Thyroid cancer is the most common endocrine cancer in the world with over 62,000 newly diagnosed cases each year in the U.S. alone. Here, we look at some of the latest research that includes a study from Endocrine Reviews on radiation-induced thyroid cancer; a JCEM Case Reports paper on false positive results in metastatic thyroid cancer; and a presentation from ENDO 2023 that looks at thyroid cancer survival.

Three studies from last year delve into some of the nuances of thyroid cancer, the most common endocrine carcinoma. One study goes deep into examining the risks of developing thyroid cancer after radiation exposure, whether due to a planned, existing, or an emergency situation.

Next, as thyroid cancer is commonly overtreated, often due to unnecessary or overly aggressive thyroid surgery, the second study examines thyroid cancer surveillance, offering excellent guidance and potential opportunities on how to personalize thyroid cancer management, including psychosocial aspects. Lastly, the third study explores thyroid cancer survivorship.

Radiation and Thyroid Cancer

In “Radiation-Related Thyroid Cancer,” from the July 2023 issue of Endocrine Reviews, study authors Vladimir Saenko, PhD, and Norisato Mitsutake, MD, PhD, both from the Department of Radiation Medical Sciences at the Atomic Bomb Disease Institute of the University of Nagasaki in Japan, provide a comprehensive accounting of thyroid cancer epidemiology, treatment, and prognosis, clinicopathological characteristics, and genetic alterations from the Chornobyl and Fukushima nuclear power plant accidents, as radiation-related thyroid cancers tend to be clinicopathologically more aggressive than sporadic thyroid cancers.

A new examination of the data from the Fukushima and Chornobyl nuclear disasters appear to show that radiation-induced thyroid cancers are often more aggressive than sporadic thyroid cancers.

“It makes sense to study radiation carcinogenesis in Nagasaki, a city experienced an atomic bombing,” explains Mitsutake. “On a personal note, I have several relatives who are A-bomb survivors, so concerns about Fukushima nuclear power plant accident consequences need to be addressed carefully and scientifically. In addition, there has been growing concern in recent years about potential attacks on nuclear facilities and the potential use of nuclear weapons.” These reasons as well as recognizing that the peaceful use of radiation must be promoted, such as by the increasing usage of radioisotopes in the medical field, which exposes patients and medical staff, are what prompted the authors’ analysis, in view of determining how to reduce thyroid cancer risk from radiation exposure.

Notably, the Fukushima nuclear accident did not cause thyroid cancer, unlike that of Chornobyl,

“because the radiation doses to the thyroid appear to be extremely low compared to Chornobyl,” Mitsutake says. Risk is dose-dependent and persists for decades after exposure.  “The restrictions on distribution and consumption by the Japanese government were effective. In addition, residents of the most contaminated territories were rapidly evacuated or relocated. Again, this decreased their radiation doses.”

“Medical exposures to radiation should be performed carefully, especially for children. Much of the evidence discussed in [our] article suggests that radiation-induced cancer does not require special treatment options, including both clinically advanced and low-risk tumors.”

Norisato Mitsutake, MD, PhD, Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, University of Nagasaki, Japan

They also found that the risk of developing thyroid cancer is not equal, with children being more susceptible than adults: “For radiation-related thyroid cancer, the radiation dose to the thyroid and younger age at exposure have been identified as etiology-specific risk factors,” Saenko says. In other words, age at exposure, attained age, and time since exposure were risk modifiers (but gender was not, despite the presumption that thyroid cancer is more common in females, which has recently been suggested to be an oversimplification — thyroid cancer is instead more commonly detected in females, while incidence rates at autopsy were comparable between females and males). “In the Chornobyl thyroid cancer,” he continues, “only stable iodine supplementation was a risk modifier (risk was higher if there was no supplementation) but not sex, age at exposure, other thyroid diseases, or body mass index. Iodine sufficiency is also a protective factor that reduces the risk for thyroid cancer from internal irradiation with radioiodine isotopes.”

