antiapoptotic pathways. The results indicate that Se-supplementation improves FRTL5 growth rate. Furthermore, Se reduces the proportion of cell death and modulates both proapoptotic (p53 and Bim) and antiapoptotic (NF-kB and Bcl2) mRNA levels. In addition, incubation with high doses of Na-Se might prevent the ER-stress apoptosis induced by tunicamycin, as assessed by membrane integrity maintenance, reduction in caspase 3/7 activities, and reduction in Casp-3 and PARP cleavage. Taken together, these results provide molecular evidences indicating the role of Se supplementation on cell death and apoptosis modulation in thyroid follicular cells. These observations may be useful to understand the effects of this micronutrient on the physiopathology of the thyroid gland. © 2016 BioFactors, 43(3):415-423, 2017.

Affymetrix Bovine GeneChip® Gene 1.0 ST Array RNA expression analysis was performed on four somatic ovarian cell types: the granulosa cells (GCs) and theca cells (TCs) of the dominant follicle and the large luteal cells (LLCs) and small luteal cells (SLCs) of the corpus luteum. The normalized linear microarray data was deposited to the NCBI GEO repository (GSE83524). Subsequent ANOVA determined genes that were enriched (≥2 fold more) or decreased (≤−2 fold less) in one cell type compared to all three other cell types, and these analyzed and filtered datasets are presented as tables. Genes that were shared in enriched expression in both follicular cell types (GCs and TCs) or in both luteal cells types (LLCs and SLCs) are also reported in tables. The standard deviation of the analyzed array data in relation to the log of the expression values is shown as a figure. These data have been further analyzed and interpreted in the companion article “Gene expression profiling of ovarian follicular and luteal cells provides insight into cellular identities and functions” (Romereim et al., 2017) [1].

Context: The neural cell adhesion molecule CD56 is an antigen important for the differentiation of the follicular epithelium. Recent studies have reported low or absent expression of CD56 in papillary thyroid carcinoma (PTC) and its presence in normal thyroid tissue, benign thyroid lesions, and most follicular non-PTC tumors. Aim: We wish to estimate the value of CD56 in the differentiation of PTC (including follicular variant-PTC [FV-PTC]) from other nontumoral lesions and follicular thyroid neoplasias. Settings and Design: This was a retrospective, case–control study. Subjects and Methods: We analyzed the expression of CD56 in normal thyroid follicular tissue, 15 nonneoplastic thyroid lesions (nodular hyperplasia, Graves' disease, and chronic lymphocytic thyroiditis/Hashimoto), and 38 thyroid follicular cell neoplasms (25 cases of PTC). The immunohistochemical reactions were performed on sections stained with anti-CD56 antibody. Statistical Analysis Used: We used the Chi-square test, values of P< 0.05 being considered statistically significant. Risk analysis was applied on these studied groups, by calculating the odds ratio (OR) value. Results: Our results indicated that CD56 immunoexpression had differentiated PTC from benign nonneoplastic lesions (P = 0.002), as well as from follicular neoplasias (P = 0.046). There were no significant differences regarding CD56 expression between FV-PTC and classical PTC (P = 0.436). The immunoexpression of CD56 has differentiated PTC from other thyroid non-PTC lesions (P < 0.001), with 26.4 OR value. Conclusions: CD56 has been proved to be a useful marker in the diagnosis of PTC, including FV-PTC. Its absence can help differentiate FV-PTC from other thyroid nodules with follicular patterns.

Thiazole-Zn is a systemic fungicide synthesized and developed in China that has been used for the prevention and treatment of bacterial and fungal diseases on fruits and vegetables. Thiazole-Zn is a new thyroid disruptor chemical. The purpose of this study was to clarify the thyroid-disrupting property of thiazole-Zn and the mechanism responsible for thyroid hormone (TH) biosynthesis inhibition in male rats induced by thiazole-Zn. First, the effects of different thiazole-Zn doses and exposure times on the thyroid weights, thyroid morphology and serum hormone levels of rats were investigated. The results showed that thiazole-Zn increased thyroid weights and serum thyroid-stimulating hormone (TSH) levels and induced thyroid cell hypertrophy and hyperplasia in a dose-related and time-related manner. Furthermore, measurement of thyroid radioiodine uptake in vivo in rats confirmed that thiazole-Zn inhibited active iodide uptake into the thyroid, which reduced circulating levels of serum T3 and T4. Decreases in circulating THs resulted in a compensatory increase in serum TSH levels through a negative feedback system. Subsequently, sustained excessive stimulation of the thyroid gland by TSH led to thyroid follicular cell hypertrophy and hyperplasia. In addition, thiazole-Zn increased sodium/iodide symporter (NIS) expression in the rat thyroid, and the increased NIS expression promoted and restored iodide uptake into the thyroids of rats. The risk of iodine intake inhibition by thiazole-Zn to humans, especially susceptible individuals, such as children and pregnant women, warrants additional attention.

