Bethesda Class Research Articles

Unique Molecular Signatures Are Associated with Aggressive Histology in Pediatric Differentiated Thyroid Cancer.

Background: Molecular testing (MT) enhances the diagnostic accuracy of thyroid fine-needle aspiration biopsy, reducing the need for diagnostic lobectomy in adult patients with indeterminate nodules (Bethesda class III/IV). However, little is known about genetic alterations in pediatric thyroid carcinoma (TC). Our aim was to analyze MT results of pediatric differentiated TC (DTC) cases to determine associations with histological and clinical features. Methods: A retrospective review identified all patients (aged <19 years) diagnosed with DTC from 2001 to 2017 at the University of Pittsburgh Medical Center. Histology was rereviewed to confirm diagnosis and identify tissue for MT using next-generation sequencing (ThyroSeq, version 3, TSv3). Correlation with histological and clinical features was analyzed using regression analysis. Results: Of 71 patients with MT results, 62 (87%) patients had papillary TC. All patients were alive at a median follow-up of 6 years (range 18 days to 18 years). Genetic alterations were identified in 65 (92%) patients. These alterations were grouped as BRAF-like point mutations or fusions (39, 55%), RAS-like mutations or fusions (21, 30%), or copy number alterations (5, 7%). On multiple regression analysis accounting for patient sex and tumor size in patients with papillary TC, increased tumor stage (β: 0.234, p < 0.001), multifocal disease (odds ratio [OR]: 3.60, p = 0.042), and lymph node metastases (OR: 6.13, p = 0.044) were associated with BRAF-like gene fusions. When considering individual mutations, ETV6/NTRK3 fusions were associated with increased tumor stage (β: 2.07, p = 0.023) and BRAF-like point mutations were associated with increased likelihood of surgery for recurrence over time (hazard ratio: 19.5, p = 0.004). Conclusions: Among our cohort of pediatric TC patients who underwent comprehensive MT, >90% had an identifiable genetic alteration. Aggressive features were primarily associated with BRAF-like gene fusions. Preoperative MT results may be useful in guiding the extent of the initial operation in pediatric patients (aged <19 years) with TC.

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.

Malignancy Rate of Bethesda Class III Thyroid Nodules Based on the Presence of Chronic Lymphocytic Thyroiditis in Surgical Patients.

BackgroundHashimoto’s thyroiditis (HT), also known as chronic lymphocytic thyroiditis (CLT), may interfere with the accurate cytological diagnosis of thyroid nodules. Recently, HT has been considered a premalignant condition for thyroid cancer development. The diagnosis of atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS) thyroid nodules is challenging and evidence for the malignancy risk of AUS/FLUS thyroid nodules coexisting with CLT is scarce. Therefore, we assessed the malignancy risk of AUS/FLUS thyroid nodules according to the presence of background CLT.MethodsThis study included 357 surgically resected thyroid nodules with AUS/FLUS cytology. Cases with concomitant malignant nodules were excluded. CLT was defined based on the pathologic report after thyroid surgery.ResultsAmong 357 tumors, 130 tumors (36%) were confirmed to have coexisting CLT, and 170 tumors (48%) were determined to be malignant after thyroidectomy. Malignancy rates were similar in both groups (48% in each) regardless of background CLT (62/130 with CLT vs. 108/227 without CLT). In the group with CLT, thyroiditis was more frequent in the final pathology (12% with CLT vs. 1% without CLT, P = 0.003). In multivariate analysis, positive BRAF V600E mutation, highly suspicious sonographic features (K-TIRADS 5), and smaller thyroid nodules were significant factors for thyroid malignancies.ConclusionThe malignancy rate of thyroid nodules with AUS/FLUS cytology was comparable irrespective of the presence of underlying CLT.

Yield and costs of molecular diagnostics on thyroid cytology slides in the Netherlands, adapting the Bethesda classification.

