136 resultados para thyroid follicular carcinoma
em Biblioteca Digital da Produção Intelectual da Universidade de São Paulo (BDPI/USP)
Resumo:
Background: Papillary thyroid carcinoma (PTC) is frequently associated with a RET gene rearrangement that generates a RET/PTC oncogene. RET/PTC is a fusion of the tyrosine kinase domain of RET to the 50 portion of a different gene. This fusion results in a constitutively active MAPK pathway, which plays a key role in PTC development. The RET/PTC3 fusion is primarily associated with radiation-related PTC. Epidemiological studies show a lower incidence of PTC in radiation-exposed regions that are associated with an iodine-rich diet. Since the influence of excess iodine on the development of thyroid cancer is still unclear, the aim of this study is to evaluate the effect of high iodine concentrations on RET/PTC3-activated thyroid cells. Methods: PTC3-5 cells, a rat thyroid cell lineage harboring doxycycline-inducible RET/PTC3, were treated with 10(-3) M NaI. Cell growth was analyzed by cell counting and the MTT assay. The expression and phosphorylation state of MAPK pathway-related (Braf, Erk, pErk, and pRet) and thyroid-specific (natrium-iodide symporter [Nis] and thyroid-stimulating hormone receptor [Tshr]) proteins were analyzed by Western blotting. Thyroid-specific gene expression was further analyzed by quantitative reverse transcription (RT)-polymerase chain reaction. Results: A significant inhibition of proliferation was observed, along with no significant variation in cell death rate, in the iodine-treated cells. Further, iodine treatment attenuated the loss of Nis and Tshr gene and protein expression induced by RET/PTC3 oncogene induction. Finally, iodine treatment reduced Ret and Erk phosphorylation, without altering Braf and Erk expression. Conclusion: Our results indicate an antioncogenic role for excess iodine during thyroid oncogenic activation. These findings contribute to a better understanding of the effect of iodine on thyroid follicular cells, particularly how it may play a protective role during RET/PTC3 oncogene activation.
Resumo:
The inhibitory effect of supraphysiological iodide concentrations on thyroid hormone synthesis (Wolff - Chaikoff effect) and on thyrocyte proliferation is largely known as iodine autoregulation. However, the molecular mechanisms by which iodide modulates thyroid function remain unclear. In this paper, we analyze the transcriptome profile of the rat follicular cell lineage PCCl3 under untreated and treated conditions with 10 (- 3) M sodium iodide (NaI). Serial analysis of gene expression (SAGE) revealed 84 transcripts differentially expressed in response to iodide (p <= 0.001). We also showed that iodide excess inhibits the expression of essential genes for thyroid differentiation: Tshr, Nis, Tg, and Tpo. Relative expression of 14 of 20 transcripts selected by SAGE was confirmed by real-time PCR. Considering the key role of iodide organification in thyroid physiology, we also observed that both the oxidized form of iodide and iodide per se are responsible for gene expression modulation in response to iodide excess. (c) 2008 Elsevier Inc. All rights reserved.
Resumo:
Thyroid cancer is the most frequent endocrine neoplasia worldwide. The route for metastasis and loco-regional invasion preferentially occurs by lymphatic vessels. For this reason, the assessment of lymphatic vessel density (LVD) is supposed to represent both a prognostic parameter and also a potential therapeutic target. In order to evaluate the value of LVD in benign and malignant thyroid lesions, we analyzed 110 thyroidectomy specimens using D2-40, a specific marker for lymphatic vessels and vascular endothelial growth factor C (VEGF-C), the most potent molecule of lymphatic proliferation. LVD was significantly different between papillary and follicular carcinomas in total (p = 0.045) and peritumoral area (p = 0.042). Follicular adenoma and follicular carcinoma showed an important difference of intra- (p = 0.019) and peritumoral (p = 0.033) LVD. VEGF-C was more markedly expressed in malignancies than in benignant lesions (p = 0.0001). Almost all cancers with high positive VEGF-C expression also exhibited increased peritumoral LVD (p = 0.049) when compared with the benignant lesions. Indeed, the high peritumoral LVD of malignant thyroid lesions is an important finding for surgery planning and supports the practice of total thyroidectomy in malignant thyroid neoplasm`s since the lymphatic peritumoral vessels definitely are an escape path for tumor cells.