Regarding the higher radiosensitivity in children, Saenko says that because children have a longer “time to death,” there is more time to observe a long-term consequence from a childhood exposure. “Ionizing radiation is largely believed to act as an initiator of carcinogenesis (delivers the first hit in multistage carcinogenesis). Since there are more cell divisions, including those of tissue-specific stem cells, in a growing organism than in an adult, and if such a hit took place during childhood, there is a higher chance that the number of cells carrying a radiation-induced hit (say, a cancer-related mutation or an epigenetic change) will become greater.”

Mitsutake has this advice for clinicians: “Medical exposures to radiation should be performed carefully, especially for children. Much of the evidence discussed in [our] article suggests that radiation-induced cancer does not require special treatment options, including both clinically advanced and low-risk tumors.” Medically responsible exposures can be achieved with the “As Low As Reasonably Achievable” (ALARA) principle, which balances the risks and benefits of exposure as well as considers patient economic and social factors.

The authors call for continued careful research into this area.

False Positives in Metastatic Thyroid Cancer

In “False-positive Imaging for Papillary Thyroid Cancer Caused by Intraosseous Hemangiomas,” published in JCEM Case Reports last September, researchers including Stephanie L. Lee, MD, PhD, of the Chobanian & Avedisian School of Medicine, Boston University, Boston, Mass., describe two patients with papillary thyroid carcinoma and elevated thyroglobulin (TG) levels, who had false-positive imaging studies from intraosseous hemangiomas (IH). Despite their similarities, these cases also had significant differences.

“In case one, the patient had aggressive disease, and his TG level was rising into the hundreds,” Lee says, “so we knew he had distant metastatic disease. A CT scan of a symptomatic palpable skull mass revealed a lytic skull lesion. Generally, in the thyroid cancer realm, lytic bone indicates metastatic thyroid cancer.” Due to this patient’s high risk and the risk of bleeding and infection with biopsying an IH, especially one located in the skull, the mass was resected and found to be an IH rather than a metastatic focus of cancer.

In the second case, the patient’s tumor was rated stage I, and her TG level was not rising, so, as Lee explained it, it did not make sense that this low-risk patient would have distant metastatic disease, despite her positive radioactive iodine whole-body scan showing a focal uptake into a lytic lesion in the skull. The clues that helped them make an accurate diagnosis were the patient’s history of headaches and a prior MRI that diagnosed the hemangioma before she had thyroid cancer. That history coupled with the fact that her lytic lesion stayed the same size in the ensuing two years led the team to take an inductive approach: “How do we prove this is not cancer so that we don’t have to do any more diagnostic testing?”

A would-be red herring in this case was that this patient had an ectopic thyroid, which caused her initially higher-than-expected TG levels. After thyroidectomy, however, her TG levels did drop to zero, which is what led to the whole-body scan. “This is where we went down the rabbit hole — but the whole-body scan showed remnant TG levels just in the thyroid bed and in the lesion in the skull,” Lee says.

“We don’t usually think of IH as a cause for false positives — it’s actually only been reported a couple of times in the distant past, and so it’s not on the differential,” Lee says. “We rely on radioactive iodine whole-body scans to detect metastatic disease. We all know that there are false negatives, especially in tumors that are not iodine avid or more aggressive, but we also need to be aware of the false positives.” False-positive radioactive iodine whole-body scans can occur anywhere a protective body of fluid exists, such as from cysts in the skin or ovaries or from a gallbladder with loculated fluid — anywhere the radioactive iodine can diffuse in without a specific transporter, becomes restricted there, and cannot diffuse back out.

“We don’t usually think of [intraosseous hemangiomas] as a cause for false positives — it’s actually only been reported a couple of times in the distant past, and so it’s not on the differential. We rely on radioactive iodine whole-body scans to detect metastatic disease. We all know that there are false negatives, especially in tumors that are not iodine avid or more aggressive, but we also need to be aware of the false positives.”

