X-ray therapy, thyroid nodules and thyroid cancer.
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Humans↗
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Compensated 131I-therapy of solitary autonomous thyroid nodules: effect on thyroid size and early hypothyroidism.
Thyroid function and thyroid gland volume, ultrasonically determined, were investigated in 27 hyperthyroid patients with solitary autonomous thyroid nodules before and during one year after 131I-treatment. Total thyroid volume decreased gradually from 40.9 +/- 3.5 ml (mean +/- SEM) before treatment to 23.9 +/- 1.8 ml (P less than 0.001) at 3 months after 131I-treatment. No further change was observed. All but two patients received only one dose of 131I, and in spite of a significant decrease also of the non-adenoma side of the gland, none became hypothyroid. We conclude that 131I-therapy has an important place in the treatment of solitary autonomous thyroid nodules since all our patients became euthyroid within 3 months, only 2 of 27 patients needed more than one dose of 131I, no cases of hypothyroidism occurred, and thyroid volume was substantially decreased.
Adenoma↗
Thyroid nodules.
Palpable thyroid nodules occur in 4 to 7 percent of the population, but nodules found incidentally on ultrasonography suggest a prevalence of 19 to 67 percent. The majority of thyroid nodules are asymptomatic. Because about 5 percent of all palpable nodules are found to be malignant, the main objective of evaluating thyroid nodules is to exclude malignancy. Laboratory evaluation, including a thyroid-stimulating hormone test, can help differentiate a thyrotoxic nodule from an euthyroid nodule. In euthyroid patients with a nodule, fine-needle aspiration should be performed, and radionuclide scanning should be reserved for patients with indeterminate cytology or thyrotoxicosis. Insufficient specimens from fine-needle aspiration decrease when ultrasound guidance is used. Surgery is the primary treatment for malignant lesions, and the extent of surgery depends on the extent and type of disease. Ablation by postoperative radioactive iodine is done for high-risk patients--identified as those with metastatic or residual disease. While suppressive therapy with thyroxine is frequently used postoperatively for malignant lesions, its use for management of benign solitary thyroid nodules remains controversial.
Algorithms↗
Managing the solitary thyroid nodule.
Solitary thyroid nodules are commonly seen in surgical outpatient clinics. A detailed history and a careful physical examination are essential. In the management of the solitary thyroid nodule, fine needle aspiration cytology has become the cornerstone investigation. Ultrasound cannot differentiate between benign and malignant nodules, however is useful in the follow-up period to identify any further nodular growth. As thyroid malignancy occurs in both hot and cold nodules, radionuclide scans are not useful in the management of solitary thyroid nodules. We have attempted to outline the process of managing the solitary thyroid nodule and discuss the options available.
Adenoma↗
The predictive value of ultrasound findings in the management of thyroid nodules.
BACKGROUND: Thyroid nodules are a common medical problem, but whether fine-needle aspiration cytology (FNAC) is mandated for smaller non-palpable nodules, is controversial. AIM: To evaluate whether ultrasonographic features of thyroid nodules are associated with histological malignancy, and to identify useful criteria for clinical decision-making. DESIGN: Prospective observational study. METHODS: From January 1991 to September 2004, 5198 patients were referred to our hospital for ultrasound evaluation of thyroid nodules. Overall, 7455 nodules (diameters from 6 to 100 mm) were examined; 2865 (38.4%) were <10 mm in diameter. All patients with suspicious or malignant cytology underwent surgery. RESULTS: Of the 349 nodules undergoing surgery, 284 were malignant. The prevalence of cancer was slightly higher in nodules>or=10 mm in diameter vs. those<10 mm (5.5% vs. 3.0%, p<0.01). However, histological type and local aggressiveness were largely independent of nodule size. Microcalcifications (72.2% vs. 28.7%; p<0.001; OR 6.4, 95%CI 4.9-8.4), blurred margins (52.8% vs. 18.8%; p<0.001; OR 4.8, 95%CI 3.8-6.1), solid hypoechoic appearance (80.6% vs. 52.4%; p<0.001; OR 3.8, 95%CI 2.8-5.1), size>or=10 mm (77.4% vs. 64.9%; p<0.001; OR 1.9, 95%CI 1.4-2.5) and intranodular vascular pattern type 2 (61.6% vs. 49.7%; p<0.001; OR 1.6, 95%CI 1.2-2.0) were all significantly more frequent in malignant than in benign nodules. These associations were similar when large and small nodules were analysed separately. DISCUSSION: No single parameter, including nodule size, satisfactorily identifies a subset of patients to be electively investigated by FNAC, although several may be useful in this regard.
