Medullary Thyroid Carcinoma

Biopsy (FNA) is a reliable way to make a diagnosis.

• If inconclusive, repeat FNA with needle washout measuring Calcitonin levels can be performed to confirm diagnosis.
  • Calcitonin is made only by MTC cells (no other cells in the body) and therefore a very specific and accurate way of detecting if MTC is present.

Once a diagnosis of MTC has been made, Calcitonin and CEA levels should be measured in the blood.

• Calcitonin and CEA are both tumor markers for MTC.
  • Help with the initial work-up and surgical planning for the cancer.
  • Also helpful during surveillance to detect for recurrence or progression of known residual cancer.

Ultrasound and CT of the Neck with Contrast should be performed.

• Evaluate for local invasion of the cancer into nearby structures and to evaluate for possible regional metastases (spread to lymph nodes in the central and lateral neck compartments).

If calcitonin levels are > 500 at the time of diagnosis, imaging of the chest, liver, and bones should be obtained due to increased risk for distant metastases.

• PET scans are not sensitive in detecting MTC.

All newly diagnosed MTC patients should have RET gene germline mutation analysis to rule out hereditary cause.

All hereditary MTC patients should be screened for:

• Pheochromocytomas
  • Catecholamines and metanephrines levels measured in the blood or a 24-hour urine collection.
    • If discovered during work-up, pheochromocytomas should be removed prior to thyroid surgery given the substantial increased risk during general anesthesia they pose (life threatening uncontrolled hear rate and blood pressure).
• Primary Hyperparathyroidism
  • Affects 20-40% of MEN2A patients.
    • Presents between ages 30-40.
  • Calcium and parathyroid hormone (PTH) levels measured in the blood (both will be elevated).
    • If diagnosis is confirmed, a concurrent 4-gland parathyroid exploration should be performed during thyroidectomy.
      • Typically presents with multiple parathyroid adenomas.
      • Treated with focused excision of adenomas only, 3.5 gland excision if all 4 glands are affected.

Examination of the vocal cords with flexible fiberoptic camera to ensure no compromised function prior to surgery.

• If there is suspicion that the cancer is affecting the recurrent laryngeal nerve (controls movement of the vocal cords and voice) based on symptoms, imaging, and/or fiberoptic camera exam, there is an increased likelihood that the nerve will need to be sacrificed (cut in order to remove all the cancer) during the surgery.

Primary treatment for MTC is surgery.

• American Thyroid Association (ATA) guidelines recommend total thyroidectomy and bilateral central neck dissection for all MTC patients.
  • Even if no obviously concerning lymph nodes in the central neck compartment are seen on imaging prior to surgery.
• Lateral neck dissection should be performed whenever spread to a lateral neck lymph node has been confirmed on FNA (biopsy) prior to surgery or on excisional biopsy during surgery.
  • Consider prophylactic lateral neck dissection (even if no biopsy proven lymph node is present) if calcitonin levels are > 50 prior to surgery.
  • Consider prophylactic contralateral (opposite to the side of cancer) lateral neck dissection if cancer is present in the ipsilateral (same side as the thyroid cancer) lateral neck compartment and calcitonin levels are > 200 prior to surgery.
    • Much higher risk for subclinical (not obviously visible on imaging) spread to lymph nodes in both the above scenarios when Calcitonin levels are above these respective levels.
• Consider prophylactic total thyroidectomy in first year of life for MEN2B and < 5 years for MEN2A.

For all types of thyroid cancer, surgical outcomes / cure rates are the highest and complication rates are the lowest when surgery is performed by a high-volume surgeon (> 50 thyroid cancer surgeries per year).

To read more about Thyroid and Neck Dissection surgeries including what to expect, as well as details regarding recovery and risks:

• Hemithyroidectomy.
• Total Thyroidectomy.
• Central Neck Dissection.
• Lateral Neck Dissection.

Parafollicular C Cells do not absorb iodine; therefore, Radioactive Iodine (RAI) is not considered in the treatment of MTC.

External beam radiation (EBRT) can be considered for patients with:

• Known persistent / residual disease in the neck that cannot be removed with surgery.
  • Usually incompletely resected due to extent of invasion into local structures.
    • Residual cancer poses a risk to the airway (breathing) if it continues to grow and invades the trachea (windpipe).
• High risk for recurrence:
  • Extrathyroidal extension – cancer invasion through the thyroid into the muscles overlying the thyroid (e.g., strap muscles), trachea, outer layers of the esophagus, etc.).
  • Extensive metastases (spread) to lymph nodes.

TSH suppression achieved by using higher doses of thyroid hormone medication (e.g., levothyroxine, Synthroid) is not indicated in the treatment of MTC, unlike in the treatment of Well Differentiated Thyroid Cancers (WDTC’s).

• Goal is to achieve euthyroid state – hormone levels within normal ranges.

AJCC T, N, M Staging – similar to Well-Differentiated Thyroid Cancers.