ObjectiveTo evaluate our institutional experience with molecular diagnostics (MD) on thyroid cytology smears, evaluate the costs and describe MD guided clinical management of indeterminate Bethesda III/V thyroid nodules.MethodsWe performed a retrospective review of 164 Bethesda III or V thyroid cytopathology reports subjected to MD from 2013 to 2020, that altered Bethesda classification or management. MD consisted of mutation and gene fusion analysis by next‐generation sequencing (NGS) of morphologically analysed and selected cytological slides. Findings were modelled to nationwide data on Bethesda incidences from ‘the Dutch Pathology Registry’ PALGA, and costs were estimated.Results82 of 164 cases received an upgrade in Bethesda class. Twenty cases changed from Bethesda III to IV/V, 62 from Bethesda III or V to VI, and 72 remained unaltered. We estimate net savings with implementing MD, by preventing 454 repeat cytology and 326 (diagnostic) hemithyroidectomies, to be at least 2 million Euro annually in the Netherlands. Per Bethesda III and V patient, net savings would be about 100 Euro and 4100 Euro, respectively.ConclusionNGS‐based MD on nucleic acids extracted directly from cytology slides is a feasible and cost saving tool for personalized management in indeterminate Bethesda III/V thyroid cytology. Based on the interpretation of our retrospective data, we assume that this approach results in less disease burden for the patient, reduced surgical interventions and complication risks, reduced sick leave, among others. Further evaluation of structural implementation of the presented approach in routine thyroid Bethesda III/V cytology in a prospective setting is warranted.

Occurrence of sporadic medullary thyroid carcinoma in Graves’ disease in association with a RET proto-oncogene mutation

ABSTRACT Background Graves’ disease may be associated with thyroid cancer, particularly differentiated thyroid cancer. Medullary thyroid cancer (MTC) is less common. The occurrence of sporadic MTC in Graves’ disease in the presence of a RET proto-oncogene has never been reported. Clinical presentation A 63-year-old woman was referred for Graves’ disease. A thyroid ultrasound disclosed five nodules, one of which was classified as Eu-Tirads 5 with a size of 6.7 × 6.5× 11 mm. Fine needle aspiration was reported as Bethesda class IV follicular neoplasm of a Hürthle cell subtype. Calcitonin level was found to be elevated. A total thyroidectomy confirmed the diagnosis of MTC and a bilateral cervical lymphadenectomy was performed, with four lymph nodes being infiltrated by MTC. Genetic testing revealed a M918T mutation in the RET proto-oncogene. Conclusion MTC may occur in Graves’ disease, especially if a nodule is present. In this case, genetic testing should always be performed even if MTC is sporadic. Increased incidence of thyroid cancer in autoimmune thyroid diseases, as well as the link existing between autoimmunity, inflammation and carcinogenesis, leads us to hypothesize that the association here reported is not coincidental.

Treatment Choices in Managing Bethesda III and IV Thyroid Nodules: A Canadian Multi-institutional Study.

ObjectivePatient-centered decision making is increasingly identified as a desirable component of medical care. To manage indeterminate thyroid nodules, patients are offered the options of surveillance, diagnostic hemithyroidectomy, or molecular testing. Our objective was to identify factors associated with decision making in this population.Study DesignThis is a retrospective cross-sectional study of patients with Bethesda III and IV thyroid nodules.SettingMulti-institutional.MethodsFactors of interest included age, sex, socioeconomic status (SES), nodule size, institution, attending surgeon, surgeon payment model, and hospital type. Our outcome of interest was the initial management decision made by patients.ResultsA total of 956 patients were included. The majority of patients had Bethesda III nodules (n = 738, 77%). A total of 538 (56%) patients chose surgery, 413 (43%) chose surveillance, and 5 (1%) chose molecular testing. There was a significant variation in management decision based on attending surgeon (proportion of patients choosing surgery: 15%-83%; P≤.0001). Fee-for-service surgeon payment models (odds ratio [OR], 1.657; 95% CI, 1.263-2.175; P < .001) and community hospital settings (OR, 1.529; 95% CI, 1.145-2.042; P < .001) were associated with the decision for surgery. Larger nodule size, younger patients, and Bethesda IV nodules were also associated with surgery.ConclusionWhile it seems appropriate that larger nodules, younger age, and higher Bethesda class were associated with decision for surgery, we also identified attending surgeon, surgeon payment model, and hospital type as important factors. Given this, standardizing management discussions may improve patient-centered shared decision making.

