Preoperative serum thyroglobulin as a useful predictive marker to differentiate follicular thyroid cancer from benign nodules in indeterminate nodules

Indeterminate cytology results increase the number of repetitive procedure and unnecessary surgery. This study was designed to find useful and simple predictive tools to differentiate malignant thyroid nodules from indeterminate nodules. We retrospectively enrolled 164 patients who had undergone thyroid surgery as a result of indeterminate cytology in the National Cancer Center. We reviewed patients' age at diagnosis, sex, preoperative biochemical markers such as thyroglobulin (Tg), anti-Tg antibody, free T4 and TSH level, and sonographical and pathological findings, which were subjected to statistical analysis. We found several clinical and sonographical predictive factors that showed significant differences. Young age, male, preoperative high Tg level, and hypoechoic nodule on sonography all increased cancer probability significantly in multivariate analysis. With a cut-off value of 187.5 ng/mL Tg, sensitivity and specificity were 54.8% and 90.1%, respectively (AUC 0.748, P < 0.001). In the case of nodule size > 1.7 cm, elevated serum Tg predicts the risk of malignancy; especially Tg > 70 ng/mL (odds ratio 3.245, 95% confidence interval 1.115-9.450, P = 0.038). Preoperative Tg levels had very high specificity in predicting thyroid cancer in case of suspicious follicular neoplasm. Therefore, Tg levels may be a useful marker for differentiating thyroid cancer from benign thyroid nodules in the cytological diagnosis of indeterminate nodules.     

Clinical use of PET/CT in thyroid cancer diagnosis and management

The incidence of thyroid cancer is low, but when it occurs, it is mainly of the papillary histopathological type. Although PET/CT has a limited role in the diagnosis, it plays a significant role in the overall post-surgery management of a patient with thyroid cancer. This follow-up role is important, especially in patients with elevated serum thyroglobulin, but negative radioiodine whole body scans. There is increasing evidence that PET/CT should be a part of routine care in the Tg positive Radioiodine scan negative patient.     

甲状腺球蛋白测定与131I全身显像在甲状腺乳头癌复发监测中的意义

探讨甲状腺球蛋白(Tg)和131I全身显像(131I-WBS)在甲状腺乳头癌(PTC)复发监测中的意义. 30例PTC患者术后6周,行131I(3.7GBq)首次清除残留甲状腺组织治疗,6个月后再给予131I 治疗1次,治疗中同时测定Tg和进行131I-WBS.结果表明,在首次清除残留甲状腺组织治疗时,显像发现淋巴、肺及骨转移6例,其余转移灶于6个月治疗时发现,有3例患者(10%)Tg测定在正常范围,而131I-WBS出现转移灶,4例患者(13.3%)Tg测定异常,而131I-WBS正常.Tg测定和131I-WBS可作为诊断PTC有无转移的重要指标,二者监测复发应联合应用,可互相补充.     

131I和99mTc-MIBI全身显像联合血清Tg和CEA检测在分化型甲状腺癌131I治疗随访中的应用

目的:评价131I-WBS和99mTc-MIBI全身显像联合血清Tg和CEA检测在分化型甲状腺癌术后放射性131I治疗随访中的应用价值.方法:48例DTC患者均行手术治疗并经131I治疗后(3～6)个月随访复查131I-WBS和血清Tg和CEA测定,131I-WBS显像阴性者于治疗后1年行99mTc-MIBI全身显像....     

利用基因转染技术长期培养人甲状腺细胞

本工作采用Ｃａ３（ＰＯ４）２ＤＮＡ共沉淀法，将含有编码ＳＶ４０病毒早期基因的ｐＳＧ５质粒转染原代培养的人甲状腺上皮细胞。在重复进行的１２次转染中，有１次细胞生存达２００ｄ，传了２６代。检测证实，转染后的细胞仍能保持少量Ｔ４的分泌和Ｔｇ的合成；细胞经长期培养后形态无异常，Ｇ带染色正常，对裸鼠无致瘤性。甲状腺滤泡上皮细胞长期培养模型的建立，为进一步研究细胞免疫在自身免疫性甲状腺炎中的作用打下了基础。     

Comparison of radioassay and haemagglutination methods for anti-thyroid microsomal antibodies.

