When you look carefully at the data, as several research teams have done, you see an increase in [thyroid] cancers of all sizes, not just the small tumors, as you would expect with overdiagnosis.
—Jennifer Sipos, MD
According to data from the Surveillance, Epidemiology, and End Results (SEER) program, rates for new cases of thyroid cancer in the United States have been rising on average 6.4% each year over the past 10 years, and death rates have been rising on average 0.9% each year over the same period.
The ASCO Post asked thyroid cancer expert Jennifer Sipos, MD, Associate Professor of Medicine at The Ohio State University (OSU), Columbus, to help us explore the rise in thyroid cancer diagnoses, and to describe where her research team’s efforts are taking the field.
Trends in Incidence and Research Funding
Mounting evidence suggests that thyroid cancer is on the rise. Is this why more money is being directed toward thyroid cancer research?
Since around 1975, the incidence of thyroid cancer has nearly tripled, from about 5 cases per 100,000 persons to more than 14, virtually all due to increases in papillary thyroid cancer.1 For the follicular, medullary, and anaplastic forms, the incidence has remained stable.
It’s shocking that if we project the current trend through 2019, the incidence will double and thyroid cancer will become the third most common cancer in women of all ages, according to a recent study.2 Managing these patients from diagnosis through treatment, and the lifetime of follow-up that is required, will cost the United States $18 billion to $21 billion, the research showed.
In spite of its growing frequency, however, thyroid cancer remains significantly underfunded. In 2009, the National Cancer Institute allotted only $14.7 million to thyroid cancer research, which makes it 30th among all cancers in NCI funding.2
Recently, OSU obtained an $11 million Thyroid Cancer SPORE (Specialized Program of Research Excellence) grant, through the leadership of Matthew Ringel, MD, who is Professor of Medicine and Director of Endocrinology, Diabetes and Metabolism. This will allow us to study several important areas, including the development of better biomarkers and treatment options for patients with progressive metastatic medullary thyroid cancer and the identification of persons most at risk for toxicity from radioactive iodine.
‘Epidemic of Diagnosis’?
A recent study by Davies and Welch suggested that the increased incidence of thyroid cancer appears to be an “epidemic of diagnosis” rather than disease, mostly due to the detection of small papillary cancers (see sidebar).1 Can you comment on this?
Their belief is that these small cancers are a casualty of overdiagnosis and are not clinically meaningful, and I agree to a certain extent. We are getting computed tomography (CT) scans for so many minor indications that we are finding disease that would otherwise go undetected. In autopsy series, we find that 10% to 15% of individuals have occult thyroid cancer, and surgical series as well suggest that up to 10% of persons undergoing surgery for reasons other than cancer end up with a diagnosis of thyroid cancer. Most are tiny tumors < 2 cm. Davies and Welch are deriving data from such registries.
But when you look carefully at the data, as several research teams have done, you see an increase in cancers of all sizes, not just the small tumors, as you would expect with overdiagnosis. Cramer at al examined the SEER cancer data registry between 1983 and 2006 and found an increase of 19.2% per year in papillary tumors < 1.0 cm, a 12.3% per year increase in tumors measuring 1.1 to 2.0 cm, a 10.3% per year increase in tumors of 2.1 to 5.0 cm, and a 12.0% per year increase in tumors > 5 cm, all statistically significant (P < .0001).3
Most new diagnoses are for cancers < 2 cm in people under the age of 45 who got CT scans for other reasons. About 40% of thyroid nodules are identified by imaging modalities that were not ordered for the thyroid. But there may be other disease-related factors besides increased diagnosis.
Other Risk Factors
What might these other risk factors be?
The primary risk factor for thyroid cancer is radiation exposure, particularly at a young age. This is primarily in the form of external-beam irradiation in the head and neck area, and especially before age 15. We believe that such radiation at this age increases the risk of nodules and probably cancer, but it is harder to quantify.
Of course, we are also all exposed to radiation through diagnostic imaging, air travel, perhaps dental x-rays, and so forth. But there are not many studies of risk from this level of exposure.
