Risk Factors for Recurrence of Follicular Thyroid Cancer: A Systematic Review.

Background: In risk assessment of recurrence, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are often grouped together as differentiated thyroid cancer (DTC). However, while risk factors affecting recurrence of PTC are well established, risk factors for recurrence of FTC are not. This systematic review examines risk factors for recurrence of FTC and evaluates their significance. Methods: A systematic search on PubMed and Embase was performed in September 2020, including studies evaluating risk factors for recurrence of FTC. A quality assessment of the enrolled studies was performed. Results: Nine studies (n = 1544 patients) from eight countries were included. The average recurrence rate was 13.6%, and distant metastasis (DM) constituted 64.8% of the recurrent cases. The risk factors examined were sex, age at diagnosis, primary tumor size, degree of invasiveness, focality, positive resection margin, lymph node (LN) metastasis, and DM at diagnosis. Risk factors correlated with recurrence of FTC were age older than 45 years, primary tumor size above 40 mm, widespread invasion, multifocality, positive resection margin, LN metastasis, and DM at diagnosis. Sex was not a statistically significant risk factor. Conclusions: We identified seven risk factors associated with recurrence of FTC. Age and multifocality were found to be of greater impact regarding recurrence risk of FTC compared with PTC. Future research needs to address the impact of different risk factors for recurrence of FTC particularly including age, primary tumor size, angioinvasion, and mutational status.

Transcription Factor Prospero Homeobox 1 (PROX1) as a Potential Angiogenic Regulator of Follicular Thyroid Cancer Dissemination.

It is well known that Prospero homeobox 1 (PROX1) is a crucial regulator of lymphangiogenesis, that reprograms blood endothelial cells to lymphatic phenotype. However, the role of PROX1 in tumor progression, especially in angiogenesis remains controversial. Herein, we studied the role of PROX1 in angiogenesis in cell lines derived from follicular thyroid cancer (FTC: FTC-133) and squamous cell carcinoma of the thyroid gland (SCT: CGTH-W-1) upon PROX1 knockdown. The genes involved in angiogenesis were selected by RNA-seq, and the impact of PROX1 on vascularization potential was investigated using human umbilical vein endothelial cells (HUVECs) cultured in conditioned medium collected from FTC- or SCT-derived cancer cell lines after PROX1 silencing. The angiogenic phenotype was examined in connection with the analysis of focal adhesion and correlated with fibroblast growth factor 2 (FGF2) levels. Additionally, the expression of selected genes involved in angiogenesis was detected in human FTC tissues. As a result, we demonstrated that PROX1 knockdown resulted in upregulation of factors associated with vascularization, such as metalloproteinases (MMP1 and 3), FGF2, vascular endothelial growth factors C (VEGFC), BAI1 associated protein 2 (BAIAP2), nudix hydrolase 6 (NUDT6), angiopoietin 1 (ANGPT1), and vascular endothelial growth factor receptor 2 (KDR). The observed molecular changes resulted in the enhanced formation of capillary-like structures by HUVECs and upregulated focal adhesion in FTC-133 and CGTH-W-1 cells. The signature of selected angiogenic genes' expression in a series of FTC specimens varied depending on the case. Interestingly, PROX1 and FGF2 showed opposing expression levels in FTC tissues and seven thyroid tumor-derived cell lines. In summary, our data revealed that PROX1 is involved in the spreading of thyroid cancer cells by regulation of angiogenesis.

Recurrent thyroid cancers have more peritumoural lymphatic vasculature than nonrecurrent thyroid cancers.

