Risk of malignancy in Thy3 thyroid nodules.

Objective. Thyroid cancer is the most common endocrine malignancy in humans. Ultrasound guided fine needle aspiration cytology (FNAC) is now considered the best diagnostic tool for the evaluation of any thyroid nodule. Thyroid cytology is graded from Thy1 to Thy5 with Thy3 being the most challenging in diagnosis. Our aim was to identify the risk of malignancy in Thy3 cytology in our centre. This risk should be explained to the patient before taking any decision. Methods. One hundred and one patients were included in our study. All patients had Thy3 cytology on preoperative ultrasound scan guided FNAC. All patients had diagnostic hemithyroidectomy. The results from the histology were compared with the cytology findings and the rates of malignancy were identified. Results. Of the 101 patients, 17 were males and 84 females. Average age for diagnosis was 52.4±15 years of age. Patients were classified into three groups; patient who had completely benign histology (n=70), patients who had incidental finding of micro-carcinoma after diagnostic hemithyroidectomy (n=10), and patients who had thyroid macro-carcinomas (n=21). Total rate of malignancy was 30.7% when combining both the malignant and the incidental groups and 20.8% when excluding the incidental group. Conclusion. Our rates of malignancy in Thy3 cytology are similar to the literature. These rates should be explained clearly to the patient during the preoperative counselling. Future advances in biomarkers technology may help to improve the preoperative diagnostic accuracy and reduce the rate of unnecessary thyroid surgery.

What is Thy3a? A study of 336 Thy3a (AUS/FLUS) thyroid FNAs with histology compares UK RCPath with other reporting systems and shows how Thy3a subclassification can improve risk stratification and help address overuse of this category.

INTRODUCTION: Thy3a (AUS/FLUS) is an indeterminate and heterogeneous category in thyroid cytology. Thy3a reporting rates vary widely, with many laboratories documenting overuse. Subclassification of Thy3a helps with risk stratification. We aimed to investigate whether subclassification can also help address Thy3a overuse. We compare the UK reporting system with other terminologies. METHODS: An audit of thyroid fine needle aspirations (FNAs) reported at our institution between 2012 and 2017 was performed. Thy3a FNAs followed by histology were reviewed and subcategorised into four subgroups: Scanty Atypia (SA), Scanty Microfollicular (SMF), Favour Benign (FB) and Thyroiditis versus Neoplasm (TVN). Review and subclassification were blinded to histology outcomes. FNAs were correlated with histology and statistical analysis was performed. RESULTS: Our Thy3a rate was high (24% of all thyroid FNAs). For 336 Thy3a FNAs with histology, the malignancy rates of the four subgroups were: SA 68%, SMF 20%, FB 4%, TVN 31%. There were significant associations between subgroup and malignancy risk, and between subgroup and tumour risk. On histology, SA had more malignancies than expected and FB had fewer. SA and SMF had more tumours than expected and FB had fewer. SMF and Thy3f FNAs were similar in terms of tumour and malignancy outcomes. CONCLUSIONS: Subclassification of Thy3a FNAs into these four subgroups is recommended. This can improve risk stratification and help address overuse of Thy3a. We propose that some FB and SMF cases could be safely diverted to Thy2 and Thy3f respectively. We compare various reporting terminologies and question how indeterminate FNAs should be classified.

Strain ratio ultrasound elastography increases the accuracy of colour-Doppler ultrasound in the evaluation of Thy-3 nodules. A bi-centre university experience.

