Ultrasound guidance improves the adequacy of our preoperative thyroid cytology but not its accuracy

AIMS: Our thyroid cytology audit results of 1990-1995 showed an unsatisfactory rate of 43.1% and prediction of neoplasia with a sensitivity of 86.8%. Increasingly, ultrasound scan (USS)-guided core sampling for cytology is proving a valuable tool instead of freehand fine needle aspiration (FNA) or following unsatisfactory freehand FNA. We present the results of freehand FNA and USS-guided core samples for cytology in two separate patient groups in our centre. METHODS: Patients who had a thyroid resection and preoperative thyroid cytology in our institution between 1996 and 2002 were included. The histological diagnoses were correlated with the preceding cytology results. RESULTS: A total of 450 FNAs were performed on 394 patients. Freehand FNAs were performed for 348 (77.3%) samples and USS-guided core for 102 (22.7%) samples; 121 (26.8%) were repeat aspirates performed on 45 patients. Using aspiration cytology (AC) grading, freehand FNA was cytologically inadequate (AC0 or AC1) in 34.8% cases whereas USS-guided core was inadequate in 17.6% cases (P = 0.001). Freehand FNA (AC3, AC4, AC5) predicted neoplasia with a sensitivity of 83.2%, specificity of 46.6%, accuracy of 63.0%, positive predictive value of 56.0% and negative predictive value of 77.1%. USS-guided core sample for cytology (AC3, AC4, AC5) predicted neoplasia with a sensitivity of 93.5%, specificity of 26.0%, accuracy of 51.9%, positive predictive value of 43.9% and negative predictive value of 86.7%. CONCLUSIONS: Although USS-guided core provides more satisfactory specimens than freehand FNA, in our centre it does not provide increased accuracy.     

Clinicopathologic analysis of fine needle aspiration cytology of the thyroid. A review of 1,613 cases and correlation with histopathologic diagnoses

OBJECTIVE: To evaluate the accuracy of fine needle aspiration (FNA) of thyroid lesions at our institution and to ascertain its usefulness in determining the therapeutic approach. STUDY DESIGN: The authors reviewed the results of 1,613 cases of FNA cytology of thyroid nodules performed from 1999 to 2001 at the Department of Pathology, Chonnam National University Hospital. Cytologic diagnoses were compared with histologic diagnoses in 207 cases that included both FNA and thyroid surgery. RESULTS: The sensitivity for the detection of neoplasms (carcinoma and follicular adenoma) was 78.4% and the specificity 98.2%. A false positive diagnosis was made in 1 case (1.8%) and false negative ones in 28 cases (21.5%). The diagnostic accuracy was 84.4%, with a positive predictive value of 99.0% and negative predictive value of 66.3%. The predictive value of a cytologic diagnosis was 100% in papillary carcinoma. CONCLUSION: FNA is a useful test in determining the therapeutic approach of thyroid lesions.     

Agreement Between American and European Thyroid Imaging,Reporting, and Data System (TIRADS) in the Diagnosis of 473 Thyroid Nodules From a Single Center in Brazil

ObjectiveTo compare 2 ultrasound-based risk stratification systems in malignancy risk assessment of thyroid nodules and the clinical applicability of these guidelines in Brazil.MethodsWe retrospectively reviewed the ultrasound findings of 314 patients (473 thyroid nodules) who underwent fine-needle aspiration (FNA) biopsy and/or surgery between February 2018 and March 2019. All nodules were classified using 2 systems: the Thyroid Imaging, Reporting, and Data System (TIRADS) of the American College of Radiology (ACR-TIRADS) and the TIRADS of the European Thyroid Association (EU-TIRADS). Both risk stratification systems were analyzed. We identified the diagnostic predictive values that yielded optimal sensitivity, specificity, positive predictive value, negative predictive value, and accuracy.ResultsOf the 473 nodules, all underwent FNA, and histopathology was performed for 332 nodules. The agreement between the ACR-TIRADS and EU-TIRADS results and that between cytology and histopathology findings was 92.6% (kappa = 0.84) and 86.7% (kappa = 0.73), respectively. The area under the curve for the ACR-TIRADS and EU-TIRADS was 0.871 and 0.828, respectively (P < .001). The EU-TIRADS had the best sensitivity and negative predictive value, whereas the ACR-TIRADS had the best specificity, positive predictive value, and accuracy. Of the 473 nodules studied, only 158 (33.4%) followed the FNA size criteria suggested by the ACR-TIRADS.ConclusionACR-TIRADS and EU-TIRADS had good diagnostic performances. However, most aspirated nodules did not follow the TIRADS indication; thus, the overuse of FNA as a diagnostic tool was observed.     