Biopsy, Fine-Needle↗
The expression of the high mobility group I(Y) mRNA in thyroid cancers: useful tool of differential diagnosis of thyroid nodules.
OBJECTIVE: Thyroid nodule is frequent and occurs in about 5% of the general population. In contrast, thyroid cancer is much less frequent and occurs in about 5-10% of thyroid nodules. Distinguishing between benign and malignant lesions is an important task that is best accomplished by fine needle aspiration. Recently, Chiappetta et al. reported that the expression of the high mobility group (HMG) I(Y) proteins correlates with the malignant phenotype of human thyroid neoplasia, and suggested that the detection of the HMG I(Y) proteins might be a valid tool for an easy and sensitive discrimination assay between benign and malignant neoplastic thyroid disease. METHODS: We evaluated the expression of the HMG I(Y) mRNA in 39 frozen thyroid tissues from patients with thyroid nodule by semiquantitative RT-PCR. RESULTS: The expression of the HMG I(Y) mRNA was low in all of 10 normal thyroid tissues. In all of 3 adenomatous goiters, 6 follicular adenomas and 2 Hürthle cell adenomas, the HMG I(Y) mRNA expression level was low. In 11 of 13 papillary carcinomas and all of 5 follicular carcinomas, the HMG I(Y) mRNA expression level was high. CONCLUSION: These results indicate that there is a correlation between the expression of HMG I(Y) and the malignant phenotype of thyroid cancer, suggesting that these proteins may be useful as a marker in thyroid cancer.
Biomarkers, Tumor↗
[Thyroid nodule].
The thyroid nodule is a frequent, most often benign, chronic, multifocal and slowly progressive disease. The first line strategy is to diagnose cancerous nodules (<5%) and relies upon fine needle aspiration (FNA), a specialised technique which in trained hands has a false negative rate of below 5%. The interest to explore small thyroid nodules is controversial since the prognosis of thyroid cancer is excellent for lesions measuring less than 20 mm. Though imaging accuracy is quite limited in assessing the diagnosis of thyroid cancer, both ultrasounds (US) and thyroid scan are helpful to enhance nodular identification (>30%), to sort the nodules relevant for cytological sampling and to optimize the follow-up, the major source of health costs. Suspicious and non contributive FNAs must have a control FNA within 6 months. Nodules with a non suspicious FNA (>85%) require long term follow-up. This follow-up is mainly morphological. New or evolutive nodules, as assessed by palpation or US, will require iterative FNAs or should be considered for surgery. In patients with hyperfunctioning nodules on the scan (10 to 20%), a yearly evaluation of the TSH level is sufficient. These nodules account either for autonomously functioning ones, which slowly develop towards thyrotoxicosis, or for hyperplastic nodules frequently disclosing a lymphocytic thyroiditis. Morbidity due to thyroid autonomy is still underestimated especially in aging patients with TSH levels < or =0.60 mU/L. An algorithmic approach to the diagnostic and follow-up evaluation of thyroid nodule is suggested.
Algorithms↗
Cost-effective evaluation of the patient with a thyroid nodule.
Although thyroid nodules are common, less than 5% prove to be malignant. Because of its accuracy, simplicity, and low cost, FNAC has virtually replaced ultrasonography and radionuclide scintigraphy as the primary diagnostic procedure in the evaluation of the patient with a thyroid nodule. In studies comparing preoperative cytodiagnosis with histopathologic diagnosis, the predictive values of benign, malignant, and indeterminate cytodiagnoses averaged 94%, 96%, and 73%, respectively. Guidelines for a cost-effective approach to management of the patient with a thyroid nodule are presented. With a benign cytodiagnosis, follow-up with repeat FNAC in about 1 year is recommended. For the nodule with malignant or indeterminate cytology, surgical resection is indicated. Surgical resection is also indicated for the cyst that recurs after aspiration, as FNAC is less reliable owing to the paucity of cells. FNAC has less diagnostic utility in the evaluation of a nodule with clinical features suggesting malignancy, a nodule that is present in the diffuse toxic goiter of Graves' disease, or a nodule that is found in a patient with a history of radiation to the head, neck, or chest. In these circumstances, surgery is indicated irrespective of the cytologic findings.
