Binary subclassification scheme (AUS-Nuclear versus AUS-Other) adequately risk-stratifies thyroid fine needle aspiration specimens classified as Atypia of Undetermined Significance.

INTRODUCTION: The Bethesda System for Reporting Thyroid Cytopathology previously described 4 subclasses of atypia within the Atypia of Undetermined Significance (AUS) category: nuclear (AUS-Nuc), architectural (AUS-A), oncocytic (AUS-Onc), and atypia not otherwise specified (AUS-NOS). Accumulating evidence supports a binary AUS subclassification scheme based primarily on the presence of nuclear atypia only. The purpose of this study is to compare the risk stratification of binary versus 4-tier AUS subclassification systems among AUS nodules with molecular and/or histologic follow-up. MATERIALS AND METHODS: Thyroid aspirates classified as AUS and tested using Afirma (Veracyte, Inc.) between 6/2013 and 7/2021 were included. For resected nodules, histological classification was considered as the final outcome. For unresected nodules, benign Afirma results were considered low-risk outcomes, similar to histologically benign nodules. Suspicious or nondiagnostic Afirma results were considered indeterminate outcomes. The prevalence of outcomes warranting surgery (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP] or cancer) was calculated for each AUS subclass. RESULTS: A total of 559 AUS nodules with Afirma testing were identified. Excluding nodules with indeterminate molecular outcomes, NIFTP/cancer prevalence for AUS-Nuc was 21% (57/266), which was higher than that for AUS-A (6%, 11/188), AUS-Onc (8%, 4/53), and AUS-NOS (0%, 0/9). A binary AUS subclassification scheme based on nuclear atypia showed a significant difference in NIFTP/cancer prevalence (21% versus 6%, P < 0.0001). CONCLUSIONS: Binary reporting of AUS subclasses based on nuclear atypia distinguishes cases with a higher risk of NIFTP/cancer. There is a low but non-negligible prevalence of NIFTP/cancer in cases without nuclear atypia.

Diagnostic models for predicting malignancy in thyroid nodules classified as Bethesda Category III in an endemic region.

BACKGROUND: This study aims to develop a diagnostic model to help physicians determine whether thyroid nodules categorized as atypia of undetermined significance (AUS) in category III of the Bethesda system are benign or malignant preoperatively. To create a diagnostic model for predicting thyroid nodules' benign or malignant with AUS cytology based on clinical, ultrasonographic, and cytopathological findings. METHODS: This is a retrospective cohort study involving patients (>19) at risk of thyroid cancer who had thyroidectomy after an AUS cytology. The dataset consists of 53 variables 204 nodules from 183 patients. Binary logistic regression and factor analysis methods were used to identify risk factors for malignancy. Finally, four prediction models were developed using different approaches, based on clinical, pathological clinical + pathological, and the factors. RESULTS: A total of 88 (48.1%) of 183 patients diagnosed with AUS were benign and 95 (51.9%) the malignant. After determining risk factors, four prediction models were developed based on different approaches to assist physicians in deciding to detect AUS nodules early. It was seen that bilaterality was found to be a risk factor for malignancy in the clinical model (pbilaterality = .03) and it was also seen that the pathological variables pale chromatin and irregular contours in the oncocyte variables were risk factors for malignancy (ppalechromatin = .02, pirregularcontoursintheoncocyte = .04). The best model obtained sensitivity and specificity values are 73% and 87% based on clinical and pathological variables. CONCLUSION: This comprehensive study may provide a more in-depth understanding of AUS and make a notable contribution to healthcare professionals before surgery.

Deep convolutional neural network model ResNeSt for discrimination of papillary thyroid carcinomas and benign nodules in thyroid nodules diagnosed as atypia of undetermined significance.

