‘Overdiagnosis’ may not fully explain rise in pediatric thyroid cancer incidence

Thyroid cancer incidence is increasing at a rate faster than that of any other cancer.

Among adults, that increase can be attributed in part to greater use of detection methods, thereby increasing the likelihood of discovering smaller tumors that may never pose significant mortality risk.

However, children may be less likely to undergo imaging studies that might reveal such small, indolent tumors, as initiatives aim to limit their exposure to ionizing radiation and thus reduce their risk for cancer later in life.

Nevertheless, data show incidence of pediatric thyroid cancer also is increasing.

Results of a SEER analysis published in 2019 in JAMA Otolaryngology-Head & Neck Surgery showed incidence of thyroid cancer among children and adolescents increased annually from 0.48 per 100,000 person-years in 1973 to 1.14 per 100,000 person-years in 2013.

Qian and colleagues calculated an annual percent change (APC) of 9.56% between 2006 and 2013 compared with 1.11% from 1973 to 2006. They also observed a marked increase in incidence during that later period of both small tumors, measuring 1 mm to 20 mm (APC, 9.66%), and tumors larger than 20 mm (APC, 8.84%).

“When we see rate increases among children that are similar to adults alongside an increase in incidence of smaller lesions, that tends to indicate an increase in detection of incidental findings via imaging that may reveal an otherwise unknown thyroid nodule,” Amy Y. Chen, MD, MPH, FACS, FACE, Willard and Lillian Hackerman professor of otolaryngology and director of endocrine surgery in the department of otolaryngology-head and neck surgery at Emory University, told HemOnc Today. “However, this SEER analysis by Qian and colleagues also showed increased rates of larger tumors and more advanced disease; but, it is uncertain whether that represents a true increase in incidence.

“Although future studies are needed to know why this is happening, overdiagnosis could be an explanation, but there could also be environmental factors at play,” Chen added.

HemOnc Today spoke with oncologists, endocrinologists and otolaryngologists about the potential drivers of this growing incidence of pediatric thyroid cancer, whether thyroid cancers are being overdiagnosed among children, and how future research aims to further characterize pediatric thyroid cancers as distinct from those occurring among adults.

Growing incidence

The increase in thyroid cancer incidence among children may be driven by a combination of both increased surveillance and environmental factors.

“There is absolutely increased surveillance,” David Goldenberg, MD, FACS, Steven and Sharon Baron professor and chair of the department of otolaryngology-head and neck surgery at Penn State College of Medicine, said during an interview with HemOnc Today. “Children, much like every other age group, are having more imaging testing done and more scans because they fell down or they had an accident and then thyroid cancer is discovered.”

Still, Goldenberg added, evidence has shown that other factors may be behind the increased incidence.

“The way we know this is because it is not only small cancers that are being diagnosed, but also large cancers,” Goldenberg said. “From this, we can extrapolate that there is probably something else going on that is causing a real increase in thyroid cancer incidence. Is it environmental? That is a good question.”

Data from a retrospective study published in Cancer suggested the increased incidence is not due to increased surveillance alone.

Bernier and colleagues used data from 39 U.S. cancer registries covering about 80% of the U.S. population to assess incidence of differentiated thyroid cancer from 1998 to 2013 among patients aged 0 to 19 years.

Results showed 7,296 diagnosed cases of differentiated thyroid cancer (papillary thyroid cancer, n = 6,652; follicular thyroid cancer, n = 644), with a significant APC of 4.43% (95% CI, 3.74-5.13).

Researchers observed significant increases for localized differentiated thyroid cancer (APC, 4.06%), and differentiated thyroid cancer with regional (APC, 5.68%) and distant (APC, 8.55%) metastasis, as well as increases for tumors smaller than 1 cm (APC, 9.46%) and larger than 2 cm (APC, 4.69%).

Given these findings, particularly the large APC for distant tumors, Bernier and colleagues wrote the growing incidence is unlikely due to increased surveillance alone — with other risk factors including obesity, endocrine-disrupting chemicals and sex-hormone changes during puberty — although the prevalence of smaller tumors means researchers “might not be able to rule out a contribution of overdetection.”

Goldenberg agreed that research is needed to determine whether environmental or lifestyle factors are behind the increase.

“Although overdiagnosis certainly occurs, this does not absolve us of the duty to seek the cause of the real rise in thyroid cancer,” he wrote in an editorial accompanying the study. “In this light, we must closely examine the factors that may be causing a true increase in thyroid cancer, as well as differentiating which thyroid cancers will behave in an indolent fashion vs. an aggressive fashion.”

Goldenberg noted that trends in obesity, as well as longer reproductive years for women, may be playing a role.

