BRAF V600E mutation analysis increases diagnostic accuracy for papillary thyroid carcinoma in fine-needle aspiration biopsies.

OBJECTIVE: Papillary thyroid carcinoma (PTC) represents the majority of differentiated thyroid cancers, presenting the V600E activating BRAF mutation in 29-83% of cases. The aim of our study is to analyze the influence of BRAF mutation analysis on the diagnostic accuracy of fine-needle aspiration biopsy (FNAB) in patients with suspected PTC. DESIGN AND METHODS: Thyroid cytoaspirates from 469 nodules (size: 1.1+/-0.8 cm) with ultrasonographic features suspicious of malignant lesion, performed in 374 patients, were submitted to cytological evaluation and to biomolecular analysis, carried out after somatic DNA isolation, specific PCR amplification, and subsequent automated direct sequencing. All PCR fragments were also processed by specific enzyme restriction analysis. RESULTS: BRAF V600E mutation was found in 48 samples, 41 of which were also cytologically diagnosed as PTC, with histologic confirmation after thyroidectomy. Total thyroidectomy was perfomed also in seven patients with negative cytology but positive BRAF mutation, with histological confirmation of PTC in all. Among the 429 BRAF-negative samples, 407 had negative cytology for PTC, while 22 were diagnosed as suspected PTC and underwent total thyroidectomy with histological diagnosis of PTC in 17 and benign lesion in five. The prevalence of BRAF V600E mutation among histologically diagnosed PTC patients was 64%. Biomolecular analysis significantly increased cytology sensitivity for PTC from 77.3 to 86.7% (P<0.01). CONCLUSIONS: These data indicate that BRAF V600E mutation analysis can significantly improve FNAB diagnostic accuracy. However, biomolecular analysis is complementary to cytology, which should always be performed.

Thyroid papillary microcarcinoma: a descriptive and meta-analysis study.

The authors review anatomical, clinical characteristics and prevalence of thyroid microcarcinoma. Diagnostic procedures and risk factors of aggressiveness at diagnosis and during follow-up are also covered. The possible clinical, pathologic and therapeutic risk factors are analyzed by meta-analysis study. Treatment procedures by different authors and guidelines suggested by societies are reported.

Differentiated thyroid cancers 11-20 mm in diameter have clinical and histopathologic characteristics suggesting higher aggressiveness than those < or =10 mm.

OBJECTIVE: To compare characteristics and outcomes of differentiated thyroid cancers < or =10 mm with those 11-20 mm in diameter. DESIGN: Retrospective chart review of 426 patients with thyroid carcinoma < or =20 mm diagnosed and treated between 1990 and 2004 in one university clinic. MAIN OUTCOMES: Lymph node metastases were more frequent at diagnosis in 11-20 mm than in < or =10 mm cancers (p < 0.001). The prevalence of distant metastases did not differ between < or =10 mm and 11-20 mm cancers. One hundred and thirty-three patients (73%) with tumors 11-20 mm were disease free 2 years after 131I treatment, and no recurrence has been observed over 2-14 years of follow-up. Forty-one patients (22%) with cancers 11-20 mm (N1 or M1) required 2-4 years to become disease free. Neck lymph node recurrence was observed in nine patients (4.9%) 4 months to 14 years after surgery and (131)I therapy. Four patients (1.6%) with cancers < or =10 mm in diameter had cancer recurrence (p = 0.05 compared to the 11-20 mm cancers). Based on the presence of distant metastases at diagnosis and recurrence of disease during follow-up, cancers 11-20 mm in diameter seemed more aggressive than those < or =10 mm (p < 0.05). CONCLUSION: Cancers 11-20 mm seem more aggressive than those < or =10 mm.

Total, free and bound leptin and thyroid function in elderly women with different body weights.

