Thyroid cancer in patients with hyperthyroidism

Thyroid cancer can be associated with thyrotoxicosis caused by Graves' disease, toxic multinodular goiter, or autonomously functioning thyroid adenoma. The objective of this study was to summarize current evidence regarding the association of thyroid cancer and hyperthyroidism, particularly with respect to the type of hyperthyroidism found in some patients, and whether this affects the outcome of the patient. A PubMed search was performed up to August 2011. Articles were identified using combinations of the following keywords/phrases: thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, hyperthyroidism, Graves' disease, auto-nomous adenoma, toxic thyroid nodule, and toxic multinodular goiter. Original research papers, case reports, and review articles were included. We concluded that the incidence, as well as the prognosis of thyroid cancer associated with hyperthyroidism is a matter of debate. It seems that Graves' disease is associated with larger, multifocal, and potentially more aggressive thyroid cancer than single hot nodules or multinodular toxic goiter. Patients with Graves' and thyroid nodules are at higher risk to develop thyroid cancer compared to patients with diffuse goiter. Every suspicious nodule associated with hyperthyroidism should be evaluated carefully.     

Messenger RNA properties of primary cultures of thyroid cells isolated from normal thyroid tissue and from patients with various thyroid diseases.

When compared to cells isolated from normal thyroid tissue, cells isolated from colloid adenoma have the same total polyadenylic acid content and total template activity. However, in both the cells isolated from diffuse non toxic goiter and from toxic adenoma, these two values are increased, the most striking effect being observed in the latter case. Moreover, as compared to normal thyroid tissue, in the three thyroid diseases and particularly in toxic adenoma, we observed an increase in the polyadenylic acid and messenger activity associated to RNA sedimenting at greater than 30 S, which correspond probably to thyroglobulin messenger RNA.     

甲状腺球蛋白及抗体测定在结节性甲状腺肿与甲状腺癌鉴别诊断中的意义

目的:对结节性甲状腺肿患者和甲状腺癌患者术前的甲状腺球蛋白(TG)、抗甲状腺球蛋白抗体(TG-Ab)水平进行回顾性分析,并对TG、TG-Ab水平在结节性甲状腺肿、甲状腺癌诊断中的意义进行研究。方法:分别选取2011年1月-2013年12月我院收治的结节性甲状腺肿患者、甲状腺癌患者和正常健康者各60例作为本研究的观察对象,对三组观察对象TG、TG-Ab水平进行比较分析。结果:结节性甲状腺肿组、健康组患者TG阳性率分别为6.67%、8.33%,差异无统计学意义(P0.05);两组患者TG-Ab阳性率则分别为8.33%和11.67%,差异无统计学意义(P0.05)。而甲状腺癌组患者TG、TG-Ab阳性率分别为33.33%、40.00%,与其他两组比较差异具有统计学意义(P0.05)。在结节性甲状腺肿患者中,其中结节液化型TG阳性率、TG-Ab阳性率明显高于非结节液化型,差异具有统计学意义(P0.05)。在甲状腺癌患者中,其中颈部淋巴结阳性者TG阳性率、TG-Ab阳性率明显高于颈部淋巴结阴性者,差异具有统计学意义(P0.05);单结节癌灶与多结节癌灶在TG阳性率、TG-Ab阳性率差异无统计学意义(P0.05)。结论:临床上采用TG、TG-Ab阳性率测定的方法对甲状腺肿、甲状腺癌进行鉴别和确诊是比较可靠的,值得推广应用。     

Function of the serotoninergic system of the thyrotoxic thyroid

The state of serotoninergic system in thyrotoxic and euthyroid gland were compared. It was shown that in patients with hyperthyroidism (diffuse toxic goiter) serotonin and 5-hydroxytryptophan content, velocity and the latter uptake were augmented. The authors stress the role of the delay in serotonin oxidative deamination as one of the reasons for increased serotonin content in thyrotoxic thyroid gland. Possible ways of increasing intrathyroid serotonin accumulation and its role in the development of thyroid hyperfunction are discussed.     

