For patients with differentiated thyroid cancer (DTC), the most common form of thyroid malignancy, a special imaging technique called PET/CT (Positron Emission Tomography/Computed Tomography) has become an essential tool in specific situations—particularly for detecting cancer recurrence when standard tests are inconclusive. While PET/CT is not typically used for initial diagnosis, it plays a critical role in identifying recurrent disease in patients with elevated thyroglobulin levels and negative radioactive iodine scans, staging advanced disease, and guiding treatment decisions. This review from Journal of Clinical Medicine (2024) explores how PET/CT is used throughout the patient journey, from incidental discovery of thyroid nodules to monitoring treatment response in advanced cases, while also examining emerging radiotracers and future therapeutic applications.
Thyroid cancer is the most common cancer of the endocrine system—the network of glands that produce hormones. Differentiated thyroid cancer (DTC) accounts for more than 90% of all thyroid cancer cases and includes two main types: papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). The word "differentiated" means the cancer cells still resemble normal thyroid tissue and typically behave in a relatively slow-growing, less aggressive manner.
According to the World Health Organization (WHO), the global incidence of thyroid cancer has risen significantly in recent decades. This increase is largely due to advances in imaging technology, increased detection of small (subclinical) thyroid nodules found incidentally, and more widespread use of diagnostic tools including ultrasound and fine-needle aspiration biopsies (FNAB).
In the United States, the incidence of thyroid cancer has significantly increased over the past 40 years, mirroring global trends. It is now the 13th most common cancer overall and the sixth most common cancer among women. Most researchers attribute this rise to overdiagnosis—detecting small, localized tumors with high survival rates that may not have caused problems otherwise. However, there are also increasing instances of larger and more advanced thyroid cancers, along with rising mortality rates, suggesting that additional factors may play a role, albeit to a lesser extent than overdiagnosis.
Historically, childhood exposure to ionizing radiation was the only recognized modifiable risk factor for thyroid cancer. Recently, obesity has emerged as another significant risk factor, although the biological mechanisms remain unclear. Researchers are also studying the impact of endocrine-disrupting chemicals and thyroid dysfunction on cancer development. Advances in identifying molecular subtypes of thyroid cancer and genetic susceptibility factors have enhanced our understanding of the disease's origins.
One fascinating area of research involves the connection between gut microbiota (the bacteria living in the digestive tract) and thyroid cancer. Studies indicate that individuals with thyroid cancer often have distinct gut microbiota profiles, suggesting that changes in microbial composition may affect cancer susceptibility and progression. This "dysbiosis" (microbial imbalance) can trigger inflammatory responses that compromise immune surveillance, potentially facilitating cancer development. Some researchers believe interventions targeting gut microbiota—such as dietary modifications or probiotics—could represent novel therapeutic strategies to enhance immune responses and reduce cancer progression, though these ideas remain experimental.
The good news: most patients with DTC achieve excellent outcomes. However, approximately 20% develop recurrence or metastases (cancer spread to other parts of the body), underscoring the need for accurate imaging to guide management. Conventional imaging modalities include ultrasound, CT scans, and radioactive iodine (RAI) scintigraphy. While these techniques work well for initial diagnosis and follow-up, they have limitations—particularly in detecting dedifferentiated tumors (cancer cells that have lost their ability to take up iodine) or non-iodine-avid tumors (tumors that don't absorb radioactive iodine).
Positron emission tomography/computed tomography (PET/CT), particularly using a tracer called 18F-Fluorodeoxyglucose (FDG), offers both metabolic and anatomical imaging in a single scan. FDG is a radioactive sugar molecule that highlights areas of high metabolic activity—like aggressive cancer cells that consume large amounts of glucose. This hybrid imaging technique has emerged as an essential tool in oncology, particularly for staging, recurrence detection, and monitoring treatment response in aggressive DTC subtypes.
Thyroid nodules are remarkably common. Studies using high-resolution ultrasound show a prevalence of up to 68% in the general population. The vast majority of these nodules are benign—only about 5% represent malignancies, and most of those are DTC.
The gold standard for evaluating thyroid nodules is fine-needle aspiration biopsy (FNAB), which allows doctors to examine cells from the nodule under a microscope to differentiate between benign and malignant growths. Ultrasound is critical for guiding the FNAB needle and for characterizing nodules based on several features that are associated with an increased risk of malignancy:
However, PET/CT is typically not employed in the initial assessment of thyroid nodules. Most DTCs, especially papillary thyroid carcinomas, exhibit relatively low metabolic activity and therefore do not show high FDG uptake on PET imaging. The American Thyroid Association (ATA) does not recommend routine PET/CT for the initial evaluation of thyroid nodules, as ultrasound and FNAB are highly reliable for initial diagnostic purposes.
