Abstract
Objective:
To examine the trends in incidence of clinically relevant thyroid cancers within the overall rising incidence of thyroid cancers.
Patients and Methods:
Population-based cohort study conducted using the Rochester Epidemiology Project database to identify all new cases of thyroid cancer in Olmsted County, MN between January 1, 1935 and December 31, 2018. We extracted information about demographics and tumor pathologic type, size, and invasiveness. Clinically relevant cancers included: 1) Aggressive histology or presence of metastatic disease, 2) Size > 4 cm, 3) Gross extrathyroidal tumor invasion.
Results:
Between 1935 and 2018, 596 thyroid cancer cases were diagnosed: mean age 46.4 years, 72% female, and 87% papillary cancers and median tumor size was 1.5 cm. The sex and age-adjusted incidence of thyroid cancer increased from 1.3 per 100,000 person-years (p-y) in 1935–1949 to 12.0 per 100,000 p-y in 2010–2018, corresponding to an absolute change per decade of 1.4 (95% CI: 0.7, 2.2). There was a non-significant period absolute change for patients with tumor >4cm (0.03; 95% CI: −0.2, 0.3), with evidence of tumor invasion (0.1; 95% CI: −0.1, 0.4) and with aggressive histology or presence of metastatic disease (0.2; 95% CI: −0.1, 0.6). Thyroid cancer mortality was unchanged over the observation period.
Conclusion:
Incidence rates of clinically relevant thyroid cancers, as defined by histology, size, and invasiveness, have not changed significantly in 80 years. The rising thyroid cancer incidence is driven by indolent thyroid cancers.
Introduction
There is a rapid increase in the incidence of thyroid cancer worldwide. In the United States the incidence of thyroid cancer has increased 300% over the past four decades, from 4.9 per 100,000 person-years in 1975 to 14.63 per 100,000 person-years in 2016 (1). These changes have mostly been driven by new cases of small papillary thyroid cancers (2). During the timeframe of rising thyroid cancer incidence, thyroid cancer mortality has stayed the same or slightly increased suggesting that the rise in incidence is attributed to overdiagnosis of clinically indolent thyroid cancers (2, 3).
Others have argued that, although overdiagnosis may be playing a role, there is also evidence of a true increase in thyroid cancer incidence. A study using SEER data from 1980 to 2005 found a rising incidence of larger thyroid cancers in addition to the expected rise in small thyroid cancers. Specifically, 20% of the increased incidence was attributed to tumors greater than 2 cm, and a >200% increase was found in the incidence of tumors greater than 5 cm (4). Similarly, another study using the SEER dataset from1974–2013 showed a 6% per year increase in incidence for tumors larger than 4 cm, as well as a 4% and 2% yearly increased incidence for papillary thyroid cancer with regional and distant metastasis, respectively (2). These studies suggested that, in parallel to the obvious rise in indolent thyroid cancer cases, there may also be an increase in incidence of clinically relevant thyroid cancers. Yet, these studies are limited by case ascertainment bias and an analysis that relies on tumor size and cancer stage data restricted to specific years in which the information is reported to the registries (5). These limitations could be overcome using a population-based clinical dataset.
The goal of this study is to understand the trends in thyroid cancer incidence and mortality of clinically relevant thyroid cancers, or thyroid cancers that are associated with higher mortality or recurrence-related morbidity based on prognostic factors identified in the most recent American Thyroid Association (ATA) guidelines and AJCC/TNM staging (6, 7). To this end, using data from the Rochester Epidemiology Project (REP), we identified all thyroid cancers diagnosed between 1935 and 2018 in Olmsted County, MN and compared epidemiologic trends by decade, age, and sex, among clinically relevant cancers.
Methods
Patient Identification and Data Collection
The institutional review boards at the Mayo Clinic and Olmsted Medical Center (Rochester, MN, USA) approved the study. Using the Rochester Epidemiology Project database, all incident cases of thyroid cancer from 1935 – 2018 were captured by an experienced retrieval specialist using the Rochester Medical Index database and ICD-9 and ICD-10 billing codes for thyroid malignancy. Prior analyses of the incidence trends in thyroid cancer cases using REP cohort data have been previously published (8 – 10). Here, we present the findings of thyroid cancer incidence and mortality data for this cohort through 2018, and specifically look at how these trends have changed by different criteria for clinically relevant cancers.
