Thyroid Fine-needle Aspiration Cases Research Articles

Diagnostic implication of thyroid spherules for cytological diagnosis of thyroid nodules.

Thyroid fine-needle aspiration (FNA) is a principal diagnostic procedure for thyroid nodules. A specific cytomorphological structure, known as the thyroid spherule, is often seen in FNA specimens. The clinical significance of these spherules in terms of diagnosis and prevalence remains largely unexplored. We performed a retrospective study on 310 thyroid FNA specimens and categorized them according to the Bethesda System for Reporting Thyroid Cytopathology. The presence, size and number of thyroid spherules in each specimen were examined and these data were subsequently correlated with the clinicopathological features. Thyroid spherules were almost exclusively detected in benign cases, comprising 7.6% of all benign diagnoses. The average diameter of spherules in benign cases was 84.9 μm. Benign cases and cases with atypia of undetermined significance cases primarily exhibited low cellularity, while follicular neoplasms and malignant cases typically showed moderate to high cellularity. In the subgroup of FNA cases with moderate to high cellularity, spherules were identified in 12 (20%) of 59 benign FNA cases. Within this group, the sensitivity and specificity of thyroid spherules for detecting benign FNA cases were 20% and 100%, respectively. Our results suggest that the presence of thyroid spherules in FNA specimens can serve as a highly specific marker for benign thyroid conditions. The prevalence of spherule detection is strongly influenced by the cellularity. In cases with moderate to high cellularity, the identification of spherules can assist the cytopathologists in diagnosing thyroid FNA cases as benign.

"Copy number alteration" as the sole molecular finding of a Thyroseq test is more commonly seen in Hurthle cell neoplasms.

To better understand the molecular alterations associated with Hurthle cell lesions of the thyroid, we retrospectively reviewed the association of clonal DNA copy number alterations (CNAs) with fine needle aspiration (FNA) cytomorphology and surgical follow-up. Hurthle cell type (HCT) and non-Hurthle cell type (NHCT) thyroid FNAs that were classified according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as atypia of undetermined significance (AUS) and suspicious for a follicular neoplasm (SFN) with corresponding molecular testing performed by ThyroSeq v3 genomic classifier were compared to surgical follow-up. A total of 54 thyroid FNA cases were identified, distributed among the following categories: AUS-HCT (n = 15, 27.8%), SFN-HCT (n = 11, 20.4%), AUS-NHCT (n = 19, 35.2%), and SFN-NHCT (n = 9, 16.6%). The lesions classified as AUS-HCT and SFN-HCT showed a higher prevalence of CNAs (n = 10/26; 38.5%) compared to their NHCT counterparts (n = 3/28; 10.7%) (p < .03). Of the 42 patients (77.8%) with surgical follow-up, CNAs were more often seen in benign (n = 10/26, 38.5%) than malignant conditions (n = 1/16, 6.3%) (p < .03). CNAs were encountered in more lesions with Hurthle cell features on histologic examination (n = 8/14, 57.1%) than those without (n = 3/28, 10.7%) (p < .002). The presence of CNAs alone was seen only in benign adenomas and more commonly with Hurthle cell features (n = 5/7, 71.4%). In this study, CNAs were associated with Hurthle cell morphology on thyroid FNA and benign adenomas upon surgical follow-up. Therefore, if the only finding of a positive ThyroSeq v3 GC result is a CNA, conservative management can be considered if clinically indicated.

The diagnostic value of add-on thyroid cell block in the evaluation of thyroid lesions.

