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.

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.

Possible signs of parathyroid cancer include weakness, feeling tired, and a lump in the neck.

Most parathyroid cancer symptoms are caused by the hypercalcemia that develops. 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 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 symptoms as parathyroid cancer. A doctor should be consulted if any of these problems occur.

Tests that examine the neck and blood are used to detect (find) and 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 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 in the organ or tissue that makes it. 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 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.

—      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.

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

The prognosis (chance of recovery) 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.

Stages of Parathyroid Cancer

Staging is the process used to find out how far the cancer has spread. The following imaging tests may be used to determine if cancer has spread to other parts of the body such as the lungs, liver, bone, heart, pancreas, or lymph nodes:

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.

MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).

There is no standard staging process for parathyroid cancer. The disease is described as either localized or metastatic.

—      Localized parathyroid cancer is found in a parathyroid gland and may have spread to nearby tissues.

—      Metastatic parathyroid cancer has spread to other parts of the body, such as the lungs, liver, bone, sac around the heart, pancreas, or lymph nodes.

Recurrent Parathyroid Cancer

 Recurrent parathyroid cancer is cancer that has recurred (come back) after it has been treated. More than half of patients have a recurrence. The parathyroid cancer usually recurs between 2 and 5 years after the first surgery, but can recur up to 20 years later. It usually comes back in the tissues or lymph nodes of the neck. High blood calcium levels that appear after treatment may be the first sign of recurrence.

Treatment Option Overview

—      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.

—      Lifelong follow-up is important.

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. Before starting treatment, patients may want to think about taking part in a clinical trial. 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.

Clinical trials are taking place in many parts of the country.  Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.

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.

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—      A malignant tumor is a mass, or collection, of cancer cells. Malignant tumors grow rapidly and can invade nearby tissues. They can eventually metastasize (spread) to other parts of the body.

—      A benign tumor, on the other hand, is a mass of cells that is not cancerous. It will not invade nearby tissues or metastasize (spread) to other parts of the body.

Parathyroid cancer, a very rare cancer, is a disease in which cancerous (malignant) cells are found in the tissues of the parathyroid gland. The parathyroid gland is at the base of the neck, near the thyroid gland. The parathyroid gland makes a hormone called parathyroid hormone (PTH), or parathormone, which helps the body store and use calcium.

Problems with the parathyroid gland are common and are usually not caused by cancer. If parathyroid cancer is found, the parathyroid gland may be making too much PTH. This causes too much calcium to be found in the blood. The extra PTH also takes calcium from the bones, which causes pain in the bones, kidney problems, and other types of problems.

There are other conditions that can cause the parathyroid gland to make too much PTH. It is important for a doctor to determine what is causing the extra PTH. For example, hyperparathyroidism is a condition which can cause the body to make extra PTH. If hyperparathyroidism runs in the family, there is a greater chance of getting this type of cancer.

The chance of recovery (prognosis) depends on whether the cancer is just in the parathyroid gland or has spread to other parts of the body (stage), and the patient’s general health.

Staging

Once parathyroid cancer is found, more tests will be done to find out if cancer cells have spread to other parts of the body. This is called staging. A doctor needs to know the stage of the disease to plan treatment. The following stages are used for parathyroid cancer:

—      Localized: The cancer is only on the parathyroid gland and has not spread to tissues next to the parathyroid.

—      Metastatic: The cancer has spread to lymph nodes in the area or to other parts of the body, such as the lungs.

—      Recurrent: The cancer has come back (recurred) after it has been treated. It may come back in the original place or in another part of the body.

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Sensipar (cinacalcet) was approved in March 2004 to treat secondary hyper-parathyroidism in patients with chronic kidney disease who are on dialysis. In secondary hyperparathyroidism, elevated levels of parathyroid hormone are associated with changes in calcium and phosphorus metabolism, bone pain, fractures, and an increased risk for cardiovascular death.

The drug also was approved to treat hypercalcemia, an elevation in calcium levels in the blood, that results from a rare cancer of the parathyroid glands. Elevated levels of serum calcium can cause mental confusion, lethargy, dehydration, nausea, vomiting, constipation, and kidney damage.

Nearly all of the more than 300,000 kidney dialysis patients in the United States experience hyperparathyroidism.

Treatment with Sensipar, manufactured by Amgen Inc. of Thousand Oaks, Calif., lowers blood levels of parathyroid hormone as well as the amount of calcium and phosphorus in the blood.

