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e18090 Background: In the growing era of precision medicine and tumor-agnostic therapies, the molecular testing of DTC is becoming mandatory to optimize diagnostic and therapeutical strategies. Even if the most frequent oncogenic events, occurring in a mutually exclusive manner, are BRAF V600E, followed by RAS, gene fusions mainly occurring in RET, NTRK1-3, and ALK genes have been also found. In this scenario, the definition of a molecular testing algorithm to be implemented for clinical practice is needed, in order to optimize resources and time for better clinical patient management. Methods: Gene mutations and gene fusions were evaluated on DNA and RNA extracted from cytologic or histologic samples. Mutations were tested using a lab-developed multi-gene panel able to analyze the hot-spot regions of 28 genes (total of 343 amplicons, 21.77 kb); gene fusions were tested using the Oncomine Focus assay panel. Results: Molecular characterization was performed on a total of 63 DTC (50 papillary thyroid carcinoma - PTC, 8 – follicular thyroid carcinoma - FTC, 5 – hurthle cell carcinoma - HCC) by the treating clinician for diagnostic, prognostic or clinical reasons. In 27 cases (42.8%) at least one DNA mutation was detected, 17 cases (26.9%) were positive for gene fusion rearrangement, in only 2 cases (3.1%) both DNA mutations and gene rearrangements were found and in the remaining 17 (26.9%) cases no DNA mutations or rearrangements were detected. Among mutated-subgroup, BRAF V600E mutation was the most common (14 of 63 cases – 22.2%), followed by RAS mut (9 cases – 14.2%: 4 NRAS, 3 HRAS, and 3 KRAS), both as single event in 7 and 4 cases respectively. Substitutions in TERT promoter region was found in 16 cases (25.3%), of which 14 as secondary event. Other mutations in TP53 (4 cases –6.3 %, of which 2 as single event), PIK3CA (1 case – 1.5%), AKT1(1 case – 1.5%), and RNF43 (1 case – 1.5%) were detected. Among riarranged subgroup, RET fusions and NTRK1-3 was found in 8 cases respectively (12.6%), while ALK fusion was found 1 case (1.5%). The concomitant mutational and fusion events found in 2 cases were the following: 1) HRAS and PAX8/PPARG; 2) PIK3CA/TP53/TERT and RET/CCDC6. Conclusions: As expected, BRAF and RAS mutations represent the most common genetic events in DTC and occur in a mutual exclusive manner. However, in about 30% of patients, mostly of young age, with papillary histology and lymph nodal involvement, a clinically actionable gene rearrangement has been found. Thus, we propose a two-step molecular testing algorithm with a first-level test to identify the most common mutations and a second-level test, including less common mutations and gene rearrangements, if the genes analyzed with the first level test are wild-type. The second-level test may be performed up-front in cases where there are clinicopathologic features suggestive of fusion gene TC gene or in clinically aggressive unconventional cases for which molecular therapy is being considered.

ContextThe risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features.ObjectiveTo develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors.MethodsIn a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction.ResultsBy ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis.ConclusionCurrent risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering.

PURPOSE Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC. PATIENTS AND METHODS Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis. RESULTS Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers. CONCLUSION This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.