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Review Article
Published: 24 August 2020

Immunotherapy for advanced thyroid cancers — rationale, current advances and future strategies

Jena D. French ORCID: orcid.org/0000-0002-8881-6543 1 , 2

Nature Reviews Endocrinology volume 16 , pages 629–641 ( 2020 ) Cite this article

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Immunotherapy
Thyroid cancer

In the past decade, the field of cancer immunotherapy has been revolutionized by immune checkpoint blockade (ICB) technologies. Success across a broad spectrum of cancers has led to a paradigm shift in therapy for patients with advanced cancer. Early data are now accumulating in progressive thyroid cancers treated with single-agent ICB therapies and combination approaches that incorporate ICB technologies. This Review discusses our current knowledge of the immune response in thyroid cancers, the latest and ongoing immune-based approaches, and the future of immunotherapies in thyroid cancer. Physiologically relevant preclinical mouse models and human correlative research studies will inform development of the next stage of immune-based therapies for patients with advanced thyroid cancer.

Despite advances in treatment strategies, patients with advanced thyroid cancers would benefit from novel therapies.

Advanced thyroid cancers are commonly infiltrated by immune cells, including CD8 + T cells, but little is known about the tumour-specific T cell response.

A subset of patients has received clinical benefit from immune checkpoint blockade therapies; however, the majority achieve only a partial response.

Novel combination therapies that target both the tumour and the immune response are under investigation.

Additional studies are necessary to better understand the potential of the antitumour immune response and T cell-based therapies for patients with advanced thyroid cancer.

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French, J.D. Immunotherapy for advanced thyroid cancers — rationale, current advances and future strategies. Nat Rev Endocrinol 16 , 629–641 (2020). https://doi.org/10.1038/s41574-020-0398-9

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DOI : https://doi.org/10.1038/s41574-020-0398-9

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Unleashing CAR-T cell therapy to destroy solid tumors in thyroid cancer

1. There are no clear targets in solid tumors

CAR-T cells are engineered to target specific proteins and antigens that are on the surface of cancer cells. Antigens are substances that activate the body's immune system. CARs are genetically programmed to trigger an immune response and destroy cancer cells.

"However, there are few clear targets on solid tumors like we have in liquid tumors," says Dr. Kenderian. "For CAR-T cell therapy to be successful, the first thing that we need to do is identify a protein to target that is unique to cancer cells that is not also expressed on normal tissue."

The teams of Dr. Kenderian and Dr. Copland believe they have identified such a target in the thyroid stimulating hormone receptor (TSHR) which is uniquely found on thyroid cancer cells in the thyroid gland. They are engineering THSR targeting into CAR-T cell therapy for thyroid cancer. This is known as TSHR CAR-T.

2. One treatment type doesn't fit all solid tumors

Solid cancers are comprised of many cell subsets. As a result, a tumor may have genetic mutations in some cells that aren't present in others. This is known as tumor heterogeneity, and it makes it difficult to treat these cancers with a single therapy.

"To overcome the tumor heterogeneity, we are using a strategy to combine TSHR CAR-T cell therapy with small molecules to block cancer cells from growing and metastasizing," says Dr. Copland. "We are studying whether loading CAR-T cells with this synthetic receptor in combination will trigger a cancer fighting response."

3. Solid tumors may be resistant to CAR-T cell therapy

Unlike blood cancers, solid tumors exist in a microenvironment that suppresses the immune system. In addition, dense clusters of malignant cells may create a barrier that blocks the CARs from bringing their cancer fighting mechanisms into cells.

"One strategy for overcoming this challenge is to target cells that are contributing to tumor aggressiveness," says Dr. Copland. "Another is to develop technology known as dual CARs that recognize two different targets. We are studying whether that will overcome tumor resistance."

4. Treating solid tumors may cause side effects

CAR-T cell therapy could mistakenly attack nearby healthy tissue, triggering what's known as "off-target effects." The result might be adverse side effects that are hard for the patient to tolerate. TSHR is a unique target that is expressed only on thyroid cancer cells and not on normal tissues, which minimizes the risk.

On-site biomanufacturing is a bridge to clinical trials

Dr. Kenderian and Dr. Copland are refining the TSHR CAR-T cell technology in the lab and in preclinical models. Biomanufacturing at Mayo Clinic will provide a bridge to accelerate this technology from the lab to early-stage clinical trials.

The process development team within Mayo Clinic's Center for Regenerative Biotherapeutics is now conducting test runs and establishing standard operating procedures in preparation for biomanufacturing this technology at Mayo Clinic.

"On-site biomanufacturing is critical to preserving the integrity of the cells during manufacturing," says Dr. Kenderian. "This is a very complex technology with many components that would make it difficult, if not impossible, to ship to an outside manufacturer."

Dr. Kenderian and Dr. Copland are driven by a passion to provide new therapies for patients who have few or no therapeutic options. Their goal is to advance CAR-T cell therapy for thyroid cancer to a first-in-human clinical trial by early 2025 .

Learn more about CAR-T cell therapy and thyroid cancer .

Also, read these articles:

CAR-T cell therapy helps man continue community advocacy
Hope, time and new options after CAR-T cell therapy for multiple myeloma
CAR-T cell therapy restores hope for leukemia patient
CAR-T cell researchers at Mayo Clinic optimistic about future of treating blood cancers

A version of this article was originally published on the Mayo Clinic News Network .

Nurse practitioner Katherine Prinsen shares what she discusses with her thyroid cancer patients when planning for the future.

Dr. Trenton Foster explains why it's important to have thyroid nodules evaluated by a health care professional to rule out thyroid cancer.

Awareness of thyroid cancer symptoms and risk factors can help adolescents and young adults recognize early warning signs and find prompt treatment.

Clinical Trials

Thyroid cancer.

Displaying 34 studies

The purpose of this study is to determine the optimal approach to the diagnosis and treatment of patients with thyroid disorders.

The purpose of this study is to explore how using different terms (with or without the word cancer) to identify papillary thyroid cancer might affect the decisions patients would make about treatment.

The purpose of this study is to field test and update an existing conversation aid prototype designed to support shared decision making in the diagnosis and treatment of thyroid cancer, and to conduct a pilot randomized multi-center trial to test the refined conversation aid.

The objective of this project is to evaluate a treatment decision aid for patients with low risk thyroid cancer.

The purpose of this study is to evaluate microRNA biomarkers in the blood and fine-needle aspirate biopsies of thyroid nodules to determine their usefullness in pre-operative diagnosis, in particular to distinguish benign from cancerous thyroid nodules.

This randomized phase II trial is studying the side effects and how well giving intensity-modulated radiation therapy (IMRT) and paclitaxel together with or without pazopanib hydrochloride works in treating patients with anaplastic thyroid cancer. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pazopanib hydrochloride may stop the growth of tumor cells by blocking ...

The purpose of this study is to assess the use of lenvatinib to treat anaplastic thyroid cancer.

The purpose of this study is to evaluate the safety and effectiveness of Selpercatinib, compared to a standard treatment, in participants with rearranged during transfection (RET)-mutant medullary thyroid cancer (MTC) that cannot be removed by surgery or has spread to other parts of the body. Participants who are assigned to the standard treatment and discontinue due to progressive disease have the option to potentially crossover to selpercatinib.

The purpose of this study is to evaluate response, survival, safety, and tolerability of treatment with lenvatinib for patients who have anaplastic thyroid cancer.

The purpose of this study is to examine the safety and evaluate the response of VB-111 on DTC.

The objective of this study is to determine intensity of I-123 uptake in follicular thyroid lesions before surgery and correlate with final pathology findings.

The purpose of this study is to evaluate the efficiency of Radiofrequency ablation (RFA) therapy to treat papillary thyroid carcinoma.

The purpose of this first-in-human study is designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of LOXO-292 administered orally to patients with advanced solid tumors, including RET-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.

The purpose of this study is to investigate radiotracer 18F-tetrafluoroborate (18F-TFB) for imaging of patients with differentiated thyroid cancer

The purpose of this study is to determine whether an exercise program reduces fatigue and improves physical activity in thyroid cancer patients, and to determine the effect of a home-based program compared to a center- based program.

The purpose of this pilot study is to evaluate the effects of Radiofrequency Ablation (RFA) on thyroid hormones to treat thyroide nodules.

Radiofrequency ablation (RFA) of thyroid nodules would locally destroy follicular thyroid cells and could possibly impart conformational changes to the chemistry of thyroid hormones, thus altering their bioactive profiles. To evaluate this phenomenon, in vitro investigations to characterize qualitative and quantitve Mass Spectrometric chromatographic profile for thyroid hormones will be performed before and after RFA from patients undergoing ablation for thyroid nodules. {If there is a blood draw for clinical tests, we would request left over specimen from clinical ...

This randomized phase II trial studies how well iodine I-131works with or without selumetinib in treating patients with thyroid cancer that has returned or has spread from where it started to other places in the body. Many thyroid cancers absorb iodine. Because of this, doctors often give radioactive iodine (iodine I-131) alone to treat thyroid cancer as part of standard practice. It is thought that the more thyroid tumors are able to absorb radioactive iodine, the more likely it is that the radioactive iodine will cause those tumors to shrink. Selumetinib may help radioactive iodine work better in patients whose ...

This phase II trial studies how well pembrolizumab, chemotherapy, and radiation therapy work with or without surgery in treating patients with anaplastic thyroid cancer. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as docetaxel and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab, chemotherapy, and radiation therapy with or without surgery ...

The purpose of this study is to perform a comprehensive immunophenotypic analysis of peripheral bloods samples from patients with benign and malignant thyroid disease. This data will be used to determine whether patients with advanced thyroid cancers have significantly altered numbers and/or subtypes of circulating immune cells, in particular immunosuppressive monocytes.

This phase II trial studies how well inolitazone dihydrochloride (efatutazone dihydrochloride) and paclitaxel work in treating patients with anaplastic thyroid cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Drugs used in chemotherapy, such as efatutazone dihydrochloride and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

This phase II trial studies the effect of pembrolizumab, dabrafenib, and trametinib before surgery in treating patients with BRAF V600E-mutated anaplastic thyroid cancer. BRAF V600E is a specific mutation (change) in the BRAF gene, which makes a protein that is involved in sending signals in cells and in cell growth. It may increase the growth and spread of tumor cells. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with ...

The intent is to collect relevant clinical data on patients exposed to Agent Orange plus assessment of the tissue for genetic mutations known to be associated with growth of thyroid cancer and pituitary tumors and report our findings as a descriptive case series.

The purpose of this study is to establish a human biobank of thyroid-derived tissues and blood samples from patients with thyroid disorders at Mayo Clinic in Rochester.

This phase II trial studies how well cabozantinib-s-malate works in treating patients with thyroid cancer that does not respond to treatment. Cabozantinib-s-malate may stop the growth of thyroid cancer by blocking some of the enzymes needed for cell growth. Cabozantinib-s-malate may also stop the growth of thyroid cancer by blocking blood flow to the tumor.

The purpose of this study is to determine how well cabozantinib, nivolumab, and ipilimumab work in treating patients with differentiated thyroid cancer that does not respond to radioactive iodine and that worsened after treatment with a drug targeting the vascular endothelial growth factor receptor (VEGFR), a protein needed to form blood vessels. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. ...

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of BLU-667 administered orally in patients with medullary thyroid cancer, RET-altered NSCLC and other RET-altered solid tumors.

This phase II trial studies how well cabozantinib-s-malate works in treating younger patients with sarcomas, Wilms tumor, or other rare tumors that have come back, do not respond to therapy, or are newly diagnosed. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for tumor growth and tumor blood vessel growth.

The purpose of this study is to find out more about the side effects of rovalpituzumab tesirine (SC16LD6.5) and what doses of rovalpituzumab tesirine (SC16LD6.5) are safe for people with specific delta-like protein 3-expressing cancers.

The purpose of this study is to assess the safety/tolerability profile of E7386 as a single agent administered orally in participants with selected advanced or recurrent neoplasms and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of E7386.

The purpose of this multicenter prospective observational case-control study is to train and validate Adela’s cfMeDIP-seq based methylome profiling platform to detect and differentiate multiple cancer subtypes. In addition, this study includes longitudinal follow-up for a subset of participants to train and validate the methylome profiling platform to detect minimal residual disease and recurrence.

The purpose of this study is to determine the prevalence of genetic mutations in cancer patients from various ethnic populations seeking care at Mayo Clinic cancer clinics.

The purpose of this study is to evaluate the challenges, behavioral patterns, and preferences of minority patient participation in clinical trials. Also, to develop and validate a personalized clinical trial educational platform to boost participation among underserved cancer patients.

The purpose of this study is to collect blood and tissue samples from patients with and without cancer to evaluate laboratory tests for early cancer detection which may help researchers develop tests for the early detection of cancers.

GRAIL is using deep sequencing of circulating cell-free nucleic acids (cfNAs) to develop assays to detect cancer early in blood. The purpose of this study is to collect biological samples from donors with a new diagnosis of cancer (blood and tumor tissue) and from donors who do not have a diagnosis of cancer (blood) in order to characterize the population heterogeneity in cancer and non-cancer subjects and to develop models for distinguishing cancer from non-cancer.

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Home » Thyroid Cancer

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Thyroid cancer is relatively uncommon compared to other cancers. In the United States, it is estimated that in 2021 approximately 44,000 people will receive a new diagnosis of thyroid cancer, compared to over 280,000 with breast cancer and over 150,000 with colon cancer. However, despite this, approximately 2,000 patients die of thyroid cancer each year. In 2018, the last year for which statistics are available, almost 900,000 patients were living with thyroid cancer in the United States. Thyroid cancer is usually very treatable and is often cured with surgery (see Thyroid Surgery brochure ) and, if indicated, radioactive iodine (see Radioactive Iodine brochure ). Even when thyroid cancer is more advanced, effective treatment is available for the most common forms of thyroid cancer. Even though the diagnosis of cancer is terrifying, the prognosis for most patients with papillary and follicular thyroid cancer is excellent.

Thyroid Cancer FAQs

What is the thyroid gland.

The thyroid gland is a butterfly-shaped endocrine gland that is normally located in the lower front of the neck. The thyroid’s job is to make thyroid hormones, which are secreted into the blood and then carried to every tissue in the body. Thyroid hormone helps the body use energy, stay warm and keep the brain, heart, muscles, and other organs working as they should.

WHAT ARE THE TYPES OF THYROID CANCER?