Diagnostic utility of fine needle aspiration cytology in pediatric thyroid nodules based on Bethesda Classification.

The Bethesda system for reporting cytopathology (TBSRTC) has been widely adopted in the management of thyroid nodules. Based on the limited pediatric data available, the implied malignancy risk for each of thecategories may be significantly different in pediatrics vs. adults, especially in the indeterminate categories (Bethesda Class III or IV). We report the diagnostic utility of fine needle aspiration (FNA) biopsy at our institution based on the Bethesda system and the risk of malignancy in each category. We retrospectively reviewed all patients who underwent a thyroid FNA at our tertiary pediatric hospital from 12/1/2002 to 11/30/2018. FNA results were classified according to TBSRTC. Patient demographics, cytology, histopathology, radiological and clinical follow-ups were examined. A total of 171 patients were included with 203cytological samples. Average age at initial FNA was 14.7 years (range 6.9-18.6 years). The numbers of nodules reported for Bethesda categories I-VI were 29, 106, 22, 14, 6 and 26, respectively, and the rate of malignancy was: 13.8,4.7, 22.7, 35.7, 83.3 and 100%, respectively. Use of ultrasound guidance reduced the non-diagnostic rate from 38.1 to 11.5%. Introduction of on-site adequacy testing further reduced the non-diagnostic rate to 6.5% since 2014. The risk of malignancy for thyroid nodules inthis pediatric cohort is higher than reported in adults. However, rates described here are much closer to adult ranges than previously published pediatric cohorts. The addition of adequacy testing improved the non-diagnostic rate of FNA procedures performed with ultrasound guidance.

Thyroid Oncocytic Cell in Cytological and Histologic Reports: Institutional Experience

Purpose: Oncocytic cell tumors, due to historical and clinical reasons, tend to be put in a higher risk category compared with other cell type tumors. We tried to define the malignancy risk for this entity. Methods: At our institution, we studied the risk of malignancy associated with a cohort of 107 thyroid nodules aspirates containing oncocytic cells in the cytology report and we have further analyzed other clinical factors. Results: A tendency for higher risk of malignancy in male sex was found (31.3% vs. 15.4% in women), the difference, however, was not statistically significant (P = 0.291). Total thyroidectomy was the preferred surgical approach and only 10.3% of patients were submitted to lobectomy. Histopathology reports documented 46.7% hyperplastic/adenomatoid nodules, 31.8% adenomas, 12.1% papillary carcinoma, 3.7% oncocytic cell carcinoma, 2.8% lymphocytic thyroiditis and 1.9% poorly differentiated carcinoma. Benign nodules (Bethesda Class II) exhibited a 9.7% malignancy risk; Class III exhibited a 20% malignancy risk; Class IV exhibited a 18.4% malignancy; Class V exhibited a 16% malignancy risk and Class VI exhibited a 100% malignancy risk. Overall histologic data from the aspirated nodules showed a risk of malignancy of 17.8%. Conclusion: Our study seems to suggest that in the presence of oncocytic cells there may be a tendency for a higher than expected malignancy rate. Clinical factors appear to be insufficient to base our management decisions with confidence and molecular markers are still under development. Therefore, surgery may stand as the favored option in this setting.

Incidence, Clinical Characteristics, and Histopathological Results of Atypia of Undermined Significance in a Tertiary Center in UAE