Background: A deep convolutional neural network (DCNN) model was employed for the differentiation of thyroid nodules diagnosed as atypia of undetermined significance (AUS) according to the 2023 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The aim of this study was to investigate the efficiency of ResNeSt in improving the diagnostic accuracy of fine-needle aspiration (FNA) biopsy. Methods: Fragmented images were used to train and test DCNN models. A training dataset was built from 1,330 samples diagnosed as papillary thyroid carcinoma (PTC) or benign nodules, and a test dataset was built from 173 samples diagnosed as AUS. ResNeSt was trained and tested to provide a differentiation. With regard to AUS samples, the characteristics of the cell nuclei were compared using the Wilcoxon test. Results: The ResNeSt model achieved an accuracy of 92.49% (160/173) on fragmented images and 84.78% (39/46) from a patient wise viewpoint in discrimination of PTC and benign nodules in AUS nodules. The sensitivity and specificity of ResNeSt model were 95.79% and 88.46%. The κ value between ResNeSt and the pathological results was 0.847 (P<0.001). With regard to the cell nuclei of AUS nodules, both area and perimeter of malignant nodules were larger than those of benign ones, which were 2,340.00 (1,769.00, 2,807.00) vs. 1,941.00 (1,567.50, 2,455.75), P<0.001 and 190.46 (167.64, 208.46) vs. 171.71 (154.95, 193.65), P<0.001, respectively. The grayscale (0 for black, 255 for white) of malignant lesions was lower than that of benign ones, which was 37.52 (31.41, 46.67) vs. 45.84 (31.88, 57.36), P <0.001, indicating nuclear staining of malignant lesions were deeper than benign ones. Conclusions: In summary, the DCNN model ResNeSt showed great potential in discriminating thyroid nodules diagnosed as AUS. Among those nodules, malignant nodules showed larger and more deeply stained nuclei than benign nodules.

Evaluating local thyroid cytopathology practices by molecular quality metrics: A multi-institutional study on 4651 FNAs with a focus on the role of the interventional cytopathologist.

BACKGROUND: The diagnostic accuracy of thyroid fine-needle aspiration (FNA) can be highly influenced by the technical skills of the operator performing the procedure and by interobserver variability in microscopic interpretation. This is particularly true for the indeterminate categories. Recently, molecular testing has been proposed as an ancillary tool for monitoring the performance of different thyroid cytopathology practices. The objective of this multicenter study was to evaluate the quality of different local cytopathology practices by assessing the impact of interventional cytopathologists on FNA adequacy for molecular testing and the variations in mutation rates across different health care centers operating in the Campania region. METHODS: The study included 4651 thyroid FNA samples diagnosed in different Southern Italian clinical laboratories belonging to the TIRNET (the Tiroide Network). FNA samples were collected by different proceduralists and were classified by local cytopathologists according to The Bethesda System for Reporting Thyroid Cytopathology. FNAs classified as atypia of undetermined significance, follicular neoplasm, suspicious for malignancy, and malignant were centralized for a real-time polymerase chain reaction-based, seven-gene test at the authors' institution. RESULTS: Centers that employed interventional cytopathologists obtained fewer unsatisfactory FNA samples for molecular testing (11.3%) than centers that employed noncytopathologists (16.7%; p < .05). Furthermore, a significant variation in the mutation rate was observed in FNAs diagnosed by different local cytopathologists; indeterminate categories had the highest percentage of mutation rate variability among centers. CONCLUSIONS: Interventional cytopathologists obtained higher yields of diagnostic material for molecular testing. Finally, the current results suggest that the variability in mutation rates among different centers may highlight the low reproducibility of microscopic criteria among cytopathologists, particularly for indeterminate cases.

Performance of Afirma genomic sequencing classifier and histopathological outcome in Bethesda category III thyroid nodules: Initial versus repeat fine-needle aspiration.

BACKGROUND: There is limited data comparing the performance of Afirma Genomic Sequencing Classifier (GSC) in thyroid nodules carrying an initial versus a repeat diagnosis of atypia of undetermined significance (AUS). This study reported an institutional experience in this regard. MATERIALS AND METHODS: This retrospective study included consecutive thyroid nodules that had an initial or a repeat AUS diagnosis and had a subsequent GSC diagnostic result (benign or suspicious) from 2017 to 2021. All nodules were followed by surgical intervention or by clinical and/or ultrasound monitoring. GSC's benign call rate (BCR), rate of histology-proven malignancy associated with a suspicious GSC result, and diagnostic parameters of GSC were calculated and compared between the two cohorts (initial versus repeat AUS). Statistical significance was defined with a p-value of <.05 for all analysis. RESULTS: A total of 202 cases fulfilled inclusion criteria, including 67 and 135 thyroid nodules with an initial and a repeat AUS diagnosis, respectively. BCR was 67% and 66% in initial and repeat AUS cohorts, respectively. Rate of histology-proven malignancy associated with a suspicious GSC result were 22% and 24% in initial and repeat AUS cohorts, respectively. Compared with the repeat AUS cohort, the initial AUS cohort showed slightly lower sensitivity (83% vs. 100%), specificity (70% vs. 73%), PPV (23% vs. 24%), NPV (98% vs. 100%), and diagnostic accuracy (72% vs. 75%). Nevertheless, these differences did not reach statistical significance. CONCLUSION: GSC demonstrated comparable performance in thyroid nodules with a repeat AUS diagnosis versus nodules with an initial AUS diagnosis.