PAPILLARY THYROID CANCER. Papillary thyroid cancer is the most common type, making up about 70% to 80% of all thyroid cancers. Papillary thyroid cancer can occur at any age. It tends to grow slowly and often spreads to lymph nodes in the neck. Papillary cancer has a generally excellent outlook, even if there is spread to the lymph nodes.

FOLLICULAR THYROID CANCER. Follicular thyroid cancer makes up about 10% to 15% of all thyroid cancers in the United States. Follicular cancer can spread through the blood to distant organs, particularly the lungs and bones.

Papillary and follicular thyroid cancers are also known as well–Differentiated Thyroid Cancers (DTC). The information in this brochure refers to these differentiated thyroid cancers. The other types of thyroid cancer listed below will be covered in other brochures.

MEDULLARY THYROID CANCER. Medullary thyroid cancer (MTC), accounts for approximately 2% of all thyroid cancers. Approximately 25% of all MTC runs in families and is associated with other endocrine tumors (see Medullary Thyroid Cancer brochure ). In family members of an affected person, a test for a genetic mutation in the RET proto-oncogene can lead to an early diagnosis of medullary thyroid cancer and, as a result, to curative surgery. 75% of patients with Medullary thyroid cancer do not have a hereditary form.

ANAPLASTIC THYROID CANCER. Anaplastic thyroid cancer is the most advanced and aggressive thyroid cancer and the least likely to respond to treatment. Anaplastic thyroid cancer is very rare and is found in less than 2% of patients with thyroid cancer (See Anaplastic Thyroid Cancer brochure ).

WHAT ARE THE SYMPTOMS OF THYROID CANCER?

Thyroid cancer often presents as a lump or nodule in the thyroid and usually does not cause any other symptoms (see Thyroid Nodule brochure ). Blood tests generally do not help to find thyroid cancer and thyroid blood tests such as TSH are usually normal, even when a cancer is present. Neck examination by your doctor is a common way in which thyroid nodules and thyroid cancer are found. Often, thyroid nodules are discovered incidentally on imaging tests like CT scans and neck ultrasounds done for completely unrelated reasons. You may have found a thyroid nodule by noticing a lump in your neck while looking in a mirror, buttoning your collar, or fastening a necklace. Rarely, thyroid cancers and nodules may cause symptoms. You may complain of pain in the neck, jaw, or ear. If a nodule is large enough to compress your windpipe or esophagus, it may cause difficulty with breathing, swallowing, or cause a “tickle in the throat” sensation. Even less commonly, you may develop hoarseness if a thyroid cancer invades the nerve that controls your vocal cords.

Cancers arising in thyroid nodules generally do not cause symptoms, and thyroid function tests are typically normal even when you have cancer. The best way to find a thyroid nodule is to make sure that your doctor examines your neck as part of your periodic check-up.

WHAT CAUSES THYROID CANCER?

Thyroid cancer is more common in people who have a history of exposure to high doses of radiation, have a family history of thyroid cancer, and are older than 40 years of age. However, for most people, we don’t know why thyroid cancer develops.

High dose radiation exposure, especially during childhood, increases the risk of developing thyroid cancer. Radiation therapy used to treat cancers such as Hodgkin’s disease (cancer of the lymph nodes) or breast cancer has been associated with an increased risk for developing thyroid cancer if the treatment included exposure to the head, neck or chest. Routine X-ray exposure such as dental X-rays, chest X-rays and mammograms are not associated with a high risk of thyroid cancer. As always, you should minimize radiation exposure by only having tests which are medically necessary.

Exposure to radioactivity released during nuclear disasters (1986 accident at the Chernobyl power plant in Russia or the 2011 nuclear disaster in Fukushima, Japan) has also been associated with an increased risk of developing thyroid cancer, particularly in exposed children, and thyroid cancers can be seen in exposed individuals as many as 40 years after exposure.

You can be protected from developing thyroid cancer in the event of a nuclear disaster by taking potassium iodide (see Nuclear Radiation and the Thyroid brochure ). This prevents the absorption of radioactive iodine and has been shown to reduce the risk of thyroid cancer. The American Thyroid Association recommends that anyone living within 200 miles of a nuclear facility be given potassium iodide to take if a nuclear accident occurs. If you live near a nuclear reactor and want more information about the role of potassium iodide, check the recommendations from your state at the following link: www.thyroid.org/web-links-for-important- documentsabout- potassium-iodide/ .

HOW IS THYROID CANCER DIAGNOSED?

If your doctor suspects from your physical exam and ultrasound that you may have cancer, you will need to have a fine needle aspiration biopsy. The results of the biopsy can be highly suggestive of thyroid cancer and will prompt surgical treatment. Thyroid cancer can only be diagnosed with certainty after the nodule is removed surgically (see Thyroid Nodule brochure ). Thyroid nodules are very common, but less than 1 in 10 will be a thyroid cancer.

WHAT IS THE TREATMENT FOR THYROID CANCER?

Surgery. The first step in treatment for all types of thyroid cancer is surgery (see Thyroid Surgery brochure ). The extent of surgery for differentiated thyroid cancers may be removing only the lobe involved with the cancer, called a lobectomy, or removing the entire thyroid, called a total thyroidectomy. The extent of surgery will depend on the size of the tumor and whether or not the tumor has spread beyond the thyroid gland. If your tumor involves both lobes of the thyroid gland or it is found on testing to have spread beyond the gland, a total thyroidectomy will be recommended. If you have thyroid cancer present in the lymph nodes of the neck (lymph node metastases), these lymph nodes can be removed at the time of the initial thyroid surgery or sometimes, as a second procedure. However, if your cancer is small, only in one lobe of the gland and if it has not spread to lymph nodes, a lobectomy may be a good option. Recent studies even suggest that if you have a small tumor measuring less than 1cm across, called papillary thyroid microcarcinoma, you may be observed very safely without surgery. If you have a total thyroidectomy, you will need to take thyroid hormone medication for the rest of your life (see Thyroid Hormone Treatment brochure ). However, if you have a lobectomy, you may not need to take thyroid hormone replacement. Thyroid cancer is often cured by surgery alone, especially if the cancer is small. If your cancer is larger, if it has spread to lymph nodes, or if your doctor feels that you are at high risk for recurrent cancer, radioactive iodine may be used after the thyroid gland is removed.

Radioactive iodine therapy (Also referred to as I-131 therapy). Thyroid cells and most differentiated thyroid cancers absorb iodine so radioactive iodine can be used to eliminate all remaining normal thyroid tissue and potentially destroy residual cancerous thyroid tissue after thyroidectomy (see Radioactive Iodine brochure ). The procedure to eliminate residual thyroid tissue is called radioactive iodine ablation. Since most other tissues in the body do not efficiently absorb or concentrate iodine, radioactive iodine used during the ablation procedure usually has little or no effect on tissues outside of the thyroid. However, in some patients who receive larger doses of radioactive iodine for treatment of thyroid cancer metastases, radioactive iodine can affect the glands that produce saliva and result in a dry mouth. If higher doses of radioactive iodine are necessary, there may also be a small risk of developing other cancers later in life. This risk is very small, and increases as the dose of radioactive iodine increases. The potential risks of treatment can be minimized by using the smallest dose possible. Balancing potential risks against the benefits of radioactive iodine therapy is an important discussion that you should have with your doctor if radioactive iodine therapy is recommended.

If your doctor recommends radioactive iodine therapy, your TSH level will need to be elevated prior to the treatment. This can be done in one of two ways.

The first is by stopping thyroid hormone pills (levothyroxine) for 3-6 weeks. This causes high levels of TSH to be produced by your body naturally. This results in hypothyroidism, which may involve symptoms such as fatigue, cold intolerance and others, that can be significant. To minimize the symptoms of hypothyroidism your doctor may prescribe T3 (Cytomel®, liothyronine) which is a short acting form of thyroid hormone that is usually taken after the levothyroxine is stopped until 2 weeks before the radioactive iodine treatment.

Alternatively, TSH can be increased sufficiently without stopping thyroid hormone medication by injecting a synthetic form of TSH into your body. Recombinant human TSH (rhTSH, Thyrogen®) can be given as two injections in the days prior to radioactive iodine treatment. The benefit of this approach is that you can continue taking the thyroid hormone medication and avoid possible symptoms related to hypothyroidism.

Regardless of whether you become hypothyroid (stop thyroid hormone) or use recombinant TSH therapy, you may also be asked to go on a low iodine diet for 1 to 2 weeks prior to treatment (see Low Iodine Diet FAQ ), which will result in improved absorption of radioactive iodine, maximizing the treatment effect.

TREATMENT OF ADVANCED THYROID CANCER.

Thyroid cancer that spreads (metastasizes) outside the neck area is rare but can be a serious problem. Surgery and radioactive iodine remain the best way to treat such cancers as long as these treatments continue to work. However, for more advanced cancers, or when radioactive iodine therapy is no longer effective, other forms of treatment are needed.

Medications have now been approved for the treatment of advanced thyroid cancer. These drugs rarely cure advanced cancers that have spread widely throughout the body, but they can slow down or partially reverse the growth of the cancer. These treatments are usually given by an oncologist (cancer specialist) and often require care at a regional or university medical center. These agents can also be used to change a tumor that stopped responding to radioactive iodine to respond to this treatment again. This is called redifferentiation therapy.

External beam radiation directs precisely focused X-rays to areas that need to be treated. This may be tumor that has recurred locally in the neck or spread to bones or other organs. This can kill or slow the growth of those tumors.

WHAT IS THE FOLLOW-UP FOR PATIENTS WITH THYROID CANCER?

Periodic follow-up examinations are essential for all patients with thyroid cancer, because the thyroid cancer can return—sometimes several years after successful initial treatment. These follow-up visits include a careful history and physical examination, with particular attention to the neck area. Neck ultrasound is an important tool to view the neck and look for nodules, lumps or cancerous lymph nodes that might indicate the cancer has returned. Blood tests are also important for thyroid cancer patients. Most patients who have had a thyroidectomy for cancer require thyroid hormone replacement with levothyroxine once the thyroid is removed (see Thyroid Hormone Treatment brochure ). The dose of levothyroxine prescribed by your doctor will in part be determined by the initial extent of your thyroid cancer. More advanced cancers usually require higher doses of levothyroxine to suppress TSH (lower the TSH below the low end of the normal range). In cases of minimal or very low risk thyroid cancer, it is typically recommended to keep TSH in the normal range. The TSH level is a good indicator of whether the levothyroxine dose is correct and should be followed periodically by your doctor.

Another important blood test is measurement of thyroglobulin (Tg). Thyroglobulin is a protein produced by normal thyroid tissue and differentiated thyroid cancer cells. The test is useful if you have had a thyroidectomy and radioactive iodine ablation, when the thyroglobulin levels usually become very low or undetectable. If your level is low and then starts to rise, it is concerning for possible cancer recurrence. If you have thyroglobulin antibodies (TgAb) the Tg blood test can be more difficult to interpret.

In addition to routine blood tests, your doctor may want to check a whole-body iodine scan to determine if any thyroid cancer cells remain. These scans are only done for high risk patients and have been largely replaced by routine neck ultrasound and thyroglobulin measurements that are more accurate to detect cancer recurrence, especially when done together.

WHAT IS THE PROGNOSIS OF THYROID CANCER?

Overall, your prognosis with differentiated thyroid cancer is excellent, especially if you are younger than 55 years of age and have a small cancer. If your papillary thyroid cancer has not spread beyond the thyroid gland, patients like you rarely if ever die from thyroid cancer. If you are older than 55 years of age, or have a larger or more aggressive tumor, your prognosis remains very good, but the risk of cancer recurrence is higher. The prognosis may not be quite as good if your cancer is more advanced and cannot be completely removed with surgery or destroyed with radioactive iodine treatment. Nonetheless, even if this is your situation, you will likely be able to live a long time and feel well, despite the fact that you are living with cancer. It is important to talk to your doctor about your individual profile of cancer and expected prognosis. It will be necessary to have lifelong monitoring, even after successful treatment.

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What is thyroid cancer? A Mayo Clinic expert explains

Learn more about thyroid cancer from endocrinologist Mabel Ryder, M.D.

I'm Dr. Mabel Ryder, an endocrinologist at Mayo Clinic. In this video, we'll cover the basics of thyroid cancer: What is it? Who gets it? The symptoms. Diagnosis and treatment. Whether you're looking for answers for yourself or someone you love, we're here to give you the best information available. What is the thyroid? This is a butterfly shaped gland that sits at the base of your neck. It's an important gland responsible for producing hormones that control a lot of vital functions in your body, such as your heart and your heart rate, your blood pressure, your body temperature, and your weight. When thyroid cells mutate, changes to their DNA cause them to grow and multiply. Where healthy cells typically die, these abnormal cells grow and grow and eventually form a tumor. Sometimes these cells invade nearby tissue, and can spread or metastasize to other parts of the body. There are several different kinds of thyroid cancer. Some grow slowly. Others can be more aggressive. Because we're able to detect small thyroid cancers with new technology, the rate of thyroid cancer incidence has gone up. However, most cancers are very treatable and the prognosis for most patients with thyroid cancer is excellent.

There are other things that can increase your chances of developing thyroid cancer. Women are three times more likely to develop thyroid cancer. And exposure to high levels of radiation, for instance, radiation therapy to the head or neck for other cancers, can increase your risk. Certain hereditary genetic syndromes may also play a role. Different types of thyroid cancer are more likely to affect different age groups. Papillary thyroid cancer is the most common form of thyroid cancer. And although it can occur at any age, it generally affects people ages 30 to 50. Follicular thyroid cancer usually affects people older than age 50. Anaplastic thyroid cancer is a very rare type of cancer that typically occurs in adults 60 and older. And medullary thyroid cancer. Although uncommon, up to 30 percent of patients with medullary thyroid cancer are associated with genetic syndromes that can increase your risk for other tumors as well.

Typically, thyroid cancer doesn't trigger any signs or symptoms in its early stages. As it grows, you may notice a lump that can be felt through the skin in your neck. You may notice changes to your voice, including hoarseness of your voice, or difficulty swallowing. Some may develop pain in their neck or throat. Or you may develop swollen lymph nodes in your neck. If you're experiencing any of these issues and are concerned, make an appointment with your doctor.

