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Background and Aims: The International Serous Fluid Cytopathology Reporting System aimed to establish standardized protocols to ensure consistency in the reporting of serous fluid cytological specimens. In the search for higher diagnostic accuracy and a reduction in indeterminate categories, such as atypia of undetermined significance (AUS), ancillary tests like immunohistochemical (IHC) staining panels were performed. In our study, we aimed to evaluate whether the category of cases diagnosed as AUS by initial examination would change at the end of IHC studies. Materials and Methods: In total, 375 serous fluid cytology samples were examined in our laboratory for 10 months. Of these, 37 cases that were initially diagnosed as AUS were included in the study. A control group, comprising 20 cases initially diagnosed as negative for malignancy (NFM) was used. For the IHC study, sections from cell blocks were used for each group Then, the slides were stained with Ep-CAM/epithelial specific antigen (MOC31), Hector Battifora mesothelial-1 (HBME-1), and cluster of differentiation 68 (CD68). Results: Following the IHC study involving MOC31, HBME-1, and CD68, a significant reclassification was observed in cases initially diagnosed as AUS. Specifically, in 86.1% of these cases, a definitive categorization into either NFM or malignant was achieved. Statistical analysis revealed a significant difference between the two groups in terms of achieving a definitive category after the IHC study (P < 0.05). Conclusion: Our study emphasizes the critical importance of enhancing the initial IHC panel, initially composed of epithelial and mesothelial markers, with CD68. This strategic addition contributed significantly to the reduction of cases categorized as AUS. [ABSTRACT FROM AUTHOR]

Background: Thyroid fine-needle aspiration (FNA) surfaced as a vital first-line diagnostic tool to categorize them into benign or malignant, thereby reducing unnecessary surgeries in benign nodules. The Bethesda system for reporting thyroid cytopathology (TBSRTC) has established a standardized, category-based reporting system and since then it has been widely adopted by cytopathologists in worldwide. It has been shown that thyroid pathology contributes significantly to second-opinion discrepancies for cytopathology specimens. Aims and Objectives: To establish the reproducibility of TBSRTC in diagnosing thyroid lesions. To determine the interobserver variation in thyroid cytopathology using the 2023 TBSRTC. Materials and Methods: This was a 2-year retrospective study conducted in the Department of Pathology, from January 2018 to December 2019. Previous archived slides of thyroid FNA cytology were examined by three trained pathologists in a double-blinded fashion and were reclassified according to the 2023 TBSRTC. The results were evaluated for interobserver variability using Cohen's kappa statistics and Statistical Package for the Social Sciences software version 24.0. Results: The present study included a total of 156 patients with a female: male ratio of 3: 0.1 and the mean age of 37.8±2.4 years. The interobserver agreement, calculated using Kappa statistics, for observer 1 and observer 2 was 0.735; for observer 1 and 3 was 0.841; and for observer 2 and 3 was 0.838. These values together showed substantial interobserver agreement. Conclusion: The 2023 TBSRTC gives a distinctive, universal, and homogeneous terminology for reporting the thyroid cytology and its execution should be promoted due to its virtual ease of reproducibility. [ABSTRACT FROM AUTHOR]

Background: Afirma Genomic Sequencing Classifier (GSC) testing has been utilized for further risk stratification of thyroid nodules categorized as atypia of undetermined significance (AUS). The 2023 Bethesda system subcategorizes AUS diagnosis into AUS with nuclear atypia (AUS-N) and other atypia (AUS-O). The current study aims to determine if performance of GSC testing differs between the two AUS subcategories and between single AUS cohort and repeat AUS cohort. Methods: This retrospective study analyzed consecutive thyroid nodule fine-needle aspiration with a single or a repeat AUS diagnosis and a diagnostic GSC testing result (benign vs. suspicious). All AUS nodules were divided into AUS-N or AUS-O subcategory and followed by either surgical intervention or at least 12 months of clinical and/or ultrasound monitoring. We then assessed performance of GSC testing in each subcategory and subsequently compared the individual performance in AUS-N or AUS-O subcategory between single AUS cohort and repeat AUS cohort. Results: The study identified a total of 365 thyroid nodules subcategorized as AUS-N (N = 106) and AUS-O (N = 259). Both cohorts showed a significantly lower GSC benign call rate (BCR) in AUS-N nodules compared with AUS-O nodules (43% vs. 71% in single AUS, p = 0.001; 58% vs. 74% in repeat AUS, p = 0.02). The proportion of histology-proven malignancies associated with a suspicious GSC result tended to be greater in AUS-N nodules than AUS-O nodules (28% vs. 10% in single AUS, p = 0.09; 38% vs. 27% in repeat AUS, p = 0.3). Compared with AUS-N nodules, AUS-O cohorts demonstrated significantly higher specificity in the single AUS group (73% vs. 51%, p = 0.01). In both subcategories, the repeat AUS cohort yielded greater specificity, positive predictive value, and diagnostic accuracy compared with the single AUS group. However, the differences did not reach statistical significance. Conclusions: GSC BCR and diagnostic performance of GSC testing may vary in AUS-N versus AUS-O subcategories. However, there were no statistically significant differences in GSC performance between single and repeat AUS cohorts. [ABSTRACT FROM AUTHOR]

Background: ThyroSeq offers the opportunity to stratify the risk of malignancy (ROM) in the characterization of indeterminate thyroid nodules, especially those categorized as atypia of undetermined significance (AUS). However, whether ThyroSeq interpretations correlate with cytologic features, management, and surgical outcome remains unclear. Methods: Thyroid fine‐needle aspiration specimens categorized as AUS and follicular neoplasm (FN) from 2017 to 2021 were identified from a cytology database search. Patient clinical information and ThyroSeq results were collected and correlated with resection diagnosis if available. Results: A total of 520 cases were classified as AUS and 111 cases were classified as FN. Within the AUS lesions, 190 cases (36.5%) were subcategorized as cytologic atypia (III‐C), 109 cases (21.0%) as architectural atypia (III‐A), 138 cases (26.5%) as both cytologic and architectural atypia (III‐CA), and 69 cases (13.0%) as oncocytic cell aspirate (III‐O). Category III‐C showed the highest malignancy rate (16.7%; p =.29), and a higher ThyroSeq‐defined probability of cancer or noninvasive follicular thyroid neoplasms with papillary‐like nuclear features. Notably, within III‐C, intermediate‐risk mutations led to a significantly higher malignancy rate (46.7%; p =.0012). Conversely, III‐A had the lowest malignancy rate (9.7%) but this was significantly increased by concurrent high‐risk mutations (62.5%). BRAFV600E‐like mutations were frequently associated with III‐C and classical papillary thyroid carcinoma in histology. RAS‐like mutations were the most common alterations across all subcategories, and were frequently associated with follicular‐patterned lesions. Conclusions: Atypia subcategories have differential ThyroSeq‐defined ROMs and histologic outcomes. Combining atypia subcategory interpretation, ThyroSeq‐defined ROMs and molecular results aids in optimal clinical management for indeterminate thyroid lesions. Atypia subcategories have differential ThyroSeq‐defined risks of malignancy and histologic outcomes. Combining cytologic features and molecular results aids in optimal clinical management for indeterminate thyroid lesions. [ABSTRACT FROM AUTHOR]

Background: Category III (AUS; Atypia of Undetermined Significance) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was established to describe thyroid nodule features that are neither benign nor cancerous. OBJECTIVES: This study aims to evaluate the rate of thyroid malignancy in patients diagnosed with AUS at the Armed Forces Hospital Southern Region (AFHSR), Saudi Arabia. Method: The patients (508) diagnosed with AUS in their thyroid nodules underwent fine-needle aspiration cytology (FNAC). Data were collected through a chart-based approach, reviewing patients’ medical records and relevant information. Results: Among the cases, the majority were females (84.6%). Among the different age groups, individuals between 40 and 50 years had the highest prevalence of thyroid nodules (32.5%). Approximately 27% of patients exhibited tumor sizes larger than 4 cm. FNAC results revealed 16.5% benign, 26% AUS, and 22.4% follicular neoplasm cases. Histopathology indicated 54.1% of benign and 37.2% of malignant cases. Papillary carcinoma accounts for 80.4% of all malignant cases. A significant correlation was observed between FNAC and postoperative histopathology (P value < 0.05). Hypoechoic nodules exhibited 33.9% of malignant cases, and calcification was observed in 25% of the cases. A significant association was found between malignancy and echogenicity and between malignancy and calcification (P value = 0.003 and 0.001, respectively). Conclusion: The findings of this study identify malignancy in thyroid nodules with AUS cytopathology, particularly in the Southern region of Saudi Arabia. The correlation between pre-surgery FNAC and postoperative histopathology supports FNAC’s diagnostic value. Additionally, echogenicity and calcification can potentially contribute to predicting nodule malignancy.