Use of molecular testing results to analyze the overuse of atypia of undetermined significance in thyroid cytology.

INTRODUCTION: The suggested atypia of undetermined significance (AUS) rate for thyroid fine-needle aspiration biopsies is 10% or less. Prompted by a high institutional AUS rate, we examined using molecular testing results (MTR) as a potential quality metric tool to reduce the AUS rate. We correlated MTR with AUS cytologic findings, surgical pathology follow-up, and individual pathologist AUS rates. MATERIALS AND METHODS: Demographic data, cytologic diagnoses, MTR, and surgical pathology diagnoses were retrospectively obtained. MTR were classified as either positive or negative. AUS rates and MTR proportions were compared among pathologists. The cytomorphologic features of 143 AUS cases were assessed and correlated with MTR. RESULTS: Between 2017 and 2022, 710 of 3247 thyroid fine-needle aspirations were classified as AUS, with a yearly average rate of 22% (range = 19%-26%). AUS cases included: 331 (47%) with architectural atypia; 204 (29%) with oncocytic (Hürthle cell) atypia; 99 (14%) with combined architectural and cytologic atypia; and 76 (10%) with isolated cytologic atypia. Most AUS cases with molecular testing had negative MTR (360/492, 73%). AUS with cytologic atypia had higher positive MTR risk (logarithm of odds ratio = 1.27, 95% credible interval [0.5-2.04], P = 0.001). The average positive MTR rate by pathologist was 21.5% (range 0%-35%); higher positive MTR rates had better correlation with subsequent neoplastic/malignant histologic diagnoses. The MTR sensitivity for malignant disease was 89% and the negative predictive value was 91%. CONCLUSIONS: MTR analysis reveals the importance of cytologic atypia as a determinant of malignancy risk in AUS cases. Periodic analysis of MTR data alongside individual pathologist AUS rates can help refine diagnostic criteria and potentially reduce AUS overuse.

MSRSGC: A prospective study of heterogenous group atypia of undetermined significance.

Context: : Many standard books, literatures, and internet described the characteristic lineament of each salivary gland lesion. Nevertheless, there are dozens of disarray, confusion, and unmanageable morphological features regarding proper reporting. To fight with these issues, Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was introduced in 2018, but still the third category, Atypia of undetermined significance (AUS), poses difficulties for the pathologists and clinicians for a definite interpretation. Aim: : The aim is to analyze the risk of neoplasia (RON) and risk of malignancy (ROM) of Milan's category III (AUS) by subdividing into six groups based on cytolomorphology. Settings and Design: :The duration of study was from March 2018 to may 2021 with the focus on ROM and RON of all Milan's categories with especial attention on AUS. Methods and Material: : Result of total 329 Fine Needle Aspiration Cytology of salivary glands was categorized according to MSRSGC. On the basis of cytomorphology, further subtyping of AUS and its cytohistopathology correlation was done. The ROM and RON of each subtype was analyzed. Statistical Analysis: All data were calculated by existing formulas. Results: Out of 329 aspirates, 24 (07.29%) cases belong to AUS with availability of histology in 13 (54.17%) cases. RON and ROM was 84.62% and 53.85%, respectively. Cases of lymphocytes with nuclear atypia (L-NA) was the most prevalent (29.17%). The RON were 60.00%, 68.57,% 84.62%, 94.87%, 87.50%, 100%, 100% and the ROM were 20.00%, 11.42%, 53.85%, 05.13%, 43.75%, 83.33% and 100% in each Milan's categories I, II, III, IVa, IVb, V, and VI, respectively. ROM was the highest in cystic fluid with nuclear atypia (C-NA) (100.0%), followed by basaloid cells (75%), L-NA (66.675), and SC (50%), but ROM was zero in NA and oncocytic cells. Conclusions: Subgrouping of AUS helps to dissipate the muddiness and provide more exact and reproducible diagnostic and prognostic tool.

Intraoperative Assessment of High-Risk Thyroid Nodules Based on Electrical Impedance Measurements: A Feasibility Study.