Resumo:
OBJECTIVE: To investigate the expression of SMAD proteins in human thyroid tissues since the inactivation of TGF-β/activin signaling components is reported in several types of cancer. Phosphorylated SMAD 2 and SMAD3 (pSMAD2/3) associated with the SMAD4 induce the signal transduction generated by TGF-β and activin, while SMAD7 inhibits this intracellular signaling. Although TGF-β and activin exert antiproliferative roles in thyroid follicular cells, thyroid tumors express high levels of these proteins. MATERIALS AND METHODS: The protein expression of SMADs was evaluated in multinodular goiter, follicular adenoma, papillary and follicular carcinomas by immunohistochemistry. RESULTS: The expression of pSMAD2/3, SMAD4 and SMAD7 was observed in both benign and malignant thyroid tumors. Although pSMAD2/3, SMAD4 and SMAD7 exhibited high cytoplasmic staining in carcinomas, the nuclear staining of pSMAD2/3 was not different between benign and malignant lesions. CONCLUSIONS: The finding of SMADs expression in thyroid cells and the presence of pSMAD2/3 and SMAD4 proteins in the nucleus of tumor cells indicates propagation of TGF-β/activin signaling. However, the high expression of the inhibitory SMAD7, mostly in malignant tumors, could contribute to the attenuation of the SMADs antiproliferative signaling in thyroid carcinomas.
Resumo:
Context: Iodide transport defect (ITD) is an autosomal recessive disorder caused by impaired Na(+)/I(-) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Clinical manifestations comprise a variable degree of congenital hypothyroidism and goiter, and low to absent radioiodide uptake, as determined by thyroid scintigraphy. Hereditary molecular defects in NIS have been shown to cause ITD. Objective: Our objective was to perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical ITD phenotype. Design: The genomic DNA encoding NIS was sequenced, and an in vitro functional study of a newly identified NIS mutation was performed. Results: The analysis revealed the presence of an undescribed homozygous C to T transition at nucleotide -54 (-54C>T) located in the 5`-untranslated region in the NIS sequence. Functional studies in vitro demonstrated that the mutation was associated with a substantial decrease in iodide uptake when transfected into Cos-7 cells. The mutation severely impaired NIS protein expression, although NIS mRNA levels remained similar to those in cells transfected with wild-type NIS, suggesting a translational deficiency elicited by the mutation. Polysome profile analysis demonstrated reduced levels of polyribosomes-associated mutant NIS mRNA, consistent with reduced translation efficiency. Conclusions: We described a novel mutation in the 5`-untranslated region of the NIS gene in a newborn with congenital hypothyroidism bearing a clinical ITD phenotype. Functional evaluation of the molecular mechanism responsible for impaired NIS-mediated iodide concentration in thyroid cells indicated that the identified mutation reduces NIS translation efficiency with a subsequent decrease in protein expression and function. (J Clin Endocrinol Metab 96: E1100-E1107, 2011)
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Background: The vascular endothelial growth factor (VEGF) is a major promoter of endothelial growth and migration. Some studies have shown a correlation between expression of this growth factor and prognosis in several cancers, including well-differentiated thyroid cancer. Aim: We studied VEGF expression, local invasiveness, and other prognostic factors in papillary thyroid carcinoma (PTC) to test the hypothesis that the expression of VEGF is correlated with the degree of invasion of PTC. Patients and Methods: Clinical and pathological data of 76 patients with PTC were retrospectively reviewed. Group 1 consisted of patients with gross locally invasive tumors, group 2 consisted of patients with only invasion of the thyroid capsule, and group 3 consisted of patients with noninvasive PTC. Results: VEGF expression was noted within the tumor in all groups of PTC patients but was absent in the surrounding normal tissue. Older patients had higher expression of VEGF than younger patients. The age of patients with strong reaction to VEGF was 46 +/- 14 (mean +/- standard deviation), and that in patients with a weaker reaction was 39 +/- 16 (p<0.05). Only 20% of patients with a follicular variant of PTC had a strong reaction to VEGF compared with 68% of patients with classical PTC (p<0.01). Conclusions: VEGF expression appears to be an early event in the development of PTC. Whether VEGF expression promotes the progression of PTC is not known, but the answer to this question may be important in view of its greater expression in older patients, a group whose prognosis in PTC is worse.
