Follicular Neoplasm/suspicious For Follicular Neoplasm Research Articles

Factors affecting the false negativity of fine-needle aspiration biopsy in thyroid nodules with indeterminate cytology

Purpose: False negative results of fine needle aspiration biopsies (FNAB) remain one of the most important problems in the management of thyroid nodules. The aim of this study was to evaluate the factors affecting the false negative results of FNAB, especially in thyroid nodules with indeterminate cytology.
 Materials and Methods: Patients with thyroid nodules who underwent FNAB and subsequent thyroidectomy between January 2017 and January 2020 were included in the study. FNAB was performed on suspicious nodules according to the TIRADS classification. Nodules with "atypia/follicular lesion of undetermined significance (AUS/FLUS)", "non-diagnostic (ND)" cytology or "follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)" according to FNAB were defined as "indeterminate cytology (IC)". Nodules were analyzed in two groups. Nodules with false negative FNAB were included in Group-1, while nodules with true positive and true negative FNAB were included in Group-2. Demographic and clinical data, pathologic results and genetic profiles of the patients were statistically compared for all patients and IC group separately.
 Results: The results of FNAB and final pathology were discordant in 94 patients (Group-1) and concordant in 233 patients (Group-2). In the IC subgroup, 56 of 95 patients were in IC/Group-1 and 39 patients were in IC/Group-2. The accuracy of FNAB was statistically significantly higher in the presence of extrathyroidal extension (71.4% vs. 30.8%), perineural/lymphovascular invasion (60.0% vs. 29.6%), classical variants (68.5% vs. 50.7%), non-encapsulated tumors (67.9% vs. 50.0%) and multicentricity (47.2% vs. 24.1%). In the IC group, the presence of thyroiditis (75.0% vs. 49.2%) and high serum Anti-TPO levels (60.0% vs. 30.7%) increased the rate of false negativity on FNAB. High serum Neutrophil to Lymphocyte Ratio (NLR) and small tumor size also increase the false negativity of FNAB, especially in IC group patients.
 Conclusion: The diagnostic accuracy of FNAB is increased in classical variant tumors and in tumors expected to be aggressive due to presence of extra-thyroidal extension, perineural/lymphovascular invasion, non-encapsulated tumors and multicentricity. It should be kept in mind that the false negative results of FNAB increase in the presence of thyroiditis, high level of serum anti-TPO and high level of NLR.

Correlation of Thyroid Fine Needle Aspiration Biopsy With Histopathological Results.

Introduction Fine needle aspiration biopsy (FNAB) is an effective method used in the differential diagnosis of thyroid nodules. The Bethesda system has contributed to the determination of clinical approaches by bringing standardization to cytopathology reporting. However, the rate of cytological-histological incompatibility varies between 10% and 30%. Results differ according to clinics in the literature. These results create a need to reevaluate the efficacy and safety of fine needle aspiration biopsy. In this study, we aimed to evaluate the diagnostic accuracy of FNAB of thyroid nodules by correlating the cytopathology results of FNAB with the results of postoperative histopathology. Methods In this retrospective study, thyroid FNAB results and postoperative histopathology results of patients who underwent thyroidectomy operations in our clinic between January 2018 and December 2021 were compared. Accuracy, sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), false positive rate (FPR), and false negative rate (FNR) were calculated. Cases with nondiagnostic FNAB results were excluded from the calculations.FNAB results with a follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN) and suspicious for malignancy were included in the malignant group. Results A total of 304 patients were included in the study. The male/female ratio was 1:3.3. As a result of the study, malignancy was detected histopathologically in 47 (15.46%) patients. The commonest malignancy detected was papillary carcinoma. According to the Bethesda system, the results were evaluated in six categories. The incidence of malignancy in the Bethesda categories were 0%, 4%, 40%, 69.2%, 100%, and 100%, respectively. Accordingly, the specificity and sensitivity of FNAB for detecting malignancy were 98.7% and 66.6%, respectively. The accuracy was 93.5%. The false positive rate, false negative rate, positive predictive value, and negative predictive value were 1.20%, 33.3%, 91.4%, and 93.8%, respectively. Conclusion Thyroid FNAB is an effective method used with satisfactory reliability in the differential diagnosis of malignancies of thyroid nodules. Still, it has some limitations. This article demonstrates higher rates of malignancy in Bethesda categories III and IV. Therefore, clinical approaches are gaining importance in these categories.

