Risk of malignancy in thyroid nodules classified as Bethesda categories III, III - subcategories and IV: 2.5 years study

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

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.

Malignancy Rate in Thyroid Nodules with Atypia or Follicular Lesion of Undetermined Significance

Abstract Introduction Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS) is one of the six diagnostic categories of the Bethesda System for Reporting Thyroid Cytopathology. The prevalence of malignancy among Bethesda category III cytology is variable, ranging from 5% to 37% in the literature. Objective To determine the rate of malignancy in thyroid nodules reported as Bethesda category III. Methods A total of 495 patients underwent surgical intervention for thyroid nodules from January 2015 to December 2017. The present study included 81 cases reported as Bethesda category III, and their medical records were reviewed. Results Out of 495 fine-needle aspiration cytology samples, 81 (16.4%) samples were labeled as AUS/FLUS. Among these 81 patients, the mean age was 43.0 years (±13.9), with only 11 (14%) patients older than 55 years of age.Most of our patients were female (n=69; 85.2%), and the rest were male. The rate of malignancy based on the final histology was of 33.3% (n=27). The majority were 17 cases (21%) of papillary carcinoma, followed by follicular carcinoma (n=6) (7.4%). Conclusion The risk of malignancy can be higher than it is commonly believed, and guidelines should be based on the data from the institutions themselves for a better assessment of the outcomes.

Risk of malignancy in Thyroid “Atypia of undetermined significance/Follicular lesion of undetermined significance” and its subcategories – A 5-year experience

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

BRAF(V600E) Mutation is a Strong Preoperative Indicator for Predicting Malignancy in Thyroid Nodule Patients with Atypia of Undetermined Significance Identified by Fine Needle Aspiration / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: This study aimed to identify a reliable preoperative predictive factor for the development of thyroid cancer in patients with atypia of undetermined significance (AUS) identified by fine needle aspiration biopsy (FNAB). SUBJECTS AND METHOD: This was a retrospective cohort study. Two hundred and ninety-nine patients diagnosed with AUS by preoperative FNAB who underwent curative thyroid surgery at our institution between September 2005 and February 2014 were analyzed. Clinical, radiological and molecular features were investigated as preoperative predictors for postoperative permanent malignant pathology. RESULTS: The final pathologic results revealed 36 benign tumors including nodular hyperplasia, follicular adenoma, adenomatous goiter, nontoxic goiter, and lymphocytic thyroiditis, as well as 263 malignant tumors including 1 follicular carcinoma and 1 invasive follicular carcinoma; the rest were papillary thyroid carcinomas. The malignancy rate was 87.9%. The following were identified as risk factors for malignancy by univariate analysis: BRAFV600E gene mutation, specific ultrasonographic findings including smaller nodule size, low echogenicity of the nodule, and irregular or spiculated margin (p < 0.05). Multivariate analysis revealed that only BRAFV600E mutation was a statistically significant risk factor for malignancy (p < 0.05). When BRAFV600E mutation was positive, 98.5% of enrolled patients developed malignant tumors. In addition, the diagnostic rate of malignancy in these cases was approximately 16-fold higher than BRAF-negative cases. CONCLUSION: Patients with AUS thyroid nodules should undergo BRAFV600E gene mutation analysis to improve diagnostic accuracy and if the mutation is confirmed, surgery is recommended due to the high risk of malignancy.

Morphometric Analysis of Thyroid Follicular Cells with Atypia of Undetermined Significance

BACKGROUND: Atypia of undetermined significance (AUS) is a category that encompasses a heterogeneous group of thyroid aspiration cytology. It has been reclassified into two subgroups based on the cytomorphologic features: AUS with cytologic atypia and AUS with architectural atypia. The nuclear characteristics of AUS with cytologic atypia need to be clarified by comparing to those observed in Hashimoto thyroiditis and benign follicular lesions. METHODS: We selected 84 cases of AUS with histologic follow-up, 24 cases of Hashimoto thyroiditis, and 26 cases of benign follicular lesions. We also subcategorized the AUS group according to the follow-up biopsy results into a papillary carcinoma group and a nodular hyperplasia group. The differences in morphometric parameters, including the nuclear areas and perimeters, were compared between these groups. RESULTS: The AUS group had significantly smaller nuclear areas than the Hashimoto thyroiditis group, but the nuclear perimeters were not statistically different. The AUS group also had significantly smaller nuclear areas than the benign follicular lesion group; however, the AUS group had significantly longer nuclear perimeters. The nuclear areas in the papillary carcinoma group were significantly smaller than those in the nodular hyperplasia group; however, the nuclear perimeters were not statistically different. CONCLUSIONS: We found the AUS group to be a heterogeneous entity, including histologic follow-up diagnoses of papillary carcinoma and nodular hyperplasia. The AUS group showed significantly greater nuclear irregularities than the other two groups. Utilizing these features, nuclear morphometry could lead to improvements in the accuracy of the subjective diagnoses made with thyroid aspiration cytology.

