Indeterminate Fine-needle Aspiration Cytology Research Articles

Serum MicroRNA-146b Expression for Malignancy Prediction in Euthyroid Patients with Indeterminate Thyroid Nodules

Thyroid nodules are frequently found, but the vast majority of them are benign. The difficulty in managing thyroid nodules is correctly diagnosing the minority of those who have malignancy. Thyroid fine-needle aspiration cytology (FNAC) with indeterminate cytology continues to raise doubts about the presence of thyroid cancer, leading to an unnecessary thyroidectomy. Circulating miRNAs may be useful as diagnostic and prognostic markers for a variety of cancers, including thyroid cancer. The goal of the present study was to determine the predictive value of serum miRNA-146b expression level for thyroid cancer by estimating its level in a group of euthyroid patients with thyroid nodules with indeterminate FNAC results. This cross-sectional study included 45 euthyroid patients with indeterminate thyroid nodules who visited the Endocrine Outpatient Clinic and Endocrine Surgical Ward at Ain Shams University Hospitals. For all patient thyroid profiles, ultrasound of the thyroid gland and FNAC of the thyroid nodule were performed. In addition, preoperative assessment of serum microRNA-146b expression by real-time PCR was achieved and the results correlated with post-operative thyroid histopathology. There was no difference in serum miRNA-146b expression between patients with benign thyroid nodules versus patients with malignant nodules (p= 0.789). The risk of malignancy increased with the increase in size of the dominant thyroid nodules, as larger nodules had a higher risk of malignancy (p= 0.027). In conclusion, in euthyroid patients with indeterminate thyroid nodules, serum miRNA-146b is a poor predictor of thyroid malignancy, however, the larger the nodule size, the higher the risk of cancer.

A retrospective analysis of molecular testing in cytologically indeterminate thyroid nodules with histologic correlation: Experience at a heterogenous multihospital system.

Thyroid malignancy is one of the most common types of cancer in developed nations. Currently, fine-needle aspiration cytology (FNAC) is the most practical screening test for thyroid nodules. However, cytologically indeterminate samples comprise approximately 15%-30% of cases. These include cases classified as atypia of undetermined significance (AUS), follicular neoplasm (FN), and suspicious for malignancy (SFM). Indeterminate cases can be sent for molecular testing for more definitive classification to help guide management and prevent overtreatment of benign thyroid nodules. We conducted a retrospective review on molecular testing of indeterminate thyroid FNAC and reviewed subsequent histologic diagnoses in resection specimens to assess how molecular testing supported a diagnosis and its effect on clinical management of patients at our institution. A retrospective chart review was performed on all thyroid FNAC specimens, corresponding molecular testing, and subsequent surgical resection specimens over a 6-year period. A total of 10,253 thyroid FNAC were performed in our hospital system during our study period, of which 10% (n = 1102/10,253) had indeterminate FNAC results. Molecular testing was performed in 16% (n = 178/1102) of indeterminate cytology cases. Genetic alterations were identified in 39% (n = 69/178) of the cases sent for molecular testing. The majority of cytologically indeterminate cases sent for molecular testing were follicular-patterned lesions and their corresponding resection specimens revealed mostly low grade follicular derived neoplasms (i.e., follicular adenoma, non-invasive follicular thyroid neoplasm with papillary-like nuclear features, and follicular variant of papillary thyroid carcinoma). Of the cases with identified genetic alterations, 75% (n = 52/69) were treated surgically. In cases with no genetic alterations identified, only 18% (n = 20/109) were treated surgically. Molecular testing on cytologically indeterminate thyroid nodules can help provide a more accurate risk of malignancy assessment in patients with lesions that are difficult to diagnosis based solely on FNAC morphology. The types of genetic alterations identified in the resected thyroid lesions were consistent with what has been previously described in the literature. Additionally, we found that in the patients with indeterminate thyroid FNAC with adjunct molecular testing, more than half did not undergo surgical resection. This finding emphasizes the value of adding molecular testing in patients, particularly when attempting to reduce unnecessary surgical intervention.

Diagnostic Performance of 99mTc-Methoxy-Isobuty-Isonitrile (MIBI) for Risk Stratification of Hypofunctioning Thyroid Nodules: A European Multicenter Study.

