Inter- and Intraobserver Agreement in the Assessment of Thyroid Nodule Ultrasound Features and Classification Systems: A Blinded Multicenter Study.

Background: Single-center trials demonstrated moderate-substantial level of interobserver agreement in the evaluation of ultrasound (US) features of thyroid nodules. Multicenter studies on US agreement, however, are scanty, and data on intraobserver agreement are poor. Aim of the study was to assess inter- and intraobserver agreement between different thyroid centers and different specialists. Methods: A blinded analysis of 100 electronically recorded thyroid nodule US images was conducted in three large-volume thyroid centers by seven radiologists and endocrinologists. The evaluation was repeated after randomization 4 months later. The following US characteristics were evaluated: composition, echogenicity, margins, intranodular echogenic spots, vascularity, and shape. Thyroid nodules were also classified according to AACE/ACE/AME, EU-TIRADS, ATA, and ACR-TIRADS US classifications. Intra- and interobserver agreement was calculated using cross-tabulation expressed as mean Cohen's Kappa. Results: Interobserver agreement for US features: K-coefficient was 0.53 for composition, 0.47 for echogenicity, 0.46 for intranodular vascularity, and 0.33 for margins of the nodules. For echogenic foci, the K-coefficient was 0.47 for microcalcifications, 0.38 for macrocalcifications, 0.11 for the subcategory comet-tail artifacts, and 0.42 for shape. Operators resulted uncertain on hyperechoic foci definition in 16% of cases and described them as "hyperechoic foci of uncertain significance." Interobserver Cohen-K for US classification systems was 0.44 for AACE, 0.42 for ACR-TIRADS, 0.39 EU-TIRADS, and 0.34 for ATA. Intraobserver agreement: the K-coefficient for nodule US features was 0.62 for intranodular vascularity, 0.58 for composition, 0.60 for echogenicity, 0.54 for macrocalcifications, 0.55 for microcalcifications, 0.47 for comet tails, 0.39 for margins, and 0.35 for shape. Intraobserver Cohen-K for US classification systems was 0.54 for AACE, 0.49 for ACR-TIRADS, 0.38 for ATA, and 0.33 for EU-TIRADS. Conclusions: Intraobserver reproducibility for thyroid nodule US reporting and US classification systems appears fairly adequate, while the interobserver agreement between different centers is lower than that assessed in single-center trials. Reporting and rating ability of thyroid US examiners still appear not consistent. An unified lexicon of thyroid US features, a simplified method of classification, and a dedicated training in the description of thyroid US findings may increase the observers' agreement and the predictive value of US classification systems in real world practice.

Predictive Value of Malignancy of Thyroid Nodule Ultrasound Classification Systems: A Prospective Study.

Context: British Thyroid Association (BTA), American Thyroid Association (ATA), and American Association of Clinical Endocrinologists (AACE/ACE/AME) recommend for thyroid nodules an ultrasound (US)-based stratification of risk of malignancy. Aim of our study was to assess the diagnostic accuracy of US classification systems and their reliability for indication to fine-needle aspiration (FNA). Design: Prospective study on 987 thyroid nodules consecutively referred for FNA. US images were independently reviewed by four experts for assignment of malignancy risk. Cytologically benign nodules had confirmation with a second FNA, whereas Bethesda class IV, V, and VI nodules were operated upon. Class III nodules had surgery or follow-up on the basis of clinical, immunocytochemical, and US features. Results: BTA: Malignancy rate was 2.8% in benign, 10.0% in indeterminate, 51.3% in suspicion, and 80.9% in malignant US class. Sensitivity was 0.74, specificity was 0.92, and accuracy was 0.89. ATA: Malignancy rate was 0.0% in benign, 2.2% in very low suspicion, 3.0% in low suspicion, 5.8% in intermediate, and 55.0% in high suspicion US class. Sensitivity was 0.81, specificity was 0.87, and accuracy was 0.86. AACE/ACE/AME: Malignancy rate was 1.1% in low-risk, 4.4% in intermediate-risk, and 54.9% in high-risk US class. Sensitivity was 0.82, specificity was 0.87, and accuracy was 0.86. K correlation coefficient was 78.9%, 76.9%, and 82.0% for BTA, ATA, and AACE/ACE/AME classifications. Conclusions: Classification systems had elevated predictive value of malignancy in high-risk classes. ATA and AACE/ACE/AME systems were effective for ruling out indication to FNA in low-US-risk nodules. A similar diagnostic accuracy and a substantial interobserver agreement was provided by the three- and the five-category classifications.