Introduction: Bethesda classification of thyroid nodules cytology is an agreed upon method of classifying thyroid nodules according to risk of malignancy. Among them, Bethesda class III (Atypia of Undetermined Significance, AUS) has been a topic of great controversy. The reported estimated risk of malignancy associated with it varies in different studies. Our study investigates the associated incidence of malignancy in a single tertiary center in UAE. Methodology: Data were retrospectively collected over a 10-year period from January 2009 till December 2018 for cytology diagnosis of AUS. Patient charts were reviewed for method of management. Surgical and histopathology records were reviewed to compare findings on cytology versus histopathology. Results: A total of 180 cases were diagnosed Bethesda III (AUS) with a mean age of 45.09 ± 14.7 years. One hundred cases (55.6%) of them underwent surgical resection, and histopathological diagnosis was obtained. Among the operated cases, 46 were benign and 54 were malignant. Papillary thyroid cancer was the most common malignancy, seen in 39 (72.2%) of cases, and follicular cancer was the second most common, seen in 13 (24.1%) cases. Conclusion: The findings highlighted in our study suggest a higher incidence of malignancy in Bethesda III category than previously reported. It also puts in question the utility and benefit behind keeping a time gap and repeating FNA as previously recommended.

Maternal and neonatal complications in women with congenital heart disease: results from a nationwide analysis including 7,231 pregnancies

Abstract Background The number of adult patients with congenital heart disease (ACHD) is increasing. Many ACHD women aim to start a family and require adequate pre-pregnancy counselling and pregnancy care. Limited population-based data on maternal and neonatal outcome and complications are available. Purpose We analysed the association between ACHD and maternal or neonatal outcomes based on data from one of the largest German Health Insurance Companies (approx. 9 million members). All pregnancies in women with ACHD and an age-matched non-congenital control group were included. The data covered all pregnancies and deliveries (in and out of hospital) between 2005 and 2018. Results The study population comprised 25,528 ACHD patients of childbearing age. Overall, 7,231 pregnancies occurred in 3,868 ACHD women (mean age at delivery 30.7±5.4 years). An age matched group of 6,513 women without ACHD (11,247 pregnancies, mean age 30.0±5.6 years) served as controls. Miscarriages/abortions occurred in 2,501 (34.6%) and 3,586 (31.9%) cases in the ACHD and non-ACHD cohort, respectively. Overall, there were 4,551 successful deliveries (99.5% in hospital) and 59 stillbirths in ACHD patients. Cesarean deliveries (CS) were significantly more common in ACHD patients (40.4% vs. 31.5% in the control group; p&amp;lt;0.0001) and the CS rate increased with disease complexity (Bethesda class I/II/III: 39.2/42.3/44.4%; p=0.035). There was one successful maternal resuscitation in each group, but no maternal deaths during pregnancy and up to 90 days postpartum. ACHD patients had a higher rate of maternal cerebral complications (1.0% vs. 0.17%; p&amp;gt;0.0001) compared to the control group. Neonatal mortality was low but significantly higher in the ACHD group (0.76% vs. 0.22% within the first 30 days of life; p&amp;lt;0.0001). Neonates to ACHD mothers were also significantly more often afflicted by low or extremely low birth weight or extreme immaturity (p&amp;lt;0.0001), and required resuscitation (1.04% vs. 0.34%; p&amp;lt;0.0001), mechanical ventilation (8.7% vs. 3.5%; p&amp;lt;0.0001) or blood transfusions (3.11% vs. 1.08%; p&amp;lt;0.0001) significantly more often compared to offspring from non-ACHD mothers. In addition, recurrence of congenital heart disease was 6.1 times higher in infants to ACHD mothers compared to controls (p&amp;lt;0.0001). Overall, 5.87% of all children born to ACHD mothers required cardiac surgical procedures in the first 6 years of life compared to only 0.39% of children to non-ACHD mothers (p&amp;lt;0.0001). Conclusion Our analysis confirms that maternal morbidity and neonatal morbidity and mortality are significantly increased in women with ACHD and their offspring compared to non-ACHD controls. Although, maternal mortality appears limited in high resource health care systems, the elevated maternal complication rate and particularly the high mortality and complication rate in neonates justifies specialized care to address specific risks and requirements of the condition. Funding Acknowledgement Type of funding source: None

Additional Surgery for Occult Risk Factors After Lobectomy in Solitary Thyroid Nodules is Predicted by Cytopathology Classification and Tumor Size

