Parathyroid cancer is a rare disease in which malignant (cancer) cells form in the tissues of a parathyroid gland.

The parathyroid glands are four pea-sized organs found in the neck near the thyroid gland. The parathyroid glands make parathyroid hormone (PTH or parathormone). PTH helps the body use and store calcium to keep the calcium in the blood at normal levels.

A parathyroid gland may become overactive and make too much PTH, a condition called hyperparathyroidism. Hyperparathyroidism can occur when a benign tumor (noncancer), called an adenoma, forms on one of the parathyroid glands, and causes it to grow and become overactive. Sometimes hyperparathyroidism can be caused by parathyroid cancer, but this is very rare.

The extra PTH causes:

• The calcium stored in the bones to move into the blood.
• The intestines to absorb more calcium from the food we eat.

This condition is called hypercalcemia (too much calcium in the blood).

The hypercalcemia caused by hyperparathyroidism is more serious and life-threatening than parathyroid cancer itself and treating hypercalcemia is as important as treating the cancer.

The parathyroid glands are tiny, round structures usually found embedded in the posterior surface of the thyroid gland (image). A thick connective tissue capsule separates the glands from the thyroid tissue. Most people have four parathyroid glands, but occasionally there are more in tissues of the neck or chest. The function of one type of parathyroid cells, the oxyphil cells, is not clear. The primary functional cells of the parathyroid glands are the chief cells. These epithelial cells produce and secrete the parathyroid hormone (PTH) , the major hormone involved in the regulation of blood calcium levels.

The parathyroid glands produce and secrete PTH, a peptide hormone, in response to low blood calcium levels (image). PTH secretion causes the release of calcium from the bones by stimulating osteoclasts, which secrete enzymes that degrade bone and release calcium into the interstitial fluid. PTH also inhibits osteoblasts, the cells involved in bone deposition, thereby sparing blood calcium. PTH causes increased reabsorption of calcium (and magnesium) in the kidney tubules from the urine filtrate. In addition, PTH initiates the production of the steroid hormone calcitriol (also known as 1,25-dihydroxyvitamin D), which is the active form of vitamin D₃, in the kidneys. Calcitriol then stimulates increased absorption of dietary calcium by the intestines. A negative feedback loop regulates the levels of PTH, with rising blood calcium levels inhibiting further release of PTH.

Abnormally high activity of the parathyroid gland can cause hyperparathyroidism , a disorder caused by an overproduction of PTH that results in excessive calcium reabsorption from bone. Hyperparathyroidism can significantly decrease bone density, leading to spontaneous fractures or deformities. As blood calcium levels rise, cell membrane permeability to sodium is decreased, and the responsiveness of the nervous system is reduced. At the same time, calcium deposits may collect in the body’s tissues and organs, impairing their functioning.

In contrast, abnormally low blood calcium levels may be caused by parathyroid hormone deficiency, called hypoparathyroidism , which may develop following injury or surgery involving the thyroid gland. Low blood calcium increases membrane permeability to sodium, resulting in muscle twitching, cramping, spasms, or convulsions. Severe deficits can paralyze muscles, including those involved in breathing, and can be fatal.

When blood calcium levels are high, calcitonin is produced and secreted by the parafollicular cells of the thyroid gland. As discussed earlier, calcitonin inhibits the activity of osteoclasts, reduces the absorption of dietary calcium in the intestine, and signals the kidneys to reabsorb less calcium, resulting in larger amounts of calcium excreted in the urine.

Overview

Calcium is required for a variety of important physiologic processes, including neuromuscular functioning; thus, blood calcium levels are closely regulated. The parathyroid glands are small structures located on the posterior thyroid gland that produce parathyroid hormone (PTH), which regulates blood calcium levels. Low blood calcium levels cause the production and secretion of PTH. In contrast, elevated blood calcium levels inhibit secretion of PTH and trigger secretion of the thyroid hormone calcitonin. Underproduction of PTH can result in hypoparathyroidism. In contrast, overproduction of PTH can result in hyperparathyroidism.

Cancers occur when genetic mutations build up in critical genes, specifically those that control cell growth and division (proliferation) or the repair of damaged DNA. These changes allow cells to grow and divide uncontrollably to form a tumor. In most cases of parathyroid cancer, these genetic changes are acquired during a person's lifetime and are present only in certain cells in the parathyroid glands. These changes, which are called somatic mutations, are not inherited. Somatic mutations in many different genes have been found in parathyroid cancer cells. Less commonly, genetic changes present in all of the body's cells increase the risk of developing parathyroid cancer. These genetic changes, which are classified as germline mutations, are usually inherited from a parent. In people with germline mutations, changes in other genes, together with non-genetic factors, also influence whether a person will develop parathyroid cancer.