Stephanie L. Lee, MD, PhD, Chobanian & Avedisian School of Medicine, Boston University, Boston, Mass.

This is where IH becomes relevant. The tangle of blood vessels slows blood flow, making the conditions right for a false positive. “What is unique about IH is that it also can be associated with false-positive F18-FDG positron emission tomography (PET) imaging. When you see something that’s iodine avid and PET-positive, you might think that’s definitely a thyroid cancer. What looks like it’s iodine avid or hypermetabolic is really isotope ‘trapping’ rather than specific uptake,” Lee explains. “So, the key takeaway is that some false positives in whole-body scans are due to restricted diffusion, and you should assess the positive scan in the context of the patient’s specific initial and current risk for thyroid cancer recurrence.”

That’s why the team felt this case report is important: The false positive occurred in both high-risk and low-risk patients and, coincidentally, within two years of each other. “You have to think about the context of these false positives and what the chances are that it really is disease and not a falsely positive result. Then you can step back and look at the differential of a false positive in the skull, and IH should come up,” Lee says.

Thyroid Cancer Survivorship

Megan R. Haymart, MD, Nancy Wigginton Endocrinology Research Professor in Thyroid Cancer, and professor of medicine at the University of Michigan in Ann Arbor, presented “Long-Term Management of Patients with Low-Risk Thyroid Cancer” at ENDO 2023 last June. Her presentation included a series of patient scenarios with rationales gleaned from the literature, including from systematic reviews. As the title suggests, Haymart’s aim is to characterize optimal, tailored, long-term surveillance, including when to de-escalate surveillance, and how to improve the quality of thyroid cancer survivorship.

“We are now in an era of more personalized and tailored management of thyroid cancer,” Haymart says. “However, there are both advantages and disadvantages to less-intensive treatment. For example, although surgical risks are greater with more intensive treatment, the long-term follow-up is more difficult in patients who received less-intensive surgical or medical management (e.g., less use of radioactive iodine).” Determining the balance between benefits and risks in the intensity of thyroid cancer treatment and then subsequent surveillance, she says, requires both clinician and patient input: “For much of the management of low-risk thyroid cancer, there is a role for shared decision making between the patient and the clinician with patient preferences incorporated into the decision-making process.” Long-term surveillance can involve laboratory work-up such as thyroid-stimulating hormone, thyroglobulin, and thyroglobulin antibody as well as neck ultrasound.

“We are now in an era of more personalized and tailored management of thyroid cancer,” Haymart says. “However, there are both advantages and disadvantages to less-intensive treatment. For example, although surgical risks are greater with more intensive treatment, the long-term follow-up is more difficult in patients who received less-intensive surgical or medical management (e.g., less use of radioactive iodine).”

Megan R. Haymart, MD, Nancy Wigginton Endocrinology Research Professor in Thyroid Cancer; professor of medicine, University of Michigan, Ann Arbor, Mich.

However, although neck ultrasound is an excellent method of follow-up for patients with thyroid cancer, as it allows detection of structural recurrence, there is a risk of false positives. In addition, during the surveillance period, patients can experience cancer-related worry about death, harm from treatment, reduced quality of life, family impact, and recurrence. Sometimes these worries can be exacerbated by surveillance, especially when there are false positives. “Key to shared decision making,” explains Haymart, “is communication about risks and benefits as well as awareness of patient preferences. For many of the decisions in the management of low-risk thyroid cancer, there are no ‘right’ or ‘wrong’ decisions. There is just the decision that is best for that particular patient.”

Although many physicians try their best to address patient worry in the clinic visit, resources are available outside of the physician-patient relationship that can help, such as local social workers or psychology or support groups as well as online resources. “There is more work to be done in helping our patients manage their cancer-related worry,” Haymart says. “I think this is an area that needs further resources and research.”

Horvath is a Baltimore, Md.-based freelance writer. She wrote and researched the massive “Eureka 2023” in the December issue that highlighted the top endocrine discoveries of the year.