OBJECTIVE: The present study was aimed at evaluating the relationship of total leptin, and its free leptin (FL) and bound leptin (BL) fractions with adipose mass in very old euthyroid women, in relationship to thyroid function. SUBJECTS AND METHODS: Twenty-five older women (age: 73-95 years) were studied. Subjects representing underweight, normal weight and overweight/obese conditions were included. Plasma leptin, TSH, free T(4) (FT(4)) and free T(3), (FT(3)) total and HDL cholesterol were measured. FL and BL were evaluated by Fast Protein Liquid Chromatography (FPLC) analysis. RESULTS: Plasma leptin concentration was positively correlated with body mass index (BMI) (r = 0.64, P = 0.0005) and tricipital skin-fold thickness (TF) (r = 0.46, P = 0.0187). Leptin was positively correlated with TSH (r = 0.50, P = 0.0116) and inversely with FT(3) (r = -0.40, P = 0.0477). TSH correlated with the adiposity indexes BMI (r = 0.40, P = 0.05) and TF (r = 0.42, P = 0.0336). Plasma FT(3) was positively correlated with FT(4) (r = 0.49, P = 0.012). FL and BL were evaluated in 8 out of 25 subjects. FL positively correlated with BMI (r = 0.81, P = 0.0218) and leptin (r = 0.83, P = 0.0004), whereas BL did not correlate with these parameters. CONCLUSIONS: The present results indicate that in very old women, plasma leptin concentrations reflect the extent of adipose mass and suggest that a complex regulatory interaction exists between leptin and thyroid function, possibly taking place at central (hypothalamus-pituitary) and peripheral (deiodinase activity) levels.

Subclinical hypothyroidism.

PURPOSE OF REVIEW: Mild or subclinical hypothyroidism is characterized by normal serum free thyroxine concentrations with elevated serum thyroid-stimulating hormone concentrations. Subclinical hypothyroidism is relatively prevalent in the general population, especially among women and the elderly. The main cause of subclinical hypothyroidism is autoimmune chronic thyroiditis. The present report reviews the most important and recent studies on subclinical hypothyroidism, and discusses the most controversial aspects of this topic. RECENT FINDINGS: Several studies have demonstrated that subclinical hypothyroidism may affect both diastolic and systolic cardiac function. It may also worsen many risk factors for cardiovascular disease, including hypertension, abnormal endothelial function, and elevated low-density lipoprotein cholesterol concentrations. Furthermore, a growing body of evidence suggests that subclinical hypothyroidism may cause symptoms or progress to symptomatic overt hypothyroidism. SUMMARY: Prompt treatment of subclinical hypothyroidism in pregnant women is mandatory to decrease risks for pregnancy complications and impaired cognitive development in offspring. Children with subclinical hypothyroidism should be treated to prevent growth retardation. Whether nonpregnant adult patients with subclinical hypothyroidism should be treated, and at what thyroid-stimulating hormone values, is debatable.

The bioartificial thyroid: a biotechnological perspective in endocrine organ engineering for transplantation replacement.

A new concept for ex situ endocrine organ bioengineering is presented, focused on the realization of a human bioartificial thyroid gland. It is based on the theoretical assumption and experimental evidence that symmetries in geometrical coordinates of the thyroid tissue remain invariant with respect to developmental, physiological or pathophysiological transformations occuring in the gland architecture. This topological arrangement is dependent upon physical connections established between cells, cell adhesion molecules and extracellular matrix, leading to the view that the thyroid parenchyma behaves like a deformable "putty", moulded onto an elastic stromal/vascular scaffold (SVS) dictating the final morphology of the gland. In particular, we have raised the idea that the geometry of the SVS per se provides pivotal epigenetic information to address the genetically-programmed, thyrocyte and endothelial/vascular proliferation and differentiation towards a functionally mature gland, making organ form a pre-requirementfor organ function. A number of experimental approaches are explored to obtain a reliable replica of a human thyroid SVS, and an informatic simulation is designed based on fractal growth of the thyroid intraparenchymal arterial tree. Various tissue-compatible and degradable synthetic or biomimetic polymers are discussed to act as a template of the thyroid SVS, onto which to co-seed autologous human thyrocyte (TPC) and endothelial/vascular (EVPC) progenitor cells. Harvest and expansion of both TPC and EVPC in primary culture are considered, with specific attention to the selection of normal thyrocytes growing at a satisfactory rate to colonize the synthetic matrix. In addition, both in vitro and in vivo techniques to authenticate TPC and EVPC lineage differentiation are reviewed, including immunocytochemistry, reverse trascriptase-polymerase chain reaction, flow cytomery and proteomics. Finally, analysis of viability of the thyroid construct following implantation in animal hosts is proposed, with the intent to obtain a bioartificial thyroid gland morphologically and functionally adequate for transplantation. We believe that the biotechnological scenario proposed herein may provide a template to construct other, more complex and clinically-relevant bioartificial endocrine organs ex situ, such as human pancreatic islets and the liver, and perhaps a new approach to brain bioengineering.