Fine-needle aspiration (FNA) cytology plays a pivotal role in diagnosing thyroid nodules. Imaging assessment, followed by thyroid lesion sampling, is a widely applied clinical practice. Tissue fragments remnants are retrieved in cell-block providing an adjunct diagnostic tool for histopathology visualization and use of ancillary testing. This study aimed to evaluate whether the auxiliary application of cell-block adds to the diagnostic accuracy of the thyroid FNA. A total of 252 thyroid FNA cases between (2020 and 2021) were reviewed from patients aged 18-76. Of those, 150 cell-blocks were recovered and examined to assess their utility. Following categories were plotted during cell-blocks revision: (A) Inadequate material retrieved; (B) cell-block shows similar features along with their accompanying smears; and (C) value added to cytology diagnosis when using cell-block. The distribution of cell-blocks according to the aforementioned classification are as follows: A - non-diagnostic 63%, B - similar observation seen in both preparations 35%, and C - value added to the rendered diagnosis 2%. Hence, the use of cell-block improved cytology diagnosis in only 2% of total cases. Mostly were of immunostains application for diagnosis confirmation. The non-diagnostic and atypical cytology cases have not been upgraded to a more meaningful category by the incorporation of cell-block performed with the routine non-enhancement random method. On the other hand, cell-blocks contributed generously toward immunostaining application in malignant scenarios.

ODP481 Frequency and outcomes of reporting Bethesda class III thyroid cytopathology- An integrated health network's experience

Abstract Introduction Indeterminate thyroid nodule cytologic diagnosis causes anxiety and confusion to the patient and typically results in additional intervention including thyroid surgery. This increases risk of harm and cost of healthcare. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends that cytologists attempt to limit reporting 'indeterminate' [Bethesda III (B-III)] category when interpreting thyroid fine needle aspiration (FNA) specimens, and that all effort be made to limit this diagnosis to less or equal to 7% of all thyroid FNA cases. B-III encompasses follicular lesion of undetermined significance (FLUS) and atypia of undetermined significance (AUS). Because we noted a high reporting of B-III cases at our institution, we aim to review the cytologic interpretation of thyroid FNAs, specifically, the rate of indeterminate cytologic diagnoses. Our second aim is to assess the outcomes of nodules labeled as B-III category. Methods We reviewed the electronic medical records of adults who underwent FNA of thyroid nodules at Allegheny Health Network between January 1, 2016 and December 31, 2019. Results 700 patient records were reviewed, out of which 167 records were excluded (non-thyroid FNA or no relevant records). Meaningful records were available for 725 thyroid nodules biopsied during the study period (533 patient records). Mean age in our sample was 54.7±13.9 years and female-to-male ratio was 4: 1. Percent reporting of diagnostic categories based on Bethesda system were as follows: non-diagnostic/unsatisfactory (B-I) 8%; benign (B-II) 52%; FLUS/AUS (B-III) 28%; FN/SFN (B-IV) 6.2%; suspicious for malignancy (B-V)2.3%; and malignant (B-VI) 3.2%. Out of 28% reported as B-III, 73% were FLUS and 27% were AUS. Results of molecular diagnostic testing (ThyGeNEXT-ThyraMIR; Interpace Diagnostics®) were available for 95/203 of B-III category cases, of which 76% were labeled as very likely benign (probability of malignancy ≤5%) and 15% had low to moderate (10-40%) probability of malignancy. Only 9/95 (9%) had a ≥ 45% probability of malignancy. Four cases out of the 9 above cases were confirmed malignant and 1 was 'indeterminate' on surgical pathology. One in four of all B-III category nodules (n=52) underwent partial or total thyroidectomy, of which 32 were reported as benign, 18 malignant, one NIFTP, and one indeterminate by final surgical pathology. Conclusion We observed higher than recommended (28%) rate of B-III thyroid cytology at our institution. Most of these nodules underwent further interventions (molecular testing and/or thyroidectomy) where the majority were determined to be benign. All efforts should be made to decrease this rate with the ultimate goal of improving patient care, decrease unnecessary intervention, and reduce healthcare cost. Presentation: No date and time listed

Copy number variations identified in thyroid FNA specimens are associated with Hürthle cell cytomorphology.

