Predicting risk of malignancy in patients with indeterminate thyroid nodules

Thyroid cancer is the most prevalent endocrine cancer (1). The prevalence of palpable thyroid nodules in the general adult population is 4% to 7% (2). Ultrasound imaging detects thyroid nodules in 19%-68% of randomly selected individuals (3). The rate of thyroid cancer in nodules found on US is 4% to 15% (4). In order to evaluate thyroid nodules patients undergo thyroid ultrasonography and, if needed, a fine-needle aspiration biopsy. Of all fine-needle aspiration biopsies, 15-30% are indeterminate on cytology (5). While only 3% of these nodules are malignant on average, a much higher percentage of nodules are surgically removed in order to rule out malignancy after indeterminate FNA results. Our goal is to identify clinical and ultrasound predictors of benign results in indeterminate nodules, to assist physicians in selecting nodules for surgical removal versus monitoring with ultrasound imaging. Between October 2010 and November 2017 there were 129 patients with 134 thyroid nodules from Temple University Hospital, Jeanes Hospital, and Fox Chase Cancer Center who had a total or partial thyroidectomy after a cytology report of at least one AUS or FLUS thyroid nodule. These patients were evaluated for age, sex, BMI, TSH, fT4, tT3, nodule size, and ultrasonography features to determine if any features were predictive of a benign or malignant thyroid nodule. Additionally, we looked at whether any of these features were more likely to occur in an AUS nodule or a FLUS nodule. We found that none of the demographic factors, thyroid function tests, or ultrasound features were good predictors of malignancy in AUS or FLUS thyroid nodules. We found that AUS nodules are more likely to be malignant than FLUS nodules, and this held true when we accounted for age, sex, smoking history, and BMI. We concluded that demographic factors and thyroid function tests are unable to predict increased risk of malignancy in Bethesda category III nodules, AUS nodules are more likely to be malignant that FLUS nodules, and nodules with at least one suspicious ultrasound feature are more likely to be AUS nodules than FLUS nodules due to AUS nodules having nuclear atypia and FLUS nodules having architectural atypia

Acoustic radiation force impulse imaging for differentiation of thyroid nodules

Background: Acoustic Radiation Force Impulse (ARFI)-imaging is an ultrasound-based elastography method enabling quantitative measurement of tissue stiffness. The aim of the present study was to evaluate sensitivity and specificity of ARFI-imaging for differentiation of thyroid nodules and to compare it to the well evaluated qualitative real-time elastography (RTE). Methods: ARFI-imaging involves the mechanical excitation of tissue using acoustic pulses to generate localized displacements resulting in shear-wave propagation which is tracked using correlation-based methods and recorded in m/s. Inclusion criteria were: nodules $5 mm, and cytological/histological assessment. All patients received conventional ultrasound, real-time elastography (RTE) and ARFI-imaging. Results: One-hundred-fifty-eight nodules in 138 patients were available for analysis. One-hundred-thirty-seven nodules were benign on cytology/histology, and twenty-one nodules were malignant. The median velocity of ARFI-imaging in the healthy thyroid tissue, as well as in benign and malignant thyroid nodules was 1.76 m/s, 1.90 m/s, and 2.69 m/s, respectively. While no significant difference in median velocity was found between healthy thyroid tissue and benign thyroid nodules, a significant difference was found between malignant thyroid nodules on the one hand and healthy thyroid tissue (p = 0.0019) or benign thyroid nodules (p = 0.0039) on the other hand. No significant difference of diagnostic accuracy for the diagnosis of malignant thyroid nodules was found between RTE and ARFI-imaging (0.74 vs. 0.69, p = 0.54). The combination of RTE with ARFI did not improve diagnostic accuracy. Conclusions: ARFI can be used as an additional tool in the diagnostic work up of thyroid nodules with high negative predictive value and comparable results to RTE

Is thyroid nodule location associated with malignancy risk?

