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Key Points The incidence of thyroid cancer has increased over the past several decades, which, in many countries around the world, has been largely driven by new cases of papillary thyroid cancer Increased opportunities for detection and diagnosis of small, indolent thyroid cancers seem to explain much, but not all, of the patterns in thyroid cancer incidence Results from epidemiological studies suggest that a substantial proportion of thyroid cancer diagnoses (>40% in the USA) could be attributable to environmental factors, such as obesity and cigarette smoking Clinical practice guidelines have recently changed in response to an increasing awareness of the potential for unnecessary diagnosis and treatment in a subset of patients Large-scale, prospective epidemiological studies and laboratory-based investigations are needed to identify modifiable risk factors for thyroid cancer and promising targets for thyroid cancer prevention The incidence of thyroid cancer has increased substantially in many countries over the past few decades. In this Review, Kitahara and Sosa describe the changing incidence of the disease and suggest possible explanations for the trends, emphasizing implications for patients and ongoing strategies to combat this growing public health issue. During the past few decades, the incidence of thyroid cancer has increased substantially in many countries, including the USA. The rise in incidence seems to be attributable both to the growing use of diagnostic imaging and fine-needle aspiration biopsy, which has led to enhanced detection and diagnosis of subclinical thyroid cancers, and environmental factors. The latest American Thyroid Association (ATA) practice guidelines for the management of adult patients with thyroid nodules and differentiated thyroid cancer differ substantially from the previous ATA guidelines published in 2009. Specifically, the problems of overdiagnosis and overtreatment of a disease that is typically indolent, where treatment-related morbidity might not be justified by a survival benefit, now seem to be acknowledged. As few modifiable risk factors for thyroid cancer have been established, the specific environmental factors that have contributed to the rising incidence of thyroid cancer remain speculative. However, the findings of several large, well-designed epidemiological studies have provided new information about exposures (such as obesity) that might influence the development of thyroid cancer. In this Review, we describe the changing incidence of thyroid cancer, suggest potential explanations for these trends, emphasize the implications for patients and highlight ongoing and potential strategies to combat this growing clinical and public health issue.

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality. This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT , AKT1 , PIK3CA , and EIF1AX were frequently co-mutated with driver genes ( BRAF V600E and RAS ) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A ) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS -positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs. Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) come with a dismal prognosis. Here, Yoo and colleagues reveal the genomic and transcriptomic landscape of ATC and DTC, highlighting potential therapeutic vulnerabilities.

Abstract Context The relationship between the genomic profile and prognosis of advanced thyroid carcinoma requiring drug therapy has not been reported. Objective To evaluate the treatment period and overall survival time for each genetic alteration in advanced thyroid carcinoma that requires drug therapy. Methods We conducted a retrospective observational study using a national database in Japan, which included 552 cases of thyroid carcinoma out of 53 543 patients in the database. Results The database included anaplastic thyroid carcinoma (23.6%), poorly differentiated thyroid carcinoma (10.0%), and differentiated thyroid carcinoma (66.4%). The most common genetic abnormalities were TERT promoter (66.3%), BRAF (56.7%), and TP53 (32.2%). The typical driver genes were BRAF V600E (55.0%), RAS (18.5%), RET fusion (4.7%), NTRK fusion (1.6%), and ALK fusion (0.4%). The most common regimen was lenvatinib, and the time to treatment failure was not different despite the presence of BRAF or RAS mutations. In differentiated thyroid carcinoma and poorly differentiated thyroid carcinoma, TP53 alterations independently predicted worse overall survival (hazard ratio = 2.205, 95% confidence interval: 1.135-4.283). In anaplastic thyroid carcinoma, no genetic alterations were associated with overall survival. Conclusion Genetic abnormalities with treatment options were found in 62.7% of advanced thyroid carcinomas. TP53 abnormality was an independent poor prognostic factor for overall survival in differentiated thyroid carcinoma. The time to treatment failure for lenvatinib was not different based on genetic profile.

