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Thyroid Cancer: Medullary Cancer

A rare form of thyroid cancer

If a nodule is found on your thyroid, your doctor will want to evaluate the node to rule out cancer. The nodule may be benign, but if it is determined to be cancerous, there are four types of thyroid cancer: papillary, follicular, Hurthle cell or medullary.

This article will discuss common medullary thyroid cancer symptoms and treatments as well as medullary thyroid cancer diagnosis and prognosis. Medullary thyroid cancer is rare. They make up about 3% of all thyroid cancer cases.

Unlike other forms of thyroid cancer, medullary thyroid nodules may be sporadic or inherited, requiring special care.

Medullary Thyroid Cancer: Distinguishing Characteristics 

Unlike papillary and follicular thyroid cancers, which arise from thyroid hormone-producing cells, medullary thyroid cancer originates in the parafollicular cells (also called C cells) of the thyroid. These cancer cells make a different hormone called calcitonin, which has nothing to do with the control of metabolism like thyroid hormone does.  

Key factors about this type of cancer:

  • More common in females than males (except for inherited types)
  • Regional metastasis (spread to neck lymph nodes) occurs early in the disease
  • Spread to distant organs occurs later and may include the liver, bone, brain, and adrenal medulla
  • Not associated with radiation exposure
  • Usually originates in the upper central lobe of the thyroid

Medullary thyroid cancer has a much lower cure rate than the more well-differentiated type of thyroid cancers (ie, papillary and follicular), but the cure rate is higher than for anaplastic thyroid cancer. Overall, 10-year survival rates are 90% when all the disease is confined to the thyroid gland, is 70% when the cancer has spread to cervical lymph nodes, and 20% when the cancer is found in distant sites.

If the results of your biopsy indicate that medullary thyroid tumor is likely,  it is highly recommended that you seek out a thyroid cancer surgeon who has had experience with this specific type of cancer.  Here is why:

  • Medullary thyroid cancer is a rare form of cancer.
  • Most thyroid surgeons rarely ever see or treat someone with this type of thyroid cancer.
  • Management of medullary thyroid cancer requires an interdisciplinary thyroid cancer care team.
  • It's important to understand how medullary cancer differs from other types of thyroid cancer,  including the importance of the role of genetic testing and screening.
  • Occurs in one of four clinical circumstances and can be associated with other endocrine tumors

 Four Clinical Situations for the Onset of This Rare Form

  • Sporadic: Accounts for 80% of all cases of medullary thyroid cancer. They are typically unilateral and there are not associated endocrinopathies (not associated with disease in other endocrine glands). Peak onset is between 40 and 60 years old. Females out-number males by a 3:2 ratio. One third will present with intractable diarrhea. Diarrhea is caused by increased gastrointestinal secretion and hypermotility due to the hormones secreted by the tumor (calcitonin, prostaglandins, serotonin, or VIP).
  • MEN II-A (Sipple Syndrome): Multiple endocrine neoplasia syndromes (abbreviated as "MEN") are a group of endocrine disorders that occur together in the same patient and typically are seen in families because they are inherited. "Syndromes" are medical conditions that occur in groups of three. Sipple syndrome has 1) bilateral medullary carcinoma or C cell hyperplasia, 2) pheochromocytoma, and 3) hyperparathyroidism.

    This cancer form is inherited and has been linked to a defect of a gene that helps control the normal growth of endocrine tissues. This inherited syndrome is a dominant inheritable disease that, at least theoretically, is expected to arise in 50% of all offspring of a person with this genetic mutation. Because of this, males and females are equally affected. The peak incidence of medullary cancer in these patients typically occurs in the third decade of life. 
     
  • MEN II-B. With this syndrome patients may also have 1) medullary cancer, and 2) pheochromocytoma, and even more rarely hyperparathyroidism. Instead these patients are more likely to have an unusual appearance that is characterized by mucosal ganglioneuromas (tumors in the mouth) and symptoms resembling Marfan syndrome, Marfanoid habitus, which includes: very long slender body, including unusually long and hyperflexible limbs, a crowded arrangement of teeth and possibly a high arch of the palate. 
    Inheritance is autosomal dominant as in MEN II-A, but it can occur rarely without being inherited. MEN II-B patients usually get medullary carcinoma in their 30s, and males and females are equally effected. As with MEN II-A, pheochromocytomas must be detected prior to any procedure. The idea here is to remove the pheochromocytoma first to eliminate the risk of severe hypertension during surgery.
  • Inherited medullary cancer. This form of medullary carcinoma is the least aggressive. As with other types of thyroid cancer, it usually arises between the ages of 40 and 50 years old.

