Suspicious For Follicular Neoplasm Research Articles

Evaluating Postoperative Outcomes and Investigating the Usefulness of EU-TIRADS Scoring in Managing Pediatric Thyroid Nodules Bethesda 3 and 4

The aim was to assess postoperative outcomes in pediatric thyroid nodules with atypia of undetermined significance (AUS/FLUS) or suspicious for a follicular neoplasm (SFN) and their respective the European-Thyroid Imaging Reporting and Data System (EU-TIRADS) scores. Forty-four pediatric patients at a single center with thyroid nodules classified as AUS/FLUS or SFN from August 2019 to December 2022 were retrospectively reviewed. Data on demographics, thyroid function, nodule size, and ultrasonographic features were collected. Postoperative pathologies were categorized into benign, low-risk, and malignant neoplasms according to the World Health Organization 2022 criteria, and EU-TIRADS was used for retrospective radiological scoring. Among 21 (47.7%) of patients who had surgical intervention, 72% had Bethesda 3 and 28% had Bethesda 4 thyroid nodules. Post-surgical histopathological classifications were 43% benign, 19% low-risk, and 38% malignant. Of note, EU-TIRADS 3 and 5 scores were present in 44% and 56% of the benign cases, respectively. Malignant cases tended to produce higher EU-TIRADS scores, with 64% rated as EU-TIRADS 5. Bethesda category 4 nodules had a 66% malignancy rate, significantly higher than the 27% in category 3. A substantial proportion of histologically benign cases were classified as EU-TIRADS 5, suggesting that EU-TIRADS may lead to unnecessary biopsies in benign cases. Malignant cases were more likely to have a higher EU-TIRADS score, indicating a positive correlation with malignancy risk, particularly in Bethesda 4 cases. However, the EU-TIRADS system’s predictive value for malignancy in Bethesda 3 cases was poorer.

"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.

Expression of micro-ribonucleic acids in thyroid nodules and serum to discriminate between follicular adenoma and cancer in patients with a fine needle aspiration biopsy classified as suspicious for follicular neoplasm: A preliminary study.

Approximately 10% of thyroid nodules undergoing fine needle aspiration biopsy (FNAB) receive a suspicious for follicular neoplasm (SFN) classification. Currently, there is no diagnostic tool to preoperatively discriminate between follicular adenoma (FA) and thyroid cancer (TC), and most patients require surgery to exclude malignancy. To characterize the micro-ribonucleic acid (miRNA) signature of tumors assessed as SFN and define circulating miRNA patterns to distinguish FA from follicular cancer in patients with thyroid nodules biopsied using FNAB. The study included excised tumor and thyroid tissue samples from 80 consecutive patients collected by a pathologist in the operating theater. The miRNA was isolated from specimens at the Center for Medical Genomics OMICRON, and next-generation sequencing (NGS) was used to obtain target miRNAs. In addition, miRNA expression was detected in serum using polymerase chain reaction (PCR). Well-differentiated thyroid cancer (WDTC) samples had significantly higher expression levels of hsa-miR-146b-5p (p = 0.030) and hsa-miR-146b-3p (p = 0.032), while the expression levels of hsa-miR-195-3p were significantly lower (p = 0.032) in WDTC samples compared to FA specimens. The serum of TC patients showed markedly higher expression of the unique miRNA hsa-miR-195-3p (p = 0.039). The overexpression of hsa-miR-146b-5p and hsa-miR-146b-3p, and the downregulation of hsa-miR-195-3p expression could be used as biomarkers to distinguish FA from WDTC in patients with FNAB results classified as Bethesda tier IV. In addition, hsa-miR-195-3p could act as a serum biomarker for differentiating patients with FA from those with WDTC, and preoperative measurement of its expression would help avoid unnecessary surgeries. However, this concept needs further verification in a more substantial prospective study.