Unraveling the significance of TSHR mutations in indeterminate thyroid cytology specimens.

We investigated the clinical significance of thyroid-stimulating hormone receptor (TSHR) mutations detected in thyroid fine needle aspiration (FNA) specimens. The pathology archives at our institution were reviewed between 2018 and 2021 for indeterminate (Bethesda category III and IV) specimens with Thyroseq® analysis showing TSHR mutations. A total of 2184 cases diagnosed as atypia/follicular lesion of undetermined significance (AUS/FLUS), and 2625 diagnosed as follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) were identified. A total of 1735 AUS/FLUS and 2339 SFN/FN underwent Thyroseq® analysis; 69 showed TSHR mutations (1.6%, 59 female, 10 male, average age: 55 years). Ten cases showed oncocytic features. Twelve patients underwent radionuclide scans within 1 year of FNA:11 were hyperfunctioning. Nodule size and TSH levels were weakly correlated. Twenty-two different TSHR mutations were identified (most common: M453T). A second mutation was found in five cases (EZH1 n = 2, and EIF1AX n = 3). The expression of sodium-iodide transporter (NIS) mRNA was in the range of 0.01%-62.43% out of all sequencing reads, and was elevated in 49 (71%) cases. Surgical pathology follow-up was available in five cases (all benign except one). On follow-up available for 38 cases (mean: 24 months; range: 7-47 months), 34 (89.5%) nodules remained stable and 3 (8%) increased in size. TSHR mutations in thyroid FNA samples classified as indeterminate are rare, generally benign, and commonly associated with autonomy on scan if performed.

A Comprehensive Study on the Diagnosis and Management of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features.

Background: Since the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) was introduced in 2016, most retrospective studies have included cases diagnosed as encapsulated follicular variant of papillary thyroid carcinoma. We investigate a cohort diagnosed with NIFTP at resection. Methods: Retrospective institutional cohort of NIFTP from 2016 to 2022, including clinical, cytological, and molecular data for 319 cases (6.6% of thyroid surgeries, 183 cases as NIFTP-only). Results: The patient cohort had unifocal or multifocal thyroid nodules. Female:male ratio was 2.7:1, mean age was 52 years and median NIFTP size was 2.1 cm. NIFTP was associated with multiple nodules in 23% patients (n = 73) and 12% of NIFTP were multifocal (n = 39). Fine needle aspiration (FNA) of NIFTP (n = 255) were designated as nondiagnostic = 5%, benign = 13%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) = 49%, follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) = 17%, suspicious for malignancy = 12%, or malignant = 4%. Molecular alterations were identified in 93% (n = 114), RAS or RAS-like. Thyroid Imaging Reporting and Data System (TI-RADS) score 4 was recorded in 50% of NIFTP, followed by scores 3 and 5 (26% and 20%, respectively). We also investigated the factors associated with extent of surgery. In our NIFTP-only group (n = 183), 66% were identified after hemithyroidectomy (HT) and 34% after total thyroidectomy (TT). On univariate analysis, TT patients demonstrated higher Bethesda category by FNA, more often had aberrant preoperative thyroid function, and/or underwent an FNA of additional nodule(s). With multivariable regression, Bethesda V NIFTP, in the presence of other nodules being evaluated by FNA and aberrant preoperative thyroid function, independently predicts TT. Bethesda II NIFTP correlated significantly with HT. Fifty-two patients (28%) with NIFTP-only had at least one postoperative surveillance ultrasound. In the NIFTP-only cohort, no HT patients had completion thyroidectomy or received postoperative radioactive iodine. No recurrence or metastases were recorded with median follow-up of 35 months (6-76 months; n = 120). Conclusions: Given this large cohort of NIFTP, including a large subset of isolated NIFTP-only, some with >6 years of follow-up and no tumor recurrences, consensus practical guidelines are needed for adequate postoperative management. Given the American Thyroid Association (ATA) provides guidelines for management of low-risk malignancies, guidance regarding that for borderline/biologically uncertain tumors, including NIFTP, is a reasonable next step.

