Medullary Thyroid Cancer

Background

• Medullary thyroid cancer (MTC) is a neuroendocrine carcinoma that arises from thyroid parafollicular C cells, and is reported to account for 1%-2% of thyroid cancers in the United States.
  • About 75% of cases are reported to be sporadic, without a known genetic cause. However, about 1%-7% of patients presenting with suspected sporadic MTC may actually be carriers of germline RET mutations. Patients with sporadic MTC usually present in the fourth through sixth decade of life.
  • About 25% of cases are reported to be familial and occur as an isolated condition (familial MTC) or as part of multiple endocrine neoplasia type 2A or 2B syndrome. Patients with hereditary MTC usually present at a younger age than sporadic MTC.
• MTC must be differentiated from other thyroid carcinomas, including:
  • differentiated thyroid cancers (papillary and follicular), which arise from thyroid follicular cells and are reported to account for ≥ 90% of thyroid cancers
  • anaplastic thyroid cancer, the least common and most aggressive thyroid carcinoma, arising de novo or from differentiated thyroid cancer
• Clinical presentation of MTC
  • While sporadic MTC usually presents with a solitary thyroid nodule, some patients may initially present with neck lymphadenopathy due to a high risk for early metastatic spread to the cervical lymph nodes.
  • Other presentations that are suggestive of metastases include:
    • pain and compressive symptoms (such as dysphagia and hoarseness) due to local tumor extension
    • symptoms of tumor hormone secretion (calcitonin, adrenal cortical releasing hormone) such as flushing, diarrhea, weight loss, and Cushing syndrome

Evaluation

• Testing for all patients with a clinically suspected thyroid nodule
  • Perform an ultrasound of the thyroid gland and neck (Strong recommendation).
  • Measure serum thyroid-stimulating hormone (TSH) (Strong recommendation).
  • If TSH is low, perform a radionuclide scan (scintigraphy), but avoid use of radioactive agents for diagnostic purposes in pregnant women (Strong recommendation).
    • Hyperfunctioning ("hot") nodules have a low malignancy risk (patients with low TSH and a hot nodule should be evaluated and treated for hyperthyroidism).
    • Hypofunctioning ("cold") nodules require further evaluation with a fine-needle aspiration (FNA) biopsy for potential malignancy.
  • If TSH is normal or elevated, perform a fine-needle aspiration (FNA) biopsy if (Strong recommendation):
    • the nodule has ultrasound features suspicious for malignancy
    • the patient has risk factors for malignancy or abnormal cervical lymph nodes
  • See Thyroid Nodule for details.
• Once the diagnosis is confirmed:
  • Perform a neck ultrasound in all patients with confirmed MTC prior to surgery.
  • Consider the following imaging studies (in addition to a routine neck ultrasound) in patients with MTC if the patient's preoperative calcitonin levels are > 500 pg/mL or if the patient has extensive neck disease and signs or symptoms of regional or distant metastases (Weak recommendation):
    • contrast-enhanced neck and chest computed tomography (CT)
    • three-phase contrast-enhanced multidetector liver CT or magnetic resonance imaging (MRI) of the liver
    • axial skeleton MRI to assess for skeletal metastases
  • Measure tumor markers (calcitonin and carcinoembryonic antigen) in all patients with diagnosed MTC prior to surgery (Strong recommendation).
  • Consider offering genetic testing to all patients with presumed sporadic MTC to assess for germline RET mutations (Weak recommendation).
• Consider diagnostic histopathology or molecular testing of persistently nondiagnostic nodules.

