Atypia Of Undetermined Significance Cases Research Articles

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

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

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

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. 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. 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%. 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.

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

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). 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. 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. 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.

Adrenal gland cytology reporting: a multi-institutional proposal for a standardized reporting system.

With the development of new technologies and the changing patient profiles, cytopathology departments receive increasing numbers of adrenal gland cytology specimens. In this study, the authors analyzed archival adrenal gland cytology cases and attempted to implement a diagnostic reporting system. Retrospective electronic medical record search was performed for adrenal gland cytology specimens in seven tertiary care centers. The cytology diagnoses were grouped in 7 categories: nondiagnostic, nonneoplastic, benign adrenal cortical elements (BACE), primary neoplasm of noncortical origin (NONC), atypia of undetermined significance (AUS), suspicious for malignancy (SM), and malignant (MAL). If available, histopathology results of concurrent and/or follow-up biopsies and/or resections were documented. A total of 473 adrenal gland cytology cases were included. BACE cases comprised 21.8%, whereas MAL cases were 57.5% of all cases. For BACE and MAL categories, there were 100% and 98.9% correlation, respectively, in the cases with histopathology follow-up. Six of 10 NONC cases had histopathology diagnoses and there were 3 pheochromocytomas and 3 schwannomas. Twenty-one AUS cases had histology follow-up and 10 (47.6%) of them were malignant. Six cases of SM had histopathology follow-up, and all of them were malignant on the follow-up. The authors propose a 7-tier diagnostic scheme for adrenal gland cytology. The risk of malignancy was 98.9% in MAL cases (87/88) in the cohort. The only case with discordance was reported as "adrenal cortical adenoma with marked atypia"' on resection. There was no difference between endoscopic ultrasound-guided and percutaneous methods. Further studies are needed to validate and make this approach universal.

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

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. 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. 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. 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.

MOC31 Immunostaining in the Diagnosis of Metastatic Adenocarcinoma in Serous Fluid: Special Emphasis on Atypical Cytological Cases

Background: The diagnosis of atypical cases in the effusion cytology sample often poses a challenge to the cytologists. Aims and Objectives: We evaluated the diagnostic role of MOC31 in the metastatic adenocarcinoma in effusion fluid. Materials and Methods: The cytological examination and MOC31 immunostaining in the cell block sections were carried out in 64 cases of serous effusion. A total of 23 cases showed atypical cytology, out of which suspicious for malignancy (SFM) and atypia of undetermined significance (AUS) were 19 and 4 cases, respectively. In these cases, we also performed calretinin immunostaining. The cytological features, results of MOC31 immunostaining, and follow-up data were correlated to find out the sensitivity and specificity of MOC31 immunostaining in the diagnosis of metastatic adenocarcinoma. Result: The sensitivity and specificity of MOC31 were 100%. MOC31 detected all the cases of metastatic adenocarcinoma. MOC31 showed strong positivity in 19 cases of SFM. All these cases had a malignant outcome in histopathology or follow-up data. In AUS cases, MOC31 immunostaining was negative with a benign outcome. In all the atypical but malignant cases calretinin stain showed diffuse cytoplasmic and nuclear positivity. In contrast, MOC31 showed strong membranous positivity and occasionally cytoplasmic positivity. Conclusion: MOC31 is an excellent marker of metastatic adenocarcinoma in the serous effusion. The membranous positivity of MOC31 and negative calretinin immuno­staining are helpful in atypical cytological cases to avoid the diagnostic dilemma. The MOC31 positivity is significantly useful in discrete atypical cells which are more challenging to recognize.

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

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. 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. A total of 123 cases were found (76 males and 47 females with a mean age of 62years [range, 6-94years]). 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. 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.

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.

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. 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. 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. 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.

Defining thyroid spherules: A benign cytomorphologic feature that mimics microfollicles.

