Medullary carcinoma of the thyroid
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|-||Comprises 3-9% of all thyroid cancers.||+||Medullary thyroid cancer comprises 2-3% of all thyroid cancers.|
|Estimated 1300-2200 cases in 2010 in the United States.||Estimated 1300-2200 cases in 2010 in the United States.|
Revision as of 01:50, 24 April 2012
Medullary thyroid cancer comprises 2-3% of all thyroid cancers.
Estimated 1300-2200 cases in 2010 in the United States.
Clinical course is generally indolent and frequently involves early lymphatic dissemination.
More aggressive than differentiated thyroid cancers, but overall an indolent malignancy with 10 year survival rates of 69-89%.
Malignant neoplasm of neuroendocrine parafollicular C cells that represents about 5-10% of thyroid tumors.
C cells constitute approximately 1% of thyroid cells.
Cervical lymph node involvement in 31-33% of T1 cases, 53% of T2 cases and 100% of T3-4 cases.
The sporadic form of disease more often presents as a palpable nodule versus familial medullary thyroid carcinoma.
Contralateral and upper mediastinal nodes are at risk for local regional spread of the disease.
Distant metastases are observed in only 2-33% of the cases during the primary staging.
The incidence of distant metastases is 45% as the disease progresses.
Survival rate at 10 years 95% for patients with tumor limited to the thyroid.
10 year survival is less than 50%. In patients with distant metastatic disease.
Clinical course of MTC is usually more aggressive than that of differentiated thyroid cancer with higher rates of recurrence and mortality, particularly in young individuals.
10 year disease specific survival rate is approximately 75% (Kloos RT et al).
55% 10-year survival for patients stage III and IV.
All patients with preoperative diagnosis of MTC should be screened for pheochromocytoma and hyperparathyroidism.
Sporadic form 70-80% of cases, whereas the remaining 20-30% of cases are represented by three familial forms.
Sporadic disease usually presents in the fifth and sixth decades of life, while familial forms present at earlier ages.
3 hereditary forms-familial medullary thyroid carcinoma, multiple endocrine neoplasia types 2A and 2 B.
MTC tumors are vascular and have increased expression of vascular endothelial growth factor (VEGF) is associated with increased tumor growth and invasiveness.
C cells of predominantly located in the upper portion of the thyroid lobes, and therefore patients with sporadic disease present with upper pole nodules.
Cervical adenopathy and metastatic disease is seen at initial presentation in about 50% of patients.
Metastases are present in more than 70% of patients with palpable disease.
About 15% of patients upper aerodigestive symptoms related to tumor invasion or compression, in patients with sporadic disease.
5-10% of patients will have lung or bone metastases.
Surgery is the only successful treatment to cure this disease.
Recommended to have a total thyroidectomy and unilateral modified neck dissection in sporadic disease and bilateral cervicolateral dissection in the hereditary form of the disease.
In patients with palpable disease total thyroidectomy is the appropriate treatment accompanied by a central neck node dissection.
Calcitonin levels are elevated in all patients with palpable medullary thyroid cancer.
In patients with probable disease removal of all of nodal tissue in the central neck improves recurrent and survival rates when compared to procedures that remove only grossly involved lymph nodes.
Lateral compartment lymph node involvement is related to the extent of nodal disease in the central nodal compartment, and resection of lateral nodes should be based on the findings of central notable disease.
Hereditary forms associated with multicentric carcinomas in 56%-85% of patients.
The process is multifocal and the bilateral in approximately 90% of patients with hereditary forms of the disease, and only in 20% of patients with the sporadic form.
Mutations of the RET proto-oncogene leading to increased tyrosine kinase activity and cell growth, identified as the underlying cause.
Germline mutations in the RET proto-oncogene cause hereditary MTC, and somatic RET mutations are present in up to 50% of patients with sporadic disease.
Majority of patients with hereditary form have a mutation in the RET kinase gene and 25% of patients with the sporadic form have this mutation.
All patients with or who are at risk for MTC should undergo genetic screening for germline RET mutations.
The diagnosis of pheochromocytoma must be excluded in all cases of MTC prior to surgery, and if present should be removed before thyroidectomy.
After completion of primary treatment persistent or recurrent hypercalcitoninemia is reported to occur in 29-85% of the cases.
Calcitonin, a hormone secreted by thyroid C cells is used as a clinical biomarker for the detection of medullary thyroid cancer.
Calcitonin levels are almost always elevated in patients with medullary thyroid of cancer.
Calcitonin is a biomarker for detection of medullary thyroid cancer, and serum levels below 10 pg/mL are considered to be evidence of the absence of medullary thyroid cancer, whereas levels above 100 pg/mL are highly predictive of medullary thyroid cancer.
The tumor may secrete measurable levels of calcitonin and active peptides such as ACTH or calcitonin-Jean related peptide which can contribute to the presence of diarrhea, Cushing's syndrome or facial flushing in patients with extensive disease.
High levels of calcitonin are associated with diarrhea.
Most patients with sporadic disease and some patients with hereditary MTC diseasepresent with a thyroid nodule.
Patients with a thyroid nodule have clinically enlarged nodes in up to 75% of patints.
MTC cells do not concetrate radioactive iodine, and patients present with a cold nodule on thyroid scans.
Hormone therapy for suppression of the disease is ineffective.
CT scan may show thyroid nodules with calcifications and possible of extrathyroidal disease.
Fine needle aspiration of a palpable nodule or a cervical lymph node is a sensitive diagnostic tool.
The tumor may invade the adjacent larynx, trachea, esophagus, and recurrent laryngeal nerve involvement.
In familial disease the nodules are usually bilateral and multifocal.
Lymph node involvement is usually an early event, with Level VI and VII central nodes most often involved, followed by levels II through V on the ipsilateral side.
Contralateral neck lymph node involvement is also frequent, and metastases to the mediastinum may occur.
Metastases to the lung, liver and bones can occur and metastases may be miliary and difficult to diagnose.
In patients with palpable disease hoarseness, dysphagia, and respiratory problems are present in approximately 15% of patients, and 10-15% will have metastases.
Patients may develop pheochromocytoma and hyperparathyroidism.
Arises from the parafollicular C cells.
Radiotherapy and chemotherapy considered to be inefficient. 10-year survival influenced by age, stage, and postoperative basal calcitonin levels (Rendl G et al).
Patients with advanced disease respond in phase I trials to XL184 and sorafenib combined with tipifarnib which inhibit the RET kinase enzyme along with other pathways.
Vandetanib (Zactima, Caprelsa) effective treatment.
Vandetanib is a once daily oral drug that targets RET dependent, VEGF receptor dependent, and epidermal growth factor receptor dependent signaling.
Vandetanib (Zactima, Caprelsa) is recommended at a dose of 300 mg orally once daily, and for patients with moderate renal impairment with severe impairment the starting dose should be 200 mg daily.
Vandetanib (Zactima, Caprelsa) was utilized in a randomized double-blind trial involving 331 patients with unresectable locally advanced and metastatic disease and was associated with a median progression free survival of 22.6 months compared with 16 point one month with placebo.
Vandetanib (Zactima) associated with diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue and rash.