Medical treatment of benign and malignant thyroid tumors

This article discusses the multiple types of benign and malignant thyroid tumors. Benign nodules are subclassified as hypofunctioning or functioning and hyperfunctioning, and the management and treatment of these nodules are outlined. The author also discusses in detail the morphologic types, distinctive prognoses, and responses to therapies of the various malignant tumors.     

良性及恶性甲状腺肿瘤端粒酶活性的表达

甲状腺结节是甲状腺最常见的一种疾病 ,正确鉴别结节的性质 ,区分其为良性或恶性极为重要。现有的影像学 ,免疫学、细胞学诊断都存在一定的误诊率 ,迫切需要寻找一种灵敏度高、特异性强的方法。端粒酶是一种核糖核蛋白 (ｒｉｂｏｎｕｃｌｅｏｐｒｏｔｅｉｎ) ,在恶性肿瘤的发病过程中有非常重要的作用 ,人类大多数恶性肿瘤细胞具有端粒酶的高表达〔1〕。甲状腺恶性肿瘤端粒酶活性是否表达阳性 ?细针抽吸 (ｆｉｎｅ ｎｅｅｄｌｅａｓｐｉｒａｔｉｏｎ ,ＦＮＡ)细胞标本端粒酶活性测定是否能与组织测定结果一致 ?本研究对良性及恶性甲状腺肿瘤…     

Tie-2 and angiopoietin-1 expression in human thyroid tumors.

Tie-2 is an endothelial cell-specific receptor tyrosine kinase involved in vascular maturation and remodeling. Although its expression is considered to be restricted to vascular endothelial cells and hematopoietic progenitors, our immunohistochemical and in situ hybridization studies showed that Tie-2 and its ligand, angiopoietin (Ang)-l were expressed not only in benign and malignant human thyroid tumor cells but also in hyperplastic regions of adenomatous goiter. To confirm the expression in these tissues further, we used a laser capture microdissection system to isolate epithelial tumor cells from tissue specimens selectively, and demonstrated the expression of Tie-2 and Ang-1 mRNAs in tumor cells by RT-PCR analysis. Furthermore, Tie-2 and Ang-1 mRNAs and proteins were also detected in rat thyroid cell lines, FRTL-5 and PCCL-3. Our results suggest that Ang-1/Tie-2 signaling may be involved in the proliferation of thyroid epithelial cells.     

Analyses of MYC, ERBB2, and CCND1 genes in benign and malignant thyroid follicular cell tumors by real-time polymerase chain reaction.

The roles of the MYC, ERBB2, and CCND1 genes in thyroid carcinogenesis are poorly known. We used real-time quantitative polymerase chain reaction (PCR) assays based on fluorescent TaqMan methodology to quantify MYC, ERBB2, and CCND1 gene amplification and expression in 24 benign tumors (adenomas and goiter nodules) and 12 carcinomas (9 papillary, 2 follicular, and 1 anaplastic) of the thyroid. Real-time PCR is a recently developed method for nucleic acid quantification in homogeneous solutions, and has the potential to become a reference in terms of performance, accuracy, sensitivity, wide dynamic range, excellent interlaboratory agreement, and high throughput capacity, while avoiding the need for tedious post-PCR processing. Overexpression (>5 standard deviations above mean for normal thyroid tissues) of the ERBB2 and CCND1 genes was observed (3.2- to 5.2-fold and 3.8- to 8.4-fold, respectively) in 5 (14%) and 13 (36%) of 36 neoplastic thyroid RNA samples, respectively. Overexpression of the CCND1 gene was observed in both the benign and malignant thyroid tumors, whereas the ERBB2 gene was mainly overexpressed in malignant thyroid tumors. None of the neoplastic thyroid samples overexpressed MYC. No MYC, ERBB2, or CCND1 gene amplification was identified. These results suggest that the CCND1 gene plays an early role and the ERBB2 gene a later role in thyroid tumorigenesis.     

Angiogenesis in benign and malignant thyroid disease.