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(1)           Department of Oncology, Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

 (2)          Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

(3)           Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

Received: 10 April 2003  Accepted: 09 September 2003  

Purpose.  Telomerase activity (TA) has been extensively studied in tumors of many organs, but not the parathyroid gland. Therefore, we investigated TA in parathyroid tumors, and examined the mRNA expression of its catalytic subunits.

Methods.  We examined 17 single adenomas, one hyperplastic parathyroid gland, and one metastatic parathyroid cancer and quantified TA by fluorescence-based TRAP analysis. We also studied the expression of telomerase catalytic subunits in nine adenomas and one cancer by reverse transcription – polymerase chain reaction (RT-PCR) analysis.

Results.  Telomerase activity was not detected in any of the adenomas or the hyperplastic gland; however, the metastatic cancer was highly positive for TA. Both human telomerase RNA (hTR) and human telomerase-associated pretein (hTEP-1) mRNA were detected universally in every specimen tested. Conversely, human telomerase reverse transcriptase (hTERT) mRNA was not detected by the conventional electrophoresis-based technique. Faint expression of hTERT mRNA was detected by real-time RT-PCR only in the sample of parathyroid cancer.

Discussion.  We hypothesize that TA plays a role in the malignant transformation of parathyroid disease and suggest that hTERT mRNA expression could be the key step for TA as in other malignancies. Telomerase activity and hTERT may be useful molecular targets of parathyroid cancer.

Key words  Parathyroid adenoma - Parathyroid cancer - Primary parathyroidism - Telomerase - Human telomerase reverse transcriptase

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Parathyroid carcinoma is a rare malignancy, with an incidence of 0.5 to 4% of all cases of primary hyperparathyroidism. Surgery is the only curative treatment.

Case presentation

We report the case of a 66-year-old man referred for a large suspicious substernal goitre associated with severe hypercalcemia due to hyperparathyroidism. After normalization of serum calcium levels, patient underwent surgery. The voluminous cervicomediastinal firm mass could not be removed through the cervical incision; therefore a cervicothoracic approach was employed. Histopathology revealed a giant parathyroid cancer of 450 grams. A review of the literature was also undertaken to summarize the current treatment approaches for this rare malignancy.

Conclusion

Parathyroid cancer is usually not recognized either preoperatively or intra-operatively. En bloc resection of the tumour with the adjacent tissue is the treatment of choice and it is very important to avoid the rupture of the capsule during operation. Neither tumour size, nor the lymph node status appears to play a role in prognosis. The management of parathyroid carcinoma is a challenge even for experienced surgeons.

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FDA has approved Sensipar (cinacalcet), a drug to treat secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, and hypercalcemia in patients with parathyroid cancer.

Cinacalcet is the first drug in the class of compounds known as calcimimetics to be approved by the FDA. It is approved as a treatment for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Elevated levels of parathyroid hormone (PTH), the hallmark of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death. Treatment with cinacalcet lowers serum levels of PTH as well as the calcium x phosphorus ion product. The calcium x phosphorus ion product is a measure of the amount of calcium and phosphorus in the blood, and when elevated, causes harmful deposition of calcium in various parts of the body.

Cinacalcet is also approved for the treatment of hypercalcemia associated with parathyroid carcinoma, a rare cancer that causes significant elevations in serum calcium levels. Elevated levels of serum calcium can cause mental confusion, lethargy, dehydration, nausea, vomiting, constipation, and kidney damage.

In three 6-month cinacalcet clinical trials of more than 1,000 patients with chronic kidney disease receiving dialysis, the most commonly reported side effects were nausea and vomiting, which occurred in 31 percent and 27 percent, respectively, of cinacalcet-treated patients, compared with 19 percent and 15 percent, respectively, of patients who received placebo. Treatment of patients with chronic kidney disease with cinacalcet was also associated with the development of low serum calcium levels in a significant number of patients. Frequent monitoring of patients’ calcium levels is therefore recommended in the cinacalcet labeling.

Amgen, of Thousand Oaks, Calif. will market cinacalcet by the trade name, Sensipar.

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¹Department of Surgical Oncology, National Cancer Institute of Naples, Naples, Italy

²Unit of Thyroid and Parathyroid Surgery, National Cancer Institute of Naples, Naples, Italy

³Department of Pathology, National Cancer Institute of Naples, Naples, Italy

⁴Department of Nuclear Medicine, National Cancer Institute of Naples, Naples, Italy

This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Parathyroid carcinoma is a rare malignancy, with an incidence of 0.5 to 4% of all cases of primary hyperparathyroidism. Surgery is the only curative treatment.

