Classification of Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) is classified as a distinct entity separate from both well-differentiated and undifferentiated thyroid cancers—it is neither well-differentiated nor poorly differentiated, but rather represents a unique neuroendocrine tumor with its own biological behavior. 1
Histologic Classification Framework
The NCCN guidelines explicitly categorize thyroid carcinomas into three main histologic types 1:
- Differentiated thyroid carcinomas: papillary, follicular, and Hürthle cell variants
- Medullary thyroid carcinoma: a separate category entirely
- Anaplastic (undifferentiated) carcinoma: aggressive undifferentiated tumors
MTC occupies its own distinct classification because it originates from parafollicular C cells (neuroendocrine cells), not from follicular epithelial cells like differentiated thyroid cancers. 1, 2
Why MTC Is Not "Well-Differentiated"
MTC fundamentally differs from well-differentiated thyroid cancers in critical ways 2, 3:
- Cell of origin: Derives from neuroendocrine parafollicular C cells, not thyroid follicular epithelium 1
- Tumor markers: Produces calcitonin and CEA, not thyroglobulin 2, 3
- Radioiodine response: Cannot concentrate iodine or respond to radioactive iodine therapy, unlike differentiated cancers 1
- Biological behavior: Follows a distinct natural history requiring different diagnostic and therapeutic strategies 2, 3
Why MTC Is Not "Poorly Differentiated" or "Undifferentiated"
MTC maintains neuroendocrine differentiation with specific functional characteristics that distinguish it from poorly differentiated or anaplastic carcinomas 1:
- Functional differentiation: Retains the ability to produce calcitonin, demonstrating preserved C-cell function 2, 3
- Prognosis: Has an intermediate prognosis—better than anaplastic carcinoma (which is uniformly fatal with 5-month median survival) but worse than well-differentiated cancers 1, 2
- Histologic features: Shows organized neuroendocrine architecture, not the chaotic undifferentiated appearance of anaplastic carcinoma 1
Clinical Implications of This Classification
The separate classification of MTC has direct clinical consequences 1, 2:
- Diagnostic approach: Requires calcitonin immunohistochemistry for confirmation, not thyroglobulin staining 1
- Surgical strategy: Demands more extensive initial surgery than differentiated cancers, with prophylactic central neck dissection 2
- Follow-up markers: Uses calcitonin and CEA levels, not thyroglobulin 2, 3
- Systemic therapy: Requires RET-targeted tyrosine kinase inhibitors (vandetanib, cabozantinib, selpercatinib), not radioiodine 2, 4
Common Diagnostic Pitfall
A critical caveat: MTC can occasionally show glandular or follicular patterns that mimic follicular carcinoma histologically, but immunohistochemistry will reveal calcitonin positivity and thyroglobulin negativity, confirming the neuroendocrine C-cell origin. 5 This underscores why MTC should be considered in the differential diagnosis of any unusual thyroid carcinoma, even those appearing "well-differentiated" morphologically 5.