Most often, diagnosing thyroid cancer starts with the physical exam. Your doctor will feel for physical changes in your neck and the thyroid. This usually is followed by blood tests and ultrasound imaging. Armed with this information, doctors may decide to do a biopsy to remove a small sample of tissue from your thyroid. In some cases, genetic testing may be done to help determine any associated hereditary causes. If diagnosed with thyroid cancer, several other tests may be done to help your doctor determine whether your cancer has spread beyond the thyroid and outside of the neck. These tests may include blood tests to check tumor markers and imaging tests, such as CT scans, MRI, or nuclear imaging tests, such as a radioiodine whole-body scan.

Fortunately, most thyroid cancers can be beaten with treatments. Very small cancers - under 1 centimeter - have a low risk of growing or spreading and, thus, might not need treatment right away. Instead, your doctor may recommend observation with blood tests, an ultrasound, and a physical exam once or twice per year. In many people, this small cancer - under 1 centimeter - might never grow and may never require surgery. In cases where further treatment is necessary, surgery is common. Depending on your cancer, your doctor may remove just a portion of the thyroid - a procedure known as thyroidectomy. Or your doctor may remove all of the thyroid. Other treatments may include thyroid hormone therapy, alcohol ablation, radioactive iodine, targeted drug therapy, external radiation therapy, and chemotherapy, in some. Ultimately, what your treatment looks like will depend on the stage of your cancer and the type of thyroid cancer you have.

If you've been diagnosed with thyroid cancer, you might feel as if you aren't sure what to do next. And that's normal, everyone eventually find their own way of coping with a cancer diagnosis. But until you find what works for you, try the following. Learn all you can to help you make decisions about your care. Connect with other survivors. Talking to people who share your situation can be incredibly helpful. And control what you can about your health. Take steps to keep your body healthy during and after treatment. Eat a healthy diet full of a variety of fruits and vegetables. Get enough rest. And try to incorporate physical activity when you can. Being diagnosed with cancer can be frightening, but take comfort in the fact that most cases of this cancer are treatable. If you'd like to learn even more about thyroid cancer, watch our other related videos or visit mayoclinic.org. We wish you well.

Thyroid cancer occurs in the cells of the thyroid.

Thyroid cancer is a growth of cells that starts in the thyroid. The thyroid is a butterfly-shaped gland located at the base of the neck, just below the Adam's apple. The thyroid produces hormones that regulate heart rate, blood pressure, body temperature and weight.

Thyroid cancer might not cause any symptoms at first. But as it grows, it can cause signs and symptoms, such as swelling in your neck, voice changes and difficulty swallowing.

Several types of thyroid cancer exist. Most types grow slowly, though some types can be very aggressive. Most thyroid cancers can be cured with treatment.

Thyroid cancer rates seem to be increasing. The increase may be caused by improved imaging technology that allows health care providers to find small thyroid cancers on CT and MRI scans done for other conditions (incidental thyroid cancers). Thyroid cancers found in this way are usually small cancers that respond well to treatments.

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Thyroid gland

The thyroid gland is located at the base of the neck, just below the Adam's apple.

Most thyroid cancers don't cause any signs or symptoms early in the disease. As thyroid cancer grows, it may cause:

A lump (nodule) that can be felt through the skin on your neck
A feeling that close-fitting shirt collars are becoming too tight
Changes to your voice, including increasing hoarseness
Difficulty swallowing
Swollen lymph nodes in your neck
Pain in your neck and throat

When to see a doctor

If you experience any signs or symptoms that worry you, make an appointment with your health care provider.

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Thyroid cancer happens when cells in the thyroid develop changes in their DNA. A cell's DNA contains the instructions that tell the cell what to do. The changes, which doctors call mutations, tell the cells to grow and multiply rapidly. The cells go on living when healthy cells would naturally die. The accumulating cells form a mass called a tumor.

The tumor can grow to invade nearby tissue and can spread (metastasize) to the lymph nodes in the neck. Sometimes the cancer cells can spread beyond the neck to the lungs, bones and other parts of the body.

For most thyroid cancers, it's not clear what causes the DNA changes that cause the cancer.

Types of thyroid cancer

Thyroid cancer is classified into types based on the kinds of cells found in the tumor. Your type is determined when a sample of tissue from your cancer is examined under a microscope. The type of thyroid cancer is considered in determining your treatment and prognosis.

Types of thyroid cancer include:

Papillary thyroid cancer. This is the most common type of thyroid cancer. It can happen at any age, but it most often affects people ages 30 to 50. Most papillary thyroid cancers are small and respond well to treatment, even if the cancer cells spread to the lymph nodes in the neck. A small portion of papillary thyroid cancers are aggressive and may grow to involve structures in the neck or spread to other areas of the body.
Follicular thyroid cancer. This rare type of thyroid cancer usually affects people older than 50. Follicular thyroid cancer cells don't often spread to the lymph nodes in the neck. But some large and aggressive cancers may spread to other parts of the body. Follicular thyroid cancer most often spreads to the lungs and bones.
Hurthle cell thyroid cancer. This rare type of thyroid cancer was once considered a type of follicular thyroid cancer. Now it is considered its own type because the cancer cells behave differently and respond to different treatments. Hurthle cell thyroid cancers are aggressive and can grow to involve structures in the neck and spread to other parts of the body.
Poorly differentiated thyroid cancer. This rare type of thyroid cancer is more aggressive than other differentiated thyroid cancers and often doesn't respond to the usual treatments.
Anaplastic thyroid cancer. This rare type of thyroid cancer grows quickly and can be difficult to treat. However, treatments can help slow the progression of the disease. Anaplastic thyroid cancer tends to occur in people older than 60. It can cause severe signs and symptoms, such as neck swelling that worsens very quickly and may lead to difficulty breathing and swallowing.
Medullary thyroid cancer. This rare type of thyroid cancer begins in thyroid cells called C cells, which produce the hormone calcitonin. Elevated levels of calcitonin in the blood can indicate medullary thyroid cancer at a very early stage. Some medullary thyroid cancers are caused by a gene called RET that's passed from parents to children. Changes in the RET gene can cause familial medullary thyroid cancer and multiple endocrine neoplasia, type 2. Familial medullary thyroid cancer increases the risk of thyroid cancer. Multiple endocrine neoplasia, type 2, increases the risk of thyroid cancer, adrenal gland cancer and other types of cancers.
Other rare types. Other very rare types of cancer can start in the thyroid. These include thyroid lymphoma, which begins in the immune system cells of the thyroid, and thyroid sarcoma, which begins in the connective tissue cells of the thyroid.

Risk factors

Factors that may increase the risk of thyroid cancer include:

Female sex. Thyroid cancer occurs more often in women than in men. Experts think it may be related to the hormone estrogen. People who are assigned female sex at birth generally have higher levels of estrogen in their bodies.
Exposure to high levels of radiation. Radiation therapy treatments to the head and neck increase the risk of thyroid cancer.
Certain inherited genetic syndromes. Genetic syndromes that increase the risk of thyroid cancer include familial medullary thyroid cancer, multiple endocrine neoplasia, Cowden syndrome and familial adenomatous polyposis. Types of thyroid cancer that sometimes run in families include medullary thyroid cancer and papillary thyroid cancer.

Complications

Thyroid cancer that comes back.

Thyroid cancer can return despite successful treatment, and it can even come back if you've had your thyroid removed. This could happen if cancer cells spread beyond the thyroid before it's removed.

Most thyroid cancers aren't likely to recur, including the most common types of thyroid cancer — papillary thyroid cancer and follicular thyroid cancer. Your health care provider can tell you if your cancer has an increased risk of recurring based on the particulars of your cancer.

Recurrence is more likely if your cancer is aggressive or if it grows beyond your thyroid. When thyroid cancer recurrence happens, it's usually found in the first five years after your initial diagnosis.

Thyroid cancer that comes back still has a good prognosis. It's often treatable, and most people will have successful treatment.

Thyroid cancer may recur in:

Lymph nodes in the neck
Small pieces of thyroid tissue left behind during surgery
Other areas of the body, such as the lungs and bones

Your health care provider may recommend periodic blood tests or thyroid scans to check for signs that your cancer has returned. At these appointments, your provider may ask if you've experienced any signs and symptoms of thyroid cancer recurrence, such as:

A lump in the neck
Trouble swallowing
Voice changes, such as hoarseness

Thyroid cancer that spreads (metastasizes)

Thyroid cancer sometimes spreads to nearby lymph nodes or to other parts of the body. The cancer cells that spread might be found when you're first diagnosed or they might be found after treatment. The great majority of thyroid cancers don't ever spread.

When thyroid cancer spreads, it most often travels to:

Thyroid cancer that spreads might be detected on imaging tests, such as CT and MRI, when you're first diagnosed with thyroid cancer. After successful treatment, your health care provider might recommend follow-up appointments to look for signs that your thyroid cancer has spread. These appointments might include nuclear imaging scans that use a radioactive form of iodine and a special camera to detect thyroid cancer cells.

Doctors aren't sure what causes the gene changes that lead to most thyroid cancers, so there's no way to prevent thyroid cancer in people who have an average risk of the disease.

Prevention for people with a high risk

Adults and children with an inherited gene that increases the risk of medullary thyroid cancer may consider thyroid surgery to prevent cancer (prophylactic thyroidectomy). Discuss your options with a genetic counselor who can explain your risk of thyroid cancer and your treatment options.

Prevention for people near nuclear power plants

A medication that blocks the effects of radiation on the thyroid is sometimes provided to people living near nuclear power plants in the United States. The medication (potassium iodide) could be used in the unlikely event of a nuclear reactor accident. If you live within 10 miles of a nuclear power plant and are concerned about safety precautions, contact your state or local emergency management department for more information.

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AskMayoExpert. Differentiated thyroid cancer (adult). Mayo Clinic; 2018.
Niederhuber JE, et al., eds. Cancer of the endocrine system. In: Abeloff's Clinical Oncology. 6th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Jan. 21, 2022.
Melmed S, et al. Nontoxic diffuse goiter, nodular thyroid disorders and thyroid malignancies. In: Williams Textbook of Endocrinology. 14th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Jan. 21, 2022.
AskMayoExpert. Medullary thyroid cancer. Mayo Clinic; 2021.
Thyroid carcinoma. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470. Accessed Jan. 21, 2022.
Vaccarella S, et al. Worldwide thyroid-cancer epidemic? The increasing impact of overdiagnosis. The New England Journal of Medicine. 2016; doi:10.1056/NEJMp1604412.
AskMayoExpert. Multiple endocrine neoplasia type 2. Mayo Clinic; 2021.
Suteau V, et al. Sex bias in differentiated thyroid cancer. International Journal of Molecular Sciences. 2021; doi:10.3390/ijms222312992.
Health Education & Content Services (Patient Education). Follow-up for low-risk thyroid cancer. Mayo Clinic; 2018.
Frequently asked questions about potassium iodide. U.S. Nuclear Regulatory Commission. https://www.nrc.gov/about-nrc/emerg-preparedness/about-emerg-preparedness/potassium-iodide/ki-faq.html. Accessed Jan. 25, 2022.
Wang TS, et al. Thyroidectomy. https://www.uptodate.com/contents/search. Accessed Jan. 20, 2022.
Thyroid cancer. Cancer.Net. https://www.cancer.net/cancer-types/thyroid-cancer. Accessed Feb. 7, 2022.
Health Education & Content Services (Patient Education). Thyroid surgery. Mayo Clinic; 2018.
Schumm MA, et al. Frequency of hormone replacement after lobectomy for differentiated thyroid cancer. Endocrine Practice. 2021; doi:10.1016/j.eprac.2021.01.004.
I-131 radiotherapy. Society of Nuclear Medicine and Molecular Imaging. https://www.snmmi.org/AboutSNMMI/Content.aspx?ItemNumber=10563. Accessed Jan. 25, 2022.
Palliative care. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1454. Accessed Jan. 25, 2022.
Sosa JA, et al. The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Annals of Surgery. 1998; doi:10.1097/00000658-199809000-00005.
Jensen NA. Allscripts EPSi. Mayo Clinic. Nov. 11, 2021.
Creagan ET (expert opinion). Mayo Clinic. Feb. 26, 2022.
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Thyroid cancer.

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Continuing Education Activity

Thyroid cancer is a malignancy arising from the thyroid parenchymal cells. Its incidence is steadily increasing worldwide, while the mortality rate has remained stable over the past several years. The clinical behavior of thyroid cancer is highly variable, from indolent, slowly progressing tumors to highly aggressive tumors with high mortality rates. There are various new cutting-edge treatment options for advanced thyroid cancer, while there is also evidence against the overtreatment of low-risk thyroid cancers. Hence, a thorough understanding of the types of thyroid cancer and its management is of paramount importance in providing the appropriate treatment to the patient. This activity reviews the incidence, etiology, pathophysiology, diagnosis, and treatment of thyroid cancer and highlights the role of interprofessional communication in optimizing the care of these patients.

Outline the epidemiology and risk factors of thyroid cancer.
Describe the clinical presentation and detailed histopathology of the different types of thyroid cancer.
Explain the different treatment options for patients with thyroid cancer.
Highlight the importance of interprofessional teams in coordinating care to optimize outcomes for patients with thyroid cancer.
Introduction

Thyroid cancer is a malignancy of the thyroid parenchymal cells. The thyroid parenchyma consists of two major cell types, the thyroid follicular cells that give rise to differentiated thyroid cancer(DTC) and the parafollicular or C-cells that give rise to medullary thyroid carcinoma (MTC). DTC comprises papillary thyroid cancer(PTC), follicular thyroid cancer(FTC), and Hurthle cell cancer which account for 90-95% of all thyroid malignancies. MTC accounts for around 1 to 2%, and anaplastic thyroid carcinoma accounts for less than 1% of all thyroid cancers [1]

Familial occurrence of thyroid cancer is approximately 5% for PTC and FTC and 15 to 30% for MTC. [2] Over the last decades, the incidence of papillary thyroid cancer has increased worldwide, mostly due to early detection and advanced imaging technology with the risk of overdetection. [3] Mutations and translocations in the genes coding the mitogen-activated protein kinase (MAPK) cellular signaling pathway have been implicated in the genetic basis of most thyroid cancers. [4]

Some of the common mutations are as follows:

PTC - Point mutation in the BRAF gene leading to BRAF V600E mutant kinase is the most common mutation leading to PTC (29 to 69%) and PTC-associated anaplastic thyroid cancer (0 to 12%). [5] Translocation of the RET-papillary thyroid cancer(RET/PTC) occurs in about 7% of PTC. [6] Mutations in RAS proto-oncogene occur in 10-20% of follicular variant PTC (FVPTC). [2]

FTC - Mutations in RAS proto-oncogene are most common in FTC (40 to 50%). Translocation in PAX8–peroxisome proliferator-activated receptor γ (PPARγ) has been identified in around 30 to 35% of FTC. [7]

Anaplastic - Inactivating mutation of the p53 tumor suppressor gene has been identified in addition to early inactivating mutations in about 50 to 80% of the cases with anaplastic thyroid cancer. [8] [9] [10] Also, 66% of anaplastic thyroid cancers have been identified to harbor mutations in the CTNNB1 gene. [5] RAS mutations are also associated with 20 to 40% of anaplastic thyroid cancers.

