Clinical Impact of Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features on the Risk of Malignancy in the Bethesda System for Reporting Thyroid Cytopathology: A Meta-Analysis of 14,153 Resected Thyroid Nodules

Objective: It is still controversial as to how the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). This meta-analysis was aimed to investigate the impact of NIFTP on the ROM in each TBSRTC category.Methods: We accessed three electronic databases including PubMed, Web of Science, and Scopus to search for relevant data from January, 2016 to July, 2018. Relative risk and meta-analysis of proportions using the DerSimonian-Laird method, and each corresponding 95% confidence interval (CI) was pooled using a random-effect model.Results: A total of 14 studies consisting of 14,153 resected nodules were included for meta-analyses. Overall, there was a significant reduction in ROM in all TBSRTC categories following the NIFTP reclassification, except TBSRTC category I. The largest absolute and relative decrease in ROM was observed in TBSRTC category V (16%; 95% CI = 8 to 24) and category III (32%; 95% CI = 24 to 39), respectively. There was a positive correlation between the rate of NIFTP and resection rate (r = 0.83; P = .02). The decreases in ROM were more prominent in Western than in Asian cohorts.Conclusion: We confirmed the decrease in ROM due to the NIFTP reclassification for most of TBSRTC categories, which was more significant in Western than in Asian practice. The incidence of NIFTP was higher in institutions where surgical resection rates were high in patients with indeterminate cytology nodules.Abbreviations: AUS/FLUS = atypia of undetermined significance/follicular lesion of undetermined significance; CI = confidence interval; FNA = fine-needle aspiration; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NI-FVPTC = noninvasive follicular variant of papillary thyroid carcinoma; ROM = risk of malignancy; RR = relative risk; SM = suspicious for malignancy; TBSRTC = The Bethesda System for Reporting Thyroid Cytopathology     

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.     

Thyroid cytopathology: Bethesda and beyond

Thyroid nodules are commonly encountered in clinical practice. Although the overwhelming majority of them turn out to be benign, the small subset of cancerous nodules needs to be accurately identified for optimal and timely surgical management. Fine-needle aspiration has proven to be the most valuable diagnostic modality for pre-operative distinction of benign from malignant nodules. The recently introduced and much anticipated Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has standardized our diagnostic approach to reporting and cytomorphological criteria. TBSRTC has well-defined and rational management algorithms with implicit risk of malignancy in each of the 6 diagnostic categories. Recently published data supports the clinical utility and wide acceptance of TBSRTC by both practicing pathologists and clinicians. The problematic category of 'indeterminate' cytopathologic diagnoses has led to the discovery and development of unique and useful molecular markers, such as BRAF, which have displayed promising potential in recently published studies. As a result of the publication of TBSRTC, in 2009 the American Thyroid Association revised its clinical guidelines for the management of patients with thyroid disease and TBSRTC offers a useful source of information for the pathologist as well.     

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 [ATA], Korean Thyroid Imaging Reporting and Data System [Korean-TIRADS], and The American College of Radiology Thyroid Imaging Reporting and Data System [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 fine needle aspiration cytology processed by ThinPrep: an additional slide decreased the number of inadequate results

E. D. Rossi, F. Morassi, G. Santeusanio, G. F. Zannoni and G. Fadda
Thyroid fine needle aspiration cytology processed by ThinPrep: an additional slide decreased the number of inadequate results Background: Fine needle aspiration cytology is the most accurate tool for diagnosing thyroid nodules. Its accuracy is related to the rate of inadequate samples, which can be minimized with the adoption of on‐site assessment of the adequacy of the material. The introduction of liquid‐based cytology (LBC) in the thyroid does not allow checking on the adequacy of the cellularity. The possibility of making a second LBC slide for decreasing the number of non‐diagnostic cases is studied. Methods: Out of 553 cases diagnosed in a single institution from January to March 2005, 166 consecutive cases with an LBC slide reviewed by the same pathologist were evaluated. The cases were classified in a five‐tiered category system (Thy1 to 5 according to the British Thyroid Association guidelines) and all but two (with cystic degeneration) were processed by LBC and stained with Papanicolaou stain. The above‐mentioned categories are defined as follows: Thy1 inadequate or haemorrhagic, Thy2 non‐neoplastic lesion; Thy3 follicular lesion/suspected follicular neoplasm; Thy4 suspicious for malignancy; Thy5 diagnostic of malignancy. For each case the cytological diagnosis was made on the LBC slide and the adequacy of the cellularity for a conclusive diagnosis was assessed. Results: Of the 166 cases, 39 were non‐diagnostic (Thy1—inadequate), ten presented features of cystic degeneration (Thy1—haemorrhagic), 90 were benign (Thy2), 22 were diagnosed as a follicular lesion (Thy3), one as suspicious of malignancy (Thy4) and four as papillary carcinoma (Thy5). Thirty‐nine cases had a second LBC for achieving a definitive diagnosis with eventual re‐classification. Of these cases, 23 (61.5%) led to a conclusive diagnosis (18 Thy2, five Thy3) with a 18.5% decrease of the inadequacy rate. Conclusions: The making of an additional LBC slide helps in achieving a diagnosis in cases classified as non‐diagnostic on the first standard slide (52.1% recovery rate). This procedure is particularly helpful for meeting the adequacy criteria in benign and indeterminate lesions and could also be used for refining the diagnosis of suspicious for a malignant thyroid neoplasm.     