The fine-needle aspiration (FNA) diagnosis of thyroid Hürthle cell neoplasms (HCNs) remains challenging. This study explored a possible association of copy number variations (CNVs) with Hürthle cell lesions of the thyroid. Thyroid FNA cases that were diagnosed as follicular lesion of undetermined significance (FLUS) or follicular neoplasm (FN)/HCN for which the ThyroSeq version 3 genomic classifier test was performed were retrieved. A total of 324 thyroid FNA cases (228 FLUS cases, 46 HCN cases, and 50 FN cases) were included in the study. FLUS cases were further classified as Hürthle cell type (follicular lesion of undetermined significance-Hürthle cell type [FLUS-HCT]; 20 cases) or non-Hürthle cell type (follicular lesion of undetermined significance-non-Hürthle cell type [FLUS-NHCT]; 208 cases). HCN and FLUS-HCT cases showed a higher prevalence of CNVs (23 of 66 [35%]) in comparison with those classified as FN or FLUS-NHCT (14 of 258 [5%]; P < .001). A total of 105 patients had histopathologic follow-up. Cases with CNVs were more likely to be neoplastic (18 of 26 [69%]) and associated with Hürthle cell changes (14 of 26 [54%]) in comparison with cases without any molecular alterations (neoplastic, 8 of 24 [33%]; Hürthle cell changes, 2 of 24 [8%]; P < .05). In HCN/FLUS-HCT cases with CNVs (n = 14), Hürthle cell changes (13 of 14 [93%]) and neoplasms (9 of 14 [64%]) were more likely to be seen on surgical follow-up in comparison with the 17 cases without CNVs (Hürthle cell changes, 6 of 17 [35%]; neoplastic, 3 of 17 [18%]; P < .05). CNVs identified in thyroid FNA cases are associated with Hürthle cell morphology and are suggestive of a neoplasm with Hürthle cell features in thyroid FNAs classified as FLUS-HCT/HCN. This finding may be helpful in triaging patients who would benefit from surgical management.

Performance of Afirma Gene Sequencing Classifier versus Gene Expression Classifier in thyroid nodules with indeterminate cytology.

About 15% to 30% of thyroid fine-needle aspiration (FNA) nodules have indeterminate cytology. The Afirma (Veracyte Inc, South San Francisco, CA) Gene Expression Classifier (GEC)/Gene Sequencing Classifier (GSC) tests were designed to improve risk stratification of the indeterminate thyroid nodules. This study aimed to evaluate and compare the performance of the Afirma GEC and GSC tests in the indeterminate thyroid lesions. Thyroid FNA cases with indeterminate cytology were searched in the pathology database and only those with available Afirma results were selected for this study. Each patient's demographic, sonographic, cytologic, molecular, and subsequent surgical follow-up results were collected and analyzed. There were 100 cases with indeterminate thyroid FNA results, including 49 cases tested by GEC and 51 cases by GSC. In the GEC group, benign call rate (BCR) was 53% (26 of 49) and the calculated negative predictive value (NPV) and positive predictive value (PPV) were 88% and 47% respectively. In the GSC group, the BCR was 63% (32 of 51) and the calculated NPV and PPV were 100% and 64%, respectively. Whereas only 17% (1 of 6) of benign oncocytic lesions were tested benign by the GEC, 60% (3 of 5) of benign oncocytic nodules were tested benign by the GSC. We demonstrated in this study that a little more than half of the indeterminate thyroid nodules had negative Afirma GEC/GSC results and the BCR using the Afirma GSC test was higher than GEC. The Afirma GSC showed higher NPV and PPV than GEC. In addition, the Afirma GSC appeared to be superior for differentiating benign and malignant oncocytic thyroid lesions.

RAS mutation and associated risk of malignancy in the thyroid gland: An FNA study with cytology-histology correlation.