The REP is a comprehensive medical records linkage system for almost all people residing in Olmsted County, MN that connects an individual’s medical records electronically from multiple clinical settings to create a timeline of care throughout the lifespan (11). This methodology has been evaluated as both sensitive and specific for capturing the true population of the region (12). The most current registry version (version 3.0) contains an individual’s key demographic information, including birth and death records, as well as clinical notes, labs and diagnoses.
From the identified thyroid cancer cases, we searched for pathology reports to confirm the presence of one of the following diagnoses: papillary, follicular, Hürthle cell, medullary, poorly differentiated, anaplastic thyroid cancer or thyroid cancer not otherwise specified. From each medical record we abstracted the date of initial diagnosis of thyroid cancer, demographic data, histological type and clinical parameters of the tumor.
All cases of thyroid cancer from 1935 to 2018 were classified based on their clinical significance into different subgroups: a) Significant risk thyroid cancer (SRTC) as determined by Wang et al that includes patients with medullary, poorly differentiated, anaplastic cancers, or differentiated thyroid cancers with distant metastatic disease (13); b) Any thyroid cancer histology with tumor size > 4 cm, c) Any tumor with evidence of gross extrathyroidal (macroscopic) invasion to midline structures, posterior structures or muscle invasion as documented in the surgical report.
To assess mortality and cause of death for all TC cases (1935–2018), we used the Rochester Epidemiology Death Data System. This death data source includes, but is not limited to, the State of Minnesota Electronic Death Certificates, Olmsted County Electronic Death Certificates and National Death Index. Additionally, each medical record was reviewed to search for the death certificate and cause of death; using this data, we classified whether the cause of death was related to thyroid cancer.
Statistical Analysis
Data analysis was performed using JMP software, version 14.1.0 and SAS version 9.4 (SAS Inc, Cary, NC). We summarized continuous variables using mean (standard deviation) or median (interquartile range, IQR), as appropriate based on normality of distribution. Categorical variables were summarized using percentages and compared using Pearson’s chi-squared test. A probability value of P<0.05 was considered statistically significant for all tests. For incidence analysis of TC and disease specific mortality, age- and sex-adjusted incidence rates were based on direct standardization against the 2000 US standard population, with the corresponding denominators derived from annual census figures for Olmsted County, assuming that the entire population was at risk (12). To estimate overall period percentage with 95% confidence intervals (CI’s), we used a Log-linear regression model based on the Poisson distribution. A generalized linear model (Poisson distribution, identity link) was used to estimate the corresponding absolute change in incidence rates over the same time period.
Results
From 1935 to 2018, 596 cases of thyroid were diagnosed. Table 1 demonstrates that the mean age at diagnosis was 46 years (SD 16); 71% were female, 89% were PTC and the median tumor size was 1.5 cm (IQR 0.9 cm - 2.5 cm). The sex and age-adjusted incidence of thyroid cancer increased from 1.3 per 100,000 person-years (p-y) in 1935–1949 to 12.0 per 100,000 p-y in 2010–2018, corresponding to an estimated overall period percentage change of 24.3% (95% CI: 9.6–41.0; P<.001) and absolute change of 1.4 (95% CI: 0.7–2.2; P<.001). By contrast, thyroid cancer mortality was 0.3 per 100,000 p-y in 1935–1949 and 0.2 per 100,000 p-y in 2010–2018 corresponding to a non-significant period percentage change of −10.5% (95% CI: −48.2, 54.6; P=.69) and an absolute change of −0.04 (95% CI: −0.2–0.1; P=.64).
Table 1.