Thyroid cancer in patients with hyperthyroidism

OBJECTIVE: The coexistence of hyperthyroidism and thyroid cancer is considered a rare event. With the aim of assessing the clinical relevance of this association, we have retrospectively analyzed the incidence of thyroid cancer in 425 hyperthyroid patients seen and treated by surgery in our institutions. METHODS: Among these hyperthyroid patients, we observed 241 (56.7%) cases of multinodular toxic goiter, 120 (28.3%) of uninodular toxic goiter and 64 (15%) cases of Graves' disease. RESULTS: Thyroid cancer was diagnosed in 7 (1.65%) hyperthyroid patients. Histological examination revealed the presence of papillary carcinoma in 5 cases and follicular carcinoma in 2 cases. Neoplasia was detected in 4 patients with nodular toxic goiter and in 3 with uninodular toxic goiter. None of the patients with Graves' disease had thyroid cancer. During the follow-up of 74 months (range 4-154), there were no deaths or any recurrences. CONCLUSION: Although the occurrence of thyroid cancer in hyperthyroid patients is a rare event, the presence of a 'cold' nodule in a hyperfunctioning thyroid should be carefully evaluated to exclude the presence of concurrent malignancy.     

H-RAS gene expression in human multinodular goiter

The RAS protooncogene has an important, although not yet established role in thyroid neoplasia. In this study, we evaluated the H-RAS mRNA and protein levels in human samples of nontoxic and toxic multinodular goiter samples, according to serum TSH levels. The mean of H-RAS mRNA levels in nodules of nontoxic nodular goiter were significantly increased compared to nonnodular tissue (1.49+/-1.21 vs. 0.94+/-0.81 AU, P=0.016). Nine of the 18 specimens (50%) of nontoxic multinodular goiter exhibited increased levels of H-RAS mRNA. The increased H-RAS mRNA levels were paralleled by inRAcreased H-Ras protein levels in about 90% of the cases. Interestingly, no differences were observed in H-RAS expression between nodules and adjacent nonnodular tissue in toxic nodular goiters (0.58+/-0.27 vs. 0.58+/-0.20 AU, P=0.88). None of the 10 samples from toxic multinodular goiters exhibited overexpression of H-RAS. The H-RAS expression was positively correlated with thyroglobulin expression (r2=0.51; P=0.04). In conclusion, we demonstrated increased levels of H-RAS mRNA and protein in samples of nontoxic multinodular goiter, indicating that it might be involved in goiter pathogenesis. In contrast, H-RAS overexpression was not detected in any of the samples of toxic multinodular goiter, suggesting different mechanisms for cell proliferation in nodular goiter according to thyroid status.     

A novel thyroid hormone receptor-beta mutation,not anticipated to occur in resistance to thyroid hormone,causes variable phenotypes

Resistance to thyroid hormones (RTH) is a syndrome characterized by a variable tissue hyposensitivity to thyroid hormones and is linked to mutations in the thyroid hormone receptor-beta (TRbeta) gene. We report here for the first time in vivo the mutation R429W (CCG-->TCG) located in the exon 10. The artificial mutant obtained in vitro displayed a normal T(3)-binding affinity and transactivation function. Therefore, it was thought to produce little, if any, clinical effect and to escape to clinical detection. The present report is at least in part discordant with this prediction since the propositus and his grandmother had an authentic hyperthyroidism with high FT(4) plasma level in the presence of inappropriate TSH. On the other hand, spontaneous variations of clinical features and - interestingly - of plasma FT(4) concentrations with time in the propositus, and the phenotype observed in his mother who never complained with thyrotoxic symptoms, confirmed the in vitro binding and functional predictions. The most intriguing is the clinical course of the grandmother as she first presented with predominant pituitary RTH and a diffuse goiter and finally with a toxic multinodular goiter with normal T(3) and T(4) plasma concentrations and suppressed TSH. In conclusion, we report a novel mutation in the gene encoding the thyroid hormone receptor responsible for predominant pituitary RTH already described in vitro but not in vivo. The fluctuant phenotype of the propositus suggests that other factors modulate the degree of tissue resistance that is under genetic control. Toxic multinodular goiter, possibly due to chronic TSH stimulation during RTH, in addition to the phenotype variability, increases the difficulty to diagnose this thyroid disorder.     