Objective: Atypia of undetermined significance (AUS) is an indeterminate category which presents a significant challenge for pathologists and clinicians. The management options are dependent on the rate of malignancy for a given populace. Material and Methods: This is a retrospective analysis of 61 cases of the AUS Bethesda category III with grouping into neoplastic and non-neoplastic according to the histopathology data and clinical follow-up. Detailed cytomorphological features were analyzed and image morphometry was done using image J software. Student's t -test was used. Results: Out of the total 61 cases, 35 were neoplastic cases of AUS (histopathology proven), and 26 were non-neoplastic (on follow-up) cases. The risk of neoplasia and risk of malignancy observed were 57.4% and 47.5%, respectively. Neoplastic cases displayed prominent intranuclear inclusions (54%) and pseudopapillary clusters (20%). Majority of non-neoplastic cases revealed fine chromatin (96%) and pale chromatin (4%) while among neoplastic cases, 14% showed pale chromatin. Neoplastic cases showed moderate to marked nuclear pleomorphism (20%) compared to non-neoplastic cases which were monomorphic to mildly pleomorphic. None of the non-neoplastic cases exhibited frequent nuclear overlapping, nuclear grooving, or nucleoli which emphasizes the need for scrutiny of smears for these features. On image morphometry, cases with malignant outcome had larger nuclear area, perimeter, diameter, and nuclear density which were statistically significant. Conclusion: The study illustrates the importance of identifying subtle cytomorphological features and usefulness of image morphometry as an adjunctive objective tool in AUS cases. This helps in making an accurate cytological diagnosis which guides the treating clinician regarding surgical management or need for clinical follow-up. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background: Category III (AUS; Atypia of Undetermined Significance) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was established to describe thyroid nodule features that are neither benign nor cancerous. Objectives: This study aims to evaluate the rate of thyroid malignancy in patients diagnosed with AUS at the Armed Forces Hospital Southern Region (AFHSR), Saudi Arabia. Method: The patients (508) diagnosed with AUS in their thyroid nodules underwent fine-needle aspiration cytology (FNAC). Data were collected through a chart-based approach, reviewing patients' medical records and relevant information. Results: Among the cases, the majority were females (84.6%). Among the different age groups, individuals between 40 and 50 years had the highest prevalence of thyroid nodules (32.5%). Approximately 27% of patients exhibited tumor sizes larger than 4 cm. FNAC results revealed 16.5% benign, 26% AUS, and 22.4% follicular neoplasm cases. Histopathology indicated 54.1% of benign and 37.2% of malignant cases. Papillary carcinoma accounts for 80.4% of all malignant cases. A significant correlation was observed between FNAC and postoperative histopathology (P value < 0.05). Hypoechoic nodules exhibited 33.9% of malignant cases, and calcification was observed in 25% of the cases. A significant association was found between malignancy and echogenicity and between malignancy and calcification (P value = 0.003 and 0.001, respectively). Conclusion: The findings of this study identify malignancy in thyroid nodules with AUS cytopathology, particularly in the Southern region of Saudi Arabia. The correlation between pre-surgery FNAC and postoperative histopathology supports FNAC's diagnostic value. Additionally, echogenicity and calcification can potentially contribute to predicting nodule malignancy. [ABSTRACT FROM AUTHOR]

Background: The 2023 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) divides AUS diagnoses into two major subcategories: atypia of undetermined significance (AUS) nuclear atypia (AUS‐N) and other (AUS‐O). This study aims to compare the histological outcome and malignant rate of pediatric AUS thyroid nodules classified into AUS‐N and AUS‐O subcategories. Design: A search of our institutional electronic pathology database for the period from January 2012 to July 2023 was conducted to identify pediatric (<21 years old) thyroid nodules that were interpreted as AUS and subsequently had surgery. Cases were further divided into AUS‐N and AUS‐O subcategories. Results of follow‐up surgical resections were collected. The malignant rate was calculated and compared between AUS‐N and AUS‐O groups. Results: The study identified 62 thyroid nodules from 58 pediatric patients. Among these nodules, 29 and 33 were subcategorized as AUS‐N and AUS‐O, respectively. Both groups exhibited a female predominance and displayed a similar nodule size distribution. Histological analysis revealed 15 carcinomas in AUS‐N nodules, including 11 cases of classic papillary thyroid carcinoma (PTC) and four cases of follicular type of PTC. In contrast, in the AUS‐O group, a total of five carcinomas were documented, including two PTCs and three oncocytic thyroid carcinomas. Notably, the malignant rate of AUS‐N nodules (52%) is significantly higher than that of AUS‐O nodules (15%) (p =.002). Conclusion: In pediatric AUS thyroid nodules, the malignant risk in AUS‐N is significantly higher than that in AUS‐O. These findings may guide more appropriate clinical triage and/or improve management of pediatric patients with AUS thyroid nodules. This study aims to compare the histological outcome and malignant rate of pediatric atypia of undetermined significance (AUS) thyroid nodules classified into nuclear atypia (AUS‐N) and other (AUS‐O) subcategories. In pediatric AUS thyroid nodules, the malignant risk in AUS‐N is significantly higher than that in AUS‐O. These findings may guide more appropriate clinical triage and/or improve management of pediatric patients with AUS thyroid nodules. [ABSTRACT FROM AUTHOR]

Background: The atypia of undetermined significance (AUS) category is heterogeneous, leading to variations in its use. To prevent excessive usage, the AUS rate should be ≤10%. Although this recommendation aims to maintain diagnostic quality, it lacks supporting data. The AUS:Malignant (AUS:M) ratio has been proposed as a metric tool to evaluate AUS use. Furthermore, integrating ThyroSeq v3 (TSV3) positive call rate (PCR) and the molecular‐derived risk of malignancy (MDROM) have been put forward as performance improvement tools. The authors reviewed their AUS:M ratios, TSV3 PCR, MDROM, and ROM. Methods: Thyroid aspirates evaluated in the laboratory (from August 2022 to September 2023) by seven cytopathologists (CPs) were identified. AUS:M ratio, MDROM, ROM, and TSV3 PCR results for the laboratory and each CP were recorded and analyzed. Results: A total of 2248 aspirates were identified (462 AUS and 80 malignant). The AUS:M ratio for the laboratory was 5.8 (CPs range, 2.8 to 7.3). The TSV3 PCR for the laboratory was 23% (CPs range, 11% to 41%). The MDROM for the laboratory was 19% (CPs range, 9% to 31%), whereas the ROM was 36% (CPs range, 29% to 50%). Linear regression analysis of AUS:M ratio versus TSV3 PCR and MDROM demonstrated a moderate positive correlation but a weak negative correlation to the ROM. Deviations from established targets were attributed to multiple factors. Conclusion: The findings of this study underscore the importance of using a combination of metrics to evaluate diagnostic practices. By dissecting the practice patterns of each CP, the authors can measure different aspects of their performance and provide individualized feedback. Quality metric tools in thyroid cytology can offer valuable feedback to individual cytopathologists and laboratories, contributing to improving diagnostic practices. [ABSTRACT FROM AUTHOR]

