Suspicious Ultrasound Features Research Articles

Malignancy Risk Stratification in Thyroid Nodules with Benign Results on Cytology: Combination of Thyroid Imaging Reporting and Data System and Bethesda System

The indications of repeat fine-needle aspiration (FNA) for thyroid nodules with benign results of the Bethesda system were investigated. A total of 1,398 nodules were classified according to the Thyroid Imaging Reporting and Data System (TIRADS). TIRADS category 3 included nodules without solidity, hypoechogenicity or marked hypoechogenicity, microlobulated or irregular margins, microcalcifications, and taller-than-wide shape on ultrasonography (US). Categories 4a, 4b, 4c, and 5 included nodules with one, two, three or four, or five suspicious US features, respectively. The malignancy risks, and odds ratio (OR) with 95% confidence interval (CI) were calculated. Analyses were performed for all nodules, nodules >10mm, and nodules ≤10mm. Of 1.398 nodules, 43 (3.1%) were malignanct. The malignancy risks of benign nodules with categories 3, 4a, and 4b were 0.7, 1.2, and 0.7%, respectively, whereas those for nodules with categories 4c and 5 were 9.8 and 22.2%, respectively. The ORs of nodules with categories 4c and 5 were 19.4 (95% CI 5.0-76.2) and 50.6 (95% CI 10.4-245.0), respectively. In nodules >10mm, the malignancy risks of categories 4c and 5 were 2.7 and 20%, respectively, and the ORs were 10.7 (95% CI 1.2-93.7) and 236.1 (95% CI 12.6-4426.4), respectively. In nodules≤10 mm, the malignancy risks of categories 4c and 5 were 12.6 and 22.6%, respectively, and the ORs were 10.1 (95% CI 1.3-78.0) and 18.9 (95% CI 2.1-168.9), respectively. Repeat US-guided FNA should be considered in benign thyroid nodules with three or more suspicious US features regardless of size.

Predictive Factors of Malignancy in Thyroid Nodules with Repeatedly Nondiagnostic Cytology (Bethesda Category I): Value of Ultrasonography

One possible result of fine-needle aspiration (FNA) of thyroid nodules is "nondiagnostic" cytology. Consensus exists in these cases to repeat FNA guided by ultrasonography (US), but the result obtained may continue to be nondiagnostic. The objective of this study was to evaluate predictive factors of malignancy (including US) in nodules with indication for FNA whose cytology result was classified as "nondiagnostic" on 2 occasions. The sample consisted of 158 patients with thyroid nodules >5 mm with indication for FNA whose material obtained by US-guided FNA was classified as nondiagnostic on 2 occasions according to the criteria of the Bethesda classification. Papillary thyroid carcinoma (PTC) was confirmed by histology in 23/158 cases (14.5%). Sex, age, family history of PTC, palpation, number of nodules, serum TSH, or circulating antithyroperoxidase antibodies were not predictors of malignancy. Only US predicted risk of malignancy. US showed a sensitivity of 65.2% and a specificity of 90.4%. When US indicated the nodule to be "suspicious for malignancy", histology confirmed PTC in 15/28 cases (positive predictive value 53.4%). When the nodule showed no suspicious US features, histology detected malignancy in only 8/130 cases (negative predictive value 94%). The diagnostic accuracy of the US was 89.5%. The present results suggest that, in cases of patients with thyroid nodules and repeatedly nondiagnostic cytology, ultrasonographic findings represent an excellent parameter for the selection of those who could be followed up by periodic US and those who should be referred for thyroidectomy because of the risk of malignancy.