Distinctive rounded structures termed spherules have been observed in thyroid fine-needle aspiration (FNA) samples. Although they are often small and interpreted as microfollicles, spherules are notable for the even spacing of the follicular cells along the perimeter of the structure. Because they have an orderly architectural arrangement, it has been hypothesized that spherules are benign and do not carry the same risk of malignancy that traditional microfollicles do. The aim of this study was to identify the clinical significance and histopathologic correlate of spherules. Thyroid FNAs (n=637) with an interpretation of atypia of undetermined significance (AUS) were reviewed for the presence of spherules, which were defined as small follicles with a rounded, smooth, sharply defined outer contour, evenly spaced nuclei, and a 3-dimensional appearance. Cases were included if spherules accounted for >50% of follicular cell arrangements. Clinical, histopathologic, molecular, and sonographic follow-up data were obtained. Twenty-five spherule cases were identified, and they represented 3.9% of all AUS cases reviewed. All 24 cases with follow-up had a benign outcome. Eleven were tested with the Afirma gene expression classifier; 8 were benign according to the gene expression classifier, and 3 were suspicious but histologically benign after surgical resection. Four additional cases were histologically benign after surgery. Five patients had repeat benign cytology. Four patients had repeat stable ultrasound findings. Thyroid nodules diagnosed as AUS, if composed predominantly of spherules, are associated with a benign outcome. Recognizing this distinctive cytomorphologic finding may help to reduce the number of FNAs interpreted as AUS and save patients from unnecessary additional testing and surgery.

Risk of malignancy in “atypia of undetermined significance” category of salivary gland fine‐needle aspiration: A bi‐institutional experience

Many prior institutional and multi-institutional studies have applied the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) retrospectively to their specimens to determine the risk of malignancy (ROM) of each category. Most of these studies focused on general assessment of the system and risk classification. However, there seems to be less focus on the category of atypia of undetermined significance (AUS) that could be attributed to the low number of cases that could fit into this category. Herein, we present a bi-institutional experience with this category. A computerized search of the databases was performed to identify all salivary gland fine-needle aspiration (FNA) in two institutions over a period of 12 years. The final diagnosis of each case was reclassified based on MSRSGC, and histology follow-up was retrieved. Sixty AUS cases (out of 1560 salivary gland FNA) were identified with a rate of 3.8%. Forty cases (66%) had a subsequent tissue material. Correlation with histology revealed that the estimated ROM is 37.5% (15/40) and the overall ROM is 25% (15/60). Fifty percent of the cases had a prominent lymphoid component and most commonly represented lymphomas, reactive lymph node or sialadenitis. The AUS category is a heterogeneous group of lesions with predominant lymphoid-rich entities. Some variability exists between institutions with most having higher ROM than the suggested 20% by the MSRSGC atlas.

Risk of Malignancy According to the Sub-classification of Atypia of Undetermined Significance and Suspicious Follicular Neoplasm Categories in Thyroid Core Needle Biopsies.

The objective of this study was to evaluate the risk of malignancy (ROM) associated with atypia of undetermined significance (AUS) and suspicious follicular neoplasm (SFN) core needle biopsy (CNB) categories after further sub-classification. Data from 2267 thyroid nodules evaluated by ultrasound-guided CNB, from January to December 2015, were retrospectively reviewed. AUS nodules (n = 556) were sub-classified as follows: (1) architectural atypia (AUS-A; n = 369, 66.4%), (2) cytologic atypia (AUS-C; n = 35, 6.3%), (3) cytologic/architectural atypia (AUS-C/A; n = 85, 15.3%), or (4) oncocytic atypia (AUS-O; n = 67, 12.1%). SFN nodules (n = 172) were sub-classified as follows: (1) architectural atypia only (SFN-A; n = 110, 64%), (2) cytologic/architectural atypia (SFN-C/A; n = 24, 14%), or (3) oncocytic atypia (SFN-O; n = 38, 22%). Diagnostic surgery was performed in 162 (30.2%) AUS cases and 105 (61%) SFN cases. The ROM of each sub-category was evaluated. The overall ROM was 15.3-52.5% in AUS nodules and 35.5-58.1% in SFN nodules. The ROM was higher in the AUS-C (22.9-88.9%) and AUS-C/A (32.9-90.3%) groups than AUS-A (11.9-40%) and AUS-O (7.5-41.7%). In the SFN category, ROM in the SFN-C/A group was also higher than SFN-A or SFN-O (37.5-75%, 40-57.9%, and 21.1-47.1%, respectively). Our study shows that the ROM was higher in AUS or SFN sub-categories with cytologic atypia than those without cytologic atypia. Because of the heterogeneous nature of AUS and SFN categories, sub-classification may be a more effective approach for risk stratification, allowing optimal management of patients with thyroid nodules.

