Thyroid Imaging Reporting and Data System Score Combined with the New Italian Classification for Thyroid Cytology Improves the Clinical Management of Indeterminate Nodules.

The new Italian cytological classification (2014) of thyroid nodules replaced the TIR3 category of the old classification (2007) with two subclasses, TIR3A and TIR3B, with the aim of reducing the rate of surgery for benign diseases. Moreover, thyroid imaging reporting and data system (TI-RADS) score appears to ameliorate the stratification of the malignancy risk. We evaluated whether the new Italian classification has improved diagnostic accuracy and whether its association with TI-RADS score could improve malignancy prediction. We retrospectively analyzed 70 nodules from 70 patients classified as TIR3 according to the old Italian classification who underwent surgery for histological diagnosis. Of these, 51 were available for cytological revision according to the new Italian cytological classification. Risk of malignancy was determined for TIR3A and TIR3B, TI-RADS score, and their combination. A different rate of malignancy (p = 0.0286) between TIR3A (13.04%) and TIR3B (44.44%) was observed. Also TI-RADS score is significantly (p = 0.003) associated with malignancy. By combining cytology and TI-RADS score, patients could be divided into three groups with low (8.3%), intermediate (21.4%), and high (80%) risk of malignancy. In conclusion, the new Italian cytological classification has an improved diagnostic accuracy. Interestingly, the combination of cytology and TI-RADS score offers a better stratification of the malignancy risk.

Grey-Scale Analysis Improves the Ultrasonographic Evaluation of Thyroid Nodules.

Ultrasonography is the main imaging method for the workup of thyroid nodules. However, interobserver agreement reported for echogenicity and echotexture is quite low. The aim of this study was to perform quantitative measurements of the degree of echogenicity and heterogeneity of thyroid nodules, to develop an objective and reproducible method to stratify these features to predict malignancy.A retrospective study of patients undergoing ultrasonography-guided fine-needle aspiration was performed in an University hospital thyroid center. From January 2010 to October 2012, 839 consecutive patients (908 nodules) underwent US-guided fine-needle aspiration. In a single ultrasound image, 3 regions of interest (ROIs) were drawn: the first including the nodule; the second including a portion of the adjacent thyroid parenchyma; the third, the strap muscle. Histogram analysis was performed, expressing the median, mean, and SD of the gray levels of the pixels comprising each region. Echogenicity was expressed as a ratio: the nodule/parenchyma, the nodule/muscle, and parenchyma/muscle median gray ratios were calculated. The heterogeneity index (HI) was calculated as the coefficient of variation of gray histogram for each of the 3 ROIs. Cytology and histology reports were recorded.Nodule/parenchyma median gray ratio was significantly lower (more hypoechoic) in nodules found to be malignant (0.45 vs 0.61; P = 0.002) and can be used as a continuous measure of hypoechogenicity (odds ratio [OR] 0.12; 95% confidence interval [CI] 0.03-0.49). Using a cutoff derived from ROC curve analysis (<0.46), it showed a substantial inter-rater agreement (k = 0.74), sensitivity of 56.7% (95% CI 37.4-74.5%), specificity of 72.0% (67.8-75.9%), positive likelihood ratio (LR) of 2.023 (1.434-2.852), and negative LR of 0.602 (0.398-0.910) in predicting malignancy (diagnostic odds ratio 3.36; 1.59-7.10). Parenchymal HI was associated with anti-thyroperoxidase positivity (OR 19.69; 3.69-105.23). The nodule HI was significantly higher in malignant nodules (0.73 vs 0.63; P = 0.03) and, if above the 0.60 cutoff, showed sensitivity of 76.7% (57.7-90.1%), specificity of 46.8% (42.3-51.4%), positive LR of 1.442 (1.164-1.786), and negative LR of 0.498 (0.259-0.960).Evaluation of nodule echogenicity and echotexture according to a numerical estimate (nodule/parenchyma median gray ratio and nodule HI) allows for an objective stratification of nodule echogenicity and internal structure.

Association of thyroid diseases with primary extra-thyroidal malignancies in women: results of a cross-sectional study of 6,386 patients.