Mutations in the CDC73 gene are found in up to 70 percent of cases of parathyroid cancer. In approximately one-third of affected individuals with changes in this gene, the mutation is inherited from a parent and is present in all of the body's cells. In people who have parathyroid cancer with CDC73 gene mutations, the cancer is seven times more likely to metastasize than is parathyroid cancer in affected individuals without CDC73 gene mutations. Individuals with CDC73 gene mutations are also at a higher risk of recurrence of the cancer and have a decreased survival rate compared to those without CDC73 gene mutations. Mutations in other genes have also been found in parathyroid cancer, but each of these mutations has been reported in only a small number of individuals.

The CDC73 gene provides instructions for making a protein called parafibromin. This protein is found within the nucleus of cells throughout the body and is likely involved in gene transcription, which is the first step in protein production. Parafibromin functions as a tumor suppressor, which means it keeps cells from growing and dividing too rapidly or in an uncontrolled way. In individuals with a CDC73 gene mutation, either inherited from a parent or acquired during their lifetime, a second mutation in the other copy of the CDC73 gene must occur in parathyroid cells for cancer to develop. Parathyroid cells with two altered copies of the CDC73 gene produce no functional parafibromin. As a result, cells grow and divide unchecked, which can lead to parathyroid cancer.

A significantly increased risk of parathyroid cancer is also a feature of certain rare genetic syndromes. Parathyroid cancer occurs in 15 percent of individuals with hyperparathyroidism-jaw tumor syndrome and in 1 percent of individuals with familial isolated hyperparathyroidism. These conditions are both caused by mutations in the CDC73 gene. In rare cases, parathyroid cancer has also been found in people who have a tumor disorder called multiple endocrine neoplasia, which is caused by mutations in other genes.

Non-genetic factors have also been found to contribute to a person's risk of developing parathyroid cancer, including a history of hyperparathyroidism with chronic kidney failure, thyroid cancer, and previous radiation therapy on the neck.

Normal Function

The CDC73 gene (also known as HRPT2) provides instructions for making a protein called parafibromin. This protein is found primarily in the nucleus of cells and is likely involved in regulating gene transcription, which is the first step in protein production. Parafibromin functions as a tumor suppressor, which means it keeps cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. When parafibromin is found outside the nucleus, it appears to be involved in the organization of the cell's structural framework (the cytoskeleton).

Health Conditions Related to Genetic Changes

Familial isolated hyperparathyroidism

Inherited mutations in the CDC73 gene have been found in some families with familial isolated hyperparathyroidism, a condition characterized by overactivity of the parathyroid glands (primary hyperparathyroidism). These glands release a hormone that helps control the normal balance of calcium in the blood. Primary hyperparathyroidism disrupts this balance, which can lead to high blood calcium levels (hypercalcemia), kidney stones, thinning of the bones (osteoporosis), nausea, vomiting, high blood pressure (hypertension), weakness, and fatigue. Primary hyperparathyroidism is a characteristic feature of hyperparathyroidism-jaw tumor syndrome (described below); however, familial isolated hyperparathyroidism is diagnosed in people with hyperparathyroidism but not the other features of hyperparathyroidism-jaw tumor syndrome.

CDC73 gene mutations that cause familial isolated hyperparathyroidism likely result in decreased activity of the parafibromin protein. Reduced parafibromin activity can cause increased cell proliferation, leading to the formation of tumors involving the parathyroid glands. Parathyroid tumors in people with familial isolated hyperparathyroidism are usually noncancerous (benign). The tumors cause the glands to be overactive, and this overactivity leads to the signs and symptoms of the condition. The mutations associated with familial isolated hyperparathyroidism are thought to have a less severe effect on protein function than those that cause hyperparathyroidism-jaw tumor syndrome. Occasionally, individuals with familial isolated hyperparathyroidism later develop features of hyperparathyroidism-jaw tumor syndrome, although some never do. Familial isolated hyperparathyroidism caused by CDC73 gene mutations may be an early or mild form of hyperparathyroidism-jaw tumor syndrome.

Hyperparathyroidism-jaw tumor syndrome

More than 45 inherited mutations in the CDC73 gene have been found to cause hyperparathyroidism-jaw tumor syndrome, which is a condition characterized by a type of benign tumor called a fibroma in the jaw and parathyroid tumors that cause hyperparathyroidism. Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, osteoporosis, nausea, vomiting, hypertension, weakness, and fatigue in people with hyperparathyroidism-jaw tumor syndrome.