MTC - Germline mutations of RET proto-oncogene in inherited forms of MTC (approximately 25% of MTC) and RAS mutations in 25% of MTC. [11]

Several other uncommon gene mutations have been associated with the development of thyroid cancer, such as TERT mutations, especially highly aggressive PTC. [12] DTC can be inherited by autosomal dominant inheritance or appear as a part of tumor-susceptibility syndromes. [13]

Risk factors: Female sex, a family history of thyroid cancer, and radiation exposure of the thyroid gland during childhood are the major risk factors associated with DTC. [14] [15] [16] [15] [14] A recent study showed that thyroid cancer affects both genders equally, as seen in autopsy reports, but it might be detected in women more frequently than men. The difference could be explained by access to medical care. [17]

Epidemiology

Thyroid cancer represents 1% to 4% of all malignancies and is the fifth most common cancer in women in the United States. [14] It has a female preponderance of around 3:1. [18] There has been a steady rise in the incidence of thyroid cancer globally; particularly, PTC detection has risen by 240% in the last three decades. [19] This increase in the incidence has been observed in both genders and among all races and is thought to be primarily due to an increasing trend in the rate of diagnostic imaging. [20] [21]

PTC is the most common endocrine cancer, responsible for 96% of all new and 66.8% of deaths due to endocrine cancers. [22] As was mentioned earlier, most thyroid cancers derive from the follicular epithelium, with PTC and FTC being far more common than anaplastic thyroid cancer. [23] [24]

Histopathology

PTC: Microscopically, the unique characteristic feature of PTC is papillae formation. A papilla consists of layers of tumor cells surrounding a fibrovascular core. Follicles are typically absent in classic PTC. Typical cellular histomorphology includes cells with large and clear nuclei with finely granular chromatin, often described as ground-glass or "Orphan Annie-eyed" nuclei with nuclear grooving and intranuclear inclusion bodies. Psammoma bodies, which are calcified clumps of cells likely derived from necrosed papillae, are also common. [25]

Some variants of PTC do not form papillae and are termed follicular variants of PTC, provided they still have the nuclear features of PTC. Variants of PTC such as tall cell variant, columnar variant, insular carcinoma, and diffuse sclerosing variant are more aggressive than classic PTC and are termed thyroid cancers with intermediate differentiation. [26]

FTC: The histological features of FTC can be highly variable, from a well-differentiated follicular pattern to a poorly differentiated pattern with marked nuclear atypia, absence of follicles, extensive capsular or vascular invasion, and solid growth. The latter changes are associated with a poor prognosis. [27] As described above, features that are characteristic of PTC should be absent. Differentiating a follicular carcinoma from a benign follicular adenoma can only be made based on extracapsular and/or vascular invasion. FTC is further classified as minimally invasive, encapsulated, angioinvasive, and widely invasive, depending on the extent of invasion.

Hurthle cell carcinoma: This is characterized by the occurrence of eosinophilic oxyphilic cells with abundant cytoplasm (oncocytes) and prominent nucleoli. [28]

MTC: Given its origin from the parafollicular C cells, its histological features are the presence of spindle-shaped cells with no follicle formation. Amyloid deposition and calcitonin immunoreactivity are typically present.

Anaplastic thyroid carcinoma: The usual histologic variants are spindle-cell, pleomorphic giant cell, and squamoid variants. [29] Most of these cancers can consist of a mixed morphology of 2 or 3 variants. Atypical mitosis and numerous mitotic figures are very common. These cancers are less likely to stain for thyroid transcription factor 1 (TTF1), PAX 8, or thyroglobulin.

History and Physical

The most common presenting feature in DTC is either neck swelling (detected by the patient or a clinician) or incidentally detected thyroid nodules on neck imaging. The risk of malignancy of a thyroid nodule in the general population is around 5 to 10%, with the risk being higher in men and extremes of age. [30]

A careful history and physical examination will help to differentiate low-risk vs. high-risk nodules, although these signs and symptoms lack specificity. Aspects in the patient's history that could be concerning for malignancy include a sudden increase in the size of the nodule with pressure symptoms such as hoarseness of voice, dysphagia, dyspnea, or Horner's Syndrome, as well as a family history of thyroid cancer, childhood irradiation to the head and neck region, or the occurrence of systemic effects such as weight loss and fatigue. On physical examination of the neck, firmness of the nodule, immobility, and the presence of neck lymph nodes should trigger suspicion for malignancy and lead to further evaluation.

On the other hand, anaplastic thyroid cancer can present as a rapidly enlarging neck mass and rapid occurrence of compressive symptoms of the aerodigestive tract. Some patients can present with constitutional symptoms such as fever, weight loss, and anorexia. [31] [32]

A thyroid function panel is the most appropriate initial evaluation in a patient with a thyroid nodule. A hyperthyroid state often correlates with a lower risk of malignancy; in such patients, a radionuclide uptake scan is indicated. If the nodule/nodules are identified as hyperfunctioning, fine-needle aspiration biopsy (FNAB) should generally be avoided. This is because these nodules are rarely malignant, and the FNAB results for hyperfunctioning nodules are often inaccurate. [30]

Evaluation of the thyroid nodule when biochemically euthyroid or hypothyroid should begin with a high-resolution diagnostic thyroid ultrasound. This can help assess the nodules for high-risk features, detect additional nodules not felt on physical examination, evaluate for neck lymph nodes, and guide FNAB if warranted. High-risk features on ultrasound include a significant increase in size from prior imaging, hypoechogenicity, irregular margins, size taller than wide, microcalcifications, a solid internal structure, extra-thyroidal extension, and central vascularity. The features associated with a lower risk of malignancy are a purely cystic nodule, spongiform appearance, comet tail shadowing, and peripheral vascularity. The decision to subject a nodule for FNAB should be based on these radiological criteria with guidance from Thyroid Imaging Reporting and Data System (TIRADS) or American Thyroid Association (ATA) criteria, but importance should be given to clinical indications irrespective of imaging criteria. [33] [34] [35]

Limitations of FNAB

Of note, the diagnostic accuracy of FNAB depends on the skill of the person performing the procedure as well as the pathologist interpreting the results, and it ranges between 70 to 97%. Approximately 17 to 20% of FNAB are classified as insufficient samples. [36] Also, since FNAB allows for the analysis of individual cellular features and not the overall architecture of the nodule, it is excellent for diagnosing PTC, but it cannot detect capsular or vascular invasions by FTC. As a result, while FNA can categorize certain findings as suspicious for FTC, a diagnosis of FTC can only be made from the final pathology after surgical resection. [37] The same applies to Hurthle cell neoplasms.

Bethesda System for Reporting Thyroid Cytopathology

The FNAB result is usually reported by the Bethesda Criteria for Reporting Thyroid Cytology, which stratifies the biopsy results based on the cytology, and recommends a further course of action. [38]

Bethesda Category 1 is indicative of non-diagnostic FNAB; re-aspiration is indicated.

Bethesda Category 2 is suggestive of a benign nodule that can be followed clinically with periodic thyroid ultrasound as warranted.

Bethesda Categories 3 (Atypia of undetermined significance, AUS or Follicular lesion of undetermined significance, FLUS) and 4 (follicular neoplasm, FN or suspicious for follicular neoplasm) suggests that the inclusion or exclusion of thyroid cancer is not clear, and these patients may benefit from repeat FNAB (Category 3), molecular testing, or lobectomy (Categories 3 and 4).

Bethesda Categories 5 (Suspicious for malignancy) and 6 (Malignant) usually require surgery.

Role of Molecular Testing in Thyroid Cancer

Molecular testing is generally used in Bethesda categories 3 and 4, where cytology is indeterminate. [34] Recently, testing for single mutations such as BRAF V600E or RET/PTC translocations was performed. While these tests yield good specificity (100%), their sensitivity is usually poor (50 to 60%). [39] [40]

Molecular Diagnostic Approaches [41]

Gene mutation profiling panel- such as the 7-gene panel that detects multiple genes including BRAF V600E, HRAS codon 61, KRAS codons 12/13, and NRAS codon 61 point mutations, and RET/PTC1, PAX8/PPARγ, and RET/PTC3 translocations which account for approximately 70% of thyroid cancer. [41] This panel has improved the sensitivity and the negative predictive of these tests to >90%. [42] Therefore, mutation tests are good rule-in tests for thyroid cancer. [43]
A 167-Gene expression classifier provides a strong negative predictive value, while its positive predictive value is only around 50%. [41] Hence, gene expression classifier testing is a good rule-out test for thyroid cancer.

However, recently a large multi-gene panel of mutation markers has been introduced, further improving sensitivity and specificity. [43] [44]

While CT and MRI scans are not routine modalities in evaluating thyroid nodules for malignancies, their use may be appropriate in assessing local spread in more advanced diseases or those with enlarged cervical nodes in association with a suspicious mass. [45] A CT scan should be advised for patients with thyroid mass with extension into the substernal region confirmed by ultrasound or plain radiographs.

Treatment / Management

Papillary and Follicular Thyroid Cancers

Surgical Treatment

Surgical resection remains the main treatment modality of both PTC and FTC, followed by radioiodine ablation (RAI ablation) when indicated and suppression therapy with thyroid hormone. [34] [46] Systemic radiation and chemotherapy seldom play a significant role in treatment, although they may be used in advanced cases refractory to conventional methods.

To minimize the risk of complications, specifically recurrent laryngeal nerve injury and hypoparathyroidism, surgery is recommended, performed by experienced, "high-volume" thyroid surgeons. [47]

Pre-operative neck ultrasound is pivotal in deciding the appropriate surgical procedure. Surgical resection can be hemithyroidectomy or total thyroidectomy, with or without lymph node dissection. The choice of surgery depends on tumor size, presence of lymph node metastasis, extra-thyroidal extension, age of the patient, and the presence or absence of co-morbid conditions. In patients with locally advanced disease, additional imaging of the neck is advised.

A thyroid lobectomy is preferred for unilateral DTC < 1 cm, without any extra-thyroidal or lymph node invasion, unless there are clear indications for total thyroidectomy, such as childhood head and neck irradiation or a strong family history of thyroid cancer. Lately, there is also a trend for just active surveillance without immediate surgery, but more studies are needed to show the difference, if any, in the outcomes and prognosis. [48]

For tumor sizes between 1 and 4 cm with no extrathyroidal or lymphatic invasion, the procedure of choice can either be a total thyroidectomy or lobectomy, depending on patient preferences and risk factors, as described above. This decision should be made with the patient aware that a completion thyroidectomy may be necessary depending on pathology results.

For tumors > 4 cm or tumors with extra-thyroidal or lymph node invasion, a total thyroidectomy is the preferred surgical procedure as there is a high risk of multifocal carcinoma in such cancers. It is also intended to facilitate RAI ablation and future surveillance with thyroglobulin as a tumor marker.

The decision for lymph node dissection should be made on a patient-by-patient basis, and there is still a lot of controversy about the proven survival benefit of prophylactic node dissection. Regardless, all patients with proven or suspected PTC should undergo a thorough examination of both the central and lateral neck for possible nodal metastasis. The lateral neck compartments are not routinely entered in thyroidectomy and should be assessed preoperatively with ultrasound and subsequent FNAB if there is a concern for lymphatic spread. If pathologic nodes are confirmed, an ipsilateral neck dissection should be carried out, with a formal clearance of defined lymph node compartments as opposed to isolated "berry-picking" of diseased nodes. The central neck lymph nodes are difficult to assess preoperatively due to their location. A careful inspection and palpation of the central neck should be performed at the time of surgery, with subsequent compartmental neck dissection if abnormal nodes are found.

Postsurgical Risk Stratification

Postsurgical risk stratification must be performed to determine the need for additional treatment, especially with RAI ablation. The TNM (Tumor, Node, Metastasis) risk stratification by the American Joint Commission on Cancer(AJCC) predicts disease-specific mortality, while the American Thyroid Association (ATA) risk stratification system, which is widely used, helps predict the persistence or recurrence of residual cancer. [49]

The ATA system classifies patients as low, intermediate, or high risk based on clinicopathologic findings, including but not limited to tumor size, histologic type, vascular or lymph node involvement, local invasion, distant metastasis, the extent of tumor resection, post-operative thyroglobulin levels, and post-operative radioiodine uptake outside of the thyroid gland. [34] [50] [34]

The TNM-AJCC system accounts for factors such as the tumor size, the presence and extent of extra-thyroidal invasion, the number of nodal metastases, and whether there is the presence of distal metastasis. Age is a significant factor in predicting mortality in thyroid cancer patients, and its role is also significant in staging the disease. Patients under 55 years old at the time of diagnosis will receive a stage II diagnosis at the most. [51]

Radioiodine (RAI) Ablation Therapy

RAI therapy after thyroidectomy is used for remnant ablation of normal residual thyroid tissue, as adjuvant therapy for subclinical micrometastases, or as treatment of apparent local or distant metastasis. [52] High-risk and some selected intermediate-risk patients, per the ATA risk stratification system, will benefit from RAI ablation. Patients who are candidates for RAI therapy should maintain a low iodine diet for 1 to 2 weeks before the treatment to ensure iodine depletion of the cells; they should also be cautioned against large iodine administrations such as through iodinated contrast or amiodarone to improve the avidity of the thyroid follicular cells to iodine. RAI ablation works best when thyroid hormone has been withdrawn, with a goal thyroid-stimulating hormone (TSH) of 30mIU/liter or higher. This level of TSH can be achieved either through the withdrawal of thyroid hormones or the administration of exogenous recombinant human TSH.