Precise diagnosis of thyroid nodules is challenging due to non-diagnostic/inconclusive results and uncertainties about the malignancy of follicular neoplasms (FNs), even in frozen-section pathology. Therefore, surgical management, especially in Bethesda III and IV categories, may be complicated, and sometimes a second surgery may be required. The Thyroid Nodule Impedance Measurement System (TN-IMS) consists of a metallic patch attached to submental skin and a G20 I.V. cannula inserted into the targeted nodules. Two impedance-based parameters named Z1kHz and impedance phase slope (IPS) in 100 kHz to 500 kHz of the thyroid nodules are recorded and compared with their histopathological results as the gold standard. TN-IMS was intra-surgically applied to 103 human thyroid nodules and normal thyroid tissues. A remarkable consistency between defined co-ranges of Z1kHz/IPS and the histopathological status of specimens was achieved (p < 0.001). Based on these measurements, it was concluded that intraoperative bioelectrical impedance scanning of thyroid nodules would be a helpful complementary approach to detecting high-risk excision-required thyroid nodules.

Utility of the Milan System for Reporting Salivary Gland Cytology, with focus on the incidence and histologic correlates of atypia of undetermined significance (AUS) and salivary gland neoplasm of uncertain malignant potential (SUMP): A 3-year institutional experience.

BACKGROUND: Fine-needle aspiration (FNA) is the preferred diagnostic test for salivary gland lesions. The purpose of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is to standardize salivary gland cytology reporting and guide treatment decisions. The objective of the current study was to evaluate the utility and performance of the MSRSGC, with a focus on the cytomorphology of lesions diagnosed as atypia of undetermined significance (AUS) and salivary gland neoplasm of uncertain malignant potential (SUMP). METHODS: In total, 123 salivary gland FNAs were included in the study. FNA diagnoses for all cases were reviewed and recategorized, as applicable, according to the MSRSGC. Cytohistologic correlation was performed in 51 cases that had available surgical follow-up, and the risk of malignancy (ROM) was calculated. RESULTS: Most FNA samples were from the parotid gland. The mean patient age was 61.4 years, and the male-to-female ratio was 1.3:1. The ROM was 0% (categories I and II; nondiagnostic and benign nonneoplastic, respectively), 50% (category III; AUS), 0% (category IVA; benign neoplasm), 40% (category IVB; SUMP), 100% (category V; suspicious for malignancy), and 100% (category VI; malignant). Sensitivity, specificity, positive predictive value, and negative predictive value were 100% each. In addition, the primary factors for an AUS diagnosis were identified as low cellularity and/or the presence of lymphocytes. The presence of oncocytes followed by cellular atypia in an otherwise classic pleomorphic adenoma were principal factors for a SUMP diagnosis. CONCLUSIONS: The authors report an ROM comparable to that reported in the literature, with a sensitivity and specificity of 100%, supporting adaptation of the MSRSGC into the system for reporting salivary gland cytology. In addition, the findings emphasize the need to refine criteria for AUS and SUMP, thereby improving the predictive capability and subsequent management of salivary gland lesions.

Molecular testing results as a quality metric for evaluating cytopathologists' utilization of the atypia of undetermined significance category for thyroid nodule fine-needle aspirations.

INTRODUCTION: The use of the indeterminate category of atypia of undetermined significance (AUS) for thyroid fine-needle aspirations (FNAs) should be kept to a minimum. Here, we investigate the utility of combining AUS utilization rates with Afirma (Veracyte, Inc., South San Francisco, CA) genomic sequencing classifier (GSC) molecular testing results as a quality improvement metric for describing cytopathologist practice patterns. MATERIALS AND METHODS: Thyroid FNAs evaluated in our laboratory by 9 cytopathologists from December 2017 to July 2021 were stratified by Bethesda diagnostic category, and Afirma GSC testing results for AUS cases were compiled and correlated with AUS call rates. RESULTS: Over this period, the laboratory AUS rate was 22.3% (672 of 3008), with an individual cytopathologist range of 11.6% to 39.3%. Afirma GSC testing had suspicious (GSC-S) results in 29% (48 of 167) of cases, with a cytopathologist range of 5% to 67%. Linear regression analysis of individual AUS rates versus Afirma GSC-S rates demonstrated no significant relationship between these 2 variables. However, based on the pattern of AUS use and GSC-S rates, a novel conceptual framework for understanding cytopathologist practice patterns is proposed. CONCLUSIONS: Combining molecular testing results with AUS call rates of thyroid nodules can provide a more nuanced explanation of cytopathologist practice patterns, and can be utilized to provide directed feedback to bring individual cytopathologist diagnostic category use in line with laboratory averages or published benchmarks.

Probability of malignancy as determined by ThyroSeq v3 genomic classifier varies according to the subtype of atypia.

