The thyroid gland is part of the endocrine system and is a hormone-producing gland that regulates the body's functions. Thyroid cancer (TC), which occurs in thyroid cells, is the most common endocrine - related cancer, accounting for about 1% of systemic malignancies.
Thyroid cancer is more common in females, and the ratio of females to males is 3:1 in most geographical regions and population groups , making it the fifth most common cancer among females. Most thyroid cancers are curable by surgery and other means.
1. The Thyroid Gland
The thyroid gland is a butterfly-shaped gland located in front of the neck, under the throat, and above the clavicle. The thyroid gland is part of the endocrine system that controls heart rate, blood pressure, body temperature and metabolism by secreting hormones.
There are two main cell types in the thyroid gland: follicular cells and C cells.
Follicular cells use iodine in the blood to make thyroid hormones, which help regulate the body's metabolism. The amount of thyroid hormone released by the thyroid gland is regulated by the pituitary gland at the bottom of the brain, which promotes the release of thyroid hormone by producing a substance called thyroid stimulating hormone (TSH).
C cells (also known as parafollicular cells) produce calcitonin, a hormone that helps control how the body uses calcium.
Figure 1 Hormones produced by the thyroid gland
2. Type of Thyroid Tumor
Thyroid cancer can be classified into four types according to the origin of cells and the rate of cancer cell division: papillary thyroid carcinoma, follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer.
2.1 Papillary Thyroid Cancer (PTC)
It is the most common type of thyroid cancer, and 70% to 80% of thyroid cancers are papillary thyroid cancer. Although it can occur at any age, most occur between the ages of 30 and 60. The disease is three times more common in women than men, and is usually more aggressive for older patients.
Papillary thyroid cancer may spread, usually involving the neck lymph nodes, and less involving the lungs.
Most people with this type of cancer can be cured if they are diagnosed early.
2.2 Follicular Thyroid Cancer (FTC)
Follicular thyroid cancer accounts for less than 15% of all thyroid cancers. Hürthle cells are variants of FTC. This type of thyroid cancer occurs mostly in adults between the ages of 40 and 60. Women get it more often than men. Cancer cells can invade blood vessels and travel to tissues such as bones or lungs.
PTC and FTC, as well as the less common Hürthle cell carcinoma, are classified as differentiated thyroid carcinoma (DTC)  , which originated from follicular epithelial thyroid cells. Both PTC and FTC are slow to progress and usually have a good prognosis, especially if diagnosed early.
2.3 Medullary Thyroid Cancer (MTC)
It accounts for about 3% of all thyroid cancers . It is developed by C-cells or parafollicular cells that produce calcitonin (which regulates calcium and phosphate levels in the blood and promotes bone growth) , and elevated levels of calcitonin indicate cancer. It is usually diagnosed between the ages of 40 and 50, and women and men are equally affected.
Compared to other types of thyroid cancer, it is more likely to run in the family (familial medullary thyroid carcinoma, FMTC).
2.4 Anaplastic Thyroid Cancer (ATC)
Anaplastic thyroid cancer is a rare thyroid cancer, which accounts for less than 2% of all thyroid cancers (77% of women).
ATC originates from follicular cells, but it does not have its original biological characteristics . Unlike other thyroid tumors, it is characterized by rapid growth and spread and aggressive. Therefore, anaplastic thyroid cancer (ATC) is the most invasive type of thyroid cancer among all thyroid cancers . It usually occurs in patients over the age of 65, and women are slightly more affected than men. ATC is not sensitive to conventional treatment . The prognosis was the worst, with a 5-year survival rate of 5% .
There's also thyroid lymphoma. This is a rare thyroid cancer that starts with immune system cells in the thyroid gland and grows very fast. Thyroid lymphoma usually occurs in the elderly.
Figure 2 Type of thyroid cancer
3. Thyroid Tumor Symptoms
In the early stages, thyroid cancer usually shows no signs or symptoms.
