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Objective: The management of thyroid nodules with indeterminate cytology (ITN) is still a challenge. To evaluate the performance of commercial molecular tests for ITN, we performed this comprehensive meta-analysis. Methods: We performed an electronic search using PubMed/Medline, Embase, and the Cochrane Library. Studies assessing the diagnostic accuracy of Afirma gene expression classifier (GEC), Afirma gene sequencing classifier (GSC), ThyroSeq v2 (TSv2), or ThyroSeq v3 (TSv3) in patients with ITN (only Bethesda category III or IV) were selected; Statistical analyses were performed by using Stata. Results: Seventy-one samples (GEC, n = 38; GSC, n = 16; TSv2, n = 9; TSv3, n = 8) in 53 studies, involving 6490 fine needle aspirations (FNAs) with ITN cytology with molecular diagnostics (GEC, GSC, TSv2, or TSv3), were included in the study. The meta-analysis showed the following pooled estimates: sensitivity 0.95 (95% CI: 0.94-0.97), specificity 0.35 (0.28-0.43), positive likelihood ratio (LR+) 1.5 (1.3-1.6), and negative likelihood ratio (LR-) 0.13 (0.09-0.19), with the best performance for TSv3 (area under the ROC curve 0.95 (0.93-0.96), followed by TSv2 (0.90 (0.87-0.92)), GSC (0.86 (0.82-0.88)), and GEC (0.82 (0.78-0.85)); the best rule-out property was observed for GSC (LR-, 0.07 (0.02-0.19)), followed by TSv3 (0.11 (0.05-0.24)) and GEC (0.16 (0.10-0.28), and the best rule-in was observed for TSv2 (LR+, 2,9 (1.4-4.6)), followed by GSC (1.9 (1.6-2.4)). A meta-regression analysis revealed that study design, Bethesda category, and type of molecular test were independent factors. Conclusion: We showed that in patients with ITN, TSv3 has the best molecular diagnostic performance, followed by TSv2, GSC, and GEC. As regards rule-out malignancy, GSC, and rule-in, TSV2 is superior to other tests.

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RAS mutations are prevalent in indeterminate thyroid nodules, but their association with malignancy risk and utility for diagnosis remains unclear. We performed a systematic review and meta-analysis to establish the clinical value of RAS mutation testing for cytologically indeterminate thyroid nodules. PubMed and Embase were systematically searched for relevant studies. Thirty studies comprising 13,328 nodules met the inclusion criteria. Random effects meta-analysis synthesized pooled estimates of RAS mutation rates, risk of malignancy with RAS positivity, and histologic subtype outcomes. The pooled mutation rate was 31 % (95 % CI 19-44 %) among 5,307 indeterminate nodules. NRAS mutations predominated at 67 % compared to HRAS (24 %) and KRAS (12 %). The malignancy rate with RAS mutations was 58 % (95 %CI=48-68 %). RAS positivity increased malignancy risk 1.7-fold (RR 1.68, 95 %CI=1.21-2.34, p=0.002), with significant between-study heterogeneity (I2=89 %). Excluding one outlier study increased the relative risk to 1.75 (95 %CI=1.54-1.98) and I2 to 14 %. Funnel plot asymmetry and Egger's test (p=0.03) indicated potential publication bias. Among RAS-positive malignant nodules, 38.6 % were follicular variant papillary carcinoma, 34.1 % classical variant, and 23.2 % follicular carcinoma. No statistically significant difference in the odds of harboring RAS mutation was found between subtypes. In conclusion, RAS mutation testing demonstrates clinical utility for refining the diagnosis of cytologically indeterminate thyroid nodules. Positivity confers a 1.7-fold increased malignancy risk, supporting use for personalized decision-making regarding surgery vs. monitoring. Follicular variant papillary carcinoma constitutes the most common RAS-positive malignant histological subtype. See also the graphical abstract(Fig. 1).