99mTc-MIBI (MIBI) imaging is able to exclude malignancy of hypofunctioning thyroid nodules (TNs) with high probability but false positive results are frequent due to low specificity. Therefore, pre-test selection of appropriate TNs is crucial. For image evaluation visual and semiquantitative methods (Washout index, WOInd) are used. Aim of this study was to evaluate the diagnostic performance of MIBI imaging in hypofunctioning TNs with indeterminate fine-needle aspiration cytology results in a multicentric European setting. Patients with hypofunctioning TNs, EU-TIRADS 4 or 5, Bethesda III/IV and MIBI imaging were included. For visual evaluation the intensity of MIBI uptake in the TN was compared to normal thyroid tissue. 358 patients with 365 TNs (n = 68 malignant) were included. Planar imaging (SPECT) showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 96% (94%), 21% (22%), 22% (15%), 96% (96%), and 35% (32%). The WOInd (38.9% of all cases, optimal cutoff: −19%) showed a sens 100% (spec 89%, PPV 82%, NPV 100%, ACC 93%). For hypofunctioning TNs at intermediate or high risk with indeterminate cytology, a MIBI negative result on visual evaluation is an effective tool to rule-out thyroid malignancy. The semi-quantitative method could considerably improve overall diagnostic performance of MIBI imaging.

SCC Antigen Concentrations in Fine-Needle Aspiration Samples to Detect Cervical Lymph Node Metastases: A Prospective Analysis.

To determine the diagnostic value of measuring squamous cell carcinoma antigen (SCC-Ag) and cancer antigen 15-3 (CA15-3) concentrations in fine-needle aspiration (FNA) samples for the detection of squamous cell carcinoma (SCC) metastases in cervical lymph nodes. A prospective study with patients consecutively included between November 2018 and May 2021. A tertiary head and neck oncologic center. Out of 138 patients, SCC-Ag concentrations were analyzed in 168 FNA cervical lymph node samples and CA15-3 in 152 samples. Results were compared with FNA cytology (FNAC) or definitive histology to establish sensitivity and specificity rates. For the detection of cervical SCC lymph node metastases, SCC-Ag measurement had an 89.4% sensitivity and 79.3% specificity at a cutoff concentration of 0.1 µg/L. Measurement of CA15-3 concentration in addition to SCC-Ag concentration did not lead to improved accuracy for the detection of SCC. In histology-confirmed cases, FNAC had an 80.0% sensitivity and 100% specificity, as opposed to 93.3% and 57.1%, respectively, for SCC-Ag. Measurement of SCC-Ag concentration for detection of SCC lymph node metastases has a sensitivity at least comparable to FNAC and could be used as a relatively cheap screening tool in samples with nondiagnostic or indeterminate FNAC results or when multiple lymph nodes are sampled. However, SCC-Ag in FNA samples has a lower specificity than FNAC assessed by pathologists experienced in head and neck oncology. Addition of CA15-3 measurement did not lead to improved accuracy.

Thyroid Cancer Detection in a Routine Clinical Setting: Performance of ACR TI-RADS, FNAC, and Molecular Testing in Prospective Cohort Study.

The aim of our study was to address the potential for improvements in thyroid cancer detection in routine clinical settings using a clinical examination, the American College of Radiology Thyroid Imaging Reporting and Database System (ACR TI-RADS), and fine-needle aspiration cytology (FNAC) concurrently with molecular diagnostics. A prospective cohort study was performed on 178 patients. DNA from FNA samples was used for next-generation sequencing to identify mutations in the genes BRAF, HRAS, KRAS, NRAS, and TERT. RNA was used for real-time PCR to detect fusion genes. The strongest relevant positive predictors for malignancy were the presence of genetic mutations (p < 0.01), followed by FNAC (p < 0.01) and ACR TI-RADS (p < 0.01). Overall, FNAC, ACR TI-RADS, and genetic testing reached a sensitivity of up to 96.1% and a specificity of 88.3%, with a diagnostic odds ratio (DOR) of 183.6. Sensitivity, specificity, and DOR decreased to 75.0%, 88.9%, and 24.0, respectively, for indeterminate (Bethesda III, IV) FNAC results. FNA molecular testing has substantial potential for thyroid malignancy detection and could lead to improvements in our approaches to patients. However, clinical examination, ACR TI-RADS, and FNAC remained relevant factors.

