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Concepts in thyroid diagnostics are evolving. As cytopathologists, we benefit from understanding the changes taking place in cytopathology practice as well as intersecting areas that may have implications for us. In this review, we discuss recent changes to 1. Classification systems, 2. Ancillary molecular testing modalities, and 3. Key metrics that affect thyroid cytopathology. The recent World Health Organization, Bethesda Thyroid Cytopathology, and American Joint Committee on Cancer classification systems have aspects that are designed to harmonize the clinical, cytopathologic, histomorphologic, and molecular findings for improved communication and patient management. New terminologies such as thyroid follicular nodular disease and low-risk follicular cell-derived thyroid neoplasms are introduced to reflect the subtle biologic nuances involving benign non-neoplastic and low-grade neoplastic conditions. The Bethesda Thyroid Cytopathology System has simplified its terminology, updated risk of malignancy estimates, and expanded the discussions on molecular testing, clinical and imaging assessments, and pediatric cytopathology. There is now a single term for each of the 6 diagnostic categories. The American Joint Committee on Cancer has refined the staging criteria to provide improved stratification of patient prognostication. Molecular testing using next-generation technology now offers large panels of markers that are sensitive for detecting the wide range of thyroid neoplasms. These panels were developed in North America and whether other regions of the world will choose similar tests remain to be seen. Finally, metrics such as molecular-derived risk of malignancy and molecular risk group may be viewed as surrogates of resection information and used to complement diagnostics, management, and quality assurance.

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Objectives: This study aimed to explore the performance of a model based on Chinese Thyroid Imaging Reporting and Data Systems (C-TIRADS), clinical characteristics, and shear wave elastography (SWE) for the prediction of Bethesda I thyroid nodules before fine needle aspiration (FNA). Materials and methods: A total of 267 thyroid nodules from 267 patients were enrolled. Ultrasound and SWE were performed for all nodules before FNA. The nodules were scored according to the 2020 C-TIRADS, and the ultrasound and SWE characteristics of Bethesda I and non-I thyroid nodules were compared. The independent predictors were determined by univariate analysis and multivariate logistic regression analysis. A predictive model was established based on independent predictors, and the sensitivity, specificity, and area under the curve (AUC) of the independent predictors were compared with that of the model. Results: Our study found that the maximum diameter of nodules that ranged from 15 to 20 mm, the C-TIRADS category <4C, and E max <52.5 kPa were independent predictors for Bethesda I thyroid nodules. Based on multiple logistic regression, a predictive model was established: Logit (p) = -3.491 + 1.630 × maximum diameter + 1.719 × C-TIRADS category + 1.046 × E max (kPa). The AUC of the model was 0.769 (95% CI: 0.700-0.838), which was significantly higher than that of the independent predictors alone. Conclusion: We developed a predictive model for predicting Bethesda I thyroid nodules. It might be beneficial to the clinical optimization of FNA strategy in advance and to improve the accurate diagnostic rate of the first FNA, reducing repeated FNA.

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A thyroid nodule is managed according to the clinical context, ultrasound (US) findings, and fine needle aspiration (FNA) results. Most thyroid nodules are benign; however, nodule classification is crucial to avoid unnecessary thyroid surgery. We conducted this study to compare the findings of fine-needle aspiration cytology (FNAC) expressed using the Bethesda system with the features of thyroid US classified using the EU-TIRADS classification to assess the risk of malignancy. A descriptive and analytical study involving 99 patients with thyroid nodules followed up in the Department of Endocrinology-Diabetology and Nutrition. Data were collected from medical records and analyzed using SPSS software V21. FNA was performed on 121 nodules using the BETHESDA system. These nodules were classified as malignant, suspicious for follicular neoplasm, and suspicious for malignancy in 5.8%, 5%, and 1.7% of cases, respectively. As for the EU-TIRADS 2017 classification, 59.5% of benign nodules were classified as EU-TIRADS III, whereas 66.7% of malignant nodules were classified as EU-TIRADS V and significantly related to malignant prediction (P = 0.000). The size of nodules was significantly correlated to the risk of malignancy (P = 0.013). Seventy-five percent of nodules with central vascularity were malignant (P = 0.012). Irregularity of nodule contours was significantly associated with the risk of malignancy, as 30% of nodules with irregular contours were Bethesda VI (P = 0.003). Hypoechogenicity was found in 77.8% of malignant nodules (P = 0.004). Additionally, only 9.2% of the nodules were taller than wide, of which 37.5% were malignant (P = 0.012). For a safe management strategy, US-guided FNAC should be performed on each suspicious thyroid nodule, given the correlation between EU-TIRADS classification features and the risk of malignancy.