Is a five‐category reporting scheme for thyroid fine needle aspiration cytology accurate? Experience of over 18 000 FNAs reported at the same institution during 1998–2007

S. Piana, A. Frasoldati, M. Ferrari, R. Valcavi, E. Froio, V. Barbieri, C. Pedroni and G. Gardini Is a five‐category reporting scheme for thyroid fine needle aspiration cytology accurate? Experience of over 18 000 FNAs reported at the same institution during 1998–2007 Objective: Fine needle aspiration (FNA) has long been recognized as an essential technique for the evaluation of thyroid nodules. Although specific cytological patterns have been recognized, a wide variety of reporting schemes for thyroid FNA results have been adopted. This study reports our experience with a five‐category reporting scheme developed in‐house based on a numeric score and applied to a large series of consecutive thyroid FNAs. It focuses mainly on the accuracy of thyroid FNA as a preoperative test in a large subset of histologically distinct thyroid lesions. Methods: During the 1998–2007 period, 18 359 thyroid ultrasound‐guided FNAs were performed on 15 269 patients; FNA reports were classified according to a C1–C5 reporting scheme: non‐diagnostic (C1), benign (C2), indeterminate (C3), suspicious (C4), and malignant (C5). Results: Non‐diagnostic (C1) and indeterminate (C3) FNA results totalled 2 230 (12.1%) and 1 461 (7.9%), respectively, while suspicious (C4) and malignant (C5) results totalled 238 (1.3%) and 531 (2.9%), respectively. Histological results were available in 2 047 patients, with thyroid malignancy detected in 840. Positive predictive value of FNA was 98.1% with a 49.0 likelihood ratio (LR) of malignancy in patients with a C4/C5 FNA report. Conclusions: This five‐category scheme for thyroid FNA is accurate in discriminating between the virtual certainty of malignancy associated with C5, a high rate (92%) of malignancy associated with C4, and a 98% probability of a histological benign diagnosis associated with C2. Further sub‐classifications of C3 may improve the accuracy of the diagnostic scheme and may help in recognizing patients eligible for a ‘wait and see’ management.     

Ultrasound-guided fine needle aspiration cytology in the diagnosis and management of thyroid nodules

OBJECTIVE: To examine the accuracy of fine needle aspiration cytology (FNAC) in the diagnosis of thyroid nodules and compare the inadequacy rates for ultrasound-guided and freehand FNAC. METHODS: A retrospective study of 434 patients with thyroid nodules who underwent diagnostic FNAC over a 2-year period. Cytological diagnoses have been compared with the histological assessment of resection specimens in 69 cases. RESULTS: The inadequacy rate was significantly lower from ultrasound guided FNAC (24/373 cases, 6.4%) than from freehand FNAC (8/61 cases, 13.1%) (P = 0.043). Seventy-six percentage of patients had a non-neoplastic cytological diagnosis and, after multidisciplinary review, the patients were reassured and assigned to clinical follow-up. Sixty-seven patients had a resection for cytological appearances consistent with non-neoplastic disease (n = 34), suspicious of follicular neoplasia (n = 23), or suspicious of malignancy (n = 10), and two patients had resections following inadequate cytology with ultrasound appearances suspicious of a neoplasm. The overall accuracy of FNAC analysis for malignancy was 97.0%, with sensitivity 83.3%, specificity 98.0%, positive predictive value 71.4% and negative predictive value 98.4%. The overall accuracy of FNAC analysis for the prediction of neoplasia was 97.5%, with sensitivity 80.5%, specificity 97.8%, positive predictive value 89.2% and negative predictive value 95.9%. Difficulties in cytological diagnosis were associated with lymphoid infiltrates and with degenerative changes in follicular adenomas. CONCLUSION: Ultrasound-guided FNAC has a significantly lower yield of inadequate aspirates than palpable FNAC. The ability of FNAC to predict neoplasia in 89% patients and to exclude neoplasia in 95.9% patients makes an important contribution to the multidisciplinary assessment of patients.     