Background Anaplastic thyroid carcinoma (ATC) is a rare but aggressive malignancy, which accounts for only 1–2% of all thyroid cancers. The median overall survival (OS) time for all stages patients is at about 5 months. The benefit of surgery combined with adjuvant radiation and chemotherapy in stage IVC anaplastic thyroid cancer is still controversial. The aim of this study is to investigating surgery combined with adjuvant radiation and chemotherapy and survival outcomes in stage IVC ATC patients. Method Anaplastic thyroid carcinoma patients from the Surveillance, Epidemiology, and End Results database from 2004 to 2016 were used to conduct a cross-sectional study in the analysis. The endpoint of this study was overall survival. Results The median OS of the overall population was 2.0 months. Multivariate analysis showed that age (<67 vs. ≥67 years old, P  = 0.017, HR = 1.355, 95% CI: 1.057–1.738), tumor size (<7 cm vs. ≥7 cm, P  = 0.001, HR = 1.579, 95% CI: 1.202–2.073), Surgery (thyroidectomy vs. non-surgery, P  < 0.001, HR = 0.554, 95% CI: 0.401–0.766), radiation therapy ( P  < 0.001, HR = 0.571, 95% CI: 0.445–0.733) and chemotherapy ( P  = 0.003, HR = 0.684, 95% CI: 0.531–0.881) were independent prognostic factor for worse OS in stage IVC ATC patients. Surgery combined with adjuvant radiation and chemotherapy exhibited the better overall survival time for 4 months. Conclusions Surgery combined with adjuvant radiation and chemotherapy can improve overall survival in stage IVC ATC patients. We recommend surgical approach with fully evaluation combined with radiation therapy and chemotherapy for selected stage IVC ATC patients.

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) present major challenges in treatment owing to extreme aggressiveness and high heterogeneity. In this study, deep-scale analyses spanning genomic, proteomic, and phosphoproteomic data are performed on 348 thyroid-cancer and 119 tumor-adjacent samples. TP53 (48%), TERT promoter (36.5%), and BRAF (23%) are most frequently mutated in PDTC and ATC. Ribosome biogenesis is identified as a common hallmark of ATC, and RRP9 silencing dramatically inhibits tumor growth. Proteomic clustering identified three ATC/PDTC subtypes. Pro-I subtype is characterized with aberrant insulin signaling and low immune cell infiltration, and Pro-II is featured with DNA repair signaling, while Pro-III harbors high frequency of TP53 and BRAF mutation and intensive C5AR1 + myeloid infiltration. Targeting C5AR1 synergistically improves antitumor effect of PD-1 blockade against ATC cell-derived tumors. These findings provide systematic insights into tumor biology and opportunities for drug discovery, accelerating precision therapy for virulent thyroid cancers. The treatment of poorly differentiated thyroid cancer and anaplastic thyroid cancer remains challenging. Here, the authors perform multi-omic analysis of thyroid samples and identify proteomic clusters associated with distinct tumour microenvironment features.

Background Thyroid cancer is a common thyroid malignancy. The majority of thyroid lesion needs intraoperative frozen pathology diagnosis, which provides important information for precision operation. As digital whole slide images (WSIs) develop, deep learning methods for histopathological classification of the thyroid gland (paraffin sections) have achieved outstanding results. Our current study is to clarify whether deep learning assists pathology diagnosis for intraoperative frozen thyroid lesions or not. Methods We propose an artificial intelligence-assisted diagnostic system for frozen thyroid lesions that applies prior knowledge in tandem with a dichotomous judgment of whether the lesion is cancerous or not and a quadratic judgment of the type of cancerous lesion to categorize the frozen thyroid lesions into five categories: papillary thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid tumor, and non-cancerous lesion. We obtained 4409 frozen digital pathology sections (WSI) of thyroid from the First Affiliated Hospital of Sun Yat-sen University (SYSUFH) to train and test the model, and the performance was validated by a six-fold cross validation, 101 papillary microcarcinoma sections of thyroid were used to validate the system’s sensitivity, and 1388 WSIs of thyroid were used for the evaluation of the external dataset. The deep learning models were compared in terms of several metrics such as accuracy, F1 score, recall, precision and AUC (Area Under Curve). Results We developed the first deep learning-based frozen thyroid diagnostic classifier for histopathological WSI classification of papillary carcinoma, medullary carcinoma, follicular tumor, anaplastic carcinoma, and non-carcinoma lesion. On test slides, the system had an accuracy of 0.9459, a precision of 0.9475, and an AUC of 0.9955. In the papillary carcinoma test slides, the system was able to accurately predict even lesions as small as 2 mm in diameter. Tested with the acceleration component, the cut processing can be performed in 346.12 s and the visual inference prediction results can be obtained in 98.61 s, thus meeting the time requirements for intraoperative diagnosis. Our study employs a deep learning approach for high-precision classification of intraoperative frozen thyroid lesion distribution in the clinical setting, which has potential clinical implications for assisting pathologists and precision surgery of thyroid lesions.