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     

BRAF Mutation Testing of Thyroid Fine-Needle Aspiration Specimens Enhances the Predictability of Malignancy in Thyroid Follicular Lesions of Undetermined Significance

Background/Objective: The Bethesda 2007 Thyroid Cytology Classification defines atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) as a heterogeneous category of cases that are neither convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. At our institution, we refer to these cases as 'indeterminate' and they are further subclassified into two categories. BRAF mutation occurs in 40-60% of papillary thyroid carcinoma (PTC). In this study, we examined cases in the AUS/FLUS category in correlation with BRAF mutation analysis and surgical pathology outcome. Study Design: Thyroid fine-needle aspiration (FNA) cytology specimens interpreted as 'indeterminate' were selected from our files, and available remnants of thin-layer processed specimens were used for BRAF mutation analysis. Surgical pathology reports were reviewed for the final outcomes in these patients. Results: Of the 84 indeterminate cases with BRAF mutation analysis, only 49 had follow-up with surgical intervention. Sixteen cases had BRAF mutation. All of the BRAF-positive cases had a final diagnosis of PTC. Conclusions: The sensitivity and specificity of BRAF mutation in detecting PTC in FNA specimens with indeterminate diagnosis was 59.3 and 100%, respectively, while the positive and negative predictive values were 100 and 65.6%, respectively. The limited data supports the use of BRAF mutation analysis to predict the risk of malignancy in patients with indeterminate thyroid FNAs.     

The bethesda terminology for reporting thyroid cytopathology: from theory to practice in europe

Objectives: A 2007 conference held at the National Cancer Institute, Bethesda, Md., USA, proposed a new terminology for classifying the results of thyroid fine-needle aspiration (FNA) - The Bethesda System for Reporting Thyroid Cytology (TBSRTC). The need to standardize thyroid FNA terminology was emphasized during the 35th European Congress of Cytology in 2009. An interobserver review study to assess the new terminology for analyzing the results of thyroid FNA was organized by the scientific committee of the European Federation of Cytology Societies. Study Design: Four experts in thyroid FNA examined and classified 116 FNAs according to the 6 levels of TBSRTC which are: nondiagnostic (ND); benign; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS); follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN), with those of Hürthle cell type reported as follicular neoplasm, Hürthle cell type/suspicious for a follicular neoplasm, Hürthle cell type (FNHCT/SFNHCT); suspicious (SUS), and malignant. Results: The total consensus was 62.1%; the cytopathologists disagreed on 44 cases, including 8 cases of AUS/FLUS and 18 of FN/SFN; 59% of the cases had no consensus. They agreed on 73 and 80% of the cases classified as benign and malignant, respectively, and on 58.3% of the SUS cases. The percentage of no consensus for each expert was between 32 and 39%. Conclusions: Disagreement regarding the use of TBSRTC terminology for classifying the results of thyroid FNA mainly occurred in the most-often criticized categories of AUS/FLUS and FN/SFN.     

