Indeterminate Fine-needle Aspiration Research Articles

Practice of thyroid nodule management in the Gulf Cooperation Council countries.

Objectives:To assessed the current practices for the management of thyroid nodules in the Gulf Cooperation Council (GCC) Countries.Methods:We conducted a descriptive web-based survey to physicians and surgeons involved in the management of thyroid nodules. The survey included questions on referral, ultrasound (US) reporting, fine needle aspiration (FNA), management of thyroid nodules including the approach for indeterminate FNA results, and usage of molecular testing.Results:A total of 311 responders, 155 (49.8%) were endocrinologists. Results showed that referrals and US report lack a number of valuable information including family history (84.9%) and high-risk US features (92.9%). Approximately 263 (84.6%) preferred to include a scoring system or protocol to assess the nodule risk in US report. Approximately 193 (62.1%) sent the patient to interventional radiologists for FNA. Almost half (n=147, 47.3%) repeat the FNA in 2-3 months if the FNA result was a follicular lesion or atypia of undetermined significance and 142 (45.7%) opted for lobectomy for follicular neoplasm or suspicious of follicular neoplasm result. Only 44 (14.1%) performed molecular testing; however, 174 (55.9%) preferred it available. Significant variations in the approach were seen between endocrinologists versus non-endocrinologists.Conclusion:Practices variation in the management of thyroid nodules mandate a common practical guideline. Molecular testing is a preferable test for indeterminate FNA results by most of the responders though it is not widely available.

BRAF V600E as an accurate marker to complement fine needle aspiration (FNA) cytology in the guidance of thyroid surgery in the Chinese population: evidence from over 1000 consecutive FNAs with follow-up.

Currently, several commercial molecular tests have been developed for reclassifying thyroid nodules with indeterminate fine needle aspiration cytology. These tests are quite expensive and not available in China. Previous studies demonstrated a very high prevalence of the BRAF V600E mutation in Asian people. A high incidence may result in a robust sensitivity. We conducted this study to determine the prevalence of BRAF V600E mutation and its ability to reclassify cytologically indeterminate thyroid nodules in the Chinese population. Between January 2016 and October 2018, consecutive patients who underwent a fine needle aspiration procedure and agreed to provide materials for molecular analysis in our hospital were recruited in this study. All were followed up until they had a thyroidectomy and a final pathological diagnosis or until January 2019 (those did not have surgery). A total of 1960 patients were included in this study. Until January 2019, 1240 patients underwent surgery. Using histopathological diagnosis as a gold standard, the overall sensitivity and specificity of the BRAF V600E mutational analysis for the discrimination of benign nodules from cancer in thyroid fine needle aspiration samples were 83.3% (81.0-85.3%) and 96.0% (77.7-99.8%), respectively, with an area under the ROC curve of 0.90 (95% CI 0.85-0.95, P<0.001). Among cases with indeterminate cytology, BRAF-positive cases were showing malignancy in the final pathology, and BRAF-negative cases were showing safer to be followed up. The BRAF V600E mutation is highly prevalent in the Chinese population and can accurately complement cytopathology in the guidance of thyroid surgery.Mini-abstract: The BRAF V600E mutation has both high specificity and sensitivity to predict thyroid malignancy in the Chinese population. It can accurately complement cytopathology in the guidance of thyroid surgery.

Afirma Testing in Thyroid Nodules with Indeterminate Cytology: A single Medical Institute Experience

