Written by Ilaria Messuti
DEFINITION
Medullary Thyroid Carcinoma (MTC) is a malignant neoplasia that originates from the Parafollicolar C cells of the thyroid, which produce the hormone calcitonin.
The Disease Database: Medullary Thyroid Carcinoma
Calcitonin is a 32- aminoacid linear peptide encoded by the CALC1 gene, in chromosome 11, that cooperate in Calcium homeostasis (better seen in animals, where calcitonin is produced by the ultimobranchial body, than in human).
Calcitonin dosage is recommended in every patient with a thyroid nodule, once in life. (Early diagnosis of medullary thyroid carcinoma: is systematic calcitonin screening appropriate in patients with nodular thyroid disease?,2011)
Normal blood concentration of calcitonin is < 10 pg/ml. High basal level of calcitonin, in addiction to the MTC, may be founded in physiological circumstances as pregnancy, physical exercises, alcool abuse, or in other pathological circumstances as chronic renal failure, PPI therapy, chronic autoimmune thyroidite, other neuroendochrine tumors.
The pentagastrin -stimulated calcitonin test is a useful diagnostic test for MTC. (Calcitonin screening and pentagastrin testing: predictive value for the diagnosis of medullary carcinoma in nodular thyroid disease,2011)
EPIDEMIOLOGY
It represents the 5-10% of all thyroid’s neoplasia. C cells represents approximately 1% of thyroid’s cells, and they are mostly placed between the superior third and the middle third of the gland.
Almost 80% of MTC is sporadic, 20% is genetically inherited.
Sporadic MTC: They are typically unilateral and there are no associated endocrinopathies. Peak onset around 40-60's. Females outnumber males by 3:2 ratio.
Inherited MTC:
• MEN IIA. Multiple Endocrine Neoplasia Syndromes are a group of endocrine disorders which occur together in the same patient and typically are found in families because they are inherited. MEN IIA has bilateral medullary carcinoma or C cells hyperplasia (98-100%), pheochromocytoma (40-50%), hyperparathyroidism (10-50%) and amyloid cutaneous lichen (25%). This syndrome is due to a defect of the proto-oncogene RET on chromosome 10. It is autosomal dominant, that theoretically mean that 50% of all offspring would inherit the defective gene. Males and females are equally affected. Peak incidence of medullary carcinoma in these patients is in the 30's.
• MEN IIB. This rare syndrome includes medullary carcinoma (100%), pheochromocytoma (80%), mucosal ganglioneuromas (90%) and a Marfanoid habitus.
Inheritance is autosomal dominant or it can occur sporadically (without being inherited).
Both in MEN IIA and MEN IIB pheochromocytomas must be detected prior to any operation to remove the risk of severe hypertensive episodes while the thyroid or parathyroid is being operated on.
• Inherited medullary carcinoma without associated endocrinopathies. This form of medullary carcinoma is the least aggressive. Like other types of thyroid cancers, the peak incidence is between the ages of 40 and 50.
SYMPTOMS
Clinical presentation of MTC:
• Asymptomatic (casual diagnosis or screening)
• Thyroid nodule, often associated with lymphadenopathy
• Intractable diarrhea. Diarrhea is caused by increased gastrointestinal secretion and hypermotility due to the hormones secreted by the tumor (calcitonin, prostaglandins, serotonin, or VIP).
• Flushing
These last two condictions are strictly related to high blood basal level of calcitonine.
MTC is often associated with lymphadenopaty (almost half of the patients). Occasionally can be detected distance metastasis (liver, lung, bones)
DIAGNOSIS
• Blood basal level of calcitonin
• Pentagastrin-stimulated calcitonin test
• US (with the detection of a thyroid nodule)
• FNAB
• Genetic screening
• Postsurgical histopathology
PRE-TREATMENT STAGING
All patients with MTC must be screened for the possibility of a pheocromocytoma (through abdominal US and dosage of urinary metanephrines and catecholamines) and of hyperparathyroidism (through dosage of calcemia and parathormone).
Pre-Treatment Staging also includes thyroid and neck US, FNAB on suspicious lymphonode with eluate dosage of calcitonin.
Neck-thorax-abdomen CT and bones scintigraphy are recommended.
TREATMENT OPTIONS
1. Total Thyroidectomy associated with central limphadenectomy. Dissection of lateral neck area should be made only in clinical involvement.
Patients positive for genetic screening should be treated as soon as possible, even without clinical evidence of disease.
2. External radiation therapy: External radiation therapy has been used for palliation of locally recurrent tumors and of bones and cerebral metastasis, without evidence that this treatment provides any survival advantage.
Radioactive iodine has no place in the treatment of patients with MTC, because C cells don’t capture radioiodine.
3. Palliative chemotherapy: Palliative chemotherapy has been reported to produce occasional responses in patients with metastatic disease. No single drug regimen can be considered standard. Often cisplatin and doxorubicine are used together, without any resounding result.
Nowadays experimental drugs that inhibites Tyrosine-chinase activity are tested. They block RET signal and its mitogenic effect.
The adrenal gland removal must precede thyroidectomy in patients with certain pheocromocytoma .
Patients with hyperparathyroidism must be treated surgically: the adenomatous parathyroid must be removed or, in case of diffuse parathyroid iperplasia, three glands must be removen, and part of the fourth gland must be implanted on a arm or neck muscle.
FOLLOW UP
Treatment with l-T4 must be placed in patients with postsurgical hypothyroidism .
After two months from the surgery basal level of calcitonin and pentagastrin-stimulated calcitonin level must be evaluated.
Patients with undetectable level of calcitonin are considered in clinical remission.
Patients with detectable level of calcitonin must be studied in order to find the site of the residual disease, with US, CT, MRI and bones scintigraphy.
