David Goldenberg, MD, FACS, discusses possible risk factors associated with thyroid cancer, including a retrospective analysis that looked at the effect of radiation exposure.
David Goldenberg, MD, FACS
Although thyroid cancer is curable in the vast majority of patients, that is not to say these patients aren’t faced with long-term issues associated with their disease, including morbidity, test anxiety, and significant financial hardships. Moreover, the incidence of thyroid cancer has dramatically increased over the past 4 decades, said David Goldenberg, MD, FACS.
One possible reason why thyroid cancer rates have increased dramatically is overdiagnosis, as more patients are now undergoing tests that allow physicians to detect the disease. A second theory suggests that the rise in thyroid cancer rates may be linked to certain risk factors, including being a female, familial history, obesity, or exposure to radiation.
In a 2017 analysis published inThe Laryngoscopeby Goldenberg and colleagues at the Pennsylvania State University College of Medicine, they used next-generation sequencing to examine the molecular profile of patients affected by the accidental partial meltdown at the Three Mile Island nuclear power plant in the Middletown, Pennsylvania area in 1979.
In the retrospective analysis, Goldenberg and his co-authors looked at 44 patients that were diagnosed with thyroid cancer between 1974 and 2014 and found that there was a change in the patients’ molecular signal about 7 to 15 years after the Three Mile Island accident.
These findings came after a prior study published inJAMA Otolaryngol Head & Neck Surgeryin 2014, which looked at data from the Surveillance Epidemiology and End Results 9 (SEER-9) registry and the Pennsylvania Cancer Registry between 1985 and 2009 to compare the increase in cancer incidence in Pennsylvania versus the rest of the country. This study showed that the number of newly diagnosed thyroid cancer cases increased 7.1% per year in Pennsylvania (95% CI, 6.3%-7.9%) compared with 4.2% per year (95% CI, 3.7%-4.7%) in the remainder of the United States.
In an interview withTargeted Oncology,Goldenberg, professor and Chief of otolaryngology-head and neck surgery at Penn State Health, discussed the findings of the retrospective analysis and shed light on possible risk factors for developing thyroid cancer.
TARGETED ONCOLOGY:Can you start by discussing the incidence of thyroid cancer and, in particular, the incidence of thyroid cancer in Pennsylvania?
Goldenberg:The incidence of thyroid cancer has tripled in the US since the 1970s. Back in 2014, we found that the incidence of thyroid cancer was not only higher in Pennsylvania than in any other state, but that the increase rate was also greater in Pennsylvania. When we did this study back in 2014, we found an [average] growth rate of 4.2% per year compared with 7.1% in Pennsylvania.
Thyroid cancer is now the seventh leading cancer in the entire nation, and it is the fastest growing cancer in women, but we don’t know why exactly. We have 2 main theories. One of them is artificial: overdiagnosis. This means that we are looking harder and therefore finding more. We are getting more CT scans, more ultrasounds, and more doppler [ultrasounds] for other reasons, and we are discovering thyroid nodules that may not have been discovered otherwise. Some, myself NOT included, call those “clinically insignificant” or a “reservoir of thyroid cancer.” What that means is that these are thyroid cancers that, if not discovered, would not have hurt the patient. The other theory is that there is a real reason; there’s something new that is causing this thyroid cancer epidemic, if you will, and if you’re asking me, I would say the truth lies somewhere in the middle.
Thyroid cancer with no known cause is called sporadic, Thyroid cancer is 3 to 4 times more common in females than it is in males. Being a female could therefore be called a risk factor; it’s usually in the reproductive years, so being a young female is a risk factor. In a small amount of cases of low dose radiation exposure, whether therapeutic or accidental, with a lag period of say 10 to 20 years after the exposure, is a risk factor for the development of thyroid cancer.
TARGETED ONCOLOGY:How do you know there is a lag period after exposure to radiation?
Goldenberg:We know that from people who have been treated with radiation for, let’s say, a childhood cancer. If a kid was irradiated to the head and neck for Hodgkin’s lymphoma, and 10-20 years later, they develop a thyroid cancer, we see them. Those who were exposed to nuclear accidents like Chernobyl in 1986 developed thyroid cancers after a number of years as well. That’s how we know thyroid cancer can be caused by low dose radiation with a lag time.
TARGETED ONCOLOGY:Are there any other risk factors that can play a role in the development of thyroid cancer?
Goldenberg:Another even less common risk factor is family history. We think this is about 15% direct to family history. I’m not saying that we know a direct inheritance mechanism. Our lab is working on something like that when it comes to familial thyroid cancer, but it’s not all that common. In majority of the cases, we don’t know why it happens. Since we don’t know why it happens, it is very difficult for us to say why it is happening more here than there.
We published one study, showing an association between obesity and thyroid cancer. If you look, there are another studies that show the same findings. This is another place where we are looking; that could be a reason.