To carry out a clinical and morphological analysis of thyroid cancer cases in the children of the Chelyabinsk Region.Thyroid tumor pathology was verified in 50 of the 196 patients aged 7-17 years, who had been operated on in 2000-2016. Clinical and morphological features, including immunohistochemical and ultrastructural characteristics of thyroid cancer, were studied.Over the past 17 years, there has been a decline in the number of children with surgical thyroid diseases, including thyroid carcinomas. There is a predominance of papillary carcinoma (70%) that is characterized by more aggressive clinical and morphological signs than follicular and medullary thyroid carcinoma. The immunophenotype of follicular cell tumors in children is characterized by the expression of growth factors (TTF-1, EGFR-384) and malignancy markers (mesothelial cell, AMACR (P504S), S 100).The vector change (decrease) in the long-term unfavorable trend toward an increasing incidence of thyroid cancer in children of the Chelyabinsk Region is currently accompanied by the pathomorphism of thyroid carcinoma.Цель исследования - клинико-морфологический анализ случаев рака щитовидной железы у детей в Челябинской области. Материал и методы. Из 196 пациентов в возрасте 7-17 лет с заболеваниями щитовидной железы, оперированных в 2000-2016 гг., у 50 детей верифицирована опухолевая патология щитовидной железы. Изучены клинико-морфологические особенности, включая иммуногистохимические и ультраструктурные характеристики рака щитовидной железы. Результаты. За последние 17 лет отмечается снижение количества детей с хирургической патологией щитовидной железы, в том числе с тиреоидными карциномами. Преобладает папиллярный рак (70%), который характеризуется более агрессивными клинико-морфологическими признаками, чем фолликулярная и медуллярная карцинома. Иммунофенотип фолликулярно-клеточных опухолей у детей характеризуется экспрессией ростовых факторов (TTF-1, EGFR-384) и маркеров злокачественности (Mesotelial cell, AMACR (P504S), S 100). Выводы. Смена вектора (снижение) многолетней неблагоприятной тенденции роста заболеваемости раком щитовидной железы у детей в Челябинской области в настоящее время сопровождается патоморфозом тиреоидной карциномы.

Our study aimed to describe the evolution of the rate of pathological subtypes of well-differentiated follicular-cell derived thyroid carcinomas (DTCs) in the Department of Pathology, Emergency County Hospital Targu-Mures, Romania over a 15 year period and to assess the impact the new 2017 WHO and TNM classifications of thyroid tumors had on our cases. The pathological data were retrieved from the original pathological reports. After applying the exclusion criteria the remaining cases were reviewed on a double-headed microscope and reclassified according to the 2017 WHO and TNM staging system. The follow-up data were collected from the Institute of Oncology Cluj-Napoca, Romania. Our study included 396 cases of DTCs (375 papillary, 11 follicular, and 10 Hurthle cell carcinomas). PTCs revealed a significant increasing trend over the study period, whereas follicular and Hurthle cell carcinomas remain rare; 125/131 of noninvasive encapsulated follicular variant PTC (EFVPTC) were reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), resulting in a 33.3% reduction in the number of PTCs. According to 2017 TNM stage-grouping 31% of 271 patients with DTC were downstaged. Follow-up data were available for most of the patients (65.7%, mean period 58.1 months). All patients with noninvasive EFVPTC were disease free at the last clinical assessment. The increasing rate of PTC was maintained even after exclusion of NIFTP. By applying 2017 TNM criteria, a significant number of DTC cases were downstaged into a more favorable group. Follow-up data highlight the indolent behavior of noninvasive EFVPTCs reclassified as NIFTPs.

Thyroid cancer has been rapidly increasing in prevalence among humans in last 2 decades and is the most prevalent endocrine malignancy. Overall, thyroid-cancer patients have good rates of long-term survival, but a small percentage present poor outcome. Thyroid cancer aggressiveness is essentially related with thyroid follicular cell loss of differentiation and metastasis. The discovery of oncogenes that drive thyroid cancer (such as RET, RAS, and BRAF), and are aligned in the MAPK/ERK pathway has led to a new perspective of thyroid oncogenesis. The uncovering of additional oncogene-modulated signaling pathways revealed an intricate and active signaling cross-talk. Among these, microRNAs, which are a class of small, noncoding RNAs, expanded this cross-talk by modulating several components of the oncogenic network – thus establishing a new layer of regulation. In this context, TGFβ signaling plays an important role in cancer as a dual factor: it can exert an antimitogenic effect in normal thyroid follicular cells, and promote epithelial-to-mesenchymal transition, cell migration, and invasion in cancer cells. In this review, we explore how microRNAs influence the loss of thyroid differentiation and the increase in aggressiveness of thyroid cancers by regulating the dual function of TGFβ. This review provides directions for future research to encourage the development of new strategies and molecular approaches that can improve the treatment of aggressive thyroid cancer.