Solitary fibrous tumor of the thyroid gland.

Solitary fibrous tumor (SFT) is a rare spindle-cell neoplasm more commonly involving the pleura, but recognized also in other tissues. Nineteen patients with SFT arising from the thyroid gland have been reported in the literature. The present report reviews these cases and discusses epidemiology, etio-pathogenesis, clinical-pathologic characteristics, differential diagnosis, therapy, and prognosis of thyroid SFT.

Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients.

CONTEXT: The recognition of thyroid microcarcinoma has increased due to the widespread use of ultrasound-guided fine-needle aspiration biopsies. OBJECTIVE: The objective of this study was to describe histological and clinical characteristics of papillary thyroid microcarcinoma (PTMC) less than or equal to 1 cm. DESIGN: This study was a retrospective cohort. SETTING: This study was conducted at a university hospital endocrine clinic. PATIENTS: Over a 9-yr period, 243 consecutive patients with PTMC were studied. RESULTS: PTMC was an incidental finding at surgery in 21.4% of the PTMC cases. There were no differences in the clinical characteristics between those with incidental PTMC and those with suspected thyroid carcinoma. None of the patients with a cancer less than 8 mm had distant metastases, whereas distant metastases were observed in patients with cancers >/= 8 mm (P

A meta-analysis of inferior thyroid artery variations in different human ethnic groups and their clinical implications.

We have recently found ethnic differences in superior thyroid artery (STA) variational anatomy. Therefore, we now focus on the inferior thyroid artery (ITA). In particular, we analyze whether presence, numerical variations and site of origin of ITA are influenced by ethnic group and gender, whether and which neck side has the largest arterial caliber, whether differences occur between the presence of ITA and STA, to which extent a non-selective thyroid angiography is effective in visualizing ITA, also in comparison to STA, and which clinical value this information may have in selected pathologies of the thyroid, parathyroid and larynx. A meta-analysis has been performed, including 33 library- and Medline-selected publications on Caucasoids (European and non-European) and East Asians, and a set of original data on European Caucasoids. A total of 6285 Caucasoid and 847 East Asian items, comprising half bodies and arteries, were analyzed. After testing the homogeneity of the available data sources in relation to the anatomical variables under study we calculated a cumulative value for each selected anatomical parameter and evaluated differences using non-parametric statistics. The effectiveness of non-selective thyroid angiography was determined using sensitivity, specificity, positive and negative predictive values. The ITA was more frequently absent in East Asians than in Caucasoids, and respectively either more or less frequently arising from thyrocervical and subclavian arteries, in East Asians versus Caucasoids. In contrast, the ITA was less frequently present both in Caucasoids and East Asians than the STA. In addition, the ITA was more frequently present on the right than on the left side in both ethnic groups, but no neck side predominated in size of arterial caliber in European Caucasoids. Finally, the ITA was more frequently present in East Asian males than females, and the effectiveness of a non-selective thyroid angiography showed higher numbers for ITA than STA in Caucasoids. Statistically significant variations occur in some ITA parameters between Caucasoids and East Asians, and in its presence with respect to STA, within each ethnic group. These differences, together with a sexual dimorphic presence of ITA in East Asians and high effectiveness of its visualization by non-selective angiography in European Caucasoids, may represent an evidence-based supply of anatomical information for analysis in selected pathologies of the thyroid, parathyroid and larynx.

A clinical and therapeutic approach to thyrotoxicosis with thyroid-stimulating hormone suppression only.