EVALUATION AND MANAGEMENT OF THYROID NODULES AT A TERTIARY CARE PEDIATRIC CANCER CENTER IN TURKEY

The object of this study is to search the characteristics of children and adolescents with thyroid nodules and analyze our institutional experience in the management of thyroid nodules.The complaints of these patients, physical examination findings, diagnostic features, results of radiologic researches, choise of the most appropriate modality to these patients' thyroid nodule assessment, and the management of the pathology results were revealed. Patients who applied to the pediatric endocrinology or oncology outpatient clinic of Ankara City Hospital with the diagnosis of thyroid nodule were examined. All patients who has pathology result as benign, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm/ suspicious for a follicular neoplasm (FN/SFN), suspicious for malignancy (SM), and malignant were searched. A total of 130 patients presented with thyroid nodules. Female male ratio was 1,95:1. The youngest patient was 68 months old. At admission there was no goiter in 71.5% of the patients on physical examination. Of all patients 36% of them underwent fine needle aspiration biopsy and 8 of the 76 patients who underwent biopsy were diagnosed with papillary thyroid cancer. One patient diagnosed with follicular thyroid cancer Patients that diagnosed cancer, 4.6% of them treated with radioactive iodine. Although most pediatric thyroid nodules are benign, distinguishing benign from malignant lesions is crucial. Interdepartmental communication and competence are very important in the follow-up of patients with thyroid nodules. Because of an increased risk of cancer in the pediatric population, diagnostic and therapeutic procedures for pediatrics need further research including multicenter studies to attain universal consensus regarding the diagnosis and management.

Molecular Testing of Atypical Thyroid Nodules with Corresponding Surgical Correlation: Five-Year Retrospective Review in Veterans Population.

ObjectiveWe report the results of a retrospective five-year study within a veteran population aimed at correlating abnormal thyroid fine-needle aspiration (FNA) diagnosis with associated molecular testing to the histology of the surgical resection.MethodsA retrospective analysis of abnormal thyroid FNAs with associated molecular testing and surgical outcome was conducted from January 1, 2015 to December 31, 2020. Aspirates were classified using the Bethesda system for reporting thyroid cytopathology, including atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), suspicious for malignancy (SM), and malignant. Pertinent data, including patient demographics, imaging, and ancillary testing were reviewed. A thyroid cancer mutation panel assessing the most common mutations and rearrangements associated with neoplasia was utilized. The results of molecular testing were directly compared and correlated with final cytological and histological diagnosis.ResultsA total of 1850 thyroid aspirates were performed, 200 of which were given an abnormal cytologic diagnosis. Thirty-six samples were submitted for molecular testing and subsequent surgical follow-up. Four were called malignant on cytology. 32 were placed in an indeterminate category (89%). Within indeterminate cases: 53% exhibited positive molecular mutations (n=17), 34% no mutation detected (n=11), and 13% insufficient quantity for testing (n=4). Upon surgical resection in the mutation-positive group: 18% had no malignancy (n=3), and the remaining 82% were positive for malignancy (n=14). Mutations in the histologically malignant group included: 57% BRAF (n=8), 21% NRAS (n=3), 7% HRAS (n=1), 7% KRAS (n=1), and 7% PAX8/PPAR gamma (n=1). In indeterminate cases with no mutation detected, 10 cases were found to be benign, and one case of malignancy was diagnosed. The probability of indeterminate diagnosis in combination with no mutation yielded a 91% chance of benign entity and 9% chance of malignancy. We demonstrated 93% sensitivity and 91% negative predictive value (NPV) for the risk of malignancy in indeterminate cytology specimens with ancillary molecular testing. There was 77% specificity and 82% positive predictive value (PPV) for our data set.ConclusionsIn indeterminate samples, the detection of a mutation was highly predictive of malignancy and a strong indicating factor for surgery with a high sensitivity and NPV. Molecular testing refined or established the diagnosis in 89% of the cases. Our results indicate that molecular testing of thyroid nodules enhances the accuracy of FNA cytology and the subsequent surgical outcome.

Utility of mutational analysis for risk stratification of indeterminate thyroid nodules in a real-world setting.

