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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.

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 South Korea has the highest incidence of thyroid cancer in the world. Our study examined the trends in thyroid cancer incidence by the histologic type, cancer stage, and age group and explored possible factors that affected thyroid cancer trends. Methods We conducted a descriptive epidemiological study using the national cancer registry data and cause of death data from 1999 to 2016 in South Korea. Age‐standardized rates were calculated using Segi's world standard population. Joinpoint regression analysis was applied to determine the changing point of thyroid cancer trends according to histologic type; Surveillance, Epidemiology, and End Results (SEER) summary stage; and age groups by sex. Results The age‐standardized incidence of thyroid cancer in both men and women increased from 6.3 per 100,000 people in 1999 to 63.4 per 100,000 in 2012 but declined from 2012 to 2016, before the debates for over diagnosis of thyroid cancer began in 2014. The age‐standardized mortality rate of thyroid cancer, incidence of distant thyroid cancer, and incidence of regional and localized thyroid cancer started to decline since early 2000, 2010, and 2012, respectively. In addition, thyroid cancer prevalence in thyroid nodules showed decreasing trends from 1999–2000 to 2013–2014. Conclusions The incidence of thyroid cancer began declining from 2012, before the debates for over diagnosis of thyroid cancer began in 2014. Changes in guidelines for thyroid nodule examinations may have affected this inflection point. Moreover, the debates for over diagnosis of thyroid cancer may have accelerated the decline in thyroid cancer. The incidence of thyroid cancer in South Korea has peaked in 2012 and started to decline thereafter. The reduction in thyroid cancer incidence was accelerated by debates for over diagnosis of thyroid cancer in 2014, but changes in the trends of thyroid cancer by stage have already been observed before 2013.

Primary (or de novo) anaplastic thyroid carcinoma (ATC) is ATC without pre-existing history of differentiated thyroid carcinoma (DTC) and no co-existing DTC foci at the time of diagnosis. Secondary ATC is diagnosed if the patient had a history of DTC or co-existing DTC components at time of diagnosis. This study aimed to investigate the incidence, clinical presentations, outcomes, and genetic backgrounds of primary versus secondary ATCs. We searched for ATCs in our institutional databases and the Surveillance, Epidemiology, and End Result (SEER) database. We also performed a systematic review and meta-analysis to analyze the genetic alterations of primary and secondary ATCs. From our multi-institutional database, 22 primary and 23 secondary ATCs were retrieved. We also identified 620 and 24 primary and secondary ATCs in the SEER database, respectively. Compared to primary ATCs, secondary ATCs were not statistically different in terms of demographic, clinical manifestations, and patient survival. The only clinical discrepancy between the two groups was a significantly larger tumor diameter of the primary ATCs. The prevalence of TERT promoter, PIK3CA, and TP53 mutations was comparable between the two subtypes. In comparison to primary ATCs, however, BRAF mutations were more prevalent (OR = 4.70; 95% CI = 2.84–7.78) whereas RAS mutations were less frequent (OR = 0.43; 95% CI = 0.21–0.85) in secondary tumors. In summary, our results indicated that de novo and secondary ATCs might share many potential developmental steps, but there are other factors that suggest distinct developmental pathways.

•A prospectiv, nationwide cohort study of 219 Danish Anaplastic Thyroid Carcinoma patients.•Characteristics, incidence, prognostic factors, and introduction of a fast track cancer program were evaluated.•“Respiratory impairment at diagnosis” and “introduction of a national fast track cancer program” are added as prognostic indicators for ATC. Anaplastic thyroid carcinoma (ATC) is the least common but most malignant thyroid cancer. We aimed to examine the characteristics as well as evaluate the incidence, prognostic factors, and if introduction of a fast track cancer program might influence survival in a cohort of ATC patients. A cohort study based on prospective data from the national Danish thyroid cancer database DATHYRCA and the national Danish Pathology Register including 219 patients diagnosed from 1996 to 2012, whom were followed until death or through September 2014. We found the median age in the 7th decade, the majority of patients being women presenting with a growing mass at the neck, diagnosed with stage T4b disease. At diagnosis, 56% of the patients had lymph node metastasis and 38% distant metastasis. We observed one- and five-year survival of 20.7% and 11.0%, respectively. Both univariate and multivariate analyses showed age (above 73.6 years), respiratory impairment, T4b stage, and distant metastasis at diagnosis to be significant prognostic factors. Further, introduction of a national fast track cancer program increased survival nearly two-fold. As new information, our study adds “respiratory impairment at diagnosis” and “introduction of a national fast track cancer program” to the list of already established prognostic indicators for ATC.

Advanced anaplastic thyroid cancer (ATC) is a rare, but highly aggressive malignancy, and its prognostic factors need to be further explored. We examined socioeconomic factors' predictive effect for survival performance in stage IV ATC patients. Using the Surveillance, Epidemiology, and End Results database, we collected 1,048 cases with stage IV anaplastic thyroid cancer (ATC) from 2004 to 2015. Demographic, clinical, and socioeconomic factors were evaluated using univariate and multivariate analyses. Median family income showed a significant effect on overall survival (OS) and cancer-specific survival (CSS) in univariate analysis. Median family income level was found to be an independent prognostic factor for OS after multivariate adjustment Multivariate analysis for CSS showed similar results. Family income level is an independent prognostic factor for stage IV ATC.