Activating point mutations of the RAS gene (NRAS, HRAS, and KRAS) can be seen in benign and malignant thyroid tumors; among these, NRAS mutations are more commonly seen. This study was conducted to evaluate the thyroid risk of malignancy (ROM) associated with RAS mutations in thyroid fine-needle aspiration (FNA) at the authors' institution. The authors searched their electronic database system between January 2015 and May 2021 for thyroid FNA cases with any type of RAS mutation. Molecular alterations were identified with the ThyroSeq Genomic Classifier, ThyGeNEXT (thyroid oncogene panel)/ThyraMIR (miRNA classifier), or ThyroSure gene panel. A total of 127 cases (age, 51 ± 14 years; 100 females and 27 males) were identified, and 72 had histologic follow-up. The overall ROM associated with RAS mutations (with or without any other molecular alterations) was 29%, whereas the ROM was lower (18%) with RAS mutations only. Isolated NRAS, HRAS, and KRAS mutation-associated ROMs were 15%, 27%, and 14%, respectively. Among these RAS-mutated cases, the cases with a Bethesda category IV cytologic diagnosis had a higher ROM than the cases with a category III diagnosis (38% vs 17%). Twenty-one histologically confirmed malignant cases were mostly classified on cytology as category IV lesions (14 of 34; 41%), and the remainder were either category III (6 of 35; 17%) or V lesions (1 of 1; 100%). This study demonstrated that the overall RAS mutation-associated ROM in thyroid FNA was intermediate (29%), and isolated HRAS mutations appeared to have a higher ROM (27%) than NRAS and KRAS mutations (15% and 14%, respectively).

Should Liquid Based Cytology (LBC) be Applied to Thyroid Fine Needle Aspiration Cytology Samples?: Comparative Analysis of Conventional and LBC Smears.

Context:Liquid-based cytology (LBC) is a cyto-preparatory technique that may be applied to fine-needle aspiration (FNA) samples. However, its efficacy over conventional smears (CS) in thyroid is controversial.Aims:The aim of this study was to compare CS versus LBC (SurePath, BD) preparations in thyroid FNA samples for diagnostic efficacy.Settings and Design:Prospective case-control study using split sample analysis in 200 non-consecutive cases of thyroid FNA reported as per the Bethesda system.Methods and Material:Detailed cytomorphological features were evaluated in CS and LBC preparations. Cellularity was scored as 0–3. Based on diagnostic efficacy, they were categorized into three groups:(i) CS and LBC equivalent for diagnosis, (ii) CS better than LBC, and (iii) LBC better than CS for providing the diagnosis.Statistical Analysis Used:Paired t test for cellularity scores and descriptive for diagnostic efficacy.Results:There were 7 unsatisfactory, 118 benign, 10 atypia or follicular lesion of undetermined significance, 25 follicular neoplasms, 6 suspicious for malignancy, and 34 malignant thyroid FNA cases based on routine conventional smears. Cellularity of conventional smears was significantly higher than paired LBC smears (paired t test, P < 0.005). Comparison of overall diagnostic efficacy showed that LBC and CS were equivalent in 59% of cases; CS was superior to LBC in 37% cases and LBC was better than CS in 4% cases only. LBC smears showed higher unsatisfactory rate as compared to CS (18% vs. 3.5%). In category 2, the two techniques were equivalent in 87% of cases. In categories 4 and 6, CS were superior to LBC.Conclusions:In thyroid FNA cases, conventional smears are superior to LBC preparation in terms of cellularity and diagnostic efficacy and hence, LBC preparations should not replace conventional smears for making a routine cytomorphological diagnosis.

Molecular testing and thyroid nodule management in North America.

The incidence of thyroid cancer is rising for a variety of reasons. At the same time, the nomenclature revision of non-invasive encapsulated follicular-variant PTC to noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) has modified the incidence of thyroid cancer. Given that thyroid neoplasia is a molecular event, it is important for the thyroid physician to evaluate each patient systematically. Most thyroid cancers are sporadic; however, some are familial and may be associated with syndromes with genetic implications. Advances in radiologic imaging have made ultrasonography a near equivalent of gross examination. The American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) classifies nodules from TR1 to TR5 and is valuable in determining which patients should be guided toward fine-needle aspiration (FNA) sampling. While FNA procedures and processing may be varied, the key elements are cytologic diagnosis and collection of samples for potential molecular testing. The Bethesda System for Reporting Thyroid Cytology (BSRTC) is commonly used and categorizes each FNA specimen into one of six diagnoses. The indeterminate diagnoses with risk of malignancy (ROM) ranging from 10-75% comprise approximately 30% of thyroid FNA cases and for these, molecular testing is beneficial. In North America, the two most common molecular platforms are Veracyte Afirma GSC and ThyroSeq v3. Both panels cover an extensive array of genomic alterations associated with thyroid neoplasia and a negative result from either test effectively refines the ROM of an Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS) or Follicular Neoplasm/Suspicious for a Follicular Neoplasm (FN/SFN) diagnosis to 3-4%. Given that the refined ROMs are comparable to that of a Benign BSRTC diagnosis, these patients are recommended for observation of their nodules. However, differences exist in the implication of Afirma GSC-Suspicious and ThyroSeq v3-Positive molecular results with regard to the probability of cancer. For either test, the molecular test result should be integrated with other clinical parameters to determine if surgery is indicated and, if so, the extent of surgery.

