An innovative synthetic support for immunocytochemical assessment of cytologically indeterminate (Bethesda III) thyroid nodules.

Background: Fine needle aspiration (FNA) is the procedure of choice in the evaluation of thyroid nodules. Nodules with indeterminate cytological categories, Bethesda III and IV, pose challenges in clinical practice and are frequently submitted to diagnostic surgery. CytoFoam Core (CFCS) uses an absorbent foam device inserted into the needle hub to collect the cytological sample aspirated during FNA. Specimen is formalin-fixed and paraffin-embedded. Aim of the study: Assessing diagnostic efficacy of CFCS, compared to traditional cytology, in re-evaluating thyroid nodules classified as Bethesda III, using post-surgical histology as reference standard. Method: Retrospective study on 89 patients with a first indeterminate cytological report who were referred to the Department of Endocrinology of Regina Apostolorum Hospital (Albano L. Rome, Italy) for a second FNA. FNA was performed after at least one month under ultrasound guidance with a 23G needle according to the established procedure. During the second procedure, both traditional cytological (TC) smears and a single-pass CFCS specimen were obtained for each patient. On CFCS samples immunocytochemical staining for Galectin-3, HBME-1, and CK-19 was also performed. 51 patients eventually underwent surgery, and their histological diagnoses were compared to the TC and CFCS reports. Four parameters were evaluated: inadequacy rate, rate of persistent indeterminate (Bethesda III and IV) reports, rate of malignancy in persistently indeterminate nodules, and rate of cancer in lesions cytologically classified as malignant. Results: Non-diagnostic samples were 6 (11.8%) in TC vs 3 (5.9%) in CFCS (p=0.4). Persistent indeterminate samples were 31 (60.8%) in TC vs 19 (37.2%) in CFCS (p=0.01). Rate of malignancy in persistently indeterminate nodules was 8/19 (42.1%) in CFCS vs 9/31 (29%) in TC group (p=0.3). Nine/51 (17.6%) samples were classified as benign by TC vs 21/51 (41.2%) samples by CFCS (p<0.01). All nodules resulted benign at post-surgical evaluation. Five/51 (9.8%) samples were classified as suspicious for malignancy/malignant in TC group against 8/51 (15.7%) samples in CFCS (p=0.5). Post-surgical evaluation confirmed malignancy in all these cases. Conclusion: CFCS demonstrated greater diagnostic accuracy than TC in repeat FNA assessment of cytologically indeterminate nodules. CFCS increased the conclusive diagnosis rate and decreased the number of cytologically indeterminate cases.

Morphological and Molecular Assessment in Thyroid Cytology Using Cell-Capturing Scaffolds.

The increased frequency of thyroid nodules is paralleled by the rise of thyroid cancer diagnosis. To define the nature of most thyroid nodules, fine needle aspiration (FNA) followed by cytological evaluation is considered the method of choice. About 20% of FNA biopsies on thyroid nodules, however, show indeterminate cytological features and may require diagnostic surgery. Several immunocytochemical and molecular markers have been proposed to improve classification of thyroid nodules, but these tests require adequate cell amount and cytological paraffin inclusion. Polymeric matrices were recently proposed for the collection of cells for diagnostic purposes. In this study, we evaluated the diagnostic use of a new matrix (CytoMatrix). Morphological, molecular and immunohistochemical investigations were carried out on 23 FNA samples included in CytoMatrix and compared with data obtained from the definitive histology of surgical samples. Our results showed that CytoMatrix is suitable to capture and preserve the cellularity of the samples harvested by FNA and that its paraffin sections mimic the morphology of those obtained from real histological tissue. Immunohistochemistry on CytoMatrix samples was consistent with the immunophenotypical profile of the corresponding histological surgical specimens. Mutational analysis of the BRAF (V600E) gene performed on CytoMatrix inclusions and paired surgical tissue matched in all but one cases while matrix immunohistochemistry identified 91.6% of BRAF mutated samples. In conclusion, we suggest that CytoMatrix could be a reliable tool to overcome the current limits of traditional collection methods for the study of thyroid cytology, thereby improving their reliability for a conclusive diagnostic interpretation.

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.

State-of-the-Art Review on Diabetes Care in Italy.

