Alternative names for familial medullary thyroid cancer

FMTC

What is familial medullary thyroid cancer?

Medullary thyroid cancer is a rare form of thyroid cancer. The term medullary describes the type of cells in the thyroid gland affected by the cancer. The majority of patients with medullary thyroid cancer (approximately 80%) have no family history of the condition; the remaining 20% of patients inherit the condition from a parent (thus the disease is ‘familial’). Familial medullary thyroid cancer is inherited in a dominant way, which means a patient with the gene mutation for medullary thyroid cancer will have a 50% chance of passing it on to their offspring. 

The inherited form of medullary thyroid cancer is associated with three conditions: familial medullary thyroid cancer, multiple endocrine neoplasia type 2A (MEN2A) and multiple endocrine neoplasia type 2B (MEN2B). Both multiple endocrine neoplasia (MEN) syndromes are characterised by the presence of other diseases in addition to medullary thyroid cancer.

What causes familial medullary thyroid cancer?

Familial medullary thyroid cancer is caused by a mutation in a gene called “Rearranged during Transfection” (RET) proto-oncogene.

The RET gene mutation leads to increased growth (hyperplasia) of specialised cells in the thyroid gland named “C-cells”. These C-cells produce a hormone called calcitonin, which is released into the bloodstream where it lowers blood calcium levels. Increased growth of C-cells is present in 20–30% of the general population and does not necessarily lead to medullary thyroid cancer, unless it appears in people with the RET gene mutation.

Over time, C-cell hyperplasia undergoes more growth and develops into medullary thyroid cancer. In the absence of other conditions or features associated with MEN syndromes, this condition is now called familial medullary thyroid cancer. All familial medullary thyroid cancer patients with the RET gene mutation tend to develop medullary thyroid cancer by the age of 40 years.

What are the signs and symptoms of familial medullary thyroid cancer?

Medullary thyroid cancer may present as either a single swelling or nodule felt in the neck, or as symptoms of the cancer spreading to other areas of the body (e.g. lymph nodes, lungs or bone), or as symptoms and signs secondary to the release of calcitonin protein.

The commonest symptoms are associated with discomfort due to the presence of the nodule in the neck. Depending on its size and location within the thyroid, the lump can be visible and palpable; more rarely and especially if invading the surrounding tissues and organs, it can be also associated with difficulties in swallowing, breathing or hoarse voice.

Other associated symptoms can include the skin appearing flushed and diarrhoea, which are caused by excessive production of the hormone calcitonin as well as other hormones.

How common is familial medullary thyroid cancer?

Familial medullary thyroid cancer is a rare form of thyroid cancer accounting for less than 1% of all thyroid cancers. Incidence is equal in men and women and, like most thyroid cancers, it presents between 40 and 50 years of age.

How is familial medullary thyroid cancer diagnosed?

The diagnosis is based on history of a thyroid nodule or lump and also specifically on whether the patient has a family history of any similar lumps or diagnoses of thyroid cancers in family members. This would provide strong evidence of a genetic link, which is important in diagnosing familial medullary thyroid cancer and deciding on future treatment.

It may also be necessary to obtain a tissue sample to analyse what is happening to the C-cells within the nodule. To do this, a test called fine needle aspiration cytology of the thyroid nodule is required. This involves using a small thin needle to obtain a specimen of the tissue in the lump or nodule; this can be uncomfortable, but there is usually little to no pain. The specimen is then analysed under a microscope to look for certain features associated with medullary thyroid cancer, such as the hormone calcitonin, that can be present as a single protein or aggregated in a complex structure called amyloid. In case the tumour has spread to one or more lymph nodes, they can be sampled as well to make a clear diagnosis.

A blood test is carried out to measure levels of calcitonin, which are raised in medullary thyroid cancer.

The definitive diagnosis of familial medullary thyroid cancer is made through genetic analysis of the RET gene mutation. The presence of this gene mutation suggests a strong chance of the patient developing medullary thyroid cancer.

Further blood and urine tests and sometimes imaging tests need to be performed to rule out signs of MEN type 2 syndromes, which can also cause medullary thyroid cancer.

If medullary thyroid cancer is diagnosed, computerised tomography (CT) or magnetic resonance imaging (MRI) scans of the neck and body may be carried out. These scans will help identify how much the cancer has spread within the neck and to any areas outside the thyroid gland.

All of these tests can be performed as outpatient investigations.

How is familial medullary thyroid cancer treated?

The main treatment option is surgery, specifically a procedure called total thyroidectomy and central node dissection. This involves the complete removal of the thyroid gland and associated lymph nodes in the central compartment of the neck. The surgery can be performed either in patients with a confirmed diagnosis of medullary thyroid cancer or in patients with a strong family history of the condition who test positive for the RET gene mutation. In patients with confirmed familial medullary thyroid cancer, this surgery is carried out in advance, usually between 5 and 10 years of age, to prevent medullary thyroid cancer from developing in the future. If a patient who tests positive for the RET gene refuses preventative surgery, they will need regular blood tests to monitor calcitonin levels and scans of the neck to check for nodule growths.

Radiotherapy may be used to relieve symptoms in cases where surgery is not possible or where the cancer has spread. Chemotherapy is not usually used to treat medullary thyroid cancer, but can occasionally be used if the disease has spread to other organs of the body. In a small number of cases there are no curative treatment options and patients are treated in a palliative manner, that is, to relieve symptoms.

Are there any side-effects to the treatment?

Side-effects depend mainly on the extent of the cancer spread. The main side-effects result from removal of the thyroid gland with patients requiring life-long thyroid hormone (thyroxine) replacement therapy.

The parathyroid glands, which are separate organs from the thyroid gland, are located behind and attached to the thyroid and can be completely removed by the surgery causing hypoparathyroidism. Treatment for hypoparathyroidism will require vitamin D and calcium supplements. However, in some cases, one of the parathyroid glands can be preserved in the body, preventing the occurrence of hypoparathyroidism.

There are general risks of surgery and anaesthesia, which should be reviewed by the surgeon or anaesthetist. Further rarer side-effects can include damage to a nerve found near the thyroid gland in the neck, which can affect or alter a patient’s voice (causing a hoarse voice). If a patient has any questions about these possible side-effects, they should discuss them with their doctor or surgeon.

In a small number of patients the surgery may not remove the entire tumour and there may be some remnant, which would require further treatment.

What are the longer-term implications of familial medullary thyroid cancer?

If the thyroid gland is removed, the patient will need to take thyroid hormone supplement tablets for life to replace the thyroid hormone (thyroxine) no longer being produced. All thyroid hormone levels will need to be monitored with regular blood tests.

If diagnosed with familial medullary thyroid cancer, it is important to be aware that there is a chance that siblings may also carry the gene mutation and there is a 50% chance of passing the gene onto children. It is therefore important to ask your doctor for more advice about the genetic testing of any existing or future children.

Are there patient support groups for people with familial medullary thyroid cancer?

Butterfly Thyroid Cancer Trust may be able to provide advice and support to patients and their families dealing with familial medullary thyroid cancer.