Biopsy, Needle↗
Fine-needle aspiration biopsy of thyroid nodules. Impact on thyroid practice and cost of care.
We studied the impact of fine-needle aspiration biopsy on the management of patients with solitary thyroid nodules. Sixty-four patients were examined before the introduction of fine-needle aspiration biopsy, and 147 patients were examined after its introduction. The percentage of patients who underwent thyroid operation decreased from 67 percent to 43 percent, while the yield of carcinoma increased from 14 percent to 29 percent. Cost of medical care per patient declined by 25 percent. The results suggest that fine-needle aspiration biopsy provides valuable information to assist in the selection for surgery of patients with solitary nodules. Fine-needle aspiration appears to be safe, reliable, and cost-effective. The merits of the technique commend it for routine use in the evaluation of thyroid nodules.
Biopsy, Needle↗
Complementary DNA expression array analysis suggests a lower expression of signal transduction proteins and receptors in cold and hot thyroid nodules.
Autonomously functioning thyroid nodules are characterized by an increased proliferation and function, which is predominantly caused by constitutively activating TSH receptor mutations leading to an activation of cAMP. In contrast to autonomously functioning thyroid nodules, cold thyroid nodules are functionally inactive and less differentiated. Their molecular cause is still unknown. To further investigate the pathophysiological aspects of autonomously functioning thyroid nodules and to elucidate the molecular etiology of cold thyroid nodules, it is essential to identify genes with differential expression in autonomously functioning thyroid nodules and cold thyroid nodules and to compare this expression to that in normal surrounding tissue. The list of possible candidates for differential regulation ranges from growth factors and their receptors to transcription factors or oncogenes. Therefore, we evaluated the potential of cDNA arrays and studied the expression of 588 known genes from 6 different classes of proteins in thyroid nodules characterized for their function. Forty-seven genes showed a differential expression between nodular and surrounding tissue identified by the expression arrays. The differential expression of 15 transcripts was verified by real-time PCR. About 25% of the transcripts determined by LightCycler PCR are considered false positives because data from PCR and array analysis did not agree. This indicates the reliability of cDNA expression arrays to identify differentially expressed genes in thyroid nodules compared with their surrounding tissue. The 15 selected genes were additionally quantified by real-time PCR in 7 additional cold thyroid nodules, autonomously functioning thyroid nodules, and their surrounding tissues. The highest number of differentially expressed genes was in the group of signal transduction proteins (4 of 38 detectable genes) and extracellular cell signaling and communication proteins (2 of 62 detectable genes). In contrast, transcripts of other classes of proteins were unchanged (e.g. DNA-binding molecules and stress responses). Most of the transcripts were down-regulated in autonomously functioning thyroid nodule and cold thyroid nodule compared with the respective surrounding tissue. This finding could be the result of a dominant activation of a signal transduction pathway, with the cAMP pathway being the likely candidate for autonomously functioning thyroid nodules. The qualitatively similar pattern of changes in this limited number of genes in autonomously functioning thyroid nodules and cold thyroid nodules could suggest a similar dominant activation of a specific signaling cascade in cold thyroid nodules as the constitutively activating mutations in autonomously functioning thyroid nodules.
Adult↗
Proteomic profiling of cold thyroid nodules.
Cold thyroid nodules (CTNs) represent a frequent endocrine disorder accounting for up to 85% of thyroid nodules in a population living in an iodine-deficient area. Benign CTNs need to be distinguished from thyroid cancer, which is relatively rare. The molecular etiology of benign CTNs is unresolved. To obtain novel insights into their pathogenesis, protein expression profiling was performed in a series of 27 solitary CTNs (10 follicular adenoma and 20 adenomatous nodules) and surrounding normal thyroid tissues using two-dimensional gel electrophoresis combined with mass spectrometry analysis, Western blotting, and immunohistochemistry. The proteome analysis revealed a specific fingerprint of CTNs with up-regulation of three functional systems: 1) thyroid cell proliferation, 2) turnover of thyroglobulin, and 3) H2O2 detoxification. Western blot analysis and immunohistochemistry confirmed the proteome data and showed that CTNs exhibit significant up-regulation of proteins involved in thyroid hormone synthesis yet are deficient in T4-containing thyroglobulin. This is consequential to intranodular iodide deficiency, mainly due to cytoplasmic sodium iodide symporter localization, and portrays the CTN as an activated proliferating lesion with an intranodular hypothyroid milieu. Furthermore, we provide preliminary evidence that up-regulation of H2O2 generation in CTNs could override the antioxidative system resulting in oxidative stress, which is suggested by the finding of raised 8-oxo-guanidine DNA adduct formation in CTNs.