There's an important exception: PET/CT plays a significant role when thyroid nodules are incidentally discovered during imaging studies performed for unrelated conditions, such as cancer staging for another malignancy. These are called PET incidentalomas. These nodules often show increased FDG uptake, which raises suspicion for malignancy—particularly in aggressive or dedifferentiated thyroid tumors.
The numbers are striking: it is estimated that approximately 35% of thyroid nodules incidentally detected through PET/CT scans are malignant. Therefore, any incidentally discovered FDG-avid thyroid nodule (a nodule that lights up on the PET scan) warrants further evaluation with ultrasound and FNAB to rule out cancer.
One large meta-analysis of 34 studies by Treglia and colleagues analyzed incidental focal thyroid uptake detected by FDG PET/CT in over 200,000 patients, identifying a pooled malignancy risk of around 36%. Another systematic review that included 18 studies on incidental thyroid uptake (n = 55,160 patients) found that:
Among those with cancer, papillary thyroid carcinoma (PTC) was the most prevalent type, making up 82.2% of cases. This means that when a PET/CT scan done for another reason reveals a suspicious spot in the thyroid, there's roughly a one-in-three chance it's cancer—a finding that clearly requires prompt follow-up.
FDG PET/CT is also valuable for identifying non-iodine-avid tumors—cancers that don't absorb radioactive iodine. These tumors are often more aggressive and less differentiated. In these cases, PET/CT can help detect metastatic disease that might not be visible on traditional radioactive iodine scans.
Staging describes how far a cancer has spread and is critical for determining prognosis (expected outcome) and guiding treatment decisions. The most widely used system is the American Joint Committee on Cancer (AJCC) TNM staging system, which incorporates three key pieces of information:
Accurate staging is vital because it directly influences the management approach, including the need for radioactive iodine therapy and the intensity of follow-up. The standard treatment for DTC is total thyroidectomy (complete surgical removal of the thyroid gland), with or without cervical lymph node dissection based on metastatic risk. In cases of low-risk DTC, a lesser surgery called lobectomy (removing only one lobe of the thyroid) may be considered adequate.
In most cases, ultrasound and RAI scintigraphy are the primary imaging modalities used for initial staging of DTC. Ultrasounds are highly sensitive for detecting cervical (neck) lymph node metastases, while RAI scintigraphy effectively identifies distant metastases in iodine-avid tumors. However, these conventional methods may be inadequate in certain patients—particularly those with non-iodine-avid disease or aggressive tumor variants such as tall cell or Hürthle cell carcinoma.
A key concept in understanding when PET/CT is helpful is the "flip-flop phenomenon". This refers to the inverse relationship between radioiodine uptake and metabolic (FDG) activity in thyroid cancer. Simply put: tumors that are iodine-negative (they don't take up radioactive iodine) may demonstrate increased FDG uptake (they light up on PET scans). This phenomenon highlights why FDG PET/CT is so valuable in cases where traditional iodine imaging fails to identify malignant lesions—particularly in aggressive subtypes of DTC.
Because most well-differentiated thyroid carcinomas grow slowly and have low metabolic activity, they show minimal FDG uptake. Consequently, the primary role of FDG PET/CT in DTC management is typically limited to postoperative follow-up, not initial staging. Given the low incidence of distant metastasis at initial diagnosis (4–7%), routine staging with PET is often not indicated.
However, emerging literature suggests that PET/CT may have potential utility in identifying recurrence or metastasis in high-risk groups or patients with atypical presentations. Current ATA guidelines indicate that there's a lack of strong evidence or consensus to support routine PET/CT use as a preoperative tool, regardless of tumor differentiation or metastatic status.
One of the biggest challenges in the long-term management of DTC patients is identifying recurrence, which occurs in approximately 20–30% of cases, often years after the initial treatment. While DTC generally has a favorable prognosis, specific subgroups experience different outcomes. For example, young patients with small tumors often have excellent long-term survival, while older patients with aggressive histology, extensive lymph node involvement, or distant metastases face a more guarded prognosis.
Early detection of recurrent disease is crucial, particularly for patients with aggressive disease subtypes or those who develop distant metastases. The protein thyroglobulin (Tg) serves as a reliable biomarker (a biological indicator) for DTC recurrence—it's produced by thyroid cells (both normal and cancerous) and measured in the blood. Elevated Tg levels often appear before imaging findings become positive. However, in a subset of patients with elevated Tg and negative RAI scans, the disease can be very difficult to locate—and this is exactly where PET/CT shines.