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Background Ultrasonographic evaluation of thyroid nodules is challenging due to their high frequency and low malignancy rate. The risk stratification system developed by the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) focuses on addressing the primary contemporary objectives for these lesions, aiming to decrease unnecessary biopsies while maintaining a similar specificity compared with other risk stratification systems. Generally, when indicative of malignancy by ultrasound findings, the next best step in management is an evaluation by fine needle aspiration biopsy (FNAB) and cytological analysis with The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) results that determine further evaluation requirements, actions that are based on the risk of malignancy (ROM) of the assigned category, which could include surgical intervention. Objectives To validate and analyze the individual impact of each ultrasonographic finding indicative of malignancy in the ACR TI-RADS guidelines based on their respective correlation with results obtained by TBSRTC. Materials and method Reports for 212 thyroid ultrasound-guided FNABs from 2018 to 2020 were assessed. Only 117 had both ACR TI-RADS and TBSRTC reports available and were analyzed. Nodules were divided into two groups: ROM < 5% (Bethesda 1, 2; n = 58), and ROM > 5% (Bethesda 3, 4, 5, 6; n = 59). Statistical analysis was performed using the x2 test and bivariate logistic regression model for each characteristic included in ACR TI-RADS. Results Individual ultrasound characteristics with a more pronounced distribution towards the Bethesda > 5% malignancy group were: solid or almost completely solid composition (n=53, 62.3%), very hypoechoic echogenicity (n=3, 75%), wider-than-tall shape (n=50, 50.5%), lobulated or irregular margin (n=23, 65.7%), punctate echogenic foci (n=18, 72%), and thyroid isthmus location (n=6, 75%). Statistically significant individual ultrasonographic characteristics indicative of malignancy included solid or almost completely solid (p = 0.005), very hypoechoic echogenicity (p = 0.046), margin lobulated or irregular (p = 0.031), and punctate echogenic foci (p = 0.015). No significant association was found in the taller-than-wide shape for differentiating malignant from benign lesions (p = 0.969). Conclusions Specific ultrasound characteristics identified in the ACR TI-RADS system demonstrate a stronger correlation with an increased risk of malignancy when compared with cytologic evaluation results. These characteristics include a solid composition, lobulated or irregular margins, punctate echogenic foci, and very hypoechoic echogenicity. Our findings revealed that the scale points for the taller-than-wide characteristic do not adequately represent its true influence on the risk of malignancy.

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Thyroid cytology is a rapidly evolving field that has seen significant advances in recent years. Its main goal is to accurately diagnose thyroid nodules, differentiate between benign and malignant lesions, and risk stratify nodules when a definitive diagnosis is not possible. The current landscape of thyroid cytology includes the use of fine-needle aspiration for the diagnosis of thyroid nodules with the use of uniform, tiered reporting systems such as the Bethesda System for Reporting Thyroid Cytopathology. In recent years, molecular testing has emerged as a reliable preoperative diagnostic tool that stratifies patients into different risk categories (low, intermediate, or high) with varying probabilities of malignancy and helps guide patient treatment.

