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Increased expression of AP2 and Sp1 transcription factors in human thyroid tumors: a role in NIS expression regulation?

BACKGROUND: Sodium/iodide symporter (NIS) is a key protein in iodide transport by thyroid cells and this activity is a prerequisite for effective radioiodide treatment of thyroid cancer. In the majority of thyroid cancers, however, iodide uptake is reduced, probably as a result of decreased NIS protein expression. METHODS: To identify the mechanisms that negatively affect NIS expression in thyroid tumors, we performed electrophoresis mobility shift assays and immunoblot analysis of nuclear protein extracts from normal and tumoral thyroid tissues from 14 unrelated patients. RESULTS: Two proteins closely related to the transcription factors AP2 and Sp1 were identified in the nuclear extracts. Expression of both AP2 and Sp1 in nuclear extracts from thyroid tumors was significantly higher than that observed in corresponding normal tissues. CONCLUSION: These observations raise the possibility that NIS expression, and subsequently iodide transport, are reduced in thyroid tumors at least in part owing to alterations in the binding activity of AP2 and Sp1 transcription factors to NIS promoter.

Adenoma↗

[From the cytogenetics to the cytogenomics of thyroid tumors].

Benign and malignant thyroid tumors constitute a wide range of neoplasias showing recurrent chromosome abnormalities. Cytogenetic studies of thyroid hyperplasias and follicular adenomas revealed hyperdiplo d karyotypes with a characteristic sequence of trisomies (7, 5, 12, 14, 16, 17, 20 and 22) starting with trisomy 7. Comparative genomic hybridization (CGH) findings on thyroid oncocytic tumors showed similar chromosomal gains with no difference observed between adenomas and carcinomas. Follicular thyroid carcinomas exhibit losses of 3p25-pter predominantly or of 22,13 and 1p segments. Formation of fusion genes PAX8 - PPARgamma1 caused by a t(2;3)(q13;p25) has been observed in several cases of follicular carcinomas only. Loss of chromosome 22 has been found most frequently associated with widely invasive follicular carcinomas. Activation of the RET protooncogene through chromosome rearrangements involving subband 10q11.2 represent the most common and specific genetic alteration in papillary thyroid carcinoma. Several chimeric genes resulting in the fusion of the tyrosine kinase domain of RET with the 5' sequences of different genes have been described. Germline mutations in RET are associated with medullary thyroid carcinoma in multiple endocrine neoplasia type 2 (MEN2). Cytogenetics of thyroid tumors, using conventional and molecular methods (FISH, CGH) demonstrated that particular chromosome aberrations may be related to the clinical behavior of these tumors and may provide informations for their diagnosis or prognosis.

Adenoma↗

Thyroid tumors in children.

Thyroid tumors in children continue to generate tremendous interest and controversy. Despite a frequent presentation with metastatic disease, these differentiated tumors have an excellent prognosis. Because most pediatric patients have prolonged survival, long-term follow-up is mandatory. The extent of surgery for this disease continues to be controversial. Genetic testing is changing dramatically the management of patients with multiple endocrine neoplasia and will lead to further understanding of this intriguing syndrome. Over the next decade, classification of differentiated thyroid cancers by means of more clinically useful biologic markers may affect the clinical management of children with thyroid cancer.

Adolescent↗

Sporadic follicular thyroid tumors show loss of a 200-kb region in 11q13 without evidence for mutations in the MEN1 gene.

Loss of heterozygosity (LOH) in 11q13 where the tumor suppressor gene for multiple endocrine neoplasia type 1 (MEN 1) is located has been demonstrated in several tumor types, including follicular thyroid tumors, but whether the MEN1 gene is actually involved in their tumorigenesis is not known. In the present study, the involvement of the MEN1 gene in follicular thyroid tumors was investigated. By using 14 MEN1-linked microsatellite markers, LOH was demonstrated in 12 out of 60 follicular thyroid tumors: 2/18 adenomas, 4/15 atypical adenomas, 1/6 Hürthle cell adenomas, 1/9 carcinomas, 3/6 Hürthle cell carcinomas, and 1/6 anaplastic carcinomas. In the tumors with LOH, a single minimal region of overlapping deletions was mapped to the 200-kb interval between D11S4946 and D11S4939. Tumors that showed 11q13 LOH were screened for mutations of the MEN1 gene using single-strand conformation analysis. Abnormal shifts detected in seven tumors in two exons were sequenced, which revealed two different polymorphisms present in both tumor and constitutional DNA, but without somatic mutation. Taken together, these results suggest that in this region, a tumor suppressor gene other than MEN1 might be involved in the tumorigenesis of follicular thyroid tumors. Genes Chromosomes Cancer 26:35-39, 1999.