BACKGROUND: The goal of the study was to evaluate angiogenesis and lymphangiogenesis in differentiated thyroid cancer and recurrences. METHODS: Twenty-seven patients with recurrent differentiated thyroid cancer (20 papillary and seven follicular thyroid carcinomas) and 24 nonrecurrent thyroid cancers were included in this study. Additionally, 24 thyroid adenomas were included as benign controls. All thyroid cancer recurrences were operatively managed, and local recurrences in cervical lymph nodes or cervical soft tissue were histologically confirmed. Altogether, a total of 108 samples were evaluated using CD31 and D2-40 immunohistochemical staining and microscopy. RESULTS: As measured in primary tumours, the median density of CD31-positive vascular structures was 327 vessels (v)/mm(2) for recurrent cancers, 362 v/mm(2) for nonrecurrent cancers and 484 v/mm(2) for thyroid adenomas (P = 0·017). Among the subgroups, the lowest median vascular density of 316 v/mm(2) was found in recurrent papillary cancers and the highest vascular density of 604 v/mm(2) was observed in nonrecurrent follicular cancers (P = 0·018). The median density of D2-40-positive peritumoural lymphatic vessels was 101/mm(2) in recurrent cancers, 56·1/mm(2) in nonrecurrent cancers and 53·9/mm(2) for adenomas (P = 0·015). In the subgroups, peritumoural lymphatic vascular density was 102 v/mm(2) in recurrent papillary cancers and 56·0 v/mm(2) in nonrecurrent papillary cancers (P = 0·044). CONCLUSIONS: Recurrent thyroid cancers expressed less intratumoural microvessels than thyroid adenomas. A high density of peritumoural lymphatic vessels was found in recurrent papillary cancers. High blood vessel density may be a marker for less aggressive tumours, while high peritumoural lymphatic vasculature is a marker for more aggressive and recurrence-prone tumours.

Papillary thyroid carcinoma with heterotopic ossification is a special subtype with extensive progression.

An immunohistochemical study was conducted of 108 papillary carcinoma cases, including 48 cases with intratumoral heterotopic ossification (IHO). In 48 cases, papillary carcinoma with IHO was accompanied by nodular fibrosis. Cases of papillary carcinoma with IHO or nodular fibrosis showed higher incidences of lymph node metastasis, multifocal lesions, and extrathyroidal invasion than those without IHO and nodular fibrosis. A higher number of stromal myofibroblasts was observed in papillary carcinoma with IHO or nodular fibrosis than in that without fibrosis. Expression of both basic fibroblast growth factor (bFGF) and bone morphogenetic protein (BMP)-2 was the highest in papillary carcinoma with IHO. Papillary carcinoma with IHO showed higher vascular invasion and higher numbers of capillaries expressing nestin, which is associated with high expression of vascular endothelial growth factor (VEGF). Papillary carcinoma with IHO is a unique subtype with extensive progression including frequent lymph node metastasis, multifocality, and invasive behavior. Papillary carcinoma with IHO was correlated with expression of bFGF, BMP-2, and VEGF in the carcinoma cells, leading to neovascularization.

Angiogenesis and angiogenic factor expression in thyroid cancer.

PURPOSE: Increased expression of angiogenic factors and high vascular density characterize tumors with increased invasive and metastatic capability. Anti-vascular endothelial growth factor (VEGF) therapies have shown an important potentiation of chemotherapy and radiotherapy in experimental and clinical studies. The purpose of this study was to investigate whether it could be possible to identify a subgroup of thyroid cancer patients with high angiogenic activity. METHODS: Formalin-fixed paraffin-embedded tissues from 25 papillary and 18 follicular thyroid carcinomas were assessed immunohistochemically for angiogenic activity, i.e. vascular density (VD) and expression of VEGF and basic fibroblast growth factor (bFGF). RESULTS: VD was significantly higher in follicular tumors (p=0.05). Tumors > 4 cm had a significantly higher VD (p=0.001). High VEGF expression was significantly related to high VD (p=0.05). There was no association of bFGF with histological characteristics. CONCLUSIONS: Increased angiogenic activity is a common feature of thyroid carcinomas, particularly in follicular tumors and larger carcinomas. These results support the testing of anti-VEGF therapies in combination with radiotherapy and chemotherapy in advanced thyroid tumors.

[Advances in the treatment of thyroid cancer in the era of molecularly targeted therapies]. / Les progrès dans le traitement des cancers de la thyroïde à l'ère des thérapies ciblées moléculaires.

During last decade, many progresses have been made in the understanding of thyroid cancer molecular biology. This knowledge led to the development of novel targeted therapy in iodine-resistant patients. However, the management of patients remains complex because of the broad spectrum of clinical presentation of thyroid cancers, differences in their natural histories and the lack of data about randomized trials. Angiogenesis inhibitors (sorafenib, motesanib, axitinib and vandetanib) have shown promising activity in differentiated thyroid cancer. Vandetanib, an inhibitor of RET and VEGFR tyrosine-kinases, is promising in medullary thyroid cancers. Preliminary results of these trials are discussed in this review.