Thyroid Hormone Suppression Therapy

Thyroid hormone suppression therapy to suppress TSH and thereby potentially minimize its stimulation of thyroid cancer growth is recommended in most patients after surgery. For patients with ATA high-risk, the goal TSH should be no more than 0.1m IU/liter, and for patients in the intermediate-risk category, the goal TSH should be between 0.1 and 0.5 mIU/liter. For the ATA low-risk category, a goal TSH between 0.5 and 2.0 mIU/liter is acceptable. [53] [54] [53]

Persistent or Recurrent Disease

For recurrent minimal iodine-avid disease, RAI ablation is the preferred therapy. For invasive neck disease, surgical resection is recommended. Percutaneous ethanol injection [55] has been tried for cervical lymph node metastasis. For small distant metastasis to bones or lungs, radiofrequency ablation has been used. Other treatment options are external beam radiation and systemic chemotherapy.

Systemic Chemotherapy

Systemic chemotherapy is usually only considered in a group of carefully selected patients with a high metastatic disease burden or rapidly progressive metastatic disease despite the above treatment (Iodide-refractory). Because of the significant adverse effects associated with such therapy, it should be considered only when the associated benefits exceed the risks. [34]

Systemic chemotherapy for DTC is preferably administered through a clinical trial. The common agents of choice are the kinase inhibitor class of drugs such as anti-angiogenic multi-targeted kinase inhibitors (aaMKI- lenvatinib, sorafenib), BRAF kinase inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib, cobimetinib), NTR kinase inhibitors (larotrectinib), and RET inhibitor (selpercatinib). [56] The choice of agent depends on the occurrence of specific gene mutations or signaling irregularities such as those described above. For patients with no identifiable mutations, aaMKIs are the recommended first-line therapy.

Dynamic Risk Stratification

After the initial postsurgical risk stratification and appropriate treatment as above, patients should be re-stratified during each follow-up visit depending on their response to therapy into one of the following clinical outcomes: 1. Excellent response, 2. Biochemical incomplete response, 3. Structural incomplete response, 4. Indeterminate response. [57] [58] [59]

Monitoring in the first postsurgical year primarily involves a thyroid ultrasound scan every 6 to 12 months and TSH and thyroglobulin levels every 3 to 6 months, depending on risk. For higher-risk patients, additional imaging such as CT scan, MRI, FDG-PET, or whole-body radioiodine scanning is required.

After one year, the frequency of monitoring depends on the dynamic risk stratification.

Medullary Thyroid Cancer

Surgical therapy that includes total thyroidectomy with resection of local and regional metastases is the mainstay of treatment for MTC. In most patients with confirmed MTC and no evidence of pre-operative cervical lymph node metastasis on ultrasound, prophylactic central lymph node dissection should be performed at the time of the total thyroidectomy. Patients with confirmed lateral zone nodal metastases should receive lateral compartment dissection, central neck dissection, and total thyroidectomy. Serum calcitonin, carcinoembryonic antigen, and biochemical testing for coexisting hyperparathyroidism and pheochromocytoma should be performed. Patients should be monitored long-term with serial calcitonin levels, neck ultrasound, and physical examination. Of note, as MTC is not of follicular origin, there is no role for radioiodine ablation or TSH suppression in its management. [60] For refractory MTC, systemic chemotherapy with kinase inhibitors has been shown to be beneficial. RET-specific kinase inhibitors are preferred in patients with RET mutation, while in patients negative for RET mutation, aaMKIs are the preferred drugs.

Anaplastic Thyroid Cancer

In patients diagnosed with anaplastic thyroid cancer, BRAF V600E mutation testing and staging are performed. Resectable disease is surgically removed, followed by specific BRAF kinase inhibitors in patients with BRAF V600E mutations. Other patients received targeted radiation treatment and cytotoxic chemotherapy after surgery. However, distant metastases are common in patients even at initial diagnosis due to their rapidly progressive course, and local invasion into the trachea or vasculature may occur, making it unresectable. Mortality is near 100% for these cancers, and a conservative surgical approach for palliation can be considered in such high-risk patients.

Differential Diagnosis
Benign thyroid nodule
Toxic nodular goiter
Primary thyroid lymphoma
Cervical lymphadenopathy

The prognosis of thyroid cancer varies greatly, depending on its type, tumor size, the extent of metastasis, patient's age, and amenability to resection. The prognosis is generally good, with up to 95% 5-year survival rate for patients of all ages and races. Poor prognostic factors include large tumor size, the presence of extra-thyroidal extensions or metastases, older age, or unfavorable tumor types such as undifferentiated cancer. [61]

Complications

Untreated thyroid cancer can be locally invasive into the airway, esophagus, or other nearby neurovascular structures. Distant metastasis most commonly involves the lung, bone, and other soft tissue structures.

Both thyroid lobectomy and total thyroidectomy carry the potential for neurovascular injuries, with the most common involving the recurrent laryngeal nerve, leading to hoarseness of voice and potentially respiratory failure with bilateral injuries.

Treatment of thyroid cancer during pregnancy, mostly with thyroidectomy, did not show any significant increase in the complications of pregnancy. [62]

Consultations
Thyroid surgeon
Endocrinologist
Radiologist
Pathologist
Deterrence and Patient Education

As previously discussed, patients with risk factors, such as prior irradiation to the head and neck area and a family history of thyroid cancer, should be screened for thyroid cancer, especially when such a patient presents with thyroid nodules with or without pressure symptoms.

Enhancing Healthcare Team Outcomes

Thyroid cancer, as discussed, can have highly varied manifestations, from a clinically indolent low-risk disease that can be managed with only active surveillance to a highly aggressive metastatic disease that needs extensive surgical resection with or without systemic chemotherapy.

Hence, managing a patient with thyroid cancer is a highly individualized process taking into account the patient's risk of recurrence and preferences (after being educated about the different treatment strategies and risks vs. benefits of each). A close collaboration between all interprofessional team members, including but not limited to the thyroid surgeon, the endocrinologist, the pathologist, the radiologist, and possibly the oncologist, plays a vital role in providing the most appropriate treatment for the patient while avoiding overtreatment at the same time. Nursing staff should ensure the patient is involved and comfortable every step of the way, from pre-operative planning to treatment and postoperative monitoring. When pursuing chemotherapy, a specialized oncology pharmacist is also a valuable addition to the interprofessional team. Interprofessional teamwork relies on open communication channels between all team members, and the maintaining of meticulous records so that all professionals involved in the case have access to the same updated patient information and can reach out to other team members if they see anything that requires their attention. This type of interprofessional care coordination combined with open information sharing will yield the best patient outcomes. [Level 5]

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Disclosure: Kenny Lee declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.

Disclosure: Chandriya Chandran declares no relevant financial relationships with ineligible companies.

Disclosure: Sebastiano Cassaro declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Cite this Page Lee K, Anastasopoulou C, Chandran C, et al. Thyroid Cancer. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Home > Patients, Caregivers, and Advocates > About Cancer > Cancers > Thyroid Cancer

Thyroid Cancer

Thyroid cancer is cancer of the butterfly-shaped gland at the base of the throat. The thyroid uses iodine, a mineral found in some foods and in iodized salt, to help make several hormones that control heart rate, body temperature, metabolism, and the amount of calcium in the blood.

There are four main types of thyroid cancer: papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer. According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program , approximately 44,020 people in the United States will be diagnosed with thyroid cancer in 2024, and about 2,170 will die of the disease. Thyroid cancer is highly treatable, and the five-year relative survival rate is estimated at 98.4 percent.

Thyroid cancer is much more common among women than it is among men. Age and exposure to radiation are also risk factors.

Source: National Cancer Institute

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AJCC indicates American Joint Committee on Cancer Cancer Staging Manual, 8th Edition; ATA, American Thyroid Association; ATC, anaplastic thyroid carcinoma; CMTC, cribriform morular thyroid carcinoma; FTC, follicular thyroid carcinomas; IEFVPTC, invasive encapsulated follicular variant papillary thyroid carcinoma; MTC, medullary thyroid carcinomas; NA, not applicable; NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; OCA, oncocytic carcinomas of the thyroid; and PTC, papillary thyroid carcinomas.

AUS indicates atypia of undetermined significance; FN, follicular neoplasm; ND, nondiagnostic; and SFM, suspicious for malignancy.

ATC indicates anaplastic thyroid carcinoma; AUS, atypia of undetermined significance; FN, follicular neoplasm; IEFVPTC, invasive encapsulated follicular variant papillary thyroid carcinoma; ND, nondiagnostic; NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; OCA, oncocytic carcinomas of the thyroid; PTC, papillary thyroid carcinomas; and SFM, suspicious for malignancy.

eTable 1. Association of Variant Allele Fraction of RAS and BRAF V600E and TERT Promoter Variants With Clinicohistopathologic Features of Well-Differentiated Thyroid Tumors

eTable 2. Surgical Pathology Follow-up of Variant Allele Fraction Assays of RAS , BRAF V600E, and TERT Promoter Variants on the Residual FNA Biopsy Specimens From Thyroid Nodules

eTable 3. Performance of Variant Allele Fraction Assays of RAS and BRAF and TERT Variants in Differentiating Malignancy Among Thyroid Surgical Tumors and Preoperative Thyroid Nodules

eTable 4. Direct Cost of Laboratory Developed Tests for Variant Allele Fraction Assays

eFigure 1. Detection and Quantification of HRAS , NRAS , and KRAS Variants by dPCR Assays and Verification by Sanger Sequencing

eFigure 2. Variant Allele Fraction Distributions Across 3 RAS Gene Isoforms in Thyroid Tumors and Different Histology Diagnoses

eFigure 3. Clinicomolecular Characteristics of Interpatient Variabilities of RAS , BRAF V600E, and TERT Promoter Variants at the Variant Allele Fraction Level in Papillary Thyroid Carcinomas (PTC) Classified by The 2017 WHO Classification of Thyroid Neoplasms

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Fu G , Chazen RS , MacMillan C , Witterick IJ. Discriminating Interpatient Variabilities of RAS Gene Variants for Precision Detection of Thyroid Cancer. JAMA Netw Open. 2024;7(5):e2411919. doi:10.1001/jamanetworkopen.2024.11919

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Discriminating Interpatient Variabilities of RAS Gene Variants for Precision Detection of Thyroid Cancer

1 Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, Ontario, Canada
2 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health and University of Toronto, Toronto, Ontario, Canada
3 Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, Sinai Health, Toronto, Ontario, Canada
4 Department of Otolaryngology-Head and Neck Surgery, Mount Sinai Hospital, Sinai Health and University of Toronto, Toronto, Ontario, Canada

Question Is discrimination of interpatient variabilities of RAS gene variants associated with improved accuracy in malignancy diagnosis among thyroid nodules?

Findings This diagnostic study of 620 patients, including 438 surgically resected thyroid tumor tissues and 249 thyroid nodule fine-needle aspiration biopsies, delineated interpatient differences in RAS variants at the variant allele fraction (VAF) levels, ranging from 0.15% to 51.53%. While RAS variants alone, regardless of the extent of variation, were associated with low-risk thyroid cancer in 88.8% of tumor samples, they did not definitively distinguish malignancy of an unknown tumor; however, detection of interpatient variabilities of RAS , BRAF, and TERT promoter variants in combination could assist in classifying indeterminate thyroid nodules.

Meaning These findings suggest that discrimination of interpatient differences in genomic variants could facilitate precision cancer detection, including preoperative malignancy diagnosis and stratification of low-risk tumors from high-risk ones, among patients with indeterminate thyroid nodules.

Importance Interpatient variabilities in genomic variants may reflect differences in tumor statuses among individuals.

Objectives To delineate interpatient variabilities in RAS variants in thyroid tumors based on the fifth World Health Organization classification of thyroid neoplasms and assess their diagnostic significance in cancer detection among patients with thyroid nodules.

Design, Setting, and Participants This prospective diagnostic study analyzed surgically resected thyroid tumors obtained from February 2016 to April 2022 and residual thyroid fine-needle aspiration (FNA) biopsies obtained from January 2020 to March 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data were analyzed from June 20, 2022, to October 15, 2023.

Exposures Quantitative detection of interpatient disparities of RAS variants (ie, NRAS, HRAS , and KRAS ) was performed along with assessment of BRAF V600E and TERT promoter variants (C228T and C250T) by detecting their variant allele fractions (VAFs) using digital polymerase chain reaction assays.

Main Outcomes and Measures Interpatient differences in RAS , BRAF V600E, and TERT promoter variants were analyzed and compared with surgical histopathologic diagnoses. Malignancy rates, sensitivity, specificity, positive predictive values, and negative predictive values were calculated.

Results A total of 438 surgically resected thyroid tumor tissues and 249 thyroid nodule FNA biopsies were obtained from 620 patients (470 [75.8%] female; mean [SD] age, 50.7 [15.9] years). Median (IQR) follow-up for patients who underwent FNA biopsy analysis and subsequent resection was 88 (50-156) days. Of 438 tumors, 89 (20.3%) were identified with the presence of RAS variants, including 51 (11.6%) with NRAS , 29 (6.6%) with HRAS , and 9 (2.1%) with KRAS . The interpatient differences in these variants were discriminated at VAF levels ranging from 0.15% to 51.53%. The mean (SD) VAF of RAS variants exhibited no significant differences among benign nodules (39.2% [11.2%]), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) (25.4% [14.3%]), and malignant neoplasms (33.4% [13.8%]) ( P = .28), although their distribution was found in 41.7% of NIFTPs and 50.7% of invasive encapsulated follicular variant papillary thyroid carcinomas ( P < .001). RAS variants alone, regardless of a low or high VAF, were significantly associated with neoplasms at low risk of tumor recurrence (60.7% of RAS variants vs 26.9% of samples negative for RAS variants; P < .001). Compared with the sensitivity of 54.2% (95% CI, 48.8%-59.4%) and specificity of 100% (95% CI, 94.8%-100%) for BRAF V600E and TERT promoter variant assays, the inclusion of RAS variants into BRAF and TERT promoter variant assays improved sensitivity to 70.5% (95% CI, 65.4%-75.2%), albeit with a reduction in specificity to 88.8% (95% CI, 79.8%-94.1%) in distinguishing malignant neoplasms from benign and NIFTP tumors. Furthermore, interpatient differences in 5 gene variants ( NRAS, HRAS, KRAS, BRAF, and TERT ) were discriminated in 54 of 126 indeterminate FNAs (42.9%) and 18 of 76 nondiagnostic FNAs (23.7%), and all tumors with follow-up surgical pathology confirmed malignancy.

