Thyroid Cancer Increase: Is It Real?

Alexander M. Castellino, PhD

March 31, 2017

The increase in thyroid cancer seen in the United States in recent decades has been explained as a result of overdiagnosis due to an increase in screening. But new data show an increase in incidence and also ― for the first time ― an increase in cancer-specific mortality. The authors argue that the increase is real.

"While other studies have shown increasing trends in thyroid cancer incidence, this is the first study to highlight the fact that thyroid cancer mortality has increased significantly over the past 20 years," corresponding author Cari M. Kitahara, PhD, MHS, told Medscape Medical News.

Dr Kitahara is an epidemiologist at the Division of Cancer Epidemiology and Genetics at the National Cancer Institute.

This is the first study to highlight the fact that thyroid cancer mortality has increased significantly over the past 20 years. Dr Cari Kitahara

The new data were published online March 31 in the Journal of the American Medical Association.They show an increase in the incidence of thyroid cancer in the United States, driven largely by papillary thyroid cancer (PTC), in the period from 1974 to 2013.

They show an increase in the incidence of thyroid cancer in the United States, driven largely by papillary thyroid cancer (PTC), in the period from 1974 to 2013.

The incidence of thyroid cancer increased at an average rate of 3.6% annually, with PTC increasing by 4.4%.

During these years, overall thyroid cancer mortality increased by 1.1% annually, with an increase of 2.9% reported for patients diagnosed with advanced-stage PTC. The latter may be driven by an increase in advanced-stage PTC of 3.5% since 1981, the authors add.

"These findings are consistent with a true increase...and challenge the prevailing notion that all of the increase in PTC incidence in the United States is related to overdiagnosis," write the authors.

"Our data suggest that overdiagnosis explains some, but not all, of the increasing incidence of thyroid cancer in the United States," Dr Kitahara commented.

"We did observe a substantial increase in the incidence of papillary thyroid cancers that were localized and/or small at diagnosis, which is what we would expect with overdiagnosis, as many of these cancers would not have required treatment if they had gone undetected," she said.

To better understand what has been driving the increase in thyroid cancer deaths, the team made, for the first time, side-by-side comparisons of trends in thyroid cancer incidence and mortality with respect to demographic factors and characteristics of the thyroid cancer (histologic type, stage, and size) at diagnosis, Dr Kitahara explained.

"If overdiagnosis was the only factor driving the increasing trend in thyroid cancer incidence, then we would not expect to see an increase in thyroid cancer mortality," Dr Kitahara told Medscape Medical News.

Very Small Numbers

Medscape Medical News approached Louise Davies, MD, associate professor of surgery/otolaryngology at the Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, for expert comment. Dr Davies' research is focused on the epidemiology of thyroid cancer and head and neck cancer. She was not associated with current study.

"The authors are to be applauded for their work, as it can help those people who present with distant metastatic disease at the time of diagnosis," Dr Davies said.

"However, I am concerned that the numbers of cases that they have available to evaluate are small and that they do not explore alternative hypotheses for their findings," Dr Davies commented. "I do think it is possible to have a real increase in thyroid cancer in addition to overdiagnosis, but it is hard to feel certain that the increase in mortality reported is real," she added.

"This report may not change the broadly accepted interpretation of overdiagnosis for the trends in thyroid cancer that have been observed in the US, South Korea, Italy, France, Australia, and elsewhere across the developed world," Dr Davies said.

"The data reported here about very small changes in mortality for a small number of cases which are advanced at the time of presentation should not change how we think about this much more common scenario," Dr Davies said.

She indicated that the larger public health problem in thyroid cancer is in overdiagosis, but it does not lessen the suffering of the patients and families of people who present with symptomatic, advanced thyroid cancer.

"Thyroid cancer patients who present with advanced disease deserve our best efforts to identify causes and cures," Dr Davies said.

Data Extraction

Dr Kitahara and colleagues analyzed data on thyroid cancer cases were determined from the Surveillance, Epidemiology, and End Results (SEER) cancer incidence file maintained at the National Cancer Institute. Nine high-quality, population-based registries were used. Information on demographics and cancer diagnosis was available for each case.

The incidence-based mortality was determined from incidence files that link cancer characteristics at diagnosis with death certificate information.

The researchers separately looked at trends according to SEER Historic Stage A from 1974-2013 and AJCC/TNM, which is what is used in clinical practice, from 2004–2013, which were the only years for which the data were available. The results were consistent in showing increases in incidence and mortality rates among patients diagnosed with advanced-stage PTC.

Detailed analysis were undertaken to determine annual percentage changes (APC) over the period of analysis (1974-2013). The investigators determined APCs according to demographic characteristics of the patients and the histologic type, stage, and tumor size at diagnosis.

Increasing Trend More Significant for Some but Not All Thyroid Cancer

Of 77,276 thyroid cancer cases that were identified, the most common histogies were PTC (84%) and follicular thyroid cancer (11%). Thyroid cancer incidence rates (per 100,000 person-years) increased over the study period: from 4.56 in 1974-1977 to 14.42 in 2010-2013, representing an average increase of 3.6% per year. The increase was seen regardless of sex, race, and age at diagnosis.

Increases (reported as APCs) were significant for PTC (4.4%), follicular thyroid cancer (0.6%), and medullary thyroid cancer (0.7%). Thyroid cancer mortality rates increased by about 1% per year, on average, between 1994 and 2013.

The increased trend in incidence was not significant across all subgroups studied. PTC increased significantly for every stage and tumor size category, the researchers report.

For mortality, positive APCs were reported for PTCs of all known stages, but significance was seen for those with distant disease and/or stage IV disease. Also, positive APCs were reported for PTCs of all known sizes but were significant for tumors ≤2 cm and those >2 cm to ≤4 cm.