In Reply to: Fine Needle Aspiration

Dear Editor, In reply to the Letter to the Editor by Prof. Wiwanitki (1) concerning my recent study, we stated that “FNA is a useful atraumatic diagnostic technique with a high diagnostic accuracy which can provide a highly sensitive diagnosis with low false positive diagnoses in patients with nonthyroidal masses” (2). The author stated that FNA has 10.4% false negative results according to a recent study by Wharry et al.; however, this study was performed on thyroidal neck masses, while our study was conducted on nonthyroidal neck masses (3). As we demonstrated in Table 4 of the referred paper, we can see that the sensitivity and specificity of Fine Needle Aspiration (FNA) to diagnosis neck masses is high enough to consider it during the diagnostic process. Moreover, as we mentioned in our paper, the diagnostic properties of FNA depend on the properties of the mass. In masses suspicious for malignancy (such as larger masses, rapidly enlarged masses, masses in patients with history of malignancy or radiation, etc.) the cytology results and the FNA specimens should be more carefully interpreted (2). Also, as a limitation of our study we explained that pathologist experience can affect the cytology results. At our medical center, as a referral center in Iran, there is a group of pathologists who interpret the cytology results (4). There are two interesting comments that merit mentioning; the first is the rate of complications. Although many studies such as a review by Wu and Burstein declared that “FNA is used as one of the most cost-effective, complication-free, and rapid techniques for preoperative investigation of tumors and tumor-like conditions” (5, 6). Secondly, the role of radiologic modalities such as ultrasonography (US) in this paper is less discussed. Almost all studies conducted on the diagnostic accuracy of FNA, confirmed the role of Ultrasounds Imaging (US) to prepare a more useful specimen. Krishnappa et al. stated that “US-guided FNA provides a better representative sample and has a higher diagnostic rate in evaluation of thyroid lesions” (7). Also, some studies demonstrated that “the absence of suspicious US features did not reliably exclude malignancy”; others confirmed the usefulness of radiological properties to select a better site for FNA (8). For example, Moon et al. stated that “A taller-than-wide shape in either the transverse or longitudinal plane, was more accurate and sensitive in predicting thyroid malignancy” (9). Moreover, the size of the nodule is one of the most important US characteristics of a neck mass. There is a wide variety of size cut-off (between 1 to 4 cm) for neck masses suspicious for malignancy (3, 10). Moreover, US as a useful and safe radiologic modality can help find the largest, heterogeneous and more suspicious nodule for FNA.

Thyroid Nodules with Benign Findings at Cytologic Examination: Results of Long-term Follow-up with US

To investigate the natural history of thyroid nodules found to be benign at initial fine-needle aspiration biopsy (FNAB) to determine the percentage of nodules that increased in volume by more than 50% as being an indicator of malignancy. This retrospective observational cohort study was approved by the institutional review board, and the need to obtain informed consent was waived. The study included 854 FNAB-confirmed benign thyroid nodules. Suspicious ultrasonographic (US) features included marked hypoechogenicity, irregular or microlobulated margin, microcalcification, and taller-than-wide shape. Univariate and multivariate generalized linear mixed models were used to assess the association with nodule growth greater than 50% in volume. For the 854 nodules, the initial mean diameter was 19.92 mm (range, 3.10-60.00 mm), and the initial mean volume was 3.19 cm(3) (range, 0.01-4.64 cm(3)). The majority (682 [79.9%] of 854) of thyroid nodules with benign cytologic results at initial FNAB did not grow more than 50% in volume during 4 years of mean follow-up (range, 7-101 months). More than 4 years of follow-up time versus less than 2 years, younger age, a cystic component of less than 25%, and nodule size 1 cm or larger versus less than 1 cm were independently associated with growth. There was only one malignant nodule (0.6%) among 172 thyroid nodules with a volume increase of 50% or greater during the entire follow-up time. Ten malignant nodules (overall malignancy rate: 1.2%) were detected among the 854 total nodules, and eight of these 10 nodules showed suspicious features at US. Repeat FNAB for nodules showing more than 50% growth in volume is unlikely to result in a diagnosis of malignancy. A positive FNAB result for malignancy is significantly more likely in the presence of suspicious US features.

Imaging-cytology correlation of thyroid nodules with initially benign cytology.

Objective. To determine the role of imaging-cytology correlation in reducing false negative results of fine-needle aspiration (FNA) at thyroid nodules. Methods. This retrospective study included 667 nodules 1 cm or larger in 649 patients diagnosed as benign at initial cytologic evaluation and that underwent follow-up ultrasound (US) or FNA following a radiologist's opinion on concordance between imaging and cytologic results. We compared the risk of malignancy of nodules classified into subgroups according to the initial US features and imaging-cytology correlation. Results. Among included nodules, 11 nodules were proven to be malignant (1.6%) in follow-up FNA or surgery. The malignancy rate was higher in nodules with suspicious US features (11.4%) than in nodules without suspicious US features (0.5%, P < 0.001). When a thyroid nodule had discordant US findings on image review after having benign FNA results, malignancy rate increased to 23.3%, significantly higher than that of nodules with suspicious US features (P < 0.001). However, no significant difference was found in the risk of malignancy between the nodules without suspicious US features (0.5%) and imaging-cytology concordant nodules (0.6%, P = 0.438). Conclusions. Repeat FNA can be effectively limited to patients with cytologically benign thyroid nodules showing discordance in imaging-cytology correlation after initial biopsy, which reduces unnecessary repeat aspirations.