The role of thyroid fine needle aspiration (FNA) cytology in a district general hospital setting

The pilot study was undertaken to evaluate the role of FNA cytology in the clinical management of patients with thyroid swelling, in a District General Hospital (DGH) setting. One hundred and eleven patients were investigated over a period of 3 years, with a total of 142 fine needle aspirations. Statistical analysis showed a sensitivity of 71%, a specificity of 91% and a false negative rate of 2.7%. These results compare very favourably with other institutions. This study therefore shows that thyroid nodule FNA cytology can be performed in a DGH with a high standard of diagnostic accuracy, the results of which play a key role in patient management.     

Do all Thyroid Nodules >4 cm need to be Removed? An Evaluation of Thyroid Fine-Needle Aspiration Biopsy in Large Thyroid Nodules

Objective: Controversy exists regarding the ability of fine-needle aspiration (FNA) biopsy to rule out malignancy when thyroid nodules exceed 4 cm in diameter. The goal of this study was to provide data regarding FNA accuracy in a clinical setting for detecting/ruling out malignancy in large thyroid nodules (≥4 cm) and discuss FNA utility in guiding surgical decisions.Methods: All thyroid FNA cases performed at Marshfield Clinic from 1/1/2000 to 12/31/2010 followed by complete or partial thyroidectomy on nodules of at least 4 cm were identified. Demographics, medical history, nodule biopsy characteristics, surgical procedures, and diagnosis data were abstracted. FNA was compared to histologic evaluation of surgical specimens.Results: A total of 198 patients with large thyroid nodules were identified. Most had a single large nodule, but ~40% were multinodular, and 206 total nodules were assessed. Females outnumbered males, and the mean age was ~50 years. After surgery, cancer was histologically identified in 49/206 (23.8%) nodules, including 9/123 nodules that had been categorized as benign by FNA, corresponding to a false-negative rate of 7.3%. Sensitivity/specificity for detecting malignancy by FNA was ~80%. The positive predictive value (PPV) was just below 60%, and the negative predictive value (NPV) was 93% but rose to 96% when papillary microcarcinomas were excluded.Conclusion: While FNA sensitivity in large nodules was relatively low, NPV was high, especially if incidental papillary microcarcinomas were excluded. When cancer prevalence and NPV are known, FNA can be a reliable “rule out” test in nodules ≥4 cm. This information is critical and can help guide the surgery decision, especially in high-risk patients. The decision for surgery should not be solely based on nodule size but should consider additional factors including cancer prevalence, clinical history, ultrasound features, surgical risk, and life expectancy.Abbreviations:FNA = fine-needle aspirationNPV = negative predictive valuePPV = positive predictive value     

The role of liquid-based cytology in the investigation of thyroid lesions

Objective:  This study investigates the role of liquid-based cytology by ThinPrep^® technique in the detection of thyroid lesions.
Methods:  In all, 252 specimens from 157 patients for pre-operative evaluation of thyroid nodules, prepared by the ThinPrep^®, were examined. In all cases thyroidectomy followed the initial cytological evaluation. All cytological diagnoses were correlated to the histological ones.
Results:  According to our findings, a sensitivity of 87.80%, a specificity of 99.50%, a positive predictive value of 97.30%, a negative predictive value of 97.56% and an overall accuracy of 97.52% were observed in fine needle aspiration cytology in correlation to the histological diagnosis after thyroidectomy.
Conclusions:  ThinPrep^® technique is a valid method for the pre-operative cytological diagnosis of thyroid nodules, offering the possibility of ancillary techniques, such as immunocytochemical and molecular methods and can, therefore, be potentially complementary to histological evaluation for further investigation of follicular lesions.     