BACKGROUND: ThyroSeq assesses the probability of malignancy (POM) in thyroid fine-needle aspiration cytology specimens diagnosed as atypia of undetermined significance (AUS). The authors investigated whether defined AUS subcategories are associated with specific molecular alterations, the molecular-derived risk of malignancy (MDROM), and the risk of malignancy (ROM). METHODS: Fine-needle aspiration cytology reports of AUS and corresponding results from the ThyroSeq version 3 genomic classifier results were retrieved and subcategorized as follicular cells with either cytologic atypia (FC-C), architectural atypia (FC-A), both cytologic and architectural atypia (FC-CA), or a predominance of Hurthle cells (PHC). The MDROM, ROM, and frequency of molecular alterations by subcategory were computed and analyzed, and p < .05 was considered significant. RESULTS: The final analysis included 541 cases subdivided into 233 with FC-A, 104 with FC-C, 116 with FC-CA, and 88 with PHC. The benign call rate and positive call rate for the AUS category were 72% and 28%, respectively, which varied between AUS subcategories. The MDROM by subcategory was 15.9% FC-A, 20.5% FC-C, 33.8% FC-CA, and 14.4% PHC. Histologic follow-up was available for 155 (28%) AUS cases with a follow-up period ≥12 months. The 95% confidence intervals of the MDROMs overlapped with the ROMs. The highest MDROM and ROM were in the FC-CA subcategory. RAS mutations were present in all subcategories. BRAF V600E mutations and papillary thyroid carcinoma were most frequent in the FC-CA subcategory. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features was significantly more frequent in the FC-C subcategory. CONCLUSIONS: The current results demonstrated that AUS subcategories are associated with specific genetic alterations, the MDROM, and the ROM. Molecular results and an awareness of various cancer probabilities within AUS subcategories can allow for a more tailored management.

An institutional experience: A retrospective analysis of the effect of transitioning from follicular lesion of undetermined significance to atypia of undetermined significance with subclassified atypia on interobserver concordance, rates of neoplasia, and rates of malignancy.

INTRODUCTION: The rate of malignancy (ROM) in thyroid fine needle aspirations (FNA) classified under "atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS), including Hürthle cell type (HLUS)" category of The Bethesda system for reporting thyroid cytopathology (TBSRTC) in literature is highly variable. The 2018 TBSRTC was updated to note a preferred categorization of AUS cases into subcategories. This study evaluates the impact of AUS subclassification on rates of neoplasia (RON), rates of malignancy (ROM), and cytopathologist (CP) concordance. METHODS: 93 thyroid FNAs previously diagnosed as FLUS or HLUS from January 1, 2013 to December 31, 2014 with subsequent surgical resection were identified. Four CPs reclassified these cases using TBSRTC AUS subcategories of follicular cells with architectural and/or cytologic atypia, predominantly Hürthle cells, and atypical lymphocytes. RON and ROM were calculated for each diagnostic subcategory for each CP. RESULTS: The original RON and ROM for FLUS cases were 31.4% and 15.1% and were 77.8% and 22.2% for HLUS cases. 10.8% of cases showed diagnostic concordance amongst the four CPs. The most frequently utilized subcategory was architectural atypia. RON ranges for architectural atypia, cytologic atypia, architectural and cytologic atypia, and predominantly Hürthle cells were 28.1% to 35.7%, 0% to 33.3%, 35.3% to 66.7%, and 57.1% to 87.5%. The range of ROM was 13.9% to 16.7%, 0% to 33%, 0% to 42.9%, and 0% to 25%, respectively. CONCLUSION: RON for AUS predominantly Hürthle cells subcategory was higher than previously reported, which may indicate use for tailored patient management pathways. AUS subclassification can result in significant interobserver variability. Therefore, institutions may consider consensus/quality control sessions to optimize diagnostic concordance.

Risk stratification and clinical outcome in the atypia of undetermined significance category in the Milan System for Reporting Salivary Gland Cytopathology.

BACKGROUND: Atypia of undetermined significance (AUS) is a category of the Milan System for Reporting Salivary Gland Cytopathology that refers to salivary gland fine-needle aspiration (FNA) specimens that cannot be definitively diagnosed as neoplastic or nonneoplastic. METHODS: The AUS FNA samples were selected from a large academic institution from 2008 through 2018. The AUS cases were divided into 6 subgroups. The risk of malignancy (ROM), risk of neoplasm (RON), and clinical outcomes for each subgroup were evaluated. RESULTS: A total of 123 cases were found (76 males and 47 females with a mean age of 62 years [range, 6-94 years]). The parotid gland was the most common FNA site (103 cases), followed by the submandibular gland (9 cases). The overall RON and ROM were 63% and 47%, respectively. Among the subgroups, salivary gland lymph nodes or lymphoid lesions was the most common diagnosis (42%), whereas mucinous cystic lesions with no or a scant epithelial component was the least common (2%). The specimens with preparation artifacts category had the highest RON and ROM (100% for both), whereas the reactive and reparative atypia indefinite for a neoplasm category had the lowest RON and ROM (7% for both). The salivary gland lymph nodes or lymphoid lesions indefinite for a lymphoproliferative disorder category had the second highest RON and ROM at 77% and 74%, respectively. CONCLUSIONS: The overall RON and ROM for the AUS category were 63% and 47%, respectively. The RON and ROM varied among the different AUS subgroups, being highest in the specimens with preparation artifacts category and lowest in the reactive and reparative atypia category, thereby demonstrating the importance of subgrouping in the AUS specimens.

