Medullary Thyroid Carcinoma 

Updated: Feb 09, 2017
Author: Anastasios K Konstantakos, MD; Chief Editor: Neetu Radhakrishnan, MD 

Overview

Practice Essentials

Medullary carcinoma of the thyroid (MTC) is a distinct thyroid carcinoma that originates in the parafollicular C cells of the thyroid gland. These C cells produce calcitonin.

Sporadic, or isolated, MTC accounts for 75% of cases, and inherited MTC constitutes the rest. Inherited MTC occurs in association with multiple endocrine neoplasia (MEN) type 2A and 2B syndromes, but non-MEN familial MTC also occur.

Outcome depends on extent of disease, nature of tumor biology, and overall efficacy of surgical treatment.

Advances in genetic testing in have revolutionized the management of this disease, by allowing risk stratification of patients with inherited mutations and identifying molecular targets for therapy. Prophylactic thyroidectomy is indicated for patients who carry mutations that put them at risk for aggressive MTC.  

Surgery remains the standard of care for localized disease and for oligometastatic disease. Several tyrosine kinase inhibitors are approved for use in progressive, metastatic MTC, and a variety of agents have entered clinical trials. External beam radiotherapy is used in certain situations.

See Treatment and Medication.

See the figure below.

Algorithm for the management of a solitary thyroid Algorithm for the management of a solitary thyroid nodule. FNAB = fine needle aspiration biopsy; US = ultrasonography.

Pathophysiology

Medullary thyroid cancer (MTC) is usually diagnosed on physical examination as a solitary neck nodule, and early spread to regional lymph nodes is common. Distant metastases occur in the liver, lung, bone, and brain.

Sporadic MTC usually is unilateral. In association with multiple endocrine neoplasia (MEN) syndromes, it is always bilateral and multicentric, with presentation earlier in life. MTC typically is the first abnormality observed in both MEN 2A and 2B syndromes.

In addition to producing calcitonin, MTC cells can produce several other hormones, including corticotropin, serotonin, melanin, and prostaglandins; moreover, paraneoplastic syndromes (eg, carcinoid syndrome, Cushing syndrome) can occur in these patients.

Mutations in the RET (REarranged during Transfection) proto-oncogene, a receptor protein tyrosine kinase encoded on chromosome 10, have been classified into discrete subtypes, which confer varying degrees of risk[1] ; prophylactic thyroidectomy can now be offered to specific types of patients with this genetic abnormality (see Prevention).

Epidemiology

Frequency

United States

Medullary carcinoma of the thyroid (MTC) constitutes approximately 4% of all thyroid cancers in the United States.[2] This figure translates into approximately 1000 diagnoses per year.

International

The international incidence of medullary carcinoma of the thyroid is similar to that in the United States.

Mortality/Morbidity

Isolated medullary carcinoma of the thyroid (MTC) typically demonstrates a relatively indolent biologic progression. While regional lymph node metastases are possible, the lesion may not spread outside of the cervical region until several months later. MTC associated with multiple endocrine neoplasia (MEN) syndromes may have a more aggressive course, which also depends on associated comorbidity (eg, pheochromocytoma).

Despite advances in genetic screening for the RET proto-oncogene, preliminary population studies have yet to show a definitive impact on disease prognosis.[3]

Age

Peak incidence of isolated medullary carcinoma of the thyroid (MTC) occurs in the fifth or sixth decade of life, and the peak incidence of MTC associated with multiple endocrine neoplasia (MEN) 2A or 2B occurs during the second or third decade of life.

 

Presentation

History

A specific constellation of symptoms of medullary thyroid carcinoma (MTC) is not usually noted; however, one or more of the following symptoms may be observed:

  • Patients may describe a lump at the base of the neck, which may interfere with or become more prominent during swallowing

  • Patients with locally advanced disease may present with hoarseness, dysphagia, and respiratory difficulty

  • Although uncommon, patients may present with various paraneoplastic syndromes, including Cushing or carcinoid syndrome

  • Diarrhea may occur from increased intestinal electrolyte secretion secondary to high plasma calcitonin levels

  • Distant metastases (eg, lung, liver, bone) may result in weight loss, lethargy, and bone pain

Physical

See the list below:

  • Physical examination may demonstrate a dominant thyroid nodule at the base of the neck.