Parallel measurements of circulating anti-thyroid microsomal (anti-M) antibodies by radioassay and haemagglutination were performed on subjects with or without thyroid disorders. Three-quarters (75.4%) of control subjects had undetectable antibody levels (less than 10 u/ml) by radioassay and only 3.1% had concentrations of greater than or equal to 75 u/ml. Abnormally elevated levels (greater than or equal to 75 u/ml) were found in most of the patients with Hashimoto's thyroiditis (94.1%) or idiopathic myxoedema (86.7%), in the majority (75.0%) of those with Graves' disease and only in a minority of those with other thyroid disorders. The percentage of positive sera by haemagglutination was very similar in all groups to that of abnormal values observed in the radioassay. Direct comparison of parallel tests on a total of 631 sera revealed a highly significant correlation (r = 0.91, P less than 0.001) between the two methods, but elevated antibody titres by haemagglutination were found in some sera with negative radioassays. All these sera were from a single patient with thyroid carcinoma associated with Hashimoto's thyroiditis and had elevated levels of anti-thyroglobulin (anti-Tg) antibodies. Evidence that such discrepancies were due to anti-Tg antibodies reacting with microsomal-bound Tg was provided by the demonstration that the haemagglutination produced by these sera could be completely inhibited by the addition of Tg. A similar inhibition was observed with two rabbit antisera to human Tg, but not with sera from patients with thyroid autoimmune disorders containing high levels of anti-microsomal anti-bodies.     

促甲状腺激素、甲状腺球蛋白浓度在甲状腺良、恶性结节诊断中的价值

目的 探讨血清促甲状腺激素（TSH）、甲状腺球蛋白（Tg）浓度变化在甲状腺良、恶性结节诊断中临床价值.方法 选取96例因甲状腺结节病住院患者,比较甲状腺良、恶性结节患者血清TSH、Tg浓度差异,分析血清TSH、Tg浓度与甲状腺良、恶性结节的关系.结果 甲状腺恶性结节组血清TSH浓度（2.55±1.46mIU/L）与甲状腺良性结节组（1.15±1.10mIU/L）比较,差异有统计学意义（P＜0.05）;随血清TSH浓度的升高,甲状腺恶变结节比例升高;甲状腺恶性结节组血清Tg浓度（255.0±60.6ng/mL）高于甲状腺良性结节组（115.0±32.4ng/mL） （P ＜0.05）,不同血清Tg浓度组间甲状腺恶性结节数比例差异无统计学意义（P＞0.05）.结论 血清TSH、Tg浓度检测对甲状腺良、恶性结节诊断中有一定临床意义,血清TSH浓度是预测甲状腺结节恶变的危险因子.     

Thyroglobulin immunostaining in follicular thyroid carcinoma: relationship to the degree of differentiation and cell type

A series of 47 primary and seven metastatic thyroid follicular carcinomas, including well, moderately and poorly differentiated, were tested for thyroglobulin (Tg) using immunohistology. In addition, three combined follicular undifferentiated carcinomas, 17 undifferentiated carcinomas and five renal cell carcinomas metastatic to the thyroid were examined. Only two follicular carcinomas did not stain for thyroglobulin. Some inter-tumour differences in Tg staining were found but there was no absolute correlation between this and the degree of tumour differentiation. The two tumours that failed to stain for Tg were poorly differentiated; thyroglobulin positive poorly differentiated tumours demonstrated a clearly weaker staining pattern for Tg. All but one of 15 oxyphilic follicular carcinomas stained positively for Tg but the staining intensity was often weak. Five of six clear cell follicular carcinomas were positive for Tg but the staining reaction was generally faint and there were often large areas devoid of positive cells. Positive staining was demonstrated in the differentiated areas of combined follicular undifferentiated carcinomas. Undifferentiated carcinomas and metastatic renal cell carcinomas gave negative results. Thyroglobulin is a reliable marker for thyroid follicular carcinoma but the patchy staining pattern, particularly in the less well-differentiated tumours may produce less reliable results in small biopsies.     

Immunological events leading to destructive thyroiditis in the AUG rat.