Shift from Levothyroxine Tablets to Liquid Formulation at Breakfast Improves Quality of Life of Hypothyroid Patients.

BACKGROUND: Until recently, treatment of hypothyroidism has been accomplished using monotherapy of synthetic L-thyroxine (L-T4) sodium tablets that should be taken 30-60 minutes before breakfast. Nowadays, a liquid preparation of levothyroxine is available and can effectively replace tablets without the need of waiting before having breakfast. Evidence of Quality of life (QoL) improvement when shifting from the former to the latter preparation, however, is still lacking. OBJECTIVE: The study aimed to assess changes in QoL of hypothyroid patients dissatisfied with their therapy with L-T4 sodium tablets who were switched from tablets taken 30-60 minutes before breakfast to liquid L-T4 at breakfast. METHODS: A total of 418 consecutive hypothyroid subjects treated by means of L-T4 tablets were asked about their satisfaction/dissatisfaction in order to take the medication 30-60 minutes before having breakfast. Overall, 110 patients (26.3%) complained of the timing of their L-T4 therapy (30-60 minutes before breakfast). A dedicated QoL questionnaire (ThyTSQ), taking just a few minutes to be filled in was then administered to these dissatisfied patients. They were therefore switched to L-T4 to be taken at breakfast. Aiming to avoid TSH elevation due to L-T4 tablets malabsorption caused by meal interference and gastric pH changes, patients were invited to take L-T4 liquid form, as this is claimed to be scarcely affected by the non-fasting state. The questionnaire (ThyTSQ) was administered again at the control visit 3 months later. TSH, FT4, FT3 serum concentrations and metabolic parameters were also recorded. RESULTS: An improved QoL, mainly due to an easier adherence to treatment, was reported by 66.6% of 102 patients who completed the study after shifting from taking medication 30-60 minutes before breakfast to at breakfast ingestion (P<0.01). An overall 10.7% of patients found the liquid formulation distasteful. Mean values of TSH, FT4, FT3, and of metabolic parameters did not significantly change but in eight patients (7.7%) who showed a TSH increase > 2mIU/L. CONCLUSION: In hypothyroid subjects dissatisfied with L-T4 tablets ingested 30-60 minutes before breakfast, the shift to the same dose of L-T4 in liquid form taken at breakfast improved QoL in the majority of patients, without affecting thyroid function.

Ultrasound sensitivity for thyroid malignancy is increased by real-time elastography: a prospective multicenter study.

CONTEXT: Thyroid nodules are selected for biopsy on the basis of clinical and ultrasound (US) findings. Ultrasonography detects nodules at risk of malignancy, but its diagnostic accuracy does not rule out with certainty the possibility of cancer in lesions without suspicious findings. OBJECTIVE: The objective of the study was to evaluate the diagnostic accuracy of real-time elastography (RTE) in thyroid nodules and to assess the improvement provided by combination of RTE, B-mode US, and color flow Doppler (CFD). DESIGN: This was a prospective multicenter study. PATIENTS: A consecutive series of 498 thyroid nodules was blindly evaluated by US, CFD, and RTE before biopsy or surgery. Nodules were classified at RTE by four-class color scale. Patients with benign cytology underwent follow-up over 12 months, whereas patients with indeterminate, suspicious, or malignant cytology were surgically treated. RESULTS: At follow-up, 126 nodules were malignant and 372 benign. RTE classes III-IV showed 81% sensitivity and 62% specificity. The presence of at least one US risk factor (hypoechogenicity, microcalcifications, irregular margins, intranodular vascularization, and taller than wide shape) had 85% sensitivity and 91% negative predictive value. When RTE was combined with US, the presence of at least one of the six parameters had 97% sensitivity and 97% negative predictive value, with an odds ratio of 15.8 (95% confidence interval 5.7-43.8). CONCLUSIONS: RTE is a valuable tool for detecting malignant thyroid lesions with a sensitivity similar to traditional US and CFD features. By adding RTE evaluation, the sensitivity for malignancy of US findings is markedly increased and the selection of nodules that do not need cytology is made more reliable.