American Thyroid Association (ATAn) 2015 guidelines recommend repeat fine-needle aspiration with molecular marker profiling (MMP) or diagnostic lobectomy in thyroid nodules yielding atypia of unknown significance/follicular lesion of unknown significance (AUS/FLUS) or follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) cytology. Our objective is to describe the molecular profiles and histological correlates of these cytologically indeterminate nodules (CIN) to aid risk stratification. Retrospective chart review. Adults with CIN that underwent MMP from 2017 to 2020. Pearsons' χ2 , Fisher's exact test, nonparametric testing and multiple regression analysis were performed. A total of 89 CIN underwent mutational analysis. Of 55% (n = 49) were Bethesda class III AUS/FLUS and 45% (n = 40) were Bethesda class IV FN/SFN. The US phenotype of a CIN was isoechoic (53%) or hypoechoic (32%) with well-defined margins (98%), absence of calcifications (75%) and mildly increased internal vascularity (70%). A total of 84% and 87% of nodules were classified as mild/moderate or low/intermediate risk per the Thyroid Imaging Reporting and Data System and ATA classifications, respectively. Based on the Thyroseq patient management resource, 6.7% (n = 6) of nodules had a high predicted probability of cancer (≥95%), 41.6% (n = 37) were intermediate probability (40%-94%) and 51.7% (n = 46) were low probability (<40%). MMP revealed positive mutations in 45% (n = 40) of nodules, with 71% demonstrating RAS mutations. Of the nodules that underwent resection (n = 38), 39% (n = 15) had malignant pathology. Increasing the threshold to recommend surgical resection to a Thyroseq predicted probability of cancer to ≥50%, had a 100% sensitivity and 65% specificity for detecting malignant nodules (area under the ROC curve: 0.86). The positive predictive value was 37% and the negative predictive value was 100%. US phenotypes of CIN nodules were variable and did not aid in differentiating malignant from benign nodules. Of the CIN nodules with a positive MMP, most were RAS and had a benign pathology. With the exception of high-risk genetic markers for malignancy, the threshold to recommend surgical resection should be raised for CIN. Further studies to improve risk stratification in these nodules are required.

The Bethesda system for reporting thyroid FNAC: A cytohistological correlation in a newly established institute

Introduction: FNAC is an excellent modality for diagnosis of thyroid lesions because of its simplicity and cost effectiveness. Since the introduction of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) in 2007, it has become a standardized, convenient and more informative system of thyroid reporting. Aims: 1. To study cytological features of FNAC and categorization according to TBSRTC; 2. To assess statistical analysis of FNAC in detecting malignant lesions. Settings and Design: This is a cross-sectional study carried out in the Pathology Department from January 2015 to December 2017. Materials and Methods: We interpreted 329 thyroid FNAC and categorized them according to TBSRTC. 75 cases are correlated histologically. Statistical Analysis: Accuracy, specificity, sensitivity and predictive values. Result: Distribution of different categories are as follows Non-diagnostic/unsatisfactory (ND/UNS)-8.5%, Benign-85.2%, Atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)-0.6%, Follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)-2.4%, Suspicious for malignancy (SFM)-1.5% and malignant-1.8%. The malignancy risk calculated from histopathological follow up of 75 cases is as follows: ND/UNS 0%, Benign 6.9%, FN/SFN 16.7%, SFM 66.7% and malignant 100%. The positive predictive value, negative predictive value and accuracy of TBSRTC are 100%, 93.1%, 93.7% respectively. Conclusion: The malignancy risk, accuracy, specificity and predictive values are consistent with other studies. Thus TBSRTC allows more standard reporting, specific diagnosis and understanding of terminology between pathologists and clinicians. Keywords: FNAC, TBSRTC, Thyroid.

ThyroSeq v3 for Bethesda III and IV: An institutional experience.