Single or infrequent observations in patients or animals with autoimmune thyroid disease (AITD) have failed to elucidate the exact sequence of pathogenetic events leading to thyroid cell destruction. A detailed serial morphological and functional study of experimental AITD (EAITD) in the female AUG rat was therefore undertaken. Following induction of EAITD with thyroglobulin (Tg) in adjuvant antibodies to Tg were detectable one week after the initial immunization, at which stage Ia positive vascular endothelium was observed within the thyroid. This was followed by large numbers of Ia positive dendritic-like cells. With time, in almost all the animals whose titre of Tg antibody rose above a critical level, lymphocytic infiltration was observed consisting mainly of Ia positive B cell aggregates with fewer scattered T cells. This was associated with raised levels of serum TSH and concomitant focal follicular hyperplasia and necrosis. Expression of Ia was mainly restricted to the outer epithelial wall of follicular thyrocytes in direct contact with invading lymphoid cells, although occasional staining on the internal apical membrane was observed as a late event in the destructive process. The Ia expression on thyroid epithelial cells was only observed in areas of thyroid lymphoid infiltration. The immune infiltration of the thyroid in the AUG rat appears to be very similar to that observed in Hashimoto's thyroiditis, with the exception that Ia was not regularly observed on the apical surfaces of thyrocytes. Whether or not the diminished or absent epithelial Ia expression contributes to the spontaneous recovery of the disease observed in this model remains to be resolved.     

Tg与TGA在分化型甲状腺癌术后监测及其疗效观察中的应用价值

目的：探讨甲状腺球蛋白（thyroglobulin,Tg）在分化型甲状腺癌（differentiated thyroid carcer,DTC）诊断及术后疗效观察中的应用价值。方法：采用放射免疫分析,对198例行甲状腺全切及次全切的DTC患者进行术后及术后半年血清Tg水平的追踪检测,同时行甲状腺球蛋白抗体（thyroglobulin antibody,TGA）的检测,并与正常对照组与转移组进行比较。结果：160例Tg〈20ng/ml的DTC患者阴性组术后1周血清Tg水平与对照组比较无明显差异（P〉0.05）;Tg水平〈10ng/ml者为56例,占35%。38例Tg〉20ng/ml阳性组术后1周时Tg水平明显高于阴性组和正常对照组（P〈0.01）。术后半年Tg水平随着病情好转逐渐下降,与术前1周之间呈明显正相关（t=4.951,P〈0.01）。23例远处转移癌的Tg水平明显高于颈部淋巴结转移组（P〈0.01）。术后Tg阴性患者其TGA增高者为25例,占20%。术后Tg阳性组TGA增高阳性率为42%。远处转移组TGA增高阳性率为56%。结论：Tg作为DTC的肿瘤标志物,在监测DTC手术效果、预后判断、复发、转移的诊断和鉴别治疗效果中具有重要的指导作用。     

The Incidence of Thyroid Cancer Is Affected by the Characteristics of a Healthcare System

The aim of this study was to investigate the associations between the incidence of thyroid cancer and the characteristics of healthcare systems in OECD countries and to demonstrate that the increasing incidence of thyroid cancer is mainly due to overdiagnosis. We used a random effects panel model to regress the incidence of thyroid cancer on the characteristics of healthcare systems (i.e., share of public expenditure on health, mode of health financing, existence of referral system to secondary care, mode of payment to primary care physicians), controlling for macro context variables (i.e., GDP per capita, educational level) on a country level. Data were derived from 34 OECD countries for 2002 and 2008. The share of public expenditure on health was negatively associated with the incidence of thyroid cancer. However, it had no statistically significant effect on the mortality of thyroid cancer and on the incidence of stomach and lung cancer. In the case of colorectal cancer, it had a positive effect on the incidence rate. The upward trend of the incidence of thyroid cancer is closely related to the healthcare system that permits overdiagnosis. Increases in the proportion of public financing may help reduce the overdiagnosis of thyroid cancer.     

Immunohistochemical study of intrathyroidal lymph follicles

Tissue samples from 76 cases of thyroid disease containing germinal centers (GCs) were selected from 396 cases of various thyroid diseases for immunohistochemical analysis of the GC and follicular dendritic cell (FDC). These 76 cases included 28 cases of thyroid cancer, 23 of chronic thyroiditis, 12 of nontoxic goiter, 8 of adenoma, and 5 of Graves' disease. In many lymphoid GCs IgG, IgM and kappa and lambda light chains were detected with a lacy dendritic pattern. Only thyroglobulin (Tg), among the various thyroid-associated antigens sought, was stained in GCs and was found in the same distribution as immunoglobulins. Tg was found in all of the disease categories studied. Moreover, early components in the classical complement (C) pathway, that is, C1q, C4, C3c, C3d, and C5, were detected in almost all GCs in the thyroid tissues in a lacy dendritic pattern. C3d was intensely positive and was seen also by immunoelectron microscopy on the cell surface of FDCs. It is concluded that not only immunoglobulins but also Tg and early C components are closely related to the GC and FDC in the intrathyroidal lymph follicle.     

