Role of VEGF-A and its receptors in sporadic and MEN2-associated pheochromocytoma.

Pheochromocytoma (PHEO), a rare catecholamine producing tumor arising from the chromaffin cells, may occurs sporadically (76%-80%) or as part of inherited syndromes (20%-24%). Angiogenesis is a fundamental step in tumor proliferation and vascular endothelial growth factor (VEGF-A) is the most well-characterized angiogenic factor. The role of angiogenic markers in PHEO is not fully understood; investigations were therefore made to evaluate the expression of VEGF-A and its receptors in PHEO and correlate to clinical parameters. Twenty-nine samples of PHEO were evaluated for VEGF-A, VEGF receptor-1 (VEGFR-1) VEGFR-2 expression and microvessel density (MVD) by immunohistochemistry. Clinical data were reviewed in medical records. The mean age of patients was 38±14 years, and 69% were woman. VEGF-A, VEGFR-1 and VEGFR-2 staining were detected in nearly all PHEO samples. No significant correlation was observed between VEGF-A, VEGFR-1, VEGFR-2 expression or MVD and age at diagnosis, tumor size or sporadic and hereditary PHEO. However, the levels of expression of these molecules were significantly higher in malignant PHEO samples (p=0.027, p=0.003 and p=0.026, respectively).VEGF-A and its receptors were shown to be up-regulated in malignant PHEO, suggesting that these molecules might be considered as therapeutic targets for unresectable or metastatic tumors.

Reduced tissue inhibitor of metalloproteinase-2 expression is associated with advanced medullary thyroid carcinoma.

Matrix metalloproteinases (MMPs) are enzymes for extracellular matrix remodeling that are involved in tumor growth, progression and metastasis. Among them, MMP-9 has been implicated in tumor angiogenesis. Tissue inhibitor of matrix metalloproteinase (TIMP)-2, a member of the family of MMP inhibitors, induces apoptosis and inhibits various stages of angiogenesis. Previous studies analyzing the expression of MMP-9 and TIMP-2 in medullary thyroid carcinoma (MTC) are scarce. The aims of the current study were to evaluate MMP-9 and TIMP-2 expression in MTC samples and correlate the results with clinical parameters. Paraffin-embedded samples from 77 MTC patients were evaluated for expression by immunohistochemistry. The clinical data in medical records were retrospectively reviewed. In total, 77 patients aged 35.6±17.1 years were enrolled. Of these patients, 36 had hereditary disease (46.8%). Immunohistochemical staining for MMP-9 and TIMP-2 was detected in 89.6 and 93.5% of the samples, respectively. The expression of MMP-9 was not found to correlate with clinical parameters, although, a trend toward a correlation between MMP-9 and distant metastasis was observed (P=0.053). By contrast, TIMP-2 staining was found to correlate with age at diagnosis (P=0.026) and negatively correlate with tumor size and tumoral stage (P=0.002 and P=0.001, respectively). Notably, the highest levels of TIMP-2 expression were observed in patients with intrathyroidal disease. The MMP-9 enzyme involved in extracellular matrix remodeling is overexpressed in MTC lesions and may contribute to tumor vascularization and growth. Reduced levels of TIMP-2 expression may be implicated in tumor progression and spread of disease.

Increased expression of vascular endothelial growth factor and its receptors, VEGFR-1 and VEGFR-2, in medullary thyroid carcinoma.

BACKGROUND: Vascular endothelial growth factor (VEGF-A) expression is upregulated in the majority of human tumors, where it stimulates proliferation, migration, and survival of endothelial cells. Studies have suggested that VEGF inhibitors can be used as an alternative therapy in medullary thyroid carcinoma (MTC), but data about expression of VEGF-A and its receptor in this tumor are scarce. The aims of this study were to evaluate VEGF-A, VEGF receptor (VEGFR)-1, VEGFR-2, and microvessel density (MVD) expression in MTC samples and correlate it with clinical parameters. METHODS: Paraffin-embedded samples from 38 MTC patients were evaluated for VEGF-A, VEGFR-1, VEGFR-2, and MVD expression by immunohistochemistry. Clinical data were retrospectively reviewed in medical records. RESULTS: Thirty-eight patients aged 31.8 +/- 17.1 years were enrolled. Twenty-seven patients had hereditary disease (71.1%). Twenty-five of them were found to have multiple endocrine neoplasia (MEN) 2A and two were found to have MEN 2B. VEGF-A immunohistochemical staining was detected in 95% (36/38), VEGFR-1 in 96% (36/37), and VEGFR-2 in 91% (31/34) of MTC samples. Age at surgery was positively correlated with VEGFR-2 (p = 0.003). There was no correlation between VEGF-A, VEGFR-2, and tumor stage (tumor node metastasis). Nevertheless, VEGFR-1 was found to be inversely correlated with tumor node metastasis (p = 0.034). We also observed a trend toward an association between VEGFR-1 signal intensity and cure of disease, although this did not reach statistical significance (p = 0.054). Neither VEGF-A nor VEGFR-2 was associated with disease outcome after a median follow-up period of 5 years (p = 0.882 and p = 0.236, respectively). As expected, MVD was correlated with age at surgery (p = 0.005) and tumor size (p = 0.03). Patients with the hereditary form of the disease had a stronger intensity for VEGFR-1 (p = 0.039), whereas patients with sporadic disease displayed higher MVD counts (44 [27-63] vs. 21 [9-49], p = 0.018). CONCLUSION: The VEGF-A, VEGFR-1, and VEGFR-2 immunoreactive proteins are overexpressed in MTC lesions and might be implicated in tumor progression. It is not clear, however, if expression of these molecules provides prognostic information regarding the spread or outcome of MTC.