Core Needle Biopsy Is a More Conclusive Follow-up Method Than Repeat Fine Needle Aspiration for Thyroid Nodules with Initially Inconclusive Results: A Systematic Review and Meta-Analysis

BACKGROUND: This study investigated the appropriate management of thyroid nodules with prior non-diagnostic or atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) through a systematic review and meta-analysis. METHODS: This study included 4,235 thyroid nodules from 26 eligible studies. We investigated the conclusive rate of follow-up core needle biopsy (CNB) or repeat fine needle aspiration (rFNA) after initial fine needle aspiration (FNA) with non-diagnostic or AUS/FLUS results. A diagnostic test accuracy (DTA) review was performed to determine the diagnostic role of the follow-up CNB and to calculate the area under the curve (AUC) on the summary receiver operating characteristic (SROC) curve. RESULTS: The conclusive rates of follow-up CNB and rFNA after initial FNA were 0.879 (95% confidence interval [CI], 0.801 to 0.929) and 0.684 (95% CI, 0.627 to 0.736), respectively. In comparison of the odds ratios of CNB and rFNA, CNB had more frequent conclusive results than rFNA (odds ratio, 5.707; 95% CI, 2.530 to 12.875). Upon subgroup analysis, follow-up CNB showed a higher conclusive rate than rFNA in both initial non-diagnostic and AUS/FLUS subgroups. In DTA review of followup CNB, the pooled sensitivity and specificity were 0.94 (95% CI, 0.88 to 0.97) and 0.88 (95% CI, 0.84 to 0.91), respectively. The AUC for the SROC curve was 0.981, nearing 1. CONCLUSIONS: Our results show that CNB has a higher conclusive rate than rFNA when the initial FNA produced inconclusive results. Further prospective studies with more detailed criteria are necessary before follow-up CNB can be applied in daily practice.

Atypia of undetermined significance on thyroid fine needle aspiration: surgical outcome and risk factors for malignancy

PURPOSE: This study was performed to analyze the surgical pathology results of the "atypia of undetermined significance" (AUS) category from thyroid fine needle aspiration (FNA) and to describe the characteristics to distinguish a malignant from a benign nodule. METHODS: A retrospective analysis was done on 116 patients who underwent thyroid surgery from December 2008 to December 2012, following a diagnosis of AUS from preoperative thyroid FNA. We investigated the age, gender, size and site of the nodules, ultrasonographic criteria, cytological features, the number of atypia results after repeated FNAs, surgical method, and final pathologic results. RESULTS: Sixty-five out of 116 patients underwent total thyroidectomy and the rest had partial thyroidectomy. The final pathologic results were 41 malignancies (35.3%) and 75 benign diseases (64.7%). AUS was divided into group 1: 'cannot rule out malignancy' or group 2: 'cannot rule out follicular neoplasm'. After surgery, group 1 revealed papillary thyroid cancer in most cases and group 2 revealed follicular adenoma in most cases. Age over 40 years, ultrasonographic findings suggestive of malignancy, more than 2 results of atypia from repeated FNAs and nodules less than 2 centimeters were risk factors for malignancy on univariate analysis. Multivariate analysis showed that ultrasonographic findings suggestive of malignancy was a significant risk factor for malignancy. CONCLUSION: For proper evaluation of the risk for malignancy in thyroid AUS patients, the ultrasonographic criteria should be considered along with other clinicopathological findings such as age, nodule size, number of atypia, cytologic features.

The Utility of Clinical Findings Including Serum TSH and Neck Ultrasonography for Predicting Thyroid Malignancy in Atypia of Undetermined Significance/Follicular Lesions of Undetermined Significance / 대한내분비외과학회지

PURPOSE: Neck ultrasonography (NUS) is one of the most commonly used methods for evaluating thyroid nodules and preoperative higher TSH levels are known to be associated with differentiated thyroid cancers. This study was conducted to assess whether serum TSH levels and neck ultrasonography are of value in predicting malignancy in patients with atypia of undetermined significance/follicular lesions of undetermined significance (AUS). METHODS: A total of 62 patients (7 men, 55 women; mean age 48.4±11.9 years) who had indeterminate cytologic results indicating AUS underwent thyroidectomy. Preoperative clinical data including serum TSH and the findings of NUS were analyzed retrospectively between malignant and non-malignant groups. RESULTS: The final pathologic results of malignancy were reported in 53 of 62 (85.5%) patients with AUS. There was no significant difference in the mean value of preoperative serum TSH between malignant and non-malignant groups (1.5±1.3 vs. 1.9±1.2, P=NS). In NUS, the patients diagnosed with malignancy in histology showed a higher proportion of calcification, taller-than-wide shape, hypoechoic texture and irregular margin (58.5% vs. 22.2%, P=0.044; 34% vs. 0%, P=0.038; 98.1% vs. 44.4%, P<0.01; 47.2% vs. 0%, P=0.008). CONCLUSION: Serum TSH was not related to malignancy in thyroid nodules showing AUS. However, ultrasonographic features including calcifications, taller-than-wide shape, hypoechoic pattern and irregular margin could be used to predict malignancy. Ultrasonography should be the first useful methods when making decisions regarding management of thyroid nodules showing indeterminate cytologic results as AUS.