OBJECTIVES: To assess whether ultrasound elastography (USE) with strain ratio increases diagnostic accuracy of Doppler ultrasound in further characterisation of cytologically Thy3 thyroid nodules. METHODS: In two different university diagnostic centres, 315 patients with indeterminate cytology (Thy3) in thyroid nodules aspirates were prospectively evaluated with Doppler ultrasound and strain ratio USE before surgery. Ultrasonographic features were analysed separately and together as ultrasound score, to assess sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Receiver operating characteristic (ROC) curves to identify optimal cut-off value of the strain ratio were also provided. Diagnosis on a surgical specimen was considered the standard of reference. RESULTS: Higher strain ratio values were found in malignant nodules, with an optimum strain ratio cut-off of 2.09 at ROC analysis. USE with strain ratio showed 90.6% sensitivity, 93% specificity, 82.8% PPV, 96.4% NPV, while US score yielded a sensitivity of 52.9%, specificity of 84.3%, PPV 55.6% and NPV 82.9%. The diagnostic gain with strain ratio was statistically significant as proved by ROC areas, which was 0.9182 for strain ratio and 0.6864 for US score. CONCLUSIONS: USE with strain ratio should be considered a useful additional tool to colour-Doppler US, since it improves characterisation of thyroid nodules with indeterminate cytology. KEY POINTS: • Strain ratio measurements improve differentiation of thyroid nodules with indeterminate cytology • Elastography with strain ratio is more reliable than ultrasound features and ultrasound score • Strain ratio may help to better select patients with Thy 3 nodules candidate for surgery.

'Indeterminate for malignancy' (Tir3/Thy3 in the Italian and British systems for classification) thyroid fine needle aspiration (FNA) cytology reporting: morphological criteria and clinical impact.

BACKGROUND: The British system (Thy1-5), the Bethesda system for reporting thyroid cytopathology (BSRTC) and the Italian Society of Anatomic Pathology and Cytology (SIAPEC) classification represent the most important international classifications for thyroid cytopathology. Irrespective of the system used, the 'indeterminate' categories are still debated among cytopathologists, particularly with regard to diagnostic criteria, clinical impact of subclassification and role of molecular techniques. AIM: We aimed to find answers to the following questions: Are there shared criteria in cytological preparations that allow the division of indeterminate follicular lesions into subcategories? What is the true clinical impact of this possible subclassification? METHODS: Among 1150 consecutive thyroid fine needle aspiration (FNA) specimens, 80 patients had nodules with a final cytological report of Tir3 (SIAPEC)/Thy3. These 80 cases were re-evaluated and subclassified according to morphological criteria into three groups: pure follicular proliferations, Hürthle cell follicular lesions and atypical proliferations. RESULTS: Sixteen (20%) cases were categorized as pure follicular proliferations, 40 (50%) as Hürthle cell follicular lesions and 24 (30%) as atypical proliferations. Surgery was performed in 57 cases (71%). Cyto-histological correlation showed that follicular adenoma was the most frequent final diagnosis in the cases treated by surgery (24/57, 42%). The overall malignancy rate in the Tir3 category was 28% (16/57). Atypical proliferations were more often malignant than either of the follicular groups (53% versus 19%, P = 0.019). CONCLUSIONS: A five-tiered classification, subdividing the 'indeterminate for malignancy' class into 'follicular proliferations' and 'atypical lesions' could be adopted. As a result of their higher risk of malignancy, surgical management of the atypical lesions would be justified. In future, the introduction of a genetic panel might contribute to their stratification, to the determination of a more accurate risk of malignancy of the atypical lesions and to the verification of follicular proliferations that are benign.

Prevalence of thyroid carcinoma in nodules with thy 3 cytology: the role of preoperative ultrasonography and strain elastography.

BACKGROUND: Fine needle aspiration (FNA) cytology, the gold standard in assessing thyroid nodules, is limited by its inability to determine the true risk of malignancy in Thy 3 nodules. Most patients with Thy3 cytology undergo surgery to establish a histologic diagnosis. The aims of this study were to evaluate the prevalence of malignancy in Thy3 nodules, to examine the ultrasound (US) characteristics that are associated with a high cancer risk and to assess the role of real-time strain elastography. METHODS: Retrospective cohort study of 99 nodules with Thy3 cytology in 99 patients who underwent thyroidectomy over a three-year period. Grayscale US, Doppler and real-time strain elastography data were evaluated. RESULTS: Eighty-one nodules (81.82%) were benign, 18 (18.18%) were malignant, and almost all were papillary thyroid carcinoma (PTC). Univariable analysis revealed irregular margins (p = 0.02), ill-defined borders (p ≤ 0.001), a taller than wide shape (p ≤ 0.001) and the elasticity score (p = 0.02) as significant predictors of malignancy. Multivariable analysis showed that ill-defined borders and the elasticity score were significant and independent factors associated with malignancy. All soft nodules (elasticity scores 1-2) were benign (sensitivity 100%, specificity 33%, NPV 100%, and PPV 23%). There was a higher rate of malignancy in Thy3a nodules than in Thy3f nodules (42.86% versus 11.54%) (p ≤ 0.001). CONCLUSIONS: Irregular margins, ill-defined borders, a taller than wide shape and low elasticity were associated with malignancy. Elastography should be performed when evaluating Thy3 nodules.