Ultrasound-guided laser ablation of incidental papillary thyroid microcarcinoma: a potential therapeutic approach in patients at surgical risk.

BACKGROUND: Incidental papillary thyroid microcarcinoma (PTMC), a frequent clinical problem, is usually associated with a favorable outcome. During long-term follow-up, only a minority of cases show aggressive behavior with either lymph node or distant metastases. Recently, we had an opportunity to evaluate the efficacy of nonsurgical, ultrasound (US)-guided percutaneous laser ablation (PLA) for local treatment of PTMC in an otherwise inoperable patient. PATIENT AND METHODS: Neck US examination revealed an incidental, solitary, 8 × 7 × 7 mm hypoechoic nodule with microcalcifications of the right thyroid lobe. The patient suffered from decompensated liver cirrhosis, renal failure, and recent surgery followed by external beam radiation therapy for breast cancer. Cytologic diagnosis showed papillary thyroid carcinoma, but the patient declined surgery because of high risk of thyroid surgery. After local anesthesia with 2% xylocaine, PLA was performed according to the previously reported procedure with an Nd:YAG laser. SUMMARY: The procedure was well tolerated, without side effects, and the patient required no analgesics. US-guided fine-needle aspiration biopsy and core-needle biopsy were performed at 1 and 12 months after PLA, which demonstrated necrotic material and inflammatory cells with no viable neoplastic cell. At the 24 months US follow-up examination, the area of necrosis further decreased, demonstrating a 4 × 4 mm hypoechoic zone and a small hyperechoic area due to fibrotic changes. A fine-needle aspiration biopsy confirmed the absence of malignant cells. CONCLUSIONS: Laser-induced thermal ablation was a safe and effective ablative treatment for a patient with PTMC confined to the thyroid gland who was at high surgical risk. This approach should be considered only in elderly patients and/or in those with comorbidities that might expose the patients to an undue high surgical risk and only after the evaluation by neck US, computed tomography, magnetic resonance imaging, or positron emission tomography/computed tomography rules out lymph-node involvement or metastatic disease.

Percutaneous laser ablation of unresectable primary and metastatic adrenocortical carcinoma.

PURPOSE: To evaluate the feasibility, safety, and clinical benefits of percutaneous laser ablation (PLA) in patients with unresectable primary and metastatic adrenocortical carcinoma (ACC). PATIENTS AND METHODS: Four patients with hepatic metastases from ACC and a Cushing's syndrome underwent ultrasound-guided PLA. In one case the procedure was performed also on the primary tumor. RESULTS: After three sessions of PLA, the primary tumor of 15 cm was ablated by 75%. After 1-4 (median 1) sessions of PLA, five liver metastases ranging from 2 to 5 cm were completely ablated, while the sixth tumor of 12 cm was ablated by 75%. There were no major complications. Treatment resulted in an improvement of performance status and a reduction of the daily dosage of mitotane in all patients. The three patients with liver metastases presented a marked decrease of 24-h urine cortisol levels, an improved control of hypertension and a mean weight loss of 2.8 kg. After a median follow-up after PLA of 27.0 months (range, 9-48 months), two patients have died of tumor progression, while two other patients remain alive and free of disease. CONCLUSIONS: Percutaneous laser ablation is a feasible, safe and well tolerated procedure for the palliative treatment of unresectable primary and metastatic ACC. Further study is required to evaluate the impact of PLA on survival.

Treatment of benign cold thyroid nodules: a randomized clinical trial of percutaneous laser ablation versus levothyroxine therapy or follow-up.