Abstract Introduction/Objective About 10 to 30% of thyroid fine needle aspiration (FNA) nodules have indeterminate cytology, including Bethesda III, IV, and V. Afirma Gene Expression Classifier (GEC) measuring the expression of 167 mRNA was designed to classify the indeterminate thyroid nodules into benign and suspicious categories. This study aimed to evaluate the clinical performance of the Afirma GEC testing in these indeterminate thyroid lesions. Methods Medical records of patients with indeterminate thyroid FNA results and corresponding Afirma GEC results from November 2012 to December 2019 were retrieved. Subsequent surgical follow-up results were obtained. GEC results were compared to the histologic diagnoses. Results 1. There were 77 cases with indeterminate thyroid FNA results. Cytology diagnosis included 67 Bethesda III and 10 Bethesda IV. Afirma GEC results were benign for 41 cases (53%), suspicious for 32 cases (42%), and non- diagnostic for 4 cases (5%). Twenty seven of 32 cases (84%) with suspicious GEC results had surgical follow-up which revealed 12 malignant and 15 benign histologic diagnoses. Only 11 of 41 cases (27%) with benign GEC results had surgery which showed 8 benign and 3 malignant diagnoses. Based on the data, the sensitivity of this test is 80% and specificity is 65%. Positive predictive value (PPV) is 44% and negative predictive value (NPV) is 73%. The false positive cases include 5 Hurthle cell adenoma, 4 nodular hyperplasia, 3 follicular adenoma, 2 Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFPT), and 1 lymphocytic thyroiditis. The false negative cases include 2 minimally invasive follicular carcinoma (from same patient) and 1 papillary thyroid carcinoma. Conclusion 1. We demonstrated in this study that a little more than half of the cases with indeterminate thyroid cytology had negative Afirma GEC results. 2.Afirma test has relatively low specificity (65%) and PPV (44%). The sensitivity (80%) and NPV (73%) is relatively higher but is lower than the values in most literature. This could be due to the fact that majority of the Afirma GEC negative cases in this study did not have surgical follow-up and the sample size is small. 3.Afirma GEC test is a relatively good “rule-out” molecular test for indeterminate thyroid nodules but is not a reliable “rule-in” test due to the low specificity and PPV.

What is Thy3a? A study of 336 Thy3a (AUS/FLUS) thyroid FNAs with histology compares UK RCPath with other reporting systems and shows how Thy3a subclassification can improve risk stratification and help address overuse of this category.

Thy3a (AUS/FLUS) is an indeterminate and heterogeneous category in thyroid cytology. Thy3a reporting rates vary widely, with many laboratories documenting overuse. Subclassification of Thy3a helps with risk stratification. We aimed to investigate whether subclassification can also help address Thy3a overuse. We compare the UK reporting system with other terminologies. An audit of thyroid fine needle aspirations (FNAs) reported at our institution between 2012 and 2017 was performed. Thy3a FNAs followed by histology were reviewed and subcategorised into four subgroups: Scanty Atypia (SA), Scanty Microfollicular (SMF), Favour Benign (FB) and Thyroiditis versus Neoplasm (TVN). Review and subclassification were blinded to histology outcomes. FNAs were correlated with histology and statistical analysis was performed. Our Thy3a rate was high (24% of all thyroid FNAs). For 336 Thy3a FNAs with histology, the malignancy rates of the four subgroups were: SA 68%, SMF 20%, FB 4%, TVN 31%. There were significant associations between subgroup and malignancy risk, and between subgroup and tumour risk. On histology, SA had more malignancies than expected and FB had fewer. SA and SMF had more tumours than expected and FB had fewer. SMF and Thy3f FNAs were similar in terms of tumour and malignancy outcomes. Subclassification of Thy3a FNAs into these four subgroups is recommended. This can improve risk stratification and help address overuse of Thy3a. We propose that some FB and SMF cases could be safely diverted to Thy2 and Thy3f respectively. We compare various reporting terminologies and question how indeterminate FNAs should be classified.

Quality of Life Following Molecular Marker Testing for Indeterminate Thyroid Nodules