The Value of Gross Visual Assessment of Specimen Adequacy for Liquid-Based Cytology During Ultrasound-Guided,Fine-Needle Aspiration of Thyroid Nodules

Objective: Major problems of fine-needle aspiration (FNA) of thyroid nodules arise due to nondiagnostic results caused by inadequately obtained FNA specimens. The purpose of this study was to evaluate the value of visual assessment of liquid-based cytology specimens during FNA of thyroid nodules for predicting sampling adequacy.Methods: For 3 months, visual assessment of FNA specimens was used for 534 consecutive nodules in 534 patients. The FNA specimens were visually graded immediately following aspiration for each nodule, and the visual grades were classified into 2 categories: inadequate (<6 cell groups) and adequate (>6 cell groups). The cytology results were classified as diagnostic or nondiagnostic based on the Bethesda system. We compared the ultrasound features and FNA characteristics between the diagnostic and nondiagnostic results. Multiple logistic regression analysis was used to determine factors independently predictive of nondiagnostic results. We also evaluated the interobserver agreement regarding the visual assessment.Results: Visual assessment was feasible in all patients, and the nondiagnostic rate was 11.6% (62 of 534). Nondiagnostic results were more frequent in the inadequate visual assessment group (38.1%) than in the adequate visual assessment group (10.5%) (P = .001). Independent predictive factors for nondiagnostic results were inadequate visual assessment (odds ratio, 5.18), >50% vascularity (odds ratio, 3.98), and macrocalcification (odds ratio, 3.60). Interobserver agreement for the prediction of visual assessment was good (κ value, 0.767; P<.001).Conclusion: Immediate visual assessment of a specimen during FNA of a thyroid nodule is a feasible method for predicting sampling adequacy.Abbreviations: FNA = fine-needle aspiration LBC = liquid-based cytology US = ultrasound     

The role of FNA in the initial management of thyroid lesions: 7-year experience in a district general hospital

Fine needle aspiration (FNA) cytology plays a major role in the diagnosis of the thyroid lesions in university hospitals and tertiary referral institutions. Our aim was to find out if this was possible in small district hospitals with limited resources. Over a 7-year period, from October 1994 to April 2002, 303 patients with thyroid swellings underwent FNA with an overall adequacy rate of 97.7%. FNAs were performed specifically by the pathologists, so that our inadequacy rate, 2.3% was far lower than 11-29% reported elsewhere. The FNA findings were compared with subsequent histology results in 67 cases. The diagnosis of benign and neoplastic lesions was predicted accurately by FNA in 93% and 94.7% of cases, respectively. The latter reached 100% if results of FNA in follicular neoplasms were excluded. Sensitivity and specificity were 85.6% and 97.6%, respectively, which is comparable with results from tertiary institutions. The commonest thyroid lesions in our hospital were nodular goitre (52.4%), followed by thyroiditis (17.6%) and neoplasia (13.9%). We conclude that, with the availability of appropriate personnel, FNA is feasible as the major modality in district general hospitals. FNA in follicular lesions remains challenging but could be overcome in part by recognizing the criteria to differentiate follicular variant of papillary carcinoma and other follicular proliferations. Aspiration, smearing, staining and interpretation should be left to pathologists or other well-trained personnel to ensure good quality and consistency.     