The other theory pertains to exposure to environmental compounds that have an extremely long biologic half-life—hundreds of years. Polybrominated diphenyl ethers (PBDEs) are compounds used as flame retardants, building materials, electronics, plastics, and other products. They are ubiquitous in the environment and have attracted attention as health hazards. Some research suggests PBDEs are endocrine disrupters and could be implicated in the development of nodules and neoplasms.
Another theory pertains to insulin resistance, since persons with higher insulin levels are more likely to have nodules and a higher thyroid volume. Insulin is a growth factor and has some interaction with the thyroid-stimulating hormone receptor. This has led to the theory that persons with insulin resistance are at increased risk for thyroid cancer.
To some degree, there is a genetic link as well. Ohio State University has a large repository of data, which we have been mining for years, and we have documented that about 5% of persons with papillary thyroid cancer and 25% with medullary thyroid cancer have a familial history.
Nodule Assessment and Management
When there is an incidental finding of a thyroid nodule, what is your next step?
Once you know there is a nodule, you have to investigate further. You assess the risk of malignancy in that nodule based on ultrasound features and other associated findings. Further management depends on patient-related factors—for example, age and comorbidities. An 87-year-old with an incidental nodule is less concerning than a 28-year-old with the same finding, and the older patient probably has comorbidities that would prohibit surgery. The clinical context is important.
There is definite evidence that small cancers that are left alone often are not clinically meaningful. If they are never diagnosed, the person dies with them, not from them. But we can’t just disregard all small cancers. An aggressive cancer that metastasizes to a 4cm lesion in the lung began as a localized tumor less than 1 mm and grew. We have to stratify patients.
Hopefully, molecular testing will help us do this proactively in the future, to be able to determine the need for surgery and the need for radioactive iodine, which we normally wouldn’t give for a small cancer. We need to learn which cancers need close monitoring.
Genetic profiling is becoming critical in all malignancies. How are you applying this in thyroid cancer?
We believe some individual mutations may be important in thyroid cancer, though BRAF and to some extent RAS are the only ones being used clinically now. We are starting to apply these in advanced disease, and we have drugs targeting BRAF. There is also evidence to suggest that RAS-positive tumors respond better than RAS-negative tumors to the MEK inhibitor selumetinib.
Larger studies are trying to ferret out these differences. We have implemented them in advanced disease, and we are researching how to use genetics to project which cancers will be more aggressive.
Research at OSU
How is Ohio State University moving the field of thyroid research forward?
OSU has a long history of important discoveries that have changed our understanding of the pathogenesis of thyroid cancer and how we treat it. One particular researcher, Sissy M. Jhiang, PhD, was integral in outlining the role of RET/PTC translocations in the pathogenesis of thyroid cancer and in identifying the sodium-iodide symporter in salivary and breast tissues. The latter discovery led to Dr. Jhiang’s interest in the pathogenesis of salivary damage from radioactive iodine therapy. While some may view this as merely an inconvenience in the entire scheme of treating a malignancy, salivary damage—with its resultant dry mouth and occasionally, pain—can significantly impact quality of life.
Currently, we cannot predict who will develop this complication, which is generally, but not always, dose-dependent. We are studying patient factors such as age, gender, family history of autoimmune disease, and preexisting salivary conditions, and we are looking for predictive biomarkers in saliva, to determine if we can predict individual risk. The goal is to apply these data clinically in counseling patients, in modifying treatment, and in the research setting, to develop future treatments that avoid salivary injury in all patients. This is an exciting opportunity to impact patient care and a great example of the bench-to-bedside research projects that are ongoing at Ohio State. ■
Disclosure: Drs. Sipos and Jhiang reported no potential conflicts of interest.
1. Davies L, Welch HG: Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg. February 20, 2014 (early release online).
2. Aschebrook-Kilfoy B, Schechter RB, Shih Y-CT, et al: The clinical and economic burden of a sustained increase in thyroid cancer incidence. Cancer Epidemiol Biomarkers Prev 22:1252-1259, 2013.
3. Cramer JD, Fu PF, Harth KC, et al: Analysis of the rising incidence of thyroid cancer using the Surveillance, Epidemiology and End Results national cancer data registry. Surgery 148:1147-1153, 2010.