The steroid receptor coactivator-3 is a tumor promoter in a mouse model of thyroid cancer.

The molecular genetic events underlying thyroid carcinogenesis are not well understood. Mice harboring a dominant-negative mutant thyroid hormone receptor-beta (TRbeta(PV/PV) mice) spontaneously develop follicular thyroid carcinoma similar to human cancer. The present study aimed to elucidate the role of the steroid receptor coactivator-3 (SRC-3) in thyroid carcinogenesis in vivo by using the offspring from the cross of TRbeta(PV/PV) and SRC-3(-/-) mice. TRbeta(PV/PV) mice deficient in SRC-3 (TRbeta(PV/PV)SRC-3(-/-) mice) had significantly increased survival, decreased thyroid tumor growth, delayed tumor progression and lower incidence of distant metastasis as compared with TRbeta(PV/PV) mice with SRC-3 (TRbeta(PV/PV)SRC-3(+/+) mice). Further, in vivo and in vitro analyses of multiple signaling pathways indicated that SRC-3 deficiency could lead to (1) inhibition of cell cycle progression at the G(1)/S transition via controlling the expression of cell cycle regulators, such as E2F1; (2) induction of apoptosis by controlling the expression of the Bcl-2 and caspase-3 genes and (3) suppression of neovascularization and metastasis, at least in part, through modulating the vascular endothelial growth factor gene expression. Taken together, SRC-3 could play important roles through regulating multiple target genes and signaling pathways during thyroid carcinogenesis, understanding of which should direct future therapeutic options for thyroid cancer.

[Ultrasonography of thyroid cancer].

The diagnosis and management of follicular carcinoma of the thyroid gland remains a controversial topic. Color-Doppler (CD) imaging has been expected for the differential diagnosis between follicular adenoma and follicular carcinoma. CD imaging examination of follicular tumors has revealed that high-velocity pulsative blood flow penetrating the tumor is a characteristic finding of follicular carcinoma. Real-time tissue elastography (RTE), which enable to demonstrate the tissue elasticity, has begun to be applied for the thyroid disease. In follicular cancer, the difference of elasticity from core of the tumor and periphery is supposed to be depend on the difference of hypercellurality. RTE can provide new useful information for the differential diagnosis of thyroid follicular lesions.

Functional thyrotropin receptor attenuates malignant phenotype of follicular thyroid cancer cells.

Thyrotropin (TSH) is a thyroid-specific growth factor inducing differentiated function and growth of thyrocytes in vitro. In thyroid cancer, loss of TSH-receptor (TSHR) expression is a sign of de-differentiation and is believed to contribute to the malignant phenotype. The present studies aimed to determine the in vitro and in vivo effects of functioning TSHR in the follicular thyroid cancer cell line HTC, a subclone of FTC133 cells, lacking endogenous expression of TSHR, and HTCtshr+ cells transfected with human TSHR-cDNA. HTCtshr+ cells grew faster in vitro (doubling time 1.15 vs 1.56 d, p < 0.05) and TSH caused a dose-dependent growth response. Adhesion to and invasion through reconstituted basement membrane were reduced in HTCtshr+ cells, but when stimulated with TSH increased to levels comparable to naïve HTC cells. In vivo, tumor latency was 11 d for naïve HTC as compared to 21 d for HTCtshr+ xenografts. Smaller tumor volumes were registered for HTCtshr+ cells (250 +/- 217 vs 869 +/- 427 mm3, p < 0.05). Angiogenesis, as determined by vascular surface density (VSD) of experimental tumors, was enhanced in naïve HTC tumors (VSD 0.87 +/- 0.1 microm-1 vs 0.55 +/- 0.2 microm-1 in HTCtshr+, p < 0.05). VEGF secretion was more pronounced in naïve HTC cells stimulated with EGF, than in HTCtshr+ cells stimulated with either TSH or EGF. In conclusion, regained expression of functional TSHR in the follicular thyroid cancer cell line HTC alters in vitro features commonly associated with the malignant phenotype. Smaller tumors and reduced angiogenesis of xenotransplanted HTC cells with functioning TSHR suggest a less aggressive in vivo phenotype. The present data highlight the pivotal role of TSHR to affect transformed thyrocytes in vitro and in vivo. They also suggest a role for EGF as a modulator of angiogenesis in thyrocytes devoid of TSHR.

Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation.

Patients suffering from bone metastases of follicular thyroid carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of epidermal growth factor receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis using the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR2, mitogen-activated protein kinase, and Akt in culture. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis. When WRO cells were injected into the tibia of nude mice, tumor and endothelial cells within the lesions expressed phosphorylated EGFR, VEGFR, Akt, and mitogen-activated protein kinase that were inhibited by the oral administration of AEE788. Therapy consisting of orally given AEE788 and i.p. injected paclitaxel induced a high level of apoptosis in tumor-associated endothelial cells and tumor cells with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data show that blocking the phosphorylation of EGFR and VEGFR with AEE788 combined with paclitaxel can significantly inhibit experimental human FTC in the bone of nude mice.

Diagnosis of thyroid follicular carcinoma by the vascular pattern and velocimetric parameters using high resolution pulsed and power Doppler ultrasonography.

The aim of this study was to define the preoperative diagnosis of thyroid follicular carcinoma by the vascular pattern and velocimetric parameters using high resolution pulsed and power Doppler ultrasonography (US). We compared the vascular pattern and the velocimetric parameters, such as peak systolic velocity (Vmax), end-diastolic velocity (Vmin), pulsatility index (PI), or resistance index (RI) between follicular adenoma (FA, n = 25) and follicular carcinoma (FC, n = 10) and analysed them by means of receiver characteristics curves (ROC). Of 10 patients with FC, 8 (80%) patients presented a moderate increase of intranodular vascularization using power Doppler US. In contrast, the majority (84%, 21 out of 25 cases) of FA cases showed only a peripheral rim of color flow even by power Doppler US. These color flow imagings by power Doppler US were suggested to be a reliable tool for the differential diagnosis of thyroid follicular tumor with a sensitivity of 87.5% and a specificity of 92%. In velocimetric analyses, the Vmax/Vmin ratios, PI, and RI were significantly higher in the patients with FC than those with FA (p<0.001, p<0.005, and p<0.001, respectively). By means of ROC, FC could be diagnosed with a cutoff value of ratio of PI (>1.35), RI (>0.78), and Vmax/Vmin (>3.79). The diagnostic efficiency evaluated by ROC curves were 0.898 for PI, 0.876 for RI, and 0.888 for Vmax/Vmin, respectively. In conclusion, the evaluation of the vascular pattern and the velocimetric parameters using pulsed and power Doppler ultrasound may provide important information that is useful in making correct differential diagnosis of malignant or benign thyroid follicular tumor preoperatively.

Diagnosis of thyroid cancer in children: value of gray-scale and power doppler US.

PURPOSE: To prospectively analyze the accuracy of various diagnostic criteria for cancer in solid thyroid nodules in children on the basis of gray-scale and power Doppler ultrasonographic (US) findings. MATERIALS AND METHODS: The study protocol was approved by the institutional review board, and patient's parents gave full informed consent. One hundred three consecutive pediatric patients with solid thyroid nodules were included in the study. Thirty-five patients had thyroid cancer (mean age, 14.6 years +/- 2.6 [standard deviation]; range, 10-18 years), and 68 patients had benign thyroid nodules (mean age, 14.2 years +/- 2.9; range 9-18 years). Three-dimensional US was used to determine the volume of thyroid gland and thyroid nodules. Results of nodule cytologic and histologic examination and long-term clinical and US follow-up were used as a proof of final diagnosis. The following US characteristics were evaluated: location, echogenicity, echotexture, outline, presence of a halo, microcalcifications, and type of vascularization. Multivariate logistic regression analysis was used to evaluate the accuracy of US criteria for thyroid cancer in lesions with diameter of 15 mm and smaller and lesions with diameter larger than 15 mm. Qualitative variables were compared by using the chi(2) test and quantitative variables were compared by using the Student t test. Significance was defined at P < .05. RESULTS: In thyroid nodules with diameter of 15 mm and smaller, the most reliable diagnostic criteria for malignancy were an irregular outline (sensitivity, 69.6%; specificity, 86.4%; P < .001), subcapsular location (sensitivity, 65.2%; specificity, 86.4%; P < .001), and increased intranodular vascularization (sensitivity, 69.6%; specificity, 87.9%; P < .01). For thyroid nodules larger than 15 mm in diameter, the accuracy of US diagnosis was much lower than that for smaller nodules. The only reliable criterion for cancer in this group was hypoechogenicity (sensitivity, 60.0%; specificity, 84.0%; P < .01). CONCLUSION: Study findings indicate that US is most helpful in diagnosis of thyroid malignancy in thyroid nodules with diameter of 15 mm and smaller, with detection of irregular tumor outline, subcapsular location, and increased intranodular vascularization.