Thyroid cancer has a disproportionately negative effect on the quality of life (QOL) compared to malignancies with a worse prognosis. The QOL of patients with indeterminate thyroid nodules has not been previously evaluated. We aimed to assess the impact of molecular test results on the QOL of patients with indeterminate thyroid nodules. A short version of the Thyroid-Related Patient-Reported Outcome (ThyPro-39) was used to assess the QOL of patients who underwent thyroid fine needle aspiration (FNA) biopsy throughout UCLA Health from May, 2016, to June, 2017. All patients with indeterminate biopsy results underwent molecular testing with either Afirma Gene Expression Classifier or ThyroSeq v2 at the time of the initial biopsy. The QOL associated with symptoms of goiter, anxiety, depression, and impaired daily life were analyzed. Of 825 consented patients, 366 completed the assessment (44.4% response rate). FNA results included 76% benign, 7% malignant, and 17% indeterminate. There were no differences in QOL between patients with a benign FNA and patients with an indeterminate result with benign molecular testing. In patients with an indeterminate FNA, symptoms of goiter (20.5 versus 10.4; P = .033) and depression (33.3 versus 21.0; P = .026) were worse for patients with suspicious versus benign molecular test results; however, no significant differences were observed in anxiety or impaired daily life. A benign molecular test result may provide reassurance for patients with indeterminate thyroid nodules that the risk of malignancy is low. Long-term follow-up is necessary to determine if benign molecular test results maintain improved QOL.

Thyroid cytology smear slides: An untapped resource for ThyroSeq testing.

Molecular testing of thyroid nodules with indeterminate fine-needle aspiration (FNA) cytology is commonly used to guide patient management and is typically performed on freshly collected FNA samples. In this study, the authors evaluated the performance of the ThyroSeq test in cytology smear slides. Air-dried Diff-Quik (DQ)-stained and alcohol-fixed Papanicolaou (Pap)-stained smears were used to determine required cellularity and sensitivity of mutation detection and to compare ThyroSeq v3 Genomic Classifier (GC) results obtained in cytology smears and fresh FNA samples from the same nodules. ThyroSeq testing of 31 cytology smears revealed that 25 smears (81%) were adequate for ThyroSeq analysis, including 14 Pap-stained smears (100%) and 11 DQ-stained smears (65%), whereas 6 DQ-stained smears (35%) failed RNA sequencing. The overall accuracy for detecting molecular alterations was 98%, with 100% concordance for mutations and gene expression alterations, 96% concordance for fusions, and 94% concordance for copy number alterations. Cytology smears were adequate for ThyroSeq analysis when at least 200 to 300 cells were present in 1 to 3 slides. ThyroSeq detected all studied mutations down to 5% allele frequency and BRAF mutations down to 1% allele frequency. Testing of smears yielded a positive ThyroSeq GC result in all nodules originally classified as positive. Thyroid FNA cytology smear slides with adequate cellularity can be successfully used for ThyroSeq GC testing in approximately 80% of cases, with an even higher success rate in Pap-stained smears. Compared with FNA samples collected into preservative solution, 94% to 100% of different genetic alterations could be accurately detected in smears, validating cytology smears as an alternative for ThyroSeq testing in patients with indeterminate thyroid cytology.

Interobserver variability between cytopathologists and cytotechnologists upon application and characterization of the indeterminate category in the Milan System for Reporting Salivary Gland Cytopathology.

The indeterminate categories in the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) are diagnostically challenging because of inherent heterogeneity and complexity, with wide interobserver variability (IOV). Herein, the authors explore the concordance rate (CR) between cytopathologists (CPs) and cytotechnologists (CTs) in interpreting indeterminate salivary gland lesions using the MSRSGC. Between 2011 and 2016, 86 indeterminate fine-needle aspirations had slides available for review, of which 48 had follow-up. Four CPs and 2 CTs performed an independent, blinded review of these slides and categorized them according to the MSRSGC. The CRs between CTs and CPs with the final sign-out cytopathologist (FCP) were assessed, and interobserver agreement was categorized into uniform, majority, divided, minimal, or no agreement. The overall CR with the FCP ranged from 48.8% to 60.5% for CPs and from 22.1% to 36% for CTs. IOV κ scores for the entire group were 0.314 and, with the FCP as the reference, ranged from 0.403 to 0.539 for CPs and from 0.091 to 0.254 for CTs. Uniform, majority, divided, minimal, and no agreement was noted in 12.8%, 31.4%, 38.4%, 10.5%, and 6.9%, respectively, of all cases and in 16.7%, 35.4%, 31.3%, 8.3%, and 6.3%, respectively, of the cases with follow-up. Diagnostic challenges included distinguishing lymphoma from a reactive process and distinguishing mucin from mucin-like material. CPs had modestly higher CRs compared with CTs; and, although the variable CRs highlight indeterminate IOV, the MSRSGC enables reproducibility. Characterizing larger cohorts in the indeterminate categories will further improve MSRSGC criteria. Moreover, education on the MSRSGC should include CTs and CPs to improve overall diagnostic accuracy.