Assessment of diagnostic value of preoperative elastography in thyroid nodules having indeterminate cytology results

The management of nodules with indeterminate cytology [atypia of undetermined significance (AUS), follicular lesion of undetermined significance (FLUS), follicular neoplasm (FN), suspicious for a follicular neoplasm (SFN), and suspicious for malignancy (SM)] results is controversial. To assess the role of the elastography technique in the diagnosis of malignancy in the subtypes of indeterminate thyroid nodules. We included 132 patients with indeterminate cytology who underwent thyroid surgery. Sensitivity, specificity, area under the curve, and optimal cut-off points were calculated with receiver operating characteristic (ROC) analysis for elastography score (ES) and strain index (SI). Malignancy was observed in 27/95 (28.4%) of the AUS-FLUS cytology and 12/24 (50%) of FN, SFN cytology. All of the 13 patients (100 %) with SM are found to be malignant on histology. In the FLUS group, nodules with ES greater or equal to 3, the presence of malignancy was higher 17/41 (41.5%) when compared with nodules with ES smaller than 39/46 (19.6 %) (p = 0.023). In the SFN group, 2 of 2 nodules with an ES score of 4 and 1 of 1 nodule with an ES score of 5 were malignant. In the FLUS group, 4 of 10 nodules with an ES score of 4 and 2 of 2 nodules with an ES score of 5 were malignant. Thyroid elastography may reduce unnecessary surgery for both patients with AUS/FLUS and selected SFN cytology. Elastography appears to be helpful in follicular variants and other types of papillary thyroid cancer, however, not in follicular thyroid cancer.

Assessment of diagnostic value of preoperative elastography in thyroid nodules having indeterminate cytology results.

The management of nodules with indeterminate cytology [atypia of undetermined significance (AUS), follicular lesion of undetermined significance (FLUS), follicular neoplasm (FN), suspicious for a follicular neoplasm (SFN), and suspicious for malignancy (SM)] results is controversial. To assess the role of the elastography technique in the diagnosis of malignancy in the subtypes of indeterminate thyroid nodules. We included 132 patients with indeterminate cytology who underwent thyroid surgery. Sensitivity, specificity, area under the curve, and optimal cut-off points were calculated with receiver operating characteristic (ROC) analysis for elastography score (ES) and strain index (SI). Malignancy was observed in 27/95 (28.4%) of the AUS-FLUS cytology and 12/24 (50%) of FN, SFN cytology. All of the 13 patients (100 %) with SM are found to be malignant on histology. In the FLUS group, nodules with ES greater or equal to 3, the presence of malignancy was higher 17/41 (41.5%) when compared with nodules with ES smaller than 39/46 (19.6 %) (p = 0.023). In the SFN group, 2 of 2 nodules with an ES score of 4 and 1 of 1 nodule with an ES score of 5 were malignant. In the FLUS group, 4 of 10 nodules with an ES score of 4 and 2 of 2 nodules with an ES score of 5 were malignant. Thyroid elastography may reduce unnecessary surgery for both patients with AUS/FLUS and selected SFN cytology. Elastography appears to be helpful in follicular variants and other types of papillary thyroid cancer, however, not in follicular thyroid cancer.

Revised Bethesda System for Reporting Thyroid Cytology: Lessons learned from an appraisal of 5years of experience in a central hospital.

The Bethesda System for Reporting Thyroid Cytology (BSFRTC) is widely adopted in the management of thyroid nodules. The system was updated in 2017, and its impact is the subject of this paper. All thyroid fine needle aspirations from 2016-2020 using the BSFRTC, with follow-up surgical pathology, were reviewed. The risk of neoplasia (RON), risk of malignancy (ROM), RON/ROM ratio, and surgical follow-up rate were determined for each diagnostic category with cytohistological correlation. ROM was calculated in two separate manners, with non-invasive follicular tumours with papillary-like nuclear features (NIFTP) counted as malignant or non-malignant. Sensitivity, specificity, negative and positive predictive values were determined for indeterminate categories: atypia of undetermined significance (AUS), suspicious for follicular neoplasm (SFN), and suspicious for malignancy (SFM). RON, ROM, and the surgical follow-up rate increased steadily from the benign through intermediate to malignant categories. The omission of NIFTP from malignant lesions reduced the calculated ROM in indeterminate categories and improved the stratification between AUS and SFN. ROM in AUS was distinct from SFN. AUS has a well-balanced sensitivity and specificity favouring a screening rather than a diagnostic category. The calculated RON/ROM was significantly higher in AUS (1.56), compared to SFN (1.03) and SM (1.05), in agreement with current BSRTC management recommendations. AUS is an important screening category and should remain with the addition of subcategorisation. RON and surgical follow-up rates are essential quality indicators. The RON/ROM ratio could be utilised to determine appropriate management for each diagnostic category on an institutional basis.