Not All Bethesda 1 Thyroid Nodules Were Created Equal: Different B1 Subgroups

ObjectiveThe Bethesda System for Reporting Thyroid Cytopathology is a uniform method used worldwide to report thyroid fine-needle aspiration (FNA) outcomes. This study focuses on the Nondiagnostic/Unsatisfactory category, designated as Bethesda1 (B1). The documented risk of malignancy for B1 nodules can vary significantly, implying this category is not homogenous and might be composed of different subtypes. Our hypothesis was that B1 subgroups (blood only, insufficient thyrocytes, cyst content) will vary in their malignancy rate.MethodsThe study design was observational and retrospective. The study population included 154 patients in the Galilee Medical Center who underwent FNA examination of the thyroid gland from 2013-2018 and had a B1 result. We looked at the final diagnosis of malignant or benign for patients who underwent surgery and calculated the malignancy rate for each subgroup.ResultsMalignancy rates were higher in the Blood subgroup than in the other subgroups, and higher in the Thyrocytes subgroup than in the Cyst subgroup (P < .05). All malignancies were papillary thyroid carcinomas. There was no significant difference in the malignancy rate when we further divided the B1 samples into 2 groups based on the presence of epithelial cells. Many repeat FNA tests resulted in a different B1 subgroup.ConclusionThe different malignancy rates suggest that individual management approaches should be considered for each B1 subgroup.     

Improving recognition of thyroid carcinoma in rapid-consultation specimens

OBJECTIVE: To improve recognition of thyroid carcinoma in rapid consultation on Diff-Quik-stained (Fisher Diagnostics, Middletown, Virginia, USA.) fine-needle aspiration (FNA) and rapid hematoxylin-eosin (H-E)-stained intraoperative scrape preparation (ISP) specimens by assessing 3 variables (anisokaryosis, nuclear overlap [NO] and scant/absent colloid) in cases of cellular follicular lesions (CFL), an indeterminate diagnostic category. STUDY DESIGN: Thirty-seven FNAs and 28 ISPs diagnosed as CFL, with histologic follow-up, were evaluated in blinded fashion by 3 cytopathologists assessing the 3 variables. RESULTS: Over 90% of the malignant cases showed NO in both FNA and ISP, while only 22% of the benign cases did; positive and negative predictive values (PPV and NPV) were 82% and 100%. All malignant cases showed significant anisokaryosis in both FNA and ISP in contrast to 24% of benign cases; PPV and NPV were 74% and 100%. Scant/absent colloid was seen in 87% and 39% of malignancies in FNA and ISP, respectively, as compared to 55% and 20% of the benign cases. PPV and NPV were 52% and 83% in FNA and 63% and 60% in ISP, respectively. CONCLUSION: Application of these variables improves recognition of thyroid carcinoma, particularly in fine needle aspirates, while additional material may be requested. With ISP, their absence supports recommending against further surgery. Together, optimal surgical planning and outcome may be obtained.     

Repeat Diagnoses of Bethesda Category III Thyroid Nodules: What To Do Next?

Objectives

To assess the malignancy rates of thyroid nodules repeatedly classified as Bethesda category III on fine needle aspiration (FNA), and to suggest management guidelines for these lesions.

Methods

This is a retrospective study that included 395 thyroid nodules categorized as Bethesda III undergone either surgery or ultrasound (US) follow-up. There were 67 nodules classified a second time as Bethesda category III on repeat FNA. We compared malignancy rates, clinicopathologic and ultrasonographic characteristics between direct surgery and repeat FNA groups and between the initial and repeat Bethesda category III groups, each. And in the repeat Bethesda III group, clinicopathologic and US variables were compared between benign and malignant nodules.

Results

Incidence of concurrent cancer, underlying thyroiditis and positive BRAF mutation were significantly higher in 142 nodules with direct surgery than 243 nodules with repeat FNA (p < 0.05). Of the 395 nodules with Bethesda category III cytology on initial FNA, the malignancy rate was 59.5%. In 67 nodules with repeat Bethesda III classification, however, the malignancy rate was 73.1% (p < 0.05). However, none of the variables were significantly different between the initial Bethesda category III group and the repeat Bethesda category III group (p > 0.05). In the repeat Bethesda category III group, solid consistency, irregular/microlobulated margins, nonparallel shape, and number of suspicious findings or “suspicious malignant” US assessments were associated with a high malignancy rate (p < 0.05). On multivariate logistic regression analysis, the factor associated with malignancy in the repeat Bethesda category III group was irregular/microlobulated margin (odds ratio = 15.576; 95% CI, 2.097–115.6804, p = 0.007) with a sensitivity, specificity, positive and negative predictive values, and accuracy of 81.6%, 83.3%, 93.0%, 62.5% and 82.1%, respectively.

Conclusion

Thyroid nodules with repeated Bethesda category III classification and irregular/microlobulated margins on US are at increased risk of malignancy, and operative management should be considered as opposed to repeat FNA.     