Objectives Afirma has recently introduced its Xpression Atlas (XA) as an adjunct to its Genomic Sequencing Classifier (GSC) for risk stratification of cytologically indeterminate thyroid nodules. We evaluated the performance of Afirma XA and associated pathologic findings for Afirma GSC suspicious nodules. Methods Intradepartmental records of thyroid fine-needle aspirations (FNAs) from January 2021 to December 2022 were identified and reviewed for patient and nodule characteristics, FNA findings, molecular test results, and final surgical pathology, if available. Results Material for Afirma GSC testing was collected in 624 thyroid FNAs, and 148 (24%) were classified as cytologically indeterminate. Afirma GSC testing was successful in 132 (89%) of those cases, of which 35 (27%) were Afirma GSC suspicious. Afirma XA testing was positive in 11 cases (11/35 [31%]). Eight (73%) patients underwent surgery that revealed 7 patients with papillary thyroid carcinoma and 1 patient with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (risk of malignancy: 100% [8/8]). Among the 24 patients with negative Afirma XA results, 19 (79%) underwent surgery, revealing 5 patients with malignancy and 3 patients with NIFTP (risk of malignancy: 42% [8/19]). Overall, the risk of malignancy for Afirma GSC suspicious nodules was 59% (16/27). Conclusions Afirma XA improved risk stratification of thyroid disease with a high risk of malignancy in Afirma GSC suspicious nodules. A negative Afirma XA result, however, should not be used as a rule-out test. [ABSTRACT FROM AUTHOR]

Significant interobserver variabilities exist for Bethesda category III: atypia of undetermined significance (AUS) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Thus, subcategorization of AUS including AUS "nuclear" and AUS "other" is proposed in the recent 3rd edition of TBSRTC. This study investigated the impact of the nuclear features/architectural features/nuclear score (NS) (3-tiered)/subcategories and subgroups on risk of malignancy (ROM) in thyroid fine-needle aspirations (FNA). 6940 FNAs were evaluated. 1224 (17.6%) cases diagnosed as AUS were reviewed, and 240 patients (initial FNAs of 260 nodules and 240 thyroidectomies) were included. Subcategories and subgroups were defined according to TBSRTC 2nd and 3rd editions. Histological diagnostic groups included nonneoplastic disease, benign neoplasm, low-risk neoplasm, and malignant neoplasm. Overall, ROM was 30.7%. ROM was significantly higher in FNAs with nuclear overlapping (35.5%), nuclear molding (56.9%), irregular contours (42.1%), nuclear grooves (74.1%), chromatin clearing (49.4%), and chromatin margination (57.7%), and these features were independent significant predictors for malignancy. FNAs with NS3 had significantly higher ROM (64.2%). Three-dimensional groups were significantly more frequent in malignant neoplasms (35.7%). ROM was significantly higher in AUS-nuclear subcategory (48.2%) and in AUS-nuclear and architectural subcategory (38.3%). The highest ROM was detected in AUS-nuclear1 subgroup (65.2%). ROM was significantly higher in the group including AUS-nuclear and AUS-nuclear and architectural subcategories, namely "high-risk group" than the group including other subcategories, namely "low-risk group" (42.0%vs 13.9%). In conclusion, subcategorization may not be the end point, and nuclear scoring and evaluation of architectural patterns according to strict criteria may provide data for remodeling of TBSRTC categories. [ABSTRACT FROM AUTHOR]

This review summarizes changes and updates in the most recently published 2023 Bethesda System for Thyroid Cytopathology (TBSRTC). Further, the review focuses on challenges and pitfalls encountered in cytologic assessment of thyroid fine needle aspiration (FNA) specimens, with an emphasis on atypia of undetermined significance (TBSRTC category III) and the impact on risk of malignancy (ROM) among TBSRTC diagnostic categories following implementation of the terminology noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP). The role of molecular testing as an adjunct to FNA cytology will be discussed.

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is widely used for the standardized reporting of thyroid fine-needle aspiration (FNA) cytology. The 2023 revision of TBSRTC introduced specific subcategories for the classification of atypia of undetermined significance (AUS). This study tests the association between AUS subtypes and malignant diagnoses, namely AUSnuclear atypia and AUS-other, in archived thyroid - FNA specimens with atypia from 2018-2022 at King Abdulaziz University Hospital. A total of 104 thyroid - FNA specimens with AUS were re-evaluated cytologically and correlated with subsequent surgical outcomes, along with a discussion of discrepant cases. [ABSTRACT FROM AUTHOR]

This study investigated the rate of reporting and the risk of malignancy (ROM) for atypia of undetermined significance (AUS) subgroups in a Thai population. AUS, which is category III of the Bethesda System for Reporting Thyroid Cytopathology, is a problematic diagnosis for thyroid nodule management because the risks of malignancy are diverse. Patients who underwent thyroid fine needle aspirations between January 2015 and December 2019 were included in this retrospective study. Gender, age, and nodule features were described, and all slides were re-evaluated and categorized into 2 subgroups: AUS-Nuclear (including cytology atypia and cytologic and architectural atypia) and AUS-Other (including architectural atypia, oncocytic atypia, and atypia not otherwise specified). The lower and upper limits of ROM were calculated for each subgroup. Of total, 258 out of 2995 fine needle aspirations (8.6%) were diagnosed as AUS. The patients were predominantly female (88.9%), with a mean age of 54.1 years. The average nodule size was 2.5 cm. Of the 258 AUS patients, 81 (38.9%) had histological correlations. The ROM for the AUS category was 9.1% to 23.5%. The ROM of the AUS-Nuclear and AUS-Other were 11.1% to 27.3% and 2.2% to 6.7%, respectively. Features of pseudonuclear inclusions had the highest ROM (33.3%-42.9%), followed by pale chromatin (28.57%-47.06%). Less than ten percent of our interpretations were AUS, which is acceptable in our practice. Cytological atypia harbored the highest ROM. Studies of associations between cytology and histology may aid in improving diagnostic criteria for this population. • Further subcategorization of atypia of undetermined significance (AUS) achieves better risk stratification and improves clinical management. • The feature of nuclear atypia is the most common finding among the AUS subcategory. • Findings of AUS with atypical nuclei resembling nuclear features of papillary thyroid carcinoma, eg, intranuclear pseudo inclusions and pale chromatin increased risk of malignancy (ROM). • Findings of AUS -oncocytic (Hurthle cell) aspirations do not increase the ROM in this study. [ABSTRACT FROM AUTHOR]