The influence of the vascularisation of the follicular thyroid nodules on the proliferative activity of the follicular cells.

The enlargement of the thyroid is, in general, benign in origin and due to nodular goitre. Follicular cellular proliferation of thyroid nodules has been increasingly observed recently. With fine needle aspiration biopsy (FNAB) this is classified as a follicular tumour. These lesions present various patterns of vascularisation in ultrasound examination. The aim of the study was to establish the relation between follicular nodule vascularisation and the proliferative activity of various types of follicular cell. According to the manner of proliferation, patients were divided into groups as follows: (I). patients with hyperplastic nodules (46 cases), (II). patients with follicular adenoma (42 cases), and (III). patients with follicular cancer (9 cases). In each case B-mode sonography, Power Doppler, sonographically guided FNAB (S-FNAB), morphological examination and morphometry were performed. The proliferative activity was detected with immunohistochemical methods (PCNA, Ki 67 and MPM2) to determine the so-called "proliferative index". The study revealed increased proliferative activity in tumours of malignant origin and increased vascularisation in coexistence with increased proliferation of the follicular cells. As assessed by Power Doppler, an increased flow pattern in the centre of the nodules correlates with increased proliferative activity. The results suggest that Power Doppler examination could be helpful in selecting nodules for FNAB, especially in multinodular goitre.

Extensive vascular invasion is a marker of risk of relapse in encapsulated non-Hürthle cell follicular carcinoma of the thyroid gland: a clinicopathological study of 18 consecutive cases from a single institution with a 11-year median follow-up.

AIMS: To determine the prognostic value of certain clinicopathological features in a series of 18 consecutive cases of encapsulated follicular carcinoma (EFC) of the thyroid gland with long follow-up. METHODS AND RESULTS: Eighteen consecutive cases of EFC were retrieved from 1975 to 1993. Gender, age at onset, type of surgery, presence of capsular and/or vascular invasion, number of involved vessels, tumour size, and TNM/pTNM classification were evaluated and correlated with disease outcome. None of the cases presented with distant metastases. Extensive vascular invasion (defined as more than four capsular vessels involved) was present in two cases. After a median follow-up of 133 months, all patients were alive. Three cases had relapsed in lung and bone. In two out of these three cases, extensive vascular invasion was present. Radioiodine therapy was curative in two of three of the relapsed cases. CONCLUSIONS: EFC is a low-risk carcinoma, with no patients' deaths after a median follow-up of 11 years. Extensive vascular invasion should be considered as a risk factor for relapse. A conservative surgical approach is recommended. Since relapses may occur up to 14 years after the initial surgery, life-long follow-up is advisable.

sFlt-1 gene therapy of follicular thyroid carcinoma.