There are a multitude of studies that look for other etiologies, whether it is iodine, too much or too little, nitrates in foods, or female hormones because there are estrogen receptors on the thyroid gland, and it’s a woman’s disease. Unfortunately, the short answer is we don’t know. There’s certainly something to the overdiagnosis issue, and there’s no doubt about it. I don’t know if I agree with the “clinically insignificant” portion of it, but we are discovering more of these because we are looking harder.
TARGETED ONCOLOGY:Can you discuss the significance of the 1979 accident at the Three Mile Island Nuclear Generating Station?
Goldenberg:That’s a whole different ballgame. The other study that we did called the clustering of thyroid cancer did not find that [it was related to increased thyroid cancer incidence]. We published a study on thyroid cancer in the vicinity of the Three Mile Island area, and none of these found an increased incidence. In another study we did, we actually found the biggest cluster was out around Pittsburg in the west of the state, so not in the same area as Three Mile Island.
Fast forward a couple years ago, our lab performed a study where we looked at molecular markers of radiation-induced versus sporadic-induced thyroid cancer. The vast majority of thyroid cancers, again, are sporadic; we don’t know why they happen. Those typically have certain mutational signals, for instance aBRAFmutation. We know, and this was discovered by Yuri E. Nikiforov, MD, PhD, at the University of Pittsburg when he did his work on Chernobyl samples from the 1986 Chernobyl meltdown; he discovered that thyroid cancers that occur in people that had their thyroid cancer develop because of exposure to radiation had a different molecular signal. They tend to lose theBRAFmutation and getRASmutations instead.
In our study, what we did is we looked at thyroid cancer samples from before the nuclear accident at Three Mile Island in 1979 up until present day. Unfortunately, it was a small sample size. We saw there was a change in the molecular signal about 7 to 15 years after the nuclear accident, meaning something happened that caused the thyroid cancers to change from the sporadic variety to the radiation-induced variety, but that’s all we found.
TARGETED ONCOLOGY:Overall, how does the treatment landscape look now for patients with thyroid cancer?
Goldenberg:Thyroid cancer has not gotten the attention it deserves, mostly because the prognosis is excellent. In a young woman, the cure rate is between 95% and 98%. Even those who go on to develop regional metastases do fine. The vast majority of patients do well. We do however see the ones that go on to die from thyroid cancer. If there are about 52,000 new cases of thyroid cancer, there’s about 2,000 deaths from thyroid cancer, so the vast majority of these patients do not die from this disease.
That’s not to say they don’t suffer, because if you look at the statistics, it’s almost like a chronic disease such as diabetes or high blood pressure. Patients with thyroid cancer have been shown to have the highest rate of bankruptcy of any cancer and financial hardships; The reason that is because they have to live for a very long time with their disease, with surveillance, with blood tests, ultrasounds, and what not.
The treatment for thyroid cancer is surgical. We remove the thyroid gland in the adjacent lymph nodes, then they get radioactive iodine as an adjuvant treatment. Because almost all iodine in your bloodstream gets taken up by the thyroid gland, radioactive iodine (I-131) is used to destroy the thyroid cancer cells; typically, there’s no chemotherapy or external beam radiation necessary. The vast majority of patients do fine with that.
TARGETED ONCOLOGY:What are some of the latest advances in the field?
Goldenberg:The first thing that is new is that we are doing a lot less thyroid surgery for indeterminate lesions. Similar to what I described before, in the case of a thyroid nodule, we’re able to say with better certainty now whether something is a cancer or not a cancer. In the “olden days”, 5 years ago, we would take out a lot of half-thyroids just to make sure they weren’t cancerous.
Now there is a big risk stratification issue. We are now being a lot more cognizant of what each patient’s thyroid cancer will look like. We are treating some patient with smaller surgeries and active surveillance. What we are learning now is that bombarding every patients with radioiodine is both not helpful and not as innocent as we once thought, myself included. I think we are a lot more thoughtful about low-risk patients who do not need radioiodine after surgery.
TARGETED ONCOLOGY:What else is important to know about thyroid cancer treatment?
Goldenberg:There are also patients who do very poorly. Not a lot, but we see them. For those patients, there are targeted therapies. These are drugs are designed to seek out a specific characteristic in thyroid cancer cells, such as a gene mutation or a protein, and attach themselves to those cells. Many of them target the mitogen-activated protein kinase (MAPK) pathway. This really goes hand-in-hand with what we said before about molecular changes because a lot of these are the same mutations. These include drugs such as sorafenib,lenvatinib and vandetanib. Treating radioiodine-refractory thyroid cancer is challenging. Redifferentiation therapy followed by radioiodine therapy is a promising alternative therapy. Recent studies using drugs that selectively inhibit the MAPK pathway showed promising results for restoring radioiodine uptake. A recent trial showed that dabrafenib, a selective BRAF inhibitor, showed restoration of radioiodine uptake
This is exciting, and I think we have a better understanding about the molecular changes that cause thyroid cancer.
TARGETED ONCOLOGY:What would you say is particularly exciting right now in the field?
Goldenberg:The holy grail, as far as I’m concerned, is discovering, which thyroid cancers are banal and which ones turn ugly and eventually kill the patient. No one really knows the answer to that.