AIM OF THE STUDY: To compare clinical and ultrasound (US) changes induced in cold thyroid nodules by US-guided percutaneous laser ablation (PLA) versus follow-up or levothyroxine (LT4) suppressive therapy. METHODS: 62 patients randomly assigned to a single PLA (Group 1), LT4 (Group 2), or follow-up (Group 3). Entry criteria: euthyroid patients with a solid thyroid nodule >5 mL and benign cytological findings. TREATMENT: Group 1: PLA was performed with a 1.064 mum neodymium yttrium-aluminum-garnet laser with output power of 3 W for 10 minutes; Group 2: the LT4 dose was adjusted to induce thyrotropin suppression; Group 3: no treatment. RESULTS: In Group 1 a significant nodule reduction was found 6 and 12 months after PLA (delta volume: -42.7 +/- 13.6%; p = 0.001). A reduction >50% was found in 33.3% of cases. In Group 2 a nonsignificant nodule shrinkage was observed. A nonsignificant volume increase was observed in Group 3. Improvement of local symptoms was registered in 81.2% of patients in Group 1 vs. 13.3% in Group 2 and 0.0% in Group 3 ( p = 0.001). No complications were noted. CONCLUSIONS: A single PLA induced significant volume reduction and improvement of local symptoms. PLA was more effective than LT4. Follow-up was associated with nodule growth and progression of local symptoms. PLA should be considered a potential mini-invasive alternative to surgery in symptomatic patients with benign cold thyroid nodules.

Ontogenesis and cell specific localization of Fas ligand expression in the rat testis.

Over the past few years, a number of experimental evidences suggested the involvement of Fas Ligand (FasL) expressing Sertoli cells to induce apoptosis of Fas bearing germ cells. However, the FasL expression during testicular development and its cell specific localization within the testis is still a matter of debate. In the present study, we have monitored FasL expression during rat testis development by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and evaluated cell specific localization of FasL expression, by in situ RT-PCR and immunohistochemistry, on adult rat testis. RT-PCR analysis, performed on total RNA from rat testes obtained from 1 day up to 1-year-old animals, demonstrated the presence of FasL transcripts at all developmental stages examined. In situ RT-PCR analysis clearly indicated the presence of FasL mRNA in Sertoli cells of adult testis, while we could never detect FasL transcripts in germ cells. Immunohistochemistry experiments showed a strong immunostaining for FasL in Sertoli cells of adult testis and again, no immunopositivity was observed in germ cells. In conclusion, our data suggest that FasL expression in rat testis is present from the early postnatal days up to the adult, and the Sertoli cells is the main FasL expressing cell within the seminiferous tubule.

Percutaneous ethanol injection treatment in benign thyroid lesions: role and efficacy.

GOAL: To establish the role of percutaneous ethanol injection (PEI) treatment in benign thyroid lesions by evaluating: (1) the long-term efficacy and side effects of the treatment, (2) the factors predictive of efficacy of PEI, and (3) the cost effectiveness of the procedure. MATERIALS AND METHODS: Fifty-eight recurrent cystic nodules, 95 autonomously functioning nodules (AFTN), and 17 hyperfunctioning nodules causing thyrotoxicosis (toxic nodules) were treated by PEI from 1990 to 1996 in our center. Ultrasound (US) and color flow doppler (CFD) examinations were carried out before and after each treatment. In patients with AFTN, serum thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb) levels were tested before and after PEI. All patients were independently reexamined by two external reviewers after a minimum follow-up of 5 years (median, 6.9 years). RESULTS: The median number of treatments was 2.0 (range, 1.0-4.0) for cystic nodules, 4 (range, 2.0-6.0) for AFTN, and 5 (range, 3.0-7.0) for toxic nodules. At the 5-year evaluation cystic nodules showed a volume reduction greater than 75% versus baseline in 86.2% of cases and an improvement of local symptoms in 91.4% of cases. AFTN presented serum TSH within normal limits in 60.0% of patients. Toxic nodules showed a detectable serum TSH and normal FT3 and FT4 values in 35.3% of cases. Two cases of transient dysphonia were observed. In cystic lesions no significant correlation was found between the baseline and the final volume (r2 = 0.17) and no significant predictor of treatment efficacy was found. However, unilocularity was associated with a lower number of treatments than multilocularity (median, 2.0 vs. 3.0). Independent predictors of clinical efficacy in both AFTN and toxic nodules were a baseline volume less than 5.0 mL and a fluid component greater than 30% (odds ratio [OR] = 6.1 and 3.3, respectively). CONCLUSIONS: Most recurrent cystic lesions of the thyroid can be cured by PEI, which should become the first line of treatment. The majority of AFTN and toxic nodules with volume less than 5.0 mL presented a marked volume decrease and normal serum TSH levels when treated by PEI, which seems a valid alternative to clinical follow-up alone in patients refusing 131I. PEI is not indicated in large or toxic nodules, for which 131I is the treatment of choice.