Resumo:
Background: Metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) participate in the degeneration of the extracellular matrix and are associated with carcinogenesis. MMP-2 is one of the main metalloproteinases active in neoplasia and is a marker of the malignant phenotype. Since the biological behavior of medullary thyroid carcinoma (MTC) varies widely, the present study was undertaken to determine if there is a correlation between the clinical evolution of MTC and the immunohistochemically detected expression of these enzymes in thyroid surgical specimens containing MTC. If so, their expression would be a novel indicator of the prognosis of MTC. Methods: Thirty-seven patients with MTC who had undergone thyroid surgery were followed for an average of 73 months. Immunohistochemical staining for metalloproteinase-related enzymes was performed in surgical paraffin blocks. The clinical status of the patients after surgery and at the end of the study period was characterized to determine correlations between these and the immunohistochemical markers. A value of p < 0.05 was considered statistically significant. Results: At the end of the study period, 15 patients (40.5%) were alive and without evidence of MTC, 17 (45.9%) had persistent MTC, and 5 (13.5%) had a relapse of their neoplasia. Four patients (10.8%) died during the course of the study. There was a significant correlation (p = 0.0005) between the immunohistochemical staining for MMP-2 and the clinical condition of the patients at the end of the study period, and a correlation between the state of apparent cure compared to persistence of MTC after thyroid surgery (p = 0.0207). No significant correlations were observed between either TIMP-2 expression or immune marking of metastatic lymph nodes and the clinical variables studied. Conclusion: Immunohistochemical expression of MMP-2 in thyroid surgical specimens from patients with MTC is a novel indicator of the prognosis of this cancer.
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Purpose: To identify papillary thyroid carcinoma (PTC)-associated transcripts, we compared the gene expression profiles of three Serial Analysis of Gene Expression libraries generated from thyroid tumors and a normal thyroid tissue. Experimental Design: Selected transcripts were validated in a panel of 57 thyroid tumors using quantitative PCR (qPCR). An independent set of 71 paraffin-embedded sections was used for validation using immunohistochemical analysis. To determine if PTC-associated gene expression could predict lymph node involvement, a separate cohort of 130 primary PTC (54 metastatic and 76 nonmetastatic) was investigated. The BRAF(V600E) mutational status was compared with qPCR data to identify genes that might be regulated by abnormal BRAF/MEK/extracellular signal-regulated kinase signaling. Results: We identified and validated new PTC-associated transcripts. Three genes (CST6, CXCL14, and DHRS3) are strongly associated with PTC. Immunohistochemical analysis of CXCL14 confirmed the qPCR data and showed protein expression in PTC epithelial cells. We also observed that CST6, CXCL14, DHRS3, and SPP1 were associated with PTC lymph node metastasis, with CST6, CXCL14, and SPP1 being positively correlated with metastasis and DHRS3 being negatively correlated. Finally, we found a strong correlation between CST6 and CXCL14 expression and BRAF(V600E) mutational status, suggesting that these genes may be induced subsequently to BRAF activation and therefore may be downstream in the BRAF/MEK/extracellular signal-regulated kinase signaling pathway. Conclusion: CST6, CXCL14, DHRS3, and SPP1 may play a role in PTC pathogenesis and progression and are possible molecular targets for FTC therapy.
Resumo:
Purpose. Total thyroidectomy (TT) with level VI and VII central neck dissection is the initial treatment for medullary thyroid carcinoma (MTC) without identifiable neck metastasis. Level II to V lateral neck dissection is performed if neck metastasis is present or suspected. We conducted this study to identify the frequency and clinical determinants of skip neck metastasis in MTC. Methods. We reviewed the medical records of 32 patients who underwent TT and bilateral neck dissection for MTC. The clinical features were correlated with pN status in the central versus lateral compartments of the neck. Results. Neck lymph node metastasis (pN+) was found in 20 patients (62.5%) and skip metastases were found in 7 (35%) patients. The sensitivity of the pN status of the central compartment of the neck to predict the pN status of the lateral compartment of the neck was 53.8% and specificity was 63.2%. We found pN+ in 90% of the patients with lymph nodes > 15mm in diameter versus 50% in those with lymph nodes < 1.5mm in diameter. Conclusions. There is skip metastasis in MTC. It is unsafe to use the lymph node status of the central compartment of the neck to define the pN status of the lateral neck. A lymph node greater than 15 mm in diameter is related to pN status.