CONTEXT: Angiogenesis has been recognized as an important process contributing to the pathophysiology of many benign and malignant diseases. It is not surprising, therefore, that this complex process is proving to be an important regulator of both benign and malignant disease processes in the thyroid gland. This paper will review the general principles of angiogenesis and lymphangiogenesis, as well as the importance of the balance between angiogenic stimulators and inhibitors in the normal thyroid gland. We will also review how this balance is disturbed in benign and malignant thyroid conditions. Finally, we will address the role manipulation of this process may play in the development of novel treatment strategies for diseases of the thyroid. OBJECTIVE: To review the literature concerning the role of angiogenesis in the thyroid gland. CONCLUSIONS: Angiogenesis is an important process which has been shown to be involved in the pathophysiology of benign and malignant diseases of the thyroid gland. Manipulation of this process holds great promise for the development of novel treatments for these disorders. As the mechanisms regulating angiogenesis in the thyroid become increasingly clear, researchers will come ever closer to turning this promise into clinical reality.     

Expression of vascular endothelial growth factor-C in benign and malignant thyroid tumors

In contrast to vascular endothelial growth factor (VEGF), which stimulates angiogenesis, VEGF-C is thought to stimulate lymphangiogenesis. The role of VEGF-C in thyroid cancer pathogenesis has not been clarified. One might expect a different pattern of VEGF-C expression in the various types of thyroid cancer because of their different means of metastases. In this investigation, we determined whether the differential expression of VEGF-C might explain the different propensity to lymph node metastasis in thyroid cancers. One hundred eleven normal and neoplastic thyroid tissues were analyzed by real-time quantitative PCR. Papillary thyroid cancers had a higher VEGF-C expression than other thyroid malignancies (P < 0.0005 ANOVA). Among the normal thyroid tissues from patients with malignant or benign thyroid diseases, there was no significant difference in VEGF-C expression. Paired comparison of VEGF-C expression between thyroid cancers and normal thyroid tissues from the same patients showed a significant increase of VEGF-C expression in papillary thyroid cancer (1.10 +/- 0.41 vs. 0.70 +/- 0.13; P = 0.001) and a significant decrease of VEGF-C expression in medullary thyroid cancer (0.11 +/- 0.13 vs. 0.78 +/- 0.29; P = 0.001). In contrast, there was no significant difference of VEGF-C expression between cancer and normal tissues in other types of thyroid cancer. In summary, VEGF-C expression is increased in papillary thyroid cancer, compared with paired normal thyroid tissues, but not in other thyroid cancers that are also prone to lymph node metastasis. The lymphangiogenic role of VEGF-C in thyroid cancers therefore appears to be complex and other factors are likely to be also involved.     

Evaluation of insulin-like growth factor II, cyclooxygenase-2, ets-1 and thyroid-specific thyroglobulin mRNA expression in benign and malignant thyroid tumours

OBJECTIVE: We evaluated three markers (insulin-like growth factor II (IGF-II), cyclooxygenase-2 (COX-2) and ets-1) of thyroid growth stimulation and cell transformation together with a thyroid-specific marker (thyroglobulin (Tg)) for their potential to differentiate benign and malignant follicular thyroid neoplasia (FN). DESIGN AND METHODS: mRNA expression levels were determined by real-time PCR in 100 snap-frozen thyroid samples: 36 benign thyroid nodules with different histology and function (19 cold (CTN) and 17 toxic thyroid nodules (TTN)), 36 corresponding normal thyroid tissues of the same patients, eight Graves' disease (GD) thyroids, 10 follicular thyroid carcinomas (FTC) and 10 papillary thyroid carcinomas (PTC). RESULTS: Mean IGF-II and COX-2 levels were not significantly altered between benign and malignant thyroid nodules (IGF-II) or nodular (FTC, TTN, CTN) and normal thyroid tissues (COX-2). In contrast, eight- to tenfold upregulation of ets-1 was observed in PTC and three- to fourfold upregulation of ets-1 was observed in FTC (and GD) compared with benign thyroid nodules and normal thyroid tissues. In addition, thyroglobulin mRNA expression was markedly downregulated (50- to 100-fold) in FTC, PTC and GD samples compared with benign nodular and normal thyroid tissues. Hence an ets-1/Tg ratio >20 distinguished differentiated thyroid cancer from benign nodular or normal thyroid tissue. We then studied ets1- and Tg mRNA expression levels in fine needle aspiration cytology (FNAC) samples. However, in a consecutive series of 40 FNAC samples only equivocal results were obtained on 38 benign and two malignant (FTC) thyroid tumour samples. CONCLUSIONS: Upregulation of ets-1 and downregulation of Tg mRNA expression occur in differentiated thyroid cancer and may facilitate pre-operative identification of thyroid malignancy depending on further evaluation of these potentially promising markers in a larger series of benign and malignant thyroid tumours and their FNAC samples.     