Clinical practice for differentiated thyroid cancer is moving towards lobectomy rather than total thyroidectomy in patients at low risk of recurrence. However, recurrence risk assessment depends on post-operative findings, while the surgical decision is based on preoperative factors. We determined the preoperative predictors of occult higher-risk pathology and rates of completion thyroidectomy among surgical candidates with nonbenign thyroid nodules 10 to 40 mm and no evidence of extrathyroidal extension or metastasis on preoperative evaluation. Thyroid surgery cases at a single institution from 2005-2015 were reviewed to identify those meeting American Thyroid Association (ATA) criteria for lobectomy. ATA-based risk stratification from postoperative surgical pathology was compared to preoperative cytopathology, ultrasound, and clinical findings. Of 1,995 thyroid surgeries performed for nonbenign thyroid nodules 10 to 40 mm, 349 met ATA criteria for lobectomy. Occult high-risk features such as tall cell variant, gross extrathyroidal invasion, or vascular invasion were found in 36 cases (10.7%), while intraoperative lymphadenopathy led to surgical upstaging in 13 (3.7%). Intermediate risk features such as moderate lymphadenopathy or minimal extrathyroidal extension were present in an additional 44 cases. Occult risk features were present twice as often in Bethesda class 6 cases (35%) as in lower categories (12 to 17%). In multivariable analysis, Bethesda class and nodule size, but not age, race, sex, or ultrasound features, were significant predictors of occult higher-risk pathology. Most solitary thyroid nodules less than 4 cm and with cytology findings including atypia of undetermined significance through suspicious for papillary thyroid cancer would be sufficiently treated by lobectomy. ATA = American Thyroid Association; CND = central neck dissection; DTC = differentiated thyroid cancer; ETE = extrathyroidal extension; FNA = fine needle aspiration; FTC/HCC = follicular thyroid carcinoma/Hurthle cell carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; OR = odds ratio; PTC = papillary thyroid cancer; US = ultrasound.

Artificial Intelligence plus Human Interpretation for Thyroid Nodule Risk Stratification: An Image Similarity Model Keeps the Physician in the Loop

Artificial Intelligence plus Human Interpretation for Thyroid Nodule Risk Stratification: An Image Similarity Model Keeps the Physician in the Loop

Risk Stratification of Thyroid Nodules with Bethesda III Category: The Experience of a Territorial Healthcare Hospital.

BackgroundThe Bethesda System for Reporting Thyroid Cytolopathology (TBSRTC) is the standardized category-based reporting system for thyroid nodule (TN) aspirations; however, atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda category III, AUS/FLUS) is the most controversial category. The aim of this study was to identify the degree of malignancy risk and the related risk factors in the surgical pathology of the Bethesda Category III thyroid nodules. MethodsA total of 4074 patients (15-90 years, 81.5% of females) were subjected to retrospective analysis, and a total of 463 nodules were classified as Bethesda Class III and included in the analysis. Once all the thyroid cytopathological slides and ultrasound (US) reports were reviewed, they were classified according to the Bethesda System for Reporting Thyroid Cytology, the American College of Radiology (ACR) and the Thyroid Imaging Reporting and Data System (TI-RADS).ResultsAmong the 463 Bethesda class III nodules, 167 nodules were surgically excised, showing an overall malignancy of 27.6% (n = 46/167). Patients having thyroid-stimulating hormone (TSH) levels of >4.5 mIU/L (35%), TN <2 cm (34.6%), solid or nearly solid (28.7%), highly hypoechoic (58.3%), longer than wide (50%), lobulated (45.5%), punctate echogenic (48.6%), ACR TI-RAD 5 (55.2%) and falling under the ATA category of high suspicion (50%), displayed a higher risk of malignancy (ROM). The chi-square test revealed a strong association between the echogenicity, echogenic foci, ACR TI-RAD and American Thyroid Association (ATA) category between the malignant and benign nodules. The papillary thyroid carcinoma (PTC) follicular variant (39%) and PTC classical (27%) were identified, in this study population, as the commonest forms of thyroid cancer.ConclusionThe nodules with AUS/FLUS cytology malignancy rate are comparable with the earlier estimations of other countries. The ACR TI-RAD displayed more accurate diagnostic performances in predicting malignancy in the Bethesda III nodules. However, to confirm the accuracy of the molecular marker tests in specific cytological scenarios, more extensive studies are required in the future.