Impact of a genomic classifier on indeterminate thyroid nodules: an institutional experience

Indeterminate thyroid cytology (ITC) occurs in 20% to 25% of cases, and the associated risk of malignancy ranges from 5% to 30%. The genomic classifier ThyroSeq (CBLPath/UPMC, Rye Brook, NY), a targeted next-generation sequencing technology, could classify ITC nodules as malignant and nonmalignant. We sought to characterize our institutional experience with ThyroSeq testing. We retrospectively identified all patients seen from January 2015 through November 2019 who had ITC nodules analyzed with ThyroSeq. Relevant clinical, pathologic, and resection data were reviewed. Of the 133 cases identified, diagnostic categories included atypia (or follicular lesion) of undetermined significance) (n = 65 [48.9%]), suspicious for follicular neoplasm (SFN) (n = 48 [36.1%]), and suspicious for Hürthle cell neoplasm (n = 20 [15.0%]). About half of the papillary thyroid carcinoma (PTC) cases (n = 9 [56.3%]) and more than one-third of the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) cases (n = 3/8 [37.5%]) were classified as SFN. Most patients (n = 87 [65.4%]) did not undergo resection; of these, 73 (83.9%) were negative for all molecular alterations. Of the 54 cases with molecular alterations, isolated RAS or RAS-like variants were most common (n = 35 [64.8%]); 9 (25.7%) were identified in PTC and 8 (22.9%) in NIFTP. NRAS was the most common alteration (n = 20 [37.0%]), followed by HRAS (n = 6 [11.1%]), which was mostly detected in NIFTP cases (n = 4 of 6 [66.7%]). Resection was avoided in 73 patients (54.9%) because of negative ThyroSeq results. ThyroSeq v2 and v3 offered a more accurate categorization of ITC nodules, improved patient management, and reduced unnecessary surgical procedures.

The Bethesda System for Reporting Thyroid Cytopathology: A Cytohistological Study.

Introduction The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is a significant step to standardize the reporting of thyroid fine needle aspiration (FNA). It has high predictive value, reproducibility, and improved clinical significance. Aim The study was aimed to evaluate the diagnostic utility and reproducibility of “TBSRTC” at our institute. Methods and Material. The study included 646 thyroid FNAs which were reviewed by three pathologists and classified according to TBSRTC. Cytohistological correlation was done for 100 cases with surgical follow-up and the sensitivity, specificity, positive predictive value, negative predictive value, diagnostic accuracy, and risk of malignancy (ROM) were calculated. The interobserver variation among three pathologists was also assessed. Results The distribution of cases in various TBSRTC categories is as follows: I—nondiagnostic 13.8%, II—benign 75.9%, III—atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) 1.2%, IV—follicular neoplasm (FN)/suspicious for follicular neoplasm (SFN) 3.7%, V—suspicious for malignancy (SM) 2.6%, and VI—malignant 2.8%. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy are 72.4%, 94.3%, 84%, 89.2%, and 87.9%, respectively. The ROM of various TBSRTC categories were II—8.5%; III—66.7%; IV—63.6%; and V and VI—100%. Cohen's Weighted Kappa score was 0.99 which indicates almost perfect agreement among the three pathologists. Conclusions Our study substantiates greater reproducibility among pathologists using TBSRTC to arrive at a precise diagnosis with an added advantage of predicting the risk of malignancy which enables the clinician to plan for follow-up or surgery and also the extent of surgery.