Comparison of the Efficacy and Safety of the American Thyroid Association Guidelines and American College of Radiology TI-RADS

ObjectiveTo evaluate the 2015 American Thyroid Association (ATA) guidelines and 2017 American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TI-RADS) for their efficacy in predicting malignant thyroid nodules and safety in recommending fine needle aspiration (FNA).MethodsWe reviewed data of 970 thyroid nodules from 908 patients with core needle biopsy pathology. We calculated the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for each guideline to predict malignancies. We compared the areas under the curve and FNA recommendations between the 2 guidelines.ResultsAccording to the core needle biopsy pathology, 59.9% (581/970) of the thyroid nodules were malignant. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value was 68%, 91%, 33%, 67%, and 70%, respectively, for the ATA guidelines and 70%, 84%, 49%, 71%, and 68%, respectively, for the ACR TI-RADS. Areas under the curve (ATA: 0.71 vs ACR TI-RADS: 0.74; P = .054) were similar when predicting malignancies. For the 545 nodules with maximum diameter ≥1.0 cm, the ACR TI-RADS recommended FNA less often than the ATA guidelines (83.3% [454/545] vs 87.7% [478/545]; P = .01). For the 321 malignant nodules with maximum diameter ≥1.0 cm, the proportions of FNA recommendations were not significantly different (ACR TI-RADS: 90.7% [291/321] vs ATA: 92.5% [297/321]; P = .06).ConclusionThe 2015 ATA guidelines and 2017 ACR TI-RADS showed a similar ability in predicting malignancies. Reducing FNA recommendations by the ACR TI-RADS would not lead to a significant decrease in the FNA recommendations given for malignancies with maximum diameter ≥1.0 cm.     

The value of 99mTc-MIBI scan in the detection of malignancy potential of hypermetabolic thyroid incidentalomas of 18F-FDG PET/CT

Aim of the studyIncreasingly use of PET/CT leads to discovery of incidental findings. Hypermetabolic thyroid nodules are one of the unexpected lesions in PET/CT imaging with an increased risk of thyroid cancers. Our study aims to determine the malignant potential of incidentally detected 18F-FDG avid thyroid nodules by using Tc-99m MIBI imaging.Materials and methodsPET/CT scans were performed for nonthyroidal purposes and were evaluated for the presence of hypermetabolic thyroid nodules. Tc-99m MIBI scans and ultrasonography-guided fine needle aspiration biopsies were subsequently performed for all patients.ResultsPrimary thyroid malignancies were identified in 25% of patients with increased focal FDG uptake at definitive diagnosis. Among the patients with FDG avid thyroid nodules, Tc-99m MIBI scan showed true-positive results in all thyroid carcinomas (n:7) with a 36.3% (4/11) false-positivity rate. In three patients with indeterminate cytology results, Tc-99m MIBI scan findings were also negative. The sensitivity, specificity, positive predictive value of Tc-99m MIBI scan in predicting the malignancy of FDG-positive thyroid nodules were 100%, 77%, 63.6%, respectively.ConclusionThe implementation of ^99mTc-MIBI scan performed by dual phase and SPECT/CT modality might be a helpful cost-effective approach in addition to FNAB in patients with ¹⁸F-FDG-positive thyroid nodules and indeterminate cytology to improve the patients’ prognosis and reduce unnecessary thyroid operations with associated use of FNAB.     

Utility of Ultrasound Versus Gene Expression Classifier in Thyroid Nodules with Atypia of Undetermined Significance