Malignancy rates and initial management of Thy3 thyroid nodules in a district general hospital: The 'Reading' experience.

BACKGROUND: Ultrasound-guided fine-needle aspiration cytology is the gold standard for investigating thyroid nodules. Stratifying the Thy3 thyroid nodule risk of malignancy is essential for clinical decision-making. According to the Royal College of Pathologists Guidance (2016), the rate of malignancy for Thy3a is 5-15% and for Thy3f 15-30%. Our aim was to investigate the malignancy rate and the initial management of Thy3 nodules in our institution. METHODS: A retrospective review was undertaken of 115 patients with Thy3 cytology results from thyroid fine-needle aspirations performed between January 2015 and June 2020 at a single centre. A total of 90 out of 115 patients underwent surgery. RESULTS: Of the 90 patients, we had a 40% malignant rate (36/90). Specifically, 14 of 34 (41.1%) Thy3a and 22 of 56 (39.2%) Thy3f nodules were malignant. Of the malignant lesions, 52.7% (19/36) were follicular thyroid carcinoma. 58.8% (10/17) of male patients and 35.6% (26/73) of female patients had a malignant histology. Eighteen patients eventually needed a completion thyroidectomy. CONCLUSION: Compared with national data, we showed a higher risk of malignancy in Thy3 nodules in our centre. Our study should encourage other centres to audit their own data. We propose setting up a national Thy3 registry as a basis to promote research in improving preoperative diagnosis of indeterminate thyroid nodules.

An H-TERT Mutated Skin Metastasis as First Occurrence in a Case of Follicular Thyroid Carcinoma.

Differentiated thyroid cancer arising from thyroid follicular epithelial cells is the most frequent endocrine malignancy, and skin metastases are very rare. We describe a case of a 70-year-old women with a history of an indeterminate thyroid nodule on cytology. A painless, erythematous skin nodule of about 7 mm diameter was removed from the scalp and diagnosed as a metastasis from thyroid cancer. After total thyroidectomy, a histological diagnosis of follicular thyroid cancer was made. Two cycles of radioactive iodine were performed. Both the follicular thyroid carcinoma (FTC) and the metastasis were investigated for the presence of BRAF/RAS and TERT promoter mutations. The results showed that the cutaneous metastasis was BRAF wild-type and TERT promoter-mutated (position g.1,295,228 C>T); in contrast, the primary thyroid lesion was negative for both molecular markers.

BRAFV600E mutation as a predictor of thyroid malignancy in indeterminate nodules: A systematic review and meta-analysis.

BACKGROUND: Thyroid nodules are usually diagnosed using fine-needle aspiration (FNA). The sensitivity limitations of FNA result in 10-30% of nodules being classified as "indeterminate". The BRAFV600E mutation is associated with papillary thyroid carcinoma (PTC). We conducted a systemic review and meta-analysis to evaluate the diagnostic utility of the BRAFV600E mutation in indeterminate nodules. METHOD: PUBMED and EMBASE were searched for studies testing for the BRAFV600E involving indeterminate nodules (Thy3a, Thy3f, Thy4) and containing information on final surgical histopathology. Thirty two studies involving 3150 indeterminate nodules were included in the analysis. RESULTS: The overall sensitivity and specificity for BRAFV600E for the diagnosis of thyroid malignancy was 0.40 (95% CI: 0.32-0.48) and 1.00 (95% CI: 0.98-1.00) respectively. The diagnostic odds ratio (DOR) was 205.4 (95% CI: 40.1-1052). With a Fagan plot, the post-test probability of thyroid cancer, given a negative mutation was 6%, but this rose to 92% with a positive result. On subgroup analysis, for Thy3a nodules, the pooled sensitivity and specificity for thyroid malignancy was 0.21 (95% CI: 0.13-0.34) and 1.00 (95% CI: 0.98-1.00). For Thy3f nodules, the pooled sensitivity and specificity was 0.09 (95% CI: 0.03-0.20) and 1.00 (95% CI: 0.05-1.00) respectively. For Thy4 nodules, the corresponding sensitivity and specificity was 0.58 (95% CI: 0.5-0.64) and 0.99 (95% CI: 0.95-1.00) respectively. CONCLUSIONS: Despite a high specificity for thyroid cancer, BRAFV600E mutation has a low overall sensitivity and therefore has a limited diagnostic value as a single screening test.