  • Palpable cervical lymphadenopathy signifies disease that has progressed locally.

  • Abdominal pain, jaundice, and rarely, bone tenderness may occur in patients with systemic metastases.

  • Men2B may have a marfanoid habitus with mucosal neuromas

Causes

Medullary carcinoma of the thyroid (MTC) has a genetic association with multiple endocrine neoplasia (MEN) 2A and 2B; however, it can also be inherited by a non-MEN mode of transmission. Sporadic MTC occurs in 75% of patients, and familial MTC constitutes the other 25%. Mutations in RET can lead to MTC development in cells derived from neural crest tissue situated in the thyroid gland.

Physical Examination

See the list below:

  • Physical examination may demonstrate a dominant thyroid nodule at the base of the neck.

  • Palpable cervical lymphadenopathy signifies disease that has progressed locally.

  • Icterus, and rarely, bone tenderness may occur in patients with systemic metastases.

  • Men2B patients may have a marfanoid habitus with mucosal neuromas

  • Labile hypertension may be seen in those with an associated pheochromocytoma

 

DDx

 

Workup

Laboratory Studies

According to the American Thyroid Association, preoperative laboratory testing in patients with possible medullary thyroid carcinoma (MTC) has three purposes[1] :

  • To predict the extent of metastatic disease; this will determine the extent of preoperative imaging and may alter the surgical approach

  • In patients with MEN 2, to identify primary hyperparathyroidism and/or pheochromocytoma —comorbid conditions that alter the surgical approach and surgical priorities

  • To identify RET mutation carriers so that testing of appropriate family members can allow for early diagnosis and treatment of affected individuals

Calcitonin

Obtain serum calcitonin levels. Calcitonin is the principal biochemical marker in MTC; it is used for detection, staging, postoperative management, and prognosis.[1] The higher that the calcitonin levels are above normal, the greater the likelihood of MTC; basal levels of >100 pg/mL have been found to have 100% positive predictive value for MTC.[1, 4] Very rarely, patients with clinically apparent MTC may not have elevated calcitonin levels.

Occult MTC is rare, but clinically significant. If calcium stimulation testing cutoff data become well-validated, calcitonin screening is likely to be more widely used in the diagnostic workup for thyroid nodules in the United States.[5]

Machens et al found that in RET carriers who are at risk for MTC but have not yet undergone treatment, calcitonin levels can be used to determine the need for lymph node dissection.[6] In their study of 308 RET carriers, all patients with node-positive MTC had elevated basal calcitonin levels (91.4 pg/mL or higher); no patients with normal pretherapy calcitonin levels had lymph node metastasis. These researchers suggest that unless clinical evidence indicates a need for it, RET carriers with normal pretherapeutic basal calcitonin levels may forgo lymph node dissection.

Traditionally, a pentagastrin-induced rise in calcitonin secretion has been used to diagnose MTC; however, pentagastrin is not available in the United States, and DNA testing for RET has replaced this diagnostic method in familial cases. However pentagastrim stimulation testing is used in European countries to further delineate extent of disease. 

In addition to occurring in medullary thyroid cancer (MTC), elevated calcitonin results may also be seen in patients with any of the following:

  • Hypercalcemia
  • Hypergastrinemia
  • Neuroendocrine tumors
  • Renal insufficiency
  • Papillary and follicular thyroid carcinomas
  • Goiter
  • Chronic autoimmune thyroiditis
  • Prolonged treatment with omeprazole (greater than 2 to 4 months), beta-blockers, and glucocorticoids

In addition, the presence of heterophilic antibodies to calcitonin can falsely elevate serum calcitonin levels.

With treatment, serum calcitonin concentration falls slowly in some patients, with the nadir not being reached for several months. However, in patients who are surgically cured, calcitonin levels begin to rapidly decline within the first postoperative hour. Therefore, normal calcitonin levels within the first few weeks may indicate biochemical remission, although the converse is not true. Elevated levels in the immediate postoperative period do not necessarily indicate persistent disease.