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Background: Genomic profiling is now available for risk stratification of cytologically indeterminate thyroid nodules (ITNs). Mutations in RAS genes (HRAS, NRAS, KRAS) are found in both benign and malignant thyroid nodules, although isolated RAS mutations are rarely associated with aggressive tumors. Because the long-term behavior of RAS-mutant ITNs is not well understood, most undergo immediate surgery. In this multicenter retrospective cohort study, we characterize tumor growth kinetics of RAS-mutant ITNs followed with active surveillance (AS) using serial ultrasound (US) scans and examine the histopathologic diagnoses of those surgically resected. Methods: US and histopathologic data were analyzed retrospectively from two cohorts: (1) RAS-mutant ITNs managed with AS at three institutions (2010-2023) and (2) RAS-mutant ITNs managed with immediate surgery at two institutions (2016-2020). AS cohort subjects had ≥3 months of follow-up and two or more US scans. Cumulative incidence of nodule growth was determined by the Kaplan-Meier method and growth by ≥72% change in tumor volume. Pathological diagnoses for the immediate surgery cohort were analyzed separately. Results: Sixty-two patients with 63 RAS-mutated ITNs under AS had a median diameter of 1.7 cm (interquartile range [IQR] 1.2-2.6) at time of diagnosis. During a median AS period of 23 months (IQR 9.5-53.5 months), growth was observed in 12 of 63 nodules (19.0%), with a cumulative incidence of 1.9% (1 year), 23.0% (3 years), and 28.0% (5 years). Most nodules (81.0%) demonstrated stability. Surgery was ultimately performed in 6 nodules, of which 1 (16.7%) was malignant. In the cohort of 209 RAS-mutant ITNs triaged to immediate surgery, 33% were malignant (23.9% American Thyroid Association [ATA] low-risk cancers, 7.2% ATA intermediate-risk, and 1.9% ATA high-risk. During a median follow-up of 6.9 (IQR 4.4-7.1) years, there were no disease-specific deaths in these patients. Conclusions: We describe the behavior of RAS-mutant ITNs under AS and find that most demonstrate stability over time. Of the resected RAS-mutant nodules, most were benign; of the cancers, most were ATA low-risk. Immediate surgical resection of all RAS-mutant ITNs appears to be a low-value practice. Further research is needed to help define cases most appropriate for AS or immediate surgery.

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Active Surveillance is a non-invasive strategy designed to identify a minority of patients with low-risk papillary thyroid carcinoma who might experience clinical progression and benefit from additional definitive treatments. Global experience suggests that these tumors typically show minimal changes in size during active surveillance, often demonstrating very slow growth or even size reduction. Moreover, the rate of lymph node metastases is low and can be effectively managed through rescue surgery, without impacting cancer-related mortality. However, despite 30 years of experience demonstrating the safety and feasibility of active surveillance for appropriately selected patients, this approach seems to have limited adoption in specific contexts. This limitation can be attributed to various barriers, including disparities in access to accurate information about the indolent nature of this disease and the prevalence of a maximalist mindset among certain patients and medical settings. This review aims to revisit the experience from the last three decades, provide current insights into the clinical outcomes of active surveillance trials, and propose a systematic approach for its implementation. Furthermore, it intends to emphasize the importance of precise patient selection and provides new perspectives in the field.

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OBJECTIVES: Afirma has recently introduced its Xpression Atlas (XA) as an adjunct to its Genomic Sequencing Classifier (GSC) for risk stratification of cytologically indeterminate thyroid nodules. We evaluated the performance of Afirma XA and associated pathologic findings for Afirma GSC suspicious nodules. METHODS: Intradepartmental records of thyroid fine-needle aspirations (FNAs) from January 2021 to December 2022 were identified and reviewed for patient and nodule characteristics, FNA findings, molecular test results, and final surgical pathology, if available. RESULTS: Material for Afirma GSC testing was collected in 624 thyroid FNAs, and 148 (24%) were classified as cytologically indeterminate. Afirma GSC testing was successful in 132 (89%) of those cases, of which 35 (27%) were Afirma GSC suspicious. Afirma XA testing was positive in 11 cases (11/35 [31%]). Eight (73%) patients underwent surgery that revealed 7 patients with papillary thyroid carcinoma and 1 patient with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (risk of malignancy: 100% [8/8]). Among the 24 patients with negative Afirma XA results, 19 (79%) underwent surgery, revealing 5 patients with malignancy and 3 patients with NIFTP (risk of malignancy: 42% [8/19]). Overall, the risk of malignancy for Afirma GSC suspicious nodules was 59% (16/27). CONCLUSIONS: Afirma XA improved risk stratification of thyroid disease with a high risk of malignancy in Afirma GSC suspicious nodules. A negative Afirma XA result, however, should not be used as a rule-out test.