Patient characteristics
| Total (N=596) |
Clinically relevant by any of the 3 criteria (N=119) |
SRTCa (N=27) |
Size >4 cm (N=38) |
Gross Invasion (N=81) |
Mortality (N=20) |
|
|---|---|---|---|---|---|---|
| Sex, female, n (%) | 426 (71.5%) | 77 (64.7%) | 16 (59.3%) | 22 (57.9%) | 56 (69.1%) | 12 (60.0%) |
| Race, Caucasian, n (%) | 547 (91.8%) | 107 (89.9%) | 25 (92.6%) | 35 (92.1%) | 72 (88.9%) | 19 (95.0%) |
| Age at diagnosis, mean (SD) | 46.4 (16.4) | 51.8 (17.6) | 59.3 (20.0) | 55.5 (17.0) | 51.1 (17.8) | 68.1 (15.1) |
| Age at diagnosis ≥ 55 years, n (%) | 180 (30.2%) | 51 (42.9%) | 17 (63.0%) | 21 (55.3%) | 33 (40.7%) | 17 (85.0%) |
| Type of thyroid cancer, n (%) | ||||||
| Papillary cancer | 528 (88.6%) | 84 (70.6%) | 6 (22.2%) | 23 (60.5%) | 67 (82.7%) | 8 (40.0%) |
| Follicular cancer | 25 (4.2%) | 6 (5.0%) | 0 (0.0%) | 3 (7.9%) | 4 (4.9%) | 2 (10.0%) |
| Hurthle cell cancer | 23 (3.9%) | 9 (7.6%) | 1 (3.7%) | 7 (18.4%) | 3 (3.7%) | 2 (10.0%) |
| Medullary cancer | 12 (2.0%) | 12 (10.1%) | 12 (44.4%) | 0 (0.0%) | 0 (0.0%) | 1 (5.0%) |
| Anaplastic cancer | 7 (1.2%) | 7 (5.9%) | 7 (25.9%) | 4 (10.5%) | 7 (8.6%) | 6 (30.0%) |
| Poorly differentiated cancer | 1 (0.2%) | 1 (0.8%) | 1 (3.7%) | 1 (2.6%) | 0 (0.0%) | 1 (5.0%) |
| Size of primary tumor, cm, median (IQR), (n=595) | 1.5 (0.9, 2.5) | 2.5 (1.3,4.5) | 2.5 (1.8, 5.0) | 5.0 (4.6, 6.7) | 2.0 (1.2, 3.5) | 4.0 (2.5, 5.0) |
| Size category, n (%), (n=595) | ||||||
| ≤1 cm | 208 (35.0%) | 19 (16.1%) | 3 (11.1%) | 0 (0.0%) | 16 (20.0%) | 1 (5.0%) |
| > 1 cm and ≤ 2 cm | 192 (32.3%) | 30 (25.4%) | 6 (22.2%) | 0 (0.0%) | 26 (32.5%) | 3 (15.0%) |
| > 2 cm and ≤ 4 cm | 157 (26.4%) | 31 (26.3%) | 10 (37.0%) | 0 (0.0%) | 25 (31.3%) | 8 (40.0%) |
| >4 cm | 38 (6.4%) | 38 (32.2%) | 8 (29.6%) | 38 (100.0%) | 13 (16.3%) | 8 (40.0%) |
| Distant metastases, present, n (%) | 11 (1.8%) | 11 (9.2%) | 11 (40.7%) | 6 (15.8%) | 10 (12.3%) | 6 (30.0%) |
| Gross invasion, present, n (%) | 81 (13.6%) | 81 (68.1%) | 13 (48.1%) | 13 (34.2%) | 81 (100.0%) | 14 (70.0%) |
| Incidental finding, n (%), (n=333) | 181 (54.4%) | 28 (41.8%) | 2 (18.2%) | 3 (7.9%) | 24 (48.0%) | 0 (0.0%) |
Continuous data are summarized as mean and standard deviation or as median and interquartile ranges as indicated. Categorical data are presented as frequencies and percentages. Data present for all individuals unless otherwise noted in table line.
Significant risk thyroid cancer (SRTC) as described by Wang et al (13) to include medullary, poorly differentiated, anaplastic and metastatic differentiated thyroid cancers
The age-adjusted incidence trends for clinically significant cancer groups are shown in Figure 1. There was a non-significant absolute period change for patients with tumor >4cm (0.03; 95% CI: −0.2, 0.3; P=.80), patients with tumors with evidence of gross extrathyroidal (macroscopic) invasion (0.13; 95% CI: −0.1, 0.4; P=.33) and SRTC patients (0.02; 95% CI: −0.2, 0.2; P=.84) (13). Overall, the percentage change for patients with a clinically significant cancer by any of these three definitions was 18.6% (95% CI −9.6, 55.4, P=.22) and absolute period change was 0.22 (95% CI: −0.1, 0.6; P=.21). Table 2. These estimates did not change when stratified by gender. When stratified by age, the incidence of thyroid cancer for those aged less than 55 years increased from 0.72 per 100,000 p-y in 1935 to 8.42 per 100,000 p-y in 2010–2018, corresponding to a significant period percentage change of 27.5% (95% CI: 9.2, 48.8; P=.002), Figure 2 and 3 and Supplemental Table. Proportion of clinically relevant cancers by age is included, Figure 4.
Figure 1. Sex and age-adjusted incidence rates 1935–2018.
