[The morphological and immunohistochemical features and malignancy potential of a hyalinizing trabecular tumor of the thyroid].

The paper considers the morphological features of a rare hyalinizing trabecular tumor of the thyroid, which is of follicular cell origin. The signs of invasive tumor growth into to the intrinsic capsule and its blood vessels were observed in 2 of 7 cases. There was a positive immunohistochemical reaction of tumor cells with antibodies to thyroglobulin and neuron-specific enolase and a negative one to calcitonin, galectin 3, cytokeratin 19, and HBME-1. The differential diagnosis of a tumor and papillary and medullary carcinomas of the thyroid, as well as its malignancy potential are discussed in the paper.

[The inhibitory effect of vascular endothelial growth factor antisense oligonucleotides in angiogenesis of thyroid carcinoma].

OBJECTIVE: To investigate the inhibitive effect of antisense oligonucleotide (ASODN) on vascular endothelial growth factor (VEGF) expression and endothelial cell growth in thyroid carcinoma. METHODS: Targeted ASODN of VEGF was designed and synthesized, then transfected to TT (medullary thyroid carcinoma) cell line and the culture supernatant was collected in which ECV304 (endothelial cell line) was seeded. At the same time positive control [sense oligonucleotides (SODN) group] and normal control were set for comparison. Cell growth condition was observed under microscope. RT-PCR and immuocytochemistry were used for detection of VEGF mRNA and protein expression in TT cells. MTT assay was used for cell growth inhibition ratio (IR) of TT and ECV304 cells, flow cytometry (FCM) for apoptotic index (AI) of ECV304 cells and acridine orange/ethidium bromide (AO/EB) staining for apoptotic morphology of ECV304 cells. RESULTS: As compared with positive and normal control groups, VEGF mRNA and protein expressions in TT cells of ASODN transfection groups were obviously decreased (P < 0.01). Cell growth was not influenced apparently in ECV304 cells with direct ASODN administration, but ECV304 cell growth in ASODN conditioned medium was significantly inhibited and IR (0.21 +/- 0.03, 0.31 +/- 0.01, 0.42 +/- 0.22) was significantly higher than that of SODN group (0.05 +/- 0.03, P < 0.01), with the presence of apparent apoptosis. The effect mentioned above was in a dose-dependent manner. CONCLUSION: ASODN can suppress endothelial cell growth and inhibit tumor angiogenesis possibly by specifically blocking VEGF expression in thyroid carcinoma.

Evaluation of tumor angiogenesis with contrast-enhanced dynamic magnetic resonance mammography.

The goal of this research was to correlate dynamic magnetic resonance (MR) mammographic contrast enhancement and microvessel densities in breast masses. Forty-six female patients with breast masses detected by mammography and/or ultrasonography were included in the study. MR contrast enhancements of the lesions were investigated dynamically using axial three-dimensional fast low-angle shot sequences. After excisional biopsy or mastectomy, immunohistochemical staining with factor VIII-RA was performed, followed by microvessel density measurements. Contrast enhancement patterns in dynamic MR mammography were compared with microvessel density measurements using Student's t-test, Pearson's moment correlation coefficients, and one-way analysis of variance (ANOVA). Malignant lesions exhibited three different enhancement patterns: 1) a peak enhancement within 120 seconds (early phase), followed by a decrease in the delayed phase (25 cases); 2) an increase in the early phase, followed by a plateau in the delayed phase (9 cases); and 3) an increase throughout the examination without any peak (5 cases). In benign lesions, signal intensity did not exhibited a peak in five cases, whereas in two cases enhancement was increased in the early phase and made a plateau in the delayed phase. A significant correlation was found between microvessel density and the percentage of maximal signal increase following paramagnetic contrast administration (r=0.322, p<0.05). Dynamic enhancement patterns and rates of maximal signal increase predict microvessel density in breast malignancies and may possibly be used as prognostic indicators.

Medullary thyroid carcinoma: a rare presentation as a hypervascular tumour.

Sporadic medullary thyroid carcinoma (MTC) usually presents with a thyroid mass, cervical lymphadenopathy or other local cervical symptoms. Often the diagnosis is unsuspected pre-operatively. We report a unique case of a mixed follicular medullary thyroid carcinoma presenting as a tumour with extreme vascularity. The management of hypervascular thyroid tumours is discussed together with current controversies regarding persistent hypercalcitoninaemia.

Computerized nuclear morphometry and quantitation of angiogenesis in thyroid neoplasms.

The aim of this study was to investigate the nuclear and angiogenetic profile in different types of thyroid neoplasms and to make any possible statistical comparison between the different nuclear morphometric and angiogenetic parameters, in order to search for new diagnostic and prognostic criteria. Sixty two cases of thyroid neoplasms were classified as follows: 31 papillary carcinomas, 10 follicular neoplasms (5 adenomas and 5 carcinomas), 5 undifferentiated carcinomas, 6 Huerthle-cell carcinomas and 10 medullary carcinomas. Using an image analysis system, six nuclear morphometric and eight angiogenetic variables were measured for each case. Concerning nuclear morphometric variables, statistical differences were found mainly between undifferentiated and overall subtypes of differentiated carcinomas, as well as between follicular adenomas and carcinomas. Concerning angiogenesis variables, statistical differences were found only in the vessel's minor axis length between undifferentiated and overall subtypes of differentiated carcinomas, between MVD of follicular adenomas and carcinomas respectively, as well as between MVD of medullary carcinoma and follicular cell carcinomas generally. In conclusion nuclear morphometry and quantitation of angiogenesis could offer two additional parameters in the distinction between follicular adenomas and carcinomas. However, they cannot serve as absolute diagnostic criteria since they are only based on statistical differences. From a prognostic point of view, nuclear morphometry may have some relevance as far as follicular-cell neoplasms are concerned since the more aggressive anaplastic carcinomas have a distinct morphometric profile. Moreover, our study revealed differences in the angiogenetic profile between medullary and follicular cell carcinomas.