Molecular Markers in the Diagnosis of Thyroid Cancer in Indeterminate Thyroid Nodules.

The Bethesda System for the Reporting of Thyroid Cytology recognises six diagnostic categories of thyroid nodule cytology with an incremental risk of malignancy. Although the Bethesda system created a much-needed handhold by standardising the cytological diagnosis and management of thyroid nodules worldwide, the system does not provide a clear answer to the heterogeneous group of nodules with indeterminate cytology. Improvement in the assessment of indeterminate fine-needle aspiration (FNA) results with molecular testing allows better risk stratification and reduces the need for diagnostic thyroid surgery. The molecular markers are classified as a "rule out" test, which has a high negative predictive value and helpful in cases with a low pre-test probability of cancer to rule out thyroid cancer. The "rule in" test has a high positive predictive value and helps in confirming malignancy in those with a high pre-test probability of cancer. This review summarises the commonly used molecular studies in thyroid FNAC aspirates and their current role in clinical practice.

MON-511 Are Thyroid Nodule Fine Needle Aspiration Washings an Acceptable Alternative to Dedicated Fine Needle Aspirates When Obtaining Tissue Samples for Genetic Expression Classifier Analysis?

The Bethesda System for Reporting Thyroid Cytopathology stratifies thyroid nodules by risk associations. Approximately 15-30% of fine needle aspirations (FNA) fall into an indeterminate criteria, and two thirds are found to be surgically benign leading to unnecessary surgeries (1). Veracyte Inc. developed the Afirma gene expression classifier (GEC) to identify whether an indeterminate nodule had benign expression, with a NPV of 95% for AUS/FLUS (Atypia of undetermined significance/ follicular lesion of undetermined significance) nodules making it an excellent way to rule out malignancy (2). The goal of testing for thyroid cytology includes avoiding unnecessary surgery in benign nodules and identifying high risk from low risk lesions. The Afirma validation landmark study aided in the commercial approval for use in clinical practice after showing a 95.1% sample sufficiency when 2 dedicated samples were obtained in addition to the 3-5 FNA samples for cytology, but our institutional practice habits may suggest other techniques may be valid as well (2). We aimed to assess the rate of sufficient sample for GEC based on FNA washings at our institution, without using dedicated FNA for GEC. Data was gathered from all indeterminate nodule FNA washings referred for Afirma GEC from January 2015 through December 2017. Samples were determined on Afirma report as benign, suspicious, or insufficient and rate of insufficiency was determined. 95 indeterminate nodule FNA washings were sent for Afirma GEC. 93 (97.9%) samples were sufficient for RNA, with 47 (49.5%) reported as suspicious and 46 (48.4%) reported as benign, 2 (2.1%) samples were insufficient for RNA. 97.9% of our samples were sufficient when using FNA washings alone. Our experience suggests that the technique used at our clinical practice is an acceptable alternative to using an additional 2 passes for dedicated samples in collecting RNA for Afirma GEC. This method decreases need for call back for a second biopsy, is less time consuming, and potentially more cost effective. Limitations in our study are a small sample size limited to a single institution, differing number of FNA washings per total passes among practitioners, and variability of experience between providers. In conclusion thyroid nodule FNA washings are an acceptable alternative to dedicated FNA when obtaining tissue samples for genetic expression classifier analysis. Further studies with a larger sample size across different institutions are necessary.1.Prathima S, Thyroid Research and Practice, January-April 2016; Vol 13: Issue 1; p 9-14Yang SE et al, Cancer Cytopathology, February 2016, p 100-1092. Alexander EK. Kennedy GC. Baloch ZW.et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367(8):705–715.