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Indeterminate thyroid nodules (ITNs) are characterized by an expected malignancy ranging from 5% to 30%, with most patients undergoing a diagnostic, rather than therapeutic, operation. The aim of our study was to compare the approach to ITNs across different regions of the world. In this retrospective, multicentric, international study, according to the WHO classification, we identified the South East Asian Region (SEAR), the Americas Region (AMR), the Eastern Mediterranean Region (EMR), the Europe Region (EUR), and the Western Pacific Region (WPR). One high-volume thyroid centre was included for each region. Demographic, preoperative, and pathologic data were compared among the different regions. Overall, 5737 patients from five high-volume thyroid centres were included in this study. We found that the proportion of ITNs over the global activity for thyroid disease was higher in the EUR (37.6%) than in the other regions (21.1-23.6%). In the EMR, the patients were significantly younger (with a mean of 43.1 years) than in the other regions (range, 48.8-57.4 years). The proportion of lobectomy was significantly higher in the WPR, where 83.2% (114/137) of patients received this treatment, than in the other regions, where lobectomies were performed in 44.1-58.1% of patients. The pathological diagnosis of malignancy was significantly higher in the SEAR centre, being over 60%, than in centres of the other regions, where it ranged from 26.3% to 41.3%. The occurrence of lymph node metastases was higher in the WPR (27.8%), AMR (26.9%), and EMR (20%) centres than in the EUR and SEAR centres, where it was lower than 10%. In summary, we found in our study different approaches and outcomes in the diagnosis and treatment of ITNs among countries. Overall, almost 60% of patients with ITNs who underwent surgery actually presented a benign disease, potentially undergoing an unnecessary operation.

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The management of cytologically indeterminate thyroid nodules remains debatable as their malignancy is difficult to establish. Most nodules have benign postoperative histology, but an accurate assessment of their proclivity for malignant transformation is crucial. Numerous studies have investigated the effects of various tools, including clinical, radiological, and cytological features, as well as biochemical and molecular markers, on the management of these heterogeneous nodules. Collectively, strategies aim to treat malignant nodules and avoid unnecessary surgery for asymptomatic benign nodules. Currently, no clear guidelines for the optimal management of cytologically indeterminate thyroid nodules exist to determine whether a conservative approach with long-term observation or surgical intervention should be selected. Thus, personalized approaches have been recommended. Large-scale multicenter prospective studies are needed to elucidate controversial issues. As this topic has not been comprehensively covered based on publications from the Gulf region, this review aims to shed light on remaining controversies.

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Although it is the gold standard for assessing the malignancy of thyroid nodules (TNs) preoperatively, the cytological analysis of fine-needle aspiration cytology (FNAC) samples results in 20-30% of cases in indeterminate lesions (ITNs). As two-thirds of these lesions will appear benign after diagnostic surgery, improved preoperative diagnostic methods need to be developed. In this pilot study, we evaluate if the metabolomic profiles of liquid-based (CytoRich®) FNAC samples of benign and malignant nodules can allow the molecular diagnosis of TNs. We performed untargeted metabolomic analyses with CytoRich® FNAC in a monocentric retrospective study. The cohort was composed of cytologically benign TNs, histologically benign or papillary thyroid carcinomas (PTCs) cytologically ITNs, and suspicious/malignant TNs histologically confirmed as PTCs. The diagnostic performance of the identified metabolomic signature was assessed using several supervised classification methods. Seventy-eight patients were enrolled in the study. We identified 7690 peaks, of which 2697 ions were included for further analysis. We selected a metabolomic signature composed of the top 15 metabolites. Among all the supervised classification methods, the supervised autoencoder deep neural network exhibited the best performance, with an accuracy of 0.957 (0.842-1), an AUC of 0.945 (0.833-1), and an F1 score of 0.947 (0.842-1). Here, we report a promising new ancillary molecular technique to differentiate PTCs from benign TNs (including among ITNs) based on the metabolomic signature of FNAC sample fluids. Further studies with larger cohorts are now needed to identify a larger number of biomarkers and obtain more robust signatures.