Malignancy rates for Bethesda III and IV thyroid nodules: a retrospective study of the correlation between fine-needle aspiration cytology and histopathology

BackgroundFine-needle aspiration cytology (FNAC) has become a well-established modality in the diagnosis, staging and follow-up of thyroid nodules. FNAC outcomes are routinely classified using the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), facilitating appropriate clinical management. Bethesda categories III and IV encompass varying risks of malignancy. This retrospective study established a possible association between these cytological categories and malignancy rates in patients treated at a single institution.MethodsOver a 6-year period, 11,627 FNAC procedures were performed on thyroid nodules. Of these, 814 (59.63%) patients were submitted to thyroidectomy. The nodules of 108 patients were classified as Bethesda category III and 47 patients as Bethesda category IV. Patient data were reviewed to establish a correlation between the FNAC results and the final histopathological analyses.ResultsThe rates of malignancy among patients who underwent surgery were 25% for category III and 27.6% for category IV, with no significant differences between categories (p = 0.67). The pathological parameters of malignant nodules, namely tumour type, size, encapsulation, invasion into the thyroid capsule, extrathyroidal extension and lymphovascular invasion did not significantly differ between the groups (p > 0.05).ConclusionsThis paper provides a more precise correlation of malignancy rates with thyroid nodules classified as Bethesda categories III and IV, as our findings are comparable to the literature, giving malignancy rates ranging from 10 to 30% for category III and 25–40% for category IV. Use of the BSRTC is heterogeneous across institutions, and there is some degree of subjectivity in the distinction between categories III and IV; therefore, it is crucial to estimate the rates of malignancy at each institution. Molecular assays are of increasing importance in determining the need for surgical intervention for thyroid lesions. Gene expression assays using FNAC material may demonstrate a high predictive value for cytologically indeterminate thyroid nodules diagnosed as Bethesda classes III and IV.

Ultrasound-guided fine-needle aspiration or core needle biopsy for diagnosing follicular thyroid carcinoma?

We evaluated the preoperative diagnostic values of ultrasound (US), fine-needle aspiration (FNA) and core needle biopsy (CNB) leading to surgery in patients with FTC. From October 1994 to July 2016, 298 patients with FTC who had preoperative US images and underwent US-guided FNA or CNB and surgery were included in this study. We evaluated the results of preoperative FNA or CNB based on the Bethesda system and the US findings according to the Korean thyroid imaging reporting and data system (K-TIRADS). Predominant US features of FTC showed solid, hypo- or iso-echogenicity, oval smooth margin and halo with no calcification. Based on K-TIRADS, 140 (47.0%) patients with FTC were categorized as low suspicion, 133 (44.63%) as intermediate suspicion and 25 (8.4%) as high suspicion at US. Considering only FNA cytology (n=230), 6.9% were revealed as Bethesda class I, 16.1% as class II, 37.0% as class III, 29.1% as class IV and 10.9% as class V. Considering the 68 cases with CNB results, 2.9% were revealed as class I, 4.4% as class II, 20.6% as class III and 72.1% as class IV. Despite multiple FNAs, 16.7% of the 84 patients with FTC still obtained Bethesda class I or class II. CNB results in patients with FTC had a significantly higher rate of Bethesda class IV compared to the FNA results (P<.001). FTCs with distant metastasis exhibited a significantly higher rate of Bethesda classes IV and V compared to those without distant metastasis (P=.004). Surgery for FTC is deferred only with preoperative US and FNA. CNB in patients with FTC can lead to surgery better than FNA. Therefore, if the US feature is characteristic and a serially growing large nodule is suspected, the first attempt of CNB may be helpful in selecting a surgical candidate.

Molecular markers for the classification of cytologically indeterminate thyroid nodules.