Adult↗
Continuing controversies in the management of thyroid nodules.
Although thyroid nodules are common, few are malignant and require surgical treatment. A systematic approach to their evaluation is important to avoid unnecessary surgery. Fine-needle aspiration biopsy has resulted in substantial improvements in diagnostic accuracy, cost reductions, and higher malignancy yield at time of surgery. The preferred approach when repeated fine-needle aspiration biopsy fails to yield an adequate specimen remains a challenge. Management of patients with nodules "suspicious for follicular neoplasm" is difficult, since only 15% to 20% of such lesions have been shown to be malignant. Immunohistochemical markers, such as galectin-3 and human bone marrow endothelial cell (HBME-1), have shown promise in preliminary studies. Routine calcitonin measurement in patients with thyroid nodules has been advocated for early detection of medullary thyroid cancer. However, the low frequency of this cancer, coupled with the high cost associated with case detection, has resulted in a lack of general acceptance of this recommendation.
Biopsy, Fine-Needle↗
Growth factor expression in cold and hot thyroid nodules.
Hot thyroid nodules (HTNs) are predominantly caused by constitutively activating thyrotropin receptor (TSHR) mutations leading to an activation of the cyclic adenosine monophosphate (cAMP)-cascade that stimulates growth and function of thyroid epithelial cells and confers growth advantage. In contrast to HTNs, the molecular etiology of szintigraphically cold thyroid nodules (CTNs) is largely unknown. An increased prevalence of toxic multinodular goiters in iodine-deficient regions has been reported. Growth factors increase during early stages of iodine deficiency in rats. These growth factors could modulate the proliferation of thyrocytes. In order to determine if and which growth factors could modulate the increase in thyroid epithelial cell proliferation in late stages of CTNs and HTNs we investigated epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and TGF-beta1 concentrations by enzyme-linked immunosorbant assay (ELISA) in CTNs (n = 7), HTNs (n = 9), and their normal surrounding tissue (ST). Insulin-like growth factor-1 (IGF-1) was determined in CTNs (n = 5) and HTNs (n = 10) and their surrounding tissues by radioimmunoassay (RIA). We found lower concentrations of all investigated growth factors and iodine in CTNs compared to surrounding normal tissues (ST). Only iodine showed a significant difference. Furthermore, we found significantly lower concentrations of EGF and TGF-beta1 concentration in HTNs compared to their STs. Differences of TGF-alpha and IGF-1 were not significant. In conclusion, low EGF, TGF-alpha, and IGF-1 concentrations in most CTNs in spite of low iodine concentrations argue against a pathophysiologic role of EGF, TGF-alpha, or IGF-1 in late stages of CTNs. The low EGF, TGF-alpha, and IGF-1 concentrations in HTNs irrespective of their clonal origin or the presence or absence of activating mutations argue for increased cAMP as the primary cause for thyroid epithelial cell proliferation in established HTNs. However, the pathophysiologic significance of low TGF-beta1 concentrations in CTNs and HTNs remains to be elucidated. It might be possible that growth factors like EGF, TGF-alpha, TGF-beta1, and IGF-1 play a more prominent role during early clonal expansion and that aberrant intrinsic signaling through a somatic mutation (e.g., TSHR for HTNs) confers the predominant selective growth advantage in later stages of HTNs or CTNs.
Epidermal Growth Factor↗
Evaluation of a thyroid nodule.
Solitary thyroid nodules are common entities and the majority of these are benign. The main goal in evaluating these nodules is to identify the [figure: see text] nodules with malignant potentials. A multitude of diagnostic tests is available to the clinician. FNA biopsy is now considered the gold standard diagnostic test in the evaluation of a thyroid nodule. Ultrasound and nuclear scans are also useful tests, but are best used in conjunction with FNA. Clinical decisions are often based on the results of the FNA. A diagram of the clinical decision process based on FNA findings is presented in Fig. 1. Despite the clinical advantages that are provided by the FNA results, the clinician should not dismiss the importance of other clinical prognostic indicators to optimize timely treatment.
Algorithms↗
Efficacy of ultrasound-guided fine-needle aspiration biopsy in the diagnosis of complex thyroid nodules.
