Cláudia Lobo

CONTEXT: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. OBJECTIVES: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). DESIGN: This was a retrospective observational study. SETTING AND PATIENTS: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. MAIN OUTCOME MEASURES: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. RESULTS: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01-53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36-415.76; P = .03) in PTCs. CONCLUSIONS: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.

Context: Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype. Objectives: To evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases. Design and Patients: Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue. Results: We found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations. Conclusions: When the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.

OBJECTIVE: To compare the outcomes and evaluate the relative risk of thyroid cancer by using the UK thyroid fine-needle aspiration (FNA) cytological diagnostic categories, with the main objective being the clarity of patient management. STUDY DESIGN: Results of thyroid FNA reported as Thy3a, Thy3f, Thy4, and Thy5 were correlated with histological outcomes. The specificity and positive predictive value (PPV; risk of malignancy) for each reporting category was assessed. RESULTS: Of a total of 873 thyroid FNAs, 237 (27%) were reported as 'abnormal': 40 (4.6%) as Thy3a, 119 (13.6%) as Thy3f, 20 (2.2%) as Thy4, and 58 (6.6%) as Thy 5. The final outcomes were available in 136 (57%) cases which underwent surgical resection (25, 60, 55, and 74% of Thy3a, Thy3f, Thy4, and Thy5, respectively). The known outcomes of the Thy3a category were too low to be statistically significant. The specificity and PPV of the Thy3f, Thy4, and Thy5 (equivalent to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) IV, V, and VI) categories were 50, 50, and 100% and 28, 64, and 100%, respectively. The PPV of Thy3f for diagnosis of 'neoplasms' (benign and malignant) was 63%. CONCLUSION: The current thyroid FNA classification system used in the UK, which is comparable to TBSRTC, offers a sound basis for clear communication on which the management of patients with abnormal thyroid FNA findings can be based. Categories Thy3f, Thy4, and Thy5 carry a progressively rising risk of malignancy, justifying their continuing use. Diagnostic category Thy5 'malignant' is robust and can be used as a sure indication of a definitive surgical management.

BACKGROUND: Cytological analysis is part of the initial etiological evaluation of serous effusions. The newly proposed International System for Reporting Serous Fluid Cytopathology (ISRSFC) aims to standardize reporting. METHODS: All pleural and peritoneal effusion samples admitted for cytological analysis at our institution between 2012 and 2016, and pericardial effusion samples admitted between 2008 and 2018, were reviewed and reclassified according to the ISRSFC. Risk of malignancy (ROM) and performance parameters were calculated. RESULTS: 1496 pleural effusion samples were reclassified: 12(0.8%) non-diagnostic (ND), 944(63.1%) negative for malignancy (NFM), 9(0.6%) atypia of undetermined significance (AUS), 54(3.6%) suspicious of malignancy (SFM) and 477(31.9%) malignant (M). 64 pericardial effusion samples were reclassified: 23(35.9%) NFM, 1(1.6%) AUS, 4(6.3%) SFM and 36(56.2%) M. 763 peritoneal effusion samples were reclassified: 5(0.7%) ND, 457(59.9%) NFM, 12(1.6%) AUS, 37(4.8%) SFM and 252(33%) M. The ROM was, respectively, for each of the aforementioned categories, 57.1%, 23.9%, 50%, 76.2%, 100% in pleural effusions, 100%, 26.3%, 62.5%, 91.7%, 100% in peritoneal effusions and 0% for NFM, 0% for AUS and 100% for M in pericardial effusions. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were, respectively, 61.6%, 100%, 100%, 73.3%, 81.3% for pleural, 100%, 100%, 100%, 100%, 100% for pericardial and 61.2%, 100%, 100%, 70%, 79.7% for peritoneal effusion samples. CONCLUSION: Serous effusion cytology has a high specificity and positive predictive value and a modest sensitivity and negative predictive value, supporting its role in confirming the diagnosis of malignancy. The ISRSFC will increase standardization and reproducibility in reporting, leading to improved clinical decision-making.