Most of the CDC73 gene mutations that cause this condition result in a parafibromin protein that is abnormally short and nonfunctional. Without functional parafibromin, cell proliferation is not properly regulated. Uncontrolled cell division resulting from the loss of parafibromin function can lead to the formation of tumors in the parathyroid glands, jaw, and other tissues in people with hyperparathyroidism-jaw tumor syndrome. Parathyroid tumors, which can be cancerous or noncancerous, interfere with the gland's normal function and lead to primary hyperparathyroidism in people with hyperparathyroidism-jaw tumor syndrome.

Parathyroid cancer

Mutations in the CDC73 gene are found in up to 70 percent of cases of parathyroid cancer. In approximately one-third of affected individuals with changes in this gene, the mutation is inherited from a parent and is present in all of the body's cells (germline mutation). However, not everyone who inherits a mutation in the CDC73 gene will ultimately develop parathyroid cancer. Other genetic and non-genetic factors also contribute to a person's cancer risk.

In the remaining two-thirds of individuals with CDC73 gene mutations, the condition is associated with a mutation that occurs in parathyroid cells during their lifetime (somatic mutation). In individuals with either a germline or somatic CDC73 gene mutation, a second mutation in the other copy of the CDC73 gene must occur for parathyroid cancer to develop. Parathyroid cells with two altered copies of the CDC73 gene produce no functional parafibromin. As a result, cells grow and divide unchecked, which can lead to parathyroid cancer.

A significantly increased risk of parathyroid cancer is a feature of hyperparathyroidism-jaw tumor syndrome and familial isolated hyperparathyroidism (both described above). Parathyroid cancer occurs in 15 percent of individuals with hyperparathyroidism-jaw tumor syndrome and in 1 percent of individuals with familial isolated hyperparathyroidism. It is unclear why some CDC73 gene mutations cause isolated parathyroid cancer, others cause noncancerous tumors in the parathyroid glands and jaw, and still others cause only hyperparathyroidism.

Other Names for This Gene

• C1orf28
• CDC73_HUMAN
• cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)
• cell division cycle protein 73 homolog
• HRPT2
• hyperparathyroidism 2 protein
• hyrax
• HYX
• parafibromin

Genomic Location

Having certain inherited disorders can increase the risk of developing parathyroid cancer.

Anything that increases the chance of getting a disease is called a risk factor. Risk factors for parathyroid cancer include the following rare disorders that are inherited (passed down from parent to child):

• Familial isolated hyperparathyroidism (FIHP).
• Multiple endocrine neoplasia type 1 (MEN1) syndrome.

Treatment with radiation therapy may increase the risk of developing a parathyroid adenoma.

Signs and symptoms of parathyroid cancer include weakness, feeling tired, and a lump in the neck.

Most parathyroid cancer signs and symptoms are caused by the hypercalcemia that develops. Signs and symptoms of hypercalcemia include the following:

• Weakness.
• Feeling very tired.
• Nausea and vomiting.
• Loss of appetite.
• Weight loss for no known reason.
• Being much more thirsty than usual.
• Urinating much more than usual.
• Constipation.
• Trouble thinking clearly.

Other signs and symptoms of parathyroid cancer include the following:

• Pain in the abdomen, side, or back that doesn't go away.
• Pain in the bones.
• A broken bone.
• A lump in the neck.
• Change in voice such as hoarseness.
• Trouble swallowing.

Other conditions may cause the same signs and symptoms as parathyroid cancer. Check with your doctor if you have any of these problems.

Tests that examine the neck and blood are used to diagnose parathyroid cancer.

Once blood tests are done and hyperparathyroidism is diagnosed, imaging tests may be done to help find which of the parathyroid glands is overactive. Sometimes the parathyroid glands are hard to find and imaging tests are done to find exactly where they are.

Parathyroid cancer may be hard to diagnose because the cells of a benign parathyroid adenoma and a malignant parathyroid cancer look alike. The patient's symptoms, blood levels of calcium and parathyroid hormone, and characteristics of the tumor are also used to make a diagnosis.

The following tests and procedures may be used:

• Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
• Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease. To diagnose parathyroid cancer, the sample of blood is checked for its calcium level.
• Parathyroid hormone test: A procedure in which a blood sample is checked to measure the amount of parathyroid hormone released into the blood by the parathyroid glands. A higher than normal amount of parathyroid hormone can be a sign of disease.
• Sestamibi scan: A type of radionuclide scan used to find an overactive parathyroid gland. A very small amount of a radioactive substance called technetium 99 is injected into a vein and travels through the bloodstream to the parathyroid gland. The radioactive substance will collect in the overactive gland and show up brightly on a special camera that detects radioactivity.
• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

• SPECT scan (single photon emission computed tomography scan): A procedure to find malignant tumor cells in the neck. A small amount of a radioactive substance is injected into a vein or inhaled through the nose. As the substance travels through the blood, a camera rotates around the body and takes pictures of the neck. A computer uses the pictures to make a 3-dimensional (3-D) image of the neck. There will be increased blood flow and more activity in areas where cancer cells are growing. These areas will show up brighter in the picture.
• Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
• Angiogram: A procedure to look at blood vessels and the flow of blood. A contrast dye is injected into the blood vessel. As the contrast dye moves through the blood vessel, x-rays are taken to see if there are any blockages.
• Venous sampling: A procedure in which a sample of blood is taken from specific veins and checked to measure the amounts of certain substances released into the blood by nearby organs and tissues. If imaging tests do not show which parathyroid gland is overactive, blood samples may be taken from veins near each parathyroid gland to find which one is making too much PTH.