Do Ultrasound Patterns and Clinical Parameters Inform the Probability of Thyroid Cancer Predicted by Molecular Testing in Nodules with Indeterminate Cytology?

Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further inform the risk of thyroid cancer in nodules predicted to be positive or negative by MT remains unknown. The aim of this study was to test if clinical parameters, including patient age, sex, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] vs. American College of Radiology Thyroid Image Reporting and Data System [TI-RADS] systems), radiation exposure, or family history of thyroid cancer can modify the probability of thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) predicted by MT. Methods: We studied 257 thyroid nodules in 232 patients from 10 study centers with indeterminate fine needle aspiration cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression was used for data analysis. Results: The presence of cancer/NIFTP was associated with positive TSv3 results (odds ratio 61.39, p < 0.0001). On univariate regression, patient sex, age, and Bethesda category were associated with cancer/NIFTP probability (p < 0.05 for each). Although ATA (p = 0.1211) and TI-RADS (p = 0.1359) US categories demonstrated positive trends, neither was significantly associated with cancer/NIFTP probability. A multivariate regression model incorporating the four most informative non-MT covariates (sex, age, Bethesda category, and ATA US pattern; Model No. 1) yielded a C index of 0.653; R2 = 0.108. When TSv3 was added to Model number 1, the C index increased to 0.888; R2 = 0.572. However, age (p = 0.341), Bethesda category (p = 0.272), and ATA US pattern (p = 0.264) were nonsignificant, and other than TSv3 (p < 0.0001), male sex was the only non-MT parameter that potentially contributed to cancer/NIFTP risk (p = 0.095). The simplest and most efficient clinical model (No. 3) incorporated TSv3 and sex (C index = 0.889; R2 = 0.588). Conclusions: In this multicenter study of thyroid nodules with indeterminate cytology and MT, neither the ATA nor TI-RADS US scoring systems further informed the risk of cancer/NIFTP beyond that predicted by TSv3. Although age and Bethesda category were associated with cancer/NIFTP probability on univariate analysis, in sequential nomograms they provided limited incremental value above the high predictive ability of TSv3. Patient sex may contribute to cancer/NIFTP risk in thyroid nodules with indeterminate cytology.

TERT Promoter Mutation in Indeterminate Thyroid Fine Needle Aspiration Cytology: An Indicator of Unfavorable Disease?

TERT Promoter Mutation in Indeterminate Thyroid Fine Needle Aspiration Cytology: An Indicator of Unfavorable Disease?

Could Negative Tc-99m-Methoxyisobutylisonitrile (MIBI) Scintigraphy Obviate the Need for Surgery for Bethesda III and IV Thyroid Nodules?

In about 20% of all cases, the fine needle aspiration cytology (FNAC) results are equivocal, delivering the two common categories of indeterminate cytology, Bethesda III and IV. The observed rates of malignancy vary widely among institutions, with the urgent need for a more precise risk stratification. 99mcTc methoxyisobutylisonitrile scintigraphy (MIBI) is less expensive than molecular testing and has been shown to have a high negative predictive value. For this reason, the results of MIBI scintigraphy in adult patients with indeterminate FNAC were collected, and correlated with the final pathology reports of surgical specimens. Patients receiving FNAC, MIBI scintigraphy and surgery for sonographic suspicious hypofunctional thyroid nodules between 2015 and 2019 at the University Hospital of Cologne, Germany were identified. Sensitivity, specificity, positive predictive and negative predictive value of MIBI scintigraphy were calculated. Seventy-eight patients with sonographic suspicious hypofunctional thyroid nodules underwent surgery after interdisciplinary case discussion of both FNAC and MIBI results. In 49 (62.5%) cases, FNAC consisted of Bethesda III and IV results. In 39 (79.6%) of these cases, MIBI scintigraphy resulted in mismatch and intermediary results, but in only 4 (10.2%) of these cases was a carcinoma diagnosed. The negative predictive value of MIBI scintigraphy was 90–100%, respectively. Relying on the negative predictive value of MIBI match results might have obviated the need for surgery in 20.4% cases; one papillary microcarcinoma, however, would have been missed. MIBI scintigraphy has an underused potential for improving the diagnostic precision of hypofunctional thyroid nodules.

