Medullary thyroid cancer makes up about 5% of all cases of thyroid cancer and is very different from the more common papillary and follicular thyroid cancers. Medullary thyroid cancer comes from the C-cells of the thyroid. The C-cells make a hormone called calcitonin which has a weak effect on bone growth and blood calcium levels. Since calcitonin's effect is so weak, it does not need to be replaced after removal of the thyroid like thyroid hormone. Fortunately, blood calcitonin levels can be used in making the diagnosis and to look for recurrences of medullary thyroid cancer. Unlike most other thyroid cancers, medullary thyroid cancer does not absorb RAI and therefore the best chance of curing a patient is completely removing the cancer at the first operation.
The biggest risk factor for medullary thyroid cancer is a family history of medullary thyroid cancer or MEN syndrome (multiple endocrine neoplasia syndrome). Up to 20% of patients with medullary thyroid cancer will have a genetic (i.e. familial or inherited) problem. In particular, patients should be screened for MEN syndrome which is caused by a problem with the RET proto-oncogene. There are two forms of MEN syndrome that carry a risk for medullary thyroid cancer:
MEN 2A: Includes medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism
MEN 2B: Includes medullary thyroid cancer, pheochromocytoma, and multiple ganglioneuromas
If a patient is suspected of having MEN syndrome, it is critical to rule out the other associated diseases especially pheochromocytoma (a rare adrenaline-producing tumor) that can be life-threatening. Even without a family history, patients with medullary thyroid cancer should be evaluated for a genetic cause since they may be the first in the family to be diagnosed. A New York Thyroid Center genetic counselor will discuss the process, implications, and interpretation of appropriate genetic testing. In addition, the genetic counselor will help to guide and educate family members of patients with medullary thyroid cancer. Although it is critical to test for a genetic cause, most patients with medullary thyroid cancer will have sporadic disease (i.e. disease not caused by a genetic problem).
Signs and Symptoms
Most medullary thyroid cancers do not cause symptoms (i.e. they are asymptomatic). In fact, many patients will not know that they are there. Patients with large nodules may notice a palpable mass (i.e. a mass they can feel) or a visible mass (i.e. a mass they can see). Very large nodules may cause compressive symptoms which include difficulty swallowing, food or pills getting "stuck" when they swallow, and pressure or shortness of breath when lying flat. In cases of advanced cancer that are growing (i.e. invading) into surrounding structures, patients may develop hoarseness or difficulty swallowing. Enlarged neck lymph nodes that are concerning for cancer include those that are non-tender, firm, growing, and/or do not shrink over time. Patients with compressive symptoms, enlarged lymph nodes, hoarseness, and/or a rapidly growing nodule should seek medical evaluation right away.
When a thyroid nodule is discovered, a complete history and physical examination should be performed. In particular, the doctor is looking for risk factors for cancer that include: a family history of thyroid cancer, a history of radiation exposure to the head, neck, and/or chest, age less than 20, age greater than 70, male gender, very hard nodules, enlarged lymph nodes, and/or hoarseness. After the history and physical exam, a TSH level should be checked to see if the patient is euthyroid (i.e. normal thyroid function), hyperthyroid (i.e. hyperactive or overactive thyroid), or hypothyroid (i.e. underactive thyroid). In general, it is unusual for hyperthyroid patients to have cancer while patients who are hypothyroid may have a slightly higher rate of cancer. Most patients with thyroid cancer are euthyroid. If medullary thyroid cancer is suspected, calcitonin and CEA blood levels should be checked. Calcitonin levels will likely be higher than normal in patients with medullary thyroid cancer and can be used as a rough measure of how much disease there is in the body. In general, the higher the calcitonin, the more disease the patient has. High CEA (i.e. carcinoembryonic antigen) levels may be a sign of a more aggressive form of medullary thyroid cancer.
The next step in the work-up of a thyroid cancer is an ultrasound (USG) of the neck. There is no radiation associated with an USG. An USG is the best test to look at the thyroid and will allow the doctor to see the size of the thyroid and specific features of the nodule(s) including: size, number of nodules, if there are calcifications (calcium deposits), echotexture (i.e. how bright or dark it looks on USG), borders, shape, and if it is solid or cystic (i.e. fluid-filled). In general, USG findings that are concerning for thyroid cancer include microcalcifications (i.e. microcalcifications), hypoechoic nodules, hypervascularity (i.e. more blood vessels than normal), irregular borders, and enlarged suspicious lymph nodes.
The best test to determine if a thyroid nodule is benign or cancer is a fine-needle aspiration biopsy (FNAB). In this test, a small needle (like the needles used for drawing blood) is placed into the nodule either by USG or feeling the nodule with the fingers. Cells are removed from the nodule into the needle (i.e. aspirated) and looked at under the microscope by a specially trained doctor called a cytologist.
There are a number of different guidelines as to which nodules should be biopsied, but in general, nodules over 1 cm should be biopsied. If a patient has risk factors for thyroid cancer (especially a family history of thyroid cancer or exposure to radiation therapy) or suspicious findings on USG, then nodules over 0.5 cm should be biopsied. The FNAB may give one of 4 results:
This means that not enough cells were removed to make a diagnosis. Even in the best of hands, this happens in 5 to 10% of FNAB. Typically the FNAB will be repeated. If the nodule grows, then a repeat biopsy will usually be performed. In certain cases, a patient may go straight to an operation to make a diagnosis, especially if the risk of cancer is high or if the patient has had two or more non-diagnostic FNAB in the past.