The detection of antithyroglobulin activity in human serum monoclonal immunoglobulins (monoclonal gammopathies)

The sera of 159 patients with monoclonal gammopathies were examined for the presence of anti-thyroglobulin (Tg) activity. An enzyme-linked immunosorbent assay was employed. Thirty-one (19.5%) sera were found to bind Tg. The activity against Tg was further confirmed by using purified immunoglobulins and employing competition assays. The anti-Tg antibodies were found in the sera of patients with IgG, IgM and IgA gammopathies. Anti-Tg antibodies were more frequent among patients with IgG gammopathy. Autoantibodies to Tg are found in patients with Hashimoto's thyroiditis, Graves' disease and occasionally in patients with thyroid carcinoma. Natural autoantibodies directed against human Tg have been detected, as well, in healthy subjects. None of the patients in the present study whose serum was found to contain high titers of anti-Tg human monoclonal antibodies had any clinical or biochemical evidence of thyroid disease. Our results of a high incidence of anti-Tg activity in the sera of patients with monoclonal gammopathies support previous reports of autoantibody properties characteristic of these immunoglobulins.     

SPECT/CT融合显像在分化型甲状腺癌转移灶诊断中的应用价值分析

目的 探讨SPECT/CT 131I显像在诊断分化型甲状腺癌转移灶中,以及在131I放射治疗后复发和转移中的应用价值,为临床诊断和治疗甲状腺癌提供依据.方法 选择2013年5月至2016年5月我院住院治疗经病理证实的分化型甲状腺癌住院患者90例,分别实施131I-WBS,131I-SPECT/CT显像诊断,观察显像诊断结果以及Tg水平.结果 131 I-WBS共诊断出125个复发和转移病灶,其中113个经病理检查证实,其诊断灵敏度和准确度分别为85.03％,78.62％:131I-SPECT/CT共诊断出134个复发和转移病灶,其中128个经病理检查证实,其诊断灵敏度和准确度分别为91.16％,87.58％;说明131I-SPECT诊断的灵敏度要优于131 I-WBS显像,两组数据比较差异有统计学意义(P＜0.05);此外131I-WBS显像、131I-SPECT/CT显像阳性的Tg水平与阴性患者比较明显升高,且差异有统计学意义(P＜0.05).结论 SPECT/CT显像在诊断分化型甲状腺癌转移灶方面具有重要价值,值得临床广泛的应用.     

DTC术后131 I清甲治疗短期内血清Tg和TgAb变化及临床意义

目的 比较分化型甲状腺癌（DTC）患者在术后接受^131I治疗,短期内血清甲状腺球蛋白（Tg）和甲状腺球蛋白抗体（TgAb）变化及临床意义.方法 随机选取甲状腺乳头状癌（PTC）患者80例,男22例,女58例,年龄平均41.5±10.4岁,术后均接受剂量为3.7～ 5.5GBq^131I口服治疗,分别于^131I治疗前1天及治疗后第7天监测患者的Tg和TgAb,结合DTC患者治疗后^131I全身扫描结果及4～ 12个月的门诊随访结果,分析^1311I清甲治疗后短期内血清Tg和TgAb变化的临床意义.结果 治疗后血清Tg均有不同程度升高,根据Tg变化程度分组,轻微升高组42例（升高0～ 99ng/L）缓解率为47.6％,中度升高组（升高100 ～ 999ng/L） 20例缓解率为60.0％,明显升高组18例（升高≥1000ng/L）缓解率为66.7％,组间有统计学差异,上升幅度显著者缓解率高.治疗后TgAb下降组随访缓解率为75.0％ （36/48）;TgAb上升组缓解率为43.8％ （14/32）,经卡方检验,两组缓解率有统计学差异（x^2=4.0,P＜0.05）.结论 Tg在治疗后短期内上升幅度越大,提示131I的疗效和预后越好;而TgAb阳性者在治疗后短期内明显下降,也是治疗有效的征象.     