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A substantial percentage of the population remains at risk for cervical cancer due to pre-existing human papillomavirus (HPV) infections, despite prophylactic vaccines. Early diagnosis and treatment are crucial for better disease outcomes. The development of new treatments heavily relies on suitable preclinical model systems. Recently, we established a mouse papillomavirus (MmuPV1) model that is relevant to HPV genital pathogenesis. In the current study, we validated the use of Papanicolaou (Pap) smears, a valuable early diagnostic tool for detecting HPV cervical cancer, to monitor disease progression in the MmuPV1 mouse model. Biweekly cervicovaginal swabs were collected from the MmuPV1-infected mice for viral DNA quantitation and cytology assessment. The Pap smear slides were evaluated for signs of epithelial cell abnormalities using the 2014 Bethesda system criteria. Tissues from the infected mice were harvested at various times post-viral infection for additional histological and virological assays. Over time, increased viral replication was consistent with higher levels of viral DNA, and it coincided with an uptick in epithelial cell abnormalities with higher severity scores noted as early as 10 weeks after viral infection. The cytological results also correlated with the histological evaluation of tissues harvested simultaneously. Both immunocompromised and immunocompetent mice with squamous cell carcinoma (SCC) cytology also developed vaginal SCCs. Notably, samples from the MmuPV1-infected mice exhibited similar cellular abnormalities compared to the corresponding human samples at similar disease stages. Hence, Pap smear screening proves to be an effective tool for the longitudinal monitoring of disease progression in the MmuPV1 mouse model. IMPORTANCE: Papanicolaou (Pap) smear has saved millions of women's lives as a valuable early screening tool for detecting human papillomavirus (HPV) cervical precancers and cancer. However, more than 200,000 women in the United States alone remain at risk for cervical cancer due to pre-existing HPV infection-induced precancers, as there are currently no effective treatments for HPV-associated precancers and cancers other than invasive procedures including a loop electrosurgical excision procedure (LEEP) to remove abnormal tissues. In the current study, we validated the use of Pap smears to monitor disease progression in our recently established mouse papillomavirus model. To the best of our knowledge, this is the first study that provides compelling evidence of applying Pap smears from cervicovaginal swabs to monitor disease progression in mice. This HPV-relevant cytology assay will enable us to develop and test novel antiviral and anti-tumor therapies using this model to eliminate HPV-associated diseases and cancers.

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The evaluation of thyroid lesions is common in the daily practice of cytology. While the majority of thyroid nodules are benign, in recent decades, there has been increased detection of small and well-differentiated thyroid cancers. Combining ultrasound evaluation with fine-needle aspiration cytology (FNAC) is extremely useful in the management of thyroid nodules. Furthermore, the adoption of specific terminology, introduced by different thyroid reporting systems, has helped effectively communicate thyroid FNAC diagnoses in a clear and understandable way. In 1996, the Papanicolaou Society thyroid cytological classification was introduced. This was followed in 2005 by the first Japanese and then in 2007 by the Bethesda System for Reporting Thyroid Cytopathology, which subsequently underwent two revisions. Other international thyroid terminology classifications include the British, Italian, Australasian and other Japanese cytology systems. This review covers similarities and differences among these cytology classification systems and highlights key points that unify these varied approaches to reporting thyroid FNAC diagnoses.

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INTRODUCTION: Some epidemiological data suggest that there may be an inverse relationship between cholesterol levels and the risk of thyroid cancer in the overall population. The present study was aimed to evaluate the lipid profile specifically in subjects with Bethesda category IV thyroid nodules, and compare whether there were any differences between those with benign and malignant nodules. METHODS: Single-centre, retrospective study on 204 subjects treated by partial or total thyroidectomy for excision of a Bethesda category IV thyroid nodule, who had undergone a blood lipid profile test in the 12 months prior to surgery. In addition to lipid measures, other demographic, clinical, biochemical and ultrasound data were collected. RESULTS: Seventy-five subjects (36.8%) were diagnosed with thyroid carcinoma in the definitive histopathological examination. Patients with thyroid cancer had lower levels of total cholesterol, LDL-cholesterol and non-HDL-cholesterol than subjects with benign thyroid diseases. There were no differences in HDL-cholesterol, triglycerides or total cholesterol/HDL-cholesterol ratio. There were no differences either between groups in other clinical, biochemical and ultrasound variables, including the use of lipid-lowering drugs. In multivariate analysis, only LDL-cholesterol was independently associated with malignancy. Subjects with follicular carcinoma showed the lowest cholesterol levels, while those with papillary carcinoma had intermediate values between the group with follicular carcinoma and the group with benign thyroid diseases. CONCLUSIONS: In subjects with cytologically indeterminate Bethesda category IV thyroid nodules, levels of total cholesterol, non-HDL-cholesterol and, particularly, LDL-cholesterol are lower among those with malignant nodules.