This study aims to evaluate diagnostic accuracy of flow cytometry (FCM) in detecting malignant epithelial cells in serous effusions. Flow cytometric assessment of 96 serous fluids (86 ascitic, 10 pleural) was performed by using epithelial cell adhesion molecule (EpCAM) (in all 96 fluids) and MUC-1 (in a subgroup of 40 fluids) as epithelial markers and CD45 and CD14 as leucocyte markers. The percentage of EpCAM positivity and MUC-1 positivity was calculated in the CD14 and CD45 dual negative population by selective gating. The findings were then correlated with the defined gold standard criteria. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy for EpCAM was found to be 92.06%, 96.96%, 98.31%, 86.48%, and 93.75%, respectively, while that for MUC-1 was 79.16%, 93.75%, 95%, 71.4%, and 85%, respectively. The sensitivity, specificity, PPV, NPV, and diagnostic accuracy for dual positivity for EpCAM and MUC-1 was found to be 83.3%, 100%, 100%, 80%, and 90% respectively. On combining FCM with cytomorphology the sensitivity, specificity, PPV, NPV, and diagnostic accuracy all increased greatly to 95.3%, 100%, 100%, 91.4%, and 96.8%, respectively. This study highlights the importance of multicolored flow cytometric analysis in detecting epithelial malignancies in effusions specially in cases belonging to the atypia of undetermined significance and suspicious for malignancy categories and in cases with strong clinical suspicion of malignancy with negative fluid cytology. We recommend the combined use of FCM and cytology for this specific subgroup of patients in routine clinical practice for fast and accurate reporting. • The study highlights the importance of multicolored flow cytometric analysis using EpCAM and MUC-1 in detecting epithelial malignancies in effusions specially for atypical and suspicious cases. • We recommend combined use of flow cytometry and cytology for this specific subgroup of patients in routine clinical practice for fast and accurate reporting. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid fine-needle aspiration cytology (FNAC) has gained significance as a quick, safe, and relatively simple method to differentiate malignant from benign thyroid nodules and is regarded as the gold-standard first-line diagnostic test in the evaluation of thyroid nodules. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) established a standardized, category-based reporting system for thyroid FNAC with each category having an implied cancer risk. However, the optimal management of thyroid nodules in the Bethesda III and IV categories is controversial, given the variable malignancy rates. Aims/Objectives: (1) Analysis of the cytomorphological characteristics of patients with categories III and IV of “TBSRTC.” (2) Assessment of risk of malignancy of TBSRTC category III, IV, and substratification of TBSRTC category III. Materials and Methods: A retrospective and prospective study of cases categorized under TBSRTC as category III and IV at a tertiary-care center. Cytological along with their histological results were compared. Results: We identified an overall malignancy rate of 33% for nodules belonging to Bethesda category III and a malignancy rate between 19% and 33% for Bethesda category IV. Also, a significantly higher risk of malignancy in subcategories with nuclear and architectural atypia (66.6%) than only architectural atypia (28.7%). Conclusion: Although surgery is recommended in most of these cases, cytomorphology helps to predict the final histopathological findings with greater accuracy. Substratification of category III into subgroups may help reduce the heterogeneity of the atypia of undetermined significance/follicular lesion of undetermined significance category and more.

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Objectives: This study aimed to investigate ultrasound (US) features of thyroid nodules categorized as nondiagnostic (ND) and atypia of undetermined significance (AUS) according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and their potential implications for clinical management. Materials and Methods: A retrospective study was conducted on patients who underwent thyroid nodules FNAC between 2019 and 2023. Nodules falling into the ND and AUS categories were analyzed for US features, nodule size, composition, echogenicity, shape, margin, echogenic foci, the distribution of the American College of Radiology’s Thyroid Imaging Reporting and Data System (ACR TI-RADS) categories, and other parameters. The study included a total of 1,199 patients and 1,252 nodules (ND: 1110; AUS: 142). Results: No significant differences in age, gender, nodule features, echogenicity, shape, margin, echogenic foci, TI-RADS scores, localization, number of nodules, or thyroid parenchymal disease presence were found between the ND and AUS categories (p > 0.05). Also, no statistically significant difference in nodule size (

Background: Evidence guiding the management of cytologically indeterminate thyroid nodules with nondiagnostic (ND) or benign cytology on repeat fine‐needle aspiration (FNA) is limited. This study evaluates the utility of molecular testing and estimates the risk of noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) and cancer among such nodules. Methods: This was a retrospective single‐institution review of thyroid nodules from adults that were classified as atypia of undetermined significance (AUS) or follicular neoplasm (FN) on initial FNA and underwent repeat FNA for cytology and Afirma testing (June 2013–July 2021). The association between repeat FNA cytology and RNA yield for Afirma was determined. Histologic outcomes were integrated with Afirma results to define end points for each nodule. Results: A total of 691 AUS and FN nodules underwent repeat FNA and Afirma testing. Diagnostic Afirma results were obtained in 98% of cases overall and in 91% of nodules with ND cytology on repeat FNA. Using combined molecular and histologic end points, the NIFTP and/or cancer prevalence for nodules with ND cytology on repeat FNA was 9% (95% confidence interval [CI], 0.042–0.182), falling between those nodules classified as benign (5%; 95% CI, 0.029–0.094) and those classified as AUS or FN (18%; 95% CI, 0.140–0.218) on repeat FNA, although not reaching statistical significance from either subgroup (p =.38 and.10, respectively). Conclusions: AUS and FN nodules that are ND on repeat FNA have low but nonnegligible risk of NIFTP and/or cancer and may benefit from molecular testing, given the low test failure rate in this subgroup. Conversely, AUS and FN nodules reclassified as benign on repeat FNA have a very low risk of NIFTP and/or cancer and are unlikely to benefit from molecular testing. Repeat fine‐needle aspiration (FNA) biopsy is one tool for refining the cancer risk of cytologically indeterminate thyroid nodules, but there is limited evidence guiding the management of nodules reclassified as benign or nondiagnostic on the second FNA. This study integrates results of molecular testing and histologic outcomes to support different follow‐up strategies for these two subgroups of thyroid nodules. [ABSTRACT FROM AUTHOR]

Objective Thyroid cancer is the most common endocrine Malignancy, and nodules characterize its clinical presentation. 'Atypia of undetermined significance' (AUS) in biopsies performed for thyroid pathologies is an essential concern for clinicians due to different malignancy rates in the literature. In this study, we aimed to discuss the malignancy rates in patients who underwent thyroid surgery for AUS. Material and Method The demographic and histopathologic data of 174 patients diagnosed with AUS on fine needle aspiration biopsy (FNAB) and who underwent thyroid surgery in our clinic between 2016 and 2021 were retrospectively analyzed. According to histopathologic features, patients were divided into two groups, malignant and benign, and the relationship with age, gender, and nodule diameter was investigated. Statistical significance between groups was determined using Chi-square and Student t-tests. P value <0.05 was accepted. Results The mean age was 47.9±12 years (range, 20-81). The malignancy rate was 43.5%. Malignancy was detected in 42.1% of females and 50% of males. The mean nodule diameter was 19.1±13.7 mm (range, 1-97 mm). There was no statistically significant difference between gender, age, nodule diameter, and Malignancy (p>0.05). Conclusion According to the Bethesda classification, the malignancy rate for AUS is 15-30%. In our study, the malignancy rate was 43.5%, similar to studies published in our country. Because of the high malignancy rate, total thyroidectomy should be considered an alternative to lobectomy in cases planned for surgery with a diagnosis of AUS. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of cases of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) by fine needle aspiration cytology (FNAC) is challenging for both cytopathologists and clinicians. It is extremely difficult to predict the risk of malignancy based on cytological features alone. Aims and Objectives: In this study, we attempted to construct an artificial neural network (ANN) model to predict the risk of malignancy in FNAC cases of AUS/FLUS in thyroid lesions based on cytological features. Materials and Methods: We included two groups of AUS/FLUS cases: (1) 29 cases of histopathologically proven malignancy, and (2) 32 cases that had either been histopathologically proven to be benign, or for which no progress of malignancy on follow‐up had been observed in the last 2 years. Cytological characteristics were analysed semi‐quantitatively by two independent observers (TS and PD). Based on these data, we tried to generate an artificial neural network (ANN) model to differentiate between malignant and benign cases. The performance of the ANN was assessed using the confusion matrix and receiving operator curve. Results: There were 29 malignant cases of AUS/FLUS (histopathologically proven) and 32 benign/follow‐up cases in this study. There were 41 cases in the training set, 9 cases in the validation set and 11 cases in the test set. In the test group, the ANN model successfully distinguished between all benign (5/5) and malignant cases (6/6). The area under the receiver operating curve was 1. Conclusion: The present ANN model is well structured and coherent to distinguish malignant from benign outcomes in AUS/FLUS cases on cytology smears with no error. This is an open‐ended ANN model, and additional parameters and more cases could be included to make the model more robust. [ABSTRACT FROM AUTHOR]