Conclusions and Relevance This diagnostic study delineated interpatient differences in RAS variants present in thyroid tumors with a variety of histopathological diagnoses. Discrimination of interpatient variabilities in RAS in combination with BRAF V600E and TERT promoter variants could facilitate cytology examinations in preoperative precision malignancy diagnosis among patients with thyroid nodules.

Thyroid cancer, especially papillary thyroid cancer (PTC), has experienced a rapid increase in incidence since the 1980s 1 and is primarily diagnosed through ultrasonographic examinations and fine-needle aspiration (FNA) biopsy of suspicious nodules. 2 , 3 However, approximately 30% of FNAs exhibit an indeterminate diagnosis, and 10% of findings are nondiagnostic. 4 Patients with indeterminate thyroid nodule findings usually undergo diagnostic surgery, with 20% to 30% of nodules being detected as malignant. Thus, up to 70% to 80% of patients with indeterminate nodules found histologically benign have undergone unnecessary surgical procedures. Patients with nondiagnostic cytological findings are typically recommended for a repeat FNA, with 13% of nodules detected as being malignant. 4 Cancer arises along with genetic alterations. Molecular assays of FNA specimens are being increasingly used to enhance preoperative diagnostic accuracy for patients with indeterminate cytological findings and avoid unnecessary surgery for benign thyroid nodules. 2 , 5

RAS is the most frequently variated gene family in human cancer. Approximately 19% of patients with cancer harbor activating variations from 3 RAS gene isoforms: NRAS (OMIM 164790 ) in 17% of patients, HRAS (OMIM 190020 ) in 7% of patients, or KRAS (OMIM 190070 ) in 75% of patients. 6 Similarly, RAS variants are the second most common alterations in thyroid nodules, with NRAS variants being the dominant isoform followed by HRAS and KRAS . 7 - 10 In thyroid tumors, RAS gene variations are detected in tumors spanning a wide spectrum of histological diagnoses, with a prevalence of 10% to 30% in PTC, 11 - 13 40% to 50% in follicular thyroid carcinomas (FTCs), 14 , 15 12% to 85% in follicular adenoma or hyperplasia, and 5% to 46% in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs). 14 , 16 Indeterminate thyroid nodules carrying RAS variants have shown malignancy rates varying from 9% to 83%, 7 - 10 , 17 and such discrepancies can be primarily attributed to the use of small patient cohorts in these studies. Despite the widespread application of RAS variants in panel tests, assays of RAS variants often yield inconclusive results in detecting malignancy of thyroid nodules, frequently leading to a diagnostic surgery. 2 , 12 , 18 On the contrary, BRAF V600E and TERT promoter variants (C228T and C250T) are the most frequently detected genetic variants in thyroid nodules, providing a more definitive basis for cancer diagnosis. 19 - 21

Interpatient variabilities in genomic variants may reflect differences in tumor statuses among individuals. 20 However, the diagnostic impact of discriminating interpatient variabilities of RAS variants on cancer detection remains unclear, particularly under the 2022 updated fifth World Health Organization (WHO) classification of thyroid neoplasms. 22 In alignment with the WHO classification, the 2023 Bethesda System for Reporting Thyroid Cytopathology (BSRTC) 23 has updated nomenclature for each of the 6 diagnostic categories: I, nondiagnostic (ND); II, benign; III, atypia undetermined significance (AUS); IV, follicular neoplasm (FN); V, suspicious for malignancy (SFM); and VI, malignant. 23 Currently, the methods of detecting RAS variations are mainly based on polymerase chain reaction (PCR) and Sanger sequencing or next-generation sequencing (NGS). This study aimed to delineate interpatient disparities of RAS variants in thyroid tissues by quantifying variant allele fraction (VAF) using digital PCR (dPCR) assays and to examine their diagnostic associations with the preoperative detection of malignancy among patients with thyroid nodules.

This prospective diagnostic study was reviewed and approved by the Sinai Health Research Ethics Bord. All patients provided written informed consent, and samples were deidentified for data analysis. Data are reported in alignment with the Standards for Reporting of Diagnostic Accuracy ( STARD ) reporting guideline.

A total of 438 thyroid tissue specimens were obtained from surgically resected thyroid tumors with a maximum dimension of 1 cm or larger from 436 consecutive patients who underwent surgery between February 1, 2016, and April 4, 2022, and 249 FNA specimens were collected from 234 consecutive patients who underwent biopsy procedures between January 22, 2020, and March 2, 2021, at Mount Sinai Hospital, Sinai Health, Toronto, Canada. All surgical tissue specimens sampled were quickly placed in liquid nitrogen and transferred to −80 °C for long-term preservation. As for preoperative biopsies, all FNAs were routinely obtained under ultrasonographic guidance using a 23-gauge needle and subjected to CytoLyte (Hologic) fixation. After cytological examination according to the BSRTC, 4 , 23 the leftover materials of a total of 249 FNA biopsies were collected and stored at 4 °C until DNA purification. These preoperative biopsies primarily included ND and indeterminate (BSRTC categories I, III, IV, and V) specimens, along with some malignant (BSRTC category VI) and benign (BSRTC category II) specimens. A follow-up of thyroid nodules was conducted among patients who had previously undergone FNA procedures and subsequently underwent surgery. The patient clinical records, surgical pathology reports, and hematoxylin and eosin–stained sections were reviewed. The final histological diagnoses were made in accordance with the fifth WHO classification of thyroid neoplasms 22 and Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland. 24 Patients with cancer were further stratified as having low, intermediate, or high risk of recurrence based on the 2015 American Thyroid Association guidelines. 25

Molecular assays for the most prevalent RAS variants of 3 RAS genes, NRAS (Q61R or Q61K), HRAS (Q61R or Q61K), and KRAS (G12C, G12D, G12V, G12A, or G13D), were developed using locked nucleic acid probe–based droplet dPCR by following the strategy and procedures recently established for the VAF assays of BRAF V600E and TERT promoter variants (C228T and C250T). 20 , 26 The details of DNA extraction, dPCR assays, and verification of RAS variants using PCR and Sanger sequencing were documented in the eMethods in Supplement 1 .

Data were summarized as frequencies and percentages for categorical variables and means and SDs for continuous variables. Blinded central review–based 2022 WHO histologic classification and 2023 BSRTC were used as the reference standard. 22 , 23 The continuous parametric variables were compared by t test or 1-way analysis of variance test. Associations between molecular status and the clinicopathological characteristics were assessed by χ 2 or Fisher exact test with 95% CIs. Statistical tests were conducted using SPSS software version 22.0 (IBM). P values were 2-sided, with P < .05 considered statically significant. Data were analyzed from June 20, 2022, to October 15, 2023.

A total of 438 surgically resected thyroid tumor tissues and 249 thyroid nodule FNA biopsies were obtained from 620 patients (470 [75.8%] female; mean [SD] age, 50.7 [15.9] years). Of 438 thyroid tumors, 431 were follicular cell-derived neoplasms, comprising 77 benign tumors (thyroid follicular nodular disease, follicular adenoma, or oncocytic adenoma), 12 NIFTPs, and 343 malignant neoplasms, including 258 PTCs, 67 invasive encapsulated follicular variant PTCs (IEFVPTCs), 5 FTCs, 10 oncocytic carcinomas of the thyroid (OCAs), and 3 anaplastic thyroid carcinomas (ATCs). The cohort also included 5 medullary thyroid carcinomas (MTCs) and 2 cribriform morular thyroid carcinomas (CMTCs) ( Figure 1 and Table 1 ; eTable 1 in Supplement 1 ). Hence the surgical tumor cohort exhibited a high tumor malignancy rate of 79.7% (95% CI, 75.5%-83.3%). In a separate cohort of 249 FNA biopsies, there were 76 (30.5%) with ND findings, 126 (50.6%) with indeterminate findings, 34 (13.7%) with malignant findings, and 13 (5.2%) with benign findings ( Figure 2 and Table 2 ; eTable 2 in Supplement 1 ). The indeterminate FNAs comprised 83 AUS (65.9%), 26 FN (20.6%), and 17 SFM (13.5%).

Molecular VAF assays were developed for the quantitative detection of RAS variants at single-nucleotide resolution positive for NRAS , HRAS , and KRAS in tumor tissues but not in the adjacent healthy tissue, which were verified by Sanger sequencing (eFigure 1 in Supplement 1 ). Of 438 tumors that underwent surgery, 89 (20.3%) were identified with the presence of RAS variants, including 51 (11.6%) with NRAS , 29 (6.6%) with HRAS , and 9 (2.1%) with KRAS variants, in mutually exclusive existence from each other ( Figure 1 and Table 1 ). When compared with the 3 RAS gene isoforms across all tumor subtypes, the profiles of interpatient variabilities were delineated at the VAF levels ranging from 0.15% to 51.53%, specifically from 0.59% to 51.53% for NRAS , from 0.36% to 43.56% for HRAS , and from 0.15% to 46.64% for KRAS variants, with no significant difference among 3 isoforms ( P = .16) ( Figure 1 ; eFigure 2 in Supplement 1 ). Of these variants, 84 (94.4%) exhibited a VAF of greater than 1% and 5 showed a VAF of less than 1%, with 1 NRAS , 2 HRAS , and 2 KRAS variants. RAS variants were found in 5 benign neoplasms (6.4%), 5 NIFTPs (41.7%), and 79 malignant neoplasms (22.6%) ( P < .001). Of 79 malignant neoplasms, 41 (51.9%) were PTCs, from 15.9% of total PTCs; 34 (43.0%) were IEFVPTCs, from 50.7% of total IEFVPTCs; and 4 (5.3%) comprised 1 each of FTCs, OCAs, ATCs, and MTCs, from 17.4% of all these carcinomas ( P < .001) ( Figure 1 and Table 1 ). Detection of RAS variants yielded a sensitivity of 22.6% (95% CI, 18.3%-27.0%), specificity of 88.8% (95% CI, 82.2%-95.3%), positive predictive value (PPV) of 88.8% (95% CI, 82.2%-95.3%), and negative predictive value (NPV) of 22.6% (95% CI, 18.3%-27.0%) in distinguishing malignant neoplasms from benign and NIFTP tumors (eTable 3 in Supplement 1 ). Notably, the VAF distribution of RAS variants was not statistically different among benign, NIFTP, and malignant neoplasms, as well as between PTCs and IEFVPTCs (eFigure 2 in Supplement 1 ), despite a high incidence of RAS variants in both NIFTPs (5 of 12 tumors [41.7%]) and IEFVPTCs (34 of 67 tumors [50.8%]). RAS variants, whether at a low or high VAF, were significantly associated with tumors undergoing partial thyroidectomy, with tumors absent for extrathyroidal extension, lymph node metastasis, capsular invasion, lymphatic invasion, or perineural invasion ( Table 1 ). In addition, RAS variants alone had a significant association with a low-risk recurrence of thyroid carcinomas ( Table 1 ).

Of 340 well-differentiated thyroid carcinomas, 77 (22.6%) were detected with RAS variants, including 46 (13.5%) with NRAS , 25 (7.4%) with HRAS , and 6 (1.8%) with KRAS . In addition, interpatient variabilities of BRAF V600E and TERT promoter variants (C228T and C250T) were detected in 173 (50.9%) and 55 (16.2%) carcinomas, respectively, with 45 (13.2%) of them in coexistence. Hence, there were 100 carcinomas (29.4%) with neither RAS nor BRAF V600E or TERT promoter variants ( Figure 1 ; eTable 1 in Supplement 1 ). RAS variants were distributed in 41 PTCs, including 34 classical subtypes (CPTCs), 3 infiltrative follicular subtypes (IFPTCs), and 4 tall, hobnail, or columnar cell subtypes (thcPTCs); 34 IEFVPTCs; and 1 each of FTC and OCA ( P < .001) (eTable 1 in Supplement 1 ). Of 41 RAS variant PTCs, 6 (14.6%) coharbored BRAF V600E alone: 4 in CPTCs and 1 in each of IFPTC and thcPTC; 4 (9.8%) coharbored TERT promoter variants alone: 3 in CPTCs and 1 in thcPTC; and 2 (4.9%) coharbored both BRAF V600E and TERT promoter variants: 1 in each of CPTC and thcPTC. Of 34 RAS variant IEFVPTCs, 5 (14.7%) coexisted with BRAF V600E alone and 1 (2.9%) coexisted with both BRAF V600E and TERT promoter variants. For an additional 2 carcinomas with RAS variants, 1 in ATC was found coexisting with both BRAF V600E and TERT promoter variants, and the other in MTC coexisting with BRAF V600E alone. Of 57 malignant tumors harboring RAS variants alone, 29 (50.9%) were found in PTCs, with 26 CPTCs, 2 IFPTCs, and 1 thcPTC, and 28 (49.1%) were found in IEFVPTCs. No RAS variants were detected in the 2 CMTC tumors, but 1 CMTC tumor presented with the coexistence of BRAF V600E and TERT promoter variants. The inclusion of RAS variants into BRAF and TERT variant assays reached a sensitivity of 70.5% (95% CI, 65.4%-75.2%) and a specificity of 88.8% (95% CI, 79.8%-94.1%), with a PPV of 96.1% (95% CI, 92.7%-98.0%) and an NPV of 43.4% (95% CI, 36.2%-50.9%) in distinguishing malignant neoplasms from benign and NIFTP tumors. This represents a 30.2% increase in sensitivity but a 11.2% decrease in specificity compared with BRAF and TERT variant assays alone, which had a sensitivity of 54.2% (95% CI, 48.8%-59.4%) and specificity of 100% (95% CI, 94.8%-100%) (eTable 3 in Supplement 1 ).