Adenocarcinoma, Follicular↗

[Measurement of superior thyroid artery dynamics in cases of solitary thyroid tumor and its clinical evaluation].

Thyroid blood flow related with thyroid function is of great importance in diagnosing thyroid gland disease. However, there has no report on such observations of thyroid blood flow dynamics, especially non-invasively and quantitatively. In this study new developed ultrasound duplex scanning system was used to measure the superior thyroid blood flow and analyze the hemodynamics in 105 cases of solitary thyroid tumors, including 30 cases of thyroid cancers. Superior thyroid blood flows on afferent portion obviously increased both in benign and malignant tumor cases, but clear difference between them could not be found. On the other hand, in concern with the blood flows on inafferent portions, malignant thyroid tumor cases showed remarkable increase with statistical difference. The blood flow ratio between afferent and inafferent portions was considered to distinguish between benign and malignant thyroid tumors as quantitative criteria. The assumption that the tumors whose blood flow rate was below 3.0 is malignant led the fine result that accuracy was 79.8%, sensitivity; 71.5%, specificity; 81.5%. This quantitative criterion requires no surgical technique, therefore, this is useful for the tissue characterization of thyroid tumors.

Adult↗

Effects of sex difference, gonadectomy, and estrogen on N-methyl-N-nitrosourea induced rat thyroid tumors.

The occurrence of thyroid tumors induced by N-methyl-N-nitrosourea (MNU) and low iodine diet in Long-Evans (LE) rats was studied with special reference to sex difference, effect of gonadectomy, and estradiol administration. Rats of experimental groups 1-6 were given i.v. injections of 40 mg of MNU/kg of body weight at 50 days of age and fed on low iodine diet from 28 days of age to the end of the experiment (30 weeks after MNU administration). They consisted of male, female, castrated male, ovariectomized female, and gonadectomized male and female rats given 2.5 mg estradiol pellets s.c. Rats of groups 7-10 served as the respective controls without MNU or low iodine diet. Levels of serum thyroid stimulating hormone and estrogen receptor of the thyroid lesions were also examined. It was noted that the incidence of thyroid carcinoma was higher in females than in males (P less than 0.01) and did not change by castration in males but decreased in ovariectomized rats (P less than 0.01). Administration of estradiol after gonadectomy significantly increased the incidence of thyroid carcinomas in castrated and ovariectomized rats. Increase of mean serum thyroid stimulating hormone levels and thyroid and pituitary weights was also predominant in females. Mean thyroid stimulating hormone levels of both sexes were decreased by gonadectomy. Mean thyroid and pituitary weights were inhibited from increasing not by castration but by ovariectomy. Estradiol supplemented after gonadectomy significantly increased all of these factors. Estrogen receptors were detected in transplanted thyroid tumors but not in euthyroid tissues. The results suggest that estradiol promoted the thyroid tumorigenesis through activation of thyrotrophs in pituitary or direct interaction of estradiol and estrogen receptors in the thyroid.

Animals↗

Deletions of the short arm of chromosome 2 characterize a new cytogenetic subgroup of benign thyroid tumors.

Cytogenetic studies of thyroid hyperplasias and adenomas have shown that besides cases with an apparently normal karyotype different groups of cytogenetic abnormalities exist. Herein we describe the cytogenetic analyses of two benign thyroid tumors with deletions of the short arm of chromosome 2. A similar case has been described previously. Besides the previously well-established subgroups, alterations of chromosome 2 may thus characterize a new cytogenetic subgroup of benign thyroid tumors.

Adult↗

[Evaluation of accordance between cytological and histopathological findings in selected thyroid tumors].