Overall thyroid cancer incidence has increased by an estimated 24% (95% CI 9.6% to 41.0%, P<0.001) between 1935 and 2018, however the incidence of clinically relevant cancers by any definition and the mortality did not change significantly over this time.
a Significant risk thyroid cancer (SRTC) as described by Wang et al (13) to include medullary, poorly differentiated, anaplastic and metastatic differentiated thyroid cancers
b Clinically relevant criteria included: SRTC, tumor size ≥4 cm, or by presence of gross invasion.
c Modeled trend line for SEER data calculated from underlying age-adjusted rates based on SEER9 (1975–1991) and SEER13 (1992–2017) data.
Table 2.
Estimated period percentage change and absolute change over time
| Estimated Period % Change a | Confidence Interval, 95%ile | p-value | Estimated Period Absolute Change b | Confidence Interval, 95%ile | p-value | |
|---|---|---|---|---|---|---|
| Overall incidence | 24.3 | 9.6, 41.0 | < 0.001 | 1.4 | 0.7, 2.2 | <0.001 |
| Overall mortality | −10.5 | −48.2, 54.6 | 0.69 | −0.04 | −0.2,0.1 | 0.64 |
| SRTCc | 4.9 | −36.8, 73.9 | 0.85 | 0.02 | −0.2, 0.2 | 0.84 |
| Tumor size >4 cm | 5.4 | −31.9, 63.0 | 0.82 | 0.03 | −0.2, 0.3 | 0.80 |
| Gross invasion | 19.1 | −14.8, 66.4 | 0.31 | 0.13 | −0.1, 0.4 | 0.33 |
| Clinically significant by any criteriad | 18.6 | −9.6, 55.4 | 0.22 | 0.22 | −0.1, 0.6 | 0.21 |
Data reported as period percent change from 1935–2018 as overall incidence and mortality, as well as incidence by indicators of clinical significance by difference criteria. Significance reported as 95% confidence interval and as p value, where P-values <0.05 were considered significant.
Data reported as period absolute change from 1935–2018 as overall incidence and mortality, as well as incidence by indicators of clinical significance by difference criteria. Significance reported as 95% confidence interval and as p value, where P-values <0.05 were considered significant.
Significant risk thyroid cancer (SRTC) as described by Wang et al (13) to include medullary, poorly differentiated, anaplastic and metastatic differentiated thyroid cancers
Clinically relevant criteria included: SRTC, tumor size ≥4 cm, or by presence of gross invasion.
Figure 2. Age-adjusted incidence rates 1935–2018 by sex groups.
a Significant risk thyroid cancer (SRTC) as described by Wang et al (13) to include medullary, poorly differentiated, anaplastic and metastatic differentiated thyroid cancers
b Clinically relevant criteria included: SRTC, tumor size ≥4 cm, or by presence of gross invasion.
Figure 3. Sex-adjusted incidence rates 1935–2018 by age groups.
a Significant risk thyroid cancer (SRTC) as described by Wang et al (13) to include medullary, poorly differentiated, anaplastic and metastatic differentiated thyroid cancers
b Clinically relevant criteria included: SRTC, tumor size ≥4 cm, or by presence of gross invasion.
Figure 4. Age Curves by Clinical Relevance.
Clinically relevant criteria included: SRTC, tumor size ≥4 cm, or by presence of gross invasion. Significant risk thyroid cancer (SRTC) as described by Wang et al (13) to include medullary, poorly differentiated, anaplastic and metastatic differentiated thyroid cancers.
Discussion
In this population-based study of more than eight decades, we found that the incidence of clinically relevant thyroid cancers has not changed significantly, despite an overall increase in thyroid cancer incidence of 24.3% over this time. There were slight, non-statistically significant, increases in rates of grossly invasive cancers. Nonetheless, the disproportionate rise in non-clinically relevant thyroid cancers by any criteria of clinical relevance argues against other studies findings’ that suggest that a proportion of new cancers are larger, and more aggressive (2,4). While the overall incidence of thyroid cancer is similar between the REP and the SEER databases (Figure 1), the REP data’s granularity of clinical and pathologic tumor parameters allows for clearer assessment of thyroid cancer aggressiveness beyond routine staging parameters. Our data supports that most diagnosed thyroid cancers are low risk, small, papillary type cancers with excellent prognosis and this finding has important clinical and research implications.
