The Eye & Ear Foundation had its first webinar with Dr. Jessica H. Maxwell, MD, MPH, FACS, Associate Professor, Associate Residency Program Director, and Chief of Otolaryngology, Pittsburgh VA Healthcare System, on June 25, titled “Management of Thyroid Cancer in the Era of Targeted Therapy.”
The first point Dr. Maxwell made was that thyroid cancer encompasses a wide range of different types of cancer. She then described the anatomy. The thyroid is a butterfly-shaped gland that is closely approximated with the recurrent laryngeal nerve (intrinsic muscles of the larynx), superior laryngeal nerve (controls vocal pitch), and parathyroid glands (control calcium levels).
In terms of physiology, the hypothalamus releases the hormone TRH, which stimulates the pituitary gland. The pituitary gland releases the hormone TSH, which stimulates the thyroid gland. The thyroid gland makes the thyroid hormones T3 and T4. There is a feedback loop among the thyroid, pituitary gland, and hypothalamus that regulates the hormone level in the body.
Two conditions can result from thyroid function going a bit haywire. Hypothyroidism occurs when thyroid hormone levels are low and TSH is high; symptoms include fatigue, weight gain, dry skin and hair. Hashimoto’s is a common cause of hypothyroidism in the United States and is an autoimmune disorder. Hyperthyroidism is when thyroid hormone levels are too high and TSH is low. Symptoms include weight loss, feeling jittery, heart racing, and sweating. Grave’s disease is a common cause of hyperthyroidism and is also an autoimmune disorder.
Ultrasound
An ultrasound of the thyroid and lateral neck is the gold standard imaging modality to evaluate the thyroid gland. A CT is ideal if people have suspicious lymph nodes in the neck or if it seems the thyroid is extending below the level of their clavicles.
Suspicious findings on the ultrasound include:
- Solid and hypoechoic (the nodule itself is a little bit darker than surrounding tissue)
- Irregular margins
- Micro/macrocalcifications (little white dots)
- Taller than wide shape
- Extrathyroidal extension (involving the muscles surrounding the thyroid gland)
Fine Needle Aspiration
The American Thyroid Association (ATA) put together a great guideline in 2015 to describe how to manage patients with thyroid nodules. They estimate the risk of malignancy (ROM), when to do a fine needle aspiration, and detailed indications for radioactive iodine treatment and surveillance recommendations. The 2025 guidelines should be released any day now.
The ATA also has an atlas of thyroid nodules, with images and the corresponding risk/suspicion. Based on that, there are recommendations, or cut-offs, for when to perform a needle aspiration. If it is purely cystic, a biopsy is not recommended, unless it gets so big that aspirating or draining fluid will make the patient comfortable. Nodules range from low suspicion to intermediate to high. For those nodules that are very suspicious and have many of the features mentioned above, FNA should be considered when the nodule grows beyond 1 cm.
TI-RADS is a standardized method to risk stratify nodules based on ultrasound characteristics. TIRADS takes into account the composition, echogenicity, shape, margin, and echogenic foci of the nodule. A score between 1-5 is given, and based on that, a determination on whether to biopsy based on size.
Dr. Maxwell performs ultrasound guided fine needle aspirations in the clinic every week. The procedure is very straightforward, with no pre-medication or restrictions prior, and only takes about 20 minutes. Some local lidocaine is provided to make patients more comfortable before aspirating cells from the nodule. A cytologist looks at the sample under a microscope right then and there to determine whether the sample is adequate before it is sent for testing.
Molecular Testing
The Bethesda System for Reporting Thyroid Cytopathology is a standardized reporting system to predict risk of malignancy based on thyroid cytology features. Nodules range from benign to malignant, but many fall somewhere in the middle. A newer type of thyroid cancer classification – non-invasive follicular variant (NIFTP) – is a more indolent thyroid cancer that carries a much lower risk of regional spread.
For patients with Bethesda 3-4, the recommendation is to send the specimen for molecular studies to get a better sense of whether the nodule is cancerous. There are a few different tests. ThyroSeq was developed in the University of Pittsburgh’s pathology and cytology department and is great in terms of ruling cancer in or out, Dr. Maxwell said. “That’s what you want in a test,” she added. It uses next-generation sequencing, which is really genetic testing to look for mutations in thyroid cancer. If any mutations or high-risk genetic factors are found, then they are looked at more closely to figure out the percentage risk of cancer.
When should molecular testing be obtained? To improve pre-operative risk stratification and reduce unnecessary surgery. Thyroid surgery is not without risk, so targeting patients who would benefit from surgery is key.