MON-LB79 Do Ultrasound Patterns and Clinical Parameters Modify the Probability of Thyroid Cancer Predicted by Molecular Testing in Thyroid Nodules With Indeterminate Cytology?

Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further modify the risk of cancer in nodules predicted to be positive or negative by molecular testing remains unknown. Aim: To test if clinical parameters, including age, gender, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] system vs American College of Radiology TIRADS), radiation exposure, and family history of thyroid cancer (TC) can modify the probability of TC or NIFTP predicted by MT in thyroid nodules with indeterminate cytology. Methods: We studied 257 thyroid nodules from 10 study centers with fine-needle aspiration (FNA) yielding indeterminate cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression were used for data analysis. Results: In this group of thyroid nodules, out of all parameters studied using univariate regression, patient gender, age, and Bethesda category were significantly associated with TC/NIFTP probability (P<0.05 for each). The ATA US patterns showed a positive trend (P=0.1211), whereas TIRADS was not predictive (P=0.3135). A multivariate regression model incorporating the four most informative covariates (gender, age, Bethesda category, and ATA US patterns) (model #1) yielded a C index=0.653; R2=0.108. Male gender and Bethesda category V significantly increased risk, and age demonstrated a nonlinear risk profile. When TSv3 was added to model #1, the C index increased to 0.888; R2=0.572. However, age (P=0.341), Bethesda category (P=0.272), and the ATA US patterns (P=0.264) had limited predictive ability in comparison with TSv3, which dominated the predictive performance (P<0.001). Gender was the only parameter showing tendency for significance beyond MT (P=0.095). The most parsimonious model incorporated gender and TSv3 (C index=0.889; R2=0.588). Conclusions: While often useful in selecting thyroid nodules for FNA, neither the ATA US nor the TIRADS scoring systems were informative in further predicting TC/NIFTP in thyroid nodules with indeterminate FNA cytology. Although age and Bethesda category were associated with TC/NIFTP probability on univariate analysis, they had limited incremental value above the high predictive ability of TSv3. Gender was the only parameter with potential contribution to predicting TC/NIFTP in addition to MT.

Nuclear morphometry in indeterminate thyroid nodules.

Up to 30% of thyroid nodules undergoing fine needle aspiration (FNA) yield an indeterminate result. Recent research efforts have suggested that nuclear morphometry and morphology may enhance the diagnostic accuracy of FNA as an objective adjunct. We applied nuclear morphometric analysis on a diverse cohort of patients to evaluate the association between nuclear morphometry and malignancy. Forty-five randomly selected patients, who underwent thyroid surgery after an indeterminate FNA result (Bethesda III & IV) between 2012-2015, were reviewed. One hundred representative nuclei per FNA of a thyroid nodule were analyzed using ImageJ. Seven validated morphometric parameters were collected: nuclear area, perimeter, circularity, aspect ratio, roundness, and maximum/minimum Feret's diameter. L/S ratio was subsequently calculated. All 8 nuclear parameters were reported as averages with standard errors of the mean (SEM). A Student's t-test was used to assess the association of nuclear parameters with final surgical pathology. The mean age of all patients was 56.31±15.39 years, with female patients comprising 68.9% of the cohort. Twenty-two patients had malignant thyroid nodules. The mean perimeter of nuclei for the cohort was 18.48±0.45 µm, the mean area was 22.19±0.93 µm, and the mean maximum Feret's diameter was 6.67±0.13 µm. No significant differences in the 8 nuclear parameters were observed between the malignant and non-malignant groups. In the population examined, our results suggest that nuclear morphometry is not yet a tool of reliable diagnostic value in accessing malignant and non-malignant thyroid nodules. Further investigation is necessary to identify objective parameters that will enhance diagnostic accuracy of indeterminate FNA cytology to minimize the number of diagnostic thyroid surgery.

Evaluation of BRAF, RAS, RET/PTC, and PAX8/PPARg alterations in different Bethesda diagnostic categories: A multicentric prospective study on the validity of the 7-gene panel test in 1172 thyroid FNAs deriving from different hospitals in South Italy.

Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules, although up to 30% of FNAs are still classified as "indeterminate." Molecular testing of FNAs could improve preoperative diagnosis, thereby reducing unnecessary surgery. In this multicenter prospective studythe authors investigated,using a 7-gene assay, the distribution and diagnostic impact of BRAF, RAS, RET/PTC, and PAX8/PPARg, themost frequent genomic alterations occurring during thyroid oncogenesis. In total, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested, and molecular data were compared with available histology or cytologic follow-up. In particular, for atypia of undetermined significance/follicular lesion of undetermined significance cases, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%), suggesting different surgical management, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class, supporting the identification of prognostically relevant diagnostic categories. The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs, especially when considering the biologic significance of the different types of mutations. Moreover, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class.

84 - Pathology and Case Review and Whole Exome Sequencing of ThyroSPEC™ Panel False-Negatives for the Diagnosis of Indeterminate Thyroid Fine-Needle Aspiration (FNA) Cytologies

The ThyroSPEC™ assay is a cost-efficient mutation detection panel that allows for the identification of the most prevalent 118 point mutations and 25 gene fusions associated with thyroid cancer. During an ongoing prospective evaluation of indeterminate liquid FNA cytologies with available histology in the Calgary/southern Alberta health-care region, we thus far identified 11 samples which were mutation-negative on ThyroSPEC™ but histologically malignant. The goal of this study was to further investigate reasons for and the mutation profile of these false-negatives to identify possibilities for improvements to the ThyroSPEC™ panel.

Exosomal miRNAs are potential diagnostic biomarkers between malignant and benign thyroid nodules based on next-generation sequencing.

An accurate biomarker or method for diagnosis of thyroid nodule with indeterminate fine-needle aspiration result is essential for clinical treatment. Micro RNAs (miRNAs) of exosomes are advantageous in the diagnosis of tumors because they are highly stable, and be protected by a bilayer membrane structure. Exosomes were isolated from 13 papillary thyroid carcinoma (PTC) and 7 nodular goiter (NG) patients' plasma. Small RNA sequencing was performed on exosomes' RNA in next-generation sequencing (NGS) platform. Then, we performed comprehensive analysis on miRNA expression profile in exosome of two groups. One hundred and twenty-nine differentially expressed miRNAs were identified in plasma exosomes between PTC and NG patients. Forty-nine miRNAs were up-regulated, and 80 miRNAs were down-regulated in PTC patients. Receiver operating characteristic (ROC) curves of 129 miRNAs were plotted. Area under curve (AUC) of 129 miRNAs was 0.571-0.951, with distribution peak of 0.82-0.86. AUC of 11 miRNAs was above 0.9, miR-5189-3p had the most optimal performance for diagnosis between PTC and NG, with 0.951 of AUC. Target genes of 129 miRNAs were enriched into 7 cancer-related signaling pathways, including mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), NF-kappa B signaling pathway and so on. This study profiled the miRNA signature of exosomes from PTC patients and NG patients. We proposed a group of miRNAs in plasma exosomes as candidate biomarkers for thyroid nodule diagnosis.

The Role of Molecular Testing for the Indeterminate Thyroid FNA.

Thyroid nodules are common in the adult population where a majority are benign and only 4.0% to 6.5% are malignant. Fine needle aspiration (FNA) is a key method used in the early stages to evaluate and triage patients with thyroid nodules. While a definitive cytological diagnosis is provided in more than 70–75% of all thyroid FNA cases, the group of indeterminate lesions offers a challenge in terms of interpretation and clinical management. Molecular testing platforms have been developed, are recognized as an option by the 2015 American Thyroid Association Guidelines, and are frequently used in conjunction with FNA as an integral part of the cytologic evaluation. In this review, the utility of molecular testing options for nodules assigned to the group of indeterminate thyroid FNAs is described.

Anti-Thyroid Antibodies and TSH as Potential Markers of Thyroid Carcinoma and Aggressive Behavior in Patients with Indeterminate Fine-Needle Aspiration Cytology.