Case presentation

We report the case of a 66-year-old man referred for a large suspicious substernal goitre associated with severe hypercalcemia due to hyperparathyroidism. After normalization of serum calcium levels, patient underwent surgery. The voluminous cervicomediastinal firm mass could not be removed through the cervical incision; therefore a cervicothoracic approach was employed. Histopathology revealed a giant parathyroid cancer of 450 grams. A review of the literature was also undertaken to summarize the current treatment approaches for this rare malignancy.

Conclusion

Parathyroid cancer is usually not recognized either preoperatively or intra-operatively. En bloc resection of the tumour with the adjacent tissue is the treatment of choice and it is very important to avoid the rupture of the capsule during operation. Neither tumour size, nor the lymph node status appears to play a role in prognosis. The management of parathyroid carcinoma is a challenge even for experienced surgeons.

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“Patients with inoperable parathyroid cancer typically have to contend with extremely elevated levels of calcium in their blood, which can lead to mental confusion, dehydration, kidney damage and ultimately death,” said Dr. Shonni Silverberg of the College of Physicians and Surgeons at Columbia University in New York City and senior author of the study.

Management of inoperable parathyroid carcinoma has been a challenge due to the lack of effective medical therapy. In addition to treating the cancer, doctors also often need to treat hypercalcemia, or excess calcium in the blood, which can be more harmful than the parathyroid cancer itself.

“Until now, the therapeutic choices for patients with inoperable parathyroid cancer have been extremely limited,” said Silverberg. “Cinacalcet offers an important option for treating hypercalcemia in patients with metastatic disease after surgical options have been exhausted.”

Cinacalcet is a drug that mimics how calcium acts on organ tissues. It is used to treat hyperparathyroidism, or elevated parathyroid hormone levels, because it reduces parathyroid cell hormone secretion by binding to the calcium-sensing receptor on parathyroid cells.

The study was conducted at 15 centers in the United States and Europe. Twenty-nine patients with parathyroid cancer were enrolled. The study design included a variable-length titration (treatment with varying doses) phase and a maintenance phase. During the titration phase, cinacalcet was administered to patients until their serum calcium concentration were within normal levels (<10 mg/dL), the dose reached 90 mg, or the patient experienced adverse effects.

During the maintenance phase, dose increases were administered if needed, and doctors were permitted to prescribe treatments deemed necessary to provide adequate supportive care.

Serum calcium was reduced by >1 mg/dL in 62 percent of patients. The greatest reductions in serum calcium were observed in patients with highest baseline calcium levels. Adverse effects of cinacalcet included nausea, vomiting, and headache.

Parathyroid glands are endocrine organs located behind the thyroid gland in the neck. They are necessary for proper bone development, and to control the level of calcium in the blood. The parathyroid glands make parathyroid hormone, which takes calcium from bones so that it will be available in the blood for nerve conduction and muscle contraction.

“This trial is an important milestone for patients suffering from this devastating form of cancer,” said Dolores Shoback, Associate Editor of the Journal of Clinical Endocrinology and Metabolism. “Cinacalcet is the first agent to target the main control switch for parathyroid hormone secretion—the calcium receptor. All prior therapies for this disease work on the bone and patients quickly become refractory to those treatments.”

Other researchers working on the study include Drs. Mishaela Rubin and John Bilezikian of Columbia University, Dr. Charles Faiman of the Cleveland Clinic Foundation, Dr. Munro Peacock of the Indiana University School of Medicine, Dr. Dolores Shoback of the Department of Veterans Affairs Medical Center, Dr. Robert Smallridge of the Mayo Clinic College of Medicine, and Drs. Schwanauer, Olson, and Klassen from Amgen, Inc.

JCEM is a publication of The Endocrine Society. Dr. Silverberg’s article “Cinacalcet Hydrochloride Reduces the Serum Calcium Concentration in Inoperable Parathyroid Carcinoma” will appear in the October issue of the journal.

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When parathyroid cells become malignant (cancerous), they multiply out of control and typically form a firm, grayish-white tumor that can invade the nearby thyroid gland and neck muscles. As the cancerous cells grow, they usually produce too much PTH. In most cases, the end result is abnormally high levels of PTH in the blood (hyperparathyroidism) with abnormally high levels of calcium in the blood (hypercalcemia). The levels of PTH are so high that they force the bones to pour out critical amounts of calcium, which can cause bone pain and can lead to osteoporosis (thinning of the bones). The elevated PTH also forces the kidneys to retain large amounts of calcium, triggering the formation of kidney stones. Excessively high calcium levels also can cause kidney damage.