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BACKGROUND: The reported risk of malignancies (ROM) remains controversial for fine needle aspiration (FNA) of thyroid nodules in the African American (AA) population. Herein, the ROM along with frequency was assessed for each of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) diagnostic categories. MATERIALS AND METHODS: The electronic pathology archive of a large academic hospital was retrospectively searched for cytopathology reports of thyroid nodules in AA patients (2010-2019) and Non-African American (NAA) control cases. The patients' demographic, thyroid nodule characteristics, FNA results using TBSRTC and surgical diagnoses were recorded, whenever available. RESULTS: Three hundred ninety-one cases were identified, 317 females (81.1%) and 74 males (18.9%) with median age 50.0 (SD = 14.4). The mean size of the nodules was 2.1 cm (SD = 1.4). The Bethesda categories were: 5.4% (I), 35.0% (II), 35.3% (III), 7.7% (IV), 3.3% (V) and 13.3% (VI). The overall ROM of thyroid nodules was 43.8% (89/203) on surgical follow-up (203/391). The ROM in each Bethesda categories were: 33.3% (I), 11.6% (II), 35.2% (III), 15.8% (IV), 83.3% (V) and 100% (VI) on surgical follow-up. The frequency of thyroid nodules was higher in AA females; however, the ROM was higher in AA males (48.3%) compared with AA females (41.2%). CONCLUSION: The ROM in Categories I, II and III was higher than those reported in the TBSRTC while being similar in Categories IV, V and VI. The overall risk of thyroid malignancy in our AA patient population was higher than those in the literature. The overall ROM of thyroid nodules in AA males was higher than of AA females.

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INTRODUCTION: Fine needle aspiration cytology (FNAC) for thyroid nodules has a high diagnostic accuracy, according to several studies worldwide. Patients who experienced preoperative FNAC had more optimal surgical treatment than others who did not perform FNAC. Therefore, achieving an accurate FNAC procedure appears to be an important tool for the proper management of thyroid nodules. We aimed to study the accuracy and challenges of the thyroid FNAC diagnostic tool in the Al-Baha region, Kingdom of Saudi Arabia. METHODS: The study involves 52 patients with thyroid nodules who underwent preoperative FNAC and postoperative histopathology with the same surgery and pathology team at Al-Baha region in 2022-2023. RESULTS AND CONCLUSION: The mean age of the included patients was 47.7 years, with a female predominance. The diagnostic accuracy was 90%, and the main cause of inaccurate diagnosis was processing challenges, where the majority of cases were taken on the palpation-only technique, a few cases were ultrasound-guided, and the only technique used in the laboratory was conventional smears. The applied interrater reliability Cohen kappa coefficient (κ) for the clinical-histopathological agreement was "moderate agreement". We recommend using and evaluating more cytological techniques in addition to the currently used conventional smears in pathology laboratories to enhance the efficacy of the FNAC diagnosis of thyroid lesions.