Benign Aspirates on Follow-Up FNA May Be Enough in Patients with Initial Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance

Background. Management of thyroid nodules with benign aspirates following atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is not well established. We reviewed the risk of malignancy and the role of ultrasound (US) features among thyroid nodules with benign results following initial AUS/FLUS diagnoses. Methods. From December 2009 to February 2011, a total of 114 nodules in 114 patients diagnosed as benign on follow-up fine-needle aspiration (FNA) after AUS/FLUS results were included in our study. Eight among 114 nodules were confirmed pathologically and 106 were clinically observed by a follow-up FNA or US. Suspicious US features were defined as markedly hypoechogenicity, irregular or microlobulated margin, presence of microcalcifications, and taller than wide shape. Results. There were 110 (96.5%) benign nodules and 4 (3.5%) malignant nodules. Two (4.8%) among 42 nodules without suspicious US features and 2 (2.8%) out of 72 nodules with suspicious US features were confirmed as malignancy, but there were no significant associations between the malignancy rate and US features (P = 0.625). Conclusion. Clinical follow-up instead of surgical excision or continuous repeat FNA may be enough for benign thyroid nodules after AUS/FLUS. The role of US features might be insignificant in the management of these nodules.

Better understanding in the differentiation of thyroid follicular adenoma, follicular carcinoma, and follicular variant of papillary carcinoma: a retrospective study.

Background. To evaluate the role of ultrasonography (US), US-guided fine-needle aspiration (USFNA) and intraoperative frozen section (FS) in follicular neoplasm. Methods. US features, USFNA cytology, and FS results were compared based on the pathology results of patients with follicular adenoma (FA), follicular carcinoma (FC), and follicular variant of papillary thyroid carcinoma (FVPTC). Results. FC and FVPTC showed significantly higher rates of suspicious US features (P < 0.05) and positive findings on either US or cytology, 80.0% and 90.7%, compared to FA, 64.5% (P = 0.001). Intraoperative FS showed higher malignant rates in FVPTC and FC (81.8% and 75.0%, resp.), compared to FA (3.8%, P < 0.001). Conclusion. Suspicious US features were more significantly seen in FC and FVPTC compared to FA. Intraoperative FS is useful in the differential diagnosis of these lesions and supplements cytology results of USFNA.

Ultrasound features of medullary thyroid carcinoma correlate with cancer aggressiveness: a retrospective multicenter study

Poor prognosis of medullary thyroid cancer (MTC) with suspicious ultrasound (US) features has been reported. The aim of the study was to investigate the association between preoperative US presentation and aggressiveness features of MTC. Also, US features of MTC were compared with those previously reported. Study group comprised 134 MTC from nine different centers. Based on US presentation the nodules were stratified in “at risk for malignancy” (m-MTC) or “probably benign” (b-MTC) lesions. Eighty nine (66.4%) m-MTC and 45 (33.6%) b-MTC were found. Metastatic lymph nodes (p = 0.0001) and extrathyroid invasiveness (p < 0.0001) were more frequent in m-MTC. There was statistically significant correlation (p = 0.0002) between advanced TNM stage and m-MTC with an Odds Ratio 5.5 (95% CI 2.1–14.4). Mean postsurgical calcitonin values were 224 – 64 pg/ml in m-MTC and 51 – 21 in b-MTC (p = 0.003). This study showed that sonographically suspicious MTC is frequently associated with features of aggressiveness, suggesting that careful preoperative US of MTC patients may better plan their surgical approach.