“The prevalence of obesity has risen substantially in many countries in recent years and has consistently been associated in epidemiological studies with an increased risk [for] thyroid cancer,” he wrote. “Smoking [in men may be] associated with a reduced risk [for] thyroid cancer, and thus a declining smoking prevalence also may be a contributing factor toward thyroid cancer incidence. Exogenous factors such as iodine deficiency and, [conversely,] improved iodine nutrition also have been suggested as potential risk factors for thyroid cancer.”

Other risk factors specific to pediatric thyroid cancer include rare hereditary conditions, Goldenberg told HemOnc Today.

“Additional risk factors for thyroid cancer in children may be autoimmune, perhaps Hashimoto thyroiditis; nutritional iodine deficiency, which is very rare this country; or prior radiation exposure, which typically occurs in a child who was irradiated with a low dose of radiation to the area of the thyroid for Hodgkin lymphoma or a neurological cancer,” he said.

“Thyroid cancer is on the rise, whether in adults or children,” he added. “It is destined to soon become one of the most common cancers in women. I caution people who say, ‘It’s just overdiagnosis, don’t worry about it.’ I’m always very fearful about statements like that.”

Overdiagnosis

On the flip slide, some experts believe overdiagnosis is at least partially driving the increased incidence of pediatric thyroid cancer.

In a counterpoint editorial to Goldenberg’s published alongside the study by Bernier and colleagues, Chen and Louise Davies, MD, MS, senior faculty member of the VA Outcomes Group at Veterans Affairs Medical Center in White River Junction, Vermont, and associate professor at Dartmouth Institute for Health Policy and Clinical Practice, wrote that overdiagnosis should be closely examined, as it “appears to be a likely explanation.”

“If it appears to be a true increase, then efforts need to be made to determine new theories of causation,” Chen and Davies wrote. “However, if it is due to the detection of subclinical disease, then efforts are necessary to curb the use of CT scans, the inappropriate use of ultrasound and needle biopsies.”

In a 2016 study, Morris and colleagues reported a 6.7% annual percentage increase in thyroid cancer incidence from 1998 to 2009, which then stabilized at 1.75% from 2010 to 2012. According to Chen and Davies, this stabilization corresponded with 2009 guidelines from the American Thyroid Association (ATA) that discouraged sampling of small lesions, suggesting overdiagnosis had been driving the earlier increases.

“Although we agree that a true increase in the incidence of thyroid cancer is possible ... we also are once again concerned that the inferences being drawn from the U.S. cancer epidemiology data may be artifactual,” they added.

In a study published in January, Salvatore Vaccarella, PhD, scientist in the section of cancer surveillance at International Agency for Research on Cancer at WHO, and colleagues observed that global trends in thyroid cancer incidence among children and adolescents mirror that of adults, which suggests overdiagnosis may be at play.

The results, published in The Lancet Diabetes & Endocrinology, showed rapid increases in incidence between 1998 and 2002 and between 2008 and 2012, and that country-specific incidence rates among children and adolescents strongly correlated with rates among adults (r > 0.8).

“Our study suggests that overdiagnosis may be the major driver of the increases observed in incidence among children, and particularly among adolescents,” Vaccarella told HemOnc Today when the study was published. “This is because of the similarity of the geographical and epidemiological patterns with those observed in adults, for which there is a consensus that overdiagnosis plays a massive role [in increased cancer incidence].”

However, the concept of overdiagnosis should be distinguished from early diagnosis, according to Andrew J. Bauer, MD, endocrinologist and medical director of the Pediatric Thyroid Center at Children’s Hospital of Philadelphia (CHOP).

There are indolent thyroid cancers that remain intrathyroidal and do not metastasize, Bauer said.

“We know that up to 10% of us will die of old age and an incidental thyroid cancer may be found on autopsy,” Bauer told HemOnc Today. “This indicates that indolent thyroid cancers do exist. When a small, intrathyroidal papillary thyroid cancer is found and confirmed by fine needle aspiration [FNA] biopsy in adults, there are ongoing studies for active surveillance to determine if surgical resection would be indicated and beneficial. It makes sense that similar tumors exist in pediatrics; however, we lack data on active surveillance among the pediatric population as the majority of patients and families elect to have the thyroid cancer surgically resected.

“In addition, if a central neck lymph node dissection is performed at the time of resection of a small, intrathyroidal papillary thyroid cancer, approximately 30% of patients will have positive, papillary thyroid cancer metastasis to lymph nodes in the central compartment of the neck,” Bauer added, referencing a study by Sugino and colleagues published in Thyroid and additional data pending publication from his group at CHOP.

“Based on this, we lack any data to confirm ‘overdiagnosis’ and we have data to suggest that a significant portion of pediatric patients who undergo surgery for small, intrathyroidal papillary thyroid cancer may benefit from early diagnosis of a cancer that may have progressed throughout their lifetime requiring a greater extent of surgical and medical therapy,” he added.

