IMPORTANCE: Thyroid cancer incidence has increased substantially in the United States over the last 4 decades, driven largely by increases in papillary thyroid cancer. It is unclear whether the ...increasing incidence of papillary thyroid cancer has been related to thyroid cancer mortality trends. OBJECTIVE: To compare trends in thyroid cancer incidence and mortality by tumor characteristics at diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Trends in thyroid cancer incidence and incidence-based mortality rates were evaluated using data from the Surveillance, Epidemiology, and End Results-9 (SEER-9) cancer registry program, and annual percent change in rates was calculated using log-linear regression. EXPOSURE: Tumor characteristics. MAIN OUTCOMES AND MEASURES: Annual percent changes in age-adjusted thyroid cancer incidence and incidence-based mortality rates by histologic type and SEER stage for cases diagnosed during 1974-2013. RESULTS: Among 77 276 patients (mean SD age at diagnosis, 48 16 years; 58 213 75% women) diagnosed with thyroid cancer from 1974-2013, papillary thyroid cancer was the most common histologic type (64 625 cases), and 2371 deaths from thyroid cancer occurred during 1994-2013. Thyroid cancer incidence increased, on average, 3.6% per year (95% CI, 3.2%-3.9%) during 1974-2013 (from 4.56 per 100 000 person-years in 1974-1977 to 14.42 per 100 000 person-years in 2010-2013), primarily related to increases in papillary thyroid cancer (annual percent change, 4.4% 95% CI, 4.0%-4.7%). Papillary thyroid cancer incidence increased for all SEER stages at diagnosis (4.6% per year for localized, 4.3% per year for regional, 2.4% per year for distant, 1.8% per year for unknown). During 1994-2013, incidence-based mortality increased 1.1% per year (95% CI, 0.6%-1.6%) (from 0.40 per 100 000 person-years in 1994-1997 to 0.46 per 100 000 person-years in 2010-2013) overall and 2.9% per year (95% CI, 1.1%-4.7%) for SEER distant stage papillary thyroid cancer. CONCLUSIONS AND RELEVANCE: Among patients in the United States diagnosed with thyroid cancer from 1974-2013, the overall incidence of thyroid cancer increased 3% annually, with increases in the incidence rate and thyroid cancer mortality rate for advanced-stage papillary thyroid cancer. These findings are consistent with a true increase in the occurrence of thyroid cancer in the United States.
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
Background
Since the early 1980s, papillary thyroid cancer (PTC) incidence rates and the prevalence of obesity, a risk factor for PTC, have increased substantially in the United States. We ...estimated the proportion of PTC incidence in the United States attributable to overweight and obesity during 1995–2015.
Methods
National Institutes of Health-AARP Diet and Health Study cohort data (n = 457 331 participants, 50–71 years and cancer-free at baseline) were used to estimate multivariable-adjusted hazard ratios (HRs) for PTC across body mass index categories. Population attributable fractions (PAFs) were calculated using estimated hazard ratios and annual overweight and obesity prevalence estimates from the National Health Interview Survey. PAF estimates were combined with Surveillance, Epidemiology, and End Results-13 data to calculate annual percent changes in PTC incidence rates attributable (and unrelated) to overweight and obesity.
Results
Overweight (25.0–29.0 kg/m2) and obesity (≥30.0 kg/m2) were associated with 1.26-fold (95% confidence interval CI = 1.05- to 1.52-fold) and 1.30-fold (95% CI = 1.05- to 1.62-fold) increased risks of PTC, respectively, and nearly threefold (HR = 2.93, 95% CI = 1.25 to 6.87) and greater than fivefold (HR = 5.42, 95% CI = 2.24 to 13.1) increased risks of large (>4 cm) PTCs compared with normal weight (18.5–24.9 kg/m2). During 1995–2015, PAF estimates for overweight and obesity increased from 11.4% to 16.2% for all PTCs and from 51.4% to 63.2% for large PTCs. Overweight or obesity accounted for 13.6% and 57.8% of the annual percent changes in total (5.9%/y) and large (4.5%/y) PTC incidence rates, respectively, during 1995–2015.
Conclusions
Overweight and obesity may have contributed importantly to the rapid rise in PTC incidence during 1995–2015. By 2015, we estimate that one of every six PTCs diagnosed among adults 60 years or older, including nearly two-thirds of large PTCs, were attributable to overweight and obesity.
Background
The diffuse sclerosing (DSV) and tall cell (TCV) variants are considered aggressive subtypes of papillary thyroid cancer (PTC) for which data are limited.
Methods
The Surveillance, ...Epidemiology, and End Results (SEER) database (1988–2008) was used to compare the incidence and clinical/pathologic characteristics of DSV and TCV with classic PTC. Prognostic factors associated with survival were analyzed by chi-square test, analysis of variance, log rank test, and Cox multivariate regression.
Results
There were 261 DSV, 573 TCV, and 42,904 PTC patients. Compared to a 60.8% increase in classic PTC incidence, DSV and TCV incidence increased by 126% (
P
trend
= 0.052) and 158% (
P
trend
= 0.002), respectively. Aggressive variants were associated with higher rates of extrathyroidal extension, multifocality, and nodal and distant metastasis (all
P
< 0.001) compared to classic PTC. Nodal metastasis was more likely with DSV (72.2% vs. 66.8% TCV vs. 56.3% PTC,
P
< 0.001); distant metastasis was most common with TCV (11.1% vs. 7.3% DSV vs. 4.3% PTC,
P
< 0.001). After adjustment, DSV hazard ratio (HR) 1.8,
P
= 0.007 and TCV (HR 1.9,
P
< 0.001) histologies were associated with significantly reduced survival (5-year overall: 87.5% DSV, 80.6% TCV vs. 93.5% PTC,
P
< 0.001). Tumor size independently predicted worse prognosis for TCV (HR 1.29,
P
< 0.001) but not DSV patients. Thyroid surgery and radioiodine improved survival of DSV and TCV patients (all
P
< 0.05). Patients with aggressive variants who received external-beam radiotherapy did not experience improved survival.