Elastographic presentation of synchronous renal cell carcinoma metastasis to the thyroid gland

Synchronous metastasis of renal cell carcinoma (RCC) are extremely uncommon with only few sporadic cases published in the literature and data on their elastographic appearance are lacking. Here we described a case of woman with multinodular goiter bearing a RCC metastasis, in which exhaustive ultrasonographic and qualitative elastographic evaluation were performed. The metastatic lesion presented some suspicious ultrasonographic features but was mainly "soft" at qualitative elastographic evaluation, suggesting that RCC metastasis may represent a possible pitfall for the qualitative elastographic evaluation of thyroid nodules.

Application of the Thyroid Imaging Reporting and Data System in thyroid ultrasonography interpretation by less experienced physicians.

Purpose:To verify the usefulness of the Thyroid Imaging Reporting and Data System (TI-RADS) for thyroid nodule diagnosis by less experienced physicians.Methods:From March 2012 to May 2012, ultrasonography-guided fine needle aspiration was performed in 204 thyroid nodules in 195 consecutive patients by four less experienced radiologists (<1 year in thyroid imaging). The number of suspicious ultrasonography features and the total risk score of each thyroid nodule were calculated according to the previous two models suggested by Kwak et al. The Delong method was used to compare the areas under the curve (AUCs) of the two models. Associations between the two models and the risk of malignancy were analyzed using penalized B-splines and the Cochran-Armitage trend test.Results:Among 204 thyroid nodules, 65 were malignant and 139 were benign. The probability of malignancy tended to increase as the number of suspicious ultrasonography features, and the sum of risk scores increased. There was no significant difference in the AUCs of the two models (P=0.673). The Cochran-Armitage trend test demonstrated an increased risk of malignancy as the number of suspicious ultrasonography features and the total risk score increased (P=0.001).Conclusion:Both the number of suspicious ultrasonography features and the total risk score are applicable and show comparable results in the risk stratification of thyroid nodules by less experienced radiologists in thyroid imaging.

Outcome of Thyroid Nodules Characterized as Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance and Correlation With Ultrasound Features and BRAFV600E Mutation Analysis

We aimed to establish the malignancy rate of thyroid nodules initially characterized as atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) and whether they differ according to histologic subcategory. We also investigated the value of ultrasound features that predict malignancy and BRAF(V600E) mutation analysis and suggest strategies for the management of AUS/FLUS nodules. A total of 165 AUS/FLUS nodules were investigated. There are nine histologic subcategories of AUS/FLUS nodules. We compared the risk of malignancy in thyroid nodules according to the histologic subcategory using ultrasound findings and of those exhibiting the BRAF(V600E) mutation. The malignancy rate of nodules with an initial diagnosis of AUS/FLUS was 55.2% (91/165). The malignancy rates by histologic subcategory were 0% in groups 1 (0/2), 2 (0/3), 4 (0/3), 7 (0/3), and 8 (0/1); 76.5% (13/17) in group 3; 83.1% (59/71) in group 5; and 29.2% (19/65) in group 9. The malignancy rate of nodules with suspicious ultrasound features was 79.3% (73/92), and the malignancy rate of nodules with indeterminate ultrasound features was 24.7% (18/73). AUS/FLUS nodules exhibiting taller-than-wide shape, illdefined margins, and microcalcifications or macrocalcifications showed significantly higher odds ratios. The likelihood of BRAF(V600E) mutation-positive nodules showing malignancy was 97.5% (39/40), whereas 39.7% (25/63) of BRAF(V600E) mutation-negative nodules were malignant (p < 0.05). The malignancy rate of AUS/FLUS nodules in our study cohort was higher than previously reported. Nodules with suspicious features on ultrasound had a higher malignancy rate than did those with indeterminate features on ultrasound. The malignancy rate differed according to histologic subcategory; therefore, management of AUS/FLUS nodules should be tailored according to histologic subcategory.

Imaging features of complex sclerosing lesions of the breast.