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Objectives: To probe cervical cancer screening practices in local women positive for human immunodeficiency virus, and to determine the cervical cytological changes in them. METHODS: The serial cross-sectional study was conducted at the Jinnah Hospital and Services Hospital, Lahore, Pakistan, from April 2019 to October 2020, and comprised female patients aged 18-45 years who were positive for human immunodeficiency virus or acquired immunodeficiency syndrome and were registered with the relevant programme being run by the provincial government in Punjab. Blood samples of all the patients were collected for the determination of human immunodeficiency virus viral load and cluster of differentiation 4+ count. Cervical smears were taken for cytopathological analysis, while the swabs were analysed for culture sensitivity. The same individuals were subjected to the same testing one year later, and the status of the disease and clinical stability or disease progression was explored. Data was analysed using SPSS 25. RESULTS: There were 150 women with mean age 32.08±7.13 years (range: 21-45 years). Age at marriage/sexual activity was 17.33±4.73 years in 15(10%) subjects. Cytological examination showed atypical squamous cells of undetermined significance in 6(4%) of the cases whereas 3(2%) cases showed atypical squamous cells, which cannot rule out high grade squamous intraepithelial lesion on cytology, while the rest were classified as negative for intraepithelial lesion or malignancy. Cervical microbial changes revealed methicillin-resistant staphylococcus aureus infection in 9(6%) cases, extended-spectrum beta-lactamase in 15(10%) cases, whereas fungal infection and trichomonas vaginalis infection were found in 30(20%) smears. There was a significant association between cluster of differentiation 4+ cell count and stability of high-risk patients (p<0.001). After one year, 84(56%) patients remained clinically stable, while 51(34%) developed some chronic illness. There was a significant association between cluster of differentiation 4+ cell count <200/mm3 and the risk of developing a chronic illness (p<0.001). CONCLUSIONS: There was a dire need to educate healthcare workers to offer regular cervical screening to patients with high-risk sexually-transmitted infections to prevent them from the morbidity and mortality related to cervical cancer.

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Reporting fine-needle aspiration of thyroid nodules in the Bethesda classification is a practice widely used internationally and by us. The revised third edition of the Bethesda System of Reporting Thyroid Cytopathology brings changes in terminology, content, and new chapters. In terms of terminology, an obvious change is the removal of the two-word names of three categories while maintaining the six diagnostic categories of the previous versions - new: BI - non-diag- nostic, BIII - atypia of undetermined significance, BIV - follicular neoplasia. In the detailed description of the findings within the individual categories, the ter- minological changes adopted by the fifth edition of the WHO classification of thyroid neoplasia are respected - in particular, the recommended name follicular thyroid nodular disease for the most frequently represented category BII - benign. In the evaluation itself, the diagnostic specifications accepted by the current WHO classification of histopathological findings are reflected in the individual categories - if they are applicable at the cytological level. Targeted attention will need to be paid to high grade features. The revised version brings new chapters dedicated to molecular testing and evaluation of the paediatric population.

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OBJECTIVES: Few cytologically indeterminate thyroid fine-needle aspirations (FNAs) harbor BRAF V600E. Here, we assess interobserver agreement for The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) category III (atypia of undetermined significance [AUS]) FNAs harboring BRAF V600E and contrast their features with those harboring non-BRAF V600E alterations, with attention to cytopathology experience. METHODS: Seven reviewers evaluated 5 AUS thyroid FNAs harboring BRAF V600E. To blind reviewers, cases were intermixed with 19 FNAs falling within other TBSRTC categories and in which genetic alterations other than BRAF V600E had been identified (24 FNAs total). Interobserver agreement against both "index" and most popular ("mode") diagnoses was calculated. Four additional BRAF V600E cases were independently reviewed. RESULTS: Reviewers included 3 trainees and 3 American Board of Pathology (board)-certified cytopathologists. Board-certified cytopathologists, whose experience ranged from 2 to more than 15 subspecialty practice years, had known AUS rates. BRAF V600E was identified in 5 of 260 (2%) AUS FNAs. Interobserver agreement was higher among cytopathologists with more experience. Mode diagnosis differed from index diagnosis in 6 of 11 cases harboring RAS-like alterations; mode diagnosis was AUS in 4 of 5 BRAF V600E FNAs. CONCLUSIONS: Atypia of undetermined significance of thyroid FNAs harboring BRAF V600E is uncommon yet relatively reproducible, particularly among pathologists with experience. It is advisable to sequence BRAF across V600 in such cases.