Malignancy risk for solitary and multiple nodules in Hürthle cell-predominant thyroid fine-needle aspirations: A multi-institutional study.

BACKGROUND: Hürthle cell metaplasia is common in hyperplastic nodules, particularly within the setting of lymphocytic thyroiditis (LT). The Bethesda System for Reporting Thyroid Cytopathology indicates that it is acceptable to classify Hürthle cell-predominant fine-needle aspiration (HC FNA) specimens as atypia of undetermined significance (AUS) rather than suspicious for a Hürthle cell neoplasm (HUR) within the setting of multiple nodules or known LT. The goal of the current study was to address whether this approach is justified. METHODS: HC FNA specimens were identified and correlated with ultrasound and surgical pathology reports if available. Multinodularity was determined based on findings on macroscopic examination if imaging results were unavailable. RESULTS: A total of 698 HC FNA specimens were identified, including 576 resected nodules, 455 of which (79%) were benign. The overall risk of malignancy for HUR was 27%, whereas the risk of malignancy for AUS was 10%. The mean size of the benign nodules was 2.1 cm on surgical resection specimens, with multiple nodules noted in 293 cases (64%) and histologic LT noted in 116 cases (25%). The mean size of the malignant nodules was 2.8 cm, with multiple nodules and histologic LT noted in 74 cases (61%) and 22 cases (18%), respectively. The malignancy rate did not differ between solitary or multiple nodules (P = .52) or in the presence or absence of LT (P = .12). However, size did significantly differ between malignant and benign nodules (P < 0.01). CONCLUSIONS: The malignancy rate did not differ significantly in the presence of multiple nodules or LT, although the latter demonstrated a statistical trend. A diagnosis of AUS over HUR based solely on the presence of multinodularity is not warranted.

Atypia of undetermined significance/follicular lesion of undetermined significance: Asian vs. non-Asian practice, and the Singapore experience.

The Bethesda System for Reporting Thyroid Cytopathology has paved the way for comparisons of the practice of thyroid cytology in many different regions. However, there have been comparatively few studies documenting differences between Asian and non-Asian practice. Here, we aim to compare a few key parameters between the two regions, focusing on the indeterminate category of atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS). We compared its incidence, resection rates (RRs), risk of malignancy (ROM), rate of repeat fine needle aspiration (rFNA), ROMs of cytomorphologic subcategories of nuclear atypia (AUS-N) vs. architectural atypia (AUS-A), and, finally, the incidence of papillary thyroid carcinoma (PTC) vs. follicular neoplasms (FNs) in resected AUS/FLUS cases in Asian and non-Asian regions. Where possible, these metrics were compared with the Singapore experience from a tertiary referral institution. While the incidence of AUS/FLUS was similar in both regions, we found geographical differences in the RRs and ROMs, which may reflect a higher collective threshold for surgery in Asian countries. However, both cohorts showed higher ROMs in the AUS-N subcategory as compared to the AUS-A subcategory, supporting the subclassification of the AUS/FLUS based on the presence of nuclear atypia. We also observed a higher incidence of AUS-N coupled with a higher incidence of PTC in resected AUS/FLUS nodules in Asian cohorts, while AUS-A and follicular-patterned neoplasms featured more prominently in the non-Asian cohorts. These incidences may account for the starkly different molecular approaches that we noted-in Asian (chiefly Korean and Chinese) centers, BRAF mutational analysis was favored, while gene panels and gene expression classifiers were more frequently applied in non-Asian centers (chiefly in the United States of America). Overall, the data from Singapore appears more closely aligned to non-Asian trends, despite its geographical location in Southeast Asia and its predominantly Asian population. We conclude that there is significant heterogeneity in the outcomes of the AUS/FLUS categories between and within regions, which is only partially explained by regional variations, and may also reflect different regional diagnostic and management practices. This highlights the importance of understanding the local context in the interpretation of indeterminate Bethesda categories, rather than adopting a "one-size fits all" approach.

