# Thyroid cancer

Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck, difficulty swallowing or voice changes including hoarseness, or a feeling of something being in the throat due to mass effect from the tumor. However, most cases are asymptomatic. Cancer can also occur in the thyroid after spread from other locations, in which case it is not classified as thyroid cancer.
Risk factors include radiation exposure at a young age, having an enlarged thyroid, family history and obesity. The four main types are papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer. Diagnosis is often based on ultrasound and fine needle aspiration. Screening people without symptoms and at normal risk for the disease is not recommended.
Treatment options may include surgery, radiation therapy including radioactive iodine, chemotherapy, thyroid hormone, targeted therapy, and watchful waiting. Surgery may involve removing part or all of the thyroid. Five-year survival rates are 98% in the United States.
Globally as of 2015, 3.2 million people have thyroid cancer. In 2012, 298,000 new cases occurred. It most commonly is diagnosed between the ages of 35 and 65. Women are affected more often than men. Those of Asian descent are more commonly affected; with a higher rate of mortality among Filipino females. Rates have increased in the last few decades, which is believed to be due to better detection. In 2015, it resulted in 31,900 deaths.

## Signs and symptoms

Most people with thyroid cancer do not have symptoms at the time of diagnosis and thyroid nodules and thyroid cancer is usually found incidentally on imaging of the neck. Up to 65% of adults have small nodules in their thyroids, but typically under 10% of these nodules are found to be cancerous. Sometimes, the first sign is an enlarged lymph node. Later symptoms that can be present are pain in the anterior region of the neck and changes in voice due to an involvement of the recurrent laryngeal nerve.
Thyroid cancer is usually found in a euthyroid patient, but symptoms of hyperthyroidism or hypothyroidism may be associated with a large or metastatic, well-differentiated tumor. Thyroid nodules are of particular concern when they are found in those under the age of 20. The presentation of benign nodules at this age is less likely, thus the potential for malignancy is far greater.

## Causes

Thyroid cancers are thought to be related to a number of environmental and genetic predisposing factors, but significant uncertainty remains regarding their causes.
Environmental exposure to ionizing radiation from both natural background sources and artificial sources is suspected to play a significant role, and significantly increased rates of thyroid cancer occur in those exposed to mantlefield radiation for lymphoma, and those exposed to iodine-131 following the Chernobyl, Fukushima, Kyshtym, and Windscale nuclear disasters. Thyroiditis and other thyroid diseases also predispose to thyroid cancer.
Genetic causes include multiple endocrine neoplasia type 2, which markedly increases rates, particularly of the rarer medullary form of the disease. Mutations in the genes for MenA and Men2B in multiple endocrine neoplasia is responsible for 25% of medullary thyroid cancers.

## Diagnosis

After a thyroid nodule is found during a physical examination or incidentially on imaging, a referral to an endocrinologist or a thyroidologist may occur. Most commonly, an ultrasound is performed to confirm the presence of a nodule and assess the status of the whole gland. Various radiological clinical criteria, including the thyroid imaging reporting and data system (TI-RADs) score, are used to characterize the risk of malignancy. TI-RADS developed by the American College of Radiology (ACR) guides clinicians in deciding which nodules require fine-needle aspiration cytology (FNAC) and in planning follow-up. Various online tools have been developed to assist in applying these criteria to clinical practice. On ultrasound, nodules that are hypoechogenic (solid consistency), having irregular borders, increased vascularity, calcifications, or being taller than wide on transverse views are associated with malignancy. Biopsy or cytology are required if the ultrasound characteristics suggest malignancy. If ultrasound results are equivocal or unclear, or if the thyroid nodule is small (typically less than 1 cm), the nodule can be monitored over time with serial ultrasounds. Ultrasound has a sensitivity of 64-77% and a specificity of 82-90% for the detection of thyroid cancer. Measurement of thyroid stimulating hormone, free and/or total triiodothyronine (T3) and thyroxine (T4) levels, and antithyroid antibodies will help decide if a functional thyroid disease such as Hashimoto's thyroiditis is present, a known cause of a benign nodular goiter. A thyroid scan, performed often in conjunction with a radioactive iodine uptake test may be used to determine whether a nodule is hyperactive which may help to make a decision whether to perform a biopsy of the nodule. Measurement of calcitonin is necessary to exclude the presence of medullary thyroid cancer. To achieve a definitive diagnosis, a fine needle aspiration cytology test may be performed and reported according to the Bethesda system.
After diagnosis, to understand potential for spread of disease, or for follow up monitoring after surgery, a whole body I-131 or I-123 radioactive iodine scan may be performed.
In adults without symptoms, screening for thyroid cancer is not recommended.

