Medullary thyroid carcinoma (MTC) accounts for about 5% of all thyroid cancers and can occur at any age, but is common between the ages of 50 and 60, with a similar proportion of men and women.
Classification
Most MTC is sporadic, does not “cluster” within a family, and is not passed on to children.
Only about 15% to 25% of MTCs are inherited, and are called hereditary MTCs, where multiple people in the family have the disease at the same time or in sequence. There are 3 specific subtypes:
- multiple endocrine neoplasia type IIa (MEN 2A)
- multiple endocrine neoplasia type IIb (MEN 2B)
- familial endocrine neoplasia type IIb (MEN 2B)
- Familial medullary thyroid carcinoma (FMTC).
In hereditary MTC, 95% of cases are caused by mutations in the RET proto-oncogene. Therefore, doctors recommend that children with a family history of MTC go to the hospital for consultation and, if necessary, genetic testing under medical supervision to see if they carry the disease-causing gene and if they need preventive surgery.
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Symptoms
Painless thyroid nodules
Most patients present with primarily painless thyroid nodules at the first visit, and some may also have enlarged lymph nodes in the neck.
Blood markers may be elevated: calcitonin, carcinoembryonic antigen
MTCs originate from parafollicular cells in the thyroid gland and secrete “calcitonin,” a hormone that lowers serum calcium levels. Therefore, a blood test that shows a significant increase in serum calcitonin (CT) levels is a “sign” of MTC. However, due to other mechanisms in the body, such as parathyroid hormone and kidney regulation, calcium levels are not usually significantly lower.
In addition, blood levels of carcinoembryonic antigen (CEA, a common tumor marker) may also be elevated.
These characteristics of MTC make it likely that patients will have something in addition to the neck nodes
Specific symptoms
1) If blood calcium decreases, it will manifest as twitching of limbs and numbness of hands and feet.
2) When patients with hereditary MTC are complicated by other endocrine tumors (such as adrenal pheochromocytoma), they may also have corresponding symptoms, such as hypertension, headache, and palpitations.
3) Some patients may also develop carcinoid syndrome (symptoms caused by tumor tissue secreting vasoactive substances) such as facial flushing and diarrhea.
Staging
MTC is classified into stages I-IV according to the internationally accepted staging system of T (for primary tumor lesions), N (for lymph node metastases), and M (for distant metastases). The specific staging is as follows:
| Table 1: Medullary thyroid carcinoma staging and meaning | |
| Staging | Meaning |
| Phase I |
No lymph node metastases or distant metastases Primary focus is confined to the thyroid gland and is no larger than 2 cm in maximum diameter |
| Stage II |
No lymph node metastases or distant metastases A primary focus confined to the thyroid with a maximum diameter greater than 2 cm, or a primary focus invading outside the thyroid but involving only the peripheral band (a group of muscles in the anterior neck band) |
| Stage III |
No distant metastases Metastasis to lymph nodes in cervical region VI or VII, or retropharyngeal lymph nodes The primary focus is confined to the thyroid gland, or the primary focus invades outside the thyroid gland but only involves the surrounding strap muscles |
| Stage IVA |
No distant metastases, with the primary focus confined to the thyroid but with metastases in the lymph nodes of the lateral cervical region (regions II-V); or, in the absence of distant metastases, with or without lymph node metastases, the primary site involves the surrounding subcutaneous soft tissue, trachea, esophagus, or laryngeal nerve |
| Stage IVB | No distant metastases, with or without lymph node metastases, primary foci involving the spine or surrounding great vessels, invasion to the prevertebral fascia, encircling carotid arteries or mediastinal vessels |
| Stage IVC | Distant metastases, regardless of the extent of the primary site and the presence of lymph node metastases |
Treatment
MTC is more malignant than papillary carcinoma and has a higher probability of metastasis and recurrence. Surgery is the main treatment modality, and radiation and chemotherapy are not effective.
Surgery
Surgical resection is the only treatment modality that has a proven efficacy. The surgical option is usually total thyroidectomy with prophylactic central lymph node dissection.
Postoperative radioactive iodine (RAI) therapy is usually not required unless the lesion contains elements of differentiated thyroid cancer (papillary or follicular carcinoma).
Post-operative follow-up is required with periodic blood draws to monitor serum carcinoembryonic antigen and calcitonin levels, both of which help monitor for tumor recurrence.
Children or adolescent children with MTC who have a disease-causing mutation but have not yet developed the disease may be considered for prophylactic resection and will need to take thyroid hormone pills (e.g., eugenol) for life after surgery.
Other treatments
External radiation therapy (“radiotherapy”) and chemotherapy are not effective, and radiotherapy of metastases is considered only in the presence of brain or spinal cord metastases, and chemotherapy alone or in combination with multiple drugs is not recommended.
In addition, two targeted drugs – vandetanib and cabozantinib – have been approved in the United States for the treatment of advanced medullary carcinoma, and another drug, soventinib, is still in clinical trials. However, no targeted drugs for medullary-like cancer have been marketed in China.
Outcome
More than 50% to 90% of patients with MTC live more than 10 years. The following suggest a poorer outcome:
- Onset in the elderly
- with metastases to cervical lymph nodes and/or distant organs
- Requiring more extensive surgery
- Has multiple endocrine neoplasia type 2B
- Rapid increase in blood calcitonin levels, especially within 6 months
The following suggest a better outcome:
- Having familial MTC
- Slow increase in blood calcitonin levels, or reduced levels
- Continued elevation of blood calcitonin levels with no evidence of recurrence on imaging
- Local metastatic lesions less than 1 cm in diameter, especially with slow increase in calcitonin and carcinoembryonic antigen levels
Co-written by Dr. Kai Qian, Fudan University Cancer Hospital, Dr. Xiaoke Zheng, Dr. Kai Guo, Dr. Weibo Xu