TERT promoter mutation is associated with poor prognosis in differentiated thyroid carcinoma, with US features varying by mutation status. However, this correlation in anaplastic thyroid carcinoma (ATC) is understudied. We investigated the association between clinicopathological characteristics and US features of ATC with TERT mutation status and prognosis. From November 1994 to May 2022, 58 ATC nodules from 58 patients were analyzed. Two radiologists retrospectively reviewed US features based on the revised K-TIRADS and ACR-TIRADS. Of all 58 ATC nodules, 32 nodules were tested for TERT promoter mutation and detected in 11. TERT promoter-mutated ATC was larger than TERT wild-type ATC ( p  = 0.032); however, no other differences were observed. ATC with survival period of less than 12 months were more likely to have lymph node metastasis ( p  = 0.012) or distant metastasis at diagnosis ( p  < 0.001), larger size on US ( p  = 0.005), and suspicion for gross extrathyroidal extension on US ( p  = 0.04) compared to ATC with survival period of 12 months or more. Advanced disease at diagnosis was a critical factor associated with 1-year survival in patients with ATC, whereas the TERT promoter mutation status was not.

Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T cells that contribute to the antitumor response. We found that mouse BrafV600E-driven anaplastic thyroid cancers (ATCs) responded markedly to the RAF plus MEK inhibitors dabrafenib and trametinib (dab/tram) and that this was associated with upregulation of MhcII in cancer cells and increased CD4+ T cell infiltration. A subset of recurrent tumors lost MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved IFN-γ signal transduction, which could be rescued by EZH2 inhibition. Orthotopically implanted Ciita-/- and H2-Ab1-/- ATC cells into immune-competent mice became unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+, T cells also abrogated the response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.

Purpose Anaplastic thyroid carcinoma (ATC) is an orphan disease with a fatal outcome. Surgery to the primary tumor in metastatic ATC is controversial. Determination of specific surgical techniques may help facilitate local control and, hence, beneficial overall and disease-specific survival. Methods Using individualized patient data derived from our systematic review of literature and our single center study ( n  = 123), conducting a Surveillance, Epidemiology, and End Results register (SEER)-based study ( n  = 617) we evaluated surgery, its combination with systemic and local therapies in metastatic ATC. Results Pooled cohort study showed surgery ( p  < 0.001), RT ≥ 30 Gy ( p  < 0.001), ChT ( p  < 0.001) and multimodal treatment ( p  = 0.014) to result in improved OS univariately. In the multivariate analysis, surgery (1.997 [1.162–3.433], p  = 0.012) and RT ≥ 30 Gy (1.877 [1.232–2.843], p  = 0.012) were independent predictors for OS. In SEER-based study of patients undergoing any tumor-directed treatment ( n  = 445) total thyroidectomy ( p  = 0.031), administration of ChT ( p  = 0.007), RT ( p  < 0.001), combination of surgery and RT ± ChT ( p  < 0.001) and multimodal treatment ( p  < 0.001) correlated with an improved DSS univariately. On the multivariate analysis, debulking surgery was an independent predictor for a worse outcome (HR 0.535, 95%CI 0.332–0.862, p  = 0.010), whereas RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362–3.939, p = 0.002). Among operated patients from SEER register total thyroidectomy ( p  = 0.031), ChT ( p  = 0.007), RT ( p  < 0.001), combination of surgery and RT ± ChT ( p  < 0.001) and multimodal treatment ( p  < 0.001) correlated with an improved DSS in the univariate analysis, whereas debulking surgery was inversely correlated with the DSS ( p  < 0.001). On the multivariate analysis, debulking surgery was an independent predictor for a worse DSS (HR 0.535, 95%CI 0.332–0.862, p  = 0.010), whilst RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362–3.939, p  = 0.002). Conclusions Surgery to the primary tumor with the aim of R0/R1 resection, but not debulking, is associated with a significant OS and DSS benefit even in systemically metastasized disease.