Objective: Thyroid nodules with fine-needle aspiration (FNA) cytology categorized as atypia of undetermined significance (AUS) often undergo additional diagnostic analysis with the Afirma Gene Expression Classifier (GEC), which classifies these as either high probability of being benign (GEC-B) or suspicious for malignancy (GEC-S). Our goal was to assess the clinical validity and utility of GEC in the evaluation of AUS cytology and evaluate the performance of ultrasonography (USG) for predicting malignancy in this subset.Methods: We conducted a study with a retrospective cohort of patients from January 2012 to January 2014 who had FNA of thyroid nodules >1 cm in size with AUS cytology.Results: Cleveland Clinic Florida has an overall prevalence of AUS of 5%. A total of 119 cases with nodules >1 cm in size were reported as AUS. Forty-eight (40.3%) had a GEC performed after the first FNA (AUS-1), and 27 of these were GEC-S. Of those 27, 21 went for surgery and 14 (66.6%) had thyroid cancer on histopathology. The remaining 71 with AUS-1 were sent for a second FNA: 19 nodules were benign and did not undergo further evaluation, while the remaining 52 were reported as AUS for the second consecutive time (AUS-2). AUS-2 samples were sent for GEC. Of these 52 AUS-2, 38 (73.1%) were reported as GEC-S. Thirty-five went for surgery and 32 (91.4%) had confirmed malignancy on histopathology. Positive predictive value (PPV) was 91.4% for AUS-2 and 66.6% for AUS-1. Moreover, AUS-2 nodules that were hypoechoic and solid on USG showed a PPV of 92% for malignancy.Conclusion: In our practice, the diagnostic accuracy to predict malignancy with GEC for AUS-1 nodules was poor (PPV, 66.6%). The PPV of GEC testing was markedly higher at 91.4% performed after two consecutive AUS cytologies. AUS-2 nodules that were solid and hypoechoic on USG also had a high probability to be malignant (PPV, 92%). We recommend repeat FNA on AUS-1 nodules rather than proceeding directly to GEC testing. Also, we suggest that among AUS-2 nodules, surgery can be recommended when USG shows solid and hypoechoic features with GEC testing reserved for the remainder.Abbreviations:AUS = atypia of undetermined significanceFNA = fine-needle aspirationGEC = gene expression classifierGEC-B = GEC-benignGEC-S = GEC-suspicious for malignancyNPV = negative predictive valuePPV = positive predictive valueUSG = ultrasonography     

Can the American Thyroid Association,K-Tirads,and Acr-Tirads Ultrasound Classification Systems Be Used to Predict Malignancy in Bethesda Category IV Nodules?

Objective: Management of thyroid nodules with Bethesda category III and IV cytology on fine needle aspiration (FNA) is challenging as they cannot be adequately classified as benign or malignant. Ultrasound (US) patterns have demonstrated the utility in evaluating the risk of malignancy (ROM) of Bethesda category III nodules. This study aims to evaluate the value of 3 well-established US grading systems (American Thyroid Association &lsqb;ATA], Korean Thyroid Imaging Reporting and Data System &lsqb;Korean-TIRADS], and The American College of Radiology Thyroid Imaging Reporting and Data System &lsqb;ACR-TIRADS]) in determining ROM in Bethesda category IV nodules.Methods: Ninety-two patients with 92 surgically resected thyroid nodules who had Bethesda category IV cytology on FNA were identified. Nodule images were retrospectively graded using the 3 systems in a blinded manner. Associations between US risk category and malignant pathology for each system were analyzed.Results: Of the 92 nodules, 56 (61%) were benign and 36 (39%) were malignant. Forty-seven per cent of ATA high risk nodules, 53% of K-TIRADS category 5 nodules, and 50% of ACR-TIRADS category 5 nodules were malignant. The ATA high-risk category had 25% sensitivity, 82% specificity, 47% positive predictive value (PPV) for malignancy. K-TIRADS category 5 had 25% sensitivity, 85% specificity, 53% PPV for malignancy. ACR-TIRADS category 5 had 25% sensitivity, 84% specificity, 50% PPV for malignancy. None of the 3 grading systems yielded a statistically significant correlation between US risk category and the ROM (P = .30, .72, .28).Conclusion: The ATA, Korean-TIRADS, and ACR-TIRADS classification systems are not helpful in stratifying ROM in patients with Bethesda category IV nodules. Clinicians should be cautious of using ultra-sound alone when deciding between therapeutic options for patients with Bethesda category IV thyroid nodules.     