Resumo:
Background. Clinical and pathologic examinations cannot always provide a prognosis for patients with medullary thyroid carcinoma. Membrane type 1 matrix metalloproteinase (MT1-MMP) can act directly on carcinogenesis and takes part in 1 of the processes of metalloproteinase 2 activation, an enzyme related to prognostic impairment of patients with such tumor. Methods. Thirty-five patients who were submitted to surgery were followed up for an average of 74 months, Postoperative and final medical conditions were characterized for comparison with MT1-MMP immunostainings, performed in surgical paraffin blocks. A value of p < .05 was considered statistically significant. Results. Proposed index (association of proportion and intensity of immunostaining) and proportion of immunostained cells in primary specimens were correlated with cure or persistence after initial operations (p = .0216 and p = .0098, respectively). Conclusion. MT1-MMP immunostaining in primary tumor specimens is a new and complementary prognostic predictor in patients with medullary thyroid carcinomas. (C) 2009 Wiley Periodicals, Inc. Head Neck 32: 58-67, 2010
Resumo:
Objectives: To develop an index for the ratio of metalloproteinase 2 (MMP-2) to its tissue inhibitor (TIMP-2) in immunostained medullary thyroid carcinoma specimens and to correlate it with clinical and pathologic prognostic factors. Metalloproteinases, enzymes related to the degradation of the extracellular matrix, take part in carcinogenesis and have been associated with the prognosis of neoplasias. Nevertheless, medullary carcinoma is rarely considered in research analysis. Researchers tend to favor the ratio of enzymes to their inhibitors over the absolute concentrations of these enzymes. Design: Retrospective study of surgical samples. Setting: Head and Neck Surgery and Endocrinology Departments, Universidade de Sao Paulo Medical School Hospital. Patients: Surgical specimens from 33 patients who had been observed for a mean of 76.8 months (range, 4-201 months) were immunohistochemically stained for MMP-2 and TIMP-2. Only patients whose clinical and pathologic data were complete and whose specimens were preserved were included in the study. Main Outcome Measures: The ratio between the expressions of MMP-2 and TIMP-2 was based on a staining index (immunostaining extent and intensity) of each of the markers. Results: Proportionally large expressions of TIMP-2 over MMP-2 correlated with low occurrences of positive findings on initial cervical examination for the presence of thyroid nodules and/or lymphadenopathy (P = .02) and cervical lymph node metastases (P < .001), conditions correlated with prognosis. A correlation with cure at the end of follow-up (P = .01) was also observed. (P < .05 was considered statistically significant.) Conclusion: The ratio of MMP-2 to TIMP-2 expression is an additional and novel prognostic predictor of the outcome of medullary carcinoma treated surgically.
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Objectives The first objective of this study was to evaluate the radiological impact on relatives and the environment because of outpatient treatment of differentiated thyroid carcinoma with 3.7 and 5.55 GBq of ((131)I)NaI. The second objective was to determine, analyze, and evaluate whole-body radiation dose to caregivers, the production of contaminated solid waste, and the potentiality of radiation dose and surface contamination existing inside patients` households. Methods Twenty patients were treated on an outpatient basis, taking into consideration their acceptable living conditions, interests, and willingness to comply with medical and radiation-safety guidelines. The caregivers themselves, as well as the potentiality of the radiation dose inside patients` residences, were monitored with a thermo-luminescence dosimeter. Surface contamination and contaminated solid wastes were identified and measured by using a Geiger-Muller detector. Results and discussion Twenty-six monitored individuals received accumulated effective radiation doses of less than 1.0 mSv, and only one 2.8 mSv, throughout the 7 days of measurement. The maximum registered value for the potential of radiation dose inside all living areas was 1.30 mSv. The monitored surface contamination inside patients` dwellings showed a mean value of 4.2 Bq/cm(2) for all surfaces found to be contaminated. A total of 2.5l of contaminated solid waste was generated by the patients with 3.33 MBq of all estimated activity. Conclusion This study revealed that the treatment of differentiated thyroid carcinoma with 3.7 and 5.55 GBq of ((131)I)NaI, on an outpatient basis, can be safe when overseen by qualified professionals and with an adapted radiation-protection guideline. Even considering the radioiodine activity level and the dosimetric methodology applied here, negligible human exposure and a nonmeasurable radiological impact to the human environment were found. Nucl Med Commun 30:533-541 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Resumo:
Objective To evaluate the morphologic findings most encountered in anaplastic thyroid carcinomas (ATCs) and evaluate for the expression of PAX-8. Study Design The cytology specimens from 21 cases of ATC were evaluated for the following several cytologic criteria, cell morphology, pleomorphism, presence or absence of multinucleated cells, neutrophilic infiltrate and well-differentiated component. Immunohistochemical studies for PAX-8 were performed on cell blocks in selected cases. Results The most common morphology present was epithelioid, followed by spindle, multinucleated giant cell and rhabdoid, with 75% demonstrating more than 1 cell morphology. Marked pleomorphism (81%), neutrophilic infiltrate (90%) and necrosis (63%) were frequent. No nuclear grooves, colloid or well-differentiated component was idenrifled in any case. Immunocytochemical stains for PAX-8 were negative in 5 cases in which a cell block was available. Conclusion ATC is a tumor with diverse morphologic characteristics, and more than 1 cell morphology is usually present A neutrophilic infiltrate is a common finding and represents a clue to the correct diagnosis. (Acta Cytol 2010;54:668-672)
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Context: Micro-RNA have emerged as an important class of short endogenous RNA that act as posttranscriptional regulators of gene expression and are constantly deregulated inhumancancer. MiR-1 has been found down-regulated in lung, colon, and prostate cancer. Objectives: In this study, we investigated the possible role of miR-1 in thyroid carcinogenesis. Design: We have analyzed miR-1 expression in a panel of thyroid neoplasias including benign and malignant lesions and searched for miR-1 targets. Results: Our results show that miR-1 expression is drastically down-regulated in thyroid adenomas and carcinomas in comparison with normal thyroid tissue. Interestingly, miR-1 down-regulation was also found in thyroid hyperproliferative nonneoplastic lesions such as goiters. We identified the CCND2, coding for the cyclin D2 (CCND2) protein that favors the G1/S transition, CXCR4, and SDF-1 alpha genes, coding for the receptor for the stromal cell derived factor-1 (SDF-1)/CXCL12 chemokine and its ligand SDF-1/CXCL12, respectively, as miR-1 targets. An inverse correlation was found between miR-1 expression and CXC chemokine receptor 4 (CXCR4) and SDF-1 alpha protein levels in papillary and anaplastic thyroid carcinomas. Consistent with a role of the CCND2 protein in cell proliferation and CXCR4 and SDF-1 alpha proteins in cell invasion and metastasis, functional studies demonstrate that miR-1 is able to inhibit thyroid carcinoma cell proliferation and migration. Conclusions: These results indicate the involvement of miR-1 in thyroid cell proliferation and migration, validating a role of miR-1 down-regulation in thyroid carcinogenesis. (J Clin Endocrinol Metab 96: E1388-E1398, 2011)
Resumo:
Purposes: To evaluate the dosimetric effect of outpatient radioiodine therapy for thyroid cancer in members of a patient`s family and their living environment, when using iodine-131 doses reaching 7.4 GBq. The following parameters were thus defined: (a) whole-body radiation doses to caregivers, (b) the production of contaminated solid waste, and (c) radiation potential and surface contamination within patients` living quarters. Methods: In total, 100 patients were treated on an outpatient basis, taking into consideration their acceptable living conditions, interests, and willingness to comply with medical and radiation safety guidelines. Both the caregivers and the radiation dose potentiality inside patients` residences were monitored by using thermoluminescent dosimeters. Surface contamination and contaminated solid wastes were identified and measured with a Geiger-Muller detector. Results: A total of 90 monitored individuals received a mean dose of 0.27 (+/- 0.28) mSv, and the maximum dose registered was 1.6 mSv. The mean value for the potential dose within all living quarters was 0.31(+/- 0.34) mSv, and the mean value per monitored surface was 5.58 Bq/cm(2) for all the 1659 points measured. The overall production of contaminated solid wastes was at a low level, being about 3 times less than the exemption level indicated by the International Atomic Energy Agency. Conclusions: This study indicates that the treatment of thyroid cancer by applying radioiodine activities up to 7.4 GBq, on an outpatient basis, is a safe procedure, especially when supervised by qualified professionals. This alternative therapy should be a topic for careful discussion considering the high potential for reducing costs in healthcare and improving patient acceptance.