The thyroid fine-needle aspiration (FNA) is the decisive examination in the preoperative diagnostics of thyroid nodules. Different cytohistologic studies have revealed that the accuracy of FNA for thyroid nodules varied from 69% to 94%. The aim of our study was to compare the results of FNA with regard to final histopathological diagnosis among patients with follicular tumor, Hurthle cell tumor or papillary carcinoma in FNA. We retrospectively analyzed medical documentation of 51 patients (mean age 57.9 years, 49 women and 2 men) from the Endocrinology Department from 1997 to 2002 years. Based on FNA 29 patients were diagnosed as having follicular tumor, 10 as having Hurthle cell tumor and 12 as having papillary carcinoma. Carcinoma was detected histopathologically in 38% of patients with follicular tumor. Follicular carcinoma was detected histopathologically in 10% of patients with Hurthle cell tumor. Cytological diagnosis was confirmed histopathologically in 66.8% of all patients with papillary carcinoma in FNA. In accordance with our results the confirmation of malignant neoplasm can be expected in more than 80% of cases with papillary carcinoma in cytological examination. In case of follicular or Hurthle cell tumors the frequency of malignant neoplasm was less than 40% and 10% respectively.

Adenoma↗

Microsatellite instability and its correlation with clinicopathological features in a series of thyroid tumors prevalent in iodine deficient areas.

Thyroid tumors display diverse spectrum of histopathological groups with geographic variation in its prevalence. Influence of iodine deficiency (a major causative factor) in its etiology, prevalence, or aggressiveness is debatable which reflects the existence of various genetic events in pathogenesis. The present study was undertaken to study the role of Microsatellite instability (MSI) or LOH (loss of heterozygosity), an indicator of defective mismatch repair system as a genetic change and to explore it as a prognostic marker in thyroid tumors. Tumor tissues from total thyroidectomy surgical specimens and blood (matched control) of 36 patients from iodine deficient areas (10 benign; 26 malignant) were obtained after their consent. Urinary iodine analysis was done by alkali ash method for which 10 ml of urine was collected from 18 patients before surgery. Genomic DNA, isolated from tumor tissue and blood was amplified by polymerase chain reaction (PCR) using mono and dinucleotide markers - BAT-26, BAT-40, TGF(RII, IGFIIR, hMSH3, BAX, D2S123, D9S283, D9S851 and D18S58. PCR products were analysed on 8% denaturing polyacrylamide gel followed by autoradiography. Of total, 66.6% of tumors [70% (7/10) benign and 65.4% malignant cases (17/26)] showed MSI/LOH. Strong association of MSI/LOH with low iodine (P = 0.01) and with AMES risk groups i.e. age (P = 0.02), tumor size (P = 0.04) and metastases (P = 0.002) in thyroid tumors was observed. This may help in predicting the biological behaviour and strengthening the hypothesis that iodine deficiency has influence on MSI in thyroid tumors. Our results further substantiate the risk group classification and help in deciding the treatment modality in particular patient.

Adult↗

[Oncogenes and thyroid tumors].

Papillary thyroid carcinomas are characterized in 70% of cases by the presence of either a RET/PTC rearrangement, or an activating point mutation of RAS or BRAF genes that induce a constitutive activation of the MAP kinase pathway. Follicular carcinomas are characterized by the presence of a RAS mutation or of a PAX8-PPARgamma rearrangement. Inactivating mutations of the p53 gene are found only in anaplastic thyroid carcinomas.

Adenocarcinoma, Follicular↗

RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors.

We analyzed RASSF1A and NORE1A methylation and BRAF mutation in 89 thyroid tumors, 42 non-neoplastic thyroid tissues and three thyroid tumor cell lines using polymerase chain reaction (PCR), methylation-specific PCR, Western blotting and DNA sequencing in order to study thyroid tumor pathogenesis and progression. RASSF1A promoter methylation was present in all three thyroid cell lines and in 27/78 (35%) of benign and malignant thyroid tumors. We showed for the first time that there was generally good agreement between RASSF1A methylation status and RASSF1A protein expression. We also examined for the first time NORE1A promoter region methylation in thyroid cell lines and primary tumors and showed that two of three thyroid cell lines were methylated in the NORE1A promoter region, while all primary thyroid tumors analyzed (n=51) were unmethylated. BRAF mutation was present in 38% of papillary thyroid carcinomas (PTC), including 20% of PTC with a follicular variant pattern and 67% of the tall cell variant of PTC. Hyalinizing trabecular tumors (n=23), which had nuclear features similar to PTC, did not have BRAF mutations, indicating that the presence of BRAF mutations can help to separate these two tumor types. Phospho-MEK expression was increased in the NPA cell line, which had a BRAF mutation, supporting the importance of the BRAF pathway alterations in PTC pathogenesis. These results indicate that RASSF1A epigenetic changes are an early event in thyroid tumor pathogenesis and progression and that NORE1A methylation is uncommon in primary thyroid tumors. BRAF mutation occurs later in thyroid tumor progression and is restricted mainly to PTC and anaplastic thyroid carcinoma.