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Indeterminate thyroid nodules (ITN) represent 20-30% of biopsied nodules, with a 10-60% risk of malignancy. Molecular testing can stratify the risk of malignancy among ITNs, and subsequently reduce the need for unnecessary diagnostic surgery. We aimed to assess the performance of these molecular tests at a single institution. Patients with Bethesda III, IV, and V nodules with Afirma and Interpace Diagnostics genetic testing data from November 2013 to November 2021 were included. Three cohorts were formed, including GSC + XA, ThyGeNEXT + ThyraMIR, and GSC + GEC. Statistical analysis determined the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), diagnostic odds ratio (DOR), and accuracy of each type of testing. The PPV of nodules undergoing genetic testing by ThyGeNEXT + ThyraMIR (45.00%, 95%CI: 28.28-62.93%, p = 0.032) and GSC + XA (57.14%, 95%CI: 29.32-81.08%, p < 0.001) were superior to that of GEC + GSC (30.72%, 95%CI: 26.83-34.90%). The NPV was above 85% in all cohorts, suggesting overall suitable rule-out tests. The Afirma platform (GSC + XA) had the highest NPV at 96.97%. The overall accuracy for nodules undergoing ThyGeNEXT + ThyraMIR was 81.42% (95%CI: 73.01-88.11%, p < 0.001). A total of 230 patients underwent thyroidectomy, including less than 60% of each of the ThyGeNEXT + ThyraMIR and GSC + XA cohorts. Specifically, only 25% of patients in the GSC + XA cohort underwent surgery, considerably decreasing the rate of unnecessary surgical intervention. Sub-group analysis, including only patients with surgical pathology, found that PPV tended to be higher in the GSC + XA cohort, at 66.67% (95%CI: 37.28-87.06%), as compared to the ThyGeNEXT + ThyraMIR cohort, at 52.94% (95%CI: 35.25-69.92%). The Afirma genetic testing platform GSC + XA outperformed the other platforms with regards to both PPV and NPV and decreased the rate of surgery in patients with ITNs by 75%, significantly preventing unnecessary surgical intervention.

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Indeterminate follicular thyroid lesions (Thyr 3A and 3B) account for 10% to 30% of all cytopathologic diagnoses, and their unpredictable behavior represents a hard clinical challenge. The possibility to preoperatively predict malignancy is largely advocated to establish a tailored surgery, preventing diagnostic thyroidectomy. We analyzed the role of the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the lymphocyte-to-monocyte ratio (LMR) as prognostic factors of malignancy for indeterminate thyroid nodules. In patients affected by cytological Thyr 3A/3B nodules, NLR, PLR and LMR were retrospectively compared and correlated with definitive pathology malignancy, utilizing student's t-test, ROC analysis and logistic regression. One-hundred and thirty-eight patients presented a Thyr 3A and 215 patients presented a Thyr 3B. After the logistic regression, in Thyr 3A, none of the variables were able to predict malignancy. In Thyr 3B, NLR prognosticated thyroid cancer with an AUC value of 0.685 (p < 0.0001) and a cut-off of 2.202. The NLR results were also similar when considering the overall cohort. The use of cytological risk stratification in addressing the management of indeterminate thyroid nodules in patients is not always reliable. NLR is an easy and reproducible inflammatory biomarker capable of improving the accuracy of preoperative prognostication of malignancy.

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The detection of low-risk thyroid carcinoma has increased in recent decades, although disease-specific mortality remained without changes. The high prevalence of occult carcinomas in autopsy studies, and hence the underlying indolent course of this entity, prompted the emergence of active surveillance as an alternative approach to these tumors. This strategy aims to recognize the minority group of patients who will develop clinical progression and probably benefit from deferred surgery. Experience around the world has shown that during active surveillance these tumors are mostly unchanged in size, with very-slow growth and even a decrease in diameter. Moreover, the rates of lymph node metastases were low and easily handled by rescue surgery, and distant metastases have not been reported. Given the high prevalence of small thyroid carcinomas and the excellent outcomes for observation, active surveillance provides a safe and feasible alternative in properly selected patients with low-risk thyroid cancer.