The diagnosis of indeterminate lesions of the thyroid is a challenge in cytopathology practice. Indeed, up to 30% of cases lack the morphological features needed to provide definitive classification. Molecular tests have been developed to assist in the diagnosis of these indeterminate cases. The first studies dealing with the preoperative molecular evaluation of FNA samples focused on the analysis of BRAFV600E or on the combined evaluation of two or three genetic alterations. The sensitivity of molecular testing was then improved through the introduction of gene panels, which became available for clinical use in the late 2000s. Two different categories of molecular tests have been developed, the 'rule-out' methods, which aim to reduce the avoidable treatment of benign nodules, and the 'rule-in' tests that have the purpose to optimize surgical management. The genetic evaluation of indeterminate thyroid nodules is predicted to improve patient care, particularly if molecular tests are used appropriately and with the awareness of their advantages and weaknesses. The main disadvantage of these tests is the cost, which makes them rarely used in Europe. To overcome this limitation, customized panels have been set up, which are able to detect the most frequent genetic alterations of thyroid cancer. In the present review, the most recent available versions of commercial molecular tests and of custom, non-commercial panels are described. Their characteristics and accuracy in the differential diagnosis of indeterminate nodules, namely Bethesda classes III (Atypical follicular lesion of undetermined significance, AUS/FLUS) and IV (Suspicious for follicular neoplasm, FN/SFN) are fully analyzed and discussed.

Efficacy of catheter ablation for atrial fibrillation in patients with congenital heart disease.

Advances in surgical techniques allow an increasing number of children with congenital heart disease (CHD) to reach adulthood. As patients grow older, atrial fibrillation (AF) is evolving into a major clinical concern and can be difficult to manage medically. Primary AF catheter ablation may, therefore, have a role in this setting but few reports have evaluated its efficacy in CHD patients. We retrospectively reviewed 58 consecutive patients [median age 51, interquartile range (IQR) 44-63 years, 57% male] with AF (45% paroxysmal) who underwent 122 ablation procedures in our tertiary centre in the last decade. The majority had CHD of moderate or severe complexity (57%, Bethesda Class 2 or 3) with a dilated left atrium (LA) (81%) and/or right atrium (86%). At 1-year from the first ablation, 32.8% of patients remained in sinus rhythm. Multiple procedures were required in 35 (60%) patients. Freedom from AF at 1-year after the 2nd and 3rd ablation was 40.9% and 36.5%, respectively. Multivariable predictors of AF recurrence were underlying anatomic complexity [hazard ratio (HR) in Bethesda 3 1.98, P = 0.006], type of AF (HR for persistent 1.87, P = 0.004), and indexed LA dimensions (HR for cm2/m2 1.06, P = 0.03). While ablation may be a valid option for the treatment of AF in CHD patients, multiple procedures are likely to be required. Early referral and careful patient selection are essential to optimize the results of AF ablation, achieving a low rate of recurrence. Further studies are needed to validate our prognostic model and guide clinical practice.

Deep neural networks could differentiate Bethesda class III versus class IV/V/VI.

Ultrasound (US) is the most commonly used radiologic modality to identify and characterize thyroid nodules. Many nodules subsequently undergo fine needle aspiration to further characterize the nodule and determine appropriate treatment. The fine needle aspirate is most commonly classified using the Bethesda System for Reporting Thyroid Cytology (TBSRTC). It can sometimes be difficult to differentiate Bethesda class III lesions (atypia of undetermined significance/follicular lesion of undetermined significance) from Bethesda class IV, V and VI (malignant nodules). However, differentiation is important as clinical management differs between the two groups. The purpose of this study was to introduce machine learning methods to help radiologists differentiate Bethesda class III from Bethesda class VI, V and VI lesions. The authors collected 467 thyroid nodules with cytopathology results. US features were summarized using the 2017 ACR (American College of Radiology) Thyroid Imaging Reporting And Data System (TIRADS). Machine learning models [logistic regression, gradient boost, support vector machine (SVM), random forest and deep neural networks (DNN)] were created to classify Bethesda class III vs class IV/V/VI. DNN outperformed other machine learning classifiers and obtained the highest accuracy and specificity to classify thyroid nodules as either Bethesda III or IV/V/VI nodules using multiple US features. Machine learning/deep learning approaches could help differentiate Bethesda III nodules from IV/V/VI using US features which may benefit treatment decisions.