The role of frozen section biopsy for submandibular gland tumors

Background Although there have been several reports of the diagnostic accuracy of frozen section biopsy (FSB) for parotid gland tumors, few studies have focused on its diagnostic accuracy for submandibular gland tumors. Aim/objectives This study aimed to investigate the necessity of FSB with regard to its diagnostic accuracy for submandibular gland tumors (SGTs). Materials and methods About 42 SGT patients underwent both fine-needle aspiration cytology (FNAC) and FSB between 2005 and 2020. The results of FNAC and FSB were analyzed and compared with the final histological diagnoses. Results The respective sensitivity and specificity in detecting malignant tumors in 38 cases, excluding the four indeterminate FNAC cases, they were 0 and 97% for FNAC, and 100 and 97% for FSB. Considering the four indeterminate FNAC cases to be malignant, the respective sensitivity and specificity in detecting malignant tumors in the 42 cases were 50 and 92% for FNAC, and 100 and 95% for FSB. Conclusions and significance FSB may be useful for malignancy detection as a final histological diagnosis in cases that are diagnosed as benign or indeterminate by FNAC in SGTs.

Is it possible to eliminate the number of inappropriate thyroid surgeries combining scintigraphy and cytology?

Objective: Although fine needle aspiration cytology (FNAC) is the most reliable, safe and accurate method for the clinical management of abnormal thyroid nodules, 5%-15% of cases lead to indeterminate diagnoses and surgery is the recommended practice for them as they may be malignant. Nevertheless, the majority of cases with indeterminate cytology are benign, so the risk of unnecessary surgery is significant. In our study we combined FNAC and scintigraphy in order to reduce the number of inappropriate surgeries. Subjects and Methods: From 219 patients with thyroid fine needle aspiration cytology 33(9 males and 24 females) aged 18-73 years, had indeterminate FNAC diagnoses and were referred for scintigraphy. Surgery was performed in all cases. The results of FNAC, scintigraphy and histology were collected and compared. Results: From 33 cases with indeterminate cytology 32 had a benign histological diagnosis and only one was malignant (follicular Ca). That case had a positive scan. All cases with negative thyroid scans (29/33) were benign. False positive scans were 3, whereas one scan was true positive with final diagnosis follicular carcinoma. Conclusion: This study showed that combining the FNAC with the thyroid scintigraphy in cases of thyroid nodules with indeterminate cytology it is possible to reduce the number of inappropriate surgeries from 32 to 3.

Diagnostic Algorithm for Metastatic Lymph Nodes of Differentiated Thyroid Carcinoma.

Simple SummaryFine-needle aspiration cytology (FNAC) with measurement of thyroglobulin concentrations obtained through aspiration (FNA-Tg) is routinely used for the diagnosis of metastatic lymph nodes (LNs) from differentiated thyroid carcinomas. However, some areas of uncertainty remain, including the optimal FNA-Tg cutoff and its interpretation based on ultrasound (US) features. In this study, we evaluated the appropriate strategies for interpreting FNAC and FNA-Tg results based on the sonographic features of LNs. We confirmed that the malignancy rate of LNs found to be malignant by FNAC or elevated FNA-Tg was sufficiently high to be diagnosed as metastasis, regardless of the sonographic features. The malignancy rate of LNs with indeterminate or benign FNAC findings and low FNA-Tg were stratified according to their sonographic features. We propose a diagnostic algorithm, based on combined FNAC, FNA-Tg, and US features of LNs, for diagnosing metastatic LNs of differentiated thyroid carcinomas.We aimed to evaluate appropriate strategies for interpreting fine-needle aspiration cytology (FNAC) and thyroglobulin concentrations obtained through aspiration (FNA-Tg) results based on the sonographic features of lymph nodes (LNs). Consecutive patients who underwent ultrasound-guided FNAC and FNA-Tg for metastatic LNs from differentiated thyroid carcinomas (DTCs) from January 2014 to December 2018 were reviewed retrospectively. LNs were categorized sonographically as suspicious, indeterminate, or benign. The optimal FNA-Tg cutoff for metastatic LNs was evaluated preoperatively, after lobectomy, and after total thyroidectomy. The diagnostic performances of FNA-Tg, FNAC, and their combination were analyzed based on the sonographic features of LNs. The malignancy rates of LNs were analyzed based on the sonographic features, FNAC, and FNA-Tg results. Of the 1543 LNs analyzed, 528 were benign, whereas 1015 were malignant. FNA-Tg increased the sensitivity and accuracy of FNAC for LNs. The malignancy rate of LNs found to be malignant by FNAC or elevated FNA-Tg ranged from 82% to 100%, regardless of the sonographic features. The malignancy rate of LNs with indeterminate or benign FNAC findings and low FNA-Tg were stratified according to their sonographic features. We propose a diagnostic algorithm, based on combined FNAC, FNA-Tg, and ultrasound features of LNs, for diagnosing metastatic LNs of DTCs.