Thyroid Cytology and Risk of Thyroid Cancer: Differences Among Indeterminate Specimens

ObjectiveTo assess the potential for stratification of indeterminate cytologic findings on fine-needle aspiration (FNA) of thyroid nodules in an effort to improve therapeutic strategies.MethodsWe attempted to determine the malignant risk associated with various indeterminate FNA cytologic patterns by correlation of specimens with the final histologic diagnosis. For this analysis, we identified 294 computerized medical records of surgically treated thyroid nodules during a 5-year period at our institution with the corresponding FNA cytology reports available.ResultsOf the 294 surgical cases, 162 with a positive or indeterminate cytologic report were selected, reviewed, and classified. Of 52 patients with positive cytologic findings on FNA, 51 (98%) had a final histologic report of a malignant thyroid nodule. Of 110 patients with indeterminate specimens, 30 (27%) had a final histologic diagnosis of thyroid carcinoma. The presence of nuclear atypia was predictive of thyroid carcinoma in 75% of patients, a Hürthle cell cytologic pattern was associated with a malignant thyroid nodule in 33%, and a hypercellular smear was suggestive of malignant involvement in 26% of cases. The lowest rate of malignant potential was associated with cytologic microfollicular and scant colloid alone subtype (6%).ConclusionThe results of this study show that indeterminate thyroid cytologic specimens can be subdivided into groups with different malignant risks. A microfollicular cytologic pattern in the absence of a hypercellular smear or nuclear atypia does not support a recommendation of surgical treatment. A malignant cytologic diagnosis has a high positive predictive value for detection of thyroid cancer. (Endocr Pract. 2004;10:330-334)     

Beyond the suspicious thyroid fine needle aspirate. A review

Fine needle aspiration (FNA) is currently the best diagnostic tool for thyroid nodules. However, the cytologic category of indeterminate or suspicious lesion, which is found in 10-15% of cases, remains a challenge. Since neither clinical presentation nor intraoperative frozen section is often helpful in differentiating these lesions and since surgical procedures for benign and malignant lesions differ, there is a clear need to develop ancillary tests. In this review we identify 12 potential markers of thyroid malignancy that have been examined in thyroid cytologic samples. Although many of these markers hold promise as adjuncts to FNA cytology, multicenter studies have often shown limitations in the predictive value of these assays due to lack of specificity, sensitivity or both. The recent development, however, of tissue microarray techniques to validate promising new markers suggests that improvements in the approach to indeterminate thyroid FNA samples may soon be at hand. This review presents a summary of the issues facing the development of a clinically useful diagnostic test in the differential diagnosis of thyroid nodules.     

Focus: Personalized Medicine: Simultaneously Detection of 50 Mutations at 20 Sites in the BRAF and RAS Genes by Multiplexed Single-Nucleotide Primer Extension Assay Using Fine-Needle Aspirates of Thyroid Nodules

Fine-needle aspiration (FNA) is commonly used for primary evaluation of thyroid nodules. Twenty to 30 percent of thyroid nodules remain indeterminate after FNA evaluation. Studies show the BRAF p.V600E to be highly specific for papillary thyroid carcinoma (PTC), while RAS mutations carry up to 88 percent positive predictive value for malignancy. We developed a two-tube multiplexed PCR assay followed by single-nucleotide primer extension assay for simultaneous detection of 50 mutations in the BRAF (p.V600E, p.K601E/Q) and RAS genes (KRAS and NRAS codons 12, 13, 19, 61 and HRAS 61) using FNA smears of thyroid nodules. Forty-two FNAs and 27 paired formalin-fixed, paraffin-embedded (FFPE) tissues were tested. All BRAF p.V600E-positive FNA smears (five) carried a final diagnosis of PTC on resection. RAS mutations were found in benign as well as malignant lesions. Ninety-two percent concordance was observed between FNA and FFPE tissues. In conclusion, our assay is sensitive and reliable for simultaneous detection of multiple BRAF/RAS mutations in FNA smears of thyroid nodules.     

An alternate model of thyroid cytology: practical not perfect

A sample of 384 thyroid cytology specimens prepared by cytospin over a 2.5-year period was classified by original report into inadequate, non-neoplastic and suspicious of neoplasia or worse. This was then compared with subsequent histology. The resulting data showed an inadequacy rate of 33%, a sensitivity of 55%, a specificity of 59%, a positive predictive value of 64% and a negative predictive value of 93%. On review of the cytology, in knowledge of the subsequent histology, the maximum achievable results were determined to have a positive predictive value of 79% and a negative predictive value of 97%. No clinically significant adverse event was detected.     