Purpose:The purpose of this study was to evaluate the imaging features of complex sclerosing lesions of the breast and to assess the rate of upgrade to breast cancer.Methods:From March 2008 to May 2012, seven lesions were confirmed as complex sclerosing lesions by ultrasonography-guided core needle biopsy. Final results by either surgical excision or follow-up imaging studies were reviewed to assess the rate of upgrade to breast cancer. Two radiologists retrospectively analyzed the imaging findings according to the Breast Imaging Reporting and Data System classification. Results:Five lesions underwent subsequent surgical excision and two of them revealed ductal carcinoma in situ (n=1) and invasive ductal carcinoma (n=1). Our study showed a breast cancer upgrade rate of 28.6% (2 of 7 lesions). Two lesions were stable on imaging follow-up beyond 1 year. The mammographic features included masses (n=4, 57.1%), architectural distortion (n=2, 28.6%), and focal asymmetry (n=1, 14.3%). Common B-mode ultrasonographic features were irregular shape (n=6, 85.7%), spiculated margin (n=5, 71.4 %), and hypoechogenicity (n=7, 100%). The final assessment categories were category 4 (n=6, 85.7%) and category 5 (n=1, 14.3%).Conclusion:The complex sclerosing lesions were commonly mass-like on mammography and showed the suspicious ultrasonographic features of category 4. Due to a high underestimation rate, all complex sclerosing lesions by core needle biopsy should be excised.

Thyroid Nodules (≥4 cm): Can Ultrasound and Cytology Reliably Exclude Cancer?

Whether a threshold nodule size should prompt diagnostic thyroidectomy remains controversial. We examined a consecutive series of patients who all had thyroidectomy for a≥4cm nodule to determine (1) the incidence of thyroid cancer (TC) and (2) if malignant nodules could accurately be diagnosed preoperatively by ultrasound (US), fine needle aspiration biopsy (FNAB) cytology and molecular testing. As a prospective management strategy, 361 patients with 382 nodules≥4cm by preoperative US had thyroidectomy from 1/07 to 3/12. The incidence of a clinically significant TC within the≥4cm nodule was 22% (83/382 nodules). The presence of suspicious US features did not discriminate malignant from benign nodules. Moreover, in 86 nodules≥4cm with no suspicious US features, the risk of TC within the nodule was 20%. US-guided FNAB was performed for 290 nodules, and the risk of malignancy increased stepwise from 10.4% for cytologically benign nodules, 29.6% for cytologically indeterminate nodules and 100% for malignant FNAB results. Molecular testing was positive in 9.3% (10/107) of tested FNAB specimens, and all ten were histologic TC. In a large consecutive series in which all≥4cm nodules had histology and were systematically evaluated by preoperative US and US-guided FNAB, the incidence of TC within the nodule was 22%. The false negative rate of benign cytology was 10.4%, and the absence of suspicious US features did not reliably exclude malignancy. At minimum, thyroid lobectomy should be strongly considered for all nodules≥4cm.

Diagnostic Accuracy of the Ultrasonographic Features for Subcentimeter Thyroid Nodules Suggested by the Revised American Thyroid Association Guidelines

Recommendations for subcentimeter thyroid nodules that need fine-needle aspiration biopsy are renewed in the revised American Thyroid Association (ATA) guidelines published in 2009. We applied these recommendations to analyze the diagnostic performance of the ATA guidelines and compared it to that of other modified guidelines. We evaluated 1054 nodules with sizes of 6-10 mm in 991 patients. A total of 713 nodules were included in the study population by excluding nodules with insufficient results for deciding whether they had a benign or malignant cytology. Frequencies of ultrasonographic features in benign and malignant nodules were compared, and odds ratios of suspicious ultrasonographic features were obtained with univariate and multivariate analysis. Seven modified guidelines were made based on the revised ATA guidelines and from multivariate analysis results. Diagnostic performances of the guidelines were compared by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiver operating characteristic curve (Az) value. In addition to hypoechogenicity, infiltrative margin, microcalcification, and taller-than-wide shape that were suggested by the ATA guidelines, solid composition and macrocalcification were significantly associated with malignancy on multivariate analysis (p=0.001 and 0.003, respectively). Increased vascularity, however, was not significantly associated with malignant nodules (odds ratio 0.729, p=0.212). Among the eight guidelines, the ATA guidelines showed the lowest diagnostic performance (Az=0.616). Excluding increased vascularity and including solid composition with or without macrocalcification to the suspicious ultrasonographic features of the ATA guidelines improved sensitivity (96.6% vs. 97.0%), specificity (26.6% vs. 42.9%), PPV (48.3% vs. 54.7%), and NPV (91.7% vs. 95.2%), thereby resulting in the highest Az value (Az=0.699, p<0.001). This study suggests that excluding increased vascularity and adding solid composition to the suspicious ultrasonographic features of the ATA guidelines would significantly improve the diagnostic performance in subcentimeter nodules for the identification of malignant lesions.