Spectrum of risk of malignancy in subcategories of 'atypia of undetermined significance'

Objective: To determine if focal 'nuclear atypia' or 'microfollicular architecture' portends a higher risk of malignancy than other subcategories of atypia of undetermined significance (AUS) in thyroid fine-needle aspirations (FNAs). Study Design: The frequencies of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories were calculated from 3,956 thyroid FNAs interpreted over a 26-month period at The Johns Hopkins Hospital after adoption of TBSRTC. TBSRTC criteria were applied strictly. The risk of malignancy, specifically for AUS subcategories, was analyzed by cyto-histo correlation. Results: Of the 133 cases diagnosed as AUS, 32% were found to have stageable carcinoma (not incidental microcarcinoma) on resection. When the subset of AUS with 'nuclear atypia' (AUS-N) was separated from other AUS cases, 48% (30/62) of them had stageable carcinoma on resection; of the AUS subset with 'microfollicular architecture' (AUS-F), 27% (8/30) were malignant on resection. The 'suspicious for papillary thyroid carcinoma' (SPTC) group maintained a higher risk of malignancy versus AUS-N (relative risk, RR 1.57; 95% CI 1.23-1.81). Conclusion: The subcategory of 'nuclear atypia' within AUS indicates a higher risk of malignancy than other subcategories of AUS but has a lower risk of malignancy than SPTC does. Thus, it is an important distinction with potential clinical implications.     

Repeatedly nondiagnostic thyroid fine-needle aspirations do not modify malignancy risk

Objective: Thyroid nodules with nondiagnostic (ND) fine-needle aspirations (FNA) typically undergo repeat sampling. While repeat FNA is often diagnostic, little is known regarding the significance of repeatedly ND aspirates. Limited data suggest there is very low, if any, risk of malignancy for repeatedly ND FNAs. Study Design: We performed a retrospective analysis of ND thyroid FNAs over a nearly 6-year period at our institution to further address this question. Results: There were 834 ND thyroid FNAs, representing 694 distinct thyroid nodules. Repeat FNA was performed after an initial ND aspirate in 52% of cases (363/694); 19% (70/363) had at least one additional ND diagnosis on repeat FNA. Surgical follow-up was available for 57 cases. Malignancy was identified histologically in 21% (9/42) of nodules after a single ND FNA and in 20% (3/15) of nodules with 2 or more repeatedly ND aspirates. Accounting for all benign cytologic follow-up, the overall risk of malignancy was 4% [12/303; 3.5% (9/255) following a single ND FNA and 6.3% (3/48) after repeated ND FNAs]. Conclusion: We observed no modification of malignancy risk when repeated FNAs were ND. Clinical management for an ND aspirate should remain repeat aspiration along with clinical and sonographic correlation.     

The Role of Core-Needle Biopsy for Thyroid Nodules with Initially Nondiagnostic Fine-Needle Aspiration Results: A Systematic Review and Meta-Analysis

Objective: This study evaluated the prevalence of nondiagnostic results, diagnostic performance, and complications of core-needle biopsy (CNB) compared with repeat fine-needle aspiration (FNA) for thyroid nodules with previous nondiagnostic FNA findings.Methods: The Ovid-MEDLINE and EMBASE databases were thoroughly searched for studies evaluating CNB or repeat FNA for thyroid nodules with initially nondiagnostic FNA results. Pooled proportions of nondiagnostic results of CNB and repeat FNA were calculated. A meta-analysis was performed to evaluate the diagnostic accuracy of CNB and repeat FNA for a diagnosis of malignancy using a bivariate random-effects model. Complication rates were also evaluated.Results: A review of 52 articles identified 4 eligible articles, involving 1,028 patients with 1,028 thyroid nodules, which were included in the meta-analysis. CNB demonstrated significantly lower rates of nondiagnostic results (6.4%) than repeat FNA (36.5%) (P<.0001). In the 3 studies that analyzed the diagnostic accuracy of CNB in diagnosing malignancy, CNB demonstrated significantly higher summary estimates of sensitivity (89.8%) than repeat FNA (60.6%) (P = .022), but summary specificity did not differ between CNB (99.2%) and repeat FNA (99.0%) (P = .576). None of the patients who underwent CNB or repeat FNA experienced any major complications.Conclusion: CNB demonstrates lower rates of nondiagnostic results and higher diagnostic accuracy than repeat FNA. CNB, rather than repeat FNA, can be utilized to diagnose thyroid nodules previously nondiagnostic on FNA.Abbreviations:CI = confidence intervalCNB = core-needle biopsyFNA = fine-needle aspirationSROC = summary receiver operating characteristicUS = ultrasound     