We here analyzed the prevalence of extra-thyroidal malignancies (EM) in 6,386 female patients affected by different thyroid disease (TD). At first, an age-matched analysis of EM in all patients was performed. We then evaluated EM prevalence in four TD diagnostic categories: non-nodular TD (n = 2,159); solitary nodule (n = 905); multinodular TD (n = 2,871); differentiated thyroid cancers (n = 451). Finally, patients were grouped based on the absence (n = 3,820) or presence of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (TPOAb) (n = 2,369), or anti-Thyroid Stmulating Hormone (TSH) receptor autoantibodies (n = 197). A total of 673 EM were recorded. EM prevalence in TD patients was higher compared to the general population (Odds Ratio, OR 3.21) and the most frequent EM was breast cancer (OR 3.94), followed by colorectal (OR 2.18), melanoma (OR 6.71), hematological (OR 8.57), uterus (OR 2.52), kidney (OR 3.40) and ovary (OR 2.62) neoplasms. Age-matched analysis demonstrated that the risk of EM was maximal at age 0-44 yr (OR 11.28), remaining lower, but significantly higher that in the general population, in the 45-59 and 60-74 year age range. Breast and hematological malignancies showed an increased OR in all TD, while other cancers associated with specific TD. An increased OR for melanoma, breast and hematological malignancies was observed in both TPOAb and/or TgAb autoantibody negative and positive patients, while colorectal, uterus, kidney and ovary cancers showed an increased OR only in thyroid autoantibody negative patients. In conclusions, women affected by both benign and malignant TD, especially at a younger age and in absence of thyroid autoimmunity, have an increased risk of developing primary EM, thus requiring a careful follow-up and surveillance.

A comprehensive score to diagnose Hashimoto's thyroiditis: a proposal.

The heterogeneity of diagnostic criteria of Hashimoto's thyroiditis leads to overdiagnosis and prevents strong conclusions from being drawn in clinical studies. The aim of this study is to propose a comprehensive scoring system. A case-control study compared a set of presurgical features of patients with lymphocytic infiltration of the thyroid (Hashimoto's thyroiditis) and controls, in order to design a multi-criteria scoring system. Given a dichotomous outcome (lymphocytic infiltration of the thyroid), a set of covariates was analyzed in 180 patients after total thyroidectomy. A different validation cohort of 1,171 patients was reviewed and classified according to the score. Variables associated with the diagnosis of Hashimoto's thyroiditis were first assessed by univariate analysis. Analysis showed that TPOAb (area under the ROC curve (AUC), 0.67; 95 % CI 0.57-0.77) and TgAb (0.63; 95 % CI 0.54-0.74) were univariate predictors of the diagnosis of HT, which is largely recognized. Combined covariates were then tested using stepwise logistic regression analysis. The final regression model included TPOAb, TgAb, and thyroid vascularity (AUC 0.72; 95 % CI 0.62-0.81). A scoring system was developed, which has a sensitivity of 45.5 % and a specificity of 89.0 %, with a cutoff of 1.7. The likelihood of incident hypothyroidism was higher (OR 2.30; p = 0.004) in the positive (≥1.7) score group. A scoring system has a better performance than any single predictor and is able to identify the subgroup of individuals at higher risk to develop subsequent hypothyroidism.

Thyroid autoimmunity and risk of malignancy in thyroid nodules submitted to fine-needle aspiration cytology.

BACKGROUND: Whether the risk of cancer is increased in patients with chronic autoimmune thyroiditis is a controversial issue. METHODS: Between May 2005 and October 2012, 3777 fine-needle aspiration cytologies (FNACs) were performed on 2562 patients. Serum FT4, thyroid-stimulating hormone (TSH), anti-thyroglobulin antibody (TgAb), and anti-thyroperoxidase antibody (TPOAb) were determined. RESULTS: Patients with suspicious cytology were younger and presented smaller maximum lesion diameter. In patients with TgAb positivity, suspicious cytology was detected more frequently (9.4%) than patients without TgAb (5.7%; p = .04). No significant difference was recorded between benign and suspicious cytology in the positive TPOAb rate. Risk factors for suspicious cytology were younger age (odds ratio [OR], 0.94), smaller maximum diameter (0.95), single lesion (1.85), microcalcifications (3.45), and TgAb (1.74). Mixed solid/fluid content resulted as being a protective factor (0.34). According to multivariate logistic regression analysis, age, mixed content, and microcalcification confirmed significance. CONCLUSION: Thyroid nodule malignancy in patients with Hashimoto thyroiditis is not more frequent than in patients without thyroiditis.

