Clinical utility of KAP-1 expression in thyroid lesions.

Although there are evidences of the involvement of KAP-1 in other tumors, data on differentiated thyroid carcinomas (DTC) are still lacking. We aimed to evaluate KAP-1 clinical utility in the diagnosis and prognosis of DTC. We used both visual immunohistochemistry and a semiquantitative analysis to evaluate KAP-1 expression in 230 thyroid carcinomas and 131 noncancerous thyroid nodules. There were 43 follicular carcinomas (FC) and 187 papillary thyroid carcinomas (PTC), including 130 classic (CPTC), 4 tall cells (TCPTC), and 53 follicular variants (FVPTC). Patients were followed up for 53.8 ± 41 months. They were classified as free-of-disease (142 cases) or poor outcome (25 cases--10 deaths), according to their serum Tg levels and image evidences. KAP-1 was identified in 78 % PTC, 75 % TCPTC, 74 % FC, 72 % FVPTC, 55 % FA, 44 % hyperplasia, and 11 % normal thyroid tissues. A ROC analysis identified malignant nodules with 69 % sensitivity and 75 % specificity, using a cutoff of 73.19. In addition to distinguishing benign from malignant thyroid tissues (p < 0.0001), KAP-1 expression differentiated CPTC from nodular hyperplasia (p < 0.0001), CPTC from FA (p = 0.0028), FVPTC from hyperplasia (p = 0.0039), and FC from hyperplasia (p = 0.0025). Furthermore, KAP-1 was more expressed in larger tumors (>4 cm; p = 0.0038) and in individuals who presented recurrences/metastases (p = 0.0130). We suggest that KAP-1 may help diagnose thyroid nodules, characterize follicular-patterned thyroid lesions, and identify individuals with poor prognosis.

Expression of SMAD proteins, TGF-beta/activin signaling mediators, in human thyroid tissues.

OBJECTIVE: To investigate the expression of SMAD proteins in human thyroid tissues since the inactivation of TGF-beta/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-beta and activin, while SMAD7 inhibits this intracellular signaling. Although TGF-beta 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-beta/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.

Expression of SMAD proteins, TGF-beta/activin signaling mediators, in human thyroid tissues / Expressão de proteínas SMAD, mediadores da sinalização de TGF-beta/activina, em tecidos de tiroide humana

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.

OBJETIVO: Investigar a expressão de proteínas SMAD em tecidos de tiroide humana desde que a inativação dos componentes da sinalização de TGF-β/activina é relatada em diversos tipos de câncer. SMAD 2 e SMAD3 fosforilados (pSMAD2/3) associados com SMAD4 induzem a transmissão do sinal gerado por TGF-β e activina, enquanto SMAD7 inibe essa sinalização intracelular. Embora TGF-β e activina exerçam efeitos antiproliferativos nas células foliculares da tiroide, tumores de tiroide expressam altos níveis dessas proteínas. MATERIAIS E MÉTODOS: A expressão proteica de SMADs foi avaliada em bócio multinodular, adenoma folicular, carcinomas papilífero e folicular por imuno-histoquímica. RESULTADOS: A expressão de pSMAD2/3, SMAD4 e SMAD7 foi observada tanto em tumores benignos como malignos da tiroide. Embora pSMAD2/3, SMAD4 e SMAD7 exibissem alta positividade citoplasmática em carcinomas, a positividade nuclear de pSMAD2/3 não foi diferente entre lesões benignas e malignas da tiroide. CONCLUSÕES: O achado da expressão de SMADs em células tiroidianas e a presença das proteínas pSMAD2/3 e SMAD4 no núcleo de células tumorais indicam propagação da sinalização TGF-β/activina. Contudo, a alta expressão de SMAD7 inibitório, principalmente em tumores malignos, poderia contribuir para atenuação da sinalização antiproliferativa de SMADs em carcinomas de tiroide.