VAF assays of 249 residual FNA specimens identified 36 specimens (14.5%) with RAS variants with interpatient variabilities (including 23 FNAs [9.2%] with NRAS , 10 FNAs [4.0%] with HRAS , and 3 FNAs [1.2%] with KRAS) , 50 specimens (20.1%) with BRAF V600E, and 25 FNAs (10.0%) with TERT promoter variants ( Figure 2 and Table 2 ). Of 36 FNA specimens with RAS variants, 28 (77.8%) had RAS variants alone in various BSRTC categories (4 ND, 9 AUS, 1 FN, 5 SFM, 5 malignant, and 1 benign); 5 (13.9%) coexisted with BRAF V600E: 1 AUS, 2 SFM, and 2 malignant; and 3 (8.3%) coexisted with TERT promoter variants: 1 FN and 2 SFM. Interpatient differences in the 5 gene variants ( NRAS, HRAS, KRAS, BRAF , and TERT ) were detected in 54 of 126 indeterminate FNAs (42.9%) and 18 of 76 ND FNAs (23.7%). During a median (IQR) follow-up of 88 (50-156) days for patients who underwent resections, VAF assays of 71 residual FNAs achieved a sensitivity of 56.6% (95% CI, 42.4%-69.9%), specificity of 100% (95% CI, 85.9%-100%), PPV of 100% (95% CI, 85.9%-100%), and NPV of 43.9% (95% CI, 28.8%-60.1%) in differentiating malignancy based on their surgical pathological findings (eTable 3 in Supplement 1 ). Of these FNAs, 12 (16.9%) had RAS variants (9 with RAS variants alone and 3 coexisting with BRAF V600E). Histopathologic outcomes confirmed all 12 (25.4%) nodules were malignant neoplasms, including 5 CPTCs and 7 IEFVPTCs ( Figure 3 ; eTable 2 in Supplement 1 ). All FNAs with RAS variants coexisting with BRAF V600E (except for the patient with AUS, who was not available for follow-up) were subsequently found as IEFVPTC. In addition, among 18 nodules (25.4%) identified without RAS variants but with BRAF V600E or TERT promoter variants in the prior FNAs (9 with BRAF V600E alone, 3 with TERT promoter alone, and 4 in coexistence with both variants), 14 were subsequently found as PTC, with 12 for CPTC and 2 for thcPTC; 2 were found as ATC; and 1 each was found as IEFVPTC and OCA. Among 41 nodules (57.8%) identified with neither RAS , BRAF V600E, nor TERT promoter variants, 17 were benign tumors, 1 was NIFTP, 14 were CPTCs, and 9 were IEFVPTCs. Of note, 1 nodular goiter with an NRAS variant in its prior FNA was later confirmed as CPTC. Compared with the 5 gene variants detected in the matched surgical specimens, VAF assays on residual FNA biopsies exhibited a high agreement (κ = 0.799; P < .001) ( Figure 3 ) and demonstrated a sensitivity of 87.1% (95% CI, 69.2%-95.8%), specificity of 92.5% (95% CI, 78.5%-98.0%), PPV of 90.0% (95% CI, 72.3%-97.4%), and NPV of 90.2% (95% CI, 75.9%-96.8%).

In this diagnostic study, interpatient variabilities in RAS variants were delineated in thyroid tumors with VAFs ranging from 0.15% to 51.53% using sensitive VAF assays. While RAS variants alone, regardless of the VAF levels, were associated with thyroid cancer in 88.8% of thyroid nodules harboring such variants, they did not definitively distinguish malignant tumors from NIFTP and benign ones. However, they did facilitate the stratification of low-risk tumors from high-risk ones among malignant neoplasms. Furthermore, interpatient differences in the 5 gene variants were discriminated in 42.9% of indeterminate FNAs, 23.7% ND FNAs, and all FNAs with follow-up surgical pathology-confirmed malignancy.

Currently, molecular assays of RAS variants do not effectively risk stratify tumors due to their limited sensitivities and specificities. 27 , 28 In our study, the sensitive VAF assays identified substantial interpatient differences in the most common RAS gene variants, including 57.3% of NRAS variants in predominance, 33.7% of HRAS variants, and 9.0% of KRAS variants. In a comparable PTC cohort from The Cancer Genome Atlas study, the prevalence of RAS variants was 12.9% in PTCs, including 8.5% with NRAS , 3.5% with HRAS , and 1.0% with KRAS , based on NGS assays. 11 In contrast, our study observed a prevalence of 23.1% for RAS variants in PTCs, classified by the 2017 WHO classification, 29 including 13.5% with NRAS , 7.4% with HRAS , and 2.2% with KRAS (eFigure 3 in Supplement 1 ), suggesting that VAF assays revealed higher frequencies of RAS variants in thyroid neoplasms. Hence, significant discrepancies from different methods of detecting genomic variants may result in false-negative results or missed diagnoses of clinical significance, particularly when methods with lower sensitivities are used. 28 , 30 In addition, a high agreement observed in VAF assays between residual FNA biopsies and matched surgical specimens underscores the clinical significance of using residual specimens. At a direct cost of $12.36 per laboratory-developed test reaction coupled with a turnaround time within 8 hours from specimen receipt to result (eTable 4 in Supplement 1 ), this approach facilitates the timely and rapid delivery of molecular results concurrently with cytological examination on the same source biopsies, holding promise as an effective addition to existing protocols for personalized thyroid cancer care.

High rates of RAS variants were identified in lesions exhibiting follicular architecture, such as NIFTP (41.7%) and IEFVPTC (50.7%). It is noteworthy that 70.6% of CPTCs carrying RAS variants exhibited a predominantly follicular growth pattern, with most of them presenting encapsulation. Unfortunately, discriminating variant differences did not improve the stratification power of RAS variants in distinguishing between malignant neoplasms and NIFTPs, follicular adenomas, or oncocytic adenomas, nor between lesions exhibiting differential follicular architecture, such as NIFTP and IEFVPTC neoplasms. The limited effectiveness of RAS variants in stratifying these histological types may be attributed to their close similarity in gene expression profiles. 27 , 31 , 32 Moreover, low VAF events of RAS variations, including those at VAF less than 1%, were associated with an equally high risk of cancer as high VAF events. This finding aligns with that of a 2017 study that reported an equivalent malignancy rate in RAS variants detected at VAF less than 10% compared with variants detected at VAF greater than 10%. 8 Further studies are needed to elucidate the biological role and clinical significance of the different extents of RAS variations in tumor development. 33 - 35

The widespread implementation of molecular assays as routine cancer diagnosis remains a challenge. First, interpretation of genomic variations can be complex and may vary due to interpatient differences in such variants. 36 - 38 RAS variants alone, including the low VAF events, do not confirm the malignancy of an unknown tumor; therefore, they should not solely dictate clinical decisions. 39 However, RAF variants do enhance the stratification of low-risk tumors, 12 , 27 aiding in informing the extent of operation. Second, BRAF V600E and TERT promoter variants were detected exclusively in malignant tumors and exhibited a stronger association with aggressive tumor behaviors, aligning with our prior findings and those of other studies. 20 , 21 , 40 , 41 The inclusion of RAS variants into BRAF V600E and TERT promoter variant assays significantly enhanced the sensitivity for malignancy detection, albeit with a trade-off of reduced specificity. In addition, RAS variants coexisting with BRAF V600E and/or TERT promoter variants tend to be enriched in high-risk cancers, such as thcPTC, FTC, OCA, ATC, and MTC. 42 - 44 Third, search for novel molecular markers is needed to screen the rest 29.5% of malignant tumors and 64.4% of thyroid nodules that did not have BRAF V600E, TERT promoter variants, or RAS variants. Hence, leveraging NGS with a high-fidelity read capability may help identify additional actionable molecular alterations for detecting malignancy among tumors negative for RAS, BRAF , and TERT variants.

This study has some limitations. This study was conducted at a single center, where our surgical tumor cohort exhibited a high tumor malignancy rate, potentially contributing to the observed high prevalence of RAS variants in malignant tumors. With its ultrasensitivity in absolute quantification, VAF assay stands out as a favorable choice for testing known and definitive biomarkers, be they single variants or a small panel of variants, particularly when dealing with low variant levels. However, VAF assay has a relatively limited capacity of detecting multiple genomic variants in a single reaction. To reinforce the clinical utility of our findings, further larger-scale multicenter validation is necessary, using sensitive VAF assays targeting RAS in conjunction with other genomic variants.

This diagnostic study delineated interpatient variabilities of RAS variants in thyroid tumors with various histopathological diagnoses. These findings suggest that discrimination of interpatient differences in RAS in combination with BRAF V600E and TERT promoter variants could facilitate cytology examinations in preoperative precision malignancy diagnosis among patients with thyroid nodules.

Accepted for Publication: March 18, 2024.

Published: May 17, 2024. doi:10.1001/jamanetworkopen.2024.11919

Corresponding Author: Guodong Fu, PhD, Mount Sinai Hospital, Sinai Health, 600 University Ave, Toronto, ON M5G 1X5, Canada ( [email protected] ; [email protected] ).

Author Contributions: Dr Fu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Fu, Witterick.

Acquisition, analysis, or interpretation of data: Fu, Chazen, MacMillan.

Drafting of the manuscript: Fu.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Fu.

Obtained funding: Fu.

Administrative, technical, or material support: Fu, Chazen.

Supervision: Fu, Witterick.

Conflict of Interest Disclosures: Dr Witterick reported owning stock in Proteocyte Diagnositcs, serving on an advisory board for Sanofi Canada, and receiving personal fees from Sanofi Canada, GSK Canada, and Medtronic Canada outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by The Harry Barberian Research Fund from the Department of Otolaryngology–Head & Neck Surgery of the University of Toronto (Dr Fu) and the Mount Sinai Hospital Foundation of Toronto Da Vinci Gala Fundraiser (Dr Witterick).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: David Nguyen, BASc, and the pathologists’ assistants at the Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, Ontario, Canada, assisted in the collection of thyroid tumor specimens and clinical information without compensation. The Cytopathology Laboratory of the Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada, helped with the collection of the residual fine-needle aspiration materials without compensation. We appreciate the participation of all the patients in this study.

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WHO 2022 updates on follicular cell and c-cell derived thyroid neoplasm

Affiliations.

1 Department of Pathology, All India Institute of Medical Sciences, Rajkot, Gurjat, India.
2 King George's Medical University, Lucknow, India.
3 Department of Pathology, Sharda Hospital, Greater Noida, India.
PMID: 38737660
PMCID: PMC11080517
DOI: 10.25122/jml-2023-0270

The latest edition of the WHO Classification of thyroid tumors was released in 2022 and incorporates novel concepts vital to patient management. Thyroid follicular nodular disease is a term used to collectively represent a wide variety of benign and non-neoplastic lesions, including both clonal and non-clonal proliferations that manifest clinically as multinodular goiter. Thyroid neoplasms develop from follicular cells and can be either benign, low-risk, or malignant. To avoid classifying all lesions under 1 cm in diameter as low-risk illnesses, the new classification method highlights the need for subtyping papillary thyroid cancer based on histomorphologic indicators rather than tumor size. Formerly known as the cribriform-morular variety of papillary thyroid carcinoma, this tumor is now more commonly referred to by its more accurate name, cribriform-morular thyroid carcinoma. Its histogenesis is unknown. Similar to the traditional definition of 'poorly differentiated thyroid carcinoma' according to the Turin criteria, the newly defined 'differentiated high-grade thyroid carcinoma' encompasses papillary thyroid cancer, follicular thyroid carcinomas, and oncocytic carcinomas with high-grade characteristics linked to worse prognosis. The squamous cell subtype of anaplastic thyroid cancer has also recently been characterized as a distinct morphologic pattern. In this article, we will discuss the latest revision to the World Health Organization's classification system for thyroid cancer.

Keywords: C-cell neoplasm; Follicular cell neoplasm; Thyroid neoplasm.

Adenocarcinoma, Follicular* / pathology
Thyroid Neoplasms* / classification
Thyroid Neoplasms* / diagnosis
Thyroid Neoplasms* / pathology
World Health Organization*

Management of low-risk papillary thyroid cancer. Minimally-invasive treatments dictate a further paradigm shift?

Mini Review
Open access
Published: 20 May 2024

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E. Papini 1 ,
R. Guglielmi 1 ,
R. Novizio 2 ,
A. Pontecorvi 2 &
C. Durante 3

Current management options for PTMC include lobo-isthmectomy and active surveillance (AS). Recently, ultrasound-guided minimally invasive procedures (MITs) are offered as a nonsurgical therapy for PTMC because they do not require hospitalization and general anaesthesia, and do not result in loss of thyroid function or cosmetic damage. MITs are reported to consistently provide, mostly in large retrospective series of patients, a rapid, safe, and cost-effective way to eradicate low-risk thyroid malignancies. However, conclusive data from well-conducted prospective studies on the histologically-proven completeness of tumor ablation and the long-term clinical advantages versus AS are still lacking.

This study aimed to evaluate the efficacy and safety of ultrasound-guided minimally invasive treatments (MITs) for PTMC in comparison to traditional surgical methods and active surveillance, and to assess their role in current clinical practice.

A structured literature review was conducted using keywords related to PTMC, MIT, and comparative techniques. Studies were evaluated based on treatment modality, patient selection, follow-up duration, complication rates, and clinical outcomes.

MITs have shown promising results in the management of PTMC. These treatments offer several advantages over surgery, such as reduced use of surgical resources, lower costs, minimal work disruption, and fewer major complications. However, there are still limitations, including the need for long-term surveillance and the potential risk of incomplete tumor ablation.

Conclusions

MITs represent a promising non-surgical option for managing low-risk PTMC, especially for patients ineligible for or refusing surgery. Despite favorable outcomes, more robust prospective data are needed to confirm their long-term benefits and completeness of tumor ablation. Interdisciplinary discussions and thorough patient education on the advantages and limitations of MITs are crucial for informed decision-making.

Avoid common mistakes on your manuscript.

The diagnosis of papillary thyroid carcinoma (PTC) has become more frequent during the last decades due to the widespread availability of neck imaging techniques, routine use of ultrasound (US)-guided fine needle aspiration biopsy (FNA), and, presumably, to the actual increase in the incidence of differentiated thyroid tumors [ 1 ]. Almost half of these cancers are under 10 mm in size and slow-growing, often incidental, and associated with a favorable prognosis. The majority of these tumors are low-risk papillary thyroid carcinomas (PTC), lacking aggressive histological features, extrathyroidal spread, nodal or distant metastasis, and worrisome mutations. These very low-risk cancers are generally referred to as papillary thyroid microcarcinomas (PTMC) in the literature, although the 2022 WHO classification does not consider them as distinct pathological conditions [ 2 ].