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BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends an upper limit of 10% for atypia of undetermined significance (AUS). Recent data suggest that this category might be overused when the rate of cases with molecular positive results is low. As a quality metric, the AUS and positive call rates for this facility's cytology laboratory and each cytopathologist (CP) were calculated. METHODS: A retrospective analysis of all thyroid cytology cases in a 4.5-year period was performed. Cases were stratified by TBSRTC, and molecular testing results were collected for indeterminate categories. The AUS rate was calculated for each CP and the laboratory. The molecular positive call rate (PCR) was calculated with and without the addition of currently negative to the positive results obtained from the ThyroSeq report. RESULTS: A total of 7535 cases were classified as nondiagnostic, 7.6%; benign, 69%; AUS, 17.5%; follicular neoplasm/suspicious for follicular neoplasm, 1.4%; suspicious for malignancy, 0.7%; and malignant, 3.8%. The AUS rate for each CP ranged from 9.9% to 36.8%. The overall PCR was 24% (range, 13%-35.6% per CP). When including cases with currently negative results, the PCR increased to 35.5% for the cytology laboratory (range, 13%-42.6% per CP). Comparison analysis indicates a combination of overcalling benign cases and, less frequently, undercalling of higher TBSRTC category cases. CONCLUSIONS: The AUS rate in the context of PCR is a useful metric to assess cytology laboratory and cytopathologists' performance. Continuous feedback on this metric could help improve the overall quality of reporting thyroid cytology.

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BACKGROUND: Fine needle aspiration cytology (FNAC) is the most useful tool in the diagnosis of thyroid nodules. Liquid-based cytology (LBC) is replacing the conventional smear (CS) for evaluation of thyroid FNAC. In our institution, thyroid FNAC preparation was changed from CS to LBC SurePath in July 2016. This study aimed to compare the diagnostic value of SurePath with that of CS in thyroid lesions. METHODS: A total of 35,406 samples of thyroid FNAC (11,438 CS and 23,968 SurePath), collected from January 2010 to December 2022, were included in this study. We also examined the malignant rate using the surgical pathology diagnosis as the gold standard. RESULTS: The distribution of TBSRTC cytological categories was equivalent between CS and SurePath. The rate of nondiagnostic/unsatisfactory category was higher in CS compared to SurePath (43.4% vs. 22.3%; p < .05). After routine use of SurePath, the surgical resection rate was reduced from 12.0% to 8.6% (p < .05) and the malignant rate increased from 32.2% to 41.5% (p < .05). The sensitivities of CS and SurePath were 71.0% and 82.0%, respectively, and the specificities were 99.0% and 97.3%, respectively, whereas the positive predictive values were 97.8% and 96.8%, respectively, and the negative predictive values were 85.0% and 84.6%, respectively. Diagnostic accuracy of CS and SurePath were 88.5% and 89.7% respectively. CONCLUSION: SurePath can increase the sample adequacy, increase the sensitivity and reduce the workload and avoid unnecessary surgeries with similar accuracy to CS.

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Anaplastic lymphoma kinase (ALK) gene fusions are rare in papillary thyroid carcinoma (PTC) but may serve as a therapeutic target. This study aims to evaluate the preoperative cytologic findings and clinicopathologic features of a series of eight ALK-rearranged PTCs from our pathology archives and consultations. All cases were confirmed by ALK D5F3 immunohistochemistry and six with additional targeted RNA-based next-generation sequencing (NGS). The original fine-needle aspiration (FNA) cytology diagnosis included the Bethesda System (TBS) category II in three (37.5%), TBS III in two (25%), TBS V in two (25%), and TBS VI in one (12.5%). Six cases had available FNA cytology and were reviewed. The cytologic features showed microfollicular architecture as well as limited or reduced nuclear elongation and chromatin alterations in all six. Nuclear grooves and pseudoinclusions were absent in two cases, rarely or focally noted in three, and frequently found in one. Two cases initially diagnosed as TBS II, showing microfollicular architecture without well-developed nuclear features, were revised to TBS III (with architectural atypia only). For histologic correlations, four were infiltrative follicular variant PTCs, three as classic subtype PTC with predominant follicular growth, and one as solid/trabecular subtype PTC. All eight cases demonstrated reduced PTC nuclear features with respect to nuclear elongation and chromatin alterations compared to those typically identified in "BRAF-like" PTCs. The NGS testing revealed EML4::ALK fusion in three, STRN::ALK fusion in two, and ITSN2::ALK fusion in one. In conclusion, although ALK-rearranged PTCs have been associated with neutral gene expression profile from a BRAF-RAS scoring perspective, the "RAS-like" nuclear features were more commonly identified in this series, resulting in frequent indeterminate diagnosis of preoperative FNA.