Management

• Surgery is the main treatment for MTC.
  • If present, resect any pheochromocytomas before performing surgery for MTC to avoid hypertensive crisis.
  • A total thyroidectomy with neck dissection is the preferred first-line treatment in most patients without advanced local disease or extensive distant metastases (Strong recommendation).
  • Consider less aggressive neck surgery in patients with advanced local disease or distant metastases to preserve speech, swallowing, parathyroid function, and shoulder mobility (Weak recommendation).
  • Palliative treatments are suggested (including neck surgery for tumor resection, external beam radiation therapy (EBRT), or systemic therapy) in patients with metastases causing pain, mechanical compression, or signs and symptoms of hormonal excess (Weak recommendation).
• Postoperative management
  • Consider tumor classification, the number of lymph node metastases, and postoperative serum calcitonin to plan long-term follow-up in patients treated with thyroidectomy for MTC (Weak recommendation).
  • Measure serum thyroid-stimulating hormone (TSH) within 4-6 weeks postoperatively, and provide thyroxine replacement adjusted to keep TSH levels within the euthyroid range.
  • Measure serum calcitonin and carcinoembryonic antigen (CEA) at 3 months postoperatively.
    • If the levels are normal or undetectable, measure every 6 months for 1 year, then annually thereafter.
    • If the levels are detectable, measure at least every 6 months to determine their doubling time.
• Consider postoperative adjuvant external beam radiation therapy to the neck and mediastinum in patients with either of the following (Weak recommendation):
  • risk for airway obstruction
  • high risk for local recurrence, as evidenced by any of the following:
    • microscopic or macroscopic residual MTC
    • extrathyroidal extension
    • extensive lymph node metastases
• Routine postoperative radioactive iodine (RAI) is not recommended for patients with MTC, but RAI can be considered for patients with regional or distant metastases that contain MTC mixed with either papillary or follicular thyroid cancer (Weak recommendation).
• Provide follow-up treatment and monitoring.
  • Follow-up based on elevated postoperative calcitonin levels
    • If calcitonin levels are elevated but < 150 pg/mL:
      • Perform a physical exam and ultrasound of the neck.
      • If these studies are negative, perform a physical exam, assessment of serum calcitonin and CEA levels, and neck ultrasound every 6 months.
      • In patients with calcitonin levels < 150 pg/mL following a thyroidectomy, persistent or recurrent disease is usually confined to lymph nodes in the neck.
    • If calcitonin levels are > 150 pg/mL (associated with distant metastases), perform the following studies:
      • neck ultrasound
      • chest CT
      • contrast-enhanced MRI or three-phase contrast-enhanced CT of the liver
      • bone scintigraphy and MRI of the pelvis and axial skeleton
  • Additional follow-up
    • Measure serum calcium levels postoperatively and provide oral calcium and vitamin D to patients who develop symptomatic hypocalcemia (long-term replacement therapy is necessary in patients who cannot be weaned from medication).
    • For patients with no adrenal glands (such as following an adrenalectomy for pheochromocytoma), administer glucocorticoid and mineralocorticoid replacement therapy to reduce the risk for adrenal crisis.
• For metastatic, progressive, or unresectable MTC:
  • Systemic therapy (a single agent or combination cytotoxic chemotherapeutic regimens, radiolabeled molecules or pretargeted radio-immunotherapy, and/or tyrosine kinase inhibitors) is usually not needed for asymptomatic patients with stable or slowly progressive small volume metastatic disease (Weak recommendation).
  • Consider systemic therapy (preferably tyrosine kinase inhibitors) for patients with:
    • widespread metastases that are progressing in size (Weak recommendation)
    • extensive regional or metastatic disease to help achieve local tumor control (may be used with external beam radiation therapy and other nonoperative management) (Weak recommendation)
  • Management of distant metastases
    • For isolated or limited brain metastases, consider surgical resection or EBRT, including stereotactic radiosurgery (Weak recommendation).
    • For cutaneous metastases, surgical excision is suggested when possible (multiple cutaneous lesions may require EBRT or ethanol injection) (Weak recommendation).
    • For lung metastases:
      • Consider surgical resection of large, solitary lung metastases (Weak recommendation).
      • Consider radiofrequency ablation when metastases are peripheral and small (Weak recommendation).
      • Consider systemic therapy for multiple metastases that are progressing in size (Weak recommendation).
    • For bone metastases:
      • In patents with spinal cord compression, provide urgent treatment with surgical decompression and glucocorticoid therapy.
      • For patients with bone metastases who have fractures or impending fractures, consider surgery, thermo-ablation (radiofrequency or cryotherapy), cement injection, or EBRT (Weak recommendation).
      • For painful osseous metastases, medications may include denosumab or bisphosphonates (Weak recommendation).
    • For hepatic metastases:
      • For large, isolated hepatic metastases, consider debulking surgery (Weak recommendation).
      • For disseminated tumors < 30 mm (1.2 inches) and involving less than a third of the liver, consider selective artery chemoembolization (Weak recommendation).
      • For ectopic Cushing syndrome, consider initial medical treatment, followed by a bilateral adrenalectomy for cases that are refractory to medications (Weak recommendation).
• Take measures to prevent or detect MTC and identify associated disorders.
  • Offer germline RET testing and genetic counseling to:
    • first-degree relatives of patients with proven hereditary MTC
    • parents whose infants or young children have the classic phenotype of multiple endocrine neoplasia (MEN) type 2B (MEN2B)
    • patients with cutaneous lichen amyloidosis
    • infants or young children with Hirschsprung disease (HD) and exon 10 RET germline mutations
    • adults with MEN2A and exon 10 RET mutations who have symptoms that are suggestive of HD
  • Screening for MTC and conditions associated with MTC (hyperparathyroidism and pheochromocytoma) is suggested in at-risk family members of patients with clinical MEN2A or MEN2B but no RET mutation found during entire gene sequencing (Weak recommendation).
  • Perform prophylactic total thyroidectomy for all children with RET mutations with timing based on genotype-specific risk for aggressive MTC.