Treatment Option Overview

KEY POINTS

• There are different types of treatment for patients with parathyroid cancer.
• Treatment includes control of hypercalcemia (too much calcium in the blood) in patients who have an overactive parathyroid gland.
• Four types of standard treatment are used:
  • Surgery
  • Radiation therapy
  • Chemotherapy
  • Supportive care
• New types of treatment are being tested in clinical trials.
• Treatment for parathyroid cancer may cause side effects.
• Patients may want to think about taking part in a clinical trial.
• Patients can enter clinical trials before, during, or after starting their cancer treatment.
• Follow-up tests may be needed.

There are different types of treatment for patients with parathyroid cancer.

Different types of treatment are available for patients with parathyroid cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Treatment includes control of hypercalcemia (too much calcium in the blood) in patients who have an overactive parathyroid gland.

In order to reduce the amount of parathyroid hormone that is being made and control the level of calcium in the blood, as much of the tumor as possible is removed in surgery. For patients who cannot have surgery, medication may be used.

Four types of standard treatment are used:

Surgery

Surgery (removing the cancer in an operation) is the most common treatment for parathyroid cancer that is in the parathyroid glands or has spread to other parts of the body. Because parathyroid cancer grows very slowly, cancer that has spread to other parts of the body may be removed by surgery in order to cure the patient or control the effects of the disease for a long time. Before surgery, treatment is given to control hypercalcemia.

The following surgical procedures may be used:

• En bloc resection: Surgery to remove the entire parathyroid gland and the capsule around it. Sometimes lymph nodes, half of the thyroid gland on the same side of the body as the cancer, and muscles, tissues, and a nerve in the neck are also removed.
• Tumor debulking: A surgical procedure in which as much of the tumor as possible is removed. Some tumors cannot be completely removed.
• Metastasectomy: Surgery to remove any cancer that has spread to distant organs such as the lung.

Surgery for parathyroid cancer sometimes damages nerves of the vocal cords. There are treatments to help with speech problems caused by this nerve damage.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:

• External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.
• Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.

The way the radiation therapy is given depends on the type and stage of the cancer being treated. External radiation therapy is used to treat parathyroid cancer.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

Supportive care

Supportive care is given to lessen the problems caused by the disease or its treatment. Supportive care for hypercalcemia caused by parathyroid cancer may include the following:

• Intravenous (IV) fluids.
• Drugs that increase how much urine the body makes.
• Drugs that stop the body from absorbing calcium from the food we eat.
• Drugs that stop the parathyroid gland from making parathyroid hormone.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI website.

Treatment for parathyroid cancer may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

As you go through treatment, you will have follow-up tests or checkups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. These tests are sometimes called follow-up tests or check-ups.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

Parathyroid cancer often recurs. Patients should have regular check-ups for the rest of their lives, to find and treat recurrences early.

Treatment of Localized Parathyroid Cancer

Treatment of localized parathyroid cancer may include the following:

• Surgery (en bloc resection).
• Surgery followed by radiation therapy.
• Radiation therapy.
• Supportive care to treat hypercalcemia (too much calcium in the blood).

Treatment of Metastatic Parathyroid Cancer

Treatment of metastatic parathyroid cancer may include the following:

• Surgery (metastasectomy) to remove cancer from the places where it has spread.
• Surgery followed by radiation therapy.
• Radiation therapy.
• Chemotherapy.
• Supportive care to treat hypercalcemia (too much calcium in the blood).

Treatment of Recurrent Parathyroid Cancer

Treatment of recurrent parathyroid cancer may include the following:

• Surgery (metastasectomy) to remove cancer from the places where it has recurred.
• Surgery (tumor debulking).
• Surgery followed by radiation therapy.
• Radiation therapy.
• Chemotherapy.
• Supportive care to treat hypercalcemia (too much calcium in the blood).

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on the following:

• Whether the calcium level in the blood can be controlled.
• The stage of the cancer.
• Whether the tumor and the capsule around the tumor can be completely removed by surgery.
• The patient's general health.