Optimal indication of thyroglobulin measurement in fine-needle aspiration for detecting lateral metastatic lymph nodes in patients with papillary thyroid carcinoma

The purpose of this study was to evaluate optimal indication of thyroglobulin (Tg) measurement in fine-needle aspiration (FNA) for detecting lateral metastatic lymph nodes in patients with papillary thyroid carcinoma (PTC). We performed a retrospective study of 241 lymph nodes of 220 patients who underwent ultrasound-guided FNA with Tg in FNA (FNA-Tg) washout fluid measurements for suspicious lymph nodes. On multivariate analysis, hyperechogenicity, cystic change, presence of calcifications, and peripheral vascularity were independent factors predictive of lymph node metastasis. After adding FNA-Tg, sensitivity and accuracy were significantly increased when the lymph node had 1 or 2 suspicious ultrasound features. However, sensitivity and accuracy were not significantly increased when the lymph node had multiple suspicious ultrasound features. Additional FNA-Tg can help diagnose a metastatic lymph node with 1 or 2 suspicious ultrasound features. However, additional FNA-Tg is not beneficial in lymph nodes with highly suspicious ultrasound features, in which FNA alone is sufficient for diagnosis of predictive of lymph node.

Optimized Cutoff Value and Indication for Washout Thyroglobulin Level According to Ultrasound Findings in Patients with Well-Differentiated Thyroid Cancer

Washout thyroglobulin provides evidence for metastatic or recurrent lesions, However, the cutoff value is still controversial. We investigated an optimized cutoff value and indication for the use of washout thyroglobulin from fine-needle aspiration in neck lymph nodes from preoperative or postoperative patients with well-differentiated thyroid cancers. A total of 177 lymph nodes from 161 patients underwent sonographically guided fine-needle aspiration cytology and washout thyroglobulin measurement and then underwent surgery and clinical follow-up. We assessed an optimized cutoff value of washout thyroglobulin for diagnosing metastasis and compared its diagnostic performance with that of washout thyroglobulin > 10 ng/mL, the currently accepted cutoff value. We also analyzed diagnostic performances of fine-needle aspiration cytology alone and of the combination of fine-needle aspiration cytology and washout thyroglobulin on the basis of the presence or absence of suspicious ultrasonographic findings. Of the 177 lymph nodes, 77 were metastases and 100 were benign. An optimized cutoff value for washout thyroglobulin was 1.8 ng/mL. The sensitivity and negative predictive value in diagnosing metastasis improved significantly with a cutoff value of 1.8 ng/mL compared with a cutoff value of 10 ng/mL (P = .0412 for sensitivity, P = .0188 for negative predictive value). In patients with suspicious ultrasonographic findings, applying washout thyroglobulin along with fine-needle aspiration cytology significantly enhanced the sensitivity and negative predictive value of fine-needle aspiration cytology performances to 100% and 100%, respectively (P = .0051, and P = .0088). There was no difference in diagnostic performance between fine-needle aspiration cytology and the combination of the 2 methods in patients without suspicious ultrasonographic findings. Applying the optimized cutoff value of washout thyroglobulin of 1.8 ng/mL in patients with suspicious ultrasonographic features facilitates the diagnostic evaluation of neck lymph nodes in both preoperative and postoperative patients with well-differentiated thyroid cancer.

Proper Indication of BRAFV600E Mutation Testing in Fine-Needle Aspirates of Thyroid Nodules

BackgroundThe aim of this study was to evaluate the proper indication of adjunctive BRAFV600E mutation analysis at the time of ultrasound-guided fine-needle aspiration in the diagnosis of thyroid nodules.MethodsThis study included 518 nodules in 479 patients who underwent ultrasound-guided fine-needle aspiration with BRAFV600E mutation. We calculated and compared the diagnostic performances of cytology and cytology with BRAFV600E mutation analysis to detect malignancy among thyroid nodules according to ultrasound features and size.ResultsSensitivity, negative predictive value, and accuracy of cytology with BRAFV600E mutation analysis were significantly higher than those of cytology alone in thyroid nodules with suspicious ultrasound features, regardless of size. Diagnostic performances did not show significant differences between cytology and cytology with BRAFV600E mutation analysis in nodules without any suspicious ultrasound features, regardless of size.ConclusionThe BRAFV600E mutation analysis was a useful adjunctive diagnostic tool in the diagnosis of thyroid nodules with suspicious ultrasound features regardless of size.