The ThyroSeq v3 genomic classifier is a commercial molecular test that examines a wide spectrum of genomic alterations in a thyroid fine-needle aspiration (FNA) sample and reports test results as either negative or positive. The authors report their institutional experience with ThyroSeq v3. Thyroid FNA specimens diagnosed as either atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) (Bethesda category III [Bethesda III] according to The Bethesda System for Reporting Thyroid Cytopathology) or follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) (Bethesda IV) that had ThyroSeq v3 results available from December 2017 through October 2019 were retrieved for analysis. FNA diagnoses were correlated with ThyroSeq v3 results and follow-up histopathology. In total, 415 cases (AUS/FLUS, n = 251; FN/SFN, n = 164) were retrieved: 294 (71%) were reported as ThyroSeq v3-negative, and 121 (29%) were reported as ThyroSeq v3-positive. The benign call rate (BCR) of ThyroSeq v3 for AUS/FLUS (82%; 206 of 251 cases) was significantly higher (P < .001) than that for FN/SFN (BCR, 54%; 88 of 164 cases). Histopathologic follow-up was available for 127 cases (ThyroSeq v3-positive, 96; ThyroSeq v3-negative, 31), of which 57 were benign and 70 were malignant (including noninvasive follicular thyroid neoplasm with papillary-like nuclear features). The negative predictive value of ThyroSeq v3 was significantly higher for AUS/FLUS (99.5%) than for FN/SFN (95.4%; P < .0294), given malignancy rates of 10% for AUS/FLUS and 30% for FN/SFN. Forty-five unique combinations of genetic alterations were detected in the operated ThyroSeq-positive cases, and there were only 5 false-negative cases, comprised of 4 low-risk neoplasms. The high BCR of ThyroSeq v3 for AUS/FLUS prevents surgery in a majority of patients. The ThyroSeq v3 genomic classifier reveals the complexity of the genetic signature of indeterminate nodules.

Molecular testing and thyroid nodule management in North America.

The incidence of thyroid cancer is rising for a variety of reasons. At the same time, the nomenclature revision of non-invasive encapsulated follicular-variant PTC to noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) has modified the incidence of thyroid cancer. Given that thyroid neoplasia is a molecular event, it is important for the thyroid physician to evaluate each patient systematically. Most thyroid cancers are sporadic; however, some are familial and may be associated with syndromes with genetic implications. Advances in radiologic imaging have made ultrasonography a near equivalent of gross examination. The American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) classifies nodules from TR1 to TR5 and is valuable in determining which patients should be guided toward fine-needle aspiration (FNA) sampling. While FNA procedures and processing may be varied, the key elements are cytologic diagnosis and collection of samples for potential molecular testing. The Bethesda System for Reporting Thyroid Cytology (BSRTC) is commonly used and categorizes each FNA specimen into one of six diagnoses. The indeterminate diagnoses with risk of malignancy (ROM) ranging from 10-75% comprise approximately 30% of thyroid FNA cases and for these, molecular testing is beneficial. In North America, the two most common molecular platforms are Veracyte Afirma GSC and ThyroSeq v3. Both panels cover an extensive array of genomic alterations associated with thyroid neoplasia and a negative result from either test effectively refines the ROM of an Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS) or Follicular Neoplasm/Suspicious for a Follicular Neoplasm (FN/SFN) diagnosis to 3-4%. Given that the refined ROMs are comparable to that of a Benign BSRTC diagnosis, these patients are recommended for observation of their nodules. However, differences exist in the implication of Afirma GSC-Suspicious and ThyroSeq v3-Positive molecular results with regard to the probability of cancer. For either test, the molecular test result should be integrated with other clinical parameters to determine if surgery is indicated and, if so, the extent of surgery.

PD-L1 and thyroid cytology: A possible diagnostic and prognostic marker.