Currently, there is robust evidence supporting a minimalistic approach to the management of PTMC. The recommended surgical treatment for unifocal PTMC is lobo-isthmectomy but active surveillance (AS) is increasingly being proposed as an alternative management option. Several long-term studies, conducted in various thyroid centers across different countries, have demonstrated the safety of clinical and US monitoring without immediate intervention [ 3 , 4 , 5 , 6 , 7 ]. Recently, a third management option has been proposed to prevent the risk of overtreatment of clinically insignificant tumors and is now being tested worldwide [ 8 ]. Minimally invasive treatments (MIT), performed under US guidance, are established as effective and safe therapeutic tools for symptomatic benign thyroid nodules [ 9 , 10 , 11 , 12 ]. MITs are now being considered also as a possible nonsurgical therapy for PTMC because they do not require hospitalization, general anaesthesia, and do not result in loss of thyroid function or cosmetic damage [ 9 , 11 , 12 , 13 ]. Over the last 10 years, several clinical studies have shown that thermal ablation procedures—performed either with laser (LTA), radiofrequency (RFA), or microwaves (MWA) devices—can be used to selectively ablate PTMC with a diameter of up to 10 mm. Thus, the choice of the most appropriate management—surveillance, thermal ablation, or surgery—for these typically indolent tumors necessitates a thorough assessment of individual needs, clinical circumstances, and preferences.

Aim of the present paper is to assess the level of evidence for the outcomes of MITs in the treatment of PTMC, in order to evaluate the advantages and limitations of these innovative techniques in comparison to surgery and AS and to define their present role in current clinical practice.

To conduct the literature review on the management of Papillary Thyroid Microcarcinoma (PTMC), especially focusing on minimally invasive treatments, a structured search strategy using both specific keywords and Boolean operators has been employed. Keywords such as “PTMC”, “Papillary Thyroid Microcarcinoma”, “Thermal ablation”, “Laser”, “Radiofrequency”, “Microwave”, “Active Surveillance” guided the initial search. The search included Boolean combinations such as (“Papillary Thyroid Microcarcinoma” OR “PTMC” OR “Low-risk Papillary Thyroid Carcinoma”) AND (“minimally invasive procedures” OR “thermal ablation” OR “minimally invasive treatment” OR “ablation” OR “ablat*”) and Thyroid NEAR/3 Ablation to focus on articles discussing specific techniques used in the minimally invasive approach. Additionally, the comparison between surgical and non-surgical techniques has been explored using the string “Thyroid Surgery” VS “Non-Surgical Techniques” AND “PTMC”, allowing for a focused retrieval of studies comparing these approaches. For broader technology-based searches, (“Papillary Thyroid Microcarcinoma” OR “PTMC” OR “PTCM” OR “Papillary Thyroid Carcinoma”) AND (“laser” OR “LTA” OR “LT” OR “radiofrequency” OR “RFA” OR “microwaves” OR “MWA”) has been used to include various technologies applied in PTMC treatments. To investigate the long-term efficacy and patient-centered outcomes, strings such as “Active Surveillance” AND (“Papillary Thyroid Microcarcinoma” OR “PTMC” OR “PTCM” OR “Papillary Thyroid Carcinoma”) AND “outcomes” and (“Cost-Effectiveness” OR “Quality of Life”) AND (“Thermal Ablation” OR “Minimally Invasive”) AND “Thyroid Cancer”.

Available evidence

After the initial feasibility studies and pilot trials [ 14 , 15 , 16 ], several studies, performed with various minimally invasive technologies, investigated the efficacy, safety, and long-term outcomes of these treatment. Table 1 includes the main studies on the use of MIT for low-risk PTMC and summarizes modalities of treatment, patients’ selection, follow-up duration, complications rate, and clinical outcomes.

Advantages of minimally invasive treatments versus surgery

The benefits of thermal ablation in the management of low-risk PTMC are potentially relevant and encourage considering them as an alternative to surgery in selected conditions:

No use of surgical resources. Reducing the number of thyroid surgeries for low-risk PTMC could led to more appropriate allocation of resources and time towards surgery for patients with advanced thyroid cancer or large goiter that cause local pressure symptoms [ 9 , 10 , 11 , 12 ].

Low cost of the procedure. Due to the absence of general anaesthesia, surgical staff employment, and in-hospital stay, a relevant decrease of the costs may be achieved in comparison to thyroidectomy [ 17 , 18 ].

Minimal loss of working days. The persistence of local symptoms is generally limited to 24–48 h and the general clinical conditions and working ability are only minimally affected by MIT [ 18 ].

Low risk of major complications. Lower occurrence of peri-operatory complications and of permanent dysphonia are consistently reported in comparison to surgery [ 19 ].

Loss of thyroid function. Replacement therapy is only anecdotally required after MIT while is necessary, over time, in a sizable number of patients treated with lobectomy [ 19 , 20 ].

Absence of cosmetic damage. Cervical scars are avoided without the need for complex, and more expensive, trans-axillary or trans-oral surgical techniques [ 18 , 20 , 21 , 22 ].

Advantages of minimally invasive treatments versus AS

A few advantages can be attributed to MITs due to the following considerations:

A linear growth of PTMC volume may occur in about 8% of AS patients and may eventually prompt a delayed surgical treatment [ 6 , 23 ].

A minority of patients, especially young subjects, may develop over time cervical lymph node metastases that could require a more extensive, and potentially more disfiguring, neck surgery [ 23 ].

A substantial number of patients in AS programs eventually undergo thyroidectomy for reasons unrelated to cancer growth, mostly anxiety due to the awareness of harboring an untreated malignancy [ 24 ].

It can be speculated that only a limited number of centers can offer a reliable life-long clinical and US surveillance for a steadily increasing number of patients.

A conclusive definition of the role of MITs as a first line therapeutic option in the management of PTMC still has limitations that should be specifically addressed in future trials:

Completeness of tumor ablation . The histological confirmation of the complete ablation of malignant tissue is based on few anecdotal cases and on minute series of patients who, for unrelated reasons, underwent thyroidectomy after MITs [ 15 , 25 ]. Only few papers report the regular use of FNA or core needle biopsy (CNB) for ruling out the persistence of viable tumor cells in the treated area (Table 2 ). A retrospective cohort study, performed with long-term US follow up and systematic assessment with CNB of the ablation zone provided reassuring information [ 26 ]. Conversely, the risk of an incomplete ablation cannot be excluded with certainty in the majority of MIT studies which used US evaluation alone for the clinical outcome assessment. This issue is of pivotal importance because the eradication of any viable tumor cell represents the major advantage of MITs versus AS in the management of PTMC. The challenges of achieving complete tumor ablation are further compounded by the following factors. First, nearly all the available series include a relevant number of very small size (5 mm or less in diameter) PTMC (Table 3 ). Due to the need of a 2 mm circumferential safety margin of ablation around the PTMC circumference [ 8 ] the risk of an oncologically incomplete ablation rapidly increases with the increment in tumor size and is, consequently, much greater for tumors close to 10 mm. Second, the location of PTMC in areas difficult to be treated—close to the trachea, major vessels, or laryngeal nerve course—may hamper the radicality of the ablation even after a well conducted hydrodissection. Third, in case of incomplete ablation, the sonographic changes induced by MIT might hinder the persistence or recurrence of the treated PTMC.

Risk of complications . Head-to-head randomized prospective studies comparing MITs vs lobectomy are lacking. The current evidence is mostly based on retrospective studies comparing two cohorts of patients after non-randomized enrolment (Table 4 ). Besides this methodological limitation, most available studies compare thermal ablation, performed with different technologies and variable modalities, to surgery performed with lobectomy, total thyroidectomy, or thyroidectomy with central compartment resection. Differences in complications are most significant when comparing MITs to the most extensive surgical options, favoring MITs, but diminish when compared to lobectomy, the current recommended choice for managing unifocal carcinomas.

Quality of life . Surgical interventions are expected to negatively affect quality of life. and a better tolerability of MIT procedures may be postulated. Yet, controlled studies comparing the peri-operative and long-term impact on the QoL of the three management alternatives with validated and internationally accepted questionnaires are scarce.

Long-term surveillance . Surgery rules out the risk of tumor recurrence in the affected lobe and provides accurate information about tumor multifocality, extrathyroidal extension, aggressive histology, or clinically significant lymph node involvement. If these data, which conclusively define the risk of recurrence, are lacking, a prolonged though not intensive clinical and sonographic follow-up is required after thermal ablation, similarly to AS.

Access to treatment : a limited number of centers currently offer MIT for treating PTMC and specific training courses and certifications are not available in most countries.

Conclusions for clinical practice

Thermal ablation is a promising approach for non-surgical management of low-risk PTMC. Minimally invasive treatments could provide a rapid, safe, and cost-effective way to eradicate these common malignancies. However, conclusive data from well-conducted prospective studies on the histologically-proven completeness of tumor ablation and the long-term clinical advantages versus active surveillance are still lacking.

Presently, MIT should be considered in high-volume thyroid centers for patients with PTMC who are not candidates for surgery or refuse it, but still seek treatment to decrease the risk of progressive growth or extrathyroidal spread of their malignancy over time.

The three available therapeutic options—lobectomy, thermal ablation, and active surveillance—should always be discussed in an interdisciplinary manner. This discussion should be based not only on the preliminary clinical and US staging but also on the patient’s preferences, available resources, and local expertise.

Patients undergoing MIT for PTMC should be fully informed about the advantages and limitations of the procedure. Due to the presently incomplete level of evidence, long-term clinical and US follow-up is still required.

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Papini, E., Guglielmi, R., Novizio, R. et al. Management of low-risk papillary thyroid cancer. Minimally-invasive treatments dictate a further paradigm shift?. Endocrine (2024). https://doi.org/10.1007/s12020-024-03864-7

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Thyroid cancer

The thyroid is a small butterfly shaped gland that makes and releases hormones. It’s found at the front, lower part of your neck, just behind the small hollow where your collar bones meet.

Thyroid cancer is quite rare. It’s more common in women than in men. There are different types of thyroid cancer and your treatment depends on what type you have.

What is thyroid cancer?

Thyroid cancer is when abnormal cells in the thyroid gland start to divide and grow in an uncontrolled way.

Symptoms of thyroid cancer

The symptoms of thyroid cancer include a lump in your neck, a hoarse voice, a sore throat or difficulty in swallowing.

Getting diagnosed with thyroid cancer

You usually start by seeing your GP. They will ask about your symptoms. They might refer you to a specialist and organise tests.

Survival for thyroid cancer

Survival for thyroid cancer depends upon the type and stage of your thyroid cancer. Survival is generally very good for papillary and follicular thyroid cancers.

Stages and types of thyroid cancer

The type of thyroid cancer refers to the type of cell the cancer started in. The stage of a cancer tells you its size and whether it has spread.

Treatment for thyroid cancer

Possible treatments include surgery, radiotherapy, targeted drugs and chemotherapy. What treatment you have depends on your type and stage of thyroid cancer.

Research and clinical trials for thyroid cancer

Researchers are looking at ways to improve the treatment for thyroid cancer.

Living with thyroid cancer

Practical and emotional support is available to help you cope with thyroid cancer.

Risks and causes of thyroid cancer

Some factors might increase your risk of developing thyroid cancer. These include your age, being very overweight and some non cancerous thyroid conditions.

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May 13, 2024

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Variations in telomere lengthening genes may predispose some people to papillary thyroid cancer

by Johns Hopkins University

Johns Hopkins Medicine researchers say they have found that specific variations in three genes related to maintaining the length of telomeres—the protective DNA endcaps on chromosomes—may explain up to 4.5% of papillary thyroid cancers. Papillary thyroid cancer is the most common form of thyroid cancer.

The findings, published online April 29 in The American Journal of Human Genetics , follow previous research results from the Johns Hopkins scientists that very long telomeres are linked to development of certain cancers.

"This study provides a better understanding of what may predispose some people to papillary thyroid cancer, including multiple individuals in families," says Mary Armanios, M.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center, professor of genetic medicine, molecular biology and genetics, and pathology at the Johns Hopkins University School of Medicine, and director of the Telomere Center at Johns Hopkins.

"We now may be able to identify people who could benefit from closer monitoring for secondary cancers common among this population."

Of 18 people with variants in three telomere -related genes, 15 (83%) developed a second cancer. Most frequently, these cancers were melanoma, sarcoma and cancer of lymphocytes (such as lymphoma and multiple myeloma). Their family members , who carried the same gene variants, were also prone to papillary thyroid cancers as well as other malignancies.

However, Armanios cautions that more work is needed to understand how to interpret these sequence variants and the role of telomere length, and genetic counseling and testing is best reserved for people with papillary tumors and secondary cancers, and those with a family history of thyroid cancers.

Armanios adds, this research contributes to mounting evidence of the role of long telomeres and telomere lengthening as risk factors for development of cancer.

Thyroid cancer occurs in more than 40,000 people in the U.S. each year and is one of the top 10 cancers in women in the country. Early stage disease is nearly always treatable. Most (about 80%) of these cancers are papillary thyroid cancers.

Scientists have known that 5%–10% of papillary thyroid cancers are heritable in some families, and that people with the condition may be prone to developing other cancers.

The researchers say the findings suggest that a mechanism underlying this risk may be longer telomeres.

The scientists analyzed the genetic sequence of five genes related to telomere maintenance in 200 people with papillary thyroid cancer from 189 families who had volunteered to be included in a registry at the Ohio State University.

About one-quarter of the 200 people had hereditary thyroid cancer or secondary cancers to thyroid tumors, or were males who developed thyroid cancer at a young age. They found nine people from seven families (4.5% of the 200) had genetic variations in at least one of three genes (POT1, TINF2, or ACD) already linked to telomere maintenance.

Of the people with those gene variants, the scientists measured their telomere lengths and discovered that five of them had very long telomeres—longer than 90% of most people—and three had ultra-long telomeres—longer than 99% of the population.

In another group of 270 people with papillary thyroid cancer not included in the hereditary cancer registry, four of the 270 (1.5%) had variants in those same three genes .

Researchers Emily DeBoy, Anna Nicosia, Sandya Liyanarachchi and Sheila Iyer from Johns Hopkins, and Manisha Shah, Matthew Ringel and Pamela Brock from the Ohio State University contributed to the study.

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Thyroid Research is an online journal that aims to present the newest knowledge related to thyroid hormones, thyroid diseases and any related fields. The journal's regular readership includes researchers, clinicians and healthcare providers across the world. Thyroid Research encompasses a wide range of thyroidology topics including, diagnosis, pharmacological and other treatment methods ...
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Variations in telomere lengthening genes may predispose some people to
Armanios adds, this research contributes to mounting evidence of the role of long telomeres and telomere lengthening as risk factors for development of cancer. Thyroid cancer occurs in more than ...

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