Cytomorphologic features of thyroid disease in patients with DICER1 mutations: A report of cytology-histopathology correlation in 7 patients.

Germline and somatic mutations of DICER1 have been identified in various types of neoplastic lesions, with germline DICER1 mutation being linked to autosomal dominant hereditary pleiotropic tumor syndrome (DICER1 syndrome). Patients with DICER1 syndrome are at increased risk of developing thyroid disease, including thyroid cancer. The goal of this study was to identify diagnostic cytologic features in thyroid fine-needle aspiration (FNA) samples from patients with DICER1 mutation. Cytology cases of thyroid FNA from 7 patients with DICER1 mutation were identified. Clinical, imaging, cytomorphologic, and molecular data were analyzed. Cytologic preparations from reviewed cases showed thyroid lesions of follicular derivation with scant colloid, moderate cellularity, uniform follicular cells with round nuclei and inconspicuous nucleoli arranged in small crowded groups and microfollicles. Follicular neoplasm was diagnosed in 4 cases and follicular lesion of undetermined significance in 3 cases, based on the Bethesda System for Reporting Thyroid Cytopathology. Histopathological analysis of thyroid tissue confirmed neoplastic process in 6 out of 7 cases: follicular carcinoma (FC, 3 cases), papillary thyroid carcinoma (2 cases), poorly differentiated thyroid carcinoma (PDTC, 1 case). Genetic studies identified 3 different somatic variants of DICER1 gene, including transcript consequence c.5428G>T, which was detected in FC and PDTC (and has been described previously in multinodular goiter). DICER1 mutation in all analyzed patients was identified as a result of thyroid FNA evaluation, emphasizing the critical role of FNA in the screening of patients with thyroid nodules, proper diagnosis of thyroid disease, and monitoring of patients with DICER1 mutation.

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.

Role of Immunohistochemistry in Fine Needle Aspiration and Core Needle Biopsy of Thyroid Nodules.

ObjectivesImmunohistochemistry (IHC) has been used for the diagnosis of indeterminate results in fine needle aspiration (FNA) of thyroid nodules. However, the role of IHC in core needle biopsy (CNB) is not clear and the efficacy of testing for molecular markers following CNB has not been evaluated. The aim of this study is to compare the role of IHC staining in CNB with that in FNA when examining thyroid nodules and to compare the sensitivity and usefulness of different molecular markers.MethodsConsecutive cases of thyroid FNA and CNB accompanied by IHC from 2004 to 2014 were included in this study with retrospective review of medical record. The rate of remaining nondiagnostic result (unsatisfactory, atypia of undetermined significance or follicular lesion of undetermined significance [AUS/FLUS]) and rate of strong expression of each molecular marker according to the diagnosis were evaluated.ResultsIHC was more frequently performed in CNB with multiple molecular markers compared to FNA (38.1% vs. 2.8%, 3 or 4 markers [Gal-3, HBME-1, CK19, and CD56] vs. 1 marker [Gal-3]). In the CNB group, 11.3% remained as AUS/FLUS after IHC, and the rate remaining nondiagnostic was significantly less than in the FNA group (42.9%). Gal-3 and CK19 showed higher specificity and expressed mainly in conventional type of papillary carcinoma and HBME-1 showed higher sensitivity for the diagnosis of carcinoma with expression in both conventional type and follicular variant papillary thyroid carcinoma.ConclusionWith these data, we could conclude that IHC was more effective following CNB than following FNA.