Malignancy Risk Analysis in Patients with Inadequate Fine Needle Aspiration Cytology (FNAC) of the Thyroid

Background

Thyroid fine needle aspiration cytology (FNAC) is the standard diagnostic modality for thyroid nodules. However, it has limitations among which is the incidence of non-diagnostic results (Thy1). Management of cases with repeatedly non-diagnostic FNAC ranges from simple observation to surgical intervention. We aim to evaluate the incidence of malignancy in non-diagnostic FNAC, and the success rate of repeated FNAC. We also aim to evaluate risk factors for malignancy in patients with non-diagnostic FNAC.

Materials and Methods

Retrospective analyses of consecutive cases with thyroid non diagnostic FNAC results were included.

Results

Out of total 1657 thyroid FNAC done during the study period, there were 264 (15.9%) non-diagnostic FNAC on the first attempt. On repeating those, the rate of a non-diagnostic result on second FNAC was 61.8% and on third FNAC was 47.2%. The overall malignancy rate in Thy1 FNAC was 4.5% (42% papillary, 42% follicular and 8% anaplastic), and the yield of malignancy decreased considerably with successive non-diagnostic FNAC. Ultrasound guidance by an experienced head neck radiologist produced the lowest non-diagnostic rate (38%) on repetition compared to US guidance by a generalist radiologist (65%) and by non US guidance (90%).

Conclusions

There is a low risk of malignancy in patients with a non-diagnostic FNAC result, commensurate to the risk of any nodule. The yield of malignancy decreased considerably with successive non-diagnostic FNAC.     

Cytology and mRNA expression analysis of fine needle aspirates of thyroid nodules in an East German region with borderline iodine deficiency.

Fine needle aspiration cytology (FNAC) is widely recommended as an important tool for pre-operative identification of malignancy in patients with nodular thyroid disease. To assess the diagnostic contribution of FNAC and the potential of quantitative mRNA analysis in fine needle aspirates in daily practice, we conducted a prospective study in thyroid clinics (n=2) and endocrine practices (n=3), respectively in an East German region with borderline iodine deficiency. Two-hundred and forty-four consecutive FNACs were obtained over a period of 2 years (2002-2004) from euthyroid patients presenting for first evaluation of a solitary thyroid nodule. The mean nodule size for FNAC was 27 mm (range: 10-79 mm). In 55% of patients FNAC was performed after scintiscan detection of a cold or normal functioning thyroid nodule (CTN), while in the remainder FNAC was performed as a primary investigation. FNAC outcomes were: 57.8% benign, 22.1% indeterminate, 2.5% suspicious for malignancy, 17.6% non-diagnostic. Messenger RNA levels for a house keeping gene (beta-actin) and a thyroid specific marker (thyroglobulin, Tg) were studied as basic molecular markers using real-time PCR. Both in the IN VIVO and EX VIVO FNA series, beta-actin and Tg mRNA levels were positively correlated with the thyrocyte cell yield/respective FNA smear. However, subgroup analysis showed that FNAC with histologically confirmed follicular thyroid cancer and/or microfollicular adenoma exhibited significantly lower Tg mRNA expression despite high beta-actin levels. Sufficient mRNA quantities were obtained in >90% of FNA specimen to allow quantitative mRNA analysis of at least 5 further genes. In conclusion, quantitative mRNA analysis is feasible in FNA on a routine basis and provides a perspective for a molecular distinction of thyroid nodules, once specific marker genes have been defined for benign and malignant thyroid tumours respectively.     

