Differentiated Thyroid Cancer

Differentiated thyroid cancer

This group includes papillary (PTC), follicular (FTC), Hurthle (HCC), and follicular variant (FVPTC) types of thyroid cancer.

  1. PTC is the most common type of thyroid cancer making up to 80-90% of all thyroid cancer cases. Papillary thyroid cancer can occur at any age, and its incidence has been increasing over the last few decades. There are about 65,000 new cases of papillary thyroid cancer in the United States each year. It is now ranked as the 5th most common cancer in women in the United States, and the most common cancer in women ages 15-34, and the second for ages 35-49. Papillary thyroid cancers are most often slow growing tumors, and most can be removed surgically. Although slow-growing, papillary thyroid cancer can sometimes spread to the lymph nodes in the neck. Unlike some other tumors, positive lymph nodes do not usually worsen the generally excellent prognosis. The involved lymph nodes can be surgically removed along with the thyroid. Most people diagnosed with PTC will not die from it.
  2. FVPTC is a cross between papillary and follicular cancer, but tends to behave more likely PTC, spreading to the lymph nodes than to the lungs. Recently, studies have shown that the behavior depends on the specific mutation found in the cancer (ie, BRAF+ tumors behave more like PTC and RAS+ tumors behave more like FTC). Treatment is the same as for PTC. FVPTCs used to be classified as either ‘encapsulated’ or ‘non-encapsulated’, with the encapsulated tumors having minimal potential for recurrence or spread, but the non-encapsulated behaving similar to a PTC with extracapsular extension. ‘Encapsulated’ tumors have now been re-classified as Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP), which are indolent, ‘pre-cancerous’ tumors that still need removal and some follow-up, but do not need a completion thyroidectomy or further treatment.
  3. FTC and HCC are two different types of cancer, but they are often considered in the same category. Together, these cancers are the second most common thyroid cancer, after papillary cancer. They can occur at any age, but are more likely in older people. These cancers can be hard to diagnose on FNA biopsy because although the cells look “funny” or abnormal, there is nothing about the individual cells that are definitive for cancer (unlike PTC where the cells have a very classic appearance). In cases of follicular and Hurthle cell lesions, the only way to tell if it is a cancer is look at the capsule surrounding the nodule and see if there is invasion (i.e. growth) outside the nodule. Follicular thyroid cancer does not tend to spread to lymph nodes, but rather spreads through blood vessels to other organs, such as the lungs and bones. Hurthle cell cancers, on the other hand, will sometimes spread to lymph nodes in the neck region, but less commonly than papillary thyroid.

If the cancer is very small and found only one side of the thyroid, or there is only a small amount of capsular invasion, without any evidence of vascular or lymphatic invasion, it is classified as a ‘minimally invasive’ FTC, and there is no need to remove the other half of the thyroid and the risk of recurrence is almost miniscule. . This decision will be made with your surgeon and medical doctors and depends on certain factors such as age, gender, size of the thyroid cancer, location of the cancer, and existence of enlarged or suspicious lymph nodes in the neck.

Risk factors for differentiated thyroid cancer

For most patients, we do not know the specific reason why they develop thyroid cancer, though it does appear to be more common in women. It is important to note that some patients with multiple risk factors never develop thyroid cancer. In fact, most people who have thyroid cancer have no obvious known risk factor. Known risk factors for papillary thyroid cancer include:

Radiation exposure
Papillary thyroid cancer is more common in people who have a history of exposure to significant ionizing radiation. Radiation induced thyroid cancer can happen at anytime between a few years after exposure to as long as 30 to 50 years later. Radiation exposure is broken down into three major categories:

Childhood exposure
X-ray (radiation) treatments were widely used in the 1940s and 1950s. This radiation was used to treat acne, enlarged tonsils, lymphomas, ringworm, enlarged thymus glands, and other ailments. X-rays were also used to measure foot sizes in shoe stores, and many people fondly remember seeing their “glowing green feet” and playing in these shoe fluoroscopes for hours while siblings were fitted for shoes. Children, younger than 15 years old, are most sensitive to radioactive damage to their thyroids.

Medical Therapy
Radiation therapy to the head, neck, and upper chest are an increasingly common cause of radiation induced thyroid cancer. Lymphoma, head and neck cancers, lung cancer, and breast cancer are some of the more common cancers that are associated with radiation exposure to the thyroid.