As a thyroid tumor grows, it may produce the following symptoms:
Neck mass or node: This is the most common symptom of thyroid cancer. A hard, fixed mass with an uneven surface was found in the thyroid gland. The glands are less mobile up and down during swallowing.
Persistent hoarseness or changes in voice, and frequent coughs unrelated to a cold may occur.
Difficulty swallowing or breathing.
Swollen lymph nodes in the neck.
Pain in the ear, pillow, shoulder, etc. may occur in the late stage.
4. Risk Factors for Thyroid Tumors
Risk factors for thyroid cancer include ionizing radiation, family history, gender, obesity, alcohol consumption, and smoking. Recent studies have also demonstrated the relationship between exposure to flame retardants and PTC .
4.1 Gender and Race
Thyroid cancer is more common in women than men. White or Asian people are more likely to develop thyroid cancer.
Most thyroid cancer patients are between 20 and 55 years old.
4.3 Radiation Exposure
Exposure to high levels of radiation may increase the risk of thyroid cancer.
4.4 Genetic Factors
Most TC cases are sporadic, only 5% of DTC is characterized as familial (mainly PTC), and about 25% of MTC is inherited as an autosomal trait .
Certain genetic syndromes increase the risk of thyroid cancer. These include familial myeloid thyroid cancers and multiple endocrine neoplasms (type 2A and type 2B). Multiple endocrine neoplasms (MEN2A and MEN2B) affect glands of the endocrine system such as the thyroid, parathyroid, and adrenal glands.
Mutations in certain genes are also important causes of thyroid cancer. Mutations in BRAF  and RAS family  also occur frequently in thyroid cancer. Chromosomal translocations also occur in thyroid cancer, such as peroxisome proliferation-activated receptor (PPAR gamma) translocations in about 30% of follicular thyroid cancer cases .
Key molecular signaling pathways involved in thyroid cancer include mitogen activated protein kinase (MAPK) pathway, PI3K / mTOR pathway, p53 tumor suppressor factor, etc.
Figure 3 Risk factors of thyroid cancer
5. Diagnosis of Thyroid Tumor
First, the doctor needs to understand the basic condition of the patient and whether there are common clinical symptoms of thyroid tumor. For patients with a family history of medullary thyroid cancer, your doctor will test your blood for calcitonin and calcium levels. Elevated levels of calcitonin suggest cancer.
The main methods of diagnosis of thyroid tumors are as follows:
5.1 Thyroid Scan
Thyroid scans are used to test the function of the glands. Test results may be reported as normal function, cold (insufficient activity), or hot (excessive activity). Suspected cold nodules can be further evaluated by fine needle aspiration (needle biopsy).
5.2 Ultrasound Guided Fine Needle Aspiration Biopsy (FNA)
Fine needle aspiration (FNA) is a diagnostic method for thyroid cancer. Cancer cells usually look different from normal cells, so the type of thyroid cancer is determined by microscopic examination of thyroid cells found in nodules (neck masses) or growth.
5.3 Molecular Detection
Many genetic changes are thought to play an important role in thyroid cancer formation. The frequent occurrence of RAS mutations in follicular adenoma suggests that the activated RAS may play a role in the early stage of tumorigenesis. Molecular tests (classification of gene expression) can be used to help make a diagnosis when the result of a fine needle biopsy is uncertain.
6. Treatment of Thyroid Tumor
Cancer treatment strategies need to be developed according to the stage of the tumor.
6.1 Tumor Staging
Thyroid cancer staging is a classification by doctors based on the characteristics of malignant thyroid tumors. Tumor staging can help doctors determine the best treatment for thyroid cancer. The TNM staging system was developed by the American joint cancer commission (AJCC). “T” represent tumor, “N” represent lymph node, and “M” represent metastasis. The following table shows the staging of thyroid cancer using the TNM staging system.
