Medullary thyroid carcinoma (MTC) is a type of thyroid carcinoma that arises from the parafollicular cells of the thyroid gland. This cancer can develop sporadically or in conjunction with other diseases as part of a hereditary syndrome.
Sporadic MTC presents with a unilateral tumor, which is in contrast to the bilateral and multiple MTC masses found in MEN2 cases. Another notable characteristic regarding hereditary forms is that MTC is the initial presenting disease in the MEN2 syndromes.
With regards to the clinical picture, patients with MTC typically complain of a lump at the base of the neck that often appears during swallowing. Furthermore, larger tumors may cause manifestations such as hoarseness, dysphagia, and dyspnea. Additionally, there are consequences of elevated serum calcitonin levels since this in turn will increase the intestinal secretion of electrolytes, which results in diarrhea. Flushing is another feature of raised calcitonin values.
When a patient presents clinically with symptoms suggestive of thyroid cancer, the assessment should include a thorough personal and family history, a physical exam with emphasis on the thyroid gland and lymph nodes, as well as the pertinent studies. Preoperative investigations aim to determine if the tumor is local or metastatic, which will guide the management and treatment of these patients. Additionally, testing will help identify those with RET mutation carrier status and patients with MEN2 . The latter will be discussed in the prevention chapter.
Patients with suspicious cases of MTC will undergo FNA of the new nodule. Immunohistochemical staining for calcitonin, chromogranin A, or carcinoembryonic antigen (CEA) can provide accuracy and verification of the disease .
With regards to tumor markers, CEA is present in more than half of patients with MTC. Moreover, a CEA level greater than 30ng/mL is associated with poor prognosis despite surgery  and a level above 100ng/mL indicates metastasis.
According to the American Thyroid Association (ATA), there is no preference for or against screening with calcitonin. However, levels above 100 pg/mL should raise suspicion for MTC  .
Ultrasonography is the initial imaging technique used in the evaluation of patients with FNA findings suggestive of MTC or elevated calcitonin levels. This modality is very beneficial in the diagnosis and treatment of thyroid nodules as it provides information about the mass and detects other existing lesions or lymph nodes. Neck ultrasonography is particularly useful in sporadic cases as these typically manifest with a thyroid mass and/or cervical lymphadenopathy . Ultrasound also provides guidance during the FNA procedure.
If advanced disease is suspected, the neck and chest will be surveyed with computed tomography (CT) or magnetic resonance imaging (MRI) in order to identify lymph nodal and mediastinal metastasis. Furthermore, the liver is imaged with three-phase CT with contrast or MRI with contrast enhancement in cases with lymph node involvement or if preoperative calcitonin is above 400pg/mL .
The treatment and management of patients with MTC is best provided by a multidisciplinary care of a team consisting of a head and neck surgeon, oncologist, endocrinologist, general physician or pediatrician, and other specialists as needed. Generally, the therapy depends on whether the disease is local or advanced.
When cancer confined to the thyroid gland, total thyroidectomy is the treatment of choice. This seeks to control the disease and to preserve the functions of speaking and swallowing. Additionally, at least 75% of MTC patients have palpable lymph nodes and therefore routine central neck dissection is recommended . The prognosis is very promising in localized cases.
Locally relapsing cancer can be treated with external radiation therapy although it has not been shown to increase survival .
Drugs that target the genetic defects of MTC can be used in metastatic disease and palliative care. One promising agent, vandetanib, inhibits the RET kinase, as well as the vascular endothelial growth-factor receptor (VEGFR) and epidermal growth-factor receptor (EGFR).
The prognosis of MTC is good overall with a 10-year survival rate of 75% to 85%. Furthermore, localized tumors are associated with an approximately 96% 10-year survival rate . Patients with distant metastases have a poor outcome as their 10-year survival percentage is 40% .
Almost half of MTC patients will experience recurrence. A sensitive biomarker for residual tumor or tumor recurrence is the calcitonin level. If it is greater than 100pg/mL, this is suggestive of residual neck tumor or metastasis. A value above 1000pg/mL is indicative of liver disease  .
MTC develops sporadically in approximately 75% of MTC cases . In the remaining patients, it occurs as part of a hereditary syndrome such as MEN 2 syndromes, which are transmitted through an autosomal dominant trait. There are 3 subtypes of MEN 2 syndromes: MEN 2A, MEN 2B, and familial MTC (FMTC). The first two are characterized by a constellation of diseases.
The RET proto-oncogene plays a key role in all patients with MEN2A, MEN2B and FMTC. Similarly, it is central in almost half of all cases with sporadic MTCs   . The RET proto-oncogene, located on chromosome 10, codes for a tyrosine kinase transmembrane receptor which is found on cells of neural crest origin such as thyroid parafollicular cells (C cells), parathyroid cells, and others as well.
In MEN2A, the mutations of RET are of the missense type, while the genetic defects of MEN2B occur as a result of a specific mutation on exon 16 and the resultant structural abnormality of RET protein. In FMTC, the RET gene is characterized by germ-line mutations  .
MTC comprises 1% to 2% thyroid malignancies in the United States . This number was previously reported as 3% to 5% but the decrease in incidence observed has been attributed to the relative rise in the incidence of papillary thyroid carcinoma (PTC).
