Medullary thyroid cancer

Sub-section: Thyroid Section: Endocrine

Definition

• Originates in Parafollicular cells (C cells)
  • Upper /middle areas of the thyroid lobes
  • Neural crest origin – 4th and 5th Branchial Pouch
    •  Join the thyroid during development
  • C-cells produce calcitonin in the thyroid

Incidence

• 4% to 10% of Thyroid Carcinomas
• 13% of Thyroid Ca deaths

Classification

• Sporadic (75%)
• Hereditary (25)
  • MEN 2A syndrome
    • Medullary Thyroid Ca
    • Phaeochromocytoma
    • Parathyroid Hyperplasia
  • MEN 2B syndrome
    • Medullary Thyroid Ca
    • Phaeochromocytoma
    • Hirschsprung’s Disease
    • Mucosal Neuroma
  • Familial Medullary Thyroid Carcinoma (FMTC)
    • Variant of MEN2A that includes MTC but not the other features of MEN2A
  • MTC arising in MEN2A usually has more favourable long-term outcome than MEN2B or sporadic

Clinical Features

• A single palpable mass, usually painless (most cases)
• Elevated calcitonin
  • Systemic symptoms may occur due to hormonal secretion by the tumour - which includes diarrhoea and facial flushing
• In most patients, there is metastasize at diagnosis - usually to nodes.

Genetics

• MEN2 and FMTC involve different germ line activating mutations in the RET proto-oncogene
  • NB: Also 40-50% sporadic MTCs have acquired RET mutations
• Inherited MTC’s develop C-Cell Hyperplasia
  • Pre-neoplastic lesion if RET mutation
    • No/little malignant potential if no RET mutation
• MTC has high penetrance (> 90%)
• Family members of patients with MEN2 should be screened at an early age for the RET proto-oncogene.
  • Shortly after birth in MEN2B kindreds
  • Before age 5 years in FMTC and MEN2A kindreds
• Work up when any patients is diagnosed with MTC
  • History
    • Workup includes a detailed and in-depth family history
      • Cancer history
      • Inquire about the characteristics of MEN2 in the patient and family members
  • Parathyroid
    • Serum Ca2+ and PTH
  • Phaeochromocytoma
    • Urinary Catecholamines (Phaeochromocytoma)
    • Must be excluded before considering interventions in patients with MTC
  • Refer to genetics for RET testing

Investigations

• Serum Calcitonin
  • If the pre-operative calcitonin is >500pg/mL - CT neck CAP is required.
• CEA
• USS + FNA
  • USS must include evaluation of the neck nodes
• Refer to genetics
  • Genetic testing for germline RET mutation
• Biochemical evaluation for Phaeochromocytoma and parathyroid

Histopathology

• FNA
  • Round blue cells
  • Increased Amyloid deposition (Stains with Congo Red)
• Histology
  • Arise from calcitonin cells - thus is a form of neuroendocrine tumour.
  • The histopathological appearance can be quite variable - thus staining is very important
  • Stain positive for calcitonin, CEA, chromogranin, and synaptophysin.
  • Will not stain for thyroglobulin (as not from follicular cells)

Biochemical testing

• Calcitonin
  • Shown to be an effective marker for the presence of MTC
    • NB: Elevated calcitonin in absence of a thyroid mass requires further workup
      • Repeat calcitonin
      • Calcium-stimulated or gastrin-stimulated test
  • Calcitonin excess is not clinically associated with hypocalcaemia
    • May rarely result in symptoms of diarrhoea and flushing in advanced disease
  • Calcitonin levels represent volume of disease
  • Presence of a mass and an elevated calcitonin level is virtually diagnostic of MTC
• CEA
  • CEA may also be elevated in MTC

Grading

• Because it is a neuroendocrine tumour - can be defined as low grade or high grade based on Ki67, mitosis for 2mm2, and evidence of tumour necrosis.
• Low grade - <5 mitosis/10HPF, Ki67 <5 %, No tumour necrosis.
• High grade - >5 mitosis/10HPF, Ki67 >5 %, tumour necrosis

Management

• Local disease
  • Total Thyroidectomy with Prophylactic Level VI Central Nodal Dissection
  • Lateral neck dissection if positive lymph nodes
  • Lateral neck dissection based on Calcitonin
    • Controversial
      • If the calcitonin level is >200pg/mL - ipsilateral lateral lymph node dissection.
      • Bilateral neck dissection unlikely to confer benefit
        • If micomets here then likely to be elsewhere
• Known nodal metastasis in the central neck
  • Level VI Central Nodal Dissection
  • Some advocate the addition of a lateral neck dissection on the side ipsilateral to the level VI disease
    • (not universally recommended)
• Clinically detectable or ultrasound-detectable disease in the lateral neck
  • Total Thyroidectomy, Level VI node dissection and ipsilateral lateral compartment nodal dissection
  • Some people advocate for contralateral lateral neck dissection if calcitonin level is > 200pg/mL
• Distant metastatic disease
  • Less aggressive surgery in the neck to decrease the risk of morbidity
  • Palliative operations may be indicated in patients with neck pain or airway compromise
  • Other options to treat metastatic disease
    • Radiotherapy to bony metastasis
    • Embolisation
    • Tyrosine kinase inhibitors
    • Palliative cytotoxic chemotherapy - 5FU etc
• If MTC is diagnosed post-op in a pt undergoing less than Total Thyroidectomy
  • Further surgery to complete therapy as though known pre-op
  • Completion Thyroidectomy and Nodal Dissection as indicated
  • Exceptions: Incidental finding of MTC in thyroid lobectomy where:
    • MTC is sporadic and unifocal
    • No C-Cell Hyperplasia
    • Otherwise normal USS neck
    • Negative surgical margin
    • Normal serum calcitonin

Prophylactic Thyroidectomy

• MEN2B RET mutation
  • Within the 1st year or at the time of dx
• Other patients with germline RET mutations
  • Before age 5 years or at the time of dx
  • May be appropriate to wait beyond 5 years with particular RET mutations
• Don’t need to do level VI node dissection in above patients unless
  • Thyroid nodules > 5 mm
  • Elevated calcitonin
  • Lymph node metastasis

Follow-up

• Calcitonin and CEA
  • Basal and stimulated calcitonin levels to monitor for recurrence
    • Calcitonin values may increase before basal calcitonin levels
      • Can do stimulated calcitonin test but has minimal clinical utility
• Recurrent MTC found biochemically is often associated with unresectable recurrence in distant metastatic locations
  • E.g. Lung and liver
• TSH suppression and RAI scanning and therapy have no role in MTC
  • Unless there is a concomitant PTC or FTC