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1.
Rev Esp Patol ; 53(1): 27-36, 2020.
Artículo en Español | MEDLINE | ID: mdl-31932006

RESUMEN

The recent changes in the classification and staging of thyroid tumors have arisen from the need to provide an adequate response to the exponential increase of thyroid cancer, which, however, has not been accompanied by an increase in mortality. These changes pretend to reduce overdiagnoses of malignancy, unnecessary treatment, side effects as well as cost for the health system. To this end, this article reviews recommendations for the management of thyroid surgical pathology samples with emphasis on the new terminology of the WHO classification. The basic criteria for the diagnosis of malignancy in well-differentiated thyroid carcinomas are reviewed and the criteria for NIFTP (non-invasive follicular tumor with papillary-like nuclear features) diagnosis are updated. Recommendations for the elaboration of the pathological report are also included.

2.
Br J Radiol ; 93(1105): 20180677, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31674803

RESUMEN

OBJECTIVES: Our aim was to compare cancer incidence in a cohort exposed in childhood (1950-63) to a therapeutic dose of radiation in the North of Portugal and followed-up until the end of 2012, with the incidence rates for the same age and sex in the general population. METHODS: A population-based North Region cancer registry (RORENO) was used to assess which members of the cohort developed cancer. The association between radiation exposure and overall and specific cancer sites was evaluated using standardised incidence ratios (SIR). RESULTS: Over the full follow-up period, 3357 individuals of the 5356 original tinea capitis (TC) cohort (63%) were retrieved in the RORENO, and 399 new cancer cases were identified, representing an increased risk of 49% when compared with the general population (SIR = 1.49; 95% CI: 1.35-1.64). The risk was slightly higher in males than in females (SIR = 1.65; 95% CI: 1.43-1.89 vs SIR = 1.35; CI = 1.17-1.55). The risk was slightly higher in the individuals exposed to a higher radiation dose (SIR = 1.78; 95% CI: 1.22-2.51 for ≥630 R vs SIR = 1.46; 95% CI: 1.31-1.62 for 325-475 R). In females, there was an excess cancer risk in all cancers with the higher radiation dose (SIR = 2.00; 95% CI: 1.21-3.13 for ≥630 R vs SIR = 1.30; 95% CI: 1.11-1.51 for 325-475 R) which was not observed in males, and for combined dose categories significantly raised SIRs for thyroid and head and neck cancer, suggesting a possible higher radiosensitivity of females. An increased risk was also observed for some cancers located far from the irradiated area. CONCLUSIONS: The results suggest an association between radiation exposure and later increased cancer risk for cancers located near the radiation exposed area, mainly thyroid, and head and neck cancers. Further studies are necessary to disentangle possible non-radiation causes for distant cancers increased risk. ADVANCES IN KNOWLEDGE: This paper shows a possible association between childhood X-ray epilation and increased risk of cancer which was not previously investigated in the Portuguese TC cohort.


Asunto(s)
Neoplasias Inducidas por Radiación/epidemiología , Tiña del Cuero Cabelludo/radioterapia , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Masculino , Portugal/epidemiología , Sistema de Registros , Factores de Riesgo
3.
Mitochondrion ; 46: 123-133, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-29631022

RESUMEN

We conducted the first systematic omics study of the oncocytic phenotype in 488 papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas. Oncocytic phenotype is secondary to PTC, being unrelated to several pathologic scores. The nuclear genome had low impact on this phenotype (except in specific copy number variation), which was mostly driven by the significant accumulation of mitochondrial DNA non-synonymous and frameshift mutations at high heteroplasmy levels. Energy and mitochondrial-related pathways were significantly enriched in oncocytic tumors that also displayed increased levels of expression for genes involved in autophagy and fusion of mitochondria. Our in vitro tests confirmed that autophagy is increased and functional while mitophagy is decreased in these tumors.