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

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. 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. 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. 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. FNA = fine-needle aspiration NPV = negative predictive value PPV = positive predictive value.

Cytological study of thyroid lesions by fine-needle aspiration cytology

Background: Thyroid disorders are the most common endocrine disorders worldwide. Thyroid enlargement has to be investigated to rule out a neoplasm. The main purpose of fine-needle aspiration (FNA) is to provide a rational approach for management and determine the correct surgical procedure when surgery is required. Objectives are: (1) To assess the cytologic and morphological features of thyroid swellings by FNA cytology (FNAC), (2) to study the age of occurrence and sex predilection of various thyroid disorders diagnosed by FNAC, and (3) to classify all the thyroid lesions based on The Bethesda System of Reporting Thyroid Cytopathology (TBSRTC). Methods: In the present study, evaluation of 100 cases of thyroid FNA’s was undertaken and interpreted. All thyroid lesions conventionally diagnosed by FNA were classified according to TBSRTC. Results: In the present study, a total of 100 cases of thyroid swellings were analyzed, out of which 84 cases were diagnosed as non-neoplastic lesions, 3 cases as suspicious for malignancy, and 13 cases as neoplastic lesions by FNAC. The results were further classified under TBSRTC. Conclusion: FNAC is a relatively uncomplicated and safe diagnostic method, which is cost-effective. It is a helpful adjunct to pre-operative screening in the diagnosis and management of thyroid diseases.

Diagnosis of atypia/follicular lesion of undetermined significance: An institutional experience.

Background:The overall malignancy rate for the thyroid fine-needle aspiration (FNA) diagnosed as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) ranges from 5% to 30%. In this study, we present our institutional experience with thyroid nodules diagnosed as AUS/FLUS and further stratified into subcategories. In addition, we also assessed the significance of various clinicopathologic factors that may influence AUS/FLUS diagnoses and their outcomes.Design:A search of our laboratory information system was performed to identify all in-house thyroid FNA cases diagnosed as AUS/FLUS from 2008 to 2012. The data were collected and characterized by patient demographic information, cytopathology diagnosis with sub-classifiers and follow-up.Results:The case cohort included 457 cases diagnosed as AUS/FLUS. These were further sub-classified into one of six subcategories depending on the cytomorphologic findings and suspicion for or against a neoplastic process. Of the 457 cases, repeat FNA and/or surgical follow-up was available in 363 cases. There were 182 (39.8%) cases with cytologic follow-up only; 18 (9.9%) remained as AUS/FLUS, while 158 (86.8%) were re-classified with the majority being benign (142 cases). Histologic follow-up was available in 181 (39.6%) cases. There were 60 malignant cases confirmed by surgical excision, with an overall malignancy rate of 33.1%. The malignancy rate was 38.8% for cases with a repeat FNA versus 25.6% for cases that went directly to surgery without a repeat FNA. Papillary thyroid carcinoma accounted for 93.3% (56 cases) of the malignant cases.Conclusion:Based on our study, even though the malignancy rate of AUS/FLUS cases is similar to those reported for cases diagnosed as follicular neoplasm/suspicious for follicular neoplasm, we are of the belief that these comparable malignancy rates are a product of better clinical management and selection of patients diagnosed as AUS/FLUS for surgery after a repeat FNA.

Risk stratification in follicular neoplasm: a cytological assessment using the modified Bethesda classification.