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BACKGROUND: The preoperative diagnosis of cytologically indeterminate thyroid nodules (ITNs) is very challenging. In this study, we aim to provide an integrated risk assessment for thyroid nodules with indeterminate cytology to guide surgical decision-making, which includes results of blood tests, molecular tests, and repeat fine-needle aspiration biopsy (FNAB). METHODS: The study retrospectively included 265 ITNs between June 2019 and April 2022. According to our integrated risk assessment process that starts with blood testing, followed by supplementary DNA mutation detection on the first FNAB, and finally repeat FNAB, we divided the ITNs into high-risk and low-risk groups. Performance was evaluated with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the receiver operating characteristic curve (AUC), and the consistency between the risk evaluation and histological results. RESULTS: Of the 265 ITNs, 87 were included in the risk assessment process. The risk assessment had a sensitivity of 84.1%, specificity of 83.3%, PPV of 95.1%, NPV of 57.7%, and AUC of 0.837. The nodules with consistent results between the risk groups and histological outcomes, which included malignant cases in the high-risk group and benign cases in the low-risk group, accounted for 83.9% of all risk-assessed nodules. CONCLUSIONS: These data suggest that the integrated risk assessment might provide proper information for surgical decision-making in patients with ITNs.

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INTRODUCTION: Indeterminate thyroid cytology diagnoses are associated with intermediate risks of malignancy. Application of molecular testing (MT) to indeterminate specimens provides additional diagnostic and prognostic information. While a positive or suspicious MT result may prompt surgery, a negative MT result is associated with a low probability of cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features and approximates that of a benign cytology diagnosis. Furthermore, ThyroSeq v3 MT has a "currently negative" result for findings with the probability of cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear feature that is slightly greater than that for the negative ThyroSeq v3 MT result but less than 10%, suggesting active surveillance. In this report, we discuss a case of a patient for whom clinical, cytologic, and molecular surveillance led to timely surgery and management. CLINICAL DETAILS: A 53-year-old man with a thyroid isthmus nodule had a fine-needle aspiration cytology diagnosis of atypia of undetermined significance and a subsequent ThyroSeq v3 MT, which revealed an EIF1AX mutation and a "currently negative" MT result. Surveillance with additional fine-needle aspiration samples demonstrated concerning genomic alterations (fluctuating EIF1AX allelic frequency and a non-V600E BRAF mutation), culminating in the conversion to a positive MT result 3 years later. Resection revealed an encapsulated noninvasive, oncocytic solid subtype of papillary thyroid carcinoma with increased mitotic activity. CONCLUSION: The case is notable for clinical, cytologic, and molecular surveillance demonstrating sequential pathologic alterations in an indeterminate thyroid nodule with EIF1AX mutation, leading to timely resection of the neoplasm before invasion manifested.

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The risk of malignancy (ROM) of EIF1AX-mutated thyroid nodules has been theorized to be contingent on the position of the mutation within the gene and the presence of co-existing mutations. However, due to EIF1AX's low mutation frequency, sample sizes currently reported in the literature are too diminutive to appraise the clinical utility of molecular diagnostic testing. The objective of this study was to elucidate prognostic indicators of EIF1AX-mutated thyroid tumors and cancer aggressiveness by examining a large cohort of cytologically indeterminate thyroid nodules (CITNs) that underwent molecular testing and subsequent surgical resection. This is a multicenter study involving 764 subtotal and total thyroidectomy patients that underwent preoperative molecular testing at two quaternary care hospitals. A five-year retrospective review was performed on the 42 charts of patients that opted for surgery following a positive EIF1AX mutation on ThyroseqV3 results from January 2018 to May 2022. Patient demographics, cytopathology results, molecular testing results, and postoperative histopathology were reviewed. Of the 42 surgically resected nodules that harbored an EIF1AX mutation, 16 (38.1%) were benign, six (14.3%) were non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs) or well-differentiated thyroid neoplasms of uncertain malignant potential (WDT-UMPs), and 20 (47.6%) were malignant. An isolated EIF1AX mutation conferred a ROM of 47.6%, whereas the ROM for nodules with at least one additional molecular alteration was 72.7%. The ROM increased to 100% for nodules with at least one additional molecular alteration and the A113_splice site mutation. Six malignant nodules were aggressive, with five having variegated components of poorly differentiated thyroid carcinoma (PDTC). EIF1AX-mutated thyroid nodules are more susceptible to malignancy in the presence of the A113_splice site mutation and when co-mutated with RAS and/or TP53. This deleterious amalgam is associated with aggressive disease and renders these nodules PDTC. A preoperative molecular test finding of an EIF1AX mutation can be a useful tool for thyroid specialists to optimize clinical management.