Indeterminate fine-needle aspiration cytology (FNAC) imposes challenges in the management of thyroid nodules. This study aimed to examine whether preoperative anti-thyroid antibodies (Abs) and TSH are indicators of thyroid malignancy and aggressive behavior in patients with indeterminate FNAC. This was a retrospective study of thyroidectomy patients from 2008 to 2016. We analyzed Abs and TSH levels, FNAC, and histopathology. Serum antibody levels were categorized as 'Undetectable', 'In-range' if detectable but within normal range, and 'Elevated' if above upper limit of normal. 'Detectable' levels referred to 'In-range' and 'Elevated' combined. There were 531 patients included. Of 402 patients with preoperative FNAC, 104 (25.9%) had indeterminate cytology (Bethesda III-V). Of these, 39 (37.5%) were malignant and 65 (62.5%) benign on histopathology. In the setting of indeterminate FNAC, an increased risk of malignancy was associated with 'Elevated' thyroglobulin antibodies (TgAb) (OR 7.25, 95% CI 1.13-77.15, P = 0.01) and 'Elevated' thyroid peroxidase antibodies (TPOAb) (OR 6.79, 95% CI 1.23-45.88, P = 0.008). Similarly, while still 'In-range', TSH ≥ 1mIU/L was associated with an increased risk of malignancy (OR 3.23, 95% CI 1.14-9.33, P = 0.01). In all patients with malignancy, the mean tumor size was 8mm larger in those with TSH ≥ 1mIU/L (P = 0.03); furthermore, in PTC patients, 'Detectable' TgAb conferred a 4 × risk of lymph node metastasis (95% CI 1.03-13.77, P = 0.02). In this cohort, in indeterminate FNAC patients, Abs and TSH were associated with an increased risk of malignancy. Additionally, TgAb and TSH were potential markers of aggressive biology. As such, they may be diagnostic and prognostic adjuncts.

Performance of 18F-FDG PET/CT in Selecting Thyroid Nodules with Indeterminate Fine-Needle Aspiration Cytology for Surgery. A Systematic Review and a Meta-Analysis.

Thyroid nodules with indeterminate fine-needle aspiration cytology (FNA) represent a major challenge in clinical practice. We conducted a systematic review and meta-analysis evaluating the ability of hybrid imaging using fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to appropriately select these nodules for surgery. PubMed, CENTRAL, Scopus, and Web of Science were searched until July 2019. Original articles reporting data on the performance of 18F-FDG PET/CT in thyroid nodules with indeterminate FNA were included. Summary operating points including 95% confidence interval values (95% CI) were estimated using a random-effects model. Out of 786 retrieved papers, eight studies evaluating 104 malignant and 327 benign thyroid nodules were included. The pooled positive and negative likelihood ratios (LR+ and LR-) and diagnostic odds ratio (DOR) of 18F-FDG PET/CT were 1.7 (95% CI: 1.4–2.0), 0.4 (95% CI: 0.2–0.7), and 3.5 (95% CI: 1.7–7.1), respectively. No heterogeneity was found for LR+ and DOR. In patients with thyroid nodules with indeterminate FNA, 18F-FDG PET/CT has a moderate ability to correctly discriminate malignant from benign lesions and could represent a reliable option to reduce unnecessary diagnostic surgeries. However, further studies using standardized criteria for interpretation are needed to confirm the reproducibility of these findings.

Core needle biopsy in the management of thyroid nodules with an indeterminate fine-needle aspiration report.

Ultrasonography (US)-guided fine-needle aspiration biopsy (FNAB) cytology is widely used but is limited due to its pathologically indeterminate results in diagnosing thyroid nodules. Recently, US-guided core-needle biopsy (CNB) was introduced as an effective and safe technique for diagnosing indeterminate thyroid nodules. Using CNB, information about architectural histologic structure such as nodule capsule or more immunochemical staining can be obtained which lead to a more accurate diagnosis. Up to 98% of indeterminate thyroid lesions can be classified as malignant or benign when CNB is used for follow-up analysis. Other evidences revealed the effectiveness of CNB in reducing inconclusive results and improving the diagnostic performance of thyroid nodules initially diagnosed as AUS/FLUS by FNAB. In this review, we investigate how to deal with indeterminate thyroid nodules diagnosed by FNAB and determine how CNB has a role in diagnosing these indeterminate thyroid nodules.