RASMutations in Thyroid FNA Specimens Are Highly Predictive of Predominantly Low-Risk Follicular-Pattern Cancers

RAS mutations are common in thyroid tumors and confer a high risk of cancer when detected in fine-needle aspiration (FNA) specimens. Specific characteristics of RAS-positive thyroid cancers are not well described. From April 2007 to April 2009, 921 consecutive patients undergoing FNA were evaluated prospectively with a panel of molecular markers. Ultrasonographic, cytological, histological, and surgical outcomes were retrospectively assessed. Sixty-eight aspirates from 66 patients were positive for RAS mutations including 63 cytologically indeterminate (93%), 3 malignant (4%), and 2 benign (3%) specimens. Cancer was histologically confirmed in 52 of 63 aspirates (83%) including the following: 46 papillary thyroid cancers, 4 follicular thyroid cancers, 1 medullary cancer, and 1 anaplastic cancer. All 46 RAS-positive papillary thyroid cancers, including 1 metastatic cancer, had follicular variant histology papillary thyroid cancer; only 11 tumors demonstrated vascular/capsular invasion and 4 had infiltrative growth. Of 48 patients with differentiated thyroid cancer, lymph node metastasis was uncommon and bilateral cancer was present in 48%. Only 33% of malignant nodules were suspicious by preoperative ultrasonography. At a mean follow-up of 22 months, 31 of 35 differentiated thyroid cancer patients (89%) have no evidence of recurrence, 4 patients (9%) have detectable thyroglobulin, 1 patient has bone metastases, and both patients with medullary and anaplastic cancer have died. Most RAS-positive thyroid cancers have indeterminate cytology, lack suspicious ultrasound features, and are histologically low-grade follicular variant histology papillary thyroid cancer. Lymph node and distant metastases are uncommon but bilateral disease is frequent. Total thyroidectomy should be considered for initial surgical management of most patients with RAS-positive FNA results. The role of prophylactic lymphadenectomy remains unclear.

Response: Natural Course of Cytologically Benign Thyroid Nodules: Observation of Ultrasonographic Changes (Endocrinol Metab 2013;28:110-8, Dong Jun Lim et al.)

We have read Dr. Cho's letter regarding our article on the observation of ultrasonographic (US) changes in cytologically benign thyroid nodules [1] and are happy to respond to it. We see many patients with benign nodules in daily clinical practice both before and after initial confirmation of benign cytology by fine needle aspiration (FNA), and usually follow-up with US. The most notable point is that, the more effort we invest in finding thyroid cancer in nodules, the more benign nodules were left behind in our clinics afterwards. One time benign cytologic results by FNA cannot be considered to safely eliminate the possibility of malignancy because false negativity is an inherent characteristic of FNA. Besides, it isn't clear whether or when we should perform repeat FNA on nodules with initially benign cytologic results. Therefore, a thorough understanding of the natural course of benign thyroid nodules is needed to establish an appropriate follow-up scheme. In this sense, our study showed US changes of benign nodules with suspicious features over a short-term period. Partially concordant with our results, one article by Kwak et al. [2] indicated that repeat FNA of thyroid nodules with initial benign cytology is valuable only in growing nodules with suspicious US features, not in completely benign-appearing nodules. A more recent paper suggested that long-term follow-up of patients with cytologically-confirmed benign nodules is asassociated with increased repeat FNA and US without improvement in the malignancy detection rate, discouraging unlimited follow-up of benign nodules [3]. Derived from the above viewpoints, follow-up procedures for nodules with suspicious US features should be different from benign-looking nodules without suspicious US features, whether this includes more US or repeat FNA. However, this kind of protocol should be validated first with a long-term, well-designed prospective study. Regarding the question of the age factor in our study raised by Dr Cho, the fact that younger age is associated with nodule growth in women may be more supported by the recent basic research of Xu et al. [4]. Our study used a more than 50% increase in nodule volume as a cut off, which varied from previous studies and might widen the differences of the effects of younger and older ages on nodule growth.