This means that there is a 97% chance that the nodule is not cancer. In most cases, patients with a benign biopsy are watched with an USG and physical exam 6 months later, and then at regularly scheduled times. A patient with a benign nodule may still have an operation if the nodule is large, causing symptoms, or cosmetically unappealing.
This means that there is a 97% chance that the nodule is cancer, usually a papillary thyroid cancer. Much less commonly, the FNAB can show a medullary or anaplastic thyroid cancer. Most patients with a FNAB of cancer will have a total thyroidectomy (i.e. removal of the entire thyroid) with or without removal of certain lymph nodes.
This category includes different readings like: follicular lesion, follicular neoplasm, Hurthle cell lesion, Hurthle cell neoplasm, and atypical cells or atypical lesions. This means that the cytologist cannot tell if the nodule is cancer, but the cells do not look normal. There is a 15 to 20% chance of having thyroid cancer with an indeterminate biopsy. Said another way, 1 out of 5 people with an indeterminate biopsy will have cancer.
See Follicular and Hurthle Cell Cancer »
The only way to make a clear diagnosis of cancer or no cancer is to remove half or all of the thyroid and see if the cells in the nodule are invading (i.e. growing) outside of the nodule into the surrounding thyroid or outside of the thyroid.
See Thyroid Surgery »
Ultrasound guided fine needle biopsy demonstrating the needle (white line) sampling the nodule
Patients who are suspected of having medullary thyroid cancer should also have a RET proto-oncogene mutation analysis to determine if there is a genetic cause.
Of note, radioactive iodine (RAI) scans used to be performed routinely for patients with thyroid nodules because "hot" (i.e. hyperactive nodules) were rarely cancer (less than 1%) while "cold" (i.e. underactive nodules) carried a 10% risk of cancer. However, FNAB is far more accurate for determining the risk of cancer and RAI scans are mostly only used in cases of hyperthyroidism.
Since medullary thyroid cancer grows from C-cells and not thyroid cells, RAI ablation and TSH suppression are not effective treatments. The best treatment for medullary thyroid cancer is complete surgical removal during the first operation. However, completely removing the cancer at the first operation may not be possible as many patients will already have lymph node disease (i.e. metastases) at the time of diagnosis. A small percentage of patients will have distant metastases (i.e. spread to the lungs, brain, bone, and/or liver). At the very least, most patients with medullary thyroid cancer should have a total thyroidectomy with central neck dissection (i.e. removal of the whole thyroid and removal of they lymph nodes in the center of the neck surrounding the windpipe and thyroid). Prior to the operation, a lymph node mapping (i.e. an USG exam of the central and lateral compartments of the neck) should be done to see if there are suspicious lymph nodes that may need to be removed along with the thyroid. If the lateral neck lymph nodes (i.e. the lymph nodes surrounding the carotid artery and jugular vein) are involved with medullary thyroid cancer, then an operation called a modified radical neck dissection will be performed as well. This operation involves removing the lymph nodes along one side of the neck. After the operation, this area of the neck is usually numb for a period of time because the nerves to the skin in this area are purposely severed in order to remove the diseased lymph nodes. Other than this numbness, there are no long-term effects of having these lymph nodes removed. Sometimes both the left and right lateral neck lymph nodes are involved with cancer. If this is the case, then modified radical neck dissections on one side and then the other may be performed about 2 months apart. This delay is to allow time for healing on one side before operating on the opposite side. Performing the lymph node dissection on both sides at the same time could lead to unnecessary swelling (edema) of the head and face if time is not given between operations for alternate pathways of blood and lymph flow to form.
Patients with advanced medullary thyroid cancer may need chemotherapy or traditional external beam radiation therapy. External beam radiation is typically used in cases of where the cancer has invaded into surrounding structures like the esophagus or windpipe (i.e. trachea). Patients who have metastatic disease may need to join a clinical trial of chemotherapy to further treat their disease. Finally, many people want to take an active role in their recovery from thyroid cancer. The Thyroid Center advises a healthy lifestyle and diet, including regular exercise, decreased alcohol consumption, avoiding cigarette smoking, and eating a diet which is low in fat and high in fiber. These changes are recommended to reduce many types of cancers, not just thyroid.
After surgery for medullary thyroid cancer, it is important to be examined regularly for signs that the cancer may have recurred. Calcitonin and CEA levels should be checked soon after surgery to establish a baseline level. If the calcitonin and/or CEA levels go up over time, then it is likely that the cancer has returned or is growing. In general, patients should have calcitonin and CEA blood tests and USG of the neck every 6 months to a year.
Recurrence of Thyroid Cancer
If a cancer recurrence is detected, surgery to remove the disease is usually the best option. However, if the patient has metastatic disease in other organs, surgery may not be an option and the patient may need chemotherapy. Patients who have very high calcitonin and/or CEA levels after removal of the thyroid may have metastatic disease in the liver or bones that is too small to see with imaging tests. In order to determine the best treatment for recurrent medullary thyroid cancer, it is critical to work with an experienced team of thyroid specialists.