Medullary thyroid cancer is a tumor arising from the parafollicular cells, or C cells, of the thyroid gland. Medullary thyroid cancer produces calcitonin, and elevated calcitonin levels are an essential feature of this tumor. It is derived from the medullary C cells that are of neural crest origin. Recent advances in molecular pathogenesis and genetic testing has led to risk stratification of the patients and identification of molecular targets for therapy. Prophylactic thyroidectomy is recommended for patients with mutations that put them at high risk. Various tyrosine kinase inhibitors are approved for use in progressive, metastatic medullary thyroid cancer.
Seventy-five percent to 80% of medullary thyroid cancers are sporadic, and the remainder are familial as part of multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial medullary thyroid cancer (FMTC). RET mutations in neural crest tissue in the thyroid gland can lead to medullary thyroid cancer development. Germline mutations are associated with MEN2 and FMTC medullary thyroid cancers. Forty to 50% of sporadic medullary thyroid cancers have acquired RET mutations.
Medullary carcinoma of the thyroid constitutes approximately 4% to 10% of all thyroid cancers in the United States. Sporadic medullary thyroid cancer has a peak incidence in the fifth or sixth decade of life; whereas, those medullary thyroid cancers associated with MEN 2A or MEN 2B peak around the second or third decade of life.
As opposed to the sporadic medullary thyroid cancer which is usually unilateral, the medullary thyroid cancer associated with multiple MEN syndromes is usually multicentric and bilateral. Often these tumors involve the upper portions of both lobes because the C cells reside predominantly in the upper poles of the thyroid gland. Paraneoplastic syndromes like Cushing syndrome and carcinoid syndrome can occur as medullary thyroid cancer, and can also produce hormones such as corticotropin, serotonin, prostaglandins, and melanin.
Medullary thyroid cancer is characterized by nests of round or ovoid cells with fibrovascular stroma. There is no follicle development as the tumor is developed from parafollicular C cell of the thyroid.
Approximately 75% to 95% of patients with medullary thyroid cancer present as a thyroid nodule in the upper portion of the gland where C cells are primarily located. About 70% will have cervical lymphadenopathy, and a few patients have compression symptoms like dysphagia, hoarseness, or respiratory difficulty. Metastatic spread can be present in less than 10% of patients at presentation. Liver, bone, lung, and brain are common sites for metastases in medullary thyroid cancer. High calcitonin levels can cause diarrhea in a minority of patients.
The index case in FMTC and MEN syndrome presents similarly to sporadic medullary thyroid cancer, except that presentation is often at an earlier age compared to sporadic medullary thyroid cancer.
Fine needle aspiration (FNA) of the solitary thyroid nodule or dominant nodule for multinodular thyroid is potentially helpful in establishing the diagnosis. If the FNA is nondiagnostic, the diagnosis can be made after thyroid lobectomy on permanent histology. As the tumor cells originate from the parafollicular C cells, the pathology shows spindle-shaped cells without follicle development. Measuring serum calcitonin before FNA diagnosis is complicated by a high false-positive rate. Once the diagnosis of medullary thyroid cancer is made based on histology, serum calcitonin, and carcinoembryonic antigen (CEA) should be measured. These tests help with discovery if the tumor is hypersecreting, and pre-operative levels can be compared to postoperative levels to confirm the biochemical response, and can be used to measure treatment efficacy after total thyroidectomy. The postoperative calcitonin and CEA doubling time provide a sensitive marker for disease progression.
Ultrasonography, or other imaging of the neck such as computed tomography, is indicated once the histological diagnosis is made to evaluate for cervical lymph node involvement. The evaluation for systemic disease using CT neck and imaging of the liver by CT or MRI can be done in patients suspected of having metastatic disease. This can include patients with nodal disease and calcitonin levels greater than 400 pg/ml. The sensitivity of PET and the nuclear scan is variable and is not recommended for primary evaluation for metastatic disease.
It is recommended to discuss the risks and benefits of genetic testing with the patient. Genetic testing for RET protooncogene sequencing of exons 10, 11, and 13 through 16 is necessary to for all patients with parafollicular C cell hyperplasia or sporadic medullary thyroid cancer.
Since the results of genetic testing are rarely available before surgery in sporadic cases, it is recommended to do a biochemical evaluation of possible co-existing tumors associated with MEN2 syndromes before surgery. Screening for hyperparathyroidism and pheochromocytoma by using serum calcium and plasma metanephrines respectively is recommended for a patient with unknown RET mutational status and confirmed germline RET status.