Significant APC for thyroid cancer mortality was not consistent across all age groups and was significant only for patients with PTC at diagnosis. With respect to histology, the 1.7% annual increase in mortality was restricted to patients with a diagnosis of PTC, was seen for PTCs at all stages, but was significant only for patients with distant disease and stage IV disease at diagnosis.

"While the number of deaths due to thyroid cancer each year is small, the degree to which thyroid cancer mortality has risen over the past 20 years has been second only to the increase in liver cancer mortality in the United States," Dr Kitahara said.

"Our study was the first to show trends in thyroid cancer mortality linked to the specific type of thyroid cancer that the patients were previously diagnosed with," she emphasized.

Dr Kitahara agrees that the increase in incidence for small and localized thyroid cancer is consistent with an increase in overdiagnosis. However, it cannot explain why there is an increase in advanced-stage PTC or an increase in deaths due to thyroid cancer, she noted.

"However, little attention has been given to the fact that the rates for advanced-stage and larger PTCs have also been increasing rapidly, which cannot be explained by overdiagnosis, and that thyroid cancer mortality rates have been increasing over time, although more modestly, at about 1% per year," she said.

Explaining the Trend

According to Dr Davies, given the extremely small number of cases, which amount to around 56 deaths per year,the possibility of alternative explanations is likely. She pointed out that the authors used 3-year averages to show a 0.6/100,000 people increase in the mortality rate across the 20-year period.

Dr Davies also indicated that the change in mortality was only significant for people with a PTC that had spread outside the neck at the time of presentation, which represents <5% of all cases. "There was no significant change in mortality rates for people presenting at earlier stages of disease," Dr Davies said.

"But trends are increasing for these other types at nearly the same rates; the trends just do not reach statistical significance because of small numbers of deaths among patients diagnosed with earlier-stage thyroid cancer," Dr Kitahara responded.

What's Next?

According to Dr Davies, it is reasonable to be concerned that there might be a real increase in thyroid cancer in addition to overdiagnosis. "In order to gain confidence in the calculations that were made, additional work should be done to test the hypothesis and identify causative factors that could explain it," she said.

Despite improvements in early detection and diagnosis of thyroid cancer, mortality rates from the disease are increasing over time as opposed to remaining stable or declining. "The findings from our study are concerning," Dr Kitahara said.

"The increase in thyroid cancer mortality is particularly evident for patients who were previously diagnosed with advanced-stage papillary thyroid cancer, suggesting that not only have these cancers become more common over time, they are leading to an increasing number of deaths," she added.

Dr Kitahara explained that during the past 20 years, there have been significant increases in thyroid cancer mortality among patients who were diagnosed with advanced-stage PTC. "Apart from overdiagnosis, changing exposures to certain environmental risk factors and lifestyle factors likely play a role," she suggested.

The increase in incidence and a potential association with environmental risk factors have not gotten much attention, indicated coauthor and surgical oncologist Julie A. Sosa, MD, professor of surgery and medicine, chief of the Section of Endocrine Surgery, Duke University, Durham, North Carolina. Both Dr Sosa and Dr Kitahara indicated the need for epidemiologic studies to identify specific environmental factors and exposures that might be contributing to this increase incidence.

Known changes in the prevalence of certain risk factors for thyroid cancer, such as obesity (which is associated with higher risk) and smoking (which is associated with lower risk), parallel the observed trends in thyroid cancer risk, Dr Kitahara pointed out.

"There are some studies that suggest that obesity is associated with more aggressive types of papillary thyroid cancer, so we think that the large increase in the prevalence of obesity over the past 30 years is a likely contributor to the rising rates of papillary thyroid cancer in the United States," she said.

"There has been a growing appreciation that we should not overdiagnose and overtreat differentiated thyroid cancer," Dr Sosa said. In 2015, she was on the American Thyroid Association task force panel that formulated guidelines on how to manage thyroid nodules and differentiated thyroid cancer, she indicated. Being less aggressive about putting needles into thyroid nodules, performing less surgery, and utilizing less radioactive iodine, were the basic take-home message of the guidelines.

The United States Preventive Services Task Force has published a draft of its guidance for screening for thyroid cancer, which wil be released in May 2017. It recommends against thyroid cancer screening for asymptomatic patients. "[S]creening results in the identification of indolent thyroid cancers and treatment of these 'overdiagnosed' cancers can pose real patient harms," it concludes.

Against this context, Dr Sosa told Medscape Medical News that their study raises a cautionary note. "The pendulum that has swung very far in the direction of less diagnosis, less treatment, and more parsimonious surveillance might potentially now need to rest closer to the middle," she said.

"There is an increase in the incidence of bigger and advanced-stage tumors and an increase in mortality, and this appears to be real," she said.

"We have to do a better job at reducing mortality from PTC," Dr Sosa said. "There are not many cancers where mortality is increasing in the United States. With thyroid cancer, we are still losing ground" she added.

Dr Sosa added that it is "not that we do not treat aggressive thyroid cancer aggressively," but she pointed out that there are limited treatment options. Lenvatinib (Lenvima, Eisai) and sorafenib (Nexavar, Bayer) are the only two drugs approved for iodine-refractory advanced differentiated thyroid cancer. "We need to work in drug discovery and clinical trials to develop more novel, small molecule therapies against aggressive disease," she said. If additional risk factors for thyroid cancer are identified, efforts at prevention could be undertaken, she indicated.

Dr Kitahara and Dr Sosa are members of the Data Monitoring Committee of the Medullary Thyroid Cancer Consortium Registry, which is supported by Novo Nordisk, GlaxoSmithKline, Astra Zeneca, and Eli Lilly. Dr Davies has disclosed no relevant financial relationships.

JAMA. Published online March 31, 2017. Full text

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