Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential.
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Well-differentiated encapsulated tumors of the thyroid gland with a follicular architecture may cause diagnostic difficulties. Questionable vascular or capsular penetration may raise the possibility of a follicular carcinoma, while focal nuclear clearing and grooves may suggest a diagnosis of papillary carcinoma. A proposal has recently been made to designate cases showing suggestive but not conclusive morphological evidence of malignancy along these lines as well-differentiated or follicular tumors of uncertain malignant potential. The aim of the present study was to investigate the expression and diagnostic role in well-differentiated or follicular tumors of uncertain malignant potential of Galectin-3 and HBME-1, two malignancy-related markers. A total of 21 tumors fulfilling the criteria of well-differentiated or follicular tumors of uncertain malignant potential were collected from two institutions, including eight cases with questionable vascular and/or capsular invasion and 13 cases with some degree of nuclear changes in the form of clearing, grooves, and/or pseudoinclusions. Tumors in the first group expressed HBME-1 and Galectin-3 focally (less than 25% of tumor cells) in 5/8 and 3/8 cases, respectively, with 62.5% of cases reacting for at least one marker. Cases in the second category expressed HBME-1 and Galectin-3 in 9/13 and 10/13 cases, respectively, with 92.3% of cases having at least one marker expressed. These findings indicate that HBME-1 and Galectin-3 are heterogeneously distributed in these borderline tumors, but that a strong and diffuse expression of HBME-1 and to a lower extent of Galectin-3 was preferentially observed in the group characterized by nuclear changes which were similar but less developed than those of conventional papillary carcinoma. The relationship found between the markers investigated and these nuclear changes suggests that the tumors containing them are pathogenetically linked to papillary carcinomas. (+info)
Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma.
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Thyroid follicular adenomas (FA) are encapsulated tumors lacking vascular, capsular or lymphatic invasion and the typical nuclear features of papillary carcinoma (PC). However, some FA demonstrate nuclear atypia reminiscent of either follicular carcinomas (FC) or follicular variant of papillary carcinomas (FVPC), suggesting they may represent precursors of malignant transformation. We hypothesized that an objective evaluation of nuclear chromatin patterns could be used to define atypical follicular tumors (AFT) that are likely to be premalignant. To test this hypothesis, we used a computer-aided image analysis system to define the chromatin pattern of nuclei from thyroid tumors. To validate the system, we analyzed 3000 nuclei from 10 FA, 10 FC, and 10 FVPC samples and accurately distinguished between these classes of tumors. Then, we analyzed nine AFT and, in parallel, we analyzed the tumors for activating mutations of N2-RAS and over-expression of RET. The predominant chromatin pattern of AFT was of FA type in two cases, FC type in two cases, and PC type in three cases. One case contained similar numbers of FC and PC nuclei and one was comprised of a mixture of the three nuclear types. Neither RAS mutation nor RET overexpression were detected in FA. N2-RAS mutations were found in 33% of AFT, 20% of FC and 20% of FVPC without correlation with chromatin pattern. Over-expression of RET was detected in 45% of AFT, 20% of FC and 50% of FVPC and was correlated with PC nuclei. These results show that AFT are a heterogeneous group of tumors, containing genuine benign tumors and tumors that share morphological and molecular features with follicular and papillary carcinomas that might be precursors of both types of thyroid carcinomas. (+info)
BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors.
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The tumorigenesis of sporadic endocrine tumors is still not fully understood. Activating point mutations of the serine/threonine kinase gene BRAF located on 7q34 are found in a wide range of malignancies, with the highest frequency (66%) occurring in malignant melanomas. Melanomas are tumors of neural-crest-derived cells as are medullary thyroid carcinomas, pheochromocytomas and paragangliomas. BRAF has not been examined in endocrine tumors of the diffuse neuroendocrine system or of neural-crest-derived cells. We examined 130 endocrine tumors of the pancreas, parathyroid gland, adrenal medulla, paraganglia, lung and gastrointestinal tract as well as follicular and c-cell-derived thyroid tumors. We found a high rate of V559E mutations in papillary thyroid carcinomas (47%), one V599E mutation in a well-differentiated gastric endocrine carcinoma (malignant carcinoid), but no activating BRAF mutations in all other endocrine tumors examined. These results point towards different pathways in tumorigenesis of endocrine tumors of various localizations and only rare involvement of the MAP kinase (MAPK) pathway in a subset of malignant neuroendocrine tumors. (+info)
Fetal cell carcinogenesis of the thyroid: a hypothesis for better understanding of gene expression profile and genomic alternation in thyroid carcinoma.