BACKGROUND: Diabetes is a significant health problem in Italy as in other western countries. OBJECTIVE: To review available epidemiological data and the legislative framework for diabetes care in Italy. METHODS: Review of Italian Health Ministry's official documents and analysis of epidemiological data published by Italian Scientific Societies. FINDINGS: Diabetes affects more than 5% of the Italian population. The expenditures for the care of people with diabetes are about €10 billion ($US 11 billion) a year and are increasing over time. Italian law regulates the clinical care of people with diabetes and creates a clinical framework involving medical organizations, prevention programs, personnel training, and legal protection. The National Health Program is structured in essential levels of assistance that can be defined differently in the various regions. In 2013, the "National Diabetes Plan," defining priority areas for intervention, was approved and represents the main regulatory tool for the management of diabetes within the Italian National Health Service. In Italy, the status of diabetes care is being monitored using the data from 2 permanent observatories: the ARNO Observatory Diabetes and the Associazione Medici Diabetologi Annals. CONCLUSIONS: A comprehensive approach to diabetes is offered to all citizens, consonant with the constitutionally guaranteed right to health. However, this important effort translates into a relevant financial burden for the National Health Service.

The advent of ultrasound-guided ablation techniques in nodular thyroid disease: towards a patient-tailored approach.

Surgery is the long-established therapeutic option for benign thyroid nodules, which steadily grow and become symptomatic. The cost of thyroid surgery, the risk of temporary or permanent complications, and the effect on quality of life, however, remain relevant concerns. Therefore, various minimally invasive treatments, directed towards office-based management of symptomatic nodules, without requiring general anaesthesia, and with negligible damage to the skin and cervical tissues, have been proposed during the past two decades. Today, ultrasound-guided percutaneous ethanol injection and thermal ablation with laser or radiofrequency have been thoroughly evaluated, and are accessible procedures in specialized centres. In clinical practice, relapsing thyroid cysts are effectively managed with percutaneous ethanol injection treatment, which should be considered therapy of choice. In solid non-functioning thyroid nodules that grow or become symptomatic, trained operators may safely induce, with a single session of laser ablation treatment or radiofrequency ablation, a 50% volume decrease and, in parallel, improve local symptoms. In contrast, hyperfunctioning nodules remain best treated with radioactive iodine, which results in a better control of hyperthyroidism, also in the long-term, and fewer side-effects. Currently, minimally invasive treatment is also investigated for achieving local control of small size neck recurrences of papillary thyroid carcinoma in patients who are poor candidates for repeat cervical lymph node dissection. This particular use should still be considered experimental.

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.

Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features.

The aim of the study was to correlate the sonographic [ultrasound (US)] and color-Doppler (CFD) findings with the results of US-guided fine needle aspiration biopsy (FNA) and of pathologic staging of resected carcinomas to establish: 1) the relative importance of US features as risk factors of malignancy; and 2) a cost-effective management of nonpalpable thyroid nodules. Four hundred ninety-four consecutive patients with nonpalpable thyroid nodules (8-15 mm) were evaluated by US, CFD, and US-FNA. Ninety-two patients with inadequate cytology were excluded from the study. All patients with suspicious or malignant cytology underwent surgery, whereas subjects with benign cytology had clinical and US control 6 months later. Thyroid malignancies were observed in 18 of 195 (9.2%) solitary thyroid nodules and in 13 of 207 (6.3%) multinodular goiters. Cancer prevalence was similar in nodules greater or smaller than 10 mm (9.1 vs. 7.0%). Extracapsular growth (pT(4)) was present in 35.5%, and nodal involvement in 19.4% of neoplastic lesions, with no significant differences between tumors greater or smaller than 10 mm. At US cancers presented a solid hypoechoic appearance in 87% of cases, irregular or blurred margins in 77.4%, an intranodular vascular pattern in 74.2%, and microcalcifications in 29.0%. Irregular margins (RR 16.83), intranodular vascular spots (RR 14.29), and microcalcifications (RR 4.97) were independent risk factors of malignancy. FNA performed on hypoechoic nodules with at least one risk factor was able to identify 87% of the cancers at the expence of cytological evaluation of 38.4% of nonpalpable lesions. The majority of nonpalpable thyroid tumors can be identified by cytological evaluation of lesions presenting hypoechoic appearance in conjunction with one independent risk factor. Due to the nonnegligible prevalence of extracapsular growth and nodal metastasis, US-FNA should be performed on all 8-15 mm hypoechoic nodules with irregular margins, intranodular vascular spots or microcalcifications. Nonpalpable lesions of the thyroid without risk factors should be followed by means of clinical and US evaluation.