Table 1 TNM staging system for thyroid cancer
|TX=Tumor can't be evaluated
||NX=Local lymph nodes cannot be evaluated
||MX=Unable to assess distant transfer (and diffusion)
|T0=No primary tumor
||N0=Non-diffusion to regional lymph nodes
||M0=No distant transfer
|T1=Tumor size is 2 cm wide or smaller
||N1=Tumor has spread to local lymph nodes
||M1=Distant metastasis involves distant lymph nodes, internal organs, etc
|T2=Tumor size 2 - 4cm wide
||N1a= The tumor has spread to the lymph nodes around the thyroid
|T3=The tumor is larger than 4 cm or has begun to grow outside the thyroid gland
||N1b= The tumor has spread to the lymph nodes in the neck or upper chest
|T4a=Tumors (any size) have been extensively grown into local neck tissue other than the thyroid
|T4b=The tumor has grown to the spine or local large blood vessels
6.2.1 Surgical Treatment
Surgery is the basic method for treating various types of thyroid cancer except for anaplastic thyroid cancer. Other auxiliary treatment methods such as nuclide, thyroid hormone and external radiation are usually used.
Surgical treatment of thyroid cancer includes partial thyroidectomy or lobectomy and total thyroidectomy.
Partial thyroidectomy or lobectomy is the surgical removal of part of the thyroid gland, such as the left or right lobe of the tumor. Lobectomy is generally used to remove single-focal tumors less than 4 cm without evidence of external thyroid expansion or lymph node metastasis. Total thyroidectomy is a complete surgical removal of the thyroid gland.
6.2.2 Endocrine Therapy
TSH can stimulate the proliferation of thyroid cancer cells through its receptor .
Therefore, thyroid hormone therapy such as TSH inhibitors is used after surgery. This method can significantly reduce recurrence and cancer-related mortality in patients with different types of thyroid cancer .
6.2.3 Radionuclide Therapy
Some patients with papillary or follicular carcinoma may require systemic radioactive iodine (RAI) after thyroidectomy . When radioactive iodine enters the bloodstream, it selectively destroys the remaining thyroid tissue and cancer cells without affecting any other cells. The adjuvant therapy is applicable to patients over 45 years old, multiple cancerous foci, locally invasive tumors, and distant metastases.
Chemotherapy is rarely used to treat thyroid cancer, except for malignant tumors such as undifferentiated thyroid cancer.
6.2.5 External Radiation Therapy
Mainly used for anaplastic thyroid cancer.
6.2.6 Targeted Therapy
Routine treatment for thyroid cancer includes thyroidectomy, radioactive iodide therapy, and thyroid stimulating hormone (TSH) suppression therapy. Although the overall prognosis is good, there are still a small number of patients with lymph node metastasis, tumor recurrence, drug resistance and other conditions.
Therefore, it is extremely important to develop new therapeutic strategies for thyroid cancer.
Mutations in the MAPK pathway are believed to initiate the development of thyroid cancer and lead to changes in gene expression, which can promote cell proliferation, cell growth, and angiogenesis. Changes in PI3K/mTOR pathway and p53 tumor suppressor factor are believed to promote tumor progression. In thyroid cancer, anti-tumor effects have been widely used by blocking the MAPK pathway.
Figure 4 Thyroid cancer-related pathways
FDA has approved four different drugs targeting the mitogen activated protein kinase (MAPK) signaling pathway for the treatment of advanced thyroid cancer  .
Among them, Lenvatinib and Sorafenib are mainly used for the treatment of advanced, recurrent and drug resistant DTC, while Cabozantinib and Vandetanib target MTC.
In addition, BRAF mutations play an important role in the progression of thyroid cancer and account for 29-83% of all gene mutations . A class of targeted drugs called kinase inhibitors may help treat certain genetically mutated thyroid cancer cells, such as BRAF and RET/PTC. Drugs that target the BRAF gene are vemurafenib, dabrafenib, and selumetinib.
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