Parathyroid cancer is so rare that even a major medical center may see no more than two dozen patients with the illness over a period of several decades. About one out of every 2,000 people in the United States is diagnosed with hyperparathyroidism in any given year, but only 20 to 40 of these patients have parathyroid cancer. Parathyroid cancer occurs most commonly in adults between 45 and 51 years old, although cases have occurred in people as young as 19 and as old as 81. Because parathyroid cancer is so rare, researchers have not been able to determine whether there are any specific environmental or lifestyle factors that increase the risk of this illness. A few cases have shown an inherited tendency, with several generations of a single family affected.

Symptoms

Symptoms of parathyroid cancer include:

—      A small lump in the front of the neck (22% to 50% of cases)

—      Kidney stones (pain in the back or side and blood in the urine) and early signs of kidney failure (up to 90% of cases)

—      Bone pain and osteoporosis (up to 70% of cases)

—      Hoarseness (up to 10% of cases) caused by cancer invading the vocal cords or the nerves to the vocal cords

—      Various other symptoms, such as constipation, weak muscles, vomiting or decreased consciousness

Because the rise in calcium can be gradual in patients with parathyroid carcinoma, the body is able to adapt, and patients commonly have only minor symptoms even with calcium levels that would be fatal if they were reached more rapidly.

Diagnosis

Most patients with parathyroid cancer visit a doctor because they have kidney symptoms, bone symptoms or both. For this reason, the doctor usually will ask about risk factors related to various types of kidney and bone illnesses. Because parathyroid cancer is so rare, a doctor may never see even one patient with the illness throughout a lifetime of medical practice.

Your doctor probably will begin the diagnostic process with a thorough physical examination and basic laboratory tests, such as a blood tests and urinalysis. Depending on your specific symptoms, your doctor also may order X-rays or special scans of your neck, bones or kidneys. If you have parathyroid cancer, your blood tests most likely will show an abnormally high calcium level. This will lead your doctor to test for hypercalcemia, including a check for high blood levels of PTH, especially if he or she finds a lump on your neck during the physical examination.

The only way to confirm that someone has parathyroid cancer is to remove the tumor surgically and examine it under a microscope.

Expected Duration

Parathyroid cancer will continue to grow until it is treated.

Prevention

Because the risk factors for parathyroid cancer remain unknown, there is no way to prevent it.

Treatment

Once your doctor confirms that you have parathyroid cancer, your treatment will depend on whether the cancer involves only your parathyroid gland or has spread (metastasized) to other areas. Parathyroid cancer most commonly spreads to the lymph nodes, lungs, bones and liver. If you have cancer that is limited to your parathyroid, then the cancerous parathyroid gland will be removed surgically together with your thyroid gland on the same side. Before surgery, you will receive medication to control your blood calcium levels until your tumor is removed. In some medical centers, radiation treatment is given after surgery.

If your parathyroid cancer has spread to areas outside your parathyroid, then you will need surgery to remove as much of the cancer as possible. This will help to decrease the high levels of PTH and calcium in your blood. Both before and after surgery, you will receive medication to help maintain your blood calcium levels as close to normal as possible. If you cannot be treated surgically, your high calcium levels often can be controlled with plicamycin (Mithracin), pamidronate (Aredia), calcitonin (Calcimar, Cibacalcin, Miacalcin), or, less commonly, gallium nitrates (Ganite). Patients with metastatic parathyroid cancer can choose to participate in clinical trials that are evaluating alternative treatments involving radiation, surgery plus radiation, or chemotherapy.

When To Call A Professional

Call your doctor promptly if you have symptoms of parathyroid cancer, especially if you have bone pain or a lump on your neck.

Prognosis

At the time of diagnosis, most patients with parathyroid cancer have localized disease that can be treated surgically. However, even after a localized tumor is totally removed, parathyroid cancer often comes back. Usually this happens within the first 2 to 5 years after the initial treatment, but it may take more than a decade.

Even metastatic parathyroid cancer (cancer that has spread to other areas) tends to be slow growing. Overall, almost 60% of patients survive for at least 5 years after their parathyroid cancer is diagnosed, and half or more may survive for at least 10 years. The average survival time after the diagnosis of parathyroid cancer is 6 to 7 years.

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