HMGA2 Gene Expression in Fine-needle Aspiration Samples of Thyroid Nodules as a Marker for Preoperative Diagnosis of Thyroid Cancer.

There is a great interest in molecular markers that would help in the preoperative diagnosis of malignant thyroid nodules in cases of indeterminate fine-needle aspiration cytology. The aim of this study was to determine the diagnostic accuracy of HMGA2 gene expression in discriminating benign from malignant thyroid nodules. In this study, 237 preoperative thyroid fine-needle aspiration samples were analyzed prospectively for the expression of the HMGA2 gene by real-time reverse transcription polymerase chain reaction. The results were evaluated against the postoperative histopathologic diagnosis or definitive cytologic diagnosis in cases of nodular goiter and Hashimoto thyroiditis. Among 237 samples from patients with thyroid nodules that were analyzed, 231 were adequate for real-time reverse transcription polymerase chain reaction analysis. With a cutoff value of 8.71 for relative gene expression, HMGA2 was positive in 19 (16.4%) of 116 nodular goiter, 1 (2.6%) of 39 Hashimoto thyroiditis, 9 (28.1%) of 32 follicular adenoma, 0 (0%) of 5 Hurthle cell adenoma, 32 (88.9%) of 36 papillary carcinoma, and 3 (100%) of 3 follicular carcinoma samples. In discriminating between malignant and benign thyroid nodules, HMGA2 has shown specificity of 84.5%, sensitivity of 91.9%, positive predictive value of 53.1%, and negative predictive value of 98.2%. High sensitivity and negative predictive value of HMGA2 for preoperative detection of malignant thyroid nodules shown in this study indicate that it may have a role as an ancillary marker in cytology in the management of patients with thyroid nodules.

Digital image-assisted quantitative nuclear analysis improves diagnostic accuracy of thyroid fine-needle aspiration cytology.

Thyroid fine-needle aspiration (FNA) plays a key role in triaging thyroid nodules. Yet many cases are assigned to indeterminate categories. The new category "noninvasive follicular thyroid neoplasm with papillary-like features" (NIFTP) complicates thyroid cytology. Digital image-derived nuclear measurements might objectively distinguish papillary thyroid carcinoma (PTC) from benign nodules and NIFTP. All thyroid FNAs from 2012 to 2016 of atypia of undetermined significance (A; n=8) and suspicious for malignancy (S; n=2) with sufficient cellularity and surgical follow-up, all FNAs preceding NIFTP (n=6), and a random sample of PTC (n=9) and benign (n=10) cytology were studied. A modified Giemsa-stained slide from each case was scanned using the Aperio imaging system, and long (dl ) and short (ds )-axis diameters were measured for 125 nuclei per case. Nuclear area and elongation were calculated. Nuclear area was larger in PTC (mean, 77.2μm2 [range, 70.6-86.0μm2 ]) than benign (mean, 43.3μm2 [range 38.2-52.2μm2 ]) (P<.001). Nuclear areas from indeterminate FNAs segregated according to final histology (A/S PTC mean 72.7μm2 , A/S benign mean 53.7μm2 ; P=0.004), and were not significantly different from definitive FNAs of the same diagnosis. NIFTP nuclear area was smaller than PTC (mean, 54.8μm2 [range, 46.7-66.1μm2 ]; P<.001). Nuclear elongation showed similar results, but with greater group overlap. Nuclear area and elongation can be calculated using a commercial digital imager; both correlate with the final surgical pathology diagnosis of PTC versus benign, including NIFTP. Area provides greater resolution than elongation. This technique could be used to resolve indeterminate cytology in which PTC is considered.