The American Joint Committee on Cancer (AJCC) Staging
Five-year survival for stage I, II, and III MTC is 93% compared to 28% for stage IV.
Surgical resection is the primary treatment for medullary thyroid carcinoma. Medullary thyroid carcinoma does not respond to RAI or conventional chemotherapy. Thyroid-stimulating hormone (TSH) suppression is not required for medullary thyroid cancer as C cells do not have the thyroid-stimulating hormone receptor. As mentioned previously, all patients should be evaluated for hyperparathyroidism and pheochromocytoma. If a pheochromocytoma is found, it should be removed prior to thyroidectomy.
Total thyroidectomy is indicated for all patients with medullary thyroid cancer. Bilateral neck dissection (level IV LN) is indicated for tumors more than one cm in greatest dimension, as well as for bilateral disease. It should also be considered for unilateral tumors and tumors less than one cm, though definitive data are lacking. Total thyroidectomy greatly increases the efficacy and utility of postoperative calcitonin level monitoring as a marker for recurrence.
In cases of inherited disease, it is recommended to perform total prophylactic thyroidectomy by age five or when the mutation is found, especially with RET mutation codon 609, 611, 618, 630, 634. In multiple endocrine neoplasia 2B with RET codon 883, 918, or compound heterozygotes, prophylactic total thyroidectomy is recommended by age one. In patients with a less high-risk mutation in codon 768, 790, 791, 804, and 891 prophylactic surgery can be deferred if there is no family history for aggressive medullary thyroid cancer, the family agrees to postpone surgery, and annual basal calcitonin and ultrasounds are performed. Adjuvant radiotherapy has not been adequately studied but can be considered in extrathyroid extension and extensive nodal disease.
Two to three months after surgery, serum CEA and calcitonin levels should be assessed. If CEA is within normal limits and calcitonin is not detectable, then the patient is considered cured and has the best prognosis. This group needs to be monitored by annual CEA, calcitonin, and potentially with annual ultrasound (based on symptoms and physical exam). For multiple endocrine neoplasia 2A and 2b, annual exams for hyperparathyroidism and pheochromocytoma are prudent.
Detectable calcitonin or elevated CEA two to three months after surgery raises suspicion for residual disease. These patients should have a neck ultrasound, and in cases of calcitonin greater than 150 pg/ml, further imaging in the form of CT neck, chest and abdomen liver protocol evaluating for potential metastatic disease. If the imaging is negative and the patient is asymptomatic, continue close surveillance with the physical exam and calcitonin/CEA measurements. If levels remain stable, no further imaging is needed. There is no indication to treat asymptomatic elevated calcitonin. If the imaging is positive and the patient is symptomatic, surgical resection of residual lesions is indicated. In the case of unresectable disease, radiotherapy can provide potential palliative therapy. Also in cases of unresectable and symptomatic disease, tyrosine-kinase inhibitors (TKI) like vandetanib and cabozantinib may be indicated. Vandetanib is an oral receptor kinase inhibitor that inhibits RET, EGFR, and VEGFR. In a phase III study, which included 331 patients with advanced, unresectable or metastatic medullary thyroid cancer, patients showed improved PFS compared to placebo . Cabozantinib is also an oral multikinase inhibitor that inhibits MET, RET, and VEGFR2. In a phase III EXAM study, it showed improvement in PFS in advanced or metastatic medullary thyroid cancer.
Neck masses are commonly seen by primary caregivers, nurse practitioners, and internists. In most cases, the diagnosis of the neck mass is made by fine-needle aspiration. When medullary thyroid cancer is diagnosed, the patient should be referred to a surgeon and an oncologist. In about 25% of cases, MTC is associated with the MEN syndrome.
Surgical resection is the primary treatment modality for medullary thyroid cancer. Medullary thyroid cancer does not respond to RAI or conventional chemotherapy. Thyroid-stimulating hormone (TSH) suppression is not required for medullary thyroid cancer as C cells do not have the thyroid-stimulating hormone receptor. As mentioned previously all patients should be evaluated for hyperparathyroidism and pheochromocytoma. If pheochromocytoma is found, it should be removed before thyroid surgery.
Total thyroidectomy with central neck dissection is indicated for all patients with medullary thyroid cancer. Following surgery, patients need life long thyroxine and require monitoring for recurrence, which is rare. Most patients have good prognosis after surgery in early stage disease. (Level V)
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