Clinical follow up and the impact of the Paris system in the assessment of patients with atypical urine cytology.

Urinary cytology is routinely used in the diagnosis of urothelial neoplasms, with good sensitivity for high-grade urothelial carcinoma (HGUC) but less so for low-grade urothelial neoplasm (LGUN). There is significant interobserver and interinstitutional variability, especially for the atypical category. The Paris system for reporting urinary cytology (TPS) was introduced to better define the various categories, especially atypical cytology. We retrospectively reviewed 630 atypia of undetermined significance (AUS) cases and reclassified them based on TPS. In total, 501 cases previously reported as negative for malignancy had their medical records reviewed to serve as negative controls. Of 630 AUS cases, 299 (47.5%) were reclassified as negative for HGUC (NHGUC), 313 (49.7%) as atypical urothelial cells (AUCs) and 18 (2.9%) as suspicious for HGUC (SHGUC). Based on our institution's previous reporting system, the rate of underlying or subsequent HGUC was 2.8% for AUS, and 0% for negative. When AUS cases were reclassified under TPS, the rates were 1.5% for NHGUC, 4.8% for AUC, and 0% for SHGUC. Review of medical records showed that patients with AUS were more likely to be followed-up compared with those with negative urine cytology (77.8% compared with 54.3%), particularly those under the care of non-urologists. AUS diagnosis is associated with more patient follow up compared with NEG urine particularly among non-urologists. Reclassifying according to TPS results in significant reduction in the rate of AUS and thus unnecessary testing. This reduction however may be at the expense of slightly decreased detection rate of HGUC.

Northern Italy in the American South: Assessing interobserver reliability within the Milan System for Reporting Salivary Gland Cytopathology.

The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has been proposed to standardize salivary gland fine-needle aspiration (FNA) diagnoses. This study assessed salivary gland FNA results and risk of malignancy (ROM) rates at the University of North Carolina as well as the interobserver reliability (IOR) of the atypia of undetermined significance (AUS) and salivary gland neoplasm of uncertain malignant potential (SUMP) categories. The electronic medical record was searched for FNA cases from 2010 to 2017 with subsequent surgical resections. Histologic diagnosis was used for gold-standard comparison. The original cytologic results were then converted into MSRSGC categories (nondiagnostic, nonneoplastic, AUS, benign neoplasm, SUMP, suspicious, and malignant). For the assessment of IOR, 23 cases were selected with enrichment for cases diagnosed as AUS (n = 11) or SUMP (n = 9). Six boarded cytopathologists and 1 cytopathology fellow assessed representative slides and provided an MSRSGC diagnosis for each case. Fleiss' κ coefficients were calculated to determine IOR. The ROM was 33% for both AUS and SUMP cases; however, the risk of neoplasia was 56% for AUS cases and 100% for SUMP cases. Fleiss' κ for the AUS category was 0.217 (P < .05), and Fleiss' κ for the SUMP category was 0.024 (P = .74). In this study assessing the IOR of MSRSGC categories, fair agreement and slight agreement were found for the AUS and SUMP categories, respectively. Observers preferentially used the AUS or benign neoplasm category for SUMP cases, perhaps because of unfamiliarity with SUMP as a diagnostic option. The initial adoption of a new reporting system will require a quality assessment to ensure that the system is reliable and useful for clinicians. Cancer Cytopathol 2018;126:390-6. © 2018 American Cancer Society.

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

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

Diagnostic assessment of intraoperative cytology for papillary thyroid carcinoma: using a decision tree analysis.

The aim of this study was to elucidate the cytological characteristics and the diagnostic usefulness of intraoperative cytology (IOC) for papillary thyroid carcinoma (PTC). In addition, using decision tree analysis, effective features for accurate cytological diagnosis were sought. We investigated cellularity, cytological features and diagnosis based on the Bethesda System for Reporting Thyroid Cytopathology in IOC of 240 conventional PTCs. The cytological features were evaluated in terms of nuclear score with nuclear features, and additional figures such as presence of swirling sheets, psammoma bodies, and multinucleated giant cells. The nuclear score (range 0-7) was made via seven nuclear features, including (1) enlarged, (2) oval or irregularly shaped nuclei, (3) longitudinal nuclear grooves, (4) intranuclear cytoplasmic pseudoinclusion, (5) pale nuclei with powdery chromatin, (6) nuclear membrane thickening, and (7) marginally placed micronucleoli. Nuclear scores in PTC, suspicious for malignancy, and atypia of undetermined significance cases were 6.18±0.80, 4.48±0.82, and 3.15±0.67, respectively. Additional figures more frequent in PTC than in other diagnostic categories were identified. Cellularity of IOC significantly correlated with tumor size, nuclear score, and presence of additional figures. Also, IOCs with higher nuclear scores (4-7) significantly correlated with larger tumor size and presence of additional figures. In decision tree analysis, IOCs with nuclear score >5 and swirling sheets could be considered diagnostic for PTCs. Our study suggests that IOCs using nuclear features and additional figures could be useful with decreasing the likelihood of inconclusive results.