Asunto(s)
ADN Mitocondrial/genética , Perfilación de la Expresión Génica , Mutación , Células Oxífilas/patología , Neoplasias de la Tiroides/patología , Autofagia , Metabolismo Energético/genética , Humanos , Células Oxífilas/fisiología
4.
Thyroid ; 29(1): 7-26, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30484394

RESUMEN

BACKGROUND: The American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) are highly influential practice recommendations. The latest revision appeared in 2015 ("ATA 2015"). These guidelines were developed predominantly by North American experts. European experts frequently have different perspectives, given epidemiological, technological/methodological, practice organization, and medicolegal differences between the respective regions. SUMMARY: Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, four ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed the preoperative assessment of thyroid nodules, surgery and the role of pathology, radioiodine (RAI) therapy (RAIT), the assessment of initial therapy and dynamic risk stratification, and the treatment of persistent disease, recurrences, and advanced thyroid cancer. The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to the permissiveness of ATA 2015 regarding lobectomy for primary tumors ≤4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015's guidance regarding RAIT. European panelists favored wider use of postoperative RAIT than does ATA 2015. Rationales included the modality's association with favorable patient outcomes and generally limited toxicity, and lack of high-quality evidence supporting withholding RAIT. Additionally, European panelists favored recombinant human thyrotropin (rhTSH) in more settings than does ATA 2015, citing avoidance of hypothyroid morbidity and quality-of-life impairment, without apparent sacrifice in oncologic outcomes. Based on clinical evidence plus theoretical advantages, European experts advocated dosimetric versus fixed-activity RAIT approaches for advanced DTC. European panelists noted that the ATA 2015 risk-stratification system requires information sometimes unavailable in everyday practice. ATA 2015 recommendations regarding RAI-refractory DTC should consider potential palliative benefits of RAIT in patients who also have RAI-susceptible lesions. CONCLUSIONS: European panelists suggested modifications to approximately one-third of ATA 2015 recommendations. Varying European and ATA 2015 perspectives can stimulate analysis and discussion of the literature and performance of primary research to resolve discrepant recommendations and potentially improve patient outcomes.


Asunto(s)
Guías de Práctica Clínica como Asunto , Glándula Tiroides/patología , Neoplasias de la Tiroides/terapia , Nódulo Tiroideo/terapia , Adulto , Manejo de la Enfermedad , Europa (Continente) , Humanos , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/patología , Estados Unidos
5.
Int J Mol Sci ; 19(10)2018 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-30274371

RESUMEN

Osteopontin (OPN) spliced variants (OPN-SV: OPNa, OPNb, and OPNc) are aberrantly expressed in tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common type of thyroid cancer (TC). PTC often presents with desmoplasia and dystrophic calcification, including psammoma bodies (PB). This work aimed to investigate total OPN (tOPN) and OPN-SV expression and their association with the presence of PB in the PTC classical variants (cPTC), as well as the involvement of OPN-SV in matrix calcification of TC cell lines. We found that cPTC samples presenting PB showed higher OPN expression levels. In TC cell lines, OPNa overexpression promotes higher matrix calcification and collagen synthesis when compared to that of clones overexpressing OPNb or OPNc. In response to OPN knockdown, calcification was inhibited, paralleled with the downregulation of calcification markers. In conclusion, our data evidenced that OPN expression is associated with the presence of PB in cPTC samples. Among the OPN-SV, OPNa is the main contributor to matrix calcification in tested TC cells, providing clues to a better understanding on the biology and ethiopathogenesis of the calcification process in TC cells.


Asunto(s)
Calcinosis/metabolismo , Matriz Extracelular/metabolismo , Osteopontina/metabolismo , Neoplasias de la Tiroides/metabolismo , Calcinosis/patología , Colágeno/biosíntesis , Femenino , Silenciador del Gen , Humanos , Masculino , Persona de Mediana Edad , Osteocalcina/metabolismo , Osteopontina/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Coloración y Etiquetado , Cáncer Papilar Tiroideo/metabolismo , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Factores de Tiempo
6.
Endocrine ; 61(3): 489-498, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29948935