Tumor progression largely depends on blood supply and neovessel formation, and angiogenesis is emerging as a promising target for cancer therapy. Vascular endothelial growth factor (VEGF), a major proangiogenic molecule, stimulates angiogenesis via promoting endothelial proliferation, survival and migration. VEGF has been found to be up-regulated in various types of tumors and to be associated with tumor progression and poor prognosis. Inhibition of VEGF or its signaling pathway has been shown to suppress tumor angiogenesis and tumor growth. In the present study, we tested the antiangiogenic and antitumor effects of soluble VEGF receptor-1 [soluble Flt (sFlt)-1] on the growth of follicular thyroid carcinoma (FTC). We constructed a 293 embryonic kidney cell line (293-Flt1-3d) that expresses sFlt-1, which is composed of the first three extracellular domains of Flt-1. The 293-Flt1-3d cells inhibited the in vitro growth of human umbilical vein endothelial cells in a paracrine manner. The in vivo antitumor and antiangiogenic activities of the 293-Flt1-3d cells were tested. When 293-Flt1-3d cells were inoculated at a site remote to the FTC-133 tumor transplant, the growth of FTC-133 tumors were inhibited by 70.37%, as compared with the control treatment with 293 cells expressing control gene LacZ. Immunohistochemical analysis of microvessel densities in treated tumors demonstrated that 293-Flt1-3d cells robustly suppressed intratumoral angiogenesis. Our data suggest that a mammalian cell-mediated approach could effectively deliver sFlt-1 gene therapy and inhibit tumor angiogenesis and tumor growth.

Effects of PTK787/ZK222584, a tyrosine kinase inhibitor, on the growth of a poorly differentiated thyroid carcinoma: an animal study.

The process of neoangiogenesis is induced by several mediators. Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis including thyroid carcinomas. The principal aim of this study was to test the hypothesis that inhibition of VEGF activity by PTK787/ZK222584 (PTK/ZK), a specific blocker of both VEGF-receptor tyrosine kinases, could inhibit the growth of a poorly differentiated thyroid cancer. Human follicular thyroid tumor xenografts were implanted sc into nude mice. Eight days following implantation, the animals were randomized into two groups (n = 10 each group). One group received PTK/ZK daily, and the other was treated with sodium chloride (control). Treatment was orally administered using a gastric tube. All animals were killed after 4 wk. Tumors, blood, and samples of other organs were taken for further examinations. Treatment with PTK/ZK induced a 41.4% reduction in tumor volumes. Necrosis of the tumors was detectable earlier in PTK/ZK-treated mice compared with controls. Immunohistochemistry revealed a significant decrease in neoangiogenesis in tumors of PTK/ZK-treated animals. Moreover, no compensatory overexpression of VEGF protein was detectable in the treated group. The compound was well tolerated by the animals without significant side effects on body weight or in general. These results showed that VEGF receptor blockade is a rational approach to the therapy of thyroid cancer. The combination of radioiodine or external radiation with VEGF receptor tyrosine kinase inhibitors might be a new option, especially for poorly differentiated thyroid cancers with limited or no response to conventional therapy.

Vascular invasion in thyroid and gastric carcinomas.

The molecular, biological, and histopathologic features related to vascular invasiveness of gastric and thyroid carcinomas, with an emphasis on glandular (intestinal) carcinoma of the stomach and follicular thyroid carcinoma, are reviewed from a clinicopathologic standpoint.

Antiangiogenic and antitumor effects of endostatin on follicular thyroid carcinoma.

Tumor growth and metastasis depend on blood supply and blood vessel formation. Angiogenesis, therefore, represents a promising target for cancer therapy. Endostatin is one of the most potent antiangiogenic factors and has been shown to effectively inhibit angiogenesis and tumor growth in a variety of in vivo models. In this study, we tested the effects of endostatin on xenografted human follicular thyroid carcinoma (FTC) in nude mice. Our result demonstrated that recombinant endostatin significantly inhibited the growth of FTC xenografts. Furthermore, we established an endostatin-expressing FTC cell line (FTC-BmEndo) using retrovirus-mediated gene transfer approach. We found that the in vivo growth of FTC-BmEndo cells was significantly inhibited, compared with the parental FTC cells, whereas both lines grew at the same rate in vitro. High-level expression of endostatin within the FTC-BmEndo tumors was evidenced by immunohistochemical staining, paralleled with a reduced microvessel density. The systemic level of vascular endothelial growth factor was significantly lower in mice bearing the FTC-BmEndo tumors than in those bearing parental FTC tumors. By using two different approaches, namely the recombinant endostatin protein and the gene therapy strategy, our study demonstrated that endostatin could be effective in suppressing the growth of human FTC in immunodeficient mice.

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.