Young investigator challenge: Atypia of undetermined significance in thyroid FNA: Standardized terminology without standardized management--a closer look at repeat FNA and quality measures.

The Bethesda system (TBS) for the reporting of thyroid cytopathology established the category of atypia of undetermined significance (AUS) with a 7% target rate and a 5% to 15% implied malignancy risk. Recent literature has reported a broad range of AUS rates, subsequent malignancy rates, and discrepant results from repeat fine-needle aspiration (FNA) versus surgical follow-up. Therefore, this study examined AUS data from the Hofstra North Shore-LIJ School of Medicine to determine the best clinical follow-up. Thyroid aspirates interpreted as AUS in 2012-2014 at the Hofstra North Shore-LIJ School of Medicine were collected. Repeat FNA and surgical follow-up data were tabulated to establish AUS, secondary AUS (diagnosed upon repeat FNA follow-up of a primary FNA AUS diagnosis), atypia of undetermined significance/malignancy (AUS:M) ratios (according to the TBS categories), and malignancy rates for AUS. The AUS rate was 8.5% (976/11,481), and there was follow-up data for 545 cases. The AUS:M ratio was 2.0. Repeat FNA was performed for 281 cases; 57 proceeded to surgical intervention. Repeat FNA reclassified 71.17% of the cases. The malignancy rates for AUS cases proceeding directly to surgery and for those receiving a surgical intervention after a repeat AUS diagnosis were 33.33% and 43.75%, respectively. Repeat FNA resulted in definitive diagnostic reclassification for 67.61% of primary AUS cases and reduced the number of patients triaged to surgery, with 56.58% of the cases recategorized as benign. Cases undergoing surgery after repeat AUS had a higher malignancy rate than those going straight to surgery, and this emphasizes the value of repeat FNA in selecting surgical candidates. In addition, this study highlights the utility of AUS rate monitoring as a quality measure that has contributed to the ability of the Hofstra North Shore-LIJ School of Medicine to adhere closely to TBS recommendations.

Diagnosis and Management of Thyroid Nodules with Atypia: A Three-year Study at an Institution in Taiwan

Objective: According to Bethesda System for Reporting Thyroid Cytopathology, the category, atypia of undetermined significance (AUS), is estimated to have a low malignancy risk of around 5%-15%. Variable surgical malignancy rates of AUS have been reported in diverse populations. The present study evaluated the malignancy rate at our institution and associated demographic data to identify high-risk nodules. Methods: In this retrospective study, thyroid nodules with initial fine-needle aspirations (FNAs) reported as AUS from April 2010 to May 2013 were analyzed. Demographic data, clinical managements, and histopathologic results were evaluated. Results: A total of 7382 aspirations performed during the study period were analyzed; 5.7% were reported as atypia, 70.3% as benign, 1.5% as follicular neoplasm, 2.7% as suspicious for malignancy or malignant, and 19.8% as nondiagnostic. A total of 388 patients with one nodule reported as AUS were enrolled for analysis; 86 (22.2%) underwent surgical biopsy directly, 127 (32.7%) received follow-up FNAs, and 175 (45.1%) received clinical observation. The malignancy rate in the 86 patients who underwent surgical biopsy directly after first AUS was 17.4%. Out of the 127 patients who received follow-up FNAs, 105 were reclassified into the different-rank risk categories (benign, neoplasm or malignancy, and nondiagnostic) and 22 remained in AUS. Among the 33 patients out of 127 who received thyroid surgery after follow-up FNAs, the malignancy rates in the 8 patients with repeated AUS results and 11 patients with benign results in the second FNA were 50% and 9.1%, respectively. No significant difference in sex, age, nodular size, numbers, and preoperative thyroid-stimulating hormone level between the benign and malignant groups in the thyroid AUS cases was observed. Conclusion: Repeated AUS may be associated with a higher malignancy rate in final histopathology, and other supplementary techniques are required to enhance preoperative diagnostic accuracy.