Molecular Profile and Clinicopathologic Features of Follicular Variant Papillary Thyroid Carcinoma.

The non-invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) has an indolent clinical behavior. Recently, it was proposed that this tumor type should be reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). To characterize NIFTPs, we evaluated the molecular and clinicopathologic characteristics of each FVPTC subtype. This study enrolled 29 patients with FVPTC who underwent thyroidectomy between January 2007 and June 2017. They were classified as non-invasive encapsulated FVPTC (NIFTP, n = 10), invasive encapsulated FVPTC (n = 11), and infiltrative FVPTC (n = 8) by two independent pathologists. Genetic alterations were analyzed by targeted next-generation sequencing using formalin-fixed, paraffin-embedded tissue samples and the clinicopathologic characteristics were retrospectively reviewed. There was no difference in preoperative cytologic classification between NIFTPs and invasive encapsulated FVPTCs, whereas infiltrative FVPTC was more likely to be Bethesda class VI than the encapsulated type (50% versus 9.5%; P = 0.033). Lymph node metastasis was not found in NIFTPs. There was no BRAFV600E mutation in NIFTPs, whereas one of 11 invasive encapsulated FVPTCs and three of 8 infiltrative FVPTCs harbored BRAFV600E. RAS mutations were frequently detected in encapsulated FVPTCs (5 of 10 NIFTPs and 4 of 11 invasive encapsulated FVPTCs) but were only detected in one case of the infiltrative type. There were no differences in molecular or clinicopathologic profiles between non-invasive and invasive encapsulated FVPTCs, except for lymph node metastasis and the presence of BRAFV600E. NIFTP has favorable pathologic characteristics with a high frequency of RAS mutations.

Transoral endoscopic thyroidectomy using vestibular approach: A single center experience.

Background:Thyroid Natural Orifice Transluminal Endoscopic Surgery (NOTES) or transoral endoscopic thyroidectomy using vestibular approach is a recent advance embraced by the surgical community because of its potential for a scar-free thyroidectomy. In this article, we present our initial experience with this technique.Materials and Methods:We used a three-port technique through the oral vestibule, one 10 mm port for the laparoscope and two additional 5 mm ports for the endoscopic instruments required. The carbon dioxide insufflation pressure was set at 12 mm of Hg. Anterior cervical subplatysmal space was created from the oral vestibule down to the sternal notch, and the thyroidectomy was done using conventional laparoscopic instruments and a harmonic scalpel.Results:From May 2016 to December 2017, we have performed ten such procedures in the Department of General Surgery in our hospital, which is a tertiary referral center. Six patients had solitary thyroid nodules, for which a hemi-thyroidectomy was done. Four patients had multi-nodular goiter and total thyroidectomy or near-total thyroidectomy was done. The preoperative fine-needle aspiration cytology (FNAC) was suggestive of Bethesda class 2 lesions in all the patients with multinodular goiter and in five of the six patients with solitary nodular goiter. Only one patient with solitary nodular goiter had a Bethesda class 3 lesion on FNAC. The final histopathological report of the specimen was benign, either colloid goiter, or degenerative nodule in all cases of multinodular goiter and in four cases of solitary thyroid nodule. In one Bethesda class 2 solitary nodule, the histopathological report was suggestive of follicular carcinoma; in the Bethesda class 3 solitary nodule, the histopathological report was suggestive of follicular variant of papillary carcinoma. No complication such as temporary or permanent vocal cord paralysis, hypoparathyroidism, subcutaneous emphysema, pneumomediastinum, tracheal injury, esophageal injury, mental nerve palsy, or surgical site infection was found postoperatively. However, two patients developed small hematomas in the midline.Conclusion:Transoral endoscopic thyroidectomy is a safe, feasible, and minimally invasive technique with excellent cosmetic results.