🪢Medullary Thyroid Ca

Question 1

Overview of Medullary Thyroid Ca.

Answer 1

• Neuroendocrine cell (NEC) tumour of parafollicular or C cells of thyroid gland
• 5 % of all thyroid carcinoma
• C- Cells is the embyronic neural crest origin
• produce calcitonin and CEA

Question 2

Pathology of Medullary Thyroid ca.

Answer 2

• Solid nodule in upper 2/3 thyroid lobes which C cells located
• Usually bilateral and multicentric

Question 3

Types of Medullary Thyroid ca.

Answer 3

• Sporadic MTC ( 80%)
• Inherited MTC ( 20%) : Mutations in RET proto-oncogene. Autosomal Dominant. Usually bilateral and multicentric.
  3 Subtypes:
  • MEN 2A ( MTC, Pheochromocytoma, parathyroid hyperplasia)
  • MEN 2B ( MTC, pheochromocytoma, marfanoid, mucosal neuroma, intestinal ganglioneuroma
  • FTMC ( familial medullary thyroid ca) : Variant of MEN 2A. Presence of MTC only in > 3 family members

Question 4

Presentation of Medullary Thyroid ca.

Answer 4

• Sporadic MTC is usually diagnosed as advanced disease in many as they present as asymptomatic STN.
• Local symptoms - STN in 75 – 95% patients. Commonly upper 2/3 thyroid lobes
• Regional - LN present in 75% patients
• Metastatic - in 15% patients. Common to lung, liver, bones.
• Functional
  • Calcitonin related peptide (levels correlates with tumor burden) → diarrhea & facial flushing in advance disease
  • ACTH secretion → Cushing’s syndrome.
  • No functional thyroid symptoms.

Carcinoid syndrome usually suggestive of widespread metastatic disease

Question 5

Investigation for Medullary Thyroid Ca.

Answer 5

Sporadic MTC diagnosis is by FNA
- Microscopic : Nest of round cells with abundant finely granular cytoplasm. Amyloid deposits
- IHC staining positive for calcitonin & CEA.

USG Neck
- To identify neck lymph node (LN) metastasis.

• Demonstration of calcitonin on IHC (pathological examination) is mandatory for diagnosis
• Germ-line mutation for RET-proto oncogene need to be assessed if suspected for MEN
• If germ-line mutation testing not done or unavailable, biochemical testing for MEN should be performed;
• 🚨Pheochromocytoma – Plasma metanephrines (sen, spe: 99/90%) or 24-hours urine metanephrines and
  catecholamine (90/99%) (gold standard). Plasma catecholamine and urine VMA (obsolete)
• Parathyroid hyperplasia – Serum calcium and iPTH level

CE-CT neck and chest + three-phase CE liver protocol CT or CE MRI liver, and Bone scan and axial MRI are considered → in patients with:

• extensive neck disease,
• serum calcitonin levels > 400 pg/mL,
• elevated CEA levels
• signs of distant metastasis.

gallium-68-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid -octreotate (DOTATATE) PET/CT → high serum calcitonin levels (≥500 pg/mL) because of the improved localization of MTC.

FDG- PET/CT or 18F-dihydroxyphenyl-alanine (F-DOPA)-PET/CT - not recommended because they are less sensitive in detecting metastases.

Preoperative evaluation of coexisting pheochromocytoma is very important to prevent hypertensive crisis during surgery.

Question 6

Relation of Calcitonin level with LN involvement

Answer 6

🩸Calcitonin level directly related to c-cell mass and correlate tumor size and metastasis:
- <20pg/ml – almost 0% risk of nodal involvement
- 20-50pg/ml – risk of ipsilateral LN involvement
- 50-200pg/ml – associated with contralateral central LN metastasis
- 200-500pg/ml – contralateral lateral LN
- 🚨>500pg/ml – mediastinal LN and distant metastasis need to be ruled out

🍎CEA can help discriminate between Calcitonin-negative thyroid NET and secondary NET of the thyroid
(metastasis NET to the thyroid); MTC is the only neck malignancy expressing CEA

🍊Preoperative imaging should be performed especially when calcitonin level >500pg/ml; CECT neck and thorax, 3-phase MRI liver and skeletal survey with axial MRI of bone.

Question 7

Management of MTC

Answer 7

Total thyroidectomy preferred surgical approach because bilateral or multifocal disease is found in all patients with inherited MTC and approximately 10% of sporadic MTC.

ATA & ESMO Guideline

• Total thyroidectomy + CLND + involved LLND (levels II-V) → in restricted disease of the neck.
• Contralateral ND → if basal serum calcitonin level is > 200 pg/mL when the ipsilateral lateral neck LN is positive but the contralateral neck compartment is negative on preoperative imaging.

MTC is postoperatively diagnosed after lobectomy:

• Completion thyroidectomy is not routinely performed in patients without a germline RET mutation.
• Completion thyroidectomy is indicated in sporadic MTC with detectable postoperative serum calcitonin and abnormal neck US.

Question 8

Post operative management

Answer 8

• Thyroxine therapy (LT4) - Replacement rather than suppressive T4 therapy with target TSH between 0.5 and 2.5 mIU/L
• No role for RRA – not thyroid cell cancer.
• Serum calcitonin & CEA measurement
  
  • 2 - 3 months (ESMO and NCCN), 3 months (ATA Guidelines) after surgery.
  • If biochemical cure → 6 monthly for 2 years, then yearly.

Question 9

Prognosis of MTC

Answer 9

PROGNOSIS

• 5 year survival - 65 - 90%
• Worse in: ↑ CEA, Pt with flushing and diarrhea, MEN 2B
• Se calcitonin > 1000pg/ml after total thyroidectomy → distant metastasis
• Overall prognosis ~85% at 10 years