Subclassification of “atypia of undetermined significance” in thyroid fine‐needle aspirates

To identify the subtypes of atypia of undetermined significance (AUS) that confers a different magnitude for the risk of malignancy (RM), thyroid fine-needle aspiration (FNA) cases carrying a diagnosis of "atypical follicular cells" or "follicular lesion" with surgical pathology followup were included in this study. The direct smears of the aspirates were rereviewed and subclassified into four subgroups based on cytomorphology: AUS cannot exclude follicular neoplasm (AUS-FN), AUS cannot exclude Hürthle cell neoplasm (AUS-HCN), AUS cannot exclude papillary carcinoma (AUS-PTC) and AUS, not otherwise specified (AUS-NOS). Based on the followup histopathologic findings, RM not including papillary microcarcinoma (PMC), RM including PMC and the risk of neoplasm (RN) were calculated for each of the four AUS subgroups. A total of 138 AUS cases were subclassified into AUS-NOS (48), AUS-PTC (41), AUS-FN (32), and AUS-HCN (17). RM not including PMC was 32% for AUS-PTC (P < 0.001), 25% for AUS-FN, 8% for AUS-NOS, 0% for AUS-HCN, and 18% for all AUS cases. RM including PMC was 54% for AUS-PTC (P < 0.001), 34% for AUS-FN, 19% for AUS-NOS, 18% for AUS-HCN, and 33% for all AUS cases. RN was 63% for AUS-PTC (P = 0.05), 81% for AUS-FN (P < 0.01), AUS-HCN 53%, AUS-NOS 44% and 59% for all cases. In our study, subclassification enabled us to further divide AUS cases into high- and low-risk groups. The high-risk group includes AUS-PTC with a significantly higher risk of malignancy and AUS-FN with a significantly higher risks of neoplasm. AUS-HCN and AUS-NOS subgroups demonstrate a lower risk of malignancy of <10%.

"Hurthle Cell Lesion": A Clinicopathologic Study and Significance of Cytological Diagnosis

Introduction: Since the 2008 publication of the Bethesda terminology for thyroid cytopathology, diagnosis rates of atypia of undetermined significance (AUS) from 2.1% to >10% have been reported. Although a majority with benign follow-up prove to be adenomatous nodules, some show lymphocytic thyroiditis (known to be associated with cytologic atypia) on follow up. We sought to examine the proportion of AUS with a follow-up of lymphocytic thyroiditis, and if features could be identified that were characteristic of thyroiditis-associated atypia, allowing for increased comfort in the diagnosis of lymphocytic thyroiditis and a decrease in AUS. Materials and Methods: The pathology database was searched for thyroid FNA’s with an interpretation of AUS from the implementation of the Bethesda system in 2010 to 2013. The AUS rate was determined, and cytologic and/or surgical follow-up was identified. Original and follow-up slides were reviewed. Results: 86 AUS cases (6% of total thyroid FNA) were identified (61 with cytologic and/or surgical follow-up) with 61% having benign follow-up, 30% malignant follow-up, and 6% remaining as AUS on follow-up. 15% had a diagnosis of Hashimoto’s or lymphocytic thyroiditis alone (4 cases), with papillary thyroid carcinoma (PTC, 2 cases), or with incidental microcarcinoma (3 cases, PTC felt not to be represented on review of smears). Features that led to an AUS interpretation in the setting of thyroiditis were identified, including nuclear enlargement, elongation, crowding and grooves (as seen in Figure 1). Features supporting thyroiditis-associated atypia included degenerated cytoplasm, coarse chromatin, and prominent central nucleoli. Sparse malignant cells admixed with oncocytes and a polymorphous lymphoid population, including large immature lymphs, inhibited definite diagnosis in 2 cases where PTC co-existed with Hashimoto’s. Conclusions: We found an AUS rate of 6%, with 15% associated with lymphocytic thyroiditis. Increased recognition of these sometimes subtle features could lead to a decrease in the overall AUS rate.

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

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