Cystic thyroid nodules are considered to be one of the major causes of nondiagnostic and false-negative results on conventional fine-needle aspiration biopsy, thus limiting the potential of this method for the evaluation of complex (solid-cystic) thyroid nodules. Although ultrasound-guided fine-needle aspiration biopsy has emerged as a highly effective diagnostic method for the assessment of nonpalpable and difficult to palpate nodules, its role in complex nodules has not yet been carefully evaluated. In this study, we report the efficacy of ultrasound-guided fine-needle aspiration biopsy in 124 complex nodules in 113 patients. This method proved to be highly effective, yielding a satisfactory specimen for cytological evaluation in 94% of the nodules, suggesting that it is an excellent modality for the evaluation of complex nodules and also for the reevaluation of those nodules with a nondiagnostic result on conventional fine-needle aspiration biopsy.
Adult↗
Expression of adenylyl cyclase types III and VI in human hyperfunctioning thyroid nodules.
Hyperfunctioning thyroid nodules are characterized by the presence of spontaneous somatic mutations responsible for constitutive activation of the cAMP pathway. However, alterations affecting other elements of the cAMP signaling system may counteract the effects of the mutations. In this study, the expression of the adenylyl cyclase (AC) types III and VI was investigated by Western blot in 18 hyperfunctioning thyroid nodules; in 12 samples, we also assessed the presence of TSH receptor (TSHR) or gsp mutations and levels of AC VI and III mRNA. We found that the expression of nodular AC VI (but not AC III) was significantly lower (85.1% of normal, P=0.014) than the expression of both adenylyl cycles types of perinodular tissue from the same patients. Slightly, but not significant differences were detected in nodules with or without mutations and AC protein levels generally showed correlation with the levels of the transcripts detected by RT-PCR. In addition, AC III and AC VI expression levels within a given nodule were characterized by a significant positive correlation. These findings indicate that a diminished expression of AC type VI may be part of the mechanisms occurring in the hyperfunctioning nodules, independently of the presence of TSHR or gsp mutations, which influence the resulting phenotype.
Adenylyl Cyclases↗
Acute spontaneous hemorrhagic degeneration of the thyroid nodule with subacute thyroiditis-like symptoms and laboratory findings.
Seventeen consecutive patients (3 men and 14 women, aged 14-75 years) with a hemorrhagic degeneration of the thyroid nodule, which was confirmed by both ultrasonography and either reddish or brown fluid evacuated by fine-needle aspiration, were classified as either acute type with an episode of abrupt painful swelling of the thyroid (n = 4), or chronic type in which a painless thyroid nodule was incidentally found (n = 13). One of the four acute type patients demonstrated subacute thyroiditis-like symptoms and laboratory findings including transient painful thyrotoxicosis associated with high serum levels of thyroid hormones and thyroglobulin (Tg), a suppressed serum TSH level, a low thyroidal radioactive iodine uptake (RAIU), and accelerated erythrocyte sedimentation rate (ESR). In the other three acute type patients the serum level of Tg increased markedly, the serum thyroid hormones level increased in one, the thyroidal RAIU was low in two, and the ESR was accelerated in one. In the thirteen chronic type patients, the serum levels of the thyroid hormones and the thyroidal RAIU were within the normal range, and few inflammatory signs were observed. These findings suggest that acute hemorrhagic degeneration of the thyroid nodule may thus cause transient subacute thyroiditis-like symptoms and laboratory findings.
Acute Disease↗
Fine-needle aspiration biopsy of thyroid nodules.
Nodular thyroid disease is a common problem, particularly in women and the elderly population. Furthermore, 5% of thyroid nodules are likely to be malignant. Therefore, assessment for malignant potential is important, and fine-needle aspiration (FNA) biopsy is the most accurate technique. For each nodule, two to four aspirations should be attempted from different areas of the nodule. Although major complications of FNA biopsy are rare, proper cytologic interpretation necessitates special expertise. Cytologic diagnoses are usually categorized as diagnostic or nondiagnostic, and the diagnostic specimens are classified as benign, "suspicious," or malignant. Rebiopsy is indicated for enlarging nodules, recurrent cysts, and nondiagnostic cytologic findings. Because FNA biopsy is a safe, reliable, and rapid means of evaluating thyroid nodules, we recommend its routine use for diagnosis and treatment of thyroid nodular disease.
Journal Article↗