[Cancer in thyroid nodules: evaluation of ultrasound and fine-needle aspiration biopsy]. / Nódulos de tireóide: valor da ultra-sonografia e da biópsia por punção aspirativa no diagnóstico de câncer.

BACKGROUND: Thyroid nodules are a very common clinical problem and fine-needle aspiration biopsy (FNAB) is its main diagnostic test. Recently, it has been shown that some ultrasonographic features are associated to an increased risk of cancer, but a comparison between FNAB and ultrasonography (US) or its combination is not available. The aim of this study was to evaluate FNAB and US performance, isolated or combined, for cancer diagnosis in thyroid nodules. METHODS: Eighty patients, with palpable solitary thyroid nodules or multinodular goiters, who were to undergo surgery, were selected among 289 patients seen in our clinic between March, 1995 and July, 1997. US and FNAB were performed by one of us. US was considered positive for cancer when microcalcifications, absent halo or hypoechogenicity were seen. FNAB was considered positive for cancer when it was either suspicious or compatible with malignancy. Both methods (FNAB and US) were evaluated in parallel combination (positive when FNAB or US was positive) and in serial combination (positive when both, FNAB and US, were positive). RESULTS: Sensitivity and specificity of FNAB and US for cancer diagnosis in thyroid nodules were, respectively, 87% and 62%, and 81% and 70%. Serial combination of FNA and US had sensitivity of 69% and specificity of 91%, and parallel combination resulted in sensitivity of 94% and specificity of 52%. CONCLUSION: The US had good accuracy in the evaluation of thyroid nodules, and can help us take some decisions in the clinical practice, supplementary to FNA. Nevertheless, the quality of the ultrasound examination depends on the experience of the examiner and on the characteristics of the equipment, so new studies are necessary to evaluate these factors to the current usage of ultrasonographic characteristics in the evaluation diagnostic of thyroid nodules.

Nódulos de tireóide: valor da ultra-sonografia e da biópsia por punçäo aspirativa no diagnóstico de câncer / Cancer in thyroid nodules: evaluation of ultrasound and fine-needle aspiration biopsy

Os nódulos de tireóide säo um problema clínico comum e a punçäo aspirativa por agulha fina (PAAF) é o principal exame utilizado para seu diagnóstico diferencial. Recentemente, foi demonstrado que algumas características ultra-sonográficas dos nódulos estäo associadas a um maior risco de câncer. Entretanto, näo encontramos estudos que avaliassem o desempenho dos dois exames de forma comparativa e/ou complementar. OBJETIVO: Avaliar o desempenho da ultra-sonografia (US), da PAAF e de sua combinaçäo no diagnóstico de câncer em nódulos de tireóide. MÉTODOS: Oitenta pacientes com nódulos únicos ou dominantes, com indicaçäo cirúrgica, foram selecionados dentre 289 pacientes com nódulos tireoidianos atendidos entre março de 1995 e julho de 1997. Os pacientes foram submetidos à PAAF e à US de tireóide por um dos autores. A PAAF foi considerada positiva quando os achados citológicos eram suspeitos ou diagnósticos de câncer. A US foi considerada positiva quando os nódulos apresentavam pelo menos um dos seguintes achados: microcalcificações, hipoecogenicidade ou halo ausente. PAAF e US foram combinados em paralelo (o resultado positivo em qualquer um dos dois exames era considerado indicativo de malignidade) e em série (somente o resultado positivo de ambos os testes indicava presença de malignidade). RESULTADOS: A sensibilidade e a especificidade da PAAF na detecçäo do câncer em nódulos de tireóide foram, respectivamente, 87 por cento e 62 por cento, e a sensibilidade e a especificidade da US foram, respectivamente, 81 por cento e 70 por cento. A combinaçäo em série dos dois exames (PAAF e US) resultou em sensibilidade de 69 por cento e especificidade de 91 por cento, e a combinaçäo em paralelo (PAAF ou US) apresentou sensibilidade de 94 por cento e especificidade de 52 por cento. CONCLUSÄO: A US pode ser útil na avaliaçäo dos nódulos de tireóide, alternativamente ou em combinações com a PAAF. Como o resultado da US depende da experiência do operador e das características do equipamento, säo necessários estudos em diferentes centros para o seu uso na prática clínica