RESUMEN

The paired box-8 protein (Pax-8) has been observed in the nucleus of normal adult thyroids, follicular adenomas, follicular thyroid cancers, and papillary thyroid cancers (PTC) but not undifferentiated thyroid cancers. To our knowledge, Pax-8 has not been studied in pediatric thyroid cancer. Because of the more favorable prognosis for PTC in children compared to young patients, we hypothesized that Pax-8 expression might be different in pediatric thyroid cancers. To test this, we stained 47 thyroid lesions from children and young patients for Pax-8. Pax-8 was located in the cytoplasm (cPAX) or nucleus (nPAX) in the majority of samples. There was no significant difference in nPAX between benign and malignant lesions. However, cPAX was more commonly seen in PTC than autoimmune diseases (p = 0.01) and the intensity of cPAX staining correlated with tumor size (p = 0.041), metastasis, age, completeness of resection, local invasion, and tumor size (MACIS) scores (p = 0.045), and the presence of invasion, metastasis, recurrence, or persistence (p = 0.012). Disease-free survival was significantly reduced for cancers with intense cPAX staining (p = 0.0003). These data show that cPAX is common in PTC, and although limited by small sample size, suggest an association with higher MACIS scores, an aggressive clinical course, and an increased risk of clinically evident recurrence for children and young patients.

Asunto(s)

Citoplasma/patología , Proteínas de Unión al ADN/genética , Proteínas Nucleares/genética , Neoplasias de la Tiroides/patología , Transactivadores/genética , Adolescente , Adulto , Biomarcadores de Tumor , Núcleo Celular/metabolismo , Núcleo Celular/patología , Niño , Citoplasma/metabolismo , Citoplasma/ultraestructura , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Masculino , Recurrencia Local de Neoplasia/epidemiología , Factor de Transcripción PAX8 , Factores de Transcripción Paired Box , Riesgo , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/ultraestructura

RESUMEN

The immune response appears to be important in preventing metastasis and recurrence of thyroid cancer. We previously showed that papillary thyroid carcinoma (PTC) from children and adolescents that contain the most numerous proliferating lymphocytes have the best prognosis. However, the types of lymphocytes involved are not yet known. To further define this, we examined 21 PTCs from patients 21 yr of age or younger (52% were 18-21 yr of age) for the presence of CD4+ (helper), CD8+ (killer), CD19+ (B cells), and CD56+ (natural killer) cells as well as proliferating lymphocytes (Ki-67+). Nearly half the PTCs contained CD4+ (9 of 21, 43%), CD8+ (8 of 21, 38%), or CD19+ (10 of 21, 48%) lymphocytes. Only one PTC (1 of 21, 5%) contained CD56+ lymphocytes, and none contained all four cell types. By dual staining, none of these lymphocytes were proliferating (Ki-67+). However, PTCs containing either CD8+ cells (n = 8) or a combination of CD4+, CD8+, and CD19+ cells (n = 5) contained more numerous proliferating lymphocytes than did PTCs containing any other combination (14.2-fold increase, P = 0.03 and 13.1-fold increase, P = 0.003, respectively). During follow-up, none of the PTCs containing either CD8+ lymphocytes or the combination of CD4+, CD8+, and CD19+ lymphocytes recurred. However, the cohort is too small and the follow-up inadequate to provide accurate information on the clinical impact of these immunological findings. We conclude that the immune response against PTC is important and also complex, involving more than one type of lymphocyte.

Asunto(s)

Carcinoma Papilar/patología , Linfocitos/patología , Neoplasias de la Tiroides/patología , Adolescente , Adulto , Formación de Anticuerpos/inmunología , Antígenos CD19/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Antígeno CD56/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma Papilar/inmunología , Niño , Factores de Crecimiento Endotelial/metabolismo , Femenino , Humanos , Inmunidad Celular/inmunología , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocitos/inmunología , Linfocinas/metabolismo , Masculino , Recurrencia Local de Neoplasia/patología , Neoplasias de la Tiroides/inmunología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular

RESUMEN

Papillary thyroid carcinomas (PTC) are the most common thyroid cancers in children. Most are successfully treated with surgery and radioactive iodine, but some persist. PTC express high levels of vascular endothelial growth factor (VEGF) and VEGF receptor (Flt-1). PTC with the most intense expression of VEGF have the greatest recurrence risk. We hypothesized that blockade of VEGF would inhibit PTC growth. To test this, we used systemic VEGF monoclonal antibody (VEGF-MAb) to treat PTC xenografts in nude mice. Treated animals (n = 9) received 200 microg VEGF-MAb by daily i.p. injection for 10 wk, while control animals (n = 9) received vehicle alone. Tumor size was significantly reduced in the treatment group (0.28 +/- 0.06 vs 1.05 +/- 0.25 g, p = 0.008). VEGF immunostaining was more intense (2.57 +/- 0.30 vs 1.75 +/- 0.25, p = 0.06) and the number of p53 positive cells was increased (1.66 +/- 0.24 vs 0.83 +/- 0.31, p = 0.048) in treated tumors. Animal weight was similar in both groups (29.1 +/- 1.1 vs 27.4 +/- 1.1 g, p = 0.30). In conclusion, systemic VEGF-MAb significantly reduced the growth of PTC, suggesting that VEGF-MAb might be useful for treatment of resistant PTC.

Asunto(s)

Anticuerpos Monoclonales/farmacología , Carcinoma Papilar/terapia , Neoplasias de la Tiroides/terapia , Factor A de Crecimiento Endotelial Vascular/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de la Angiogénesis/farmacología , Animales , Anticuerpos Monoclonales/administración & dosificación , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patología , Línea Celular Tumoral , Técnicas para Inmunoenzimas , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Proteína p53 Supresora de Tumor/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

BACKGROUND: Anaplastic thyroid cancer (ATC) does not respond well to any treatment and is one of the most aggressive of all human cancers. Based on the importance of angiogenesis in solid tumor growth, we hypothesized that angiogenic blockade might reduce the growth of ATC. METHODS: We tested the in vivo effect of vascular endothelial growth factor monoclonal antibody (VEGF-mAb) and thalidomide against ATC (ARO-81) xenografts in nude mice. Mice were injected subcutaneously with 1 x 10(6) ARO-81 cells, allowed to implant (1 week), and then given daily intraperitoneal injections of vehicle (control; n = 9), VEGF-mAb (200 microg/d; n = 9), or thalidomide (200 mg/kg per day; n = 9). Tumors were removed, sectioned, and stained for routine histology and immunohistochemistry. RESULTS: At 6 weeks, VEGF-mAb-treated tumors were smaller (1603 +/- 296 mm(3)) than either the thalidomide-treated (6007 +/- 1498 mm(3); p = 0.008) or the control groups (4040 +/- 831 mm(3); p = 0.014) and the VEGF-mAb-treated animals maintained greater weight (30.4 +/- 0.84 g at week 6 versus thalidomide-treated, 26.0 +/- 0.94 g, p = 0.003; and control, 25.8 +/- 0.78 g, p = 0.001 animals). Central necrosis was observed in 3 of 9 VEGF-mAb-treated confidence interval (33%; 95% [CI] = 0.12-0.65) but in none of the control or thalidomide-treated tumors (0/18 total; 95% CI = 0.0-0.30; p = 0.029). VEGF staining intensity for VEGF-mAb- (2.0 +/- 0.24; p = 0.012) and thalidomide- (2.1 +/- 0.05; p = 0.052) treated tumors was greater than control (0.89 +/- 0.31) as was p53 staining grade (VEGF-mAb [1.3 +/- 0.37; p = 0.012]; thalidomide [1.0 +/- 0.41; p = 0.05]; and controls [0.11 +/- 0.11]). CONCLUSION: We conclude that systemic VEGF-mAb significantly reduces growth of ATC xenografts and is associated with increased VEGF and p53 expression. Thalidomide has no effect on tumor growth, but is also associated with increased VEGF and p53 expression. These observations provide the first evidence that VEGF-mAb-induced angiogenesis blockade may be of use for the treatment of ATC.