Adaptor Proteins, Signal Transducing↗

Growth patterns of benign and malignant thyroid tumors estimated by CT.

Thyroid tumors affect adjacent structures and reveal their nature as they grow. Differences in benign and malignant tumor growth patterns were studied by CT. Twenty-nine benign (follicular adenoma) and 29 malignant (papillary carcinoma) tumors with their findings were arranged according to size to speculate on how they grew. Benign tumors grew expansively and made a beak-like appearance in the marginal thyroid tissue (beak sign). They displaced vessels but kept a fat plane or deep sulcus between them (sulcus sign). Malignant tumors, on the other hand, grew invasively and reached the trachea rapidly without the beak sign. They destroyed the fat plane and contacted the vessels without the sulcus sign. Expansive and invasive growth forms of benign and malignant thyroid tumors could be represented schematically.

Adenoma↗

Significance of P53 in human thyroid tumors.

Mutational changes in the p53 tumor suppressor gene are the most frequent genetic alterations in human malignant tumors. Studies have shown a correlation of p53 expression in breast cancer with tumor prognosis. In contrast to mutational activation of ras and GSP in thyroid tumors, little is known about the role of p53 in thyroid tumor development. Therefore thyroid tumors and thyroid tumor cell lines were studied for the presence of p53 mutations. Snap-frozen tissues from 57 differentiated thyroid carcinomas (DTCs) and 5 goiters were studied by immunohistochemical methods. A panel of six antibodies (pAb 240, 421, 1620, 1801, DO7, and CM1) was employed by using the ABC technique. Five cell lines from DTCs (FTC133, 236, 238, PTC337, MTC164) were examined by the same technique. Additionally, genomic DNA from the cells was amplified by the polymerase chain reaction (PCR) and the PCR product studied for p53 mutations (R273H) by mutation-specific oligonucleotide hybridization (MOH) and temperature gradient gel electrophoresis (TGGE) for the p53 exon 8. None of the benign thyroid tumors and 7 of 57 (12%) DTCs strongly express p53 with a heterogeneous distribution in the tumor tissue. All seven patients have metastatic disease or dedifferentiated tumors G3 (three of seven). CM1 was positive in two cell lines (FTC-133, PTC-337), questionable in FTC-238, and negative in FTC-236 and MTC-164. All three follicular cell lines, however, and the original tumor tissue showed the same p53 mutation (R273H) in MOH analysis and TGGE. P53 mutations are rare in thyroid tumors, but the presence of p53 mutations indicates a poor prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

Thyroid tumors: cytomorphology of medullary, clinically anaplastic, and miscellaneous thyroid neoplasms.

Of 2,012 fine-needle aspirations (FNAs) of the thyroid performed between the years 1984 and 1988, detailed cytomorphologic analysis of 95 cases diagnosed as neoplastic on histology and/or cytology and those that received an equivocal cytodiagnosis are presented in this article. Discussed are medullary thyroid carcinomas (nine cases), clinically anaplastic thyroid tumors (CATT; eight cases), two cases of non-Hodgkin's lymphoma (NHL), and one primary leiomyosarcoma of the thyroid, for a total of 20 cases. Included in the category of CATT are all the thyroid tumors presenting clinically with an anaplastic growth pattern. The cytomorphology of these tumors varied, but the giant- and spindle-cell pattern was predominant. An accurate cytodiagnosis was possible, as per cytohistologic correlation, in seven cases, while in one case histological material was not available for study. Medullary carcinoma of the thyroid (MCT) showed a mixed spindle-cell and round-cell population in eight cases and an entirely spindle-cell population in one case. All cases of MCT were correctly diagnosed on cytology, and amyloid could be demonstrated in the cytologic smears in three cases. The cases of NHL and leiomyosarcoma could also be correctly interpreted on cytology.

Adult↗

Primary tissue cultures of benign and malignant human thyroid tumors: effect of TSH.