THY3 cytology: What surgical treatment? Retrospective study and literature review.

INTRODUCTION: THY3 nodules collects 20% of cytological examinations, with a rate of malignancy by about 20-30%, and represent one of the most controversial topics of scientific debate. In fact, differential diagnosis of follicular lesions, is very difficult, due to the inability of cytology to differentiate between adenomas and carcinomas. Surgery represents the only possible diagnostic and therapeutic approach, but on the type of surgery there is still absolute discordance of opinions. METHODS: We retrospectively analyzed 230 patients undergoing total thyroidectomy for THY3 cytology between May 2007 and September 2013. Subsequently we re-evaluated our results assuming a conservative surgical approach in patients without preoperative contralateral pathological evidence. RESULTS AND DISCUSSION: Our results indicate an incidence of malignancy in THY3 cytology of 29.6% (n = 68/230), in line with literature data; multifocal bilateral carcinoma in 26.5% of patients; 37 incidental carcinomas (16.5%), 15 of which located contralateral at THY3 nodule; nodular hyperplasia in 52.2% of patients. So, according to a conservative surgery, among patients ideally underwent lobectomy (n = 110), we wouldn't recognize 10 of overall 105 malignancies (9.5%) (including bilateral tumors on THY3 and contralateral incidental carcinomas). Thus, these malignancies would be neither diagnosed nor removed during surgery. CONCLUSIONS: We believe these results allow to state that total thyroidectomy is oncologically the most appropriate intervention to make the patient "disease-free". Moreover, our study could serve as a motivation for further research, but maybe is needed a new Consensus Conference to define a surgical protocol universally recognized.

Outcome of Subclassification of Indeterminate (Thy-3) Thyroid Cytology into Thy-3a and Thy-3f.

OBJECTIVES: The British Thy system is a widely used classification system for reporting thyroid fine-needle aspiration (FNA) cytology. The Royal College of Pathologists in 2009 recommended the subdivision of the Thy-3 (indeterminate) category into Thy-3a (atypia) and Thy-3f (follicular neoplasm). Our objective was to examine the malignancy rates of Thy-3a and Thy-3f cases at our institution and to investigate whether the risk of malignancy in Thy-3a cases is reduced by FNA on a different occasion showing benign cytology. METHODS: This is a retrospective study of 748 thyroid nodules undergoing 1,032 FNAs, with indeterminate (Thy-3) cytology subdivided into Thy-3a and Thy-3f. Cases were correlated with final histology in surgical cases. Incidental carcinomas occurring outside the biopsied nodule were discounted. RESULTS: A total of 109 nodules had a final cytological diagnosis of Thy-3a, of which 67 underwent surgery, with an incidence of malignancy of 13.4% (9/67); 90 nodules had a final cytological diagnosis of Thy-3f, of which 84 underwent surgery, with an incidence of malignancy of 17.9% (15/84). The difference in malignancy rates was not significant (p = 0.51). The incidence of malignancy in nodules with benign and Thy-3a cytology on separate occasions was not significantly different from cases with a single Thy-3a cytology. CONCLUSIONS: Thyroid nodules with Thy-3a cytology have a slightly lower risk of malignancy than Thy-3f cases. However, the difference is not significant and does not appear to be reduced by FNA on a separate occasion showing benign cytology. Management decisions for patients with Thy-3a cytology should be taken carefully to avoid missing cancers.