Subclinical hyperthyroidism is defined as normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations and persistently suppressed thyroid stimulating hormone (TSH) concentrations. The most common cause of subclinical hyperthyroidism is the use of suppressive doses of L-thyroxine for treatment of hypothyroidism or, less commonly, diffuse nontoxic goiter or thyroid carcinoma (exogenous subclinical hyperthyroidism). Endogenous subclinical hyperthyroidism may be caused by a variety of thyroid disorders that result in overproduction and release of thyroid hormones from the gland with normal/high 24-hour thyroid radioiodine uptake or by inflammation in the thyroid resulting in release of excess thyroid hormones and low 24-hour thyroid radioiodine uptake. Several groups have investigated whether persistent endogenous or exogenous subclinical hyperthyroidism, like overt hyperthyroidism, causes symptoms, adverse effects on the cardiovascular and the skeletal systems, and increased mortality, whether endogenous subclinical hyperthyroidism evolves to overt thyrotoxicosis, and whether or not it should be treated. The present report reviews the most important and recent studies of subclinical hyperthyroidism and attempts to draw conclusions based upon the literature and the authors' experience.

Clinical value of different responses of serum thyroglobulin to recombinant human thyrotropin in the follow-up of patients with differentiated thyroid carcinoma.

In the present study we examined the clinical value of a differential response of thyroglobulin (Tg) concentration after recombinant human thyrotropin (rhTSH) stimulation (rhTSH Tg testing) and its correlation with (131)I uptake and whole-body scanning (rhTSH-WBS) in 104 patients who had previously undergone near-total thyroidectomy and (131)I ablation for differentiated thyroid carcinoma (DTC). rhTSH Tg testing was considered negative for rhTSH-Tg less than 0.9 ng/mL, low positive for rhTSH-Tg of 1-5 ng/mL and high positive for rhTSHTg greater than 5 ng/mL. rhTSH Tg testing was negative in 70 patients, 1 of whom had a lymph-node metastasis, but no (131)I uptake. Seven patients had low positive rhTSH Tg testing and no (131)I uptake, but 2 of these patients had cervical lymph node metastases. Twenty-seven patients had high positive rhTSH Tg testing and (131)I uptake was detected in lung, bone, or mediastinum in 11. Imaging techniques (computed tomography [CT], magnetic resonance imaging [MRI], fluorine-18 2-fluoro-2-deoxy-D-glucose-positron emission tomography [FDGPET]) documented metastatic disease in 22. In conclusion, our results suggest that any rise in rhTSH-Tg, even at low level, should raise the suspicion of persistent or recurrent DTC. Patients with rhTSH-Tg at high level should be carefully evaluated, because DTC persistence is highly probable. TSH-WBS provides little adjunctive information.

Clinical value of different responses of serum thyroglobulin to recombinant human thyrotropin in the follow-up of patients with differentiated thyroid carcinoma.

In the present study, we examined the clinical value of a differential response of thyroglobulin (Tg) concentration after recombinant human thyrotropin (rhTSH) stimulation (rhTSH Tg testing) and its correlation with (131)I uptake and whole body scanning (rhTSH-WBS) in 104 patients who had previously undergone near total thyroidectomy and (131)I ablation for differentiated thyroid carcinoma (DTC). RhTSH Tg testing was considered negative for rhTSH-Tg < 0.9 ng/mL, low positive for rhTSH-Tg of 1-5 ng/mL and high positive for rhTSHTg > 5 ng/mL. RhTSH Tg testing was negative in 70 patients, one of whom had a lymph-node metastasis, but no (131)I uptake. Seven patients had low positive rhTSH Tg testing and no (131)I uptake, but two of these patients had cervical lymph-node metastases. Twenty-seven patients had high positive rhTSH Tg testing and (131)I uptake was detected in lung, bone, or mediastinum in 11. Imaging techniques (CT, MRI, FDG-PET) documented metastatic disease in 22. In conclusion, our results suggest that any rise in rhTSH-Tg, even at low level, should raise the suspicion of persistent or recurrent DTC. Patients with rhTSH-Tg at high level should be carefully evaluated, since DTC persistence is highly probable. TSH-WBS provides little adjunctive information.