• T Stage – size of primary cancer and has it grown into nearby structures.
  • T1: 2.0 cm.
  • T2: > 2.0 cm but ≤ 4.0 cm.
  • T3: > 4.0 cm but confined to the thyroid, or any size tumor and gross invasion into the strap muscles (muscles overlying the thyroid gland).
  • T4: Any size tumor invading structures of the neck including (trachea, larynx, esophagus, or recurrent laryngeal nerve).
• N Stage – extent of lymph node involvement in the neck by compartment.
  • N0: no lymph node involvement.
  • N1a: involvement of lymph node(s) in the central neck compartment.
  • N1b: involvement of lymph node(s) in the lateral neck compartment.
• M Stage – Presence of distant metastases (spread beyond the neck).
  • M0: No distant metastases.
  • M1: + distant metastases.

Overall Staging I – IV (independent of age).

• Stage I
  • T1 (largest tumor ≤ 2.0 cm) or T2 (> 2.0 cm but ≤ 4.0 cm).
  • No spread to lymph nodes in the neck (N0).
  • No spread beyond the neck (M0).
• Stage II
  • T1 (largest tumor ≤ 2.0 cm) or T2 (> 2.0 cm but ≤ 4.0 cm).
  • + spread to lymph nodes in the neck (N1).
  • No spread beyond the neck (M0).
    Or
  • T3a (≥ 4.0 cm) or T3b (any size but has grossly invaded the strap muscles overlying the thyroid).
  • No spread to lymph nodes in the neck (N0).
  • No spread beyond the neck (M0).
• Stage III
  • T4a (any size but the cancer has extensively invaded the structures nearby (larynx, trachea, esophagus, or recurrent laryngeal nerve).
  • Any N.
  • No spread beyond the neck (M0).
• Stage IVa
  • T4b (any size but the cancer has grown extensively to invade the spine or the large blood vessels in the neck – carotid artery).
  • Any N.
  • No spread beyond the neck (M0).
• Stage IVb
  • Any T.
  • Any N.
  • M1 (cancer has spread to a distant part of the body beyond the neck).

Prognosis

• Based on staging of the cancer, prognosis can be predicted with 10 year expected survival rates.
• How many patients will not die from their thyroid cancer 10 years following treatment?
  • Stage I
    • Near 100%.
  • Stage II
    • 93%.
  • Stage III
    • 71%.
  • Stage IV
    • 21%.

Combination of physical exams, ultrasound of the neck (including the central and lateral neck compartments), and tumor marker levels measured in the blood (Calcitonin and CEA).

• Initially performed at 3 months after surgery.
  • If Calcitonin levels are undetectable and no concerns for persistent cancer on ultrasound then repeat physical exam, ultrasound, and Calcitonin / CEA levels in 6 months.
    • If again Calcitonin is undetectable and no concerns for persistent cancer on ultrasound then repeat physical exam, ultrasound, and Calcitonin / CEA levels every 12 months for a total of 5 years of surveillance following surgery.
  • If Calcitonin levels are detectable but < 150 pg/ml and no obvious disease appreciated on ultrasound, Calcitonin / CEA levels should be checked every 3 – 6 months (calculate doubling time), physical exams / ultrasound every 6 months.
  • If Calcitonin levels are > 150 pg/ml at any point, CT Neck and Chest, Liver MRI should be obtained to rule out distant metastases.
    • If imaging is negative, Calcitonin / CEA levels should be checked every 3 – 6 months (calculate doubling time), physical exam and imaging repeated every 6 – 12 months.

Surgery should be considered for all recurrent cancer in the neck (aka locoregional recurrence).

• If inoperable, External Beam Radiation (EBRT) and/or targeted systemic therapy (medicine that goes throughout the entire body) can be considered.

Distant Metastases.

• Once MTC has spread beyond the neck, cure is no longer possible.
  • Treatment should be focused on extending life, preserving quality of life, and/or palliation.
• Surgical resection of a focal distant metastasis if possible is preferred if not too morbid (unfortunately this is not often possible).
• Focal external beam radiation to an isolated site of disease can be considered if possible.
• Gene sequencing and/or molecular analysis should be performed to identify any possible targets for systemic therapies.
  • Systemic therapy
    • Medication given that reaches the entire body.
      • Two classes
        • Multikinase inhibitors that target growth and division of thyroid cancer cells regardless of the driving DNA mutation.
        • Targeted molecular therapies based on identified changes in DNA causing the cancer.
    • Most distant disease is indolent (slow growing) and there is not an immediate need to start systemic therapy.
    • Criteria for starting systemic therapy include visible growth of disease on imaging, doubling time of the tumor marker (Calcitonin / CEA) measured in the blood, symptomatic disease, or compromised organ function.
    • These treatments are not curative, and their side effects can limit their use in some patients.
    • To explore these treatment options as a patient, you should be seen by a Head & Neck Cancer Oncologist who specializes in the treatment of advanced thyroid cancers (typically practicing at an academic university hospital).

If at any time the cancer is considered not curable, the patient / family / treatment team should collectively consider:

• Palliate tracheotomy to prevent future airway compromise (cancer directly invading the larynx and/or trachea effecting the patient’s ability to breathe).
• Feeding tube placement to allow for adequate nutrition and administration of medications if the cancer invades the pharynx or esophagus.
• Establish goals of treatment and advance directives / end of life care plan.