Conclusions
DSV and TCV are rare, increasing in incidence, and have a worse prognosis than classic PTC. Patients with these variants should be treated aggressively with thyroidectomy and radioiodine, regardless of tumor size.
OBJECTIVE:To determine the number of total thyroidectomies per surgeon per year associated with the lowest risk of complications.
BACKGROUND:The surgeon volume–outcome association has been ...established for thyroidectomy; however, a threshold number of cases defining a “high-volume” surgeon remains unclear.
METHODS:Adults undergoing total thyroidectomy were identified from the Health Care Utilization Project-National Inpatient Sample (1998–2009). Multivariate logistic regression with restricted cubic splines was utilized to examine the association between the number of annual total thyroidectomies per surgeon and risk of complications.
RESULTS:Among 16,954 patients undergoing total thyroidectomy, 47% had thyroid cancer and 53% benign disease. Median annual surgeon volume was 7 cases; 51% of surgeons performed 1 case/y. Overall, 6% of the patients experienced complications. After adjustment, the likelihood of experiencing a complication decreased with increasing surgeon volume up to 26 cases/y (P < 0.01). Among all patients, 81% had surgery by low-volume surgeons (≤25 cases/y). With adjustment, patients undergoing surgery by low-volume surgeons were more likely to experience complications (odds ratio 1.51, P = 0.002) and longer hospital stays (+12%, P = 0.006). Patients had an 87% increase in the odds of having a complication if the surgeon performed 1 case/y, 68% for 2 to 5 cases/y, 42% for 6 to 10 cases/y, 22% for 11 to 15 cases/y, 10% for 16 to 20 cases/y, and 3% for 21 to 25 cases/y.
CONCLUSIONS:This is the first study to identify a surgeon volume threshold (>25 total thyroidectomies/y) that is associated with improved patient outcomes. Identifying a threshold number of cases defining a high-volume thyroid surgeon is important, as it has implications for quality improvement, criteria for referral and reimbursement, and surgical education.
To determine the number of total thyroidectomies per surgeon per year associated with the lowest risk of complications.
The surgeon volume-outcome association has been established for thyroidectomy; ...however, a threshold number of cases defining a "high-volume" surgeon remains unclear.
Adults undergoing total thyroidectomy were identified from the Health Care Utilization Project-National Inpatient Sample (1998-2009). Multivariate logistic regression with restricted cubic splines was utilized to examine the association between the number of annual total thyroidectomies per surgeon and risk of complications.
Among 16,954 patients undergoing total thyroidectomy, 47% had thyroid cancer and 53% benign disease. Median annual surgeon volume was 7 cases; 51% of surgeons performed 1 case/y. Overall, 6% of the patients experienced complications. After adjustment, the likelihood of experiencing a complication decreased with increasing surgeon volume up to 26 cases/y (P < 0.01). Among all patients, 81% had surgery by low-volume surgeons (≤25 cases/y). With adjustment, patients undergoing surgery by low-volume surgeons were more likely to experience complications (odds ratio 1.51, P = 0.002) and longer hospital stays (+12%, P = 0.006). Patients had an 87% increase in the odds of having a complication if the surgeon performed 1 case/y, 68% for 2 to 5 cases/y, 42% for 6 to 10 cases/y, 22% for 11 to 15 cases/y, 10% for 16 to 20 cases/y, and 3% for 21 to 25 cases/y.
This is the first study to identify a surgeon volume threshold (>25 total thyroidectomies/y) that is associated with improved patient outcomes. Identifying a threshold number of cases defining a high-volume thyroid surgeon is important, as it has implications for quality improvement, criteria for referral and reimbursement, and surgical education.
Sixty percent of papillary thyroid cancers (PTC) have an oncogenic (V600E) BRAF mutation. Inhibitors of BRAF and its substrates MEK1/2 are showing clinical promise in
PTC. PTC progression can be ...decades long, which is challenging in terms of toxicity and cost. We previously found that MEK1/2 require copper (Cu) for kinase activity and can be inhibited with the well-tolerated and economical Cu chelator tetrathiomolybdate (TM). We therefore tested TM for antineoplastic activity in
-positive PTC.
The efficacy of TM alone and in combination with current standard-of-care lenvatinib and sorafenib or BRAF and MEK1/2 inhibitors vemurafenib and trametinib was examined in
-positive human PTC cell lines and a genetically engineered mouse PTC model.
TM inhibited MEK1/2 kinase activity and transformed growth of PTC cells. TM was as or more potent than lenvatinib and sorafenib and enhanced the antineoplastic activity of sorafenib and vemurafenib. Activated ERK2, a substrate of MEK1/2, overcame this effect, consistent with TM deriving its antineoplastic activity by inhibiting MEK1/2. Oral TM reduced tumor burden and vemurafenib in a
-positive mouse model of PTC. This effect was ascribed to a reduction of Cu in the tumors. TM reduced P-Erk1/2 in mouse PTC tumors, whereas genetic reduction of Cu in developing tumors trended towards a survival advantage. Finally, TM as a maintenance therapy after cessation of vemurafenib reduced tumor volume in the aforementioned PTC mouse model.
TM inhibits
-driven PTC through inhibition of MEK1/2, supporting clinical evaluation of chronic TM therapy for this disease.
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