A meta-analysis of superior thyroid artery variations in different human groups and their clinical implications.

We have investigated whether the presence, numerical variations and site of origin of the superior thyroid artery (STA) are influenced by the ethnic group and gender, whether the origin and caliber of this vessel are symmetrical, to what extent a non-selective thyroid angiography, either conventional or by digital subtraction, is effective in visualizing it, and whether this information may be useful in selected clinical conditions. A meta-analysis has been performed, including 24 library- and Medline-selected publications on Caucasoids (European and non-European) and East Asians and a set of original data on European Caucasoids. A total of 3453 Caucasoid and 931 East Asian items, including entire bodies, half bodies and arteries, were used. After testing the homogeneity of the available data sources in relation to the anatomical variables under study we calculated a cumulative value for each selected anatomical parameter and evaluated differences by non parametric statistics. Effectiveness of non-selective thyroid angiography was determined using sensitivity, specificity, positive and negative predictive values. A higher frequency of origin from the external carotid artery was present in Caucasoids than in East Asians. In contrast, a higher frequency of origin from common carotid artery was observed in East Asians versus Caucasoids. No gender differences were found for any of the parameters analyzed in East Asians. In addition, an equal probability of either asymmetrical or symmetrical origin on the two sides of the neck for STA was found in East Asians. In contrast, a symmetry of caliber for STA was found in European Caucasoids. Finally, only a moderate effectiveness of non-selective thyroid angiography, either conventional or by digital subtraction, was determined for visualization of STA in European Caucasoids. Statistically significant variations in some STA anatomical parameters occur between Caucasoids and East Asians. These differences, together with the high frequency of asymmetry for STA origin in East Asians and low effectiveness of STA visualization by non-selective angiography in European Caucasoids, may result in useful information for clinical reasoning in selected conditions of the thyroid region.

Anthropological variations in the anatomy of the human thyroid arteries.

Knowledge of anatomic variability of the superior (STA), inferior (ITA), and lowest accessory (IMA) thyroid arteries may be helpful in certain clinical conditions. However, details of this variability have not been thoroughly described. Specifically, whether the presence and site of origin of STA, ITA, and IMA are influenced by the anthropological group, to what extent their origin is symmetric or asymmetric, and the role played by this variability in visualizing each thyroid artery by nonselective thyroid angiography is not known. To clarify this we conducted a meta-analytical study on Caucasian and Asian subjects, the latter including only Japanese and Koreans. In Caucasians and Asians the presence of superior vessels compared to inferior vessels was more frequent and the probability of symmetric or asymmetric arterial origin for STA were equivalent. However, better recognition of inferior rather than superior vessels was achieved by nonselective angiography in Caucasians. Finally, different frequencies of presence and site of origin for each artery were identified in Caucasians compared to Asians. Our results suggest that the higher frequency of IMA in Asians than in Caucasians should result in a search for an IMA-dependent feeding artery of inferior parathyroid adenomas, primarily the mediastinal ones, especially in Asians both by imaging and transcatheter ablative approaches. In addition, we have found that a small percentage of Caucasian subjects lack an STA on the left side. Therefore, anatomic arterial compatibility should be carefully evaluated in the preoperative stage of laryngeal transplantation maintaining in situ the donor's thyroid by terminal anastomoses between donor and recipient STAs. Finally, the lack of any individual thyroid artery in either Caucasians or Asians might influence the distribution of autonomic supply that runs with thyroid vessels to the thyroid parenchyma. This appears functionally relevant in cases of traumatic or surgical lesions of the cervical sympathetic chain involving thyroid nerves. In fact, a restricted local autonomic control of thyroid activity might be related to individual rami of thyroid nerves.

Post-partum thyroiditis--a clinical update.

Since the late 1960s, many studies have focused on post-partum thyroiditis (PPT) and 295 papers whose titles mention PPT were recorded on MEDLINE as of August 2001. We refer briefly to some excellent reviews and some original articles in order to update our knowledge on PPT.