Our data found a significant 27% overall increase of thyroid cancer diagnosis in adults <55 years of age, but no increase in incidence of aggressive thyroid cancers or in mortality in this group. This is consistent with other findings that place thyroid cancer as the most common cancer in American adults 16–33 years of age (15). Similar to the drivers of thyroid cancer in the older population, it seems that more medical scrutiny rather than biological factors impact the diagnosis in this age subset as well. Our data suggests that the proportion of clinically relevant cancers is largest at the extremes of age, and that the highest incidence seen in middle age is predominantly accounted for by cancers not meeting clinical relevance criteria. Additionally, our group has previously reported that, prior to 1999, 85% of the cancer among young adults were clinically recognized (symptoms or palpable); however after 2000, more than three-quarters of cases were found among asymptomatic individuals (e.g., incidental findings in diagnostic neck imaging or on pathology review of specimens from thyroid surgery for benign conditions) (10). Surgical and medical treatment of thyroid cancer in this younger age group can predispose patients to years of follow-up care and adverse consequences of TSH suppression, despite the generally excellent prognosis in this group.
Understanding the characteristics of new thyroid cancer is important because it guides additional research investigating the mechanism behind the rising trends of thyroid cancer. For instance, over the last decade a consistent body of evidence strongly supports the notion that many of the new thyroid cancer cases are found in asymptomatic patients due to the increasing use of neck ultrasound (16). For instance, Haymart et al, using the Surveillance, Epidemiology, and End Results and Medicare dataset, found that the use of thyroid ultrasound has increased 21% per year from 2002 through 2013 in a Medicare population, and this increased use was associated with incidence of small and localized papillary thyroid cancers. They further estimated that at least 6594 patients aged ≥65 years were diagnosed with thyroid cancer in the United States due to increased use of thyroid ultrasound.
From a practical perspective, given the significant emotional, psychological and financial burdens associated with the diagnosis of thyroid cancer (17–19), understanding the indolent course of most thyroid cancers is critical in clinical decision making. Clinicians should apply this knowledge for decision-making regarding management of thyroid cancer, including choosing extent of surgery (lobectomy vs total thyroidectomy) or even active surveillance for small papillary thyroid cancers (6). Despite evidence that small papillary thyroid cancers follow an indolent course (20), adoption of active surveillance for these cancers likely remains low in the U.S as of now and the reproducibility of findings outside the United States are unknown (21). Additionally, careful attention to whether there is need for suppressive thyroid hormone therapy and also to duration of monitoring necessary for a given thyroid cancer may prevent unnecessary burden on the patient. There are certainly continued opportunities to prevent overtreatment of indolent thyroid cancers.
Our study has several limitations. We made the assumption that all clinically aggressive thyroid cancer were included within one of the three subgroups here. A different approach would have been to classify the aggressiveness based on cancer staging. Unfortunately, the REP data available prior to year 2000 would not allow for collection of all data required for accurate cancer staging using most updated staging criteria (7). Wang el al did find that using just the SRTC criteria of aggressive histology or metastatic disease was able to account for all deaths in their geriatric cohort; we combined this approach to other prognostic factors to optimally capture our somewhat younger cohort (13). Our smaller sample size may potentially not have captured a small true increase in rates of aggressive thyroid cancers. The other limitation to our data relates to its generalizability to a more ethnically diverse population than what is represented in the REP. The region captured by the REP is less ethnically diverse than the US population (our cohort was 92% Caucasian), but prior studies do suggest that the cohort is representative of the upper Midwest region (12). This must be taken into consideration, as there are potential racial differences in incidence of thyroid cancer, timing of diagnosis, and clinical relevance of the cancers in minority populations (22).
Conclusion
In our population-based study, we found that the incidence rates of clinically relevant thyroid cancers, as defined by histology, size, and invasiveness, have not changed significantly in 80 years, nor has the increased incidence in thyroid cancer resulted in significant changes in mortality. These findings emphasize continued overdiagnosis of thyroid cancers of limited clinical relevance and highlight this issue particularly in younger adults. It therefore behooves all of us in the medical community to avoid unnecessary medical diagnostic testing in an attempt to reduce the potential of harm resulting from the diagnosis and subsequent treatment of patients with clinically indolent thyroid cancers.
Supplementary Material
Acknowledgments
Financial Support:
We thank the Karl-Erivan Haub Family Career Development Award in Cancer Research at Mayo Clinic in Rochester for funding this research. This study was made possible by the Rochester Epidemiology Project (grant number R01-AG034676).
Abbreviations:
- ATA
American Thyroid Association
- REP
Rochester Epidemiology Project
- SRTC
Significant Risk Thyroid Cancer
Footnotes
Conflict of Interest:
Authors declare that they have no conflicts of interest.
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