### Classification

Thyroid cancers can be classified according to their histopathological characteristics. These variants can be distinguished (distribution over various subtypes may show regional variation):
* Papillary thyroid cancer (75 to 85% of cases) – is more often diagnosed in young females compared to other types of thyroid cancer and has an excellent prognosis. It may occur in women with familial adenomatous polyposis and in patients with Cowden syndrome. A follicular variant of papillary thyroid cancer also exists.
* Newly reclassified variant: noninvasive follicular thyroid neoplasm with papillary-like nuclear features is considered an indolent tumor of limited biologic potential.
* Follicular thyroid cancer (10 to 20% of cases) – occasionally seen in people with Cowden syndrome. Some include Hürthle cell carcinoma as a variant and others list it as a separate type.
* Medullary thyroid cancer (5 to 8% of cases) – cancer of the parafollicular cells, often part of multiple endocrine neoplasia type 2.
* Poorly differentiated thyroid cancer
* Anaplastic thyroid cancer (1 to 2%) despite constituting only 1% of thyroid cancers, the type is responsible for 20% of thyroid cancer deaths. It is characterized by a severe course with median survival of 6.5 months.
* Others
** Thyroid lymphoma
** Squamous cell thyroid carcinoma
** Sarcoma of thyroid
** Hürthle cell carcinoma
The follicular and papillary types together can be classified as "differentiated thyroid cancer". These types have a more favorable prognosis than the medullary and undifferentiated types.
* Papillary microcarcinoma is a subset of papillary thyroid cancer defined as a nodule measuring less than or equal to 1 cm. 43% of all thyroid cancers and 50% of new cases of papillary thyroid carcinoma are papillary microcarcinoma. Management strategies for incidental papillary microcarcinoma on ultrasound (and confirmed on FNAB) range from total thyroidectomy with radioactive iodine ablation to lobectomy or observation alone. Harach et al. suggest using the term "occult papillary tumor" to avoid giving patients distress over having cancer. Woolner et al. first arbitrarily coined the term "occult papillary carcinoma", in 1960, to describe papillary carcinomas ≤ 1.5 cm in diameter.

#### Staging

Cancer staging is the process of determining the extent of the development of a cancer. The TNM staging system is usually used to classify stages of cancers, but not of the brain.
* Stage M1 thyroid cancer
* Stage N1a thyroid cancer
* Stage N1b thyroid cancer
* Stage T1a thyroid cancer
* Stage T1b thyroid cancer
* Stage T2 thyroid cancer
* Stage T3 thyroid cancer
* Stage T4a thyroid cancer
* Stage T4b thyroid cancer

### Metastases

Detection of differentiated thyroid cancer metastases may be detected by performing a full-body scintigraphy using iodine-131.

### Spread

Thyroid cancer can spread directly, via lymphatics or blood. Direct spread occurs through infiltration of the surrounding tissues. The tumor infiltrates into infrahyoid muscles, trachea, oesophagus, recurrent laryngeal nerve, carotid sheath, etc. The tumor then becomes fixed. Anaplastic carcinoma spreads mostly by direct spread, while papillary carcinoma spreads so the least. Lymphatic spread is most common in papillary carcinoma. Cervical lymph nodes become palpable in papillary carcinoma even when the primary tumor is unpalpable. Deep cervical nodes, pretracheal, prelaryngeal, and paratracheal groups of lymph nodes are often affected. The lymph node affected is usually the same side as that of the location of the tumor. Blood spread is also possible in thyroid cancers, especially in follicular and anaplastic carcinoma. The tumor emboli do angioinvasion of lungs; end of long bones, skull, and vertebrae are affected. Pulsating metastases occur because of their increased vascularity.

## Treatment

Thyroidectomy and dissection of central neck compartment is the initial step in treatment of thyroid cancer in the majority of cases. Thyroid-preserving operations may be applied in cases, when thyroid cancer exhibits low biological aggressiveness (e.g. well-differentiated cancer, no evidence of lymph-node metastases, low MIB-1 index, no major genetic alterations like BRAF mutations, RET/PTC rearrangements, p53 mutations etc.) in patients younger than 45 years. If the diagnosis of well-differentiated thyroid cancer (e.g. papillary thyroid cancer) is established or suspected by FNA, then surgery is indicated. Surgical resection is the preferred treatment for all biopsy confirmed thyroid cancers. In those with very low risk tumors (such as small papillary tumors without evidence of local or metastatic spread or concerning cytologic findings), patients at high surgical risk due to medical problems, those with short expected lifespans or patients with serious medical issues precluding surgery, an active surveillance approach, in which the tumor is monitored over time (such as with serial imaging) may be pursued.
Post surgical monitoring for recurrence or metastasis may include routine ultrasound, CT scans, FDG-PET/CT, radioactive iodine whole body scans, and routine laboratory blood tests for changes in thyroglobulin, thyroglobulin antibodies, or calcitonin, depending on the subtype of thyroid cancer.
Radioactive iodine-131 is used in people with papillary or follicular thyroid cancer for ablation of residual thyroid tissue after surgery and for the treatment of thyroid cancer. Post-surgical radioactive iodine is recommended for those with high risk of cancer recurrence. Post-surgery radioactive iodine does not reduce recurrence in those with low risk thyroid cancer. Patients with medullary, anaplastic, and most Hurthle-cell cancers do not benefit from this therapy. External irradiation may be used when the cancer is unresectable, when it recurs after resection, or to relieve pain from bone metastasis.
Sorafenib and lenvatinib are approved for advanced metastatic thyroid cancer. Numerous agents are in phase II and III clinical trials.