Inducible nitric oxide synthase expression, apoptosis, and angiogenesis in in situ and invasive breast carcinomas.

In this investigation, we studied the expression of inducible nitric oxide synthase (iNOS) and its association to apoptosis and angiogenesis in 43 in situ and 68 invasive breast carcinomas. Its expression was studied immunohistochemically using a polyclonal iNOS antibody, and the staining was evaluated both in tumor and stromal cells. Apoptosis was detected by 3' end labeling of fragmented DNA (terminal deoxynucleotidyl transferase-mediated nick end labeling method). Vascularization was detected immunohistochemically using an antibody to the FVIII-related antigen, and calculated microvessel densities were determined. In addition to strong iNOS expression in stromal cells, iNOS positivity was observed in tumor cells in 46.5% of in situ and 58.8% of invasive carcinomas. In invasive carcinomas, there were more cases with iNOS positivity both in tumor and stromal cells compared to in situ carcinomas (0.007). The proportion of cases with iNOS-positive tumor cells increased in in situ carcinomas from grade I to III (20.0%, 46.2%, and 73.3%). In invasive ductal carcinomas, there were more cases with iNOS-positive tumor cells than with in situ carcinomas (P = 0.04). Carcinomas with both iNOS-positive tumor and stromal cells had a higher apoptotic index (P = 0.02) and a higher calculated microvessel densities index (P = 0.02). A high number of iNOS-positive stromal cells associated with metastatic disease (P = 0.05). The results show that breast carcinoma cells, in addition to stromal cells, express iNOS and are capable of producing NO. Carcinomas with iNOS-positive tumor and stromal cells have a higher apoptotic indices and increased vascularization, suggesting that iNOS contributes to promotion of apoptosis and angiogenesis in breast carcinoma. The association of the number of iNOS-positive stromal cells with metastatic disease might be attributable to stimulation of angiogenesis, resulting in a higher vascular density and consequently a higher probability for tumor cells to invade.

Angiogenesis in poorly differentiated medullary carcinoma of the stomach.

We studied the role of angiogenesis in patients with medullary type poorly differentiated adenocarcinoma (MTPDA) of the stomach. Immunohistochemical analyses were conducted using antibodies against factor VIII (endothelial cells), vascular endothelial growth factor (VEGF) and its receptors (KDR andflt-1), and basic fibroblast growth factor (bFGF) and its receptors (bek andflg). Archival specimens of MTPDA (n=22) and non-MTPDA (n=47) were studied. The expression of VEGF and bFGF, the vessel count, and positivity of KDR on endothelium were all significantly higher in MTPDA than in non-MTPDA. The vessel count correlated with the VEGF expression in MTPDA. The vessel count and VEGF expression increased with the increasing stage of disease in MTPDA but not in non-MTPDA. The expression of bFGF and its receptors did not correlate with the vessel count and stage of disease in either type. These findings thus suggest that the biological behavior of medullary type poorly differentiated adenocarcinoma of the stomach is angiogenesis-dependent. The correlation of the VEGF expression and its endothelial receptors with the vessel count and the stage of disease thus suggests that VEGF is a factor responsible for the induction of angiogenesis in this type.

Microvessel count: an indicator of poor outcome in medullary thyroid carcinoma but not in other types of thyroid carcinoma.

The growth of newly formed vessels (neoangiogenesis) represents an important step both in physiologic and pathologic situations. In particular, tumor growth and metastasis require angiogenesis. Microvessel count, which expresses a measure of tumor angiogenesis, has been associated with metastatic spread in cutaneous, mammary, prostatic, head, neck, and pulmonary cancer. In this study, the role of tumor angiogenesis as a prognostic indicator was examined in 157 primary thyroid cancers including 82 well-differentiated carcinomas, 52 medullary carcinomas, and 23 undifferentiated carcinomas. Microvessels were carefully counted by highlighting endothelial cells with anti-CD34 formalin-fixed tumor samples. The mean of microvessel count was 30.7 per field in papillary thyroid carcinomas, 39.4 per field in follicular thyroid carcinomas, 32.7 per field in undifferentiated carcinoma, and 41.8 per field in medullary carcinoma. We found that the number of newly formed vessels was significantly associated with poor prognosis only in medullary carcinoma. All of the dead patients with medullary carcinoma showed a microvessel count higher than 30, which resulted in a high statistical difference compared with alive patients (P = 0.00098). Multiple logistic regression analysis showed microvessel count, together with pTNM (P = 0.026). These results were also confirmed by Kaplan-Meir survival analysis (log-rank test; P = 0.04). By contrast, no differences in the number of microvessels was found between dead and living patients with well-differentiated carcinoma and undifferentiated carcinoma. In conclusion, microvessel count, as quantitation of tumor angiogenesis, plays an important prognostic role in medullary thyroid carcinomas.