Differentiated Thyroid Carcinoma
The most common type of thyroid cancer is papillary thyroid cancer (PTC), with around 80% incidence. It is generally slow growing with an excellent prognosis (greater than 98% survival). Regional spread to lymph nodes is common. Risk factors include family history and radiation exposure, though most people have no known risk factors. Treatment is surgery, observation, radio frequency ablation (RFA), and radioactive iodine therapy (RAI).
The second most common thyroid cancer, at 10-15%, is follicular thyroid cancer. It is a well-differentiated thyroid cancer originating from follicular cells and is more likely than PTC to spread to lymph nodes. It has an excellent prognosis of around 98% if diagnosed early. Surgery, however, is needed to differentiate it from benign disease.
If nodules are larger than 4 cm despite a benign FNA, a hemithyroidectomy may be needed. It is often done for small cancers confined to the thyroid gland.
For large cancers greater than 4 cm, with extrathyroidal extension, or concerning nodules in the contralateral lobe, a total thyroidectomy may be required. If patients have this procedure, they are on thyroid hormone replacement for life, which involves taking a pill every day.
A neck dissection is performed for clinically evident disease, or a lymph node that is involved with cancer.
“We always try to do the least amount of surgery to remove the cancer and prevent it from coming back,” Dr. Maxwell said.
Differentiated Thyroid Carcinoma Treatment
Radiofrequency ablation is when a needle electrode is inserted into a nodule under ultrasound guidance generating heat and ultimately cellular necrosis.
Postoperative RAI uses radioactive iodine (I-131) to destroy any remaining thyroid cells. It is given in pill/liquid form after surgery. Patients must avoid exposure to others.
Advanced, Recurrent, or RAI-refractory Differentiated Thyroid Cancer
About 7-23% of patients develop distant metastases (DM). Two thirds of patients with DMs become RAI-refractory. The 10-year survival rate drops to 10% in these patients and they are considered to have recurrent inoperable disease.
The Cancer Genome Atlas looked at genetic sequencing for 500 papillary thyroid cancers. They found that 96% had some sort of mutation that was targetable. Thyroid cancer has a high number of targetable mutations compared to other cancers.
Treatment for Advanced, Recurrent, or RAI-refractory Thyroid Carcinoma
- Classic or conventional type
- Frequently carries BRAFV600E mutation
- Less often RET or NTRK fusions
- Tall cell variant
- More aggressive type of PTC
- BRAFV600E point mutations
- Follicular variant
- Predominantly RAS mutations
A study from the New England Journal in 2017 looked at almost 400 patients with thyroid cancer that was refractory to radioactive iodine treatment. These patients were randomized into a group that got Levatinib, a tyrosine kinase inhibitor, vs another group that got a placebo. The results were impressive. The group who received treatment had a median of 18 months of progression-free survival vs 3.6 months for the placebo. In other words, this medication prevented their progression or kept them in a remission state for a long time. It is not the only medication that does this; sorafenib is another. A 2014 Lancet study with 417 randomized patients and sorafenib resulted in 10.8 months of no cancer progression with the drug vs 5.8 months without.
Medullary Thyroid Carcinoma
This kind of thyroid cancer accounts for around 3-5% and is derived from parafollicular C-cells that secrete calcitonin which lowers blood calcium. It is 25% hereditary (autosomal dominant inheritance) and 75% sporadic. Patients with hereditary MTC may have the syndrome MEN2a or MEN 2b and genetic testing is warranted. Patients with MTC often have a RET mutation as well – another targetable mutation.
Anaplastic Thyroid Carcinoma
Making up less than 2% of all thyroid cancers, this one is rare. It is also highly aggressive, undifferentiated, with rapid local invasion and distant metastases. The average survival is six months, with less than 20% five-year survival.
The Journal of Clinical Oncology published in 2018 another target therapy that has changed the way patients are managed with this cancer. Defrafenib and trametinib are targeted therapies that have impressive results for people with anaplastic thyroid carcinoma, as many carry the BRAFV600 mutation.
ATA guidelines for management of patients with anaplastic thyroid cancer came out in 2021 and include the following recommendations:
- Rapid diagnosis with molecular testing
- Early multidisciplinary engagement
- BRAFV600E mutation identified? Dabrafenib + trametinib
- ALK, NTRK, RET fusions identified? Crizotinib, pralsetinib, Larotrectinib
- Surgery + chemoradiation – maintain quality of life with surgical resection, avoid laryngectomy or esophagectomy
Targeted thyroid therapies do have side effects. Side effects include hypertension, thromboembolic events, renal failure, and QT prolongation, and GI discomfort, among others.
Conclusions
- Thyroid nodules with suspicious findings on US (ATA/TIRAD) should be considered for FNA
- FNA results with Bethesda III and IV cytology should be sent for molecular testing
- Molecular testing can drive management decisions
- For advanced, recurrent, and RAI-resistant differentiated cancer, consider targeted therapies