RESUMEN

PURPOSE: Evaluate the impact of TERTp mutation on the outcomes after initial treatment of 45 patients with thyroid carcinomas derived from follicular cells (TCDFC) with aggressive histology, in which the role of this mutation is not yet well defined. METHODS: Analysis of the presence of TERTp (-124C > T and -146C > T), BRAF (V600E), and NRAS (Q 61R) mutations by Sanger sequencing and analysis of their correlation with the patient's outcomes. RESULTS: Forty-five patients with aggressive histopathologic variants were included in the study. Of these, 68.9% had aggressive variants of papillary thyroid cancer (PTC), 22.2% had poorly differentiated thyroid carcinoma (PDTC)/insular carcinoma, and 8.9% had invasive follicular thyroid cancer (FTC) with Hurthle cell features (Hurthle cell carcinoma). Lymph node metastases were present in 46.7% and distant metastases in 54.6%. The response to the initial therapy was excellent in 45.5% and structurally incomplete in 50%. During the follow-up period (median of 56 months; 5-360 months), 47.7% presented with disease progression and 17.8% experienced disease-related death. In 53.3% of the cases at least one molecular alteration (TERTp in 33.4%, BRAF in 24.5%, RAS in 8.9%) was detected. In the multivariate analysis, TERTp mutation was the factor associated with the highest risk (6 times) of having structural disease after initial therapy (p = 0.01), followed by vascular invasion (p = 0.02), gross extrathyroidal extension (ETE) (p = 0.02) and distant metastasis (p = 0.04). Regarding mutational status, only TERTp mutation was associated with disease progression, and diminished disease progression-free survival (PFS). The presence of distant metastasis, vascular invasion and gross ETE were significantly associated with the risk of disease progression. CONCLUSIONS: TERTp mutation appears be an indicator of both persistence and progression of structural disease after initial therapy in aggressive variants of TCDFC, and associates with a shorter progression free survival regardless of the therapy employed.


Asunto(s)
Adenocarcinoma Folicular/genética , Mutación , Telomerasa/genética , Neoplasias de la Tiroides/genética , Adenocarcinoma Folicular/mortalidad , Adenocarcinoma Folicular/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Regiones Promotoras Genéticas , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología , Factores de Tiempo , Adulto Joven
7.
Int J Mol Sci ; 19(5)2018 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-29757257

RESUMEN

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression.


Asunto(s)
Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Transducción de Señal , Simportadores/genética , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Carcinoma Papilar/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/patología
8.
Mod Pathol ; 31(8): 1168-1179, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29785019

RESUMEN

Cribriform-morular variant of thyroid carcinoma is classically associated with familial adenomatous polyposis but, it can also occur as a sporadic neoplasm. This neoplasm is much more frequently observed in women than in men (ratio of 61:1). In familial adenomatous polyposis patients, tumors are generally multifocal and/or bilateral (multinodular appearance), whereas in the sporadic cases tumors tend to occur as single nodules. The tumors are well delimited, and characteristically show a blending of follicular, cribriform, papillary, trabecular, solid, and morular patterns. Neoplastic cells are tall or cuboidal with the occasional nuclear features of classic papillary thyroid carcinoma. The morules include cells with peculiar nuclear clearing and show positivity for CDX2 and CD10. Angioinvasion and capsular invasion have been described in about 30 and 40% of cases, respectively, with lymph node metastases in less than 10% of patients and distant metastases in 6%. Although this tumor has good prognosis, neuroendocrine and/or poor differentiation have been associated with aggressive behavior. Tumor cells can be focally positive or negative for thyroglobulin, but are always positive for TTF-1, estrogen and progesterone receptors, and negative for calcitonin and cytokeratin 20. Nuclear and cytoplasmic staining for ß-catenin is the hallmark of this tumor type; this feature plays a role in fine needle aspiration biopsy. Cribriform-morular variant of thyroid carcinoma has a peculiar endodermal (intestinal-like) type phenotype, activation of the WNT/ß-catenin signaling pathway, and belongs to the non-BRAF-non-RAS subtype of the molecular classification of thyroid tumors. Elevated expression of estrogen and progesterone receptors and activation of the WNT/ß-catenin pathway may prove useful as putative therapeutic targets in cases that do not respond to conventional therapy. Clinicians should be alerted to the possibility of familial adenomatous polyposis when a diagnosis of cribriform-morular variant of thyroid carcinoma is made. Instead of being considered as a variant of papillary thyroid carcinoma its designation as cribriform-morular thyroid carcinoma seems more appropriate.


Asunto(s)
Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Vía de Señalización Wnt/fisiología , Poliposis Adenomatosa del Colon/complicaciones , Femenino , Humanos , Masculino , Fenotipo , Cáncer Papilar Tiroideo/metabolismo , Neoplasias de la Tiroides/metabolismo
9.
Genes (Basel) ; 9(5)2018 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-29751586

RESUMEN

Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance. In this review, we address seven different TMMs in tumour cells: mutations of the TERT promoter (TERTp), amplification of the genes TERT and TERC, polymorphic variants of the TERT gene and of its promoter, rearrangements of the TERT gene, epigenetic changes, ALT, and non-defined TMM (NDTMM). We gathered information from over fifty thousand patients reported in 288 papers in the last years. This wide data collection enabled us to portray, by organ/system and histotypes, the prevalence of TERTp mutations, TERT and TERC amplifications, and ALT in human tumours. Based on this information, we discuss the putative future clinical impact of the aforementioned mechanisms on the malignant transformation process in different setups, and provide insights for screening, prognosis, and patient management stratification.