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Thyroid nodules can be classified as benign, malignant, or indeterminate, the latter of which make up 10-30% of nodules. Radiofrequency ablation (RFA) has become an attractive and promising therapy for the treatment of benign thyroid nodules. However, few studies have investigated the safety and efficacy of RFA for the management of indeterminate thyroid nodules. In this study, 178 patients with thyroid nodules diagnosed as benign (Bethesda II) or indeterminate (Bethesda III/IV) by preoperative cytopathological analysis were included. Patients in the benign and indeterminate cohorts had similar thyroid nodule volume reduction rates at 65.60% and 64.20%, respectively (p = 0.68). The two groups had similar nodular regrowth rates, at 11.2% for benign nodules and 9.40% for indeterminate nodules (p = 0.72). A total of three cases of transient dysphonia were reported. RFA of indeterminate thyroid nodules was comparable to that of benign thyroid nodules in all parameters of interest, including volume reduction rate. To our best knowledge, our work is the first North American analysis comparing benign and indeterminate thyroid nodules and suggests RFA to be a promising modality for the management of indeterminate thyroid nodules.

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OBJECTIVES: To estimate the risk of malignancy in indeterminate thyroid nodules and to determine whether certain clinical or radiological parameters can predict the risk of malignancy. METHODS: This retrospective study enrolled all adult patients (age ≥14 years) with a cytological diagnosis of atypia/follicular lesion of undetermined significance and follicular neoplasm/suspicious for a follicular neoplasm between January 2014 and January 2020. Fifty patients with surgically treated primary thyroid nodules, documented final histological diagnosis, and ultrasound examination records were included. Thyroid nodules were evaluated radiologically using Thyroid Imaging Reporting and Data System introduced by the American College of Radiology (2017). RESULTS: Forty-two (84.0%) female and 8 (16.0%) male patients were enrolled in the study. The malignancy risks were 44.8% for Bethesda III and 28.6% for Bethesda IV. The malignancy risks for the Thyroid Imaging Reporting and Data System categories were 33.3% (TR2), 39.1% (TR3), 35.3% (TR4), and 50% (TR5). No significant associations were observed between age, gender, Bethesda category, and Thyroid Imaging Reporting and Data System and the risk of malignancy. CONCLUSION: None of the clinical or radiological characteristics evaluated in this study contributed to the cancer risk stratification of thyroid nodules with indeterminate cytology. A prospective multicenter study is needed to better understand cytologically indeterminate thyroid nodules.

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Pregnancy-associated plasma protein A (PAPPA) acts as an oncogene, and its expression is increased in multiple malignancies, including thyroid cancer. Molecular tests represent a useful tool in the management of indeterminate thyroid nodules; however, they are not conducted in all centers, and they contribute to increase the per-patient cost of nodule evaluation. In this study, we examined whether PAPPA expression could represent a promising new screening test in the management of indeterminate thyroid nodules. Toward this aim, PAPPA expression was evaluated in 107 fine needle aspiration cytologies (FNAC) belonging to Bethesda III-IV categories that had been sent to molecular biology to discriminate the nature of the nodules. We found that the PAPPA expression increased and showed an elevated sensitivity (97.14%) and negative predictive value (98%) in indeterminate cytological samples positive for mutations. The enhanced expression was not linked to a specific oncogene. Our findings demonstrated that assessing the PAPPA expression in indeterminate thyroid cytologies could represent a useful screening tool to select all patients that effectively need to be sent to molecular testing, thereby, leading to a potential cost reduction in the management of patients.

