The American Association of Endocrine Surgeons, Patient Education Site

Thyroid cancer: Medullary Thyroid Cancer (MTC)

1. Overview

Medullary thyroid cancer is a rare form of thyroid cancer and accounts for 3 to 10% of all thyroid cancers. MTCMTC - Medullary thyroid cancer grows from specialized thyroid cells called parafollicular cellsParafollicular cells - C-cells; specialized thyroid cells that secrete calcitonin and play a major role in medullary thyroid cancer, or C-cells that make a hormone called calcitoninCalcitonin - hormone, secreted by C-cells, which plays a role in bone formation and deposition of calcium; can be used in the diagnosis and as a marker of recurrent disease in patients with MTC.. Calcitonin helps control bone formation and blood calcium levels, but its action in humans is not very powerful. Unlike thyroxine (T4T4 - thyroxine thyroid hormone), calcitonin does not need to be replaced in adults if the thyroid is removed. Calcitonin can be used to make the diagnosis and as a marker of recurrent disease in patients with MTC. C-cells, unlike other cells in the thyroid, do not concentrate iodine and therefore MTC does not respond to radioactive iodine therapy.

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2. Symptoms and signs

Most patients with thyroid cancer do not have any symptoms. Typically, patients present with a thyroid nodule that on further evaluation is found to be cancer. As with all thyroid disease, a thorough history is important, such as a family history of thyroid cancer, personal history of radiation exposure, or enlarged lymph nodes. Your physician will review with you any symptoms such as pain, swelling in the neck, difficulty with swallowing, shortness of breath, difficulty with breathing or changes in your voice. If the nodule is large, it may cause symptoms such as difficulty swallowing, choking sensations, or a large mass in the neck. Rarely, the cancer can grow into the nerves (i.e. the recurrent laryngeal nerves) that control the voicebox and cause hoarseness. If the disease is quite advanced, a few patients can present with symptoms of flushing and diarrhea, which is caused by very high blood levels of calcitoninCalcitonin - hormone, secreted by C-cells, which plays a role in bone formation and deposition of calcium; can be used in the diagnosis and as a marker of recurrent disease in patients with MTC. and other hormones made by the MTCMTC - Medullary thyroid cancer. However, this is a very rare presentation.

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3. Risk factors

The major risk factor for MTCMTC - Medullary thyroid cancer is genetics. Approximately 20% of cases of medullary thyroid cancer are associated with one of three familial syndromes known as multiple endocrine neoplasia (MEN) 2A, MEN 2BMEN 2B - multiple endocrine neoplasia consisting of medullary thyroid cancer, pheochromocytoma, and neuromas, and familial medullary thyroid carcinoma (FMTCFMTC - familial medullary thyroid carcinoma). MEN 2AMEN 2A - multiple endocrine neoplasia consisting of medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia is a syndrome consisting of medullary thyroid cancer, pheochromocytomaPheochromocytoma - adrenal gland tumor that secretes adrenalin-like substances; associated with MEN 2A and MEN 2B (See Adrenal → Pheochromocytoma), and parathyroidParathyroid - 4 little glands that are located by the thyroid and regulate calcium hyperplasia (See Parathyroid). MEN 2B is a syndrome comprised of medullary thyroid cancer, pheochromocytoma, and neuromas. These syndromes are caused by mutations in a gene called the RETRET - protooncogene that causes MEN 2A, MEN 2B, and FMTC proto-oncogene. This gene mutation can be passed on from generation to generation. There is a 50% chance that the affected person will pass it on to each of his or her children (called an autosomal dominant inheritance pattern). It is crucial that all patients who are diagnosed with MTC should also be screened for other diseases associated with the familial syndromes. Most importantly, patients with MTC should be evaluated for a pheochromocytoma. This tumor secretes adrenaline and can cause dangerously high blood pressures, heart palpitations, sweating, flushing, headaches, stroke, and sudden death. The screening for pheochromocytoma is usually made by measuring blood or urine levels of adrenaline and its breakdown products called metanephrines. If present, a pheochromocytoma must be removed before any surgery for MTC.

Even if a patient has no family history of MTC or one of these inherited familial syndromes, he/she may be the first in the family to have the mutation, known as the index case. It is now recognized that different mutations tend to run in families. Each mutation tends to cause a similar type of MTC in aggressiveness and timeline of presentation. Treatment can be tailored specifically for patients based on their specific mutation.

All patients diagnosed with MTC should be tested for the genetic mutations associated with familial forms of the disease. A genetic counselor or other skilled professional should be involved in the process to discuss the implications of genetic testing and assist in the interpretation of these results. They will also make recommendations regarding the possible testing of family members.

While a genetic syndrome must be ruled out in all patients with MTC, most cases are sporadic (i.e. occur randomly and are not genetically inherited from a parent). Still, a small number of patients who are deemed to have sporadic MTC, can still have RET gene mutations.

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4. Diagnosis

The diagnosis of MTCMTC - Medullary thyroid cancer is most frequently made by a combination of FNAFNA - fine needle aspiration biopsy biopsy of the thyroid nodules and specific blood tests. There are several tests used to evaluate and diagnose a thyroid nodule suspicious for medullary thyroid cancer. These tests include:

Calcitonin — A blood test to check the level of calcitoninCalcitonin - hormone, secreted by C-cells, which plays a role in bone formation and deposition of calcium; can be used in the diagnosis and as a marker of recurrent disease in patients with MTC. in the blood should be done in patients with an established or suspected diagnosis of MTC. It can also be used as a screening test for patients with a family history of MTC, who are at risk of developing the disease. Calcitonin levels can be used to estimate how much cancer is in a person's body, as well as monitor for persistent or recurrent disease after surgery (i.e. tumor marker). Depending on the initial calcitonin level, additional radiographic studies such as a CTCT - computed tomography scan; special imaging to get a better picture of the anatomy scan of the chest, neck, and/or liver may be ordered.