Risk Stratification Study of Indeterminate Thyroid Nodules with a next-generation Sequencing Assay with Residual ThinPrep® Material.

Objective: The management of indeterminate thyroid nodules is challenging. Molecular testing has emerged as a promising method for stratifying this gray area of fine-needle aspiration (FNA) cytology. Next-generation sequencing (NGS) can be used to test a large variety of genetic changes with very small amounts of nucleic acids obtained from FNA samples.Methods: Thyroid FNA assays were classified according to the Bethesda System for Reporting Thyroid Cytopathology after routine ThinPrep® slide preparation. Indeterminate nodules with surgical outcomes were assayed with an 18-gene NGS panel with the residual ThinPrep® material, including nodules categorized as atypia of undetermined significance (AUS)/follicular lesions of undetermined significance (FLUS) or follicular neoplasm (FN)/suspicious for a follicular neoplasm (SFN). We evaluated the diagnostic efficacy of the 18-gene panel for thyroid malignancies and potential malignancies and compared it with a well-accepted examination, ThyroSeq v2 testing.Results: A total of 36 indeterminate nodules were assayed, seven were categorized as AUS/FLUS and 29 as FN/SFN. All of them had adequate DNA for the NGS procedure. When noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was considered malignant, the risk of malignancy was 71.4% for AUS/FLUS nodules, and 69.0%for FN/SFN nodules. The 18-gene panel showed 72.0% sensitivity, 72.7% specificity, 85.7% positive predictive value (PPV), and 53.3% negative predictive value (NPV) in identifying malignancies and potential malignancies in the indeterminate nodules. Compared with a multicenter report from ThyroSeq v2 testing, 18-gene panel showed a lower NPV (p=0.005), but a higher PPV (p=0.02).Conclusions: NGS assays are feasible on residual ThinPrep® material, with the advantage of not requiring additional FNA procedure. The 18-gene panel testing can be used as a 'rule in' test for surgical management based on indeterminate nodules and showed a lower NPV but a higher PPV compared to ThyroSeq v2 testing.

Molecular markers for the classification of cytologically indeterminate thyroid nodules.

The diagnosis of indeterminate lesions of the thyroid is a challenge in cytopathology practice. Indeed, up to 30% of cases lack the morphological features needed to provide definitive classification. Molecular tests have been developed to assist in the diagnosis of these indeterminate cases. The first studies dealing with the preoperative molecular evaluation of FNA samples focused on the analysis of BRAFV600E or on the combined evaluation of two or three genetic alterations. The sensitivity of molecular testing was then improved through the introduction of gene panels, which became available for clinical use in the late 2000s. Two different categories of molecular tests have been developed, the 'rule-out' methods, which aim to reduce the avoidable treatment of benign nodules, and the 'rule-in' tests that have the purpose to optimize surgical management. The genetic evaluation of indeterminate thyroid nodules is predicted to improve patient care, particularly if molecular tests are used appropriately and with the awareness of their advantages and weaknesses. The main disadvantage of these tests is the cost, which makes them rarely used in Europe. To overcome this limitation, customized panels have been set up, which are able to detect the most frequent genetic alterations of thyroid cancer. In the present review, the most recent available versions of commercial molecular tests and of custom, non-commercial panels are described. Their characteristics and accuracy in the differential diagnosis of indeterminate nodules, namely Bethesda classes III (Atypical follicular lesion of undetermined significance, AUS/FLUS) and IV (Suspicious for follicular neoplasm, FN/SFN) are fully analyzed and discussed.

Genetic heterogeneity of indeterminate thyroid nodules assessed preoperatively with next-generation sequencing reflects the diversity of the final histopathologic diagnosis.