Environmental exposure
Thyroid cancer can be caused by radioactivity released from nuclear incidents such as the 1986 nuclear accident at the Chernobyl power plant in Russia and the more recent 2011 Fukishima accident. Many of the children in areas of Russia and the Eastern Block countries and now Japan were inadvertently exposed to radiation and went on to develop thyroid cancer. Some people may also be exposed to radiation at work. However, routine X-ray exposure (for example dental X-rays, chest X-rays, mammograms) have NOT been shown to cause thyroid cancer.

Papillary thyroid cancer can run in the family and may be associated with genetic syndromes. Known mutations/syndromes associated with thyroid cancer are MEN, Cowden’s, FAP, Garner’s, Lynch, Carney complex I, and CHEK2. Therefore, a thorough family history should be obtained from any newly diagnosed thyroid cancer patient, and if positive for other cancers, such as colon, breast, prostate, or other endocrine tumors, referral to be made to a geneticist.

Management of Differentiated thyroid cancer

Active Surveillance

Active surveillance is now a viable option for select patients with well differentiated thyroid carcinoma. The option is generally offered to “older” patients that have well-encapsulated, intra-thyroidal tumors <1-1.2cm, without evidence of nodal disease. Patients should be under the care of a multi-disciplinary team that has experience with active surveillance. Patients usually have ultrasounds every 6 months for a years that can then be spaced out to once a year. As long as no changes are detected (growth, new nodal metastases), then a patient can continue active surveillance. Any change is reason for surgical removal.


Pre-operative evaluation

Once the decision has been made to proceed with surgery, all patients should have ultrasound lymph node mapping (if not already done). Patients with more advanced cancer demonstrating invasion (to muscles, vital structures) or bulky lymph nodes on ultrasound should have a CT and/or MRI (if cystic nodes) to improve operative planning. Some clinicians may also test a pre-operative thyroglobulin and thyroglobulin-antibody to have a baseline level.

Extent of surgery for thyroid cancer

Patients that have surgery for thyroid cancer will have one of two basic operations: a thyroid lobectomy or total thyroidectomy. The addition of a central or lateral neck dissection will be made based on clinically evident disease, or sometimes central neck lymph nodes will be removed prophylactically in more aggressive appearing tumors.

A thyroid lobectomy is recommended for tumors <2-4cm confined to the thyroid gland, without evidence of contralateral thyroid nodules, nodal metastases, or diffuse hyperthyroidism. The entire unilateral lobe is removed along with the isthmus (middle bridge). They contralateral side should not be explored. About 30% of patients will need some form of thyroid hormone replacement afterwards.

In very select cases these days, a PTC/FTC/HCC that is of intermediate/high risk is discovered after only half the thyroid is removed. When this occurs, it may be necessary to perform a second operation soon after to remove the remaining thyroid gland (completion thyroidectomy). This happens much less frequently with the new staging and risk classification systems.

A total thyroidectomy (i.e. removing the whole thyroid) is the appropriate surgical procedure for larger tumors, those that extend beyond the thyroid capsule or have nodal/distant metastases, and when there is contralateral nodules >1cm and/or diffuse hyperthyoidism. All thyroid tissue should be removed, with care to preserve the parathyroid glands and recurrent laryngeal nerve.  After total thyroidectomy, patients need to take thyroid hormone replacement pills for the rest of their life. Most patients are given a slightly higher dose of thyroid hormone than normal to decrease TSH and suppress growth of thyroid tissue. The starting dose for levothyroxine for patients with cancer is approximately 1.8-2 mcg/kg.

A lymph node dissection is performed when abnormal lymph nodes are discovered either before or during surgery. When a lymph node dissection is performed, all nodes in a given compartment are removed – there is no role for ‘berry picking’ individual abnormal nodes.

A central neck dissection (level VI +/-VII) is performed when any node in the area around the thyroid is abnormal. This operation involves the removal all of the lymph nodes between the carotid arteries on each side and from the hyoid bone (just above the Adam’s apple) to the innominate vessels (just below the top of the breast bone or sternum). Occassionally, with larger tumors or those with more aggressive clinical features, a ‘prophylactic’ central neck dissection may be performed because of the high rate of micrometastases to central neck nodes.

A modified radical neck dissection (levels II-IV +/-V) is performed whenever there are abnormal lateral cervical nodes. The lymph nodes which are usually removed in a modified radical lateral neck dissection are those within the following borders: top to bottom – the jaw to the collarbone, side to side – windpipe to the trapezius muscle edge. The important structures such as the major muscles in the neck, carotid artery, jugular vein, and the nerves which supply movement to the neck, arm, and diaphragm are preserved. If any one of these important structures mentioned above have to be removed surgically because the cancer is growing into them, it is called a radical neck dissection. This is very rarely performed today.

