Medullary Thyroid Cancer

Overview

Medullary thyroid cancer arises from the C-cells within the thyroid and distinctly different and much less common than the differentiated forms of thyroid cancer (papillary and follicular).  The c-cells are neuroendocrine derived and secrete calcitonin.  This form of thyroid cancer can arise sporadically (80% of cases), but 20% of patients harbor a genetic mutation of the RET proto-oncogene (familial).  Patients with familial disease typically present at a younger age, often have multifocal disease and may have an associated syndrome (MEN 2).

In addition to medullary thyroid cancer, the MEN 2 A syndrome is also associated with hyperparathyroidism and pheochromocytoma.  MEN 2B syndrome is also associated with pheochromocytoma and neurofibromatosis.  Patients with medullary thyroid cancer should be screened for pheochomocytoma prior to surgery and should have a genetic evaluation.

Signs and Symptoms

While some patients may present with a large tumor causing difficulty swallowing or breathing, most patients have an asymptomatic nodule that is discovered on physical exam or on an imaging study done for some other purpose.  These tumors do not overexpress thyroid hormone, so the thyroid function blood tests are typically normal.  Medullary thyroid cancer often involves the regional lymph nodes, and some patients will present with a palpable enlarged lymph node in the neck.

Diagnosis

The diagnosis of medullary thyroid cancer is determined using the algorithm outline above for the work up of a thyroid nodule.  On physical exam, these tumors tend to be hard and sometimes fixed or immobile.  There may be palpable lymph nodes within the side of the neck along the jugular vein.  Ultrasound will allow your physician to accurately measure and locate the tumor.  There are also several characteristics on ultrasound that, when present, are worrisome for malignancy.  These include calcifications, irregular borders, and hypervascularity (increased number of blood vessels).  The ultrasound is also used to map the lymph node basins that drain the thyroid to identify possible spread of the disease which will also need to be addressed at the time of surgery.

Once a nodule greater than 1 cm or with worrisome ultrasound characteristics is identified, the next step is a fine needle aspiration biopsy.  This procedure can be performed by an endocrinologist, and endocrine surgeon or a radiologist.  Under ultrasound guidance, a 21 to 25 gauge needle is advanced into the nodule which is aspirated to obtain cellular material.  The obtained material is place on glass slides and then put into fixative for review by the cytopathologist.  The needle used for the biopsy is a little smaller than the one typically used to draw blood.  Sometimes the nodule needs to be aspirated more than once to obtain adequate material.

The cytopathologist will review the slides and score the biopsy using the Bethesda classification system.  The diagnosis of medullary thyroid cancer can be challenging.  Needle biopsy will reveal spindle cells that stain positive for calcitonin in the absence of follicular cells yielding a Bethesda classification of V or VI.

Patients will typically have elevated levels of calcitonin and CEA in the blood.  These blood tests can help confirm the diagnosis, give some estimate about the extent of disease, and be useful as a marker for response to therapy.

Patients should be assessed for the presence of a pheochromocytoma (adrenaline producing tumor of the adrenal glands that is part of the MEN syndrome) and these patients should be sent for genetic counseling to determine if there is a genetic component to their disease.  A mutation of the RET protoconcogene will be found in up to a fifth of patients.

Treatment

Medullary thyroid cancer is primarily a surgical disease. These malignancies do not absorb radioactive iodine and most chemotherapy drugs remain in clinical trials. Treatment begins with a total thyroidectomy and removal of the lymph nodes around the trachea. If the cancer has spread to the lymph nodes in the side of the neck (lateral compartment), then these nodes will need to be removed at the time of surgery also.  The operation is called a modified radical lymph node dissection and is designed to remove the lymph nodes around the jugular vein. Often, the jugular vein itself needs to be removed as well, which does not result in any clinical deficit. Multiple vital structures are identified and preserved when performing this operation including the spinal accessory nerve (which allows you to shrug), the vagus nerve (partly responsible for the swallowing mechanism and for voice), the phrenic nerve (enabling the diaphragm to move up and down to breath), the hypoglossal nerve (providing motor function to the tongue), the carotid artery (supplying blood to the brain), and the thoracic duct (on the left side only). Several small nerves to the skin are severed during this operation, which is unavoidable and results in most patients having some numbness along their jaw following the operation.

In some patients, the disease in the neck cannot be controlled surgically.  These patients may benefit from external beam radiation.  Patients with metastatic disease to distant organs will need systemic chemotherapy, often in the context of a clinical trial.

Follow-up

Patients with medullary thyroid cancer do require routine follow up every 6 months to a year.  During this visit a physical examination is performed and blood work is sent for a calcitonin and CEA level.  An ultrasound of the lymph nodes in the neck is also performed.  The most common site of tumor recurrence in in the lymph nodes in the neck and the recurrence is often heralded by a rise in the calcitonin level.  In this setting, patients are typically referred for a biopsy of the suspicious node and may benefit from further surgery to remove the involved lymph nodes.

Recurrence of Medullary Thyroid Cancer

Medullary thyroid cancer is primarily a surgical disease.  Recurrence is not uncommon in the lymph nodes in the neck, and patients not infrequently require further surgery.  Patients with high calcitonin level, but no evidence of disease in the neck often have metastases to the bone or the liver and these patients may benefit from systemic chemotherapy.