Carcinoembryonic antigen (CEA)CEACEA - carcinoembryonic antigen; tumor marker is a substance that may be made by advanced MTC that should be tested for in the blood along with calcitonin. CEA can also be used as a marker for possible later recurrence of disease. More aggressive MTC often make more CEA.

Ultrasound — A thyroid ultrasound is a non-invasive imaging study in which sound waves are used to see an accurate picture of the thyroid gland as well as any enlarged lymph nodes. The ultrasound can tell the nodule's size, exact location, and whether it is solid or fluid-filled (i.e. cystic). An ultrasound cannot differentiate between cancer and benign tumors, but there are certain things that suggest cancer such as hypoechoic nodules with increased vascularity (i.e. blood vessels), and irregular borders. An ultrasound is also useful to evaluate the neck lymph nodes in the neck (i.e. lymph node mapping) for possible spread (metastasis) of cancer to these lymph nodes. Metastasis occurs frequently in MTC, and the lymph nodes in the neck are the most common first site. By the time a medullary thyroid cancer nodule can be felt (palpable), more than 50% of patients with MTC will have lymph node metastasesMetastases - spread of cancer in the neck. If suspicious or large lymph nodes are seen, they can be tested with a FNA biopsy. For patients with a diagnosis of cancer, a full neck ultrasound looking specifically for enlarged lymph nodes should be performed prior to any surgery.

Fine needle aspiration (FNA)— FNA biopsy is the most accurate test for evaluating thyroid nodules. The biopsy may be performed under ultrasound guidance. A very thin needle is guided into the thyroid nodule and a small sampling of cells is aspirated or sucked into the needle. These cells are then examined under a microscope by a cytologist. An experienced thyroid cytologist is important to increase the accuracy of diagnosis. The diagnosis of MTC on FNA biopsy is about 95-98% accurate. Some centers may perform special stains or molecular studies on these cells to help determine if they are in fact cancerous.

Magnetic resonance imaging (MRI), Computed Tomography (CTCT - computed tomography scan; special imaging to get a better picture of the anatomy scan) or Positron Emission Tomography (PETCT) scans — These advanced imaging tests may be needed to see if large cancers are invading (i.e. growing into) or in close proximity to the large vital structures in the neck. They can also be used to identify involved lymph nodes, spread, or recurrence.

Genetic testing — In patients whom the MTC is related with a genetic RETRET - protooncogene that causes MEN 2A, MEN 2B, and FMTC mutation, specific gene mutations should be examined by the genetic laboratory. All family members of a patient diagnosed with a genetic basis for their MTC should be tested for these mutations. It is very important that testing, treatment, and follow up of families who carry these syndrome mutations is carried out in centers with significant experience in these rare genetic diseases.

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5. Treatment

Surgery
The best treatment for MTCMTC - Medullary thyroid cancer is surgery. The goal of surgery is to completely remove all disease at the first operation. A complete resection can be difficult since a high percentage of patients with a palpable nodule will already have lymph node metastasesMetastases - spread of cancer in the neck. The extent of disease can be estimated in most patients based on their calcitoninCalcitonin - hormone, secreted by C-cells, which plays a role in bone formation and deposition of calcium; can be used in the diagnosis and as a marker of recurrent disease in patients with MTC. and CEACEA - carcinoembryonic antigen; tumor marker levels. These levels can sometimes help guide the surgeon in determining how extensive an operation is needed. A small number of patients will have distant spread to other organs (i.e. metastases), such as the lungs or liver. If this spread is microscopic, it may too small to be seen on any imaging studies, but the blood level of calcitonin may remain high even after surgery.

The minimum recommended operation for MTC is a total thyroidectomyTotal thyroidectomy - removal of the whole thyroid with central lymph node dissection. This operation involves the removal of the entire thyroid gland and 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 inominate vessels (just below the top of the breast bone or sternum). More extensive surgery may be required, depending on the individual needs of the patient and the surgeon's preference. This may include removing the lymph nodes in the lateral neck around the jugular veins (i.e. modified radical lateral neck dissectionNeck dissection - removal of the cancerous lymph nodes and surrounding lymph nodes in that region). 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. Some surgeons recommend routine lateral neck dissection on the same side as the main thyroid tumor.

After surgery, blood levels for calcitonin and CEA should be monitored routinely, usually every 6 months to a year. If calcitonin and CEA levels rise above the immediate post-operative level, a neck ultrasound and computed tomography (CAT) scan, should be performed to look for recurrent disease. If there is recurrent disease, then another operation may be needed.

Other treatments
RAI ablationRAI ablation - the use of radioactive iodine to destroy thyroid cells (either benign or cancer) does not work for MTC. Very few patients with thyroid cancer need external beam radiation or chemotherapy. 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, or have spread to nonsurgically treatable areas (metastases). These treatments are used as a palliative measure to control the growth of the disease, and not to cure it. For very advanced disease, or for documented metastatic disease, conventional chemotherapy has little use, but new drugs are being developed and are offering some hope. 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 MTC.

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6. Prognosis

Overall, people who have MTC only in the thyroid gland have a 10-year survival rate of greater than 95%. If the cancer has spread to the lymph nodes in the neck, the survival rate decreases to 75%. For those whose cancer has spread outside of the neck to other parts of the body including the liver, lungs, and bones (i.e. metastatic disease), the 10-year survival rate is 20-40%. (Stage and prognosis of thyroid cancer)

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