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Since the 1980s, cancer cells have been considered to be generated from well-differentiated benign cells by transformation caused by accumulating damage in their genomes. However, recent progress in gene expression analysis in thyroid malignancies has raised the possibility of another model of thyroid carcinogenesis. We propose a novel hypothesis of thyroid carcinogenesis, the fetal cell carcinogenesis hypothesis, in which cancer cells are derived from the remnants of fetal thyroid cells, instead of from normal thyroid follicular cells. This hypothesis explains well the clinical and biological features and recent molecular evidence of thyroid carcinoma. It suggests the importance of clarifying the molecular mechanism of thyroid development and the identification of fetal thyroid cells such as thyroid stem cells (TSCs), since such data will lead to a better understanding of thyroid carcinogenesis and thyroid regeneration. (+info)
Prognostic significance of successful ablation with radioiodine of differentiated thyroid cancer patients.
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OBJECTIVES: Currently, little is known about the prognostic significance of achieving successful ablation with the first dosage of I-131 in patients with differentiated thyroid cancer. This study aimed to assess the following: (i) whether successful or unsuccessful ablation at post-ablation follow-up has prognostic consequences; (ii) possible factors predicting success of ablation in a patient. METHODS: In order to do this, we retrospectively studied 180 patients with a median follow-up of 55 months. Ablation was considered to be successful if 1 year after the initial dosage of I-131 patients fulfilled all of the following criteria: not dead from thyroid cancer, no additional therapy needed for any kind for thyroid cancer within the first year, undetectable thyroglobulin (Tg) levels under TSH stimulation, and negative I-131 scintigraphy. Tg levels at the time of ablation (P < 0.001), lymph node metastasis (P = 0.04) and distant metastasis (P < 0.001) have a significant influence on the success of ablation. P values were calculated by Mann-Whitney U test and Chi-square test, respectively. RESULTS: Patients with successful ablation had a better prognosis than those with unsuccessful ablation: disease-free survival was 87% versus 49% after 10 years; additionally, thyroid-cancer related survival was 93% versus 78%. CONCLUSION: We conclude that the extent of the remaining normal or neoplastic thyroid tissue influences the outcome of ablation, and that successful ablation leads to a better prognosis. It seems that it is very important to achieve complete ablation as soon as possible in order to ensure the best possible prognosis for a patient. (+info)
Follow-up of differentiated thyroid carcinoma.