The median age at diagnosis for individuals with MTC is 52 years with a range that spans ages 40 to 65 . Note that patients with MEN 2 syndrome present a decade earlier compared to those with sporadic MTC . The patient demographics demonstrate a slight preference for females .
The RET proto-oncogene codes for a receptor tyrosine kinase, which plays a role in signaling pathways that regulate cell growth, proliferation, differentiation, migration, and survival. A mutation in RET causes a disruption in these mechanisms. All hereditary forms of MTC manifest from these RET mutations.
MTC emerges from the parafollicular C cells of the thyroid gland, which produce numerous hormones including calcitonin, corticotropin, serotonin, melanin, vasoactive intestinal peptide, carcinoembryonic antigen (CEA) and prostaglandins. In rare cases, the release of these hormones and peptides can result in the development of paraneoplastic syndromes.
MEN 2 syndromes
MEN2A is composed of MTC, pheochromocytoma, and primary hyperparathyroidism while MEN2B is comprised of MTC, pheochromocytoma, ganglioneuromatosis, and marfanoid habitus. The onset of MTC occurs earlier in these diseases in contrast to sporadic form.
On gross inspection, the tumor is colored white or gray; it is also firm on palpation. Furthermore, the histologic evaluation reveals a nested pattern of uniform cells with stromal amyloid deposits. Hereditary forms of MTC are characterized by “C-cell hyperplasia," which describes a specific quantity of C cells. Since these cells release various chemicals, immunohistochemical stains can be used to diagnose MTC.
According to the ATA, all patients with MTC should undergo genetic testing. Additionally, first-degree family members of patients with hereditary MTC should be offered genetic testing for RET mutations as well as parents of children affected with MEN2B . The ATA has a list of other groups who should also be screened.
Very importantly, the clinician should understand the implications of genetic detection of RET mutation. Since children with MEN2B and RET mutations usually manifest with an aggressive and an early onset MTC, the ATA recommends prophylactic thyroidectomy for these individuals .
Genetic counseling is paramount for all RET mutation carriers of childbearing age, especially for individuals with MEN2B. They should be offered testing prior to conception or antenatally. Those who decline genetic testing should be educated about the tests available to the child, especially prior to the age of 5 .
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine cancer that comprises 1% to 2% of thyroid cancers in the United States . It occurs spontaneously, or as a component of the multiple endocrine neoplasia 2 syndrome (MEN2). The latter accounts for at least 25% of all cases of MTC. A mutation in the RET (REarranged during Transfection) gene is implicated in all hereditary cases and almost 50% of sporadic MTC.
The clinical presentation of this disease features a solitary neck nodule that is typically bothersome during swallowing. Patients may develop a hoarse voice, difficulty in swallowing, and difficulty breathing. Other manifestations may arise if there are metastases to the liver, lung, and bone.
The diagnosis is achieved through a detailed personal and family history, a physical and neck exam, and pertinent studies. Fine needle aspiration (FNA) of the new mass is obtained and analyzed for characteristic findings of MTC. Additionally, calcitonin levels are measured in cases that are suspicious for MTC. Moreover, imaging tools such as ultrasonography are instrumental in diagnosis and management of MTC. Other imaging techniques are warranted if metastatic disease is indicated.
The mainstay of therapy is the surgical resection of the entire thyroid. In patients with metastasis, chemotherapy is used. Radiation therapy does not play a significant role in the primary treatment of individuals with MTC but is used to treat locally recurrent disease.
Other crucial elements in the management of MTC are genetic counseling and testing. These approaches are essential in all individuals with MTC as well first-degree relatives of patients with RET mutations. Experts recommend prophylactic thyroidectomy in children with specific mutations that are associated with aggressive forms of MTC.
What is Medullary Thyroid Cancer (MTC)?
This is a rare type of thyroid cancer. It develops from the parafollicular cells of the thyroid gland, which produces various hormones such as calcitonin. This hormone helps regulate the levels of calcium in the body.
What are the causes?
This type of thyroid cancer can occur spontaneously or it can develop as part of an inherited syndrome. In all inherited cases and almost half of spontaneous cases, the disease is caused by a mutation (change) in the RET gene. The mutation causes the uncontrollable growth and increase of cells. Note that all patients with RET mutations will develop MTC.
In the hereditary forms, the mutations are inherited in an autosomal dominant pattern. This means that the patient inherits one good copy and one bad copy of the gene. In other words, a child of an affected parent has a 50% probability of inheriting the disease.
What are the signs and symptoms?
Patients with MTC may complain of:
It can spread to the liver, lung, bone, and lymph nodes. Once it spreads, symptoms may include:
On the physical exam, the physician will feel a thyroid nodule at the base of the neck. If the cancer has spread locally, the neck lymph nodes will be enlarged.
How is it diagnosed?
In patients suspected to have MTC, the clinician will obtain a detailed personal and family history, perform a careful exam especially of the neck and lymph nodes, and perform important tests such as:
How is it treated?
Can it be prevented?
Children with RET mutations will usually have their thyroid gland removed before the cancer develops. This is called prophylactic thyroidectomy. Fortunately, once the thyroid is removed, they do not typically have a risk for relapse.
Note that genetic counseling is important for all individuals with RET mutations of childbearing age. Also, relatives of individuals with hereditary forms of MTC should also be offered genetic counseling and testing, especially in young children who may be eligible for prophylactic thyroidectomy.
What is the prognosis?
The prognosis is generally good if the cancer has not spread.