Quality management is integral to the practice of cytopathology, especially given the heavily manual workflows and expanding ancillary testing requirements inherent to the cytopathology laboratory. Monitoring quality data like turnaround time, specimen unsatisfactory rates, and diagnostic category utilization rates allows for better understanding of performance with opportunities for targeted improvement if there are variations from that which is expected. However, there are costs to quality monitoring including the time and resources needed, and, in already taxed systems, quality management risks being viewed as just another box to check. While there are mandated quality metrics that must be collected by cytology laboratories, thoughtful selection of key performance indicators can be of tremendous benefit in helping to better understand complex laboratory processes and directing improvement endeavors where needed. The following short communication is a discussion on quality management in the cytopathology laboratory from 3 Cytopathology Quality Management Directors. The discussion focuses on monitoring the atypical reporting category with an emphasis on how trending and visualizing quality metrics can provide laboratories with key data. [ABSTRACT FROM AUTHOR]

Background: Data on Afirma's genomic sequencing classifier (GSC) performance in atypia of undetermined significance (AUS) subcategories is limited. This study investigated GSC performance in AUS nodules with architectural atypia (AUS‐A), cytological atypia (AUS‐C), architectural and cytological atypia (AUS‐AC), and predominantly Hürthle cells (AUS‐HC). Methods: This study retrieved consecutive thyroid nodules having a recurrent cytologic diagnosis of AUS with qualifiers and a concurrent GSC diagnostic result. All nodules were followed by either surgical intervention or clinical and/or ultrasound monitoring (≥6 months). GSC benign call rate (BCR), rate of histology‐proven malignancy, and diagnostic parameters of GSC were calculated for individual AUS subcategories. Statistical analysis was performed using the Fisher exact test. Results: A total of 135 AUS nodules fulfilled inclusion criteria, including 79 AUS‐A, 9 AUS‐C, 29 AUS‐AC, and 18 AUS‐HC. BCR was 72.2%, 66.7%, 44.8%, and 77.8% in AUS‐A, AUS‐C, AUS‐AC, and AUS‐HC, respectively. AUS‐A showed a greater BCR than AUS‐AC (p <.05). All GSC‐benign nodules were considered benign on clinical or surgical follow‐up. Among GSC‐suspicious nodules, histology‐proven malignancies represented 4.5% of AUS‐A, 0% of AUS‐C, 56.3% of AUS‐AC, and 25.0% of AUS‐HC cases. AUS‐AC demonstrated a higher malignant rate compared with AUS‐A (p <.05). GSC offers 100% NPV and a wide range (5%–56%) of PPV across all AUS subcategories. AUS‐AC demonstrated a greater PPV compared with AUS‐A (p <.05). Conclusion: BCR of GSC and malignant rates associated with suspicious GSC may differ in various AUS subcategories. GSC‐suspicious nodules with both architectural and cytologic atypia are more likely to be malignant. These findings may improve clinical triage and/or management of patients with AUS thyroid nodules. Benign call rate of Afirma genomic sequencing classifier (GSC) testing may differ among atypia of undetermined significance subcategories. GSC‐suspicious nodules with both architectural and cytologic atypia are more likely to be malignant. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid biopsy results are evaluated according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) worldwide. The most ambiguous result from these categories is the Bethesda-III which is defined as “atypia of undetermined significance” (AUS). Neutrophil to lymphocyte ratio (NLR) is still evaluated in thyroid disorders and malignancy. The purpose of this study was to evaluate the NLR results in Bethesda Categories and whether the NLR can discriminate a clinical benefit for the AUS category. Methods: In this retrospective study, 1771 patients who had fine needle aspiration biopsy(FNAB) were examined. Demographic characteristics, NLR, Bethesda scores, operation rates and postoperative histopathological results were recorded. Results: The categories were; Bethesda-I for 298(16,8%), Bethesda-II for 1320(74,5%), Bethesda-III for 60(3,4%), Bethesda-IV for 27(1,5%), Bethesda-V for 36(2%), Bethesda-VI for 30(1,7%) results respectively. The mean NLR was 2,68. There was no statistically significant difference between groups in terms of NLR(p=0.250). Overall, 226 (12,76%) patients were undergoing thyroidectomy. The AUS group was founded by 3.4%, operation rate was 21,66% and malignancy rate was 23,07%. There was a statistically significant difference between Bethesda scores and malignancy rates(p

Thyroid-stimulating hormone (TSH) is a growth factor associated with the initiation and progression of well-differentiated thyroid cancer (WDTC). Atypia of undetermined significance and follicular lesion of undetermined significance (AUS/FLUS) are the most uncertain cytological diagnoses of thyroid nodules. The aim of the study was to determine the association of histopathological diagnosis with preoperative serum TSH levels in patients with AUS/FLUS thyroid nodule diagnosis. Among 5028 individuals with thyroid nodules, 342 (6.8%) with AUS/FLUS diagnoses were analyzed. The frequency of all histopathology diagnoses was assessed for associations with preoperative serum TSH levels. The median TSH concentration was significantly higher in patients with AUS/FLUS diagnosis and histopathology of WDTC than in patients with the same cytology result and histopathology of a benign tumor (p < 0.0001). The diagnostic potential of serum TSH level was determined to evaluate risk of malignancy in patients with thyroid nodules classified into the Bethesda III category. ROC analysis showed the TSH concentration at a cutoff point of 2.5 mIU/L to be an acceptable prognostic factor for WDTC. For this optimal cutoff point, the AUC was 0.877, the sensitivity was 0.830, and the specificity was 0.902. Preoperative serum TSH levels in patients with AUS/FLUS thyroid tumor diagnosis should be taken into consideration in the decision-making process and clinical management. [ABSTRACT FROM AUTHOR]

Objective: Molecular testing is recommended for risk stratification of atypia of undetermined significance (AUS) nodules in the USA; however, it is not routinely performed in some countries owing to limited availability and affordability. Here, we propose a risk stratification algorithm for AUS nodules when molecular testing is unavailable., Methods: We examined 304 (4.3%) AUS nodules among 7073 thyroid fine-needle aspiration cytology specimens examined at Kuma Hospital from January 2020 to December 2020. Clinical data were obtained from the medical records of Kuma Hospital., Results: AUS with nuclear atypia and AUS-other each accounted for half of the total AUS nodules. The repeat aspiration rate was 19.7%; 61.7% of the nodules were reclassified as benign or malignant upon repeat aspiration. Resection rate and overall risk of malignancy (ROM) were 32.6% and 12.8%, respectively. Architectural atypia showed the lowest (1.1%) overall ROM in the AUS nodules. For AUS with nuclear atypia, nodules ≤ 10 mm in size showed significantly lower overall ROM than those of > 10 mm, and nodules with ultrasonographically low suspicion showed significantly lower overall ROM than those with intermediate to high suspicion. AUS nodules with atypical lymphoid cells, possible medullary thyroid carcinoma, or possible parathyroid lesion were confirmed using flow cytometry, biochemical testing using needle washout fluid or immunocytochemistry, respectively., Conclusions: Our proposed clinical management algorithm for each subdivision according to cytological findings, based on repeat aspiration rates, ROM, ultrasound findings and results of ancillary tests except for molecular testing, should be useful for the clinical management of AUS nodules., (© 2025 The Author(s). Cytopathology published by John Wiley & Sons Ltd.)