The outcomes and decision-making process for neck lymph nodes with indeterminate fine-needle aspiration cytology.

ObjectivesThis study aims to propose a cytological classification, to evaluate predictive factors of the final malignancy, and to suggest a proper management strategy for neck lymph nodes (LNs) with indeterminate cytology.MethodsPatients who had neck lymphadenopathy with indeterminate cytology between 2007 and 2017 were analyzed retrospectively in a tertiary medical center. Cytological classification was conducted according to the cytological descriptions. We examined the clinical characteristics according to the final diagnosis of the neck lymphadenopathy.ResultsAccording to the final diagnoses, there were 142 malignant and 95 benign neck LNs among 237 patients. Multivariate analyses using a stepwise logistic regression model showed that cytological classification [p < 0.001, OR = 5.67 (3.48–9.23)], prior history of malignancy [p = 0.01, OR = 2.97 (1.26–6.99)], long axis [p = 0.01, OR = 3.06 (1.33–7.06)], short-to-long axis (S/L) ratio [p = 0.047, OR = 2.15 (1.01–4.57)] and internal echogenicity [p = 0.01, OR = 2.72 (1.26–5.86)] were independent predictors of malignancy.ConclusionsIn patients who have neck LNs with indeterminate cytology, a cytological classification and four other predictors (prior history of malignancy, long axis ≥ 1.93 cm, S/L ratio ≥ 0.64 and heterogeneity of internal echogenicity) are statistically associated with the risk of malignancy and helpful in guiding further management.

BRAF V600E as an accurate marker to complement fine needle aspiration (FNA) cytology in the guidance of thyroid surgery in the Chinese population: evidence from over 1000 consecutive FNAs with follow-up.

Currently, several commercial molecular tests have been developed for reclassifying thyroid nodules with indeterminate fine needle aspiration cytology. These tests are quite expensive and not available in China. Previous studies demonstrated a very high prevalence of the BRAF V600E mutation in Asian people. A high incidence may result in a robust sensitivity. We conducted this study to determine the prevalence of BRAF V600E mutation and its ability to reclassify cytologically indeterminate thyroid nodules in the Chinese population. Between January 2016 and October 2018, consecutive patients who underwent a fine needle aspiration procedure and agreed to provide materials for molecular analysis in our hospital were recruited in this study. All were followed up until they had a thyroidectomy and a final pathological diagnosis or until January 2019 (those did not have surgery). A total of 1960 patients were included in this study. Until January 2019, 1240 patients underwent surgery. Using histopathological diagnosis as a gold standard, the overall sensitivity and specificity of the BRAF V600E mutational analysis for the discrimination of benign nodules from cancer in thyroid fine needle aspiration samples were 83.3% (81.0-85.3%) and 96.0% (77.7-99.8%), respectively, with an area under the ROC curve of 0.90 (95% CI 0.85-0.95, P<0.001). Among cases with indeterminate cytology, BRAF-positive cases were showing malignancy in the final pathology, and BRAF-negative cases were showing safer to be followed up. The BRAF V600E mutation is highly prevalent in the Chinese population and can accurately complement cytopathology in the guidance of thyroid surgery.Mini-abstract: The BRAF V600E mutation has both high specificity and sensitivity to predict thyroid malignancy in the Chinese population. It can accurately complement cytopathology in the guidance of thyroid surgery.