Milan System for Reporting Salivary Gland Cytopathology- An Experience from Western Indian Population.

INTRODUCTION: Fine-needle aspiration cytology (FNAC) can be challenging to provide a precise diagnosis in salivary gland cytopathology due to diversity of lesions and cytomorphological convergence between the tumors and within the same tumor of salivary gland. The recently proposed Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) provides a risk stratification-based classification system with an intrinsic risk of malignancy (ROM) for each diagnostic category, which aims to furnish useful information to the clinicians. This study was undertaken to evaluate the diagnostic utility and validity of MSRSGC. METHODS AND MATERIAL: In this retrospective study, FNAC done for all salivary gland lesions over a period of two years were retrieved. All cases were categorized according to MSRSGC and correlated with histopathological follow-up, wherever available. ROM was calculated for each category. RESULTS: The cases belong to following categories: non-diagnostic (1.27%), non-neoplastic (30.38%), atypia of undetermined significance (5.06%), benign neoplasm (46.84%), salivary gland neoplasm of uncertain malignant potential (1.27%), suspicious for malignancy (1.27%), and malignant (13.92%). Out of 79 cases, 50.63% had follow-up. The ROM were 0% for category II and IVa, 50% for category III, and 100% for category IVb, V, and VI. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were recorded as 77.78%, 100%, 100%, 91.3%, and 93.33%, respectively. CONCLUSIONS: Application of MSRSGC has immense value for standardization of reporting of salivary gland FNAC. Our data corresponds to the studies done worldwide and recommends the use of MSRSGC for future diagnostic purposes.

Application of the Milan System for Reporting Submandibular Gland Cytopathology: An international, multi-institutional study.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a 6-tier diagnostic category system with associated risks of malignancy (ROMs) and management recommendations. Submandibular gland fine-needle aspiration (FNA) is uncommon with a higher frequency of inflammatory lesions and a higher relative proportion of malignancy, and this may affect the ROM and subsequent management. This study evaluated the application of the MSRSGC and the ROM for each diagnostic category for 734 submandibular gland FNAs. METHODS: Submandibular gland FNA cytology specimens from 15 international institutions (2013-2017) were retrospectively assigned to an MSRSGC diagnostic category as follows: nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), benign neoplasm, salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SM), or malignant. A correlation with the available histopathologic follow-up was performed, and the ROM was calculated for each MSRSGC diagnostic category. RESULTS: The case cohort of 734 aspirates was reclassified according to the MSRSGC as follows: nondiagnostic, 21.4% (0%-50%); nonneoplastic, 24.2% (9.1%-53.6%); AUS, 6.7% (0%-14.3%); benign neoplasm, 18.3% (0%-52.5%); SUMP, 12% (0%-37.7%); SM, 3.5% (0%-12.5%); and malignant, 13.9% (2%-31.3%). The histopathologic follow-up was available for 333 cases (45.4%). The ROMs were as follows: nondiagnostic, 10.6%; nonneoplastic, 7.5%; AUS, 27.6%; benign neoplasm, 3.2%; SUMP, 41.9%; SM, 82.3%; and malignant, 93.6%. CONCLUSIONS: This multi-institutional study shows that the ROM of each MSRSGC category for submandibular gland FNA is similar to that reported for parotid gland FNA, although the reported rates for the different MSRSGC categories were variable across institutions. Thus, the MSRSGC can be reliably applied to submandibular gland FNA.

The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the rate of malignancy for atypia of undetermined significance subcategories.

BACKGROUND: The recent revision in terminology, with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) replacing noninvasive follicular variant of papillary thyroid carcinoma, has reclassified the clinically indolent tumor as nonmalignant. The objective of this study was to evaluate the impact of this change on the rate of malignancy (ROM) for subcategories of an atypia of undetermined significance (AUS) diagnosis on fine-needle aspiration (FNA) cytology. METHODS: Consecutive thyroid FNAs interpreted as AUS over a period of 4 years were retrospectively analyzed. The ROM for AUS subcategories, including atypia of undetermined significance with nuclear atypia (AUS-N), atypia of undetermined significance with a microfollicular pattern (AUS-F), atypia of undetermined significance with nuclear atypia and a microfollicular pattern (AUS-N/F), atypia of undetermined significance with Hürthle cells (AUS-H), and atypia of undetermined significance, not otherwise specified (AUS-NOS), were analyzed. RESULTS: Of the 426 nodules interpreted as AUS, 244 were surgically excised. The incidence of NIFTP in each subcategory was as follows: 18% for AUS-N, 18% for AUS-F, 9% for AUS-N/F, 3% for AUS-H, and 0% for AUS-NOS. After the reclassification of NIFTP as nonmalignant, the ROM based on histologic follow-up significantly decreased from 43% to 26% for AUS-N (P < .001) and from 29% to 10% for AUS-F (P = .008). The ROM for AUS-N remained significantly higher than the ROM for AUS-F (P = .030). CONCLUSIONS: A subset of resected AUS nodules can be reclassified as NIFTP, and that significantly decreases the ROM, especially for AUS-N and AUS-F. Nonetheless, AUS-N still harbors a substantially higher ROM than AUS-F. Cancer Cytopathol 2018;126:309-16. © 2018 American Cancer Society.