Telomerase activity in benign and malignant adrenal tumors.

Histological analysis of surgically removed adrenal masses often fails to differentiate between benign and malignant tumors. In normal cells, the telomeric ends of the chromosomes are shortened with each cell division, leading to chromosome destabilization and cellular senescence after a critical number of cell cycles. In tumor cells, telomere shortening is prevented by a specific DNA polymerase, called telomerase. In an effort to clarify the role of telomerase in the pathogenesis of adrenal tumors, and to test whether its activity could serve as marker of malignancy, we measured telomerase activity in 41 human adrenal tissue samples that were classified both by the clinical course and by histological examination. Telomerase activity was determined by TRAP ELISA and expressed as high (>50% of positive control telomerase activity), medium (31-50%), low (11-30%), very low (< or = 10%), or absent (0%). The 8 normal adrenal tissue samples showed very low levels of telomerase activity. Mean telomerase activity also very low in 3/3 incidentalomas, 6/6 Cushing adenomas, 6/6 Conn adenomas, 7/7 adrenocortical carcinomas, 8/8 benign pheochromocytomas, and 2/3 malignant pheochromocytomas. In contrast, one malignant pheochromocytoma showed high telomerase activity. These data indicate that telomerase activity may not be a suitable marker for malignancy in the adrenal gland. Our results also challenge the current dogma of close correlation between cell dedifferentiation and telomerase activity.     

半乳糖凝集素3表达在良恶性甲状腺肿瘤鉴别中的意义

目的　探讨半乳糖凝集素3表达对鉴别良恶性甲状腺肿瘤的临床价值。方法　采用免疫化学染色法(SP法)观察72例手术切除的甲状腺肿瘤标本半乳糖凝集素3的表达。结果　半乳糖凝集素3在恶性肿瘤的细针抽吸(FNA)细胞涂片与组织切片中均高水平表达,在良性肿瘤中不表达或低表达。良性与恶性甲状腺肿瘤在FNA细胞涂片或组织切片中半乳糖凝集素3的表达差异有统计学意义(χ2 =43. 73,χ2 =48. 16,均P<0. 01)。相同性质的甲状腺肿瘤FNA细胞涂片与组织切片的半乳糖凝集素3表达一致,两者之间差异无统计学意义(χ2 =0. 04,χ2 =0. 19,均P>0. 05)。结论　半乳糖凝集素3在良恶性甲状腺肿瘤中表达不同,恶性肿瘤中表达显著增高,是鉴别良恶性甲状腺肿瘤可靠的分子标记物,可用于FNA涂片标本及组织标本检测。     

Galectin-3 messenger ribonucleic acid and protein are expressed in benign thyroid tumors

Galectin-3 is a protein of the lectin family that has been associated with neoplastic processes in various tissues. In the thyroid, expression of this protein has been described in differentiated follicular cancer, suggesting that the immunohistochemical study of galectin-3 may be a potential marker of malignancy in thyroid neoplasms. The confirmation of these results may represent an extremely useful tool for presurgical diagnosis and medical conduct. In this study, galectin-3 protein and mRNA expression were analyzed in the thyroid tissues from 87 patients with histomorphological diagnosis of multinodular goiter (MNG) (n = 24), follicular adenoma (n = 31), follicular carcinoma (n = 20), papillary carcinoma (n = 12), and five normal tissues. Galectin-3 protein expression was detected by immunohistochemical method in light, fluorescence, and confocal microscopy, using monoclonal antibody. Galectin-3 mRNA expression was detected by the RT-PCR method. Our results showed that the majority of carcinomas expressed galectin-3 protein (follicular, 90%; papillary, 100%). However, in contrast to the previously published data, benign lesions also expressed galectin-3 (adenoma, 45%; MNG, 17%). We further demonstrated by RT-PCR that thyroid tissues with diagnosis of adenoma and MNG-expressed galectin-3 mRNA. Although the galectin-3 immunostaining demonstrated a sensitivity of 93.8% in the identification of cancer, the accuracy in the distinction between benign and malignant tissues was 77.0%. This accuracy was even lower (68.6%) when the galectin-3 expression in follicular adenoma was compared with follicular carcinoma. Thus, the use of galectin-3 immunodetection as a molecular marker for thyroid carcinoma must be interpreted with caution, particularly in the differentiation between thyroid follicular carcinoma and follicular adenoma.     