Analytical and clinical validation of pairwise microRNA expression analysis to identify medullary thyroid cancer in thyroid fine-needle aspiration samples.

BackgroundMedullary thyroid carcinoma (MTC) is an aggressive malignancy originating from the parafollicular C cells. Preoperatively, thyroid nodule fine‐needle aspiration cytology (FNAC) and pathogenic gene mutations are definitive in approximately one‐half of cases. MicroRNAs (miRNAs) are endogenous, noncoding, single‐stranded RNAs that regulate gene expression, a characteristic that confers the potential for identifying malignancy. In the current study, the authors hypothesized that differential pairwise (diff‐pair) analysis of miRNA expression levels would reliably identify MTC in FNA samples.MethodsThe relative abundance of 10 different miRNAs in total nucleic acids was obtained from ThyraMIR test results. Diff‐pair analysis was performed by subtracting the critical threshold value of one miRNA from the critical threshold values of other miRNAs. Next‐generation sequencing with the ThyGeNEXT panel identified oncogenic gene alterations. The discovery cohort consisted of 30 formalin‐fixed, paraffin‐embedded benign and malignant thyroid neoplasms, including 4 cases of MTC. After analytical validation, clinical validation was performed using 3 distinct cohorts (total of 7557 specimens).ResultsIn the discovery cohort, 9 diff‐pairs were identified as having significant power using the Kruskal‐Wallis test (P < .0001) to distinguish MTC samples from non‐MTC samples. The assay correctly classified all MTC and non‐MTC samples in the analytical validation study and in the 3 clinical validation cohorts. The overall test accuracy was 100% (95% confidence interval, 99%‐100%). In indeterminate FNAC samples, the sensitivity of the diff‐pair analysis was greater than that of the MTC‐specific mutation analysis (100% vs 25%; P = .03).ConclusionsPairwise miRNA expression analysis of ThyraMIR results were found to accurately predict MTC in thyroid FNA samples, including those with indeterminate FNAC findings.

Thyroid cytology smear slides: An untapped resource for ThyroSeq testing.

Molecular testing of thyroid nodules with indeterminate fine-needle aspiration (FNA) cytology is commonly used to guide patient management and is typically performed on freshly collected FNA samples. In this study, the authors evaluated the performance of the ThyroSeq test in cytology smear slides. Air-dried Diff-Quik (DQ)-stained and alcohol-fixed Papanicolaou (Pap)-stained smears were used to determine required cellularity and sensitivity of mutation detection and to compare ThyroSeq v3 Genomic Classifier (GC) results obtained in cytology smears and fresh FNA samples from the same nodules. ThyroSeq testing of 31 cytology smears revealed that 25 smears (81%) were adequate for ThyroSeq analysis, including 14 Pap-stained smears (100%) and 11 DQ-stained smears (65%), whereas 6 DQ-stained smears (35%) failed RNA sequencing. The overall accuracy for detecting molecular alterations was 98%, with 100% concordance for mutations and gene expression alterations, 96% concordance for fusions, and 94% concordance for copy number alterations. Cytology smears were adequate for ThyroSeq analysis when at least 200 to 300 cells were present in 1 to 3 slides. ThyroSeq detected all studied mutations down to 5% allele frequency and BRAF mutations down to 1% allele frequency. Testing of smears yielded a positive ThyroSeq GC result in all nodules originally classified as positive. Thyroid FNA cytology smear slides with adequate cellularity can be successfully used for ThyroSeq GC testing in approximately 80% of cases, with an even higher success rate in Pap-stained smears. Compared with FNA samples collected into preservative solution, 94% to 100% of different genetic alterations could be accurately detected in smears, validating cytology smears as an alternative for ThyroSeq testing in patients with indeterminate thyroid cytology.

MON-LB79 Do Ultrasound Patterns and Clinical Parameters Modify the Probability of Thyroid Cancer Predicted by Molecular Testing in Thyroid Nodules With Indeterminate Cytology?

Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further modify the risk of cancer in nodules predicted to be positive or negative by molecular testing remains unknown. Aim: To test if clinical parameters, including age, gender, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] system vs American College of Radiology TIRADS), radiation exposure, and family history of thyroid cancer (TC) can modify the probability of TC or NIFTP predicted by MT in thyroid nodules with indeterminate cytology. Methods: We studied 257 thyroid nodules from 10 study centers with fine-needle aspiration (FNA) yielding indeterminate cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression were used for data analysis. Results: In this group of thyroid nodules, out of all parameters studied using univariate regression, patient gender, age, and Bethesda category were significantly associated with TC/NIFTP probability (P<0.05 for each). The ATA US patterns showed a positive trend (P=0.1211), whereas TIRADS was not predictive (P=0.3135). A multivariate regression model incorporating the four most informative covariates (gender, age, Bethesda category, and ATA US patterns) (model #1) yielded a C index=0.653; R2=0.108. Male gender and Bethesda category V significantly increased risk, and age demonstrated a nonlinear risk profile. When TSv3 was added to model #1, the C index increased to 0.888; R2=0.572. However, age (P=0.341), Bethesda category (P=0.272), and the ATA US patterns (P=0.264) had limited predictive ability in comparison with TSv3, which dominated the predictive performance (P<0.001). Gender was the only parameter showing tendency for significance beyond MT (P=0.095). The most parsimonious model incorporated gender and TSv3 (C index=0.889; R2=0.588). Conclusions: While often useful in selecting thyroid nodules for FNA, neither the ATA US nor the TIRADS scoring systems were informative in further predicting TC/NIFTP in thyroid nodules with indeterminate FNA cytology. Although age and Bethesda category were associated with TC/NIFTP probability on univariate analysis, they had limited incremental value above the high predictive ability of TSv3. Gender was the only parameter with potential contribution to predicting TC/NIFTP in addition to MT.

Nuclear morphometry in indeterminate thyroid nodules.

Up to 30% of thyroid nodules undergoing fine needle aspiration (FNA) yield an indeterminate result. Recent research efforts have suggested that nuclear morphometry and morphology may enhance the diagnostic accuracy of FNA as an objective adjunct. We applied nuclear morphometric analysis on a diverse cohort of patients to evaluate the association between nuclear morphometry and malignancy. Forty-five randomly selected patients, who underwent thyroid surgery after an indeterminate FNA result (Bethesda III & IV) between 2012-2015, were reviewed. One hundred representative nuclei per FNA of a thyroid nodule were analyzed using ImageJ. Seven validated morphometric parameters were collected: nuclear area, perimeter, circularity, aspect ratio, roundness, and maximum/minimum Feret's diameter. L/S ratio was subsequently calculated. All 8 nuclear parameters were reported as averages with standard errors of the mean (SEM). A Student's t-test was used to assess the association of nuclear parameters with final surgical pathology. The mean age of all patients was 56.31±15.39 years, with female patients comprising 68.9% of the cohort. Twenty-two patients had malignant thyroid nodules. The mean perimeter of nuclei for the cohort was 18.48±0.45 µm, the mean area was 22.19±0.93 µm, and the mean maximum Feret's diameter was 6.67±0.13 µm. No significant differences in the 8 nuclear parameters were observed between the malignant and non-malignant groups. In the population examined, our results suggest that nuclear morphometry is not yet a tool of reliable diagnostic value in accessing malignant and non-malignant thyroid nodules. Further investigation is necessary to identify objective parameters that will enhance diagnostic accuracy of indeterminate FNA cytology to minimize the number of diagnostic thyroid surgery.

Preoperative serum thyroglobulin levels as a predictor of thyroid carcinoma

Background: Incidence of thyroid nodules varies according to the methods of diagnosis, 4-7% by palpation and 17-67% by high resolution ultrasound. The gold standard of diagnosis for thyroid nodules is fine needle aspiration (FNA); however, fine needle aspiration cytology (FNAC) alone is insufficient to detect cancer because of inadequate cytology (5-15%) and in cases of follicular neoplasm (15-25%) where only surgery is diagnostically conclusive. Therefore, other factors in addition to FNA should be considered to predict malignancy. This study was done to evaluate the association between elevated pre-operative thyroglobulin levels and histopathologically proven thyroid carcinoma.Methods: This retrospective study was conducted in Bowring and Lady Curzon Hospital, from December 2017 to November 2018. All patients above 18 years, undergoing total thyroidectomy, with normal antithyroglobulin levels and with indeterminate thyroid nodules or disease on FNAC were included. Patients proven to have malignancy by FNAC, who underwent hemithyroidectomy and patients with thyroglossal cyst or ectopic thyroid swellings were excluded.Results: A total of 50 patients were included. The Fischer’s exact test shows significant value of 0.037 and also the two-tailed test showed a p value &lt;0.05, hence it is significant to conclude that the mean value of thyroglobulin levels among histopathologically proven malignant thyroid cancers is significantly higher compared to the benign thyroid disease.Conclusions: In addition to thyroid-stimulating hormone, thyroid nodules with elevated thyroglobulin levels were independently associated with the presence of thyroid cancer; therefore, the evaluation of pre-operative thyroglobulin level in patients with indeterminate FNAC might give additional information to predict malignancy.