Inconclusive cytologic results of thyroid fine‑needle aspiration biopsy (FNAB) include atypia or follicular lesion of undetermined significance (FLUS) and follicular neoplasm or suspicious for follicular neoplasm (SFN). We aimed to assess the genetic background of indeterminate thyroid nodules and to identify new genetic pathways potentially involved in the development of follicular thyroid cancer. Genomic DNA was isolated from FNAB samples from 25 white patients (2 men; 23 women) diagnosed preoperatively with FLUS (n = 16) and SFN (n = 9). Next‑generation sequencing (NGS) was performed. The results were compared with clinical data, including final postsurgical diagnoses. The malignancy rate was 28%. KDR, RET, and TP53 gene mutations were most frequent in FLUS and SFN samples finally diagnosed as cancers, whereas alterations in RET, TP53, FLT3, APC, and PDGFRA predominated in benign tumors. KDR tended to be more common in malignant samples (75% vs 20%, P = 0.1). A total number of mutated genes was higher in patients with benign tumors (17 vs 11, P = 0.02), but there was no difference between groups in the mean number of mutations per patient (4.9 [range, 1-9]). We showed that the heterogeneity in the genetic background of indeterminate thyroid nodules corresponds to their histopathologic diversity. The role of KDR as a possible malignancy marker needs to be confirmed. Glass slides with FNAB samples may constitute a reliable source of genetic material for NGS studies, providing a better insight into the molecular profile of thyroid nodules.

Hürthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation.

Hürthle cell lesions often pose diagnostic challenges, despite their common occurrence on thyroid fine-needle aspiration cytology (FNAC). The associated molecular alterations are also not well understood. Therefore, our study aimed to delineate the molecular profile of Hürthle cell lesions classified as Bethesda Categories III or IV (atypia of undetermined significance (AUS) or suspicious for follicular neoplasm (SFN)) on FNAC and to correlate this molecular profile with surgical resection findings. This study consisted of 188 Hürthle cell lesions with indeterminate cytology and ThyroSeq® v2/v3 molecular testing results. Surgical follow-up was available for 33 cases. The majority of indeterminate Hürthle cell lesions had negative ThyroSeq® results (61%) and were benign on available surgical follow-up. The most prevalent mutations involved the RAS gene (21%), which were associated with benign lesions, non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and malignancy. The remaining mutations involved less than 18% of the cases, including PAX8/PPARG (3.7%), TSHR (3.7%), EIF1AX (2.7%), MET (2.1%), PTEN (1.6%), clonal copy number alteration (1.6%), TERT (1.1%), and 0.5% each of GNAS, PIK3CA, and TP53 mutations. On follow-up, 45% were benign, 24% were NIFTP, and 30% were malignant. The malignant cases had different molecular alterations. No single molecular alteration defines cytologically indeterminate Hürthle cell lesions; the majority of cases have low-risk or no molecular alterations and are benign on follow-up. These findings suggest that molecular testing may be useful, but is not definitive, in determining which cases may be managed conservatively; additional studies are needed to fully determine the negative predictive value in ruling out malignancy.

Malignancy Rates of Thyroid Cytology: Cyst Fluid Benign or Non-Diagnostic?

BackgroundWe sought to investigate subgroup distribution using Bethesda classification and risks for malignancy. We also compared the malignancy risk of cases that were denoted as non-diagnostic due to cystic contents, with cases that were denoted as non-diagnostic due to presence of other features.Material/MethodsThe study included pathology test results of 1,440 thyroid nodule samples diagnosed using Bethesda classification. Results of 305 thyroidectomy excision specimens from these patients were also compared with cytology results to determine the frequency of malignancy. The non-diagnostic group was divided into two categories: those with cystic contents, and others. Malignancy rates were separately calculated for the two groups, and compared with the other classification groups.ResultsDistribution of malignancy rates by Bethesda classification were as follows: non-diagnostic 12.5% (6/48), benign 1.5% (3/198), atypia of undetermined significance/follicular lesion of undetermined significance (AFLUS) 9% (1/11), suspicious for follicular neoplasm (SFN) 37.5% (3/8), suspicious malignancy 70% (8/26), malignancy 100% (14/14).ConclusionsDespite the limited number of cases, our study concluded that cystic content was closer to the benign category than the non-diagnostic category if the assessment was based on malignancy rates. In this group, similar to aspirations containing plenty of lymphocytes that indicates colloid or lymphocytic thyroiditis, it is still controversial whether criterion for adequacy of follicular epithelial cells should be sought, or if they should be regarded as benign in order to prevent unnecessarily performance of repeat aspirations.