Thyroid Hormone Suppression – all patients that had their entire thyroid removed will be on thyroid hormone replacement. For all cancer patients, some form of suppression is recommended to help prevent regrowth or benign or cancerous cells. The degree of suppression is based on the risk of disease recurrence.

Radioactive iodine (RAI) — Thyroid cells normally take up iodine from the bloodstream and use it to produce thyroid hormone. In general, there are no other cells in the body that have the ability to concentrate iodine. Once the thyroid has been removed, RAI ablation therapy may be used to reduce the chance of the cancer coming back and to destroy any remaining thyroid cells (called remnant ablation). (See Radioactive Iodine). Follicular thyroid cancers tend to take up RAI very well whereas Hurthle cell cancers tend not to take up RAI as well as other cancers, but some do.

The decision to use or not use RAI ablation for patients with Hurthle cell cancers will be made with your surgeon and medical team. Generally, once thyroid cancer has spread to the lymph nodes or beyond, some dose of RAI is recommended. RAI is particularly useful for small lung metastases that may not be visible by CAT scan, but are seen on a radioactive iodine scan.

Other treatments — Very few patients with papillary thyroid cancer need external beam radiation or targeted therapy. These treatments are usually only used for very advanced or severe disease. These large cancers may have grown into important neighboring structures which cannot be safely removed, or are very bulky, have spread to non-surgically treatable areas (metastases), or lose the ability to take up radioactive iodine. These treatments are used as a palliative measure to control the growth of the disease, and not to cure it. Clinical trials (see below) with new targeted agents are available for such patients. Examples are Sorafenib (Nexavar) and lenvatinib (Lenvima). They are targeted drugs known as kinase inhibitors that work by helping block tumors from forming new blood vessels, which the tumors need to grow as well as target some of the proteins made by cancer cells that normally help them grow. These drugs can help stop cancer growth for a time, though It isn’t yet clear if these drugs help patients live longer. Other therapies are on the horizon, and enrolling in a clinical trial at a center which has experience with this rare disease may be an option for patients with non-surgically treatable and distant metastatic DTC.

Thyroid Cancer Prognosis and Staging

The extent, or stage of cancer, is used to determine the prognosis (i.e. the chance that a patient will recover, have a recurrence, or die of a disease) and the best treatment plan for an individual. Though there are multiple staging systems for thyroid cancer, the two most common are the TNM system Tumor size, lymph Node status, distant Metastasis), which predicts the risk of death from thyroid cancer, and the ATA risk classification system, which predicts disease recurrence. The prognosis for differentiated thyroid cancer is generally excellent, with long-term survival rates >95%. One of the most important factors in staging thyroid cancer (papillary, follicular and Hurthle cell) is the patient’s age. Patients who are younger than 55 years old at the time of diagnosis are a stage I no matter how large the tumor is or whether or not there are positive lymph nodes. If they are younger than 55 years old at the time of diagnosis and the cancer has spread to distant sites (i.e. metastasis), such as lungs, bones, or other organs, then they are considered stage II.

Patients older than 55 years at the time of diagnosis with papillary, follicular, and Hurthle cell thyroid cancers are staged as described below:

The different parts of the TNM staging system are:

Tumor size:

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: 2 cm or smaller
T2: 2 to 4 cm
T3: > 4 cm limited to the thyroid or gross extrathyroidal extension to the strap muscles only

T3a: > 4 cm limited to the thyroid

T3b: gross extrathyroidal extension to the strap muscles only

T4a: Any size tumor that has grown beyond the thyroid gland into nearby tissues of the neck (soft tissues, larynx, trachea, esophagus, recurrent laryngeal nerve)

T4b: Any size that has grown back toward the spine (invades prevertebral fascia) or into nearby large blood vessels (carotid artery/vein, mediastinal vessels)

Lymph nodes:

NX: Regional (nearby) lymph nodes cannot be assessed
N0: No spread to nearby lymph nodes
N1: Spread to nearby lymph nodes
N1a: Spread to lymph nodes next to the thyroid (central neck, VI, VII)

N1b: Spread to lymph nodes in the sides of the neck (lateral neck I-V) or to the retropharyngeal lymph nodes

Distant metastasis:

MX: Presence of distant metastasis (spread) cannot be assessed
M0: No distant metastasis
M1: Distant metastasis is present, involving distant lymph nodes, internal organs, bones

The ATA risk classification system, as summarized in the figure below, takes into account various aspects of the tumor’s pathology to help predict the risk of disease recurrence (Haugen et al. Thyroid 26:1, 2016). It is used to determine need for RAI therapy, thyroid hormone suppression, and what surveillance strategy to take.

risk of structural disease recurrence