Programmed death-ligand 1 (PD-L1) expression is emerging as an important predictive biomarker in anti-PD-L1 cancer immunotherapy. Its role has been clearly defined in various human cancers and is linked to a poor prognosis and resistance to anticancer therapies. The role of PD-L1 in thyroid cancers has not been well defined in fine-needle aspiration cytology (FNAC). The authors examined the performance of PD-L1 immunostaining in liquid-based cytology (LBC) to determine whether it could be a biomarker of malignancy or aggressive disease. From January 2018 to March 2019, 236 thyroid lesions, which had been diagnosed by FNAC as indeterminate lesions, suspicious for malignancy (SFM), and malignant, were enrolled. PD-L1 immunostaining was performed on both LBC and corresponding histology samples. The FNAC cohort included 50 benign negative controls, 42 samples of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 33 samples of follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 53 samples that were suspicious for malignancy (SFM), and 58 malignant samples. AUS/FLUS samples included 3 goiters, 32 follicular adenomas (FAs), 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), 5 invasive follicular variants of papillary thyroid carcinoma (I-FVPTCs), and 1 follicular carcinoma; whereas FN/SFN samples included 24 FAs and 9 malignancies (4 I-FVPTCs, 1 NIFTP, 3 papillary thyroid carcinomas [PTCs], and 1 oncocytic follicular carcinoma). The 53 SFM samples were diagnosed on histopathology as 2 FAs, 5 NIFTPs, 15 I-FVPTCs, and 31 PTCs; whereas the 58 malignant specimens included 5 NIFTPs, 5 I-FVPTCs, and 48 PTCs. Increased plasma membrane and cytoplasmic PD-L1 expression was found in 79 cases (38.5%), including 61 PTCs (conventional and variants). Negative PD-L1 expression was found in NIFTPs and FAs. A BRAF V600E mutation was identified in 15% of PD-L1-positive malignancies. The current data suggest that PD-L1 expression in the thyroid gland might represent a marker of malignancy that correlates with PTC, but not with NIFTP. Thyroid neoplasms with PD-L1 expression also ae enriched with BRAF V600E mutations, suggesting that they are associated with more aggressive behavior.

Bethesda System for Reporting Thyroid Cytopathology in Pediatric Thyroid Nodules: Experience of a Tertiary Care Referral Center.

The Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer from The American Thyroid Association recommends fine-needle aspiration (FNA) as an essential tool for evaluation and management of pediatric thyroid nodules, and The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as a guideline to categorize FNA cytologic findings. A few publications have focused on TBSRTC categorization in children. To evaluate our institutional experience of using TBSRTC in the pediatric population. We conducted a retrospective data search for thyroid FNA specimens from patients younger than 21 years who were assessed by using TBSRTC categorization between January 1, 2011, and September 30, 2017. Cytologic and histologic diagnoses, rate of surgical follow-up, rate of histology-proven malignancy, and cytologic-histologic concordance were assessed in comparison with our previously published adult experience. Among a total of 201 specimens, benign category accounted for 103 (51.2%), followed by 35 (17.4%) malignant, 30 (14.9%) atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 14 (7.0%) nondiagnostic, 10 (5.0%) follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), and 9 (4.5%) suspicious for malignancy (SFM) categories. Surgeries were subsequently performed in 100 of the 201 cases (49.8%). All surgically removed nodules categorized as malignant and SFM by FNA showed malignancy, while malignancy was evident in various proportions of specimens classified as AUS/FLUS (5 of 16; 31.3%), FN/SFN (1 of 9; 11.1%), and nondiagnostic (1 of 7; 14.2%). No malignancy was identified in the benign category. Cytologic-histologic concordance achieved 100% in malignant, SFM, and FN/SFN categories, and exceeded beyond 85% and 50% for benign and AUS/FLUS categories, respectively. TBSRTC is effective for appropriate categorization of pediatric thyroid nodules. Risk of malignancy in thyroid nodules is higher for the pediatric than adult population. Understanding the difference in TBSRTC categorization between children and adults may aid in achieving more appropriate evaluation and management of pediatric thyroid nodules.

American College of Radiology thyroid imaging report and data system combined with K-RAS mutation improves the management of cytologically indeterminate thyroid nodules.

We investigated whether use of American College of Radiology thyroid imaging report and data system (ACR TIRADS) in combination with K-RAS mutation status may facilitate risk stratification of patients with cytological Bethesda Category III and IV thyroid nodules. Ultrasonographic, cytological, and histopathological diagnoses were retrospectively correlated with K-RAS mutation status in a series of 43 cytologically indeterminate thyroid nodules (CITNs) that were referred for surgical excision. K-RAS mutations were detected in 8/43 (18.6%) fine-needle aspiration (FNA) samples as against 11/43 (25.6%) surgical specimens. ACR TIRADS level (TR) TR3 lesions had a malignancy risk of 40%; the K-RAS mutation rate in FNA samples and surgical specimens of category TR3 lesions was 40% and 60%, respectively. K-RAS mutation-positive malignancy was significantly more frequently detected in follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) lesions than that in atypia or follicular lesion of undetermined significance (AUS/FLUS) (P<0.01). Combined use of ACR TIRADS (TR5 as the diagnostic threshold) and K-RAS mutation status helped identify 83.3% (10/12) malignant nodules (58.6% specificity, 45.5% positive predictive value, 89.5% negative predictive value, and 65.9% accuracy). CITNs with ACR TIRADS category TR3 showed an unexpectedly high risk of malignancy. K-RAS mutation-positive FN/SFN nodules have a 50% risk of malignancy and surgery should be recommended. Combined use of ACR TIRADS and K-RAS mutation may facilitate risk-stratification of patients with CITNs. The high negative predictive value (NPV) for malignancy seems sufficient to allow conservative management of patients with active surveillance.