The Use of the Bethesda System for Reporting Thyroid Cytopathology in Korea: A Nationwide Multicenter Survey by the Korean Society of Endocrine Pathologists.

BackgroundThe Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has standardized the reporting of thyroid cytology specimens. The objective of the current study was to evaluate the nationwide usage of TBSRTC and assess the malignancy rates in each category of TBSRTC in Korea. MethodsQuestionnaire surveys were used for data collection on the fine needle aspiration (FNA) of thyroid nodules at 74 institutes in 2012. The incidences and follow-up malignancy rates of each category diagnosed from January to December, 2011, in each institute were also collected and analyzed. ResultsSixty out of 74 institutes answering the surveys reported the results of thyroid FNA in accordance with TBSRTC. The average malignancy rates for resected cases in 15 institutes were as follows: nondiagnostic, 45.6%; benign, 16.5%; atypical of undetermined significance, 68.8%; suspicious for follicular neoplasm (SFN), 30.2%; suspicious for malignancy, 97.5%; malignancy, 99.7%. ConclusionsMore than 80% of Korean institutes were using TBSRTC as of 2012. All malignancy rates other than the SFN and malignancy categories were higher than those reported by other countries. Therefore, the guidelines for treating patients with thyroid nodules in Korea should be revisited based on the malignancy rates reported in this study.

The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the performance of the Afirma gene expression classifier.

A recent revision in thyroid tumor nomenclature has resulted in a change from a malignant diagnosis (noninvasive follicular variant of papillary thyroid carcinoma) to one that is nonmalignant (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP]). The objective of the current study was to evaluate the impact of this change on the performance of the Afirma gene expression classifier (GEC). The authors retrospectively analyzed consecutive thyroid fine-needle aspiration specimens with indeterminate diagnoses on which GEC was performed. Surgical pathology material was reviewed with the reclassification of nodules into NIFTP. GEC testing was performed on 384 fine-needle aspiration specimens diagnosed as atypia of undetermined significance (AUS) (304 cases) and suspicious for a follicular neoplasm (SFN) (80 cases) and yielded a suspicious result in 152 of the AUS cases (50%) and 50 of the SFN cases (63%). Thyroidectomy was performed on 177 patients. After reclassifying NIFTP, the positive predictive value of GEC decreased from 42% (95% confidence interval [95% CI], 39%-45%) to 24% (95% CI, 22%-26%) in the AUS group and from 23% (95% CI, 19%-27%) to 13% (95% CI, 9%-18%) in the SFN group. Total thyroidectomy was performed more frequently than a partial thyroidectomy in patients with AUS with a suspicious GEC result compared with pre-GEC controls (68% vs 49%; P = .037). Reclassification of NIFTP significantly decreases the positive predictive value of GEC in indeterminate thyroid nodules. Nevertheless, the majority of patients with indeterminate thyroid nodules with a suspicious GEC result in the study institution have undergone total thyroidectomy. This finding raises concerns over reliance on a suspicious GEC result by clinicians to justify total thyroidectomy. Cancer Cytopathol 2017;125:683-91. © 2017 American Cancer Society.

Correlation Between Histological Diagnosis and Mutational Panel Testing of Thyroid Nodules: A Two-Year Institutional Experience