10.
Am J Clin Pathol ; 149(5): 379-386, 2018 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-29538609

RESUMEN

Objectives: Multinodular goiter (MNG) and well-differentiated thyroid carcinoma (WDTC) are emerging phenotypes of DICER1 syndrome. Methods: Histologic and molecular findings of botryoid-type embryonal rhabdomyosarcoma (bERMS) and thyroid nodules from a 12-year-old DICER1 mutation carrier (p.Arg1060Ilefs*7) were investigated, providing interesting clues for understanding thyroid carcinogenesis. Results: The patient had bERMS at age 7 years. The thyroid was enlarged and multinodular (61 g). Histologically, some nodules were classified as adenomatous and others as tumors with "intermediate" nuclei. One displayed vascular invasion and was classified as WDTC not otherwise specified (NOS). Somatic DICER1 mutations were identified in bERMS, two tumors with "intermediate" nuclei and WDTC. No somatic DICER1 mutations were found in adenomatous nodules. No molecular alterations were detected in BRAF600, NRAS61, HRAS12/61, KRAS12/61, TERT promoter, RET/PTC1, RET/PTC3, and PAX8/PPARγ. Conclusions: The findings obtained from this single case support the assumption that DICER1 syndrome-related WDTC NOS may develop on a background of MNG, via a stepwise process, involving DICER1 somatic mutations and additional molecular events, distinct from the classic pathways of papillary/follicular carcinoma.


Asunto(s)
ARN Helicasas DEAD-box/genética , Bocio Nodular/genética , Rabdomiosarcoma Embrionario/genética , Ribonucleasa III/genética , Neoplasias de la Tiroides/genética , Carcinogénesis , Niño , Progresión de la Enfermedad , Femenino , Bocio Nodular/diagnóstico , Bocio Nodular/patología , Humanos , Mutación , Rabdomiosarcoma Embrionario/patología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/patología , Tiroidectomía
14.
Radiat Res ; 189(4): 418-424, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29461943

RESUMEN

Nontargeted late effects of radiation include an increased risk of cardiovascular disease, although this is still debatable in the context of low-dose radiation. Tinea capitis patients treated in childhood with X rays to induce scalp epilation received a low dose of radiation to their carotids. To better clarify this issue, we evaluated carotid atherosclerosis in a cohort of such patients treated in 1950-1963 in Portugal. A group of 454 individuals randomly chosen from previously observed Portuguese tinea capitis patients and a control group mainly composed of their spouses (n = 280) were enrolled. Cardiovascular risk factors such as waist circumference, body mass index, blood pressure and tobacco consumption, as well as biochemical measurements were obtained. Ultrasound imaging of carotid arteries for intima media thickness and stenosis evaluation were performed according to a standardized protocol. In comparison to the control group, the irradiated cohort members were significantly older, more frequently never smokers, hypertensive, and presented higher glycated hemoglobin and alkaline phosphatase levels. In addition, the irradiated cohort showed a higher frequency of carotid stenosis ≥30% than the nonirradiated group (13.9% vs. 10.7%), although this was not significant ( P = 0.20). Stenosis was ≥50% in 2.9% of the irradiated group and 0.4% of the nonirradiated group ( P = 0.02). Likewise, the frequency of intima media thickness ≥1 mm was significantly higher in the irradiated group (16.8% vs. 10.7%; P = 0.02). Multivariate analysis, including other cardiovascular risk factors, showed that exposure to low-dose radiation increased the risk of carotid stenosis by ≥50% [odds ratio (OR) = 8.85; P = 0.04] and intima media thickness by ≥1 mm (OR = 1.82; P = 0.02). These findings confirm that low-dose exposure is a risk factor of carotid atherosclerotic disease.