Methylation profile in benign,borderline and malignant ovarian tumors

Purpose Promoter hypermethylation is a common phenomenon in neoplasm. The aims of this study were (a) to compare the methylation profiles in different types of ovarian tumors and (b) to determine the possible relationship between the methylation status and different clinicopathologic characteristics. Methods We examined the promoter methylation status of 9 tumor suppressor genes (RARβ2, TMS1, RIZ1, P15, P16, PTEN, MINT31, APC and HIC1) in 89 ovarian cancers, 16 borderline ovarian tumors, 19 benign ovarian tumors, 16 normal ovarian tissue and 5 ovarian cancer cell lines. The methylation status was examined with respect to clinicopathologic characteristics of the ovarian cancer patients. Results Methylation indices for ovarian cancer, borderline ovarian tumor, benign ovarian tumor, normal ovarian tissue and ovarian cancer cell lines were 28.8, 20.1, 10.5, 11.8 and 42.2%, respectively. It was significantly higher in ovarian cancer, borderline ovarian tumor and ovarian cancer cell lines (X ² test, P < 0.001, P = 0.01 and P < 0.001, respectively) than benign or normal ovarian tissues. In ovarian cancer, concurrent methylation of at least two genes (CM2) was associated with early stage disease (X ² test, P = 0.035) and less recurrence (X ² test, P = 0.020). When the methylation statuses of the nine genes as well as CM2 were included in multivariate Cox Regression analysis, CM2 was the only independent predictor for survival (P = 0.013). Conclusion CM2 was an independent predictor for survival in ovarian cancer.     

高频超声对甲状腺肿块良恶性的临床诊断价值

目的 分析甲状腺肿块的二维声像图特点及多普勒检查中的血流峰值变化,探讨高频超声对甲状腺肿块的良恶性诊断价值.方法 收集80例病人的104个甲状腺肿块声像图,根据二维声像图中肿块的形态、边界、侧壁回声失落或后方回声衰减、内部回声、微小钙化及多普勒检查中的收缩期血流峰值(Vmax)和阻力指数(RI),将肿块预期分为良性和恶性两组,将高频超声预期结果与术后病理结果进行对比,比较二者的符合率和误差率.结果 高频超声预测良性肿块66个,病理检查为61个,二者的符合率为92.4%;预测恶性肿块为38个,病理检查为32个,二者的符合率为84.2%;预测总符合率为89.4%(93/104),误差率为11.6%(11/104).结论 根据高频超声检测甲状腺肿块的声像图特点,能对甲状腺肿块的良恶性进行初步判断,对患者及临床治疗有重要的意义.

Abstract：

Objective To detect and analyze thyroid tumor by two-dimensional sonogram and Doppler parameter, and evaluate the value of high-frequency ultrasound in diagnosing thyroid benign and malignant tumors. Methods The ultrasonic images of 104 thyroid tumor from 80 patients with typical features were collected. Thyroid tumor was classified into benign and malignant nodules, based on the shape, border, or the rear wall echo, echo attenuation loss, internal echo, and microcalcifications in two-dimensional sonogram and systolic blood peak velocity (Vmax) and resistant index (RI) in Doppler examination. The expected results of high frequency ultrasound were compared with pathological results on consistency and error rate. Results Prediction of benign tumor by high frequency ultrasound was 66, and pathology 61, consistency rate of the two was 92.4%. Prediction of malignant lesions was 38, and pathological examination 32, consistency rate of the two was 84.2%. The total coincidence rate was 89.4%(93/104) and the error rate was 11.6%( 11/104). Conclusions The typical features of thyroid tumor on high-frequency ultrasound are helpful in diagnosis of benign or malignant nodules, which is valuable in guiding clinical treatment.     