Indeterminate thyroid fine-needle aspiration (FNA) cytology, including atypia of undetermined significance (AUS/FLUS) and suspicious for follicular neoplasm (SFN), continues to generate uncertainty about the presence of malignancy, resulting in repeated follow-up, repeat FNA, or diagnostic surgery. Mutational panel testing may improve the malignancy risk prediction in indeterminate nodules, but the general application of such testing has not been investigated extensively. A retrospective review was performed of all patients undergoing thyroidectomy at a tertiary care facility over a two-year period. Mutational panel test results, when present, were analyzed relative to FNA cytologic result and surgical histopathologic diagnosis. Malignancy rates, sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and positive and negative likelihood ratios (LR) were calculated. A total of 261 operated thyroid nodules had the following initial FNA cytology results: 2% non-diagnostic, 23% benign, 28% AUS/FLUS, 11% SFN, 9% suspicious for malignancy (SUSP), and 27% malignant. The histopathologic malignancy rate was 48%, subcategorized by cytology into benign 7%, AUS/FLUS 30%, SFN 38%, and SUSP 83%. Mutations were more frequent in indeterminate nodules that were histologically malignant versus benign (p < 0.0001) or versus adenoma (p = 0.001). Mutational analysis in 44 AUS/FLUS nodules resulted in a malignancy detection sensitivity of 85%, a specificity of 65%, a PPV of 50%, a NPV of 91%, and a positive LR of 2.4. In 12 SFN nodules analyzed with ThyroSeq(®) testing, sensitivity was 100%, specificity 57%, PPV 63%, NPV 100%, and LR 2.3. Performance of the seven-gene mutational panel was not significantly different from the ThyroSeq(®) panel in the AUS/FLUS group. The malignancy yield, comparing the mutation positive AUS/FLUS group with the untested AUS/FLUS surgical cohort, did not reach statistical significance (p = 0.17). In a surgical cohort, a similar NPV but a lower PPV was found with the use of mutational panel testing compared to the published literature. Following the identification of a mutation, the prevalence of malignancy in the AUS/FLUS or SFN category was increased by nearly 15% to 45% and 53%, respectively. Further study is needed to confirm these results and to analyze clinical outcome subcategories relative to the utility of mutational testing.

Noninvasive Follicular Variant of Papillary Thyroid Carcinoma and the Afirma Gene-Expression Classifier.

It is now recognized that noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) is a distinct subset of FVPTC with an exceedingly indolent clinical course. The Afirma gene-expression classifier (GEC) helps guide clinicians in the management of thyroid nodules with indeterminate fine-needle aspiration (FNA) results. Thyroid surgery is recommended for nodules with a suspicious Afirma result, whereas observation is deemed reasonable for most nodules with a benign result. The aim of this study was to confirm that the Afirma test detects NFVPTCs and to determine how many carcinomas detected by the Afirma GEC represent NFVPTCs. From a database of 249 FNAs sent for Afirma testing between January 2012 and October 2014, a search was conducted for cases with a preceding FNA diagnosis of atypia/follicular lesion of undetermined significance (AUS/FLUS) or suspicious for a follicular neoplasm (SFN), a suspicious Afirma result, and a corresponding resection specimen reviewed at Brigham and Women's Hospital. The diagnoses of the prior FNAs and subsequent resection specimens were recorded. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify NFVPTCs. Sixty-three cases met the inclusion criteria. The preceding FNA diagnosis was AUS/FLUS in 34 (54%) cases and SFN in 29 (46%) cases. The surgical resection specimen demonstrated 16 (25%) FVPTCs, five (8%) follicular thyroid carcinomas, one (2%) classical type PTC, and 41 (65%) benign tumors/nodules. Of the 16 FVPTCs, 14 (88%) were NFVPTCs. Thus, NFVPTCs accounted for 64% of the carcinomas in the cohort. These results indicate that the Afirma GEC detects NFVPTCs and that many of the carcinomas detected by Afirma are NFVPTCs. While all care should be individualized and include clinical and sonographic assessment, these results suggest lobectomy as opposed to total thyroidectomy should be considered for nodules with a preceding AUS/FLUS or SFN on cytology and a suspicious Afirma result.