Thyroid cancer is the most common endocrine cancer with predominant prevalence of papillary thyroid cancer (PTC) histotype. MAPK signaling genetic alterations are frequent in PTC, affecting more than 80% of cases. These alterations constitutively activate MAPK signaling cross-regulating different pro-oncogenic pathways. However, additional molecular alterations associated with thyroid cancer are not completely understood. In this extent, the new family of proteins named FAM83 (FAMily with sequence similarity 83) was recently identified as mediator of oncogenic signaling in different types of cancer. Here we report FAM83F as a novel highly expressed protein in PTC. We evaluated FAM83F levels in 106 PTC specimens, 34 goiter, and 41 adjacent non-tumoral human thyroid, and observed FAM83F cytoplasmic overexpression in 71% of PTC (76 of 106) while goiter tissues showed nuclear positivity and normal thyroid showed no staining by immunohistochemistry. Moreover, TSH-induced goiter and BRAF T1799A -induced PTC animal models also showed FAM83F activation. In vitro, we generated a stable thyroid cell line PCCL3 with FAM83F overexpression and observed that FAM83F deregulates thyroid follicular cell biology leading to loss of thyroid differentiation genes such as Sodium-Iodide Symporter (NIS), reactivation of stem cell markers such as LIN28B and SOX2, induction of cell migration and resistance to doxorubicin-induced apoptosis. Moreover, FAM83F activates MAPK signaling through interaction with BRAF and RAF while impairs TGFβ antiproliferative signaling transduction. In this study, we showed FAM83F as a new pro-oncogenic protein overexpressed in thyroid cancer that modulates thyroid follicular cell biology and differentiation through cross-regulation of MAPK and TGFβ signaling.

Adequate levels of iodine, a trace element variably distributed on the earth, are required for the synthesis of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). The iodide cycle consists of a series of transport, oxidation and coupling steps in thyroid follicular cells to produce thyroid hormone. The sodium/iodide symporter (NIS) transports iodide into the thyrocyte. Competitive inhibitors of NIS, such as perchlorate and thiocyanate, can decrease the entrance of iodide into the follicular cell. Pendrin is the primary protein that is responsible for iodide efflux out of the thyrocyte and into the follicular lumen. T4 is deiodinated in target tissues to produce the active form of thyroid hormone, T3, and other metabolites. Exposure to excessive iodine or chronic iodine deficiency may result in various clinical disorders. The Wolff-Chaikoff effect and Jod-Basedow phenomenon describe mechanisms of thyroid autoregulation and dysregulation, respectively, during iodine excess. Population studies have determined that iodine deficiency exists in approximately 38% of the world's population, is the leading cause of preventable mental retardation, and is of particular concern to women and their infants. Finally, the unique role of iodine utilization in thyroid physiology has applications in many important clinical areas.

The differential diagnosis of well-differentiated tumors of follicular cell origin remains the most problematic task in thyroid pathology. Specific morphologic criteria (capsular and/or vascular invasion, nuclear characteristics) are crucial in the diagnosis of these neoplasms. However, the assessment of malignant features is inconclusive in some cases. Moreover, oncocytic thyroid tumors remain controversial in a respect to their pathobiology, behavior and management. Therefore, the useful diagnostic/prognostic thyroid markers are awaited. The aim of our study was to evaluate the expression of galectin-3 and thyroid peroxidase (TPO) in benign and malignant thyroid tumors of follicular cell origin. A total of 186 archival thyroid samples including 38 non-oncocytic follicular adenomas, 53 oncocytic (Hurthle cell) adenomas, 6 non-oncocytic follicular carcinomas, 23 oncocytic (Hurthle cell) carcinomas, 43 non-oncocytic papillary carcinomas, and 23 oncocytic papillary carcinomas were analyzed for galectin-3 and TPO expression by immunohistochemistry. Both types of papillary carcinomas showed significant upregulation of galectin-3 in comparison with the other tumor types, likewise, significant differences in galectin-3 expression were discovered between non-oncocytic and oncocytic variants of studied tumors excluding follicular carcinoma. Significant lowering of TPO was revealed in oncocytic adenomas and papillary carcinomas. In conclusion, the combined use of galectin-3 and TPO markers could help to improve the differential diagnosis of thyroid tumors. Differences in the galectin-3 and TPO expression between some oncocytic and non-oncocytic tumors support their separation in the latest WHO classification of thyroid tumors.