Computerized Cytological Features for Papillary Thyroid Cancer Diagnosis-Preliminary Report.

Fine needle aspiration cytology (FNAC) is the final diagnosis of thyroid nodules before surgery. It is important to further improve the indeterminate FNAC diagnosis results using computerized cytological features. This retrospective cross-sectional study included 240 cases, of whom 110 had histologic diagnosis of papillary thyroid cancers (PTC), 100 had nodular/adenomatous goiters/hyperplasia (benign goiters), 10 had follicular/Hurthle cell carcinomas, and 20 had follicular adenomas. Morphological and chromatic features of FNAC were quantified and analyzed. The result showed that six quantified cytological features were found significantly different between patients with a histologic diagnosis of PTC and patients with histologic diagnosis of benign goiters in multivariate analysis. These cytological features were used to estimate the malignancy risk in nodules with indeterminate FNAC results. The Area Under the Receiver Operating Characteristics (AUROC) of the diagnostic accuracy with a benign or malignant nature was 81.3% (p < 0.001), 78.7% (p = 0.014), and 56.8% (p = 0.52) for nodules with FNAC results of atypia, which is suspicious for malignancy and follicular neoplasm, respectively. In conclusion, quantification of cytological features could be used to develop a computer-aided tool for diagnosing PTC in thyroid nodules with indeterminate FNAC results.

Anti-Thyroid Antibodies and TSH as Potential Markers of Thyroid Carcinoma and Aggressive Behavior in Patients with Indeterminate Fine-Needle Aspiration Cytology.

Indeterminate fine-needle aspiration cytology (FNAC) imposes challenges in the management of thyroid nodules. This study aimed to examine whether preoperative anti-thyroid antibodies (Abs) and TSH are indicators of thyroid malignancy and aggressive behavior in patients with indeterminate FNAC. This was a retrospective study of thyroidectomy patients from 2008 to 2016. We analyzed Abs and TSH levels, FNAC, and histopathology. Serum antibody levels were categorized as 'Undetectable', 'In-range' if detectable but within normal range, and 'Elevated' if above upper limit of normal. 'Detectable' levels referred to 'In-range' and 'Elevated' combined. There were 531 patients included. Of 402 patients with preoperative FNAC, 104 (25.9%) had indeterminate cytology (Bethesda III-V). Of these, 39 (37.5%) were malignant and 65 (62.5%) benign on histopathology. In the setting of indeterminate FNAC, an increased risk of malignancy was associated with 'Elevated' thyroglobulin antibodies (TgAb) (OR 7.25, 95% CI 1.13-77.15, P = 0.01) and 'Elevated' thyroid peroxidase antibodies (TPOAb) (OR 6.79, 95% CI 1.23-45.88, P = 0.008). Similarly, while still 'In-range', TSH ≥ 1mIU/L was associated with an increased risk of malignancy (OR 3.23, 95% CI 1.14-9.33, P = 0.01). In all patients with malignancy, the mean tumor size was 8mm larger in those with TSH ≥ 1mIU/L (P = 0.03); furthermore, in PTC patients, 'Detectable' TgAb conferred a 4 × risk of lymph node metastasis (95% CI 1.03-13.77, P = 0.02). In this cohort, in indeterminate FNAC patients, Abs and TSH were associated with an increased risk of malignancy. Additionally, TgAb and TSH were potential markers of aggressive biology. As such, they may be diagnostic and prognostic adjuncts.