Impact of the Afirma Gene Expression Classifier Result on the Surgical Management of Thyroid Nodules with Category III/IV Cytology and Its Correlation with Surgical Outcome

Objective: The Afirma gene expression classifier (GEC) is a molecular test to further classify indeterminate fine-needle aspiration (FNA) as benign or suspicious for malignancy. Study Design: A total of 158 FNAs with Bethesda category III/IV cytology were sent for an Afirma GEC test. We correlated the Afirma GEC results with surgical outcome and also compared the data after Afirma's implementation with the data before. Results: Among the 158 FNAs, the Afirma result was benign in 63 (40%), suspicious in 85 (54%) and unsatisfactory in 10 (6%). In total, 73 (86%) suspicious Afirma cases had surgery and 28 (38%) showed carcinoma. In contrast, only 8 (13%) benign Afirma cases had surgery and all of them were benign. The sensitivity, specificity, negative predictive value and positive predictive value (PPV) of Afirma were 100, 15, 100 and 38%, respectively. The PPV was 20% in cases with follicular lesion of undetermined significance, but was 50% in cases suspicious for follicular neoplasm (SFN). The surgical excisional rate was significantly decreased in SFN cases after the Afirma test. Conclusions: The Afirma GEC is useful for further risk stratifying SFN cases.

Should Core Needle Biopsy be Used in the Evaluation of Thyroid Nodules?

Fine needle aspiration (FNA) is the first choice in thyroid nodules suspected of harboring malignancy on sonography in routine practice. However, sampling with core needle biopsy (CNB) is also being used, especially in cases with repeated nondiagnostic/indeterminate diagnoses. The aim of this study was the retrospective evaluation of CNB samples. A total of 604 thyroid CNB samples registered in the Department of Pathology at Bezmialem Foundation University Medical Faculty within the 1-year period between June 2014 and June 2015 were re-evaluated by correlation with previous FNA and later resection results. CNB was divided into diagnostic groups of insufficient, malignant, suspicious for malignancy, no evidence of malignancy/benign, atypia of uncertain significance (AUS)/follicular lesions of uncertain significance (FLUS), and follicular neoplasm (FN)/suspicious for follicular neoplasm (SFN). Among the 604 cases, 15 cases (2.48%) were classified as malignant and 9 cases (1.49%) as suspicious for malignancy. No evidence of malignancy was seen in 512 cases (84.76%). There were 26 (4.3%) cases in the AUS/FLUS-FN/SFN group, and the sample was inadequate in 42 cases (6.95%). Resection was performed for 17 of the cases classified as malignant or suspicious for malignancy, and all were found to be malignant. There were also 10 resected cases with a diagnosis of no evidence of malignancy, and all were found to be benign. We think that sampling with CNB may be useful especially in repeating inadequate biopsies or cases diagnosed with AUS/FLUS that have hesitations regarding clinical management. Larger series including comparisons with FNA and resection results are required.

The Effect of Implementing Gene Expression Classifier on Outcomes of Thyroid Nodules with Indeterminate Cytology.

Thyroid nodules are classified into six cytological categories under the Bethesda classification system. Two of these categories, atypical of undetermined significance (AUS) and suspicious for a follicular neoplasm (SFN), are further labeled as "indeterminate" diagnosis. Starting in June, 2012, Kansas University-Wichita Endocrine clinic implemented Afirma® Gene Expression Classifier (AGEC) to evaluate the need for surgical resection of thyroid nodules in patients with an indeterminate diagnosis. Electronic medical records of patients who underwent thyroid nodule fine-needle aspiration from 2004-2014 were reviewed. The aim of this study was to find whether implementing AGEC was associated with decreased surgical recommendation rate, decreased cost, and increased incidence of thyroid malignancy diagnosed by surgery in patients with indeterminate diagnosis. A total of 299 consecutive patients' charts were screened. Sixty-one (20%) patients had an indeterminate diagnosis. Out of these, 27 (44%) patients underwent evaluation before and 34 (56%) patients underwent evaluation after AGEC implementation, respectively. Surgical recommendation for patients with indeterminate finding decreased from 81.5 to 50% (p = 0.01) after AGEC implementation. Surgical pathology was read as malignant in 20 and 85.7% (p < 0.01) of patients before and after AGEC implementation, respectively. Primary cost-benefit estimate showed implementing AGEC has saved $1048/patient in medical evaluation and initial management of patients with indeterminate diagnosis. AGEC implementation has decreased the number of surgical recommendations, has lowered financial burden, and has increased incidence of thyroid malignancy diagnosed by surgical pathology in patients with indeterminate diagnosis of thyroid nodules.