Medullary Thyroid Cancer: Distinctive Symptoms 

Early in the course of medullary thyroid cancer, there are usually no symptoms. It almost never causes hyperthyroidism (increased thyroid function) or hypothyroidism (decreased thyroid function). It doesn't make people feel tired or any different.

As such, the early detection of sporadic (non-hereditary) medullary thyroid cancer typically is found by the patient or someone else noticing an unusual lump in the neck or throat, or by a doctor feeling a lump or nodule when examining a patient's thyroid gland. Because sporadic early medullary thyroid cancer doesn’t present with any symptoms, it is difficult to assess how long the cancer has been growing.

Although rare among thyroid cancers, medullary thyroid tumors may be tender to the touch and can even be painful either where they originated in the thyroid or where they spread to in the lymph nodes of the neck. But, almost all cancers that spread to the neck lymph nodes do not produce any noticeable discomfort.  

Medullary thyroid cancer produces many proteins and sheds other substances that may lead to another common symptom of advanced medullary thyroid cancer—diarrhea. Diarrhea might arise from an interaction of several factors including increased calcitonin, prostaglandins, and the presence of several other substances. This diarrhea can be managed either by surgical removal of the tumor (and any involved lymph nodes) and/or appropriate medications.

Medullary Thyroid Cancer: How Is It Diagnosed?

Medullary thyroid cancer starts as a growth of abnormal cancer cells within the thyroid. These special cells are the parafollicular C cells. In the hereditary form of medullary thyroid cancer, the growth of these cells is due to a mutation in the RET gene which was inherited. This mutated gene may first produce a premalignant condition called C cell hyperplasia. The parafollicular C cells of the thyroid begin to have unregulated growth. In the inherited forms of medullary thyroid cancer, the growing C cells may form a bump or nodule in any portion of the thyroid gland. With this type of cancer, patients may not be diagnosed until the cancer has spread to the lymph nodes of the neck and presented with a “lump in the neck.

For patients with a sporadic (non-hereditary) form of medullary thyroid cancer, they may form a bump or "nodule" within the thyroid that often sticks out of the side or front of the thyroid gland. For this reason, most medullary thyroid cancers, like all thyroid cancers, are diagnosed after a doctor feels the neck of a patient or an ultrasound or other x-ray notices a lump within a thyroid gland. In examining a thyroid gland, most doctors stand behind the patient to feel the thyroid for nodules or bumps.

Sometimes, these growths and nodules can be seen when looking at the neck of thin women as a small bump under the skin that moves when the person swallows. Sometimes people are undergoing scans or x-rays of the neck for some other reason and a nodule or worrisome area of the thyroid is seen. Either way, your physician feeling this mass or seeing it as a surprise on some other scan will typically order a thyroid ultrasound to look at the thyroid closely and take pictures of the mass or nodule.

Ultrasound for medullary thyroid cancer is far more sensitive than any of the most experienced of hands. It is critically important in determining the extent of the medullary thyroid cancer. Since medullary thyroid cancer spreads so commonly to the lymph nodes of the central neck and sides of the neck, very close examination of these areas is required in every neck ultrasound for medullary thyroid cancer. If there are any suspicious lymph nodes in the side(s) of the neck, needle biopsy should be performed.

This will assist the thyroid cancer surgeon in knowing the exact extent of surgery required to address all the medullary thyroid cancer patient’s neck disease in a single operation!!! Failure to have a high quality (resolution) ultrasound and expert thyroid cancer surgeon will greatly increase the medullary thyroid cancer patient’s risk for persistent or recurrent disease.

For all medullary thyroid cancer patients, because the cancer may so commonly spread to lymph nodes along the sides of the neck, the patient is frequently diagnosed with a lump in the neck that is actually spread of the cancer to the neck lymph nodes. Fine needle aspiration biopsy of a neck lymph node can adequately provide a diagnosis such that biopsy of the thyroid abnormality may not be required when the neck lymph node biopsy has already provided that information.