Value of Repeating A Nondiagnostic Thyroid Fine-Needle Aspiration Biopsy

ObjectiveTo assess the value of repeating a biopsy when the initial thyroid fine-needle aspiration (FNA) biopsy is nondiagnostic.MethodsBetween 1990 and 2003, 4,311 thyroid FNAs were performed at the Cleveland Clinic Foundation, of which 220 (5%) were nondiagnostic. Among 189 patients whose medical records were available for retrospective review, 106 underwent a repeated FNA (FNA #2), and 14 had a second repeated FNA (FNA #3). Thyroid ultrasonography was used in the evaluation in 113 FNAs.ResultsThe first and second repeated FNAs were diagnostic in 58% (62 of 106 patients) and 50% (7 of 14 patients), respectively. The rate of malignant disease in patients with no repeated FNAs versus 1 or more repeated FNAs was 4.8% (4 of 83) versus 11.3% (12 of 106), respectively. Ultrasound-guided FNA yielded a diagnosis among 33 of 113 biopsies (29.2%), and FNA without ultrasound guidance provided a diagnosis in 30 of 159 biopsies (18.9%). Thus, the use of thyroid ultrasonography significantly improved the likelihood of establishing a diagnosis (P = 0.017). We found that repeating the FNA up to 2 times provides a diagnosis in up to 60% of cases.ConclusionThe overall prevalence of thyroid cancer in patients with nondiagnostic FNA is not trivial—8.5% in our study group of 189 patients. An aggressive approach toward nondiagnostic FNA biopsies is recommended, with performance of at least 2 repeated FNA biopsies, preferably with the help of ultrasound guidance. (Endocr Pract. 2007;13:735-742)     

Management of Nondiagnostic Thyroid Fine-Needle Aspiration Biopsy: Survey of Endocrinologists

ObjectiveTo evaluate the approach of endocrinologists in the setting of nondiagnostic thyroid fine-needle aspiration (FNA) biopsies.MethodsIn 2002, we surveyed physicians attending the national annual meetings of the American Association of Clinical Endocrinologists and the Endocrine Society of North America, using a 13-item questionnaire. The responses were tallied and analyzed.ResultsOf the 143 respondents, 139 were endocrinologists, with a male:female ratio of 2.5:1. Most respondents were involved in a medical practice in North America, but Europe, Asia, New Zealand, and Australia were also represented. Of those performing thyroid FNA biopsy, 31% used thyroid ultrasound guidance. Among the survey respondents, 16%, 49%, 20%, and 15% performed less than 2, 2 to 5, 6 to 10, and more than 10 thyroid FNA biopsies per month, respectively. Among the respondents, 13.5%, 44%, 28.5%, 10%, and 4% had nondiagnostic rates of less than 5%, 5 to 10%, 11 to 20%, 21 to 30%, and more than 30%, respectively. The approach of the respondents to an initially nondiagnostic FNA was repeated FNA biopsy in 87%, observation in 7%, levothyroxine suppression in 4%, and thyroid scintigraphy in 2%. Respondents believed that the most cost-effective approach in a patient with nondiagnostic FNA was repeated biopsy (82%), monitoring the size of the thyroid nodule (17%), and surgical referral (< 1%). No one was willing to repeat the thyroid biopsy more than three times.ConclusionOn the basis of findings in our survey, most endocrinologists repeat thyroid FNA at least once when confronted with a nondiagnostic result. No published studies have demonstrated the cost-effectiveness of this approach versus proceeding to surgical intervention or observation. We hope that this survey will encourage further studies on this issue. (Endocr Pract. 2004;10: 317-323)     

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     

Q-Elastography in the Presurgical Diagnosis of Thyroid Nodules with Indeterminate Cytology

Quantitative ultrasound (US) elastography (Q-USE), able to evaluate tissue stiffness has been indicated as a new diagnostic tool to differentiate benign from malignant thyroid lesions. Aim of this prospective study, conducted at the Department of Surgical Sciences, of the “Sapienza” University of Rome, was to evaluate the diagnostic accuracy of Q-USE, compared with US parameters, in thyroid nodules with indeterminate cytology (Thy3).The case study included 140 nodules from 140 consecutive patients. Patient’s thyroid nodules were evaluated by Q-USE, measuring the strain ratio (SR) of stiffness between nodular and surrounding normal thyroid tissue, and conventional US parameters prior fine-needle aspiration cytology. Those with Thy3 diagnosis were included in the study. Forty of the nodules analyzed harbored a malignant lesion. Q-USE demonstrated that malignant nodules have a significant higher stiffness with respect to benign one and an optimun SR cut-off value of 2.05 was individuated following ROC analysis. Univariate analysis showed that hypoechogenicity, irregular margins and SR >2.05 associated with malignancy, with an accuracy of 67.2%, 81,0% and 89.8%, respectively. Data were unaffected by nodule size or thyroiditis. These findings were confirmed in multivariate analysis demonstrating a significant association of the SR and the irregular margins with thyroid nodule’s malignancy. In conclusion, we demonstrated the diagnostic utility of Q-USE in the differential diagnosis of thyroid nodules with indeterminate cytology that, if confirmed, could be of major clinical utility in patients’ presurgical selection.