Many thyroid carcinomas seem to be dependent upon the thyroid growth-promoting properties of the thyroid stimulating hormone (TSH). The purpose of the present investigation was to compare the in vitro effect of TSH on tissue cultures derived from malignant and benign thyroid tumors. The results indicate that TSH can affect the morphology and protein synthesis of primary tissue cultures derived from benign and malignant thyroid tumors differently. The addition of TSH to cultures derived from benign tumors resulted in a reorganization of follicle-like structures of the monolayer and in a reduction of protein synthesis. In contrast to this, monolayers derived from carcinomas of the thyroid were not able to reorganize and their protein synthesis was not inhibited in the presence of TSH. For a better understanding of TSH suppressive therapy, we suggest testing the influence of TSH on a large number of tissue cultures derived from benign and malignant tumors of the thyroid.

Culture Techniques↗

Transient vocal cord paralysis after fine-needle aspiration biopsy of thyroid tumor.

OBJECTIVE: Complications of thyroid fine-needle aspiration biopsy (FNAB) are exceedingly rare. Hematoma formation is the most commonly encountered complication. Infection and seeding of carcinoma cells in the needle track has also been reported in a rare case. Here we describe patients diagnosed as having transient vocal cord paralysis after FNAB of benign thyroid tumor. DESIGN: Retrospective review of patients with concurrent diagnosis of vocal cord paralysis after FNAB. MAIN OUTCOME: Among 10,974 patients who underwent FNAB, 4 patients showed vocal cord paralysis on laryngoscopy. These patients had solid and/or cystic lesion in the thyroid. Routine FNAB of the nodule was performed using a 23-gauge needle. Cytologic findings were benign tumor. Change of voice in the patients occurred 1 or 2 days after FNAB and vocal cord paralysis ipsilateral to FNAB was determined by flexible laryngoscopy. Vocal cord paralysis of all patients resolved spontaneously within 6 months (average, 4 months). CONCLUSION: Although the incidence of vocal cord paralysis in patients with thyroid tumor after FNAB is reported to be 0.036%, the true incidence is unknown because asymptomatic subjects are not screened. This report should alert the examiner to the possibility of vocal cord palsy after FNAB.

Aged↗

Expression of laminin in thyroid gland and thyroid tumors: an immunohistologic study.

Thirty-five thyroid tumors and four normal thyroids were immunohistochemically investigated for the presence of laminin, a major basement membrane component. The thyroid follicles in normal tissues and in nodular goiters were surrounded by a continuous rim of laminin positivity, as were also the papillae of papillary carcinomas. Follicular adenomas and well-differentiated follicular carcinomas also showed laminin positivity around most of the follicles. Anaplastic thyroid carcinoma lacking a distinct compartmentalization of tumor cells also lacked pericellular laminin. However, in contrast to all other thyroid tumors, an intense laminin positivity was found in scattered tumor cells of anaplastic carcinomas. Laminin positivity is thus a feature reflecting the differentiation level of thyroid tumors, but, unlike most other carcinomas, differentiated thyroid tumors have basal laminae surrounding the differentiated structural units.

Adenoma↗

[Thyroid tumors in childhood].

The thyroid pathology in the paediatric population represents 5% of the total and 1.2% only thyroid pathology correspond to the infantile solitary thyroid nodules. Most of them are asymptomatic and as only sign an increase of volume is observed in the neck. Always we have to ask about the family history because the possibility of medullary carcinoma related with multiple endocrine neoplasias should be investigated (a patient of our series). The thyroid tumor represents 0.5% of all the tumors and of these 10% is in younger than 21 years old. We present 13 patients with thyroid pathology that have required surgical treatment, since 1983 to 1997. Five papillary carcinomas (ages: 7 to 14 years old) that started with a cervical nodule, normal thyroid function and a case of medullary carcinoma, in a multiple endocrine neoplasia (MEN II 2A). In the 5 cases of carcinoma papillary we were carried out total thyroidectomy and later on, postoperative ablative dose of 131I was administered. In the case of the girl with medullary carcinoma was carried out a total tumorectomy and lymph node excision. Finally, seven patients with nodule thyroid were thyroid benign tumors (benign 6 adenomas and 1 cyst colloid, ages: 8 to 15 years old). In all of them we were carried out total surgical excision of the thyroid nodules. Our protocol of study of nodule thyroid includes: 1) thyroid gammagraphy to know the intensity of reception of the isotope; 2) cervical ultrasound; and 3) biopsy or cytopathology of fine needle aspiration of the thyroid gland in children that it dissuades to base the surgical strategy on this test.

Adenoma↗