Subclassification of Bethesda Atypical and Follicular Neoplasm Categories According to Nuclear and Architectural Atypia Improves Discrimination of Thyroid Malignancy Risk.

BACKGROUND: Although The Bethesda System for Reporting Thyroid Cytopathology has provided clinicians with a standardized classification scheme for the diagnosis of thyroid fine-needle aspiration cytology (FNAC) specimens, the indeterminate categories of Bethesda III (B3)-atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)-and Bethesda IV (B4)-follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)-continue to pose challenges with regards to ideal diagnostic and therapeutic management. Having previously demonstrated the presence of nuclear atypia as a high-risk subgroup in B3, the objective of this study was to evaluate the malignancy rates in the B4 subgroup with nuclear atypia. METHODS: A retrospective review of all thyroid FNACs diagnosed as B4 (FN/SFN) between 2008 and 2015 was conducted at a tertiary referral center in Singapore. Data on patient demographics, sonographic features, and final histological diagnosis were collected. This was compared to data from a previous analysis on all nodules diagnosed as B3 (AUS/FLUS) over a similar period. RESULTS: A total of 137/309 (44.3%) and 88/111 (79.3%) FNACs diagnosed as B3 and B4, respectively, underwent surgical excision yielding final histopathological diagnoses. The malignancy rate of B4 was 31/88 (35.2%) compared to B3, which was 37/137 (27.0%). Subclassification based on the presence of architectural versus nuclear atypia showed significantly higher malignancy rates in B4 nodules with nuclear atypia (21.8% vs. 57.6%; p < 0.01). These findings corroborate previous results within the B3 category (malignancy rate of 14.7% vs. 36.8%; p < 0.01). The only sonographic features predictive of malignancy were the presence of macrocalcifications in B4 compared to irregularity of margins in B3. CONCLUSION: The presence of nuclear atypia identifies subgroups with significant differential malignancy risks within both the B3 and B4 categories. This supports the notion that subclassification is a useful risk stratification tool that can guide diagnostic and therapeutic management of indeterminate thyroid nodules with heterogenous risk profiles.

Prevalence and associated malignancy of Bethesda category III cytologies of thyroid nodules assigned to the "cytological atypia" or "architectural atypia" groups. / Prevalencia y malignidad asociada de las citologías de categoría Bethesda III de nódulos tiroideos según el grupo «atipia citológica¼ o «atipia arquitectónica¼.

OBJECTIVE: To ascertain the prevalence of Bethesda category III cytologies and their malignancy rate, and to analyze differences in the second cytology, malignancy rate, type of carcinoma, and TNM stage between the cytological atypia (CA) and architectural atypia (AA) groups. PATIENTS AND METHOD: A retrospective study of 973 biopsies. Bethesda category III cytologies were classified as CA when nuclear atypia was seen but they were not diagnostic or suspicious of malignancy, and as AA when smears had few cells but had a predominantly microfollicular pattern and minimal or absent colloid. The cytological and pathological results were correlated. RESULTS: There were 87 (8.9%) Bethesda category III cytologies (34 CC, 53 AA). Second cytologies were performed in 23 patients (16 with CA, 7 with AA), and a benign result was found in 68.7% of CA and 71.4% of the AA group. Sixty-four patients (23 CA, 41 AA) underwent surgery and 15 of these (23.4%) had a malignant disease: 39.1% CA vs 14.6% AA (P=.029). There was a false negative result in the CA group. The follicular variant of papillary thyroid carcinoma was the most common malignancy (60%). There were no differences in type of carcinoma or TNM stage between CA and AA patients. CONCLUSIONS: The reported prevalence of Bethesda category III cytologies was as expected. The malignancy rate was significantly higher in the CA group, but there were no differences in the result of the second cytology, type of carcinoma found, or TNM stage. The division of Bethesda category III cytologies is useful to provide a better stratification of the risk of malignancy.