Medullary Thyroid Cancer: Treatment and Management  

Medullary Thyroid Cancer Treatment

In contrast to papillary and follicular type thyroid cancers, there is little discussion as to the best way to treat medullary thyroid cancer: the answer is surgery. After you have been assessed and treated for any associated endocrine conditions, such as pheochromocytomas, (if present) all patients undergo a total thyroidectomy in which all lymph nodes and fatty tissues in the central area of the neck are removed. Just the presence of enlarged lymph nodes does not mean medullary thyroid cancer has spread. The lymph nodes on the side of the neck will only be removed if there is confirmed presence of cancer or in the case of a very large tumor.

Medullary Thyroid Cancer Surgery. However, the precise procedure will depend upon staging of the cancer (its size and spread), the patients overall health, and surgeon's expertise. Since the goal of surgery is to achieve a comprehensive removal of the entire thyroid gland and all of the affected and high at risk lymph nodes of the neck, this requires an expert thyroid cancer surgeon who is capable of accomplishing the procedure by addressing all of the neck disease while maintaining the patient's appearance, function, and quality of life. In this way, all critical structures, including the nerves to the voice box and all parathyroid glands which are not directly involved by cancer are preserved.

How to find the right surgeon and ask the right questions.  See this video about questions to ask your surgeon! 

In a total thyroidectomy, a small incision is made at the lower neck. Even patients with a known RET mutation but without ultrasound evidence of medullary thyroid cancer or elevated calcitonin levels may opt for this procedure; this is considered a prophylactic thyroidectomy, which offers the individual a lifetime cure of medullary thyroid cancer.  

When the medullary thyroid tumor is small, surgery is not only the first treatment but is commonly the only treatment needed.

If medullary thyroid cancer should recur or persist due to an incomplete surgery, a secondary surgery of the central compartment may be required.

•           Here is a video of what a complete thyroid surgery and central compartment surgery for medullary thyroid cancer should look like.  This is a real operation and there is no blood loss, but viewing this is very very vivid surgery and real images.  So if you are faint of heart, this is not for you.  video of total thyroidectomy and central compartment neck dissection

Extended or Complicated Thyroidectomy

Medullar thyroid cancer may sometimes be more aggressive than ultrasound or CT imaging suggested prior to undergoing surgery. In these cases, the surgeon will recognize these unanticipated aggressive intraoperative findings such as growth or extension of the cancer outside of the thyroid gland or invasion of the cancer into adjacent structures such as the nerve to the voice box (recurrent laryngeal nerve), breathing tube (trachea), voice box, or esophagus-must adapt the surgery to adequately address the complete removal of the cancer. A highly skilled thyroid surgeon will be prepared to make the necessary adjustments to perform a complete surgical resection of all cancerous tissue.

Radioactive iodine in medullary thyroid cancer. Although thyroid cells have the cellular mechanism to absorb iodine, medullary thyroid cancer does not arise from this type of thyroid cell.Therefore, radioactive iodine therapy has no role for the treatment of medullary thyroid cancer. Similarly, if medullary cancer spreads to distant sites, it cannot be found by iodine scanning the way cancer metastasis of papillary or follicular thyroid cancer can.

For those individuals which are interested in seeing what these operations look like, you can go to the following link and see what a thyroidectomy with central neck dissection and anterolateral neck dissection look like.  There is no bleeding or blood loss during these operations.   Blood loss averages on a teaspoon level.  These are real videos of real operations, therefore if you feel uncomfortable with seeing such an operation, then do not go to this link. 

What Kind of Long-term Follow Up Is Necessary?

In addition to the usual cancer follow up, patients should receive a yearly chest x-ray as well as calcitonin and CEA levels. Serum calcitonin is very useful in the follow up of medullary thyroid cancer because no other cells of the body make this hormone. A high serum calcitonin level that had previously been low following total thyroidectomy is indicative of recurrence.  There is no direct relationship between serum calcitonin levels and extent of medullary thyroid cancer.  However, trending serum calcitonin and CEA levels can be a useful tool in determining the pace of change of a patient’s medullary thyroid cancer. 

Under the best circumstances, medullary thyroid cancer surgery will remove all of the thyroid and all lymph nodes in the neck that harbor metastatic spread. In this case, post-operative calcitonin levels will go to zero. This is often not the case, and calcitonin levels frequently remain elevated, but less than pre-operatively. These levels should still be checked every six months, and when they begin to rise, a more diligent examination is in order to find the source.For a general overview of the different types of thyroid cancer, read our Introduction to Thyroid Cancer article, and you can also visit our Patient Guide to Thyroid Cancer to learn about thyroid cancer diagnosis and treatments. 

We want to acknowledge and thank James Norman, MD, who wrote the original content on this topic for EndocrineWeb.

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