FDG PET/CT has proven to be a powerful tool in identifying sites of recurrence, particularly in patients with elevated Tg levels and negative RAI scans. The technique works by detecting non-iodine-avid metastatic disease—cancer that has lost its ability to take up iodine—by targeting cells with high metabolic activity, such as dedifferentiated thyroid cancer cells that have lost their iodine-uptake ability.
A study investigated the relationship between Tg kinetics (how quickly Tg levels rise over time, measured as doubling time and velocity) and metabolic activity in DTC patients. The results showed that patients with higher Tg levels and faster Tg kinetics were more likely to have positive PET/CT scans. Importantly, Tg kinetics were found to be independent prognostic factors for overall survival—meaning they predict outcomes regardless of other risk factors.
PET/CT has also demonstrated clinical utility in patients with biochemically incomplete responses to initial treatment—that is, patients who have persistently elevated Tg levels after surgery and RAI therapy but no evidence of disease on conventional imaging. This patient group is at increased risk for recurrence, and early identification of metastatic or recurrent disease with PET/CT can significantly alter the treatment approach. For instance, it can guide decisions regarding re-surgery, targeted therapy, or external beam radiation.
Multiple studies have examined PET/CT's accuracy in detecting recurrence. Here are the key numbers:
PET/CT also outperformed PET alone (without the CT component) in detecting small metastatic lesions—one of the advantages of the hybrid imaging approach.
While a TSH-stimulated Tg level of 10 ng/mL is often used as a cutoff for deciding when to pursue PET/CT, this may need to be adjusted in cases of aggressive thyroid cancer subtypes. Importantly, dedifferentiated thyroid carcinoma cells may have a reduced capacity to produce and secrete Tg. This means that a low Tg level in a patient with a negative iodine scan does not necessarily reflect a minimal tumor burden—the cancer could be widespread but simply not producing much Tg.
Albano and colleagues explored the effectiveness of Tg doubling time (Tg-DT) versus absolute Tg levels in identifying patients with non-iodine-avid DTC who might benefit from FDG PET/CT imaging. They found that Tg-DT offered a more reliable threshold than Tg levels alone in identifying patients likely to benefit from PET/CT. Faster Tg-DT was associated with a higher likelihood of detecting metastases, suggesting its potential to guide personalized treatment strategies. This study highlights the prognostic value of Tg kinetics—the rate of change—over static Tg levels in managing DTC patients with negative radioiodine scans.
Another study investigated the long-term prognostic value of FDG PET/CT in patients with DTC undergoing empiric RAI therapy. The researchers found that FDG PET/CT was more effective than post-therapy whole-body scans in predicting disease recurrence. Patients with negative FDG PET/CT and normalized Tg levels had a better prognosis, with higher rates of disease-free and overall survival. These findings suggest that FDG PET/CT can be a valuable tool for risk stratification—determining which patients need more aggressive monitoring and which can be reassured.
While the impact of thyroid-stimulating hormone (TSH) levels on radioiodine scans is well recognized, there is currently no agreement on how TSH levels affect the accuracy of FDG PET/CT. Some experts have proposed that TSH suppression may be advantageous for patients with low Tg levels (<10 ng/mL) who adhere to hypothyroidism management, whereas TSH stimulation using recombinant TSH (a synthetic hormone injection) should be considered for those unable to tolerate hypothyroid symptoms. This remains an area of ongoing debate and research.
The American Thyroid Association (ATA) guidelines recommend periodic follow-up for DTC patients based on risk stratification, with imaging primarily using ultrasound and RAI scans in low-to-intermediate-risk patients. However, patients with high-risk DTC—particularly those with persistent disease after initial treatment or aggressive histologic variants—may require more intensive surveillance. PET/CT is increasingly recognized as a valuable tool in these cases because of its ability to detect early recurrence and non-iodine-avid metastases.
A study highlighted the significant role of PET/CT in patients with suspicious RAI scans or aggressive tumor variants. FDG PET/CT proved valuable for monitoring high-risk thyroid carcinoma, particularly in patients whose post-therapeutic iodine-131 whole-body scans were inconclusive or not proportional to stimulated Tg levels, as well as those with aggressive DTC variants. Furthermore, the study demonstrated that FDG PET/CT findings were linked to disease progression and effectively revealed undifferentiated lesions, aiding clinical decisions regarding surgical interventions or "watchful waiting" strategies.
When used alongside Tg measurements, FDG PET/CT provides important prognostic information and is crucial for informing clinical decisions in patients with DTC who have negative iodine scans. Age appears to influence PET positivity: Vural et al. noted a higher prevalence of PET positivity in patients over 40 years compared to younger individuals (70% vs. 53%). Since the age at which thyroid cancer is diagnosed is a well-established prognostic factor, this finding reinforces the value of PET/CT in older patients who may face more aggressive disease.