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BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) has evolved since it was first introduced in 2009 to become a worldwide accepted cytologic analysis reference, due to its simplicity and reproducibility. To date, the consistency of BSRTC throughout time has yet to be investigated. METHODS: Retrospective single institution case series with chart review of all patients who underwent fine-needle aspirations for a thyroid nodule in our institution between the years 2010 and 2018 with a documented BSRTC classification. Data collection included demographics, risk factors, sonographic evaluation, nodule size, and final pathology when feasible. The main outcome is the difference in the rates of BSRTC categories benign, atypia of undetermined significance (AUS), follicular neoplasm, suspicious for malignancy, and malignant (BSRTC II-VI, respectively) between the study years. RESULTS: A total of 2830 thyroid nodules were included. BSRTC II-VI distribution was 83.9% (2373), 8.2%, (232), 2.7% (75), 3.3% (93), and 2.0% (57), respectively. There was no significant change in the overall trend of each BSRTC category distribution throughout the study. There was a significant increase in the benign cytology rate (BSRTC II) in 2011 compared to 2015 and 2018 (76.4% compared to 88.7% and 87.6%, respectively. P < .005) alongside a significant decline in the AUS category rate (BSRTC III) between the same years (13.0% compared to 4.8% and 5.5%, respectively. P < .005). CONCLUSION: BSRTC showed consistency throughout the study across all observed categories. An overlap between AUS and benign may exist, possibly due to the heterogenic definition of AUS as reflected in the 2023 BSRTC subclassification for AUS.

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BACKGROUND: The Bethesda system classifies all fine-needle aspiration specimens into 1 of 6 categories. We speculated that cancers within each Bethesda category would have distinct clinical behavior. METHODS: This is a retrospective analysis of patients from a single academic medical center with a histologic diagnosis of thyroid cancer who had an initial diagnosis of Bethesda III, IV, V, or VI cytology. RESULTS: A total of 556 cases were included, with 87 cases of Bethesda III, 109 cases of IV, 120 cases of V, and 240 cases of VI. Bethesda III showed similarities with V/VI compared to IV with a predominance of papillary thyroid cancer. The interval from diagnosis to surgery was longer in Bethesda III compared to Bethesda V/VI (median 78 vs 41 days, P < .001) (Fig. 1). Yet, patients with Bethesda III had a higher probability of achieving remission (62% vs 46%, P < .03), a lower possibility of recurrence (8% vs 24%, P < .001), and a shorter interval to achieve remission (median 1218 vs 1682 days, P = .02) compared to Bethesda V/VI, which did not change after adjusting for age, sex, radioactive iodine therapy, mode of surgery, and tumor size. More than 70% of Bethesda III that later presented with recurrence had T3/T4 disease or distant metastasis. CONCLUSION: Cancers with Bethesda III cytology had a less aggressive clinical phenotype with better prognosis compared to V/VI despite histological similarities. The time to remission was shorter in Bethesda III despite a longer interval between diagnosis and surgery. The initial cytological diagnosis may guide management.

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The increasing prevalence of thyroid cancer emphasizes the need for a thorough assessment of risk of malignancy in Bethesda III nodules. Various methods ranging commercial platforms of molecular genetic testing (including Afirma® GEC, Afirma® GSC, ThyroSeq® V3, RosettaGX®, ThyGeNEXT®/ThyraMIR®, ThyroidPRINT®) to radionuclide scans and ultrasonography have been investigated to provide a more nuanced comprehension of risk estimation. The integration of molecular studies and imaging techniques into clinical practice may provide clinicians with improved and personalized risk assessment. This integrated approach we feel may enable clinicians to carefully tailor interventions, thereby minimizing the likelihood of unnecessary thyroid surgeries and overall crafting the optimal treatment. By aligning with the evolving landscape of personalized healthcare, this comprehensive strategy ensures a patient-centric approach to thyroid nodule and thyroid cancer management.

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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.

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