Incidental Thyroid Cancer in Toxic and Nontoxic Goiter: is TSH Associated with Malignany Rate? Results of A Meta-Analysis

ObjectiveIn the last 6 years, several studies reported a positive association between thyrotropin (TSH) and papillary cancer risk. The rationale is based on stimulatory action exerted by TSH on thyroid cell proliferation and/ or progression of a pre-existing papillary carcinoma. To validate this hypothesis, we performed a meta-analysis comparing the incidence of thyroid cancer in 2 groups of patients who underwent surgery for toxic or nontoxic nodular goiter.MethodsUsing data from 2,150 patients with toxic multinodular goiter (TMNG) and 873 patients with toxic adenoma (TA), the overall incidence of thyroid cancer (and 95% confidence interval [CIs]) was estimated to be 5.9% (3.9 to 8.3) for patients with TMNG and 4.8% (2.5 to 7.9) for patients with TA. Four studies were included in the meta-analysis with a total of 1,964 subjects undergoing thyroidectomy for allegedly benign thyroid disease (520 patients with TMNG or TA and 1,444 for multinodular goiter [MNG] or uninodular goiter [UNG]).ResultsWe did not find any significant differences in the risk of incidental thyroid cancer (ITC) in patients with TMNG versus MNG (odds ratio [OR]: 0.91, 95% CI: 0.47 to 1.77, I⁴: 62.6%), TA versus uninodular goiter (UNG) (OR: 0.46, 95% CI: 0.12 to 1.79, I⁵: 12%), and TMNG or TA versus MNG or UNG (pooled analysis) (OR: 0.86, 95% CI: 0.46 to 1.60, I⁶: 51.5%).ConclusionsThe results of this meta-analysis did not confirm an association between low TSH values and lower thyroid cancer rate, at least in patients with nodular disease. (Endocr Pract. 2013;19:212-218)     

Physiological and Morphological Specific Features of the Formation of the Thyroid Status in the Aboriginal and Migrant Populations of Magadan Oblast

Ultrasonographic determinations of the thyroid gland volumes and measurement of the blood plasma content of thyroxin and triiodothyronine were carried out in 1176 apparently healthy residents of the Magadan oblast, all those examined being divided by sex, age, and the adaptation time in the North. Special attention was given to the thyroid system parameters of the aborigines 17 to 40 years old living in the urban area and not involved in the traditional life style. The indigenous population of the Extreme North and migrants were shown to have marked functional adaptive hyperplasia of the thyroid gland and diffuse goiter in 15% of cases. The size of the thyroid gland and the level of the thyroid hormones in the aboriginal population are within the average European range. Diffuse goiter manifestations in males virtually do not occur; in women, the incidence does not exceed 5%. The assumption is advanced as to the formation in aborigines of the northern hypothyroid phenotype providing for the sustained optimal level of the thyroid system functioning without an increase in the thyroid volume.     

Sonographic Appearance of Primary Thyroid Lymphoma-Preliminary Experience

Objective

Primary thyroid lymphoma (PTL) is an uncommon thyroid malignancy. Despite the rarity of PTL, it is important to recognize PTL promptly because its management differs from that of all the other thyroid neoplasms. This study was designed to investigate the sonographic features of PTL.

Methods

Twenty-seven pathologically confirmed PTLs were categorized into diffuse and non-diffuse type. Sonographic features including thyroid size, thyroid background echotexture, lesion size, echogenecity, calcification, vascularity, cervical lymphadenopathy of each type were retrospectively analyzed.

Results

All 27 PTLs were diffuse large B-cell lymphomas and were accompanied by diffuse Hashimoto''s thyroiditis. Ten were diffuse type and seventeen were non-diffuse type sonographically. The observations in diffuse group included goiter (10/10, 100.0%), marked echogenesity (10/10, 100.0%), heterogeneous echotexture (10/10, 100.0%), and cervical lymphadenopathy (4/10, 40.0%). The observations in non-diffuse group included marked hypoechogenicity (17/17, 100.0%), heterogeneous background thyroid gland (17/17, 100.0%), goiter (15/17, 88.2%), increased vascularity (8/13, 61.5%), mulifocality (10/17, 58.8%), and cervical lymphadenopathy (7/17, 41.2%).