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Molecular testing of indeterminate thyroid nodules informs about the presence of point mutations, insertions/deletions, copy number variants, RNA fusions, transcript alterations and miRNA expression. American Thyroid Association (ATA) guidelines suggest molecular testing of indeterminate thyroid nodules may be considered to supplement risk of malignancy (ROM). Although these recommendations have been incorporated in clinical practices in the United States, molecular testing of indeterminate thyroid nodules is not common practice in Asia. Here, we performed molecular testing of 140 indeterminate nodules from Chinese patients using a novel molecular platform composed of RNA and DNA-RNA classifiers, which is similar to Afirma GEC and ThyroSeq v3. Compared with reports from North America, the new RNA and DNA-RNA classifiers had a higher positive predictive value (p1 = 0.000 and p2 = 0.020) but a lower negative predictive value (p1 = 0.004 and p2 = 0.098), with no significant differences in sensitivity (p1 = 0.625 and p2 = 0.179) or specificity (p1 = 0.391 and p2 = 0.264). Out of 58 resected nodules, 10 were borderline and 33 malignant, indicating a 74.1% ROM, which was higher than reports in North America (10-40% ROM). Our findings emphasize molecular testing with the newly reported RNA and DNA-RNA classifiers can be used as a 'rule-in' test when ROM is high.

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INTRODUCTION: Hürthle cells are modified follicular thyroid cells, whose development and proliferation have been related to different stimuli inducing cellular stress. Most thyroid aspirates containing Hürthle cells are classified as indeterminate, although the specific risk of malignancy for this subtype of atypia remains unclear. The aim of our study was to assess if the presence of Hürthle cells in indeterminate thyroid nodules correlates with the risk of malignancy. We further evaluated if this risk can be modified by the presence of an underlying Hashimoto's thyroiditis. MATERIALS AND METHODS: We retrospectively analyzed all indeterminate thyroid nodules that were surgically treated at our institution between January 2010 and March 2019. For each nodule, we inferred the presence of Hürthle cells in the cytological report. Cytological findings were then correlated with histological reports. RESULTS: 354 indeterminate thyroid nodules were included in the study. The rate of malignancy resulted significantly lower in nodules exhibiting Hürthle cells compared to those negative for this cellular pattern (11.4% vs 22.5%, p = 0.01). Although there was no difference in the rate of malignancy in the whole population according to the presence or absence of Hashimoto's thyroiditis (21.5 vs 18.5%, p = 0.63), the significantly lower prevalence of malignant lesions in nodules with Hürthle cells was confirmed only in the presence of a histologically documented Hashimoto's thyroiditis (6.2% vs 32%, p = 0.005). CONCLUSIONS: The finding of Hürthle cells in indeterminate thyroid nodules is associated with a low risk of malignancy in patients with an underlying Hashimoto's thyroiditis. The clinical management of these lesions may therefore be more conservative.

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OBJECTIVE: To analyze the association of clinical, anatomical, and ultrasound (US) characteristics of malignancies in Bethesda III or IV (III-B or IV-B) thyroid nodules. METHODS: The association between malignancies and the following variables were analyzed: III-B or IV-B, age < 55 years and ≥ 55 years, sex, family history of thyroid cancer, history of irradiation, nodule size, and ACR TI-RADS classification in 62 participants who underwent thyroidectomy. RESULTS: Of the 62 participants, 87.1% (54/62) were women, 74.2% were < 55 years old, 95.2% had no family history of thyroid cancer, 56.5% had nodules < 2 cm in size, 62.9% were IV-B, and 69.4% were ACR TI-RADS 4. Thirty-two patients had thyroid carcinoma, and 30 had benign histology. Among all factors associated with malignancy, only ACR TI-RADS 5 classification on US was found to be statistically significant (p = 0.014), while III-B with architectural atypia cytological classification was the only one significantly associated with benign status (p = 0.004). CONCLUSION: Only a high risk of malignancy as assessed using US was able to refine the indication for molecular tests in a group of patients with indeterminate nodules. We found 85% (53/62) of III-B or IV-B thyroid nodules would benefit from available molecular diagnostic tests.

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