Introduction: Indeterminate oncocytic/Hürthle cell lesions on thyroid cytology are reflexed to molecular testing. This study aims to examine the cytologic characteristics of thyroid fine-needle aspiration (FNA) smears with oncocytes classified as atypia of undetermined significance (AUS) with particular molecular patterns that can aid in determining a more conclusive Bethesda category upfront thus decreasing unnecessary testing and associated costs., Materials and Methods: Our pathology database was searched for thyroid FNAs with AUS for oncocyte predominance from 2019 to 2022. Sixty six cases that underwent ThyroSeq testing (33 positive and 33 negative) were selected. Two cytopathologists reviewed the smears for cellularity, colloid: cell ratio, artifacts, lymphocytes, microfollicles, and oncocytic nuclear atypia. Molecular results and surgical follow-up were obtained through chart review. Statistical analysis was done using STATA16.1 (StataCorp LLC College Station, TX)., Results: Among the 33 ThyroSeq-positive cases, 20 had surgical follow-up. Only 1 case was malignant. Hypercellularity, microfollicular architecture, and oncocytic atypia were associated with a higher incidence of molecular alterations. Five of 66 cases demonstrated microfollicles. Four of these had positive molecular findings, and one was negative. Twenty of 33 (61%) cases with positive molecular findings had no oncocytic nuclear atypia. Of the molecular positive cases with oncocytic atypia that underwent resection, seven of nine (78%) were neoplastic. RAS mutations were the most common finding detected in non-neoplastic and neoplastic lesions., Conclusions: Microfollicles were infrequently seen in nodules with oncocytic predominance; however, those that had microfollicles had high incidence of positive molecular findings. Oncocytic nuclear atypia was present in all the resected neoplastic cases. NRAS and KRAS mutations were the most common molecular abnormalities detected., (© 2024 Wiley Periodicals LLC.)

Background: The Bethesda System for Reporting Thyroid Cytopathology contains an atypia of undetermined significance (AUS) category with heterogeneous and distinct inclusion criteria. The purpose of this study was to investigate differences in malignancy rates and molecular alterations based on the presence of different criteria. Methods: A laboratory information search was conducted to identify thyroid fine‐needle aspiration specimens signed out as AUS. The cases were reclassified as architectural atypia (3A), cytologic atypia (3C), both architectural and cytologic atypia (3B), or Hürthle cell aspirate (3H). Surgical follow‐up and concurrent molecular test results, if available, were collected. Results: Five hundred ten specimens, including 258 reclassified as 3A, 40 reclassified as 3B, 119 reclassified as 3C, and 86 reclassified as 3H, were identified. The risks of malignancy for the subcategories were 13.4%, 26.3%, 44.1%, and 13.8%, respectively. Additionally, BRAF V600E mutations were more prevalent in specimens with cytologic atypia (3B/3C), whereas low‐risk alterations, including KRAS, PTEN, and PAX8‐PPARy2, were more prevalent in those with architectural atypia (3A). Conclusions: Subdividing AUS specimens on the basis of the type of atypia can yield categories associated with distinct molecular alterations and risks of malignancy. Subdividing the atypia of undetermined significance category in thyroid cytopathology results in different categories with significantly different risks of malignancy. Additionally, different molecular alterations are seen in specimens in these different categories. [ABSTRACT FROM AUTHOR]

BackgroundHashimoto’s thyroiditis (HT), also known as chronic lymphocytic thyroiditis (CLT), may interfere with the accurate cytological diagnosis of thyroid nodules. Recently, HT has been considered a premalignant condition for thyroid cancer development. The diagnosis of atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS) thyroid nodules is challenging and evidence for the malignancy risk of AUS/FLUS thyroid nodules coexisting with CLT is scarce. Therefore, we assessed the malignancy risk of AUS/FLUS thyroid nodules according to the presence of background CLT.MethodsThis study included 357 surgically resected thyroid nodules with AUS/FLUS cytology. Cases with concomitant malignant nodules were excluded. CLT was defined based on the pathologic report after thyroid surgery.ResultsAmong 357 tumors, 130 tumors (36%) were confirmed to have coexisting CLT, and 170 tumors (48%) were determined to be malignant after thyroidectomy. Malignancy rates were similar in both groups (48% in each) regardless of background CLT (62/130 with CLT vs. 108/227 without CLT). In the group with CLT, thyroiditis was more frequent in the final pathology (12% with CLT vs. 1% without CLT, P = 0.003). In multivariate analysis, positive BRAFV600E mutation, highly suspicious sonographic features (K-TIRADS 5), and smaller thyroid nodules were significant factors for thyroid malignancies.ConclusionThe malignancy rate of thyroid nodules with AUS/FLUS cytology was comparable irrespective of the presence of underlying CLT.

Background: Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis (CLT), may interfere with the accurate cytological diagnosis of thyroid nodules. Recently, HT has been considered a premalignant condition for thyroid cancer development. The diagnosis of atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS) thyroid nodules is challenging and evidence for the malignancy risk of AUS/FLUS thyroid nodules coexisting with CLT is scarce. Therefore, we assessed the malignancy risk of AUS/FLUS thyroid nodules according to the presence of background CLT. Methods: This study included 357 surgically resected thyroid nodules with AUS/FLUS cytology. Cases with concomitant malignant nodules were excluded. CLT was defined based on the pathologic report after thyroid surgery. Results: Among 357 tumors, 130 tumors (36%) were confirmed to have coexisting CLT, and 170 tumors (48%) were determined to be malignant after thyroidectomy. Malignancy rates were similar in both groups (48% in each) regardless of background CLT (62/130 with CLT vs. 108/227 without CLT). In the group with CLT, thyroiditis was more frequent in the final pathology (12% with CLT vs. 1% without CLT, P = 0.003). In multivariate analysis, positive BRAF V600E mutation, highly suspicious sonographic features (K-TIRADS 5), and smaller thyroid nodules were significant factors for thyroid malignancies. Conclusion: The malignancy rate of thyroid nodules with AUS/FLUS cytology was comparable irrespective of the presence of underlying CLT. [ABSTRACT FROM AUTHOR]

Background: It has been known that the “atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS)” category is the most problematic category in Bethesda system due to its highly heterogeneous morphological features. Recently, it has been reported that aspirates including nuclear atypia in the AUS/FLUS category have a higher risk of malignancy. Aims: This study aimed to assess each nuclear property in aspirates with cytological atypia and also to determine the relationship with the risk of malignancy. Material and Methods: We reviewed 980 AUS/FLUS fine-needle aspirations (FNAs) performed between '2012 and 2019' at a single institution. We classified these aspirates into four groups: AUS-N (nuclear atypia), AUS-A (architectural atypia), AUS-H (Hurthle cell change), and AUS-O (other). Nuclear features were detailed sub-classified; size and shape (enlargement, elongation, and overlapping), membrane irregularities (irregular contours, grooves, pseudoinclusion), and chromatin characteristics (pale chromatin). The estimated risk of malignancy (ROM) was calculated for each subgroup. Results: Of 980 AUS/FLUS cases, follow-up histological outcome data were available for 209 cases. Among these cases, the estimated ROM was 27.8%. The ROM were 26.4%, 15.4%, and 22.5% for AUS-N, A, and H, respectively. The most common nuclear findings associated with ROM were nuclear groove (67.9%); irregular contours (76.9%) suspected pseudoinclusion (100%) and overlapping (56%) (P < 0,001). But nuclear findings such as nuclear enlargement, mild pleomorphism, or pale chromatin have a similar ROM as architectural atypia. Conclusion: Although it is known that the presence of cytological atypia in an AUS/FLUS nodule increases the estimated risk of malignancy, all nuclear properties are not equally effective in predicting malignancy risk. Emphasizing nuclear atypia details in reports of AUS case may be a more sensitive way to identify nodules with a high risk of malignancy.