The 2007 Bethesda classification for thyroid cytology defines follicular neoplasm as a category of cases with cellular specimens demonstrating abundant follicular cells arranged in a microfollicular pattern with little or no colloid. The current recommendation for the management of these cases is diagnostic lobectomy. There has been great difficulty and variability in triaging and reporting follicular neoplasm. To increase diagnostic accuracy, at the study institution, this category is subclassified further into 3 categories: 1) microfollicular-patterned neoplasm (MN); 2) Hürthle cell neoplasm (HN); and 3) follicular lesion with some features suggestive of but not diagnostic of the follicular variant of papillary thyroid carcinoma (FL). The authors reviewed the cases of follicular neoplasm observed over a period of 5 years to document the follow-up trend using this modified classification. A search of the cytology records was performed for the period between January 2008 and December 2012. All thyroid fine-needle aspiration cases were reviewed and those with a diagnosis of follicular neoplasm (including Hürthle cell neoplasm) were identified. Correlating follow-up surgical pathology reports were reviewed. A total of 399 cases of follicular neoplasm with surgical follow-up were identified. Malignancy was identified in 32% of all cases of follicular neoplasm and was found to be disproportionately higher in the FL category (73%). A cytological diagnosis of FL is more likely to be called malignant (73%) than benign neoplastic (9%) or benign nonneoplastic (18%). A cytological diagnosis of MN or HN is more likely to be benign neoplastic (46% and 46%, respectively) than malignant (29% and 26%, respectively) or benign nonneoplastic (25% and 28%, respectively). Of the cytological features examined, 2 (nuclear enlargement and nuclear grooves) were significantly associated with the follicular variant of papillary thyroid carcinoma. The results of the current study clearly indicate that follicular lesions with even subtle nuclear atypia have a high positive predictive value for malignancy and therefore should be distinguished from other follicular lesions because these cases require more aggressive surgical management. The current study also raises an important issue concerning the current thyroid classification based on the 2007 Bethesda classification for thyroid cytology. Future thyroid fine-needle aspiration classification schemes should consider subclassifying follicular neoplasms for the purpose of risk stratification.

Reply to can a gene‐expression classifier with high negative predictive value solve the indeterminate thyroid fine‐needle aspiration dilemma?

Rossi and colleagues aptly identify an important issue in the search for appropriate ancillary tests for indeterminate thyroid fine-needle aspiration (FNA) specimens. Given the current expensive price tag of molecular testing, including the Afirma Thyroid FNA Analysis (Veracyte, South San Francisco, Calif), the use of less-expensive alternatives, possibly including immunocytochemical markers as proposed by Rossi et al, could provide a large cost savings, at least until the time (most likely within the not-too-distant future) that molecular testing becomes more affordable. This is not a trivial point. In the current health care climate, in which cost containment is paramount, balancing the efficacy of a particular testing method with its overall cost versus savings to the system is critical. In agreement with Rossi et al, this is one reason why the first-line response to an indeterminate thyroid FNA diagnosis of atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) should be repeat FNA, as supported by the Bethesda System for Reporting Thyroid Cytopathology.1 A significant aspect omitted by Alexander et al's discussion of the Afirma test is the role of repeat FNA in the decision-making process.2 Several groups, including ours, have shown that repeat FNA can accurately reclassify greater than 50% of nodules in the AUS/FLUS category as benign by cytologic evaluation alone without the use of any ancillary molecular tests. Thus, for the AUS/FLUS group of specimens, which accounts for the largest percentage of indeterminate thyroid FNA cases, a repeat thyroid FNA appears to be at least as good if not better than the Afirma test for guiding patient management. Specifically with regard to the application of immunocytochemical studies to indeterminate thyroid FNAs, Rossi et al have cited their work using galectin-3 and HBME-1 to triage these thyroid FNAs into low-risk and high-risk categories.3 Although the negative predictive value of those markers is only 77%, the use of immunocytochemistry in the study by Rossi et al relies not so much on a definitive classification of the thyroid FNA but on a more general sorting of FNAs into 2 management groups. That being said, there is a steep hurdle to overcome to convince laboratories to use immunocytochemistry for thyroid FNAs, namely demonstrating that such testing is reproducibly accurate. In addition to mixed results using galectin-3 and HBME-1 in individual laboratories, there are conflicting reports about the use of these markers within the literature. Nevertheless, even if immunocytochemistry were to be used to evaluate indeterminate thyroid FNAs, its success as an ancillary test is likely to be short-lived as molecular strategies become both more precise and much more affordable. The author made no disclosures. William C. Faquin, MD, PhD Department of PathologyMassachusetts General HospitalHarvard Medical SchoolBoston, Massachusetts