Conclusions

Although some common features were found, the sonographic appearance of PTL is unspecific, especially for the diffuse type. Therefore, interventional diagnostic procedures should be warranted in the clinical settings when PTL is suspected.     

Expression of Bcl-2 family proteins in thyrocytes from young patients with immune and nonimmune thyroid diseases

The Bcl-2 family proteins that control homeostasis of cells play an important role in apoptosis. This group consists of antiapoptotic (Bcl-2, Bcl-XL) and proapoptotic (Bcl-2 associated protein X, Bax; B-cell homologous antagonist/killer, Bak) molecules. In the thyroid, abnormal apoptotic activity may be involved in a variety of diseases such as autoimmune thyroid diseases. The aim of the current study was to estimate the expression of pro- and antiapoptotic proteins in thyroid tissues from young patients with Graves' disease (GD), nontoxic nodular goiter and toxic nodular goiter using Western Blot and immunohistochemistry. Identification of the antiapoptotic Bcl-2 and Bcl-XL molecules in the thyrocytes revealed higher expression of both proteins in patients with GD (assessed as +++/++ and ++/+, respectively). In adolescents with toxic and nontoxic nodular goiter, this expression was lower (Bcl-2 ++/+ , ++/+; Bcl-XL +, +). The tissue material was additionally subjected to Western Blot analysis, which in GD patients showed the presence of Bcl-2 and Bcl-XL in one band p26 kDa. In patients with toxic and nontoxic nodular goiter, the intensity of expression for these two antiapoptotic proteins was lower (referred to band 26 kDa for Bcl-2 and Bcl-XL). Identification of the proapoptotic proteins Bax and Bak revealed their predominance in thyrocytes of GD patients (+, ++/+, respectively) as compared to patients with toxic and nontoxic nodular goiter (0/+, 0/+ for Bax and 0/+, 0/+ for Bak). In GD patients, Western Blot analysis showed Bax expression in one band 21 kDa and Bak in two bands p50, p24 kDa. In patients with nodular goiter, the degree of expression of both proapoptotic proteins was lower and referred to band 21 kDa for Bax (toxic and nontoxic goiter) and 24 kDa for Bak (toxic goiter only). Patients with GD showed a statistically significant correlation between Bcl-2 expression and antibodies against receptor for thyroid stimulating hormone (R = 0.47, p < 0.03); however, such a correlation was not observed in patients with nodular goiter. In conclusion, our findings suggest that the changes in the expression of regulatory proteins of the Bcl-2 family in the thyroid follicular cells indicate the involvement of apoptosis in the pathogenesis of GD.     

Increased incidence of euthyroid and hyperthyroid goiters independently of thyrotropin in patients with acromegaly

The incidence of palpable goiters, the thyroid functional state and thyroid radioisotope uptake was analyzed retrospectively in 80 patients with acromegaly and 80 patients with prolactinomas. 71% of all patients with acromegaly had an enlargement of the thyroid (goiter); 49% of them had diffuse and 39% nodular goiters. The incidence of goiters in patients with prolactinomas from the same iodine deficient geographic region was only 35% (82% diffuse and 18% nodular). 17.5% of acromegalic patients underwent thyroid surgery before diagnosis of growth hormone excess. 17.5% of acromegalic patients with goiters had autonomous areas in their thyroids and 5% were clearly hyperthyroid. Goiters developed slightly more often in females (74%) than in males (67%). The mean preoperative growth hormone level was higher in acromegalic patients with goiter. The incidence of goiters was positively correlated with the documented time of elevated growth hormone concentration in serum. Two patients with exaggerated response of thyrotropin (TSH) (delta TSH greater than 20 mU/l) to the application of thyrotropin-releasing hormone (TRH) had no goiters. On the other hand most patients (61%) with goiters had a low TSH-response to TRH (delta TSH less than 10 mU/l) representing in part occult autonomy of thyroid function. No patient with prolactinoma has had previous thyroid surgery nor thyroid autonomy. One patient with prolactinoma suffered from Graves' disease and none of the acromegalic patients had this disease. We finally conclude that the elevation of growth hormone leads to increased incidence of euthyroid and hyperthyroid (autonomous) goiters independently of the influence of TSH.     