The influence of the reclassification of NIFTP as an uncertain tumour on risk of malignancy for the diagnostic categories according to the Bethesda system for reporting thyroid cytopathology.

The noninvasive encapsulated, follicular variant of papillary thyroid carcinoma was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The exclusion of NIFTP from the group of malignant tumours decreases the risk of malignancy (RoM) as defined by the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The aim of the present study was to evaluate the RoM for each category in TBSRTC with and without exclusion of NIFTP from the tally of malignancies. The present study included 998 thyroid nodules cases. All patients underwent diagnostic tests, including fine-needle aspiration cytology, and received surgical treatment. Slides for all resection specimens with a diagnosis of cancer were reviewed to identify NIFTP. The RoM for each of the categories in TBSRTC with and without exclusion of NIFTP from the malignant tumours was evaluated. The RoM decreased with the exclusion of NIFTP from malignant categorisation with the following values for the different TBSRTC categories: non-diagnostic (ND): 0%; benign: 0%; atypia/follicular lesion of undetermined significance (AUS/FLUS): 1.6%; follicular neoplasm/suspicious for follicular neoplasm (FN/SFN): 0.7%; suspicious for malignancy (SUS): 6.9%; and malignant: 2.5%. The difference of 2.5% in the malignant category was statistically significant (p = 0.0253). The RoM for specific TBSRTC categories needs to be defined for each treatment centre because it is important for the selection of the appropriate surgical treatment for thyroid tumours.

Value of the detection of BRAF(V600E) gene mutation and protein expression in auxiliary cytological diagnosis of papillary thyroid carcinoma

Objective: To evaluate the utility of the BRAF(V600E) mutation detection in different cytoloy categories and to determine if the VE1 antibody can serve as a screening tool for the detection of BRAF(V)600E mutation in thyroid fine needle aspiration (FNA) specimens. Methods: A total of 273 FNA residual specimens were collected. BRAF(V600E) testing was performed on these liquid-based specimens. And also 78 specimens with enough residual cells were stained with VE1 antibody. Comparisons of molecular and immunocytochemistry results with clinicopathological outcomes were performed. SPSS 17.0 software was used to analyze the data. Results: There were 70 indeterminated diagnoses in 273 cases with FNAs. Fifty-eight cases were proven to be papillary thyroid carcinoma (PTC) by histology, including 9 cases of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 3 cases of follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), and 46 cases of suspicious for malignancy (SM). BRAF(V600E) analysis detected PTC in 3 of 9 cases with AUS/FLUS, and in 31 (67.4%) of 46 cases with SM. The sensitivity of immunostaining with VE1 antibody was 62.8%(27/43) and the specificity was 91.4% (32/35). VE1 expression showed moderately concordance with the molecular mutation (κ=0.524, P<0.001). Conclusions: Additional BRAF(V600E) detecting can improve the diagnostic efficacy for PTC in AUS/FLUS and SM. VE1 expression may be an alternative method for BRAF(V600E) detecting when molecular detecting is unavailable.

In Brief

In Brief

Impact of non-invasive follicular thyroid neoplasm with papillary-like nuclear features on the Bethesda system for reporting thyroid cytopathology: a multi-institutional study in five Asian countries