PURPOSE: Nodules located in the upper pole of the thyroid may carry a greater risk for malignancy than those in the lower pole. We conducted a study to analyze the risk of malignancy of nodules depending on location. METHODS: The records of patients undergoing thyroid-nodule fine-needle aspiration cytology (FNAC) at an academic thyroid cancer unit were prospectively collected. The nodules were considered benign in cases of a benign histology or cytology report, and malignant in cases of malignant histology. Pathological findings were analyzed based on the anatomical location of the nodules, which were also scored according to five ultrasonographic classification systems. RESULTS: Between November 1, 2015 and May 30, 2018, 832 nodules underwent FNAC, of which 557 had a definitive diagnosis. The prevalence of malignancy was not significantly different in the isthmus, right, or left lobe. Among the 227 nodules that had a precise longitudinal location noted (from 219 patients [155 females], aged 56.2±14.0 years), malignancy was more frequent in the middle lobe (13.2%; odds ratio [OR], 9.74; 95% confidence interval [CI], 1.95 to 48.59). This figure was confirmed in multivariate analyses that took into account nodule composition and the Thyroid Imaging, Reporting, and Data System (TIRADS) classification. Using the American College of Radiologists TIRADS, the upper pole location also demonstrated a slightly significant association with malignancy (OR, 6.92; 95% CI, 1.02 to 46.90; P=0.047). CONCLUSION: The risk of thyroid malignancy was found to be significantly higher for mid-lobar nodules. This observation was confirmed when suspicious ultrasonographic features were included in a multivariate model, suggesting that the longitudinal location in the lobe may be a risk factor independently of ultrasonographic appearance

CORRELATION OF FINE NEEDLE ASPIRATION AND FINAL HISTOPATHOLOGY IN THYROID DISEASE: A SERIES OF 702 PATIENTS MANAGED IN AN ENDOCRINE SURGICAL UNIT

Thyroid nodules are a common clinical entity found among the adult general population. With increasing use of imaging investigations like ultrasonography, there has been a significant rise in the detection of non-palpable thyroid nodules that require further evaluation and management. The routine use of FNAC has reduced the number of unnecessary surgical procedures for thyroid nodules. Taking a decision as to whether to operate on a thyroid nodule is dependent on accurate FNAC testing. This study describes the experience with FNAC in a consecutive series of patients with thyroid nodules who underwent thyroidectomy at a tertiary care hospital in the department of endocrine surgery. 

Thyroid ultrasonography reporting: consensus of Italian Thyroid Association (AIT), Italian Society of Endocrinology (SIE), Italian Society of Ultrasonography in Medicine and Biology (SIUMB) and Ultrasound Chapter of Italian Society of Medical Radiology (SIRM)

Thyroid ultrasonography (US) is the gold standard for thyroid imaging and its widespread use is due to an optimal spatial resolution for superficial anatomic structures, a low cost and the lack of health risks. Thyroid US is a pivotal tool for the diagnosis and follow-up of autoimmune thyroid diseases, for assessing nodule size and echostructure and defining the risk of malignancy in thyroid nodules. The main limitation of US is the poor reproducibility, due to the variable experience of the operators and the different performance and settings of the equipments. Aim of this consensus statement is to standardize the report of thyroid US through the definition of common minimum requirements and a correct terminology. US patterns of autoimmune thyroid diseases are defined. US signs of malignancy in thyroid nodules are classified and scored in each nodule. We also propose a simplified nodule risk stratification, based on the predictive value of each US sign, classified and scored according to the strength of association with malignancy, but also to the estimated reproducibility among different operators

Frequency and significance of Ras, Tert promoter, and Braf mutations in cytologically indeterminate thyroid nodules: A monocentric case series at a tertiary-level Endocrinology unit

PurposeThe management of thyroid nodules of indeterminate cytology is controversial. Our study aimed to establish the frequency and significance of H-,K-,N-RAS, TERT promoter, and BRAF gene mutations in thyroid nodes of indeterminate cytology and to assess their potential usefulness in clinical practice.MethodsH-,K-,N-RAS, TERT promoter and BRAF gene mutations were examined in a series of 199 consecutive nodes of indeterminate cytology referred for surgical excision.Results69/199 (35%) were malignant on histopathological review. RAS mutations were detected in 36/199 (18%), and 19/36 cases (53%) were malignant on histological diagnosis. TERT promoter mutations were detected in 7/199 (4%) nodules, which were all malignant lesions. BRAF mutations were detected in 15/199 (8%), and a BRAF K601E mutation was identified in 2 follicular adenomas and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Altogether, this panel was able to identify 48% of the malignant lesions, achieving a specificity, positive predictive value, and negative predictive value for malignancy of 85, 62, and 75%, respectively.ConclusionThe residual malignancy risk in mutation-negative nodes is 25%. These nodes still need to be resected, but mutation analysis could help to orient the appropriate surgical strategy

Follicular nodules (Thy3) of the thyroid: is total thyroidectomy the best option?