Ultrasound study in the differential diagnosis of thyroid focal lesions of various origin

The present study deals with the ultrasound differential diagnosis of thyroid lesions. A hundred and ninety-two patients, including 130 patients with benign diseases (nodular colloidal goiter) (36.9%), chronic autoimmune thyroiditis (30.7%), and adenomas (32.3%) and 62 patients with malignant diseases (thyroid cancer (88%), lymphoproliferative diseases (6.4%), and recurrent thyroid cancer) (4.8%), were clinically examined. Ultrasound studies (USS) were performed in the B- and (see text symbols) modes. The diagnosis was verified from cytological and histological findings with mandatory morphological confirmation. Interdisease comparison has shown that USS is both a screening and diagnostic technique in revealing thyroid changes and determining their site, sizes, and structure. Ultrasound pathognomonic signs were detected in different morphological types of adenomas, thyroiditis, and nodular colloidal goiter, in the classical, pseudoadenomatous and pseudocystic types of thyroid cancer. At the same time there were characteristic ultrasound parameters at the stage of pronounced changes in undifferentiated thyroid cancer (pseudothyroiditis), lymphoproliferative diseases, and acute thyroiditis. The exception was the diffuse form of chronic autoimmune thyroiditis in which both thyroid lobes were always altered.     

Ultrasound and morphological diagnosis of thyroid diseases in radiation-exposed persons

The purpose of the present investigation was to enhance the efficiency of diagnosis of thyroid diseases in irradiated persons. Three hundred persons exposed to radiation in doses of 5 to 250 SeV and the postexposure period was 9 to 48 years. A control group comprised 100 military men unexposed to ionizing radiation. Thyroid ultrasound study and morphological diagnosis revealed diffuse nodular goiter transformation in 66% of the irradiated persons and malignant thyroid neoplasms in 3.7% whereas 38% of the control patients were found to have only benign diffuse nodular thyroid alterations and autoimmune thyroiditis (AIT). The investigation identified the echosemiotic features of nodular masses and AIT in the study group patients and established their association with the pathomorphological changes of the thyroid. The authors note the high efficiency of complex clinicoradiation and morphological studies in detecting thyroid pathology and the priority in establishing an accurate diagnosis at the preoperative stage and in determining management tactics.     

A case of Graves' disease associated with an autonomously functioning thyroid nodule (AFTN) (Marine-Lenhalt syndrome) which spontaneously became a cold nodule

We report a 31-year-old female with Graves' disease associated with an autonomously functioning thyroid nodule (AFTN) (Marine-Lenhalt syndrome) in which the AFTN spontaneously became a cold nodule. Initially the patient was thyrotoxic and had diffuse goiter with an elevated radioiodine uptake. She became euthyroid following six months of antithyroid drug therapy, and in addition to diffuse goiter, the solitary hot nodule was palpable in the left lobe. Fourteen months later, hyperthyroidism recurred and the thyroid scan revealed diffuse radioiodine uptake with a cold area in the nodular region. The resected nodule showed extensive degeneration and the histological diagnosis was follicular adenoma with Graves' disease. We discussed the significance of recognizing the syndrome and also compared the frequency of spontaneous degeneration in AFTN and in solitary cold nodules.     

Metal-binding functions and antioxidant properties in human thyroid gland under iodine deficient nodular colloidal goiter

Copper and zinc levels in the tissue of thyroid gland (TG) and their metal-binding proteins metallothioneins (MT) as well as state of the antioxidant system in persons that had no thyroid disease and patients with endemic iodine deficiency nodular colloidal goiter has been investigated. In the patients with thyroid disease, oxidative damage was indicated despite elevated levels of MT-SH and glutathione, and elevated copper and decreased zinc concentration in TG tissue. MTs partly bound the excess of copper but its concentration in the unbound to MT form was two-fold compared to the control value.     