## Prognosis

The prognosis of thyroid cancer is related to the type of cancer and the stage at the time of diagnosis. For the most common form of thyroid cancer, papillary, the overall prognosis is excellent with 97%, 95%, and 90% 10, 15 and 20 year overall survival respectively. The 5 year survival of all thyroid cancers, with treatment, is 98%.
Many small thyroid cancers (mostly papillary type) rarely grow or metastasize. Some have stated that thyroid cancers are overdiagnosed and will rarely cause symptoms, illness, or death, even without treatment. Low grade thyroid cancer is very commonly seen during autopsy studies, with the person dying from other causes. Increasingly, small thyroid nodules are discovered as incidental findings on imaging (CT scan, MRI, ultrasound) performed for another purpose. Few of these people with incidentally discovered, subclinical thyroid cancers will ever have any symptoms, and overtreatment may be present.
Thyroid cancer is three times more common in women than in men. The overall relative 5-year survival rate for thyroid cancer is 85% for females and 74% for males.
The identification of some molecular or DNA abnormalities has led to the development of therapies that target these molecular defects. The first of these agents to negotiate the approval process is vandetanib, a tyrosine kinase inhibitor that targets the RET proto-oncogene, two subtypes of the vascular endothelial growth factor receptor, and the epidermal growth factor receptor. For differentiated thyroid carcinoma, strategies are evolving to use selected types of targeted therapy to increase radioactive iodine uptake in papillary thyroid carcinomas that have lost the ability to concentrate iodide. This strategy would make possible the use of radioactive iodine therapy to treat "resistant" thyroid cancers.
Mitogen-activated protein kinase (MAPK) variants are the most common genetic variants seen in thyroid cancer. The BRAF 600E genetic variant is seen in 60% of papillary thyroid cancers. It is associated with increased risks of cervical lymph node metastasis, blunted response to radioactive iodine, and increased rates of local recurrence. RasGTPase mutations are seen in 13% of papillary and 25-50% of follicular cancers and are associated with increased risk of vascular invasion and higher response to radioactive iodine.
Prognosis is better in younger people than older ones.
Prognosis depends mainly on the type of cancer and cancer stage.
| Thyroid cancer type | 5-year survival | 5-year survival | 5-year survival | 5-year survival | 5-year survival | 10-year survival |
| Thyroid cancer type | Stage I | Stage II | Stage III | Stage IV | Overall | Overall |
| Papillary | 100% | 100% | 93% | 51%51% | 96% or 97% | 93% |
| Follicular | 100% | 100% | 71% | 50% | 91% | 85% |
| Medullary | 100% | 98% | 81% | 28% | 80%, 83% or 86% | 75% |
| Anaplastic | (always stage IV) | (always stage IV) | (always stage IV) | 7% | 7% or 14% | (no data) |

## Epidemiology

Thyroid cancer, in 2010, resulted in 36,000 deaths globally up from 24,000 in 1990. Obesity may be associated with a higher incidence of thyroid cancer, but this relationship remains the subject of much debate.
Thyroid cancer accounts for less than 1% of cancer cases and deaths in the UK. Around 2,700 people were diagnosed with thyroid cancer in the UK in 2011, and around 370 people died from the disease in 2012.
However, in South Korea, thyroid cancer was the 5th most prevalent cancer, which accounted for 7.7% of new cancer cases in 2020.
The incidence of thyroid cancer in the United States increased by 313% from a 1974-1977 incidence of 4.6 cases per 100,000 people to 14.4 cases per 100,000 people in 2010-13. This increase is thought to be due to more widespread use of head and neck imaging (which may incidentally detect thyroid masses) as well as increased use of fine needle aspiration biopsies.

## Notable cases

* Callum Ainley, English footballer
* Ann-Katrin Berger, German women footballer
* Emre Can, German footballer
* Jerry Dipoto, former Major League Baseball pitcher
* Roger Ebert, American film critic
* Jennifer Grey, American actress
* Uhm Jung-hwa, South Korean singer, actress and dancer
* Lee Moon-sae, South Korean ballad singer
* Joe Piscopo, American actor
* William Rehnquist, Chief Justice of the United States (1986–2005) died September 3, 2005, from anaplastic thyroid cancer
* Katee Sackhoff, American actress
* Karen Smyers, American swimmer
* Daniel Snyder, American owner of the Washington Football Team
* Rod Stewart, British singer
* Scott Thompson, American businessman
* Sofía Vergara, American actress
* Julia Volkova, Russian singer
* April Winchell, American actress