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive undifferentiated follicular-derived thyroid neoplasm. This rare type of thyroid carcinoma (1–2% of all thyroid malignancies) usually develops in elderly patients, presenting as a rapidly growing large and deeply infiltrative thyroid mass. ATC is almost universally rapidly lethal with a median survival less than 6 months. It is typically diagnosed based on clinical symptoms and history. The major role of the pathologist is to differentiate ATC from other primary and secondary thyroid malignancies, which is necessary to direct a treatment. The tumor cells typically show complete loss of differentiation toward follicular cell lineage. Most cases display a mixture of spindle cell, giant cell, and epithelioid patterns rather than pure morphology. Irrespective of the pattern, malignant cells demonstrate a high degree of pleomorphism and brisk mitoses, accompanied by extensive invasion and tumor necrosis. More than half of adequately sampled cases of ATC contain the well-differentiated component. Cases of differentiated thyroid cancer with ATC foci (

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was developed to address terminology and other issues related to thyroid fine-needle aspiration cytology (FNAC) [1, 2]. According to the system, recommended diagnostic categories are classified into six groups: “nondiagnostic or unsatisfactory (ND/UNS),” “benign,” “atypia of undetermined significance or follicular lesion of undetermined significance,” “follicular neoplasm or suspicious for a follicular neoplasm,” “suspicious for malignancy,” and “malignant.” ND/UNS applies to specimens that are unsatisfactory owing to the following: (1) fewer than six groups of well-preserved, well-stained follicular cell groups with ten cells each; (2) poorly prepared, poorly stained, or obscured follicular cells; or (3) cyst fluid, with or without histiocytes, and fewer than six groups of ten benign follicular cells. Cystic papillary thyroid carcinoma cannot be excluded in the last “cyst fluid only (CFO)” scenario, resulting in these cases being classified as ND/UNS [1, 2]. In reporting system of Japanese Society of Thyroid Surgery in 2015, however, CFO is handled differently from TBSRTC.

Background. Thyroid dysfunction is the most common endocrine disorder in clinical practice, and about half of the population with thyroid dysfunction remains undiagnosed. There is a fairly wide spectrum of thyroid dysfunction, which can be identified by patterns of thyroid function test results. The prevalence of thyroid dysfunction among the population varies in different studies. Methods. A cross-sectional study was conducted from February 8th to April 8th, 2017, among patients who requested for the thyroid function test in an endemic goiter area at the Gondar Hospital, University of Gondar. A pretested structured questionnaire was used to collect the data. Three milliliters of blood samples was collected in a plain test tube and centrifuged for serum separation. The thyroid function test was done by using the MINI-VIDAS automation following the manufacturer manual (Setema PLC, Italy). Data were entered and analyzed using SPSS version 20. Descriptive statistics were used for data presentation, and P value Result. Of the total 384 study participants, 346 (90.1%) were females and the study participants’ mean age was 38 ± 13.9 years. The overall thyroid dysfunction prevalence was 26.3% (101): 1.6% was identified as subclinical hypothyroidism, 0.5% hypothyroidism, 9.6% subclinical hyperthyroidism, and 14.6% hyperthyroidism, and 23.4% had goiter. Furthermore, for cytological pattern analysis, 144 study participants who fulfilled indications for fine-needle aspiration cytology (FNAC) in thyroid nodules were included. Of the total, 3 (2.1%) had thyroid carcinoma, 46 (32%) had cystic degenerated follicular cells, and 82 (57%) had nodular thyroid goiter. In addition, a clinical presentation of a total of 144 study participants, showed lymphadenites in 7 participants (4.8%), hypertension in 9 (6.2%), and cardiac failure in 12 (8.3%). Conclusion. The prevalence of thyroid dysfunction was high. The majority of thyroid dysfunction cases were newly diagnosed and more common in females. In addition, the most common disorders were subclinical hyperthyroidism and hyperthyroidism. Follicular cell with cyst degeneration and thyroid nodular goiter were the predominant FNAC findings. For early diagnosis and appropriate intervention in goiter endemic areas, the thyroid function test should be closely monitored.

In 1983, Sakamoto et al. proposed poorly differentiated thyroid carcinoma (PDTC) as a clinicopathologic entity for a high-risk group of papillary and follicular thyroid carcinomas. In 1984, Carcangiu et al. reported the poorly differentiated insular carcinoma, which presented solid clusters “insulae” of tumor cells containing a variable number of small follicles. Subsequently, various diagnostic criteria and terms concerning PDTC have been employed. In 2017, the World Health Organization adopted the Turin proposal that defined PDTC as a follicular cell neoplasm that shows limited evidence of follicular cell differentiation and is morphologically and behaviorally intermediate position between differentiated (papillary and follicular) and anaplastic thyroid carcinomas. Herein, we present a case of PDTC and discuss the cytological features of PDTC and its differential diagnoses.