Background Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies in humans, often demonstrating resistance to multimodal therapeutic approaches. The median survival of ATC patients after initial diagnosis was reported to be < 6 months due to the rapid progression of disease by dissemination and/or invasion. There have been several reports describing possible effective chemotherapies, but these studies might be biased by the nature of retrospective accumulations of clinical experiences, and thus reliable data concerning the efficacies of the treatment efforts are required. Design In 2009, we established the research organization Anaplastic Carcinoma Research Consortium Japan (ATCCJ) to investigate this highly malignant disease. Using this nationwide organization, we conducted a prospective clinical study to investigate the feasibility, safeness, and efficacy of chemotherapy with weekly paclitaxel for ATC patients. This trial is registered on the clinical trials site of the University Hospital Medical Information Network Clinical Trials Registry Web site (UMIN000008574). The study was started in 2012, and enrollment was closed in March 2014 after accumulating 71 patients from 28 registered institutes. The follow-up data will be available in April 2015. Discussion Important information concerning the management of this disease is expected to be revealed by this study. The concept and design of the study are described herein.

Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are considered the most aggressive cancers of the head and neck. The aim of the study was to evaluate and compare survival outcomes in PDTC and ATC in a large population-based cohort. Patients with PDTC and ATC diagnosed from 1973 to 2008 were obtained from Surveillance, Epidemiology, and End RESULTS database. Kaplan-Meier survival analysis and log-rank analyses were performed to evaluate (1) The effect of histology on cause-specific survival (CSS) and (2) the influence of factors such as treatment, treatment sequence, race, sex, and age on CSS. Multivariate analysis was performed to assess the independent effect of these factors on CSS. A total of 1352 patients with PDTC and ATC were identified. PDTC constituted 52.4% of patients versus 47.6% for ATC. Median CSS was similar in the two histology groups (P = 0.14). Both PDTC and ATC patients receiving radioisotopes showed a significantly better CSS compared to external beam radiation (P < 0.0001). PDTC and ATC Patients receiving radiation prior to surgery demonstrated a significantly lower CSS compared to patients receiving radiation postoperatively (P < 0.0001). Female gender and black/nonwhite race tended to improve CSS in PDTC and ATC patients (P = 0.29 and P = 0.03, for gender and race, respectively). However, multivariate analysis revealed only type of radiation treatment and age to be independently associated with CSS. This is the first large population-based study evaluating PDTC and ATC outcomes in patients who received radiation treatment. Radioisotope use and timing of radiotherapy (postoperative vs. preoperative) were associated with improved CSS in both histologies.

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.

Key Points Anaplastic thyroid carcinoma (ATC) is a rare but almost invariably lethal disease The histological diagnosis of ATC requires an expert pathologist who can distinguish the anaplastic features of ATC from those of poorly differentiated thyroid cancer The molecular and genetic alterations that define ATC have been characterized by next-generation sequencing analysis and have confirmed a major role for TP53 alterations Conventional therapies are unable to prolong the survival of patients with ATC; however, in certain cases, conventional treatments might improve symptoms and quality of life New targeted therapies have been tested in the past 10 years in phase II clinical trials; however, no therapies have yet been officially approved for the treatment of ATC Additional drugs are under evaluation for the treatment of ATC in phase I and phase II clinical trials, with promising results to date Although anaplastic thyroid carcinoma (ATC) is a rare form of thyroid cancer, the limited efficacy of conventional treatment options and challenges in histological diagnosis make this an almost invariably lethal disease. In this Review, the authors describe the clinical and pathological features of ATC, highlight recent advances in uncovering the genetics and molecular biology of this disease, and discuss both conventional and future treatment modalities. Anaplastic thyroid carcinoma (ATC) is a rare malignancy, accounting for 1–2% of all thyroid cancers. Although rare, ATC accounts for the majority of deaths from thyroid carcinoma. ATC often originates in a pre-existing thyroid cancer lesion, as suggested by the simultaneous presence of areas of differentiated or poorly differentiated thyroid carcinoma. ATC is characterized by the accumulation of several oncogenic alterations, and studies have shown that an increased number of oncogenic alterations equates to an increased level of dedifferentiation and aggressiveness. The clinical management of ATC requires a multidisciplinary approach; according to recent American Thyroid Association guidelines, surgery, radiotherapy and/or chemotherapy should be considered. In addition to conventional therapies, novel molecular targeted therapies are the most promising emerging treatment modalities. These drugs are often multiple receptor tyrosine kinase inhibitors, several of which have been tested in clinical trials with encouraging results so far. Accordingly, clinical trials are ongoing to evaluate the safety, efficacy and effectiveness of these new agents. This Review describes the updated clinical and pathological features of ATC and provides insight into the molecular biology of this disease. The most recent literature regarding conventional, newly available and future therapies for ATC is also discussed.