Gene expression profiles of primary breast tumors maintained in distant metastases

It has been debated for decades how cancer cells acquire metastatic capability. It is unclear whether metastases are derived from distinct subpopulations of tumor cells within the primary site with higher metastatic potential, or whether they originate from a random fraction of tumor cells. Here we show, by gene expression profiling, that human primary breast tumors are strikingly similar to the distant metastases of the same patient. Unsupervised hierarchical clustering, multidimensional scaling, and permutation testing, as well as the comparison of significantly expressed genes within a pair, reveal their genetic similarity. Our findings suggest that metastatic capability in breast cancer is an inherent feature and is not based on clonal selection.     

Peroxidase and coupling activities of thyroid peroxidase in benign and malignant thyroid tumor tissues.

The coupling activity of thyroid peroxidase (TPO) in thyroid glands from patients with benign adenoma, papillary carcinoma, and diffuse goiter (Graves' disease) was measured for the first time, in addition to the peroxidase activity of these tissues. The peroxidase activity of TPO in the mitochondria-microsomes fraction was measured with guaiacol or iodide as the second substrate. In the case of papillary carcinoma, the mean protein-based specific activity obtained by the guaiacol assay was about 1/7 of that of diffuse goiter. The iodide oxidation activity of carcinoma was very low, about 1/25 [corrected] of that in diffuse goiter and 1/70 of that in adenoma. The peroxidase activity in adenoma was almost similar in the guaiacol oxidation assay and approximately one half in the iodide oxidation assay as compared with that in diffuse goiter. There was a close correlation between the guaiacol and iodide oxidation assays in individual patients with adenoma and diffuse goiter, but not in patients with papillary carcinoma. The coupling activity of TPO was measured with thyroglobulin purified from pooled toxic diffuse goiters and chemically iodinated to contain little additional T3 and T4. The specific coupling activity of TPO in mitochondria-microsomes from carcinoma was significantly lower (about 1/5) than that of diffuse goiter, and the activity in adenoma was not significantly different (about 1/2) from that of diffuse goiter. The data of coupling activities has a close correlation with that of peroxidase activities in individual patients with adenoma but not in patients with carcinoma. Based on these findings, the qualitative abnormality of TPO and its relation to the cold 123I scintigram in thyroid tumors are discussed.     

Histiocytic differentiation in benign and malignant bone tumors

Summary In this study fresh frozen tissue samples of benign osseous tumors (five non-osteogenic fibromas, one fibrous dysplasia, one chondromyxoidfibroma), tumors of uncertain biological behaviour (eight cases of histiocytosis X, two giant-cell tumors), and of malignant intraosseous tumors (two malignant fibrous histiocytomas, two malignant histiocytosis, four osteosarcomas, one chondrosarcoma and two Ewing sarcomas) were studied with a panel of monoclonal antibodies reactive with monocyte/macrophages and various types of dendritic cells. In addition, tumors were further defined with a broad spectrum of antibodies against filamentous proteins and lymphocyte differentiation antigens. The specimens were stained with a triple-layer immunoalkaline phosphatase protocol. Tumors stained with these antibodies could be roughly divided into two groups. The first group comprised tumors with one predominant cell population reactive with one particular monoclonal antibody. In this group, cases of histiocytosis X were found to be consistently labelled with CD-1 antibodies. The giantcell tumors showed a very homogeneous staining with certain monocyte/macrophage antibodies (Ki-M8). Nevertheless, even in these tumors, heterogeneity was demonstrated by the occurrence of cells with monocytic differentiation in histiocytosis X and conversely by the occurrence of cells with differentiation antigens of the dendritic cell system in giant-cell tumors. An exception has to be made for the two cases of malignant histocytosis examined. These tumors were selectively labelled with antibodies against monocyte/macrophages (Ki-M8, IOM-1). The second group comprised tumors showing a high degree of heterogeneity demonstrated by the varying amounts of tumor cells reacting with the applied markers of the monocyte/macrophage and dendritic cell systems. In most cases it was difficult to ascribe labelled cells to the tumor cell population as opposed to an innocent bystander inflammatory cell population. This distinction was especially difficult in malignant fibrous histiocytomas underlining the current concept that these tumors are of primitive mesenchymal rather than true histiocytic origin.This study was supported by Deutsche Forschungsgemeinschaft and Hamburger Stiftung zur Förderung der Krebsbekämpfung