Spontaneous thyroglobulin autoantibody production by peripheral blood lymphocytes is regulated by T cells and is augmented by soluble T cell factors

In this study we report the spontaneous production of autoimmune anti-thyroglobulin antibodies (Tg Ab) by peripheral blood lymphocytes from patients with autoimmune thyroid disease and the use of these cells to study the regulation of this production in vitro. Using a mitogen free microculture system we have found a significant correlation between an individuals' serum titre and the amount of Tg Ab produced in vitro. At low B:T cell ratios Tg Ab production decreased. Specific depletion of suppressor T cells and helper T cells was accomplished using the monoclonal antibodies OKT 8 and OKT 4 respectively. Suppressor cell depletions resulted in increases in Tg Ab production while depletion of helper cells had no consistent effect. The addition of pokeweed mitogen had no stimulatory effect on spontaneous thyroglobulin antibody production. In contrast, when T cell conditioned media was added to the cells, Tg Ab production increased substantially in all patient cultures tested but not in normal control cultures. The results of this study are consistent with the existence of functional thyroid-antigen specific suppressor cells in the peripheral blood which are actively involved in the regulation of autoantibody producing B cells. The results obtained with the cultures maintained in conditioned media show that autoimmune lymphocytes are extremely sensitive to one or more stimulatory factors present in the media and suggests an important role for the production of soluble lymphocyte factors and the expression of receptors for these factors in the aetiology of autoimmune thyroid disease.     

Severe combined immunodeficient (SCID) mice: a model for investigating human thyroid autoantibody synthesis

We have studied the ability of lymphocytes from the blood, thyroid and lymph nodes of patients with autoimmune thyroid disease (AITD) to produce autoantibodies to thyroglobulin (Tg) and/or thyroid peroxidase (TPO) in SCID mice. Human IgG class Tg and/or TPO antibodies were detectable in plasma from SCID mice 7 days after transfer of 15-25 x 10(6) cells/mouse and the highest levels were recorded 2-3 weeks later. In contrast, Tg and/or TPO antibodies were undetectable in recipients of lymphocytes from thyroid antibody negative controls. AITD thyroid lymphocytes produced the most antibody in recipient mice and lower levels were observed in recipients of AITD blood and lymph node lymphocytes. The amounts of Tg and/or TPO antibody detected were in accordance with the ability of thyroid and lymph node lymphocytes to secrete these autoantibodies spontaneously in culture (indicating the presence of cells activated in the patient) and with the capacity of blood lymphocytes (probably B memory cells) to secrete Tg and/or TPO antibodies in culture in response to pokeweed mitogen. Tg antibodies in plasma from SCID recipients of thyroid lymphocytes were of subclasses IgG1, IgG2 and IgG4 and the proportions closely resembled those of the donor's serum Tg antibodies. Blood lymphocytes transferred to SCID recipients were also able to produce Tg antibodies of subclasses 1, 2 and 4 but the subclass distribution varied between mice and the reason for this is not clear at present. Since SCID mice provide an environment in which B lymphocytes from patients with AITD can be activated without mitogen to secrete thyroid antibodies, this model will provide a powerful system for elucidating the mechanisms regulating the secretion of human antibodies to Tg and TPO.     

Langzeitbeobachtung bei 15 Patienten mit differenziertem Schilddrüsenkarzinom und unklar erhöhten Plasmathyreoglobulinspiegeln (Tg)

Summary The follow-up of 15 patients with differentiated cancer of the thyroid was analysed retrospectively. All patients had persistent or developed elevated thyroglobulin (Tg) plasma levels (>10 ng/ml) after total thyroidectomy and 131 I therapy. There was no evidence of thyroid remnants or metastases in the 131 I whole body scan, bone scan, chest X-ray or clinical investigation. Nine of 15 patients developed local or distant metastases during a follow-up period of 3–39 months (mean=18 months). Only one of seven recurrences tested were 131 I positive, Tg values of 9 from 12 patients showed no correlation to the Thyroid-stimulating hormone (TSH) level. It is concluded that: (1) this group of patients is at high risk of developing a recurrence (2) new methods have to be developed for the localization of 131 I negative but Tg positive metastases.

Teile dieser Arbeit wurden beim 27. Symposium der Deutschen Gesellschaft für Endokrinologie 1983 in Frankfurt vorgetragen [19]