Objective: We aimed to detect if there were any radiologic, demographic, or clinical findings that were valuable for differentiating benign nodules from malignant nodules in old aged patients, when the results of the first fine-needle aspiration biopsy (FNAB) were reported as atypia of undetermined significance (AUS). Materials and Methods: Patients aged 65 years and older who were biopsied from thyroid nodules were analyzed retrospectively in this study. A total of 1264 patients with 1374 nodules were enrolled and of these, 203 patients with 216 nodules were recorded to have diagnosis of AUS in pathological evaluation. We excluded 104 nodules on which FNAB had been performed only once and included 112 nodules, on which FNAB had been performed twice. Out of these included patients, a total of 43 patients were thyroidectomized. Preoperative ultrasonographic nodular findings, echogenicity, marginal [ir]regularity, calcification, exophytic configuration, and halo were recorded. Results: The median patient age was 69 years. There was no statistically significant difference between the results of the first and second FNABs. Hypoechogenicity was the only statistically significant different characteristic found in thyroid nodules that could effectively discriminate between malignant and benign groups. Conclusion: The second FNAB does not increase the likelihood of diagnosing malignancy in old aged patients and there is no need for this procedure when recommending surgery. Suspicious USG findings are more frequent among malignant nodules, as reported in the histopathological evaluation of the old aged patients. A multidisciplinary team should take part in the decision-making process for the treatment of old aged patients after the first FNAB, with due consideration of the history, physical examination, USG, FNAB laboratory findings, and patient preference.

Thyroid cancer is the most common malignant tumor of the endocrine system. An increase in the incidence of thyroid cancer has been noted over the past decade, mainly due to papillary cancer. The influence of environmental factors, increased availability of medical care, including sensitive diagnostic tests, such as ultrasound and fine - needle aspiration (FNA), can affect the fact of the growth of this incidence. Palpation of thyroid gland has very low diagnostic value for detecting thyroid cancer, while thyroid ultrasound and FNA can detect malignant tumors in 20% of cases. Today, the FNA is the fastest, most accurate, economically accessible, and quite safe method for cytological diagnosis of the thyroid nodules. And molecular genetic testing of FNA samples could serve as an additional reliable diagnostic tool in the case of atypia of undetermined significance.

Background: The atypia of an undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is a heterogeneous category, which includes various cell patterns. The subclassification of AUS/FLUS was suggested in the 2017 TBSRTC. However, the risk of malignancy (ROM) associated with different subgroups remains unresolved. Herein, AUS/FLUS aspirates were subclassified, from which the ROM of each subgroup was determined. Methods: All cases undergoing fine‐needle aspiration (FNA) from July 2013 to December 2018 were reviewed. Of 12,913 thyroid FNAs, 1053 (8.2%) were AUS/FLUS. The slides of 222 patients with AUS/FLUS with surgical follow‐up were reviewed and subclassified according to the recommendations of the 2017 TBSRTC. There were 195 aspirates consistently diagnosed as AUS/FLUS and subclassified as cytologic atypia 1 (AUS‐C1); cytologic atypia 2 (AUS‐C2); architectural atypia (AUS‐A); cytologic and architectural atypia (AUS‐C&A); Hürthle cell aspirates (AUS‐H); atypia, not otherwise specified (AUS‐NOS); and atypical lymphoid cells, rule out lymphoma (AUS‐L). Results: Malignancy was identified in 83.3% (185 of 222) of the AUS/FLUS nodules. The AUS‐C1 group was the most common (62.1%), followed by the AUS‐C&A (12.8%), AUS‐C2 (10.8%), AUS‐H (6.7%), AUS‐NOS (5.6%), AUS‐L (1.5%), and AUS‐A (0.5%) groups. AUS‐C1 had the highest ROM (92.6%) among the groups and varied significantly from that of the AUS‐C&A (P =.171), AUS‐C2 (P =.001), AUS‐H (P =.001), and AUS‐NOS (P <.001) groups. Conclusions: As a heterogeneous category of TBSRTC, the ROM for AUS/FLUS varies greatly among medical centers. Subclassification of AUS/FLUS might be helpful in identifying nodules with a high ROM in this category and improving the management of such nodules. As a heterogeneous category of the Bethesda System for Reporting Thyroid Cytopathology, the risk of malignancy for undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) varies greatly among medical centers. The subclassification of AUS/FLUS might be helpful in identifying nodules with a high risk of malignancy in this category and improve the management of such nodules. [ABSTRACT FROM AUTHOR]

Background: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is widely utilised by cytopathologists. The American College of Radiology (ACR) has also proposed a thyroid imaging reporting and data system (TIRADS) to classify thyroid nodules and guide their selection for fine needle aspiration (FNA). The current study aimed to analyse the usefulness of TBSRTC in thyroid cytology reporting, to examine its histological correlation with TIRADS, and to compare the management of lesions in each cytological category in our institute to the TBSRTC recommendations. Materials and methods: A retrospective study was performed on all thyroid FNAs from a 2‐year period at a tertiary care centre. Histological correlations of TBSRTC and ACR TIRADS were examined for cases with surgical follow‐up, and the risk of malignancy in each TBSRTC category, and sensitivity and specificity of FNA and TIRADS, were calculated. Results: A total of 337 thyroid FNAs were examined, with histological follow‐up in 99 cases. Risk of malignancy in categories I‐VI was 9.5%, 2.3%, 0.0, 8%, 87.5% and 100.0%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of FNA were 60.0%, 99.0%, 85.7%, and 97.5%, respectively, while those values for thyroid ultrasound were 90.3%, 72.2%, 92.9% and 65%, respectively. Conclusion: The study substantiates the usefulness of TBSRTC in arriving at a more precise diagnosis. Hurthle cell lesions with atypia were the common cause of misdiagnosis. The combination of TIRADS and TBSRTC aids in better stratification of thyroid nodules and in decision making for management of lesions. The reporting of AUS/FLUS lesions with a supplementary note describing the presence of architectural and/or cytological atypia may be helpful in treatment decisions since cytological atypia could suggest the possibility of NIFTP or malignancy. TIRADS score in conjunction with TBSRTC cytological diagnosis can aid in better stratification of thyroid nodules. [ABSTRACT FROM AUTHOR]

Thyroid-stimulating hormone (TSH) is a growth factor associated with the initiation and progression of well-differentiated thyroid cancer (WDTC). Atypia of undetermined significance and follicular lesion of undetermined significance (AUS/FLUS) are the most uncertain cytological diagnoses of thyroid nodules. The aim of the study was to determine the association of histopathological diagnosis with preoperative serum TSH levels in patients with AUS/FLUS thyroid nodule diagnosis. Among 5028 individuals with thyroid nodules, 342 (6.8%) with AUS/FLUS diagnoses were analyzed. The frequency of all histopathology diagnoses was assessed for associations with preoperative serum TSH levels. The median TSH concentration was significantly higher in patients with AUS/FLUS diagnosis and histopathology of WDTC than in patients with the same cytology result and histopathology of a benign tumor (p < 0.0001). The diagnostic potential of serum TSH level was determined to evaluate risk of malignancy in patients with thyroid nodules classified into the Bethesda III category. ROC analysis showed the TSH concentration at a cutoff point of 2.5 mIU/L to be an acceptable prognostic factor for WDTC. For this optimal cutoff point, the AUC was 0.877, the sensitivity was 0.830, and the specificity was 0.902. Preoperative serum TSH levels in patients with AUS/FLUS thyroid tumor diagnosis should be taken into consideration in the decision-making process and clinical management.

Atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS) refers to an intermediate histologic category of thyroid nodules in The Bethesda System for Reporting Thyroid Cytopathology. Although the risk of malignancy in this category was originally cited as 5–15%, recent literature has suggested higher rates of related malignancy ranging from 38% to 55%. Malignant nodules warrant surgery with total thyroidectomy or thyroid lobectomy, whereas benign nodules can be observed or followed with serial ultrasounds (US) based on their imaging characteristics. The management of nodules with a cytopathologic diagnosis of AUS/FLUS can be difficult because theses nodules lie between the extremes of benign and malignant. The management options for such nodules include observation, repeat fine-needle aspiration, and surgery. The use of molecular genetics, the identification of suspicious US characteristics, and the recognition of additional clinical factors are all important in the development of an appropriate, tailored management approach. Institutional factors also play a crucial role. [ABSTRACT FROM AUTHOR]

Introduction: Fine needle aspiration cytology (FNAC), along with thyroid ultrasound, is an important tool in evaluation of thyroid nodules that helps in further management of these patients in making a decision of surgical intervention vs follow‐up. The Bethesda System for Reporting Thyroid Cytopathology category III of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) has risk of malignancy (ROM) ranging from 5% to 15%. The aim of the present study was to describe the frequency of AUS/FLUS in thyroid gland FNACs and the surgical outcomes of these cases. Methods: The integrated laboratory management system retrieved the thyroid FNACs from 2010 to 2018 and subsequent surgical pathology specimens. For the AUS/FLUS cases, data regarding patient demographics, cytology and histological diagnoses were recorded. The results were tabulated as the overall frequency of AUS/FLUS in thyroid FNACs, cytohistological correlation (benign and malignant) and ROM. Results: Over a period of 9 years, 256 (10.9%) cases out of 2342 thyroid FNACs were reported as AUS/FLUS at our institution. Mean age was 43.5 years. The majority (70.3%) of patients were female. Seventy‐two of 104 resection specimens (69.2%) were reported as benign and 32 cases (30.7%) had malignant diagnosis. Upper‐bound ROM was 30.7% (32 cases with malignant diagnosis out of 104 resection specimens). Lower‐bound ROM was calculated as 12.5% (32 cases with malignant diagnosis out of 256 total AUS diagnosis). Conclusion: The AUS/FLUS category of thyroid cytology and associated ROM remain an evolving area. Individual institutions should monitor the frequency and include ROM in the dashboard indicators to remain within the recommended range. This study describes the frequency of AUS/FLUS in thyroid gland fine needle aspiration cytology in a single institute in Pakistan and correlates this with the surgical outcomes of these cases. All institutions should monitor their performance and aim to be within the recommended range. [ABSTRACT FROM AUTHOR]

Context: Atypia of undetermined significance/Follicular lesion of undetermined significance [AUS/FLUS] is a heterogeneous category with a wide range of risk of malignancy [ROM] reported in the literature. The Bethesda system for reporting thyroid cytopathology [TBSRTC], 2017 has recommended subcategorization of AUS/FLUS. Aims: To evaluate the ROM in thyroid nodules categorized as AUS/FLUS, as well as separate ROM for each of the five subcategories. Settings and Design: Retrospective analytic study. Methods and Materials: A retrospective audit was conducted for all thyroid fine-needle aspiration cytology (FNAC) from January 2013 to December 2017. Slides for cases with follow-up histopathology were reviewed, classified into the five recommended subcategories, and differential ROM was calculated. Statistical Analysis Used: z test for comparison of proportions was done to evaluate the difference in ROM among different subcategories of AUS/FLUS. The P value of less than 0.05 was taken as statistically significant. Results: Total number of thyroid FNACs reported was 1,630, of which 122 were AUS/FLUS (7.5%). Histopathology was available in 49 cases, out of which 18 were malignant (ROM = 36.7%). The risk of malignancy (ROM) for nodules with architectural and cytologic atypia was higher (43.8%) than ROM for nodules with only architectural atypia (16.7%). Conclusions: The sub-classification of AUS/FLUS into subcategories as recommended by TBSRTC, 2017 may better stratify the malignancy risk and guide future management guidelines.

Introduction: Atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has emerged as the most controversial category because of its heterogeneity and inconsistent reporting. There is a definite paucity in data available from the Indian subcontinent about the outcome of nodules carrying Bethesda category III or Bethesda category IV diagnoses. Aims and Objectives: The primary objective of our study was to determine the malignancy rate in Bethesda categories III and IV nodules. The secondary objectives were to determine predictive value of BRAFV600E mutation analysis on indeterminate thyroid nodules, predictive value of Thyroid image reporting and data system (TI-RADS) in malignancy prediction and to study the common histological variants in indeterminate nodules. Materials and Methods: This prospective study included 176 consecutive nodules of Bethesda categories III and IV, diagnosed over a period of 2 years from August 2015 to August 2017. A part of the fine needle aspirate was used to perform the BRAFV600E mutation analysis. The malignancy risk associated with these Fine needle aspiration Cytology categories were discussed with the patients. Those with Bethesda category IV diagnosis was advised surgery, whereas those with Bethesda category III were given the options of close follow-up with repeat FNA in 3 months or immediate surgery. Results: In our prospective study, there were 176 consecutive samples of categories III (140/79.5%) and IV (36/20.5%). Seventy-five (53.6%) category III nodules and 29 (80.6%) category IV nodules underwent immediate surgical excision. Fifty-five consecutive indeterminate cytology nodules were subjected for BRAFV600E. One of the samples was found to be positive for BRAF T1799A (V600E) mutation. The second sample harboured a missense mutation at position 1819 (TCC--GCC), wherein the codon 607 (TCC) coding for serine was substituted by alanine (GCC) which is a variant of unknown significance. In our study, the malignancy rate of Bethesda categories III and IV, which were triaged for immediate surgery were 54.6% and 72.4%, respectively. Conclusion: Malignancy rate in Category III at our center was much higher than that described by ATA and by other studies published from centers around the world, including the only two studies from India. In view of the strikingly high malignancy rate in these indeterminate nodules, strong consideration to surgery should be given to patients with FNA results suggesting these two categories. BRAFV600E mutation analysis in FNA specimen has limited utility in improving the preoperative diagnostic rate for malignancy.

Background: The International System for Reporting Serous Fluid Cytopathology was recently proposed as a tiered structure to provide consistent reporting terminology for serous effusions. Because of the variation in reporting practices for indeterminate serous effusions, namely, the atypia of undetermined significance (AUS) and suspicious for malignancy (SFM) groups, the authors retrospectively reviewed cases in these 2 categories at their institution and determined the associated risk of malignancy (ROM). Methods: Pleural, peritoneal, and pericardial effusions that were reported as AUS or SFM over a 1‐year period were reviewed, and their associated ROMs were calculated based on confirmation of malignancy by previous and/or subsequent fluid and/or tissue biopsy specimens from the same general location. Results: In total, 145 AUS and 98 SFM serous effusion cases were identified. The AUS category was used when the cells in question lacked the requisite quantitative (cell number) and/or qualitative (morphologic) features for a definitive diagnosis. Immunohistochemistry (IHC) or flow cytometry (FCM) was available in 15% of cases (n = 22) with inconclusive results. The ROM based on 69 cases with available follow‐up results was 39%. In contrast, the SFM category demonstrated cells that were morphologically suspicious for malignancy but sparse, precluding IHC or FCM (n = 63; 64%) or yielding inconclusive results (n = 35; 36%). The ROM in the SFM category, based on follow‐up results of 61 cases, was 64%. Conclusions: The ROM for SFM was significantly higher than that for AUS (P <.01), supporting separate diagnostic categories for these 2 groups. There is considerable variation in the reporting practices for indeterminate serous effusions, namely, the categories atypia of undetermined significance and suspicious for malignancy, with limited literature on their associated risk of malignancy. The reporting practice at a single institution is examined and demonstrates that the risk of malignancy in the suspicious for malignancy category is significantly higher than that for the atypia of undetermined significance category, thus providing support for retaining these as 2 separate diagnostic categories in the tiered reporting system for serous effusions. [ABSTRACT FROM AUTHOR]