Several Western studies showed that the recent introduction of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) significantly decreased risk of malignancy for cytological diagnostic categories. We aimed to determine the impact of NIFTP on risk of malignancy within a cohort of thyroid nodules from Asian countries, and to compare distribution of diagnostic categories between NIFTP and invasive encapsulated follicular variant of papillary thyroid carcinoma (eFV-PTC). Consecutive thyroid fine-needle aspirates from six institutions were retrospectively analysed. Histopathology slides with a diagnosis of eFV-PTC were reviewed and reclassified into invasive eFV-PTC and NIFTP. The risk of malignancy was calculated with and without NIFTP. Of 11,372 thyroid nodules, 2044 had available surgical follow-up. NIFTP was diagnosed in 59 cases, which constituted 2.9% of all excised nodules, and 5.3% of malignant nodules. Preoperative cytological diagnoses for NIFTP were non-diagnostic (10.2%), benign (18.6%), atypia of undetermined significance/follicular lesion of undetermined significance (22.0%), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) (32.2%), suspicious for malignancy (SM) (11.9%), and malignant (5.1%). The only category which showed a relative reduction in risk of malignancy after reclassification of more than 20%, was FN/SFN (24.4%). There was a significantly higher prevalence of benign cytology in NIFTP (p= 0.04) and SM/malignant in invasive eFV-PTC (p= 0.05). A majority of NIFTP cases were classified in indeterminate categories, which decreased the corresponding risk of malignancy. However, the magnitude of NIFTP impact was much lower than in the Western reports. Asian countries may not experience significant effects of NIFTP reclassification on the practice of thyroid cytopathology.

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

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. 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. 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. 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.

Risk factors associated with malignancy and with triage to surgery in thyroid nodules classified as Bethesda category IV (FN/SFN).

Thyroid nodules diagnosed as Bethesda category IV [follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)] are recommended for surgery. However, only 10%-40% of these nodules turn out to be malignant on histopathological examination. Therefore, selection for surgery of nodules diagnosed as Bethesda category IV is important. We aimed to define predictive factors for malignancy and factors associated with triage to surgery. The records of all patients with nodules who underwent fine needle aspiration biopsy (FNAB) and classified by Bethesda reporting system as FN/SFN between January 2011 and July 2017 at our institution were reviewed. Univariate and multivariate analysis were performed to select independent factors associated with thyroid cancer, and with triage to surgery. Using independent risk factors for malignancy predictive index categories were created. Among 6910 nodules that underwent FNAB, 180 (2.6%) were diagnosed as FN/SFN. Of the 180 patients, 139 (77%) underwent surgery with the associated malignancy rate of 37% (51/139) (upper boundary). Risk of malignancy among all FN/SFN nodules was 28% (lower boundary). Solid structure, size ≥ 4 cm, microcalcification, hypoechogenicity, and increased vascularization were found to be significant and independent risk factors associated for malignancy. None of the clinical and ultrasound factors were associated with triage to surgery. Our findings showed that using predictive factors for malignancy in the Bethesda IV category as risk indices, 17% of patients who had nodules without any risk factors could be spared surgery. Predictive indices could be considered for the malignancy risk and for selection of patients for surgery.

Reproducibility of "The Bethesda System for Reporting Thyroid Cytopathology:" A Retrospective Analysis of 107 Patients.

Objectives:Fine-needle aspiration cytology (FNAC) has emerged as an indispensable tool to discriminate thyroid lesions into benign or malignant for appropriate management. The need for simplicity of communication and standardization of terminology for thyroid FNAC reporting led to introduction of “The Bethesda system for reporting Thyroid Cytopathology” (TBSRTC) in a conference held at the National Cancer Institute in 2007. This study aims at establishing the reproducibility of TBSRTC for diagnosing thyroid lesions.Materials and Methods:The present study comprised thyroid FNAC from 107 patients retrospectively over a period of 1.5 year (June 2013 to December 2014), which were reviewed by two trained cytopathologists and re-categorized according to TBSRTC. The interobserver variation and reproducibility of the reporting system was statistically assessed using Cohen's kappa.Results:The cytopathologists were in agreement in 98 out of 107 cases (91.5%). Maximum concordance was noted in benign category (91 of 96 cases; 92.85%), followed by 2 cases each in nondiagnostic/unsatisfactory (ND/US) and follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) category (2.04% each) and 1 case each in atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), suspicious for malignancy (SUS), and malignant category (1.02% each). The highest diagnostic disagreement was noted among ND/US and benign and benign and FN/SFN categories.Conclusion:The utilization of TBSRTC for reporting thyroid cytology should be promoted in our country because it provides a homogeneous, standardized, and unanimous terminology for cytological diagnosis of thyroid lesions. The present study could substantiate the diagnostic reproducibility of this system.