Prevalence of breast cancer in thyroid diseases: results of a cross-sectional study of 3,921 patients.

Results from national cancer registries reveal an association of thyroid cancers with extra-thyroidal malignancies. In this study, we evaluated the prevalence of breast cancer (BC) in women affected by both benign and malignant thyroid diseases (TD) in comparison to the general population. To this end, 3,921 female patients from central and southern regions of Italy were evaluated. Age-matched analysis of the prevalence of BC was carried out after dividing the patients into three diagnostic categories: (1) 1,149 patients with non-nodular TD; (2) 2350 patients with nodular TD; (3) 422 patients affected by differentiated thyroid cancers. Furthermore, the patients were grouped according to the absence (2,344 patients) or presence (1,453 patients) of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (TPOAb) or anti-TSH receptor auto-antibodies (124 patients). BC prevalence in TD patients as a whole was significantly higher compared to the general population, with an odds ratio (OR) of 3.33. Age-matched analysis showed that the risk of a BC in TD patients was higher in younger patients (age 0-44 years), with an OR of 15.24, which decreased with increasing age. Patients without thyroid auto-antibodies showed a higher OR for BC (p = 0.0005) than TD patients with TgAb and/or TPOAb. The results demonstrate that women affected by either benign or malignant thyroid disease have a significantly greater risk of BC, which is higher at a younger age. Furthermore, thyroid auto-antibodies appear to be protective against BC. These findings may contribute to the identification of common genetic and environmental factors underlying this disease association.

Intrinsic factors affecting adequacy of thyroid nodule fine-needle aspiration cytology.

OBJECTIVE: To evaluate intrinsic nodule features predictive of an inadequate report in fine-needle aspiration cytology (FNAC). DESIGN: Single-centre cross-sectional study. METHODS: Between May 2005 and April 2011, 3279 ultrasonography-assisted FNACs were carried out and features of nodules recorded prospectively. Univariate logistic regression analyses were performed to estimate the association between nondiagnostic cytology and variables such as age, gender, single nodule, maximum nodule diameter and estimated volume. RESULTS: Inadequate or nondiagnostic samples were reported in 1195 FNACs. All diameters were found to be predictors of nondiagnostic cytology; estimated nodule volume, on the other hand, was not. Nodules with a diameter <10 mm were more frequently nondiagnostic (OR 1.65, 95% CI 1.40-1.94, P < 0.001). Neither micro- nor macrocalcification increased the risk of inadequacy. On the contrary, mixed lesions were more frequently diagnostic (OR 0.68, 95% CI 0.85-0.80, P < 0.001). Solid nodule aspiration was performed more easily on isoechogenic nodules (OR 0.64, 95% CI 0.54-0.77, P < 0.001); the same procedure was more cumbersome on hypoechogenic lesions (OR 1.87, 95% CI 1.62-2.16, P < 0.001). Increased vascularization did not cause a significant increase in the nondiagnostic results. Blurred margins increased the inadequacy rate (OR 1.45, 95% CI 1.24-1.69, P < 0.001), while presence of a hypoechogenic halo decreased it (OR 0.67, 95% CI 0.54-0.82, P < 0.001). CONCLUSIONS: Some ultrasonographic features suggestive of malignancy may be predictive of inadequate cytology. Patients must be notified that the FNA report may be nondiagnostic and that this represents a limitation of the technique related to the structure of lesions.

In papillary thyroid carcinoma BRAFV600E is associated with increased expression of the urokinase plasminogen activator and its cognate receptor, but not with disease-free interval.