The risk of malignancy of the thyroid nodule/focal lesion – an assessment by ultrasound, based on our own scoring system

Ultrasonography (US) is the most commonly performed test used to visualize the thyroid. This examination is safe and readily available, hence it is very often carried out. Ultrasound observations allow the description of structural abnormalities of the thyroid gland evaluated in whole, or of nodules/focal lesions present in the thyroid. An ultrasound examination measures the acoustic density of tissues. The image is displayed on the apparatus screen in grayscale (B-mode). An assessment of blood flow, showing the location and intensity of thyroid vascularity is a newer US technique that uses the Doppler effect for measurements. In turn, elastography is the latest application of US, i.e. the examination which is based on the assessment of the, so-called, stiffness of lesions in comparison with the stiffness of normal thyroid tissue (i.e., the tissue of morphologically normal appearance). A common performance of US of the neck region, often carried out because of the indications that are not related to the thyroid gland (e.g., evaluation of salivary glands, assessment of blood flows in carotid and vertebral arteries) leads to the disclosure of a number of lesions detected incidentally in the thyroid gland itself. In turn, it results in the need for proper interpretation of US images in order to optimize further diagnostic and therapeutic procedures. Previous studies on the use of US to determine the nature of focal lesions/thyroid nodules in terms of their vs. character did not allowed to give a clear answer. These studies have not led to the general acceptance of cancer risk US patterns. Thus, at the present stage of knowledge, it is not possible to accept the categorical and definitive determination of the nature of lesions in terms of malignant vs. benign – on the basis of US image only. However, the studies have helped to determine the characteristics of a group of US image features, the presence of which is associated with a higher risk of cancer diagnosis. Endocrinologists diagnosing the patients with thyroid diseases are expecting to have exact guidelines and recommendations that would make easier to decide on the appropriate management. This applies in particular to answer the question: what is a greater risk to the patient - whether to undergo a surgical treatment, or abandon it? Analysis of data from the medical literature and our personal experience indicate the possibility of assigning certain patterns of US appearance to the risk of lesion malignancy. The multiplicity of possible combinations of co-occurrence of different US characteristics indicates that the most appropriate way of an objective assessment of the image is the introduction of an appropriate scoring system which reflects the accumulation of suspicious US features and the of US risk of malignancy expressed by a number of assigned points. This is precisely our issue that we have decided to propose; our scale divides the patterns of US image risk into 3 levels: high, intermediate and low risk. In our scoring system, the finding of pathologically altered lymph nodes (usually enlarged) and/or a confirmation of the fast growing lesions/thyroid nodules (augmentation) is equal to granting 3 points for each of these characteristics. Hypoechogenicity, the presence of microcalcifications, shape of lesion - close to the rotational ellipsoid with the longest axis of a vertical (shape of an egg in upright position), as well as the presence of abnormal vascular flows (the increased and chaotic blood flows centrally located in the lesion, or totally absent blood flows in hypoechogenic lesions) is equal to the grant 1 point for each of the features. The absence of a regular thin halo, solid structure (composition) of the lesion, the focus/nodule diameter of 3 cm and more and its uneven, blurred outlines (margins) are associated with granting 0.5 points for each of the features. The sum of granted points, resulting from the presence of US features specified above, is the basis of qualification for US risk levels. The score ranging from 0 to 4 points, awarded on the basis of thyroid US, speaks for a low risk of thyroid cancer, the score from 4 to 7 points – corresponds to intermediate risk, and the granting of 7 points or more qualifies to the group of US high-risk of malignancy. The use of this scoring system can help make the right clinical decisions, especially in patients with non-diagnostic smears (category I of The Bethesda System for Reporting Thyroid Cytopathology - TBSRTC), also in patients with the smears, in case of which it is impossible to determine the exact nature of the smear (category III TBSRTC, being also called category of exclusion), as well as in patients with lesions (category II TBSRTC) when such a cytological diagnosis seems unlikely in combination with the US image indicating a high risk of malignancy.