Moreover, the term “overdiagnosis” may minimize the patient experience and perspective.

“The head of my translational science program, Aime T. Franco, PhD, who is also a thyroid cancer survivor, told me, ‘Because quality of life is not studied in many of these populations, death is reported as the only outcome that matters. Just because a patient does not die of thyroid cancer does not mean that it should not be diagnosed or treated,’” Bauer said.

Treatment and outcomes

Whether papillary thyroid cancer — the most common form, representing 90% of cases and characterized by slow growth and high likelihood to spread to the regional lymph nodes — or follicular thyroid cancer, which is less common and less likely to metastasize in children, differentiated thyroid cancers have been associated with extremely low disease-specific mortality among children even when metastatic, with a 30-year survival rate of more than 95%.

The explanation for high survival is a matter of ongoing investigation, but experts suggest it is likely due to maintenance of differentiation and excellent response to radioactive iodine therapy.

“What is also clear is that symptoms at the time of diagnosis and disease-specific mortality are not useful metrics in judging overdiagnosis vs. early diagnosis, as the majority of adults and children are asymptomatic at the time of diagnosis, and the mortality rate of patients aged younger than 45 years with papillary thyroid cancer is 2% or lower, and less than 1% in children,” Bauer added.

But, because pediatric thyroid cancer is a small part of the overall “thyroid cancer pie,” with less than 2% of all cases occurring among those aged younger than 20 years, only recently has the ATA developed specific guidelines for the pediatric population, according to Douglas S. Hawkins, MD, researcher at University of Washington Medical Center, Fred Hutchinson Cancer Research Center and Cancer and Blood Disorders Center at Seattle Children’s Hospital.

“The guidelines home in on specific issues unique to children, including the difference in the risk for metastatic disease and specific molecular features that are seen in pediatric thyroid cancer and some of the side effects that are more of a concern to children,” Hawkins told HemOnc Today. “In addition, some of the guidelines for adults would not necessarily line up for children, in particular very small children.”

The current paradigm of care as established by the ATA guidelines recommends that the most children with thyroid cancer first undergo thyroidectomy followed by radioactive iodine therapy.

“Radioactive iodine therapy is limited to patients based upon surgical pathology, including the presence or absence of lymph node metastases to the central neck. During the past 6 years, increasing efforts to more thoughtfully stratify both surgery, as well as radioactive iodine, have been made,” said Bauer, co-chair of the ATA guidelines.

Factors used to inform treatment include:

• thyroid and neck ultrasound — ultrasound features of thyroid nodules correlate with the risk for invasive behavior, and all patients who undergo FNA must have an accurate and complete ultrasound interrogation of the central and lateral neck for lymphadenopathy;
• results of the FNA based on the Bethesda System for Reporting Thyroid Cytopathology;
• somatic oncogene testing — accumulating data show a correlation between oncogene alteration and invasive behavior, with mutations in RAS, PTEN and DICER1 associated with low risk for extrathyroidal disease and alterations in BRAF V600E, RET/PTC and NTRK fusions associated with a high risk for invasive behavior; and
• surgical pathology, where the presence of multifocal disease, lymphatic invasion, vascular invasion and extrathyroidal extension correlate with invasive behavior.

When choosing treatments, clinicians also must consider the risk for long-term treatment effects.

“For surgery, the long-term concerns are twofold and every effort needs to be made to reduce the risk for recurrent laryngeal nerve damage (and damage to other nerves), as well as the risk for permanent hypoparathyroidism,” Bauer said. “For radioactive iodine, the goal is to reduce the risk for salivary gland damage, pulmonary fibrosis and radioactive iodine-induced second malignancy.”

That risk associated with radioactive iodine means clinicians must be judicious about its use among children, Goldenberg added, which again raises the importance of considering whether some children are overdiagnosed and overtreated.

“Also, if we take out someone’s thyroid, we render them hypothyroid for life and dependent on medication,” he added. “For a child, even a teenager, giving a lifelong medication can cause a problem with compliance. The dosage has to be tailored as they grow and go through puberty and other changes. For women, that means adjustment due to menstruation, pregnancy and lactation, which affect the amount of thyroid hormone. The patient has a lifelong relationship with this medication, and long-term treatment is absolutely a concern.”

It is these long-term concerns that necessitate a multidisciplinary team approach to care, Chen said.

“Because thyroid cancers are fairly rare among children, it would be important to have a multidisciplinary team evaluate the patient to render treatment recommendations and follow-up care,” she said. “Thyroid cancer surgery can be risky for any patient and particularly for children because any sort of complication from the surgery will be with the child for the rest of his or her life. It is important to go to a high-volume surgeon with specialized expertise in thyroid surgery and in the head and neck for their care. Data show that going to a high-volume surgeon can decrease risk for complications.”