CONTEXT: It has been suggested that patients with papillary thyroid cancer (PTC) harbouring the BRAF(V600E) mutation have a worse prognosis. We showed in PTC that high levels of urokinase plasminogen activator (uPA) and its cognate receptor (uPAR) inversely correlate with disease-free interval (DFI). OBJECTIVES: To investigate the effects of BRAF(V600E) on the expression of uPA and uPAR and to evaluate the prognostic relevance of BRAF(V600E) alone or in combination with uPA and uPAR. DESIGN/SETTING/PATIENTS/INTERVENTION: The case study included 91 patients with PTC. All patients underwent thyroidectomy and radioiodine therapy. Follow-up was available for 75 patients. MAIN OUTCOME MEASURES: The BRAF(V600E) mutation was analysed by sequencing and mutant allele-specific PCR amplification; uPA and uPAR expression by quantitative RT-PCR. RESULTS: BRAF(V600E) was found in 44 of the 91 patients and associated with older age, but not with high-risk clinicopathological features. Urokinase PA and uPAR mRNA levels were higher in tumour tissues by 9·51 ± 1·30 and 4·64 ± 0·44 fold, respectively, compared to normal matched tissues, being significantly higher in BRAF(V600E) -positive patients. In vitro induction of BRAF(V600E) in PCCL3 cells caused a significant increase in both uPA and uPAR mRNAs. Higher levels of uPA and uPAR correlated with lymph node metastases, TNM stage and disease recurrences. Kaplan-Meier and multivariate analyses demonstrated that uPA and uPAR were associated with shorter DFI, while the BRAF(V600E) was not. CONCLUSION: In PTC, BRAF(V600E) induces uPA and uPAR expression. The latter, but not BRAF(V600E) , associates with advanced stages and shorter DFI. If confirmed in larger case studies, they may represent reliable prognostic markers for more accurate risk stratification and postoperative decision-making in patients with PTC.

Interpretation of serum calcitonin in patients with chronic autoimmune thyroiditis.

Calcitonin (CT) is an important clinical marker for the diagnosis and follow-up of medullary thyroid carcinoma, although it is not absolutely specific. Some authors have reported C-cell hyperplasia in a number of thyroid specimens affected by Hashimoto's thyroiditis. The association between thyroiditis and hypercalcitoninemia is still controversial because some authors have reported low CT levels. The aim of this study is to evaluate the basal CT values in patients with and without thyroid autoimmunity. From May 2005 to February 2010, 1073 patients underwent ultrasonography-guided fine-needle aspiration cytology at the Thyroid Center of Sapienza University of Rome, with evaluation of basal serum FT4, FT3, TSH, and antithyroid peroxidase (anti-TPO) antibodies as well as CT levels. Forty-one patients presented a basal CT level above the reference upper limit. The mean serum CT was significantly lower in women than in men (4.28 ± 6.63 vs 7.50 ± 25.50  pg/ml; P<0.01). Basal serum CT was not significantly higher in patients showing anti-TPO Ab positivity (4.71 ± 6.46 vs 4.84 ± 13.11  pg/ml; P>0.05). Importantly, the rate of 'suspicious' CT values (above the 10  pg/ml cutoff) was not significantly different between patients with or without thyroid autoimmunity (3.9 vs 3.0%). Patients with hypercalcitoninemia suffering from chronic autoimmune thyroiditis should undergo the same clinical evaluation procedure as patients do without thyroid autoimmunity.

Aurora kinases are expressed in medullary thyroid carcinoma (MTC) and their inhibition suppresses in vitro growth and tumorigenicity of the MTC derived cell line TT.

BACKGROUND: The Aurora kinase family members, Aurora-A, -B and -C, are involved in the regulation of mitosis, and alterations in their expression are associated with cell malignant transformation. To date no information on the expression of these proteins in medullary thyroid carcinoma (MTC) are available. We here investigated the expression of the Aurora kinases in human MTC tissues and their potential use as therapeutic targets. METHODS: The expression of the Aurora kinases in 26 MTC tissues at different TNM stages was analyzed at the mRNA level by quantitative RT-PCR. We then evaluated the effects of the Aurora kinase inhibitor MK-0457 on the MTC derived TT cell line proliferation, apoptosis, soft agar colony formation, cell cycle and ploidy. RESULTS: The results showed the absence of correlation between tumor tissue levels of any Aurora kinase and tumor stage indicating the lack of prognostic value for these proteins. Treatment with MK-0457 inhibited TT cell proliferation in a time- and dose-dependent manner with IC50 = 49.8 ± 6.6 nM, as well as Aurora kinases phosphorylation of substrates relevant to the mitotic progression. Time-lapse experiments demonstrated that MK-0457-treated cells entered mitosis but were unable to complete it. Cytofluorimetric analysis confirmed that MK-0457 induced accumulation of cells with ≥ 4N DNA content without inducing apoptosis. Finally, MK-0457 prevented the capability of the TT cells to form colonies in soft agar. CONCLUSIONS: We demonstrate that Aurora kinases inhibition hampered growth and tumorigenicity of TT cells, suggesting its potential therapeutic value for MTC treatment.