BACKGROUND: Identification of the best management strategy for nodules with Thy3 cytology presents particular problems for clinicians. This study investigates the ability of clinical, cytological and sonographic data to predict malignancy in indeterminate nodules with the scope of determining the need for total thyroidectomy in these patients. METHODS: The study population consisted of 249 cases presenting indeterminate nodules (Thy3): 198 females (79.5%) and 51 males (20.5%) with a mean age of 52.43 ± 13.68 years. All patients underwent total thyroidectomy. RESULTS: Malignancy was diagnosed in 87/249 patients (34.9%); thyroiditis co-existed in 119/249 cases (47.79%) and was associated with cancer in 40 cases (40/87; 45.98%). Of the sonographic characteristics, only echogenicity and the presence of irregular margins were identified as being statistically significant predictors of malignancy. 52/162 benign lesions (32.1%) and 54/87 malignant were hypoechoic (62.07%); irregular margins were present in 13/162 benign lesions (8.02%), and in 60/87 malignant lesions (68.97%). None of the clinical or cytological features, on the other hand, including age, gender, nodule size, the presence of microcalcifications or type 3 vascularization, were significantly associated with malignancy. CONCLUSIONS: The rate of malignancy in cytologically indeterminate lesions was high in the present study sample compared to other reported rates, and in a significant number of cases Hashimoto’s thyroiditis was also detected. Thus, considering the fact that clinical and cytological features were found to be inaccurate predictors of malignancy, it is our opinion that surgery should always be recommended. Moreover, total thyroidectomy is advisable, being the most suitable procedure in cases of multiple lesions, hyperplastic nodular goiter, or thyroiditis; the high incidence of malignancy and the unreliability of intraoperative frozen section examination also support this preference for total over hemi-thyroidectomy

Interobserver agreement of Thyroid Imaging Reporting and Data System (TIRADS) and strain elastography for the assessment of thyroid nodules

Background: Thyroid Imaging Reporting and Data System (TIRADS) was developed to improve patient management and cost-effectiveness by avoiding unnecessary fine needle aspiration biopsy (FNAB) in patients with thyroid nodules. However, its clinical use is still very limited. Strain elastography (SE) enables the determination of tissue elasticity and has shown promising results for the differentiation of thyroid nodules. Methods: The aim of the present study was to evaluate the interobserver agreement (IA) of TIRADS developed by Horvath et al. and SE. Three blinded observers independently scored stored images of TIRADS and SE in 114 thyroid nodules (114 patients). Cytology and/or histology was available for all benign (n = 99) and histology for all malignant nodules (n = 15). Results: The IA between the 3 observers was only fair for TIRADS categories 2–5 (Coheńs kappa = 0.27,p = 0.000001) and TIRADS categories 2/3 versus 4/5 (ck = 0.25,p = 0.0020). The IA was substantial for SE scores 1–4 (ck = 0.66,p<0.000001) and very good for SE scores 1/2 versus 3/4 (ck = 0.81,p<0.000001). 92–100% of patients with TIRADS-2 had benign lesions, while 28–42% with TIRADS-5 had malignant cytology/histology. The negative-predictive-value (NPV) was 92–100% for TIRADS using TIRADS-categories 4&5 and 96–98% for SE using score ES-3&4 for the diagnosis of malignancy, respectively. However, only 11–42% of nodules were in TIRADS-categories 2&3, as compared to 58–60% with ES-1&2. Conclusions: IA of TIRADS developed by Horvath et al. is only fair. TIRADS and SE have high NPV for excluding malignancy in the diagnostic work-up of thyroid nodules

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

Analysis of tissue surrounding thyroid nodules by ultrasound digital images

Since US is not easily reproducible, the digital image analysis (IA) has been proposed so that the image evaluation is not subjective. In fact, IA meets the criteria of objectivity, accurateness, and reproducibility by a matrix of pixels whose value is displayed in a gray level. This study aims at evaluating via IA the tissue surrounding a thyroid nodule (backyard tissue, BT) from goitres with benign (b-BT) and malignant (m-BT) lesions. Sixty-nine US images of thyroid nodules surrounded by adequate thyroid tissue was classified as normoechoic and homogeneous were enrolled as study group. Forty-three US images from normal thyroid (NT) glands were included as controls. Digital images of 800 × 652 pixels were acquired at a resolution of eight bits with a 256 gray levels depth. By one-way ANOVA, the 43 NT glands were not statistically different (P = 0.91). Mean gray level of normal glands was significantly higher than b-BT (P = 0.026), and m-BT (P = 0.0001), while no difference was found between b-BT and m-BT (P = 0.321). NT tissue boundary external to the nodule was found at 6.0 ± 0.5 mm in cancers and 4.0 ± 0.5 mm in benignancies (P = 0.001). These data should indicate that the tissue surrounding a thyroid nodule may be damaged even when assessed as normal by US. This is of interest to investigate the extranodular effects of thyroid tumors