Low Iodine in the Follicular Lumen Caused by Cytoplasm Mis-localization of Sodium Iodide Symporter may Induce Nodular Goiter

Iodine is a key ingredient in the synthesis of thyroid hormones and also a major factor in the regulation of thyroid function. A local reduction of iodine content in follicular lumen leads to overexpression of local thyroid-stimulating hormone receptor (TSHr), which in turn excessively stimulates the regional thyroid tissue, and result in the formation of nodular goiter. In this study, we investigated the relationship between iodine content and sodium iodide symporter (NIS) expression by using the clinical specimens from patients with nodular goiter and explored the pathogenesis triggered by iodine deficiency in nodular goiter. In total, 28 patients were clinically histopathologically confirmed to have nodular goiter and the corresponding adjacent normal thyroid specimens were harvested simultaneously. Western blot and immunohistochemistry were performed to assay NIS expression and localization in thyrocytes of both nodular goiter and adjacent normal thyroid tissues. NIS expression mediated by iodine in follicular lumen was confirmed by follicular model in vitro. Meanwhile, radioscan with iodine-131were conducted on both nodular goiter and adjacent normal thyroid. Our data showed that NIS expression in nodular goiter was significantly higher than that in adjacent normal tissues, which was associated with low iodine in the follicular lumen. Abnormal localization of NIS and lower amount of radioactive iodine-131 were also found in nodular goiter. Our data implied that low iodine in the follicular lumen caused by cytoplasm mis-localization of NIS may induce nodular goiter.     

Predictors of Hypothyroidism Following Empirical Dose Radioiodine in Toxic Thyroid Nodules: Real-Life Experience

ObjectiveWe aimed to determine the factors predicting hypothyroidism after radioactive iodine (RAI) treatment in patients with toxic adenoma and toxic multinodular goiter.MethodsWe retrospectively collected the data of 237 patients with toxic multinodular goiter or toxic adenoma who had consecutively received RAI treatment between 2014 and 2020 at 2 medical centers. Patients who received the second RAI treatment and whose medical records could not be accessed were excluded from the study. Finally, 133 patients were included in the study. RAI was administered at an empirical dose of 15 or 20 mCi.ResultsThe median age of the 133 participants was 69 years (interquartile range, 62-75 years), and 64.7% of the participants were women. A total of 42.1% of the patients had toxic adenoma, whereas 57.9% of patients had toxic multinodular goiter. The median follow-up was 24 months (interquartile range, 11-38 months). During the follow-up, 61.7% of patients became euthyroid, 30.8% developed hypothyroidism, and 7.5% remained hyperthyroid. The median month of hypothyroidism onset was 4 months (interquartile range, 2-9 months). Regression analysis revealed 2 factors that could predict hypothyroidism: thyroid-stimulating hormone (odds ratio, 2.548; 95% CI, 1.042-6.231; P = .04) and thyroid volume (odds ratio, 0.930; 95% CI, 0.885-0.978; P = .005).ConclusionOverall, 30.8% of the cases developed hypothyroidism after the RAI treatment. Approximately 78% of hypothyroidism developed within the first 10 months. The risk of hypothyroidism was higher in patients with higher thyroid-stimulating hormone and smaller thyroid volume.     

Congenital iodide organification defect accompanied by a large nodular goiter: a case report

A girl who had a nontoxic diffuse goiter with a congenital organification defect of iodide was first seen at the age of 8 years, and since then she has been followed up for a long period. The nodularity of the thyroid gland had gradually progressed, because of intermittent failure of ingestion of thyroid hormone preparation which was followed by excess TSH secretion. 18 years later, a nodular goiter developed and the patient underwent subtotal thyroidectomy. In order to prevent the development of nodular change in the thyroid gland in this disorder, supplemental thyroid hormone medication should be started as soon as the diagnosis is confirmed, and the therapy should be carried out regularly.