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Thyroid cancer is the most common endocrine malignancy. More than 90% of primary thyroid cancers are differentiated papillary or follicular types. The treatment of differentiated thyroid carcinoma (DTC) consists of total thyroidectomy and radioactive iodine ablation therapy, followed by L-thyroxine therapy. The extent of initial surgery, the indication for radioiodine ablation therapy and the degree of TSH-suppression are all issues that are still being debated cancers are in relation to the risk of recurrence. Total thyroidectomy reduces the risk of recurrence and facilitates (131)I ablation of thyroid remnants. The aim of radioiodine ablation is to destroy any normal or neoplastic residuals of thyroid tissue. These procedures also improve the sensitivity of thyroglobulin (Tg) as a marker of disease, and increase the sensitivity of (131)I total body scan (TBS) for the detection of persistent or recurrent disease. The aim of TSH-suppressive therapy is to restore euthyroidism and to decrease serum TSH levels, in order to reduce the growth and progression of thyroid cancer. After initial treatment, the objectives of the follow-up of DTC is to maintain adequate thyroxine therapy and to detect persistent or recurrent disease through the combined use of neck ultrasound (US) and serum Tg and (131)I TBS after TSH stimulation. The follow-up protocol should be adapted to the risk of recurrence. Recent advances in the follow-up of DTC are related to the use of recombinant human TSH (rhTSH) in order to stimulate Tg production and the ultrasensitive methods for Tg measurement. Undetectable serum Tg during TSH suppressive therapy with L-T4 does not exclude persistent disease, therefore serum Tg should be measured after TSH stimulation. The results of rhTSH administration and L-thyroxine therapy withdrawal are equivalent in detecting recurrent thyroid cancer, but the use of rhTSH helps to avoid the onset of hypothyroid symptoms and the negative effects of acute hypothyroidism on cardiovascular, hepatic, renal and neurological function. In low-risk DTC patients serum Tg after TSH stimulation, together with ultrasound of the neck, should be used to monitor persistent disease, avoiding diagnostic TBS which has a poor sensitivity. These recommendations do not apply when Tg antibodies are present in the serum, in patients with persistent or recurrent disease or limited thyroid surgery. Low-risk patients may be considered to be in remission when undetectable Tg after TSH stimulation and negative US evaluation of the neck are present. On the contrary, detectable Tg after TSH stimulation is an indicator in selecting patients who are candidates for further diagnostic procedures. (+info)
Initial experience in use of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography in thyroid carcinoma patients with elevated serum thyroglobulin but negative iodine-131 whole body scans.
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INTRODUCTION: This study aims to examine the usefulness of fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in thyroid carcinoma patients with elevated serum thyroglobulin (Tg) but negative iodine-131 (I-131) whole body scans. METHODS: 17 patients with differentiated thyroid carcinoma who underwent FDG PET/CT scans were reviewed retrospectively over a period of one year from July 2003 to June 2004. All these patients had completion thyroidectomy and subsequently presented with elevated serum Tg but negative post-therapy I-131 whole body scans. Nine of these patients underwent FDG PET/CT in a hypothyroid state, while the remainder underwent FDG PET/CT while on thyroxine replacement. RESULTS: 15 out of 17 PET/CT scans revealed lesions consistent with metastases, giving a sensitivity of 88.2 percent. Four of these patients were amendable to surgical treatment. Two scans were negative. CONCLUSION: FDG PET/CT is a sensitive diagnostic tool to detect radioiodine-negative recurrences/metastases in patients with thyroid carcinoma. Our preliminary results are comparable with published results based on PET. (+info)
TSH receptor mutation V509A causes familial hyperthyroidism by release of interhelical constraints between transmembrane helices TMH3 and TMH5.
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Mutations of the human thyrotrophin receptor (TSH-R) are a cause of thyroid adenomas and hyperthyroidism. Here we study mechanisms of receptor activation in a genomic TSH-R variant V509A located in transmembrane helix (TMH) 3, which we identify in a family with congenital hyperthyroidism, multiple adenomas and follicular thyroid cancer. Using molecular modelling and dynamic simulation, we predicted the release of amino acid residue A593 (located opposite in domain TMH5) from a tight 'knob-and-hole' interaction with TMH3, physiologically constrained in the native receptor state by the bulky side chain of V509. To experimentally validate this concept, we generated mutant TSH-R expression constructs for functional in vitro studies. TSH-R mutant V509A showed a 2.8-fold increase in basal cAMP production, confirming constitutive TSH-R activation. The addition of a second site suppressor mutant A593V to TSH-R V509A resulted in the normalization of basal cAMP release, and the dose-responsiveness to TSH ligand was maintained. These data thus demonstrate that TSH-R V509A activation is caused by the release of TMH3-TMH5 interhelical constraints, while the native TSH-R conformation is re-stabilized by the introduction of a spacious valine residue at position 593. In conclusion, we delineate a novel mechanism of constitutive TSH-R activation, leading to thyroid hyperfunction and neoplasia. (+info)