Galectin-3 immunostaining in thyroid neoplasms

A punção aspirativa por agulha fina de tireóide é o método pré-cirúrgico mais importante na definição da malignidade de uma lesão nodular. Entretanto esse procedimento apresenta limitações, como características morfológicas comuns entre neoplasias malignas e benignas. A expressão de uma lectina ligante de b-galactosídeos chamada galectina-3, aumentada em neoplasias malignas de tireóide, poderia ser utilizada como marcador de malignidade para neoplasias de tireóide. Cinqüenta e sete casos, entre eles 14 carcinomas papilares, 22 carcinomas foliculares e 21 adenomas foliculares, foram estudados quanto à expressão da galectina-3 por métodos imuno-histoquímicos. O tecido tireoidiano normal, adjacente ao tecido neoplásico, também foi avaliado em 48 casos. Todos os casos de carcinoma papilar e 18 casos de carcinoma folicular apresentaram marcação citoplasmática; um caso de adenoma folicular apresentou marcação nuclear. Nenhum caso de tecido tireoidiano normal demonstrou imunomarcação. Sensibilidade, especificidade, valor preditivo positivo e negativo foram respectivamente 88 por cento, 98 por cento, 96 por cento e 94 por cento. A expressão da galectina-3 é uma evidência valiosa de malignidade nos casos em que as características citomorfológicas não forem conclusivas. A marcação por imunocitoquímica poderá aumentar a exatidão diagnóstica nos exames citológicos por aspiração de tireóide, tornando a indicação cirúrgica mais precisa.

[Low galectin-3 capacity to discriminate thyroid lesions]. / Baja capacidad de galectina-3 para discriminar lesiones tiroideas.

UNLABELLED: Galectin-3 is considered useful in identifying lesions included in the term follicular tumour. OBJECTIVE: To evaluate galectin-3's power to discriminate among diverse thyroid lesions and to identify a set point of expression at which there is the least possible false positive results. METHODS: 26 follicular carcinomas and 104 assorted thyroid lesions were analysed (8 Hashimoto's thyroiditis, 18 goiter, 44 adenoma, 27 papillary carcinoma and 7 normal glands). Immunohistochemistry for galectin-3 was performed way (NCL-GAL-3, 1:100, Novocastra, UK). In a blinded manner intensity and percentage of expression were evaluated, as was its capacity to identify the previously mentioned thyroid entities with 2 x 2 tables. Minimum reactivity set point values were identified and the one which presented the least false positive cases was selected. RESULTS: A reaction was considered positive when 25% of the cells were marked, in which case neither the Hashimoto's thyroiditis, goiter, nor the residual tissue were positive for galectin-3. A positive galectin-3 reaction was identified in 4/44 adenomas, 5/26 follicular carcinomas and 18/27 papillary carcinomas. From a total of 53 carcinomas, 23 showed positive and 30 a negative reaction to galectin-3. Thus, galectin-3's sensitivity to discriminate between benign and malignant lesions was 94% while its specificity was 43%. When comparing follicular carcinoma with adenoma, sensibility was 19% while specificity was 91%. The positive predictive value was 56% and the negative predictive value 66%. Galectin-3 was most useful for identifying papillary thyroid carcinoma. CONCLUSIONS: Galectin-3 has limited value to distinguish benign from malignant thyroid lesions. The reaction must be considered positive when at least 25% of cells are marked.

Thyroid hormone-producing metastases in differentiated thyroid cancer.

Thyroid hormone production by metastases of differentiated thyroid carcinoma is very rare and its pathogenesis is still unknown. The aim of this study was to present some clinical and demographic evidence that thyroid hormone-producing metastases of differentiated thyroid carcinoma are related to environmental factors, probably iodine deficiency. A cross-sectional study was performed on thirty-five patients with distant metastases, identified in a group of 125 patients with differentiated thyroid carcinoma previously submitted to total or near total thyroidectomy. In 6 patients (5 females, 1 male; age range, 50 to 64 yr) we had evidence that the metastases were actively producing thyroid hormones and in 29 patients (21 females, 8 males; age range 8 to 84 yr) the metastases were considered to be nonthyroid hormone-producing. Serum levels of T3, T4, and thyroglobulin were measured by RIA, TSH by IRMA, and 131I whole-body scintigraphy was performed 72 h after 187 Mbq of 131I. All patients with metastases producing thyroid hormones presented a pure follicular thyroid carcinoma. They also differed from patients with nonproducing metastases in the frequent presence of goiter of long duration as the first clinical manifestation of thyroid disease (p < 0.01), and a higher proportion of patients coming from an iodine deficient area (5/6 vs. 6/29, p < 0.05). In these patients the serum thyroglobulin levels tended to be higher (p = 0.069) as compared with the nonproducing metastases group. In conclusion, a late diagnosis of follicular carcinoma in patients with long-standing multinodular goiter allowed the development of well differentiated and bulky metastases retaining the ability to produce thyroid hormones.