Cross-sectional imaging (MRI and CT) may be useful for prognostic assessment in patients with metastatic disease or those at high risk of rapid progression, while PET/CT is often preferred for evaluating response to systemic or local therapies after treatment. However, the decision between conventional imaging and PET/CT for this purpose remains a subject of debate. The European Thyroid Association (ETA) guidelines suggest that PET/CT can provide additional insights into tumor biology; however, their prognostic or management implications are yet to be fully established.
The review also explores future directions in PET/CT imaging, including the development of novel radiotracers beyond FDG. These emerging tracers may offer more specific targeting of thyroid cancer cells and could provide information about tumor biology that FDG cannot. Additionally, the theragnostic potential of PET/CT—combining diagnostic imaging with targeted therapy in a single approach—represents an exciting frontier. This "see and treat" concept could allow doctors to visualize a tumor and deliver targeted radiation therapy based on the same molecular target.
Research is also exploring the role of interventions targeting gut microbiota, such as dietary modifications or probiotics, as potential novel therapeutic strategies to enhance immune responses and reduce cancer progression. While still experimental, this represents one of many avenues of ongoing investigation in thyroid cancer management.
For patients, this review offers several important takeaways about when PET/CT might be recommended:
The clinical utility of PET/CT extends beyond just finding disease. By identifying the extent and location of recurrence, PET/CT directly guides management decisions—whether that means additional surgery, targeted therapy with tyrosine kinase inhibitors, external beam radiation, or careful observation. In patients being treated with tyrosine kinase inhibitors for iodine-refractory disease, serial PET/CT scans can objectively measure treatment response and help determine whether the therapy is working.
It's important for patients to understand what this review does and doesn't tell us. As a review article, it synthesizes findings from multiple studies rather than presenting new original research. The authors acknowledge several important limitations:
Based on this review, here's what patients should know and discuss with their healthcare team:
The bottom line is reassuring: while not every patient with thyroid cancer needs a PET/CT scan, this technology offers a powerful safety net for those facing the most challenging clinical situations—finding cancer that other tests can't see, guiding treatment for advanced disease, and providing the information needed to make the best possible treatment decisions.
PET/CT is not usually used for initial diagnosis. It is most valuable during follow-up when your thyroglobulin level is elevated but a radioactive iodine scan is negative, for staging aggressive tumor subtypes, or for monitoring treatment response in advanced disease. It helps find cancer that standard imaging may miss.
A thyroid nodule that lights up on a PET/CT is called a PET incidentaloma. Studies show about 35% of these nodules are malignant. Your doctor will likely recommend an ultrasound and fine-needle aspiration biopsy to check if it is cancer. Prompt follow-up is important.
The flip-flop phenomenon describes how thyroid cancer cells that lose their ability to take up radioactive iodine often show increased FDG uptake on PET/CT scans. This means a tumor that is invisible on iodine scans may light up on PET/CT, making these tests complementary rather than interchangeable.
Thyroglobulin is a protein made by thyroid cells, both normal and cancerous. Rising levels can signal recurrence. If your thyroglobulin is elevated but your radioactive iodine scan shows nothing, PET/CT can locate the cancer. The rate of rise, or doubling time, may be more useful than a single value.
A TSH-stimulated thyroglobulin level of 10 ng/mL is a common threshold for considering PET/CT. However, one study found 88% of patients with positive PET/CT scans had thyroglobulin above 5.5 ng/mL. Your doctor may adjust the threshold for aggressive subtypes, as some cancers produce less thyroglobulin.
PET/CT shows the exact extent and location of recurrent or metastatic disease. This helps your doctor decide whether surgery, targeted therapy, external beam radiation, or careful observation is most appropriate. In patients receiving tyrosine kinase inhibitors, serial PET/CT scans can objectively measure whether the treatment is working.
Original Article: "The Role of Positron Emission Tomography/Computed Tomography in the Management of Differentiated Thyroid Cancer: Current Applications and Future Perspectives"
Authors: Emmanouil Panagiotidis, MD, PhD (Theageneio Cancer Center, Thessaloniki, Greece) and Jules Tianyu Zhang-Yin, MD (Clinique Sud Luxembourg, Arlon, Belgium)
Journal: Journal of Clinical Medicine, 2024, Volume 13, Issue 22, Article 6918
Publication Details: Received 23 September 2024; Revised 31 October 2024; Accepted 14 November 2024; Published 17 November 2024. DOI: 10.3390/jcm13226918
Academic Editor: Pedro Iglesias
Copyright: © 2024 by the authors. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) license.
Note: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace individualized medical advice from your healthcare team. Always discuss your specific situation with your doctor.
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