Asunto(s)
Aterosclerosis/etiología , Traumatismos por Radiación/etiología , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo
15.
Genes (Basel) ; 9(2)2018 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-29466320

RESUMEN

Mitochondrial dynamics are known to have an important role in so-called age-related diseases, including cancer. Mitochondria is an organelle involved in many key cellular functions and responds to physiologic or stress stimuli by adapting its structure and function. Perhaps the most important structural changes involve mitochondrial dynamics (fission and fusion), which occur in normal cells as well as in cells under dysregulation, such as cancer cells. Dynamin-related protein 1 (DRP1), a member of the dynamin family of guanosine triphosphatases (GTPases), is the key component of mitochondrial fission machinery. Dynamin-related protein 1 is associated with different cell processes such as apoptosis, mitochondrial biogenesis, mitophagy, metabolism, and cell proliferation, differentiation, and transformation. The role of DRP1 in tumorigenesis may seem to be paradoxical, since mitochondrial fission is a key mediator of two very different processes, cellular apoptosis and cell mitosis. Dynamin-related protein 1 has been associated with the development of distinct human cancers, including changes in mitochondrial energetics and cellular metabolism, cell proliferation, and stem cell maintenance, invasion, and promotion of metastases. However, the underlying mechanism for this association is still being explored. Herein, we review the published knowledge on the role of DRP1 in cancer, exploring its interaction with different biological processes in the tumorigenesis context.

16.
Endocr Relat Cancer ; 25(4): R247-R258, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29439059

RESUMEN

The 2017 edition of the WHO book on Classification of Tumours of Endocrine Organs includes a new section entitled 'Other encapsulated follicular-patterned thyroid tumours', in which the newly created NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) is identified and described in detail. Despite deleting the word 'carcinoma' from its name, NIFTP is not a benign tumor either and is best regarded as a neoplasm with 'very low malignant potential'. The main goal of the introduction of NIFTP category is to prevent overdiagnosis and overtreatment. Sampling constraints, especially when dealing with heterogeneous and/or large nodules, and difficulties in the invasiveness evaluation, are the major weaknesses of the histological characterization of NIFTP. At the cytological level, NIFTP can be separated from classic papillary carcinoma (cPTC) but not from encapsulated, invasive follicular variant PTC. The impact of NIFTP individualization for cytopathology is the drop of rates of malignancy for each Bethesda category in general and for indeterminate categories in particular. The biggest impact will be seen in institutions with a high frequency of FVPTC. The introduction of NIFTP has changed the utility of predictive values of molecular tests because RAS mutations and PAX8-PPARg rearrangements are frequently detected in NIFTP. This turns less promising the application of mutation detection panels as indicators of malignancy and will probably contribute to switch to a rule-out approach of molecular testing. Selection for surgery will go on being determined by a combined detection of clinical, cytological and ultrasound suspicious features.


Asunto(s)
Adenocarcinoma Folicular/patología , Carcinoma Papilar/patología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/patología , Adenocarcinoma Folicular/clasificación , Carcinoma Papilar/clasificación , Humanos , Neoplasias de la Tiroides/clasificación , Nódulo Tiroideo/clasificación
17.
Endocr Connect ; 7(1): 78-90, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29298843

RESUMEN

Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the SLC5A5 gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied SLC5A5 expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database. In our series, SLC5A5 expression was lower in carcinomas with vascular invasion and with extrathyroidal extension and in those harboring BRAFV600E mutation. Analysis of SLC5A5 expression from TCGA database confirmed our results. Furthermore, it showed that larger tumors, with locoregional recurrences and/or distant metastases or harboring RAS, BRAF and/or TERT promoter (TERTp) mutations presented significantly less SLC5A5 expression. Regarding immunohistochemistry, 12/211 of the cases demonstrated NIS in the membrane of tumor cells, those cases showed variable outcomes concerning therapy success, prognosis and all but one were wild type for BRAF, NRAS and TERTp mutations. SLC5A5 mRNA lower expression is associated with features of aggressiveness and with key genetic alterations involving BRAF, RAS and TERTp. Mutations in these genes seem to decrease protein expression and its targeting to the cell membrane. SLC5A5 mRNA expression is more informative than NIS immunohistochemical expression regarding tumor aggressiveness and prognostic features.

