Introduction
Medullary thyroid carcinoma (MTC) is a rare but clinically significant malignancy of the thyroid gland, arising from the parafollicular C-cells (also known as C-cells) that produce the hormone calcitonin. Unlike papillary and follicular thyroid carcinomas, which derive from follicular epithelial cells, MTC is a neuroendocrine tumor accounting for about 3–5% of all thyroid cancers. It presents unique diagnostic, genetic, and therapeutic challenges. While MTC often has a slower course than anaplastic thyroid carcinoma, its prognosis is less favorable compared to differentiated thyroid cancers, particularly when diagnosed at advanced stages.
Epidemiology
MTC can occur in both sporadic and hereditary forms:
- Sporadic MTC accounts for about 70–80% of cases and typically presents in middle-aged adults.
- Hereditary MTC constitutes 20–30% of cases and is associated with multiple endocrine neoplasia (MEN) type 2 syndromes, including MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC).
The hereditary form follows an autosomal dominant inheritance pattern and is strongly associated with germline mutations in the RET proto-oncogene. Men and women are affected equally, and the mean age at diagnosis varies depending on whether the tumor is sporadic or hereditary.
Pathophysiology and Molecular Genetics
MTC originates from the parafollicular C-cells of the thyroid, which are derived embryologically from neural crest cells. Unlike follicular cells, C-cells do not concentrate iodine, making radioactive iodine therapy ineffective for this cancer.
Molecular alterations:
- RET proto-oncogene mutations – Found in nearly all hereditary cases and in about 50% of sporadic cases. RET encodes a receptor tyrosine kinase, and activating mutations drive tumorigenesis.
- MEN2A is usually associated with mutations in codon 634.
- MEN2B is commonly associated with codon 918 (M918T mutation).
- RAS mutations – Seen in some sporadic MTCs without RET mutations.
The secretion of calcitonin and carcinoembryonic antigen (CEA) by tumor cells forms the basis for biochemical diagnosis and follow-up. In advanced disease, ectopic secretion of other hormones, such as vasoactive intestinal peptide (VIP), can cause severe diarrhea and electrolyte disturbances.
Clinical Features
The presentation of MTC varies depending on whether it is sporadic or hereditary.
- Sporadic MTC: Usually presents as a solitary thyroid nodule, sometimes with cervical lymphadenopathy.
- Hereditary MTC: May present at a younger age, often multifocal and bilateral.
- Symptoms and signs:
- Neck mass or thyroid nodule
- Enlarged cervical lymph nodes
- Hoarseness due to recurrent laryngeal nerve involvement
- Dysphagia or dyspnea due to compression of the trachea or esophagus
- Diarrhea (in advanced cases, due to hormone secretion)
Because hereditary forms can be detected through genetic screening, early prophylactic thyroidectomy in at-risk individuals prevents disease development.
Diagnosis
The diagnostic approach to MTC involves a combination of biochemical, imaging, and cytological studies:
- Serum calcitonin – A highly sensitive marker for MTC; elevated levels suggest disease presence. Levels correlate with tumor burden.
- Carcinoembryonic antigen (CEA) – Another useful marker; rising levels may indicate disease progression.
- Fine-needle aspiration biopsy (FNAB) – Useful for cytological confirmation, though not as sensitive as in papillary thyroid carcinoma. Immunocytochemistry for calcitonin improves accuracy.
- Genetic testing – RET mutation analysis is essential for all patients with MTC to identify hereditary cases and screen family members.
- Imaging studies – Neck ultrasound for initial evaluation; CT, MRI, or PET scanning in advanced disease to assess metastases.
Common metastatic sites include cervical and mediastinal lymph nodes, lungs, liver, and bones.
Management
Treatment of MTC requires a multimodal approach, focusing on surgery, targeted therapy, and long-term surveillance.
1. Surgical Management
Surgery is the mainstay of treatment:
- Total thyroidectomy is recommended for all patients.
- Central neck dissection (level VI lymph nodes) is performed routinely.
- Lateral neck dissection is indicated if cervical nodes are clinically or radiologically positive.
Prophylactic thyroidectomy is indicated in individuals carrying RET mutations, with the timing based on the specific mutation and its associated risk profile. For example:
- MEN2B (M918T mutation): Thyroidectomy within the first year of life.
- MEN2A (codon 634 mutation): Thyroidectomy typically before age 5.
2. Radioactive Iodine Therapy
Unlike papillary and follicular carcinoma, MTC does not uptake iodine, and hence radioactive iodine therapy is ineffective.
3. External Beam Radiotherapy
May be considered for unresectable disease, residual tumor, or palliation in metastatic cases.
4. Systemic Therapy
- Tyrosine kinase inhibitors (TKIs) such as vandetanib and cabozantinib are approved for progressive or metastatic MTC. These drugs target RET, VEGFR, and other pathways.
- Selective RET inhibitors such as selpercatinib and pralsetinib offer promising efficacy with fewer side effects compared to multikinase inhibitors.
5. Symptomatic Management
In advanced disease, diarrhea caused by VIP secretion can be managed with somatostatin analogs or symptomatic therapy.
Prognosis
The prognosis of MTC is less favorable compared to papillary and follicular thyroid cancers but better than anaplastic carcinoma. Survival depends on stage, presence of lymph node metastasis, and distant spread.
- 10-year survival rates:
- Localized disease: 90–95%
- Regional lymph node involvement: 70–80%
- Distant metastases: 30–40%
Prognostic factors include:
- Age at diagnosis (younger patients fare better).
- Tumor stage and size.
- RET mutation type (MEN2B is associated with more aggressive disease).
- Biochemical markers (calcitonin and CEA doubling times predict disease progression).
Follow-up and Surveillance
Postoperative monitoring is crucial:
- Calcitonin levels: Should be undetectable after complete resection; persistent or rising levels indicate residual or recurrent disease.
- CEA levels: Useful for detecting tumor progression.
- Imaging studies: Regular ultrasound, CT, or MRI depending on calcitonin trends.
- Genetic counseling: Essential for patients and their families in hereditary cases.
Conclusion
Medullary thyroid carcinoma is a distinct thyroid malignancy with unique clinical and molecular features. Early diagnosis, timely surgery, and genetic counseling are critical for favorable outcomes. While surgery remains the only curative option, the advent of targeted therapies such as selective RET inhibitors has revolutionized the management of advanced disease. Lifelong follow-up with biochemical markers and imaging is essential due to the high risk of recurrence and metastasis. A multidisciplinary approach involving endocrinologists, surgeons, geneticists, and oncologists is fundamental in optimizing care for patients with MTC.
References
- Wells, S. A., et al. (2015). Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 25(6), 567–610.
- Mulligan, L. M. (2014). RET revisited: expanding the oncogenic portfolio. Nature Reviews Cancer, 14(3), 173–186.
- Leboulleux, S., et al. (2016). Treatment of advanced medullary thyroid cancer. Nature Reviews Endocrinology, 12(6), 331–341.
- Wells, S. A., et al. (2012). Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. Journal of Clinical Oncology, 30(2), 134–141.
- Subbiah, V., et al. (2021). Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer: a multicentre, open-label, phase 1/2 study. The Lancet Diabetes & Endocrinology, 9(8), 491–501.
- Schlumberger, M., et al. (2021). Long-term outcomes of medullary thyroid carcinoma: lessons from clinical practice. Endocrine-Related Cancer, 28(5), R241–R256.