Molecular testing of BRAF,RAS and TERT on thyroid FNAs with indeterminate cytology improves diagnostic accuracy

Objective

Liquid‐based (LB)‐FNA is widely recognized as a reliable diagnostic method to evaluate thyroid nodules. However, up to 30% of LB‐FNA remain indeterminate according to the Bethesda system. Use of molecular biomarkers has been recommended to improve its pathological accuracy but implementation of these tests in clinical practice may be difficult. Here, we evaluated feasibility and performance of molecular profiling in routine practice by testing LB‐FNA for BRAF, N/HRAS and TERT mutations.

Methods

We studied a large prospective cohort of 326 cases, including 61 atypia of undetermined significance, 124 follicular neoplasms, 72 suspicious for malignancy and 69 malignant cases. Diagnosis of malignancy was confirmed by histology on paired surgical specimen.

Results

Mutated LB‐FNAs were significantly associated with malignancy regardless of the cytological classification. Overall sensitivity was 60% and specificity 89%. Importantly, in atypia of undetermined significance and follicular neoplasm patients undergoing surgery according to the Bethesda guidelines, negative predictive values were 85.4% and 90% respectively. TERT promoter mutation was rare but very specific for malignancy (5.5%) suggesting that it could be of interest in patients with indeterminate cytology.

Conclusions

Mutation profiling can be successfully performed on thyroid LB‐FNA without any dedicated sample in a pathology laboratory. It is an easy way to improve diagnostic accuracy of routine LB‐FNA and may help to better select patients for surgery and to avoid unnecessary thyroidectomies.

     

Follow‐up of atypia and follicular lesions of undetermined significance in thyroid fine needle aspiration cytology

N. Dincer, S. Balci, A. Yazgan, G. Guney, R. Ersoy, B. Cakir and G. Guler
Follow‐up of atypia and follicular lesions of undetermined significance in thyroid fine needle aspiration cytology Objective: To report our experience of atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) rate and outcome. Methods: Among 7658 patients with 19 569 nodules, 524 (2.7%) nodules were diagnosed as AUS/FLUS on fine needle aspiration (FNA). After exclusion of patients with simultaneous nodules that were suspicious for follicular neoplasm or malignancy or that were malignant, 368 (4.8%) patients were diagnosed as AUS/FLUS. The outcome of 146 patients who had undergone surgery or repeated fine needle aspirate at the time of preparation of this study was evaluated. The original FNAs were matched to repeated FNAs and thyroidectomy or diagnostic lobectomy specimens. Results: Seventy‐two (19.6%) of the 368 patients had directly undergone surgery, either a lobectomy or a thyroidectomy: of these, 27 (37.5%) had neoplastic nodules (21 were malignant). Seventy‐four (20.1%) of the 368 patients had repeat FNA. On second FNA, 47 of 74 (63.5%) were benign, three were suspicious for follicular neoplasm, one was malignant and 23 (31.1%) were non‐diagnostic. Four patients had a third FNA: two were AUS/FLUS, one was malignant and one non‐diagnostic. One patient had a fourth FNA, which was diagnosed as AUS/FLUS. Sixteen (21.6%) of 74 patients with repeat FNA had surgery: three of these had neoplastic nodules (two were malignant). Overall, 88 of the 368 (23.9%) patients had a thyroidectomy of which 30 (34.1%) were neoplastic and 23 (26.1%) malignant. The neoplastic rate for patients who were once diagnosed with AUS/FLUS was 8.2% and the malignancy rate 6.3%. The malignancy rate for patients on follow‐up at the time we prepared the study was 15.7% (23/146); 222 remained on follow‐up without surgery or repeat FNA or were managed elsewhere. Conclusions: Although in this category repeat FNA is expected rather than excision, we suggest evaluation of all AUS/FLUS patients in multidisciplinary meetings to decide management and recommend follow‐up of all patients with this diagnosis.