18.
BMC Cancer ; 18(1): 68, 2018 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-29321030

RESUMEN

BACKGROUND: The prognostic variability of thyroid carcinomas has led to the search for accurate biomarkers at the molecular level. Follicular thyroid carcinoma (FTC) is a typical example of differentiated thyroid carcinomas (DTC) in which challenges are faced in the differential diagnosis. METHODS: We used high-throughput paired-end RNA sequencing technology to study four cases of FTC with different degree of capsular invasion: two minimally invasive (mFTC) and two widely invasive FTC (wFTC). We searched by genes differentially expressed between mFTC and wFTC, in an attempt to find biomarkers of thyroid cancer diagnosis and/or progression. Selected biomarkers were validated by real-time quantitative PCR in 137 frozen thyroid samples and in an independent dataset (TCGA), evaluating the diagnostic and the prognostic performance of the candidate biomarkers. RESULTS: We identified 17 genes significantly differentially expressed between mFTC and wFTC. C1QL1, LCN2, CRABP1 and CILP were differentially expressed in DTC in comparison with normal thyroid tissues. LCN2 and CRABP1 were also differentially expressed in DTC when compared with follicular thyroid adenoma. Additionally, overexpression of LCN2 and C1QL1 were found to be independent predictors of extrathyroidal extension in DTC. CONCLUSIONS: We conclude that the underexpression of CRABP1 and the overexpression of LCN2 may be useful diagnostic biomarkers in thyroid tumours with questionable malignity, and the overexpression of LCN2 and C1QL1 may be useful for prognostic purposes.


Asunto(s)
Adenocarcinoma Folicular/diagnóstico , Lipocalina 2/genética , Receptores de Ácido Retinoico/genética , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Complemento C1q/genética , Diagnóstico Diferencial , Proteínas de la Matriz Extracelular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Pronóstico , Pirofosfatasas/genética , Transcriptoma/genética
19.
PeerJ ; 5: e3778, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28929017

RESUMEN

BACKGROUND: Calcitonin expression is a well-established marker for medullary thyroid carcinoma (MTC); yet the role of calcitonin receptor (CTR), its seven-transmembrane G-protein coupled receptor, remains to be established in C-cells derived thyroid tumors. The aim of this work was to investigate CTR expression in MTC and to correlate such expression with clinicopathological features in order to evaluate its possible role as a prognostic indicator of disease aggressiveness and outcome. METHODS: Calcitonin receptor expression was analyzed in a series of 75 MTCs by immunohistochemistry, and by qPCR mRNA quantification in specimens from four patients. Statistical tests were used to evaluate the correlation between CTR expression and the clinicopathological and molecular characteristics of patients and tumors. RESULTS: Calcitonin receptor expression was detected in 62 out of 75 samples (82.7%), whereas 13 of the 75 samples (17.3%) were completely negative. CTR expression was significantly associated with expression of cytoplasmatic phosphatase and tensin homologue deleted on chromosome 10 and osteopontin, as well as with wild type RET/RAS genes and absence of tumor stroma, suggesting that CTR expression do not associate with clinicopathological signs of worse prognosis. DISCUSSION: Calcitonin receptor expression appears to be associated in MTC with more differentiated status of the neoplastic cells.

20.
Horm Cancer ; 8(5-6): 314-324, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28924876

RESUMEN

Growth hormone-releasing hormone (GHRH) is a peptide hormone secreted by the hypothalamus that regulates the synthesis and secretion of growth hormone (GH) in the pituitary. The extra-hypothalamic GHRH and its cognate receptors (GHRHR and splice variants) play a mitogenic role by stimulating cell proliferation and preventing apoptotic cell death. It is well established that GHRH antagonists inhibit the growth, tumorigenicity, and metastasis of various human malignancies. In this work, we studied the effect of two new GHRH antagonists, MIA602 and MIA690, on thyroid cancer. We studied the effect of MIA602 and MIA690 on thyroid cancer in vitro, using human thyroid cancer cell lines, and in vivo, using chicken embryo chorioallantoic membrane (CAM) assays. We found that mRNA for GHRH and GHRH receptor is expressed in thyroid cell lines and in samples of thyroid tumors. Immunohistochemistry confirmed the expression of GHRHR protein in specimens of thyroid tumor. We observed that GHRH antagonists inhibited the growth and increased apoptosis of thyroid cancer cells. In vivo, the antagonists inhibited growth and angiogenesis of engrafted thyroid tumors. Our results suggest that GHRH expression may play a role in growth of thyroid cancer and that GHRH antagonists can be a therapeutic option for thyroid cancer patients.


Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/antagonistas & inhibidores , Neoplasias de la Tiroides/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Embrión de Pollo , Expresión Génica , Hormona Liberadora de Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Humanos , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , ARN Mensajero/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología
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