Asunto(s)

Anticuerpos Monoclonales/farmacología , Carcinoma/terapia , Factores de Crecimiento Endotelial/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Linfocinas/inmunología , Neoplasias de la Tiroides/terapia , Inhibidores de la Angiogénesis/farmacología , Animales , Peso Corporal , Carcinoma/patología , División Celular/efectos de los fármacos , Factores de Crecimiento Endotelial/análisis , Factores de Crecimiento Endotelial/biosíntesis , Humanos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular/análisis , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Linfocinas/análisis , Linfocinas/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Necrosis , Talidomida/farmacología , Neoplasias de la Tiroides/patología , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/biosíntesis , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The sodium-iodide symporter (NIS) is expressed by papillary (PTC) and follicular (FTC) thyroid carcinoma, and is essential for iodine uptake. We hypothesized that PTC and FTC with detectable NIS immunostaining would be more amenable to radioactive iodine ((131)I) treatment and follow a more benevolent course. To test this, we determined NIS expression by immunohistochemistry in 23 PTC, 9 FTC, and 12 benign thyroid lesions from children and adolescents. NIS expression was determined by two blinded examiners and graded as absent = 0, minimal = 1, moderate = 2, intense = 3, and very intense = 4. NIS was detected in 35% (eight of 23) of PTC, 44% (four of 9) of FTC, 25% (two of eight) of benign tumors, and 100% (four of four) of autoimmune lesions. The intensity of NIS expression was similar in PTC (0.61 +/- 0.24), FTC (0.56 +/- 0.24), and benign tumors (0.50 +/- 0.33) but was more intense in autoimmune lesions (3.0 +/- 0.7, p < 0.005). Distant metastases were found only among PTC with undetectable NIS (two of 15, 13%), and recurrence developed exclusively from PTC and FTC with undetectable NIS (four of 20, 20% versus zero of 12, p = 0.043). The dose of iodine 131 required to achieve remission in the five patients with PTC who had undetectable NIS (213.3 +/- 53 mCi) was greater than that required by patients with similar age and extent of disease for whom NIS expression is unknown (109 +/- 22 mCi, p = 0.06). We conclude that NIS expression is associated with a lower risk of recurrence for PTC and FTC of children and adolescents.

Asunto(s)

Adenocarcinoma Folicular/química , Carcinoma Papilar/química , Proteínas de Neoplasias/análisis , Simportadores/análisis , Neoplasias de la Tiroides/química , Adenocarcinoma Folicular/epidemiología , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/cirugía , Adolescente , Adulto , Biomarcadores , Carcinoma Papilar/epidemiología , Carcinoma Papilar/patología , Carcinoma Papilar/radioterapia , Carcinoma Papilar/cirugía , Diferenciación Celular , Niño , Terapia Combinada , Enfermedad de Graves/metabolismo , Enfermedad de Graves/patología , Humanos , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/uso terapéutico , Metástasis de la Neoplasia , Pronóstico , Recurrencia , Riesgo , Método Simple Ciego , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Tiroiditis Autoinmune/metabolismo , Tiroiditis Autoinmune/patología

RESUMEN

Previous observations suggest that an immune response against thyroid carcinoma could be important for long-term survival. We recently found that infiltration of thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival, but the factors that control lymphocytic infiltration and proliferation are largely unknown. We hypothesized that the antigen presentation coactivators (B7-1 and B7-2), which are important in other immune-mediated thyroid diseases, might be important in lymphocytic infiltration of thyroid carcinoma. To test this, we determined B7-1 and B7-2 expression by immunohistochemistry [absent (grade 0) to intense (grade 3)] in 27 papillary (PTC) and 8 follicular (FTC) thyroid carcinomas and 9 benign thyroid lesions. B7-1 and B7-2 were expressed by the majority of PTC and FTC (78% of PTC and 100% of FTC expressed B7-1; 88% of PTC and 88% of FTC expressed B7-2). B7-1 expression was more intense in PTC (1.4 +/- 0.2; P = 0.01) and FTC (2.6 +/- 0.2; P < 0.001) than in benign tumors (0.57 +/- 0.30) or presumably normal adjacent thyroid (0.07 +/- 0.07) and was more intense in carcinoma that contained lymphocytes (1.95 +/- 0.21) than in carcinoma that did not (1.08 +/- 0.26; P = 0.016). B7-2 expression was of similar intensity in benign and malignant tumors (PTC, 1.6 +/- 0.2; FTC, 2.1 +/- 0.4; benign, 1.86 +/- 0.4), but was more intense than in presumably normal adjacent thyroid (0.64 +/- 0.25; P

Asunto(s)

Antígenos CD/análisis , Antígeno B7-1/análisis , Glicoproteínas de Membrana/análisis , Enfermedades de la Tiroides/epidemiología , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/inmunología , Adolescente , Antígeno B7-2 , Niño , Femenino , Humanos , Inmunohistoquímica , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Enfermedades de la Tiroides/inmunología