Future research

Given the rising incidence of pediatric thyroid cancer, evaluating how its pathogenesis differs from that of adults is one area of active investigation.

“We talk about ionizing radiation as a risk factor for thyroid cancer, but there must be other factors at play in order for the carcinogenesis to begin,” Chen said. “That is where a lot of the research regarding environmental or hormonal factors could impact care.”

According to Bauer, children are more likely to have lymph node and lung metastasis at diagnosis than adults. However, he added that survival remains high in the pediatric population, the reason for which is unknown and an area of ongoing investigation.

“On a molecular basis, the same driver mutations found in pediatric papillary thyroid cancers are also seen in adult cases. Fusion alterations involving RET and NTRK are more commonly associated with invasive disease in children, whereas mutations in BRAF are more commonly associated with invasive and refractory disease in adults. Similar between children and adults, somatic mutations in PTEN, DICER1 and RAS are more commonly associated with low risk for invasive behavior.”

Identifying targetable mutations in thyroid cancer may be important to inform systemic treatment, Chen said.

“A lot of the current research is exploring how best to treat patients who have widespread thyroid cancer with systemic treatment,” she said. “What are the targetable mutations in the thyroid cancer itself that we can act upon in order to arrest the growth of these cancers with newer agents such as tyrosine kinase inhibitors and immunotherapies?”

Research in this area continues, according to Bauer. He referenced a review published in JAMA Otolaryngology-Head & Neck Surgery in which Kazahaya and colleagues concluded children with advanced invasive thyroid cancer should be included in clinical trials of oncogene-specific targeted therapy.

“We are actively involved in clinical and translational research to help identify clinical characteristics and molecular markers to help guide stratification of therapy, including surgery and radioactive iodine, with the goal of minimizing intervention for patients with low-invasive disease while still achieving remission and maintaining a low risk for recurrence,” Bauer said. “Based on the fact that there is low disease-specific mortality associated with thyroid cancer in pediatric patients, the metrics of therapy are to achieve remission, decrease the risk for lifetime recurrence and minimize the complications of therapy.”

The first step in this process, Bauer added, is to ensure that children are evaluated and managed across centers with a dedicated, multidisciplinary thyroid team that has an established protocol for evaluation and treatment.

“Ideally, there should be at least one center in every state and each center should be obligated to report metrics of complications and outcomes,” Bauer said. “To this end, in 2020, CHOP established an international, collaborative Child and Adolescent Thyroid Consortium, along with other executive members, including The University of Texas MD Anderson Cancer Center, The Hospital for Sick Children in Toronto, Boston Children’s Hospital and Yale Cancer Center. More than 20 other pediatric thyroid disease centers are in the queue to bring on board during the next 2 to 3 years. The mission of the consortium is to expand our pediatric thyroid community and improve care for pediatric patients with thyroid disease, not limited to thyroid cancer.”

Such research can stand to elucidate the relationship between Hashimoto thyroiditis and thyroid cancer, Goldenberg said.

“A lot of women and female children have Hashimoto thyroiditis,” he said. “Most of them do not go on to develop thyroid cancer, but some of them do and we do not know the relationship between the autoimmune thyroid disorder and thyroid cancer. We think it may be an increase in thyroid-stimulating hormone, which is encouraging the growth of the cancer, but we are not yet certain.

“In a nutshell, so many cool things are going on in the pediatric thyroid cancer area,” Goldenberg added. “Still, as a thyroid cancer surgeon and researcher, I know that there is a lot more to learn.”

• References:
• Bernier MO, et al. Cancer. 2019;doi:10.1002/cncr.32125.
• Chen AY and Davies L. Cancer. 2019;doi:10.1002/cncr.32124.
• Francis GL, et al. Thyroid. 2015;doi:10.1089/thy.2014.0460.
• Kazahaya K, et al. JAMA Otolaryngol Head Neck Surg. 2020;doi:10.1001/jamaoto.2020.1340.
• Morris LGT. JAMA Otolaryngol Head Neck Surg. 2016;doi:10.1001/jamaoto.2016.0230.
• Qian ZJ, et al. JAMA Otolaryngol Head Neck Surg. 2019;doi:10.1001/jamaoto.2019.0898.
• Sugino K, et al. Thyroid. 2020;doi:10.1089/thy.2019.0231.
• Vaccarella S, et al. Lancet Diabetes Endocrinol. 2021;doi:10.1016/S2213-8587(20)30401-0.

• For more information:
• Andrew J. Bauer, MD, can be reached at bauera@chop.edu.
• Amy Y. Chen, MD, MPH, FACS, FACE, can be reached at achen@emory.edu.
• David Goldenberg, MD, FACS, can be reached at dgoldenberg@pennstatehealth.psu.edu.
• Douglas S. Hawkins, MD, can be reached at doug.hawkins@seattlechildrens.org.

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