Assessment of Malignancy for Atypia of Undetermined Significance in Thyroid Fine-Needle Aspiration Biopsy Evaluated by Whole-Slide Image Analysis

Atypia of undetermined significance (AUS) in thyroid fine-needle aspiration (FNA) has a low to intermediate incidence of malignancy, and objective criteria could allow for improved assessment of malignancy. Consecutive thyroid FNA AUS cases with surgical excision were selected. Whole-slide images (WSIs) were evaluated for basic criteria by image analysis, including total groups and nuclear/cytoplasmic (N/C) ratio. The 44 cases encompassed 23 benign and 21 malignant entities. Seventeen (81%) of 21 malignant cases and 11 (48%) of 23 benign cases had an N/C ratio of 0.50 or less. An N/C ratio of 0.50 or less had an odds ratio for malignancy of 4.64 (P = .03). A combined category of an N/C ratio of 0.50 or less and greater than 20 cell groups had an odds ratio for malignancy of 7.0 (P = .04). Establishing defined objective WSI criteria has the potential to provide an assessment of malignancy for AUS thyroid FNA cases.

Impact of the bethesda system for reporting thyroid cytology in the Illawarra Shoalhaven regions of NSW

<h3>Aim</h3> To investigate the impact of the Bethesda classification on reporting of thyroid fine needle aspiration (FNA) biopsies in our practice. <h3>Method</h3> Thyroid FNA cases from 2008 to August 2012 were retrieved from the computer files of Southern IML and the Wollon-gong Hospital, where most of the cytology and histology cases in the Illawarra/Shoalhaven regions of NSW are reported. The first half of 2008 (before the Bethesda system was published) was compared to the second half of 2011, after the Bethesda system was formally adopted in our practice. <h3>Results</h3> We analysed 150 cases pre-Bethesda (1.1.08–31.5.08) and 361 cases post-Bethesda (1.5.11–31.12.11). Cases from 2008 and 2011 were classified as follows: insufficient (25.3% vs 16.9%), benign (66% vs 73%), atypical (4% vs 4.4%), atypical follicular pattern/follicular neoplasm (4% vs 1.9%), suspicious for malignancy (0.7% vs 0.8%), malignant (0 vs 1.1%). <h3>Discussion</h3> In our practice, use of the Bethesda System for Reporting Thyroid Cytology has improved consistency of reporting by providing standardised criteria which was reflected in the pathology reports. The increased numbers of benign cases is consistent with change in ultrasound biopsy practices (re-flected in the different population characteristics) and current literature.

Image Cytometry of Fine Needle Aspiration of Thyroid Epithelial Lesions

Fine needle aspiration (FNA) biopsy has been documented as a reliable, cost-effective test, diagnosing different thyroid lesions. However, its sensitivity declines much in some settings. This study aimed to investigate the value of computerized morphometry and DNA ploidy in differential diagnosis of different thyroid epithelial follicular lesions diagnosed on FNA smears. In this study, 68 cases of thyroid FNA were cytologically examined, and classified according to their postthyroidectomy histopathologic diagnosis as follow: 10 cases of nodular goiter, 14 cases of adenomas, 10 cases of follicular carcinoma, 20 cases of papillary carcinoma, 10 cases of anaplastic carcinoma, and 4 cases of poorly differentiated carcinoma. Using Leica Qwin 500 image analysis system, nuclear area as a morphologic variable, and the DNA ploidy, DNA index, and proliferation indices were measured for each case. Sensitivity of FNA in the studied cases was optimum (100%) in papillary carcinomas and anaplastic carcinomas. However, the sensitivity declined sharply in discriminating nodular goiter and follicular adenoma from well-differentiated follicular carcinoma, thus, most of these cases were diagnosed as follicular lesions. A significant difference in mean values of nuclear area was found between benign and malignant lesions, with no statistical differences within the benign group. Aneuploidy was significantly associated with malignancy. Therefore, image analysis may become an important ancillary test in the initial evaluation of patients with thyroid epithelial lesions.