Carcinoembryonic antigen

Assessment of carcinoembryonic antigen (CEA) levels is used for detection, postoperative management, and determining prognosis. However, elevated CEA levels can also occur in patients with any of the following:

  • Heterophilic antibodies
  • Gastrointestinal tract inflammatory disease
  • Benign lung disease
  • Nonthyroid malignancies (eg, lung cancer, colon cancer)
  • Cigarette smoking

Screening studies in patients with MEN

Consider a 24-hour urinalysis for catecholamine metabolites (eg, vanillylmandelic acid [VMA], metanephrine) to rule out concomitant pheochromocytoma in patients with MEN type 2A or 2B. Pheochromocytoma must be treated before MTC.[1]

Obtain screening for the development of familial MTC in family members of patients with a history of MTC or MEN 2A or 2B. Screen all family members for missense mutation in RET in leukocytes. Finding a RET mutation in an asymptomatic family member should lead to discussion and pursuit of a prophylactic total thyroidectomy (see Treatment).

Imaging Studies

Patients in whom medullary thyroid carcinoma (MTC) is diagnosed or suspected on the basis of fine needle aspiration findings or calcitonin levels should undergo preoperative ultrasonography to detect lymph node metastases. The study should be performed by an experienced operator and should include the superior mediastinum and the central and lateral neck compartments.[1]

In a study of 134 patients with MTC, suspicious findings on preoperative ultrasonography were associated with disease aggressiveness. Patients judged to be at risk for malignancy on the basis of ultrasound (n= 89) more often had metastatic lymph nodes and extrathyroid invasiveness. Suspicious ultrasound results were significantly correlated with advanced stage disease, with an odds ratio of 5.5. Mean serum calcitonin values before and after surgery were significantly higher in the suspicious ultrasound group.[7]

Patients with regional lymph node involvement or calcitonin levels >400 pg/mL should undergo preoperative computed tomography (CT) scanning of the chest and neck, as well as three-phase, contrast-enhanced, multidetector liver CT or contrast-enhanced magnetic resonance imaging (MRI) to detect metastatic disease.[1]  The liver is the most common site of metastases in patients with MTC, occurring in approximately 45% of patients with advanced disease. Liver metastases are best identified with three-phase contrast-enhanced liver CT or contrast-enhanced liver MRI. 

The sensitivity of FDG-PET scanning for detecting metastatic disease is variable but improves with higher calcitonin levels (sensitivity 78% for basal calcitonin value above 1000 pg/mL, versus 20% for levels below 1000 pg/mL in one study. Imaging with 111-In-octreotide or 99m-Tc-DMSA is not currently recommended for routine initial screening for metastatic disease.

Procedures

Fine-needle aspiration (FNA) yields cytologic information, allowing diagnosis of MTC.[8] The sensitivity of FNA is improved by the addition of immunohistochemical staining for calcitonin.

Histologic Findings

Grossly, medullary thyroid carcinoma (MTC) resembles a well-circumscribed off-white nodule with a rough texture. Microscopically, it contains nests of round or ovoid cells without follicle development because these cells originate from the calcitonin-producing parafollicular C cells of the thyroid. A fibrovascular stroma is usually intercalated between cells. Sometimes, amyloid material, consisting of calcitonin prohormone, may occur in the MTC stroma. Perhaps most importantly, immunohistochemical diagnosis of MTC can be made by demonstrating calcitonin using radioactive calcitonin antiserum against MTC cells.

Staging

A 2009 article argued that using the 1997 TNM staging criteria is more accurate for medullary thyroid carcinoma than the 2002 criteria in terms of assessing prognosis. Under the 2002 criteria, a significantly higher percentage of patients were classified as having stage IV disease. The authors indicated that elevated calcitonin that remains stable often does not indicate a poor outcome, and patients with lymph node metastases but no distant disease would be better classified as having stage III cancer.[9]

See Thyroid Cancer Staging for summary tables.

Other Tests

 

 

 

Treatment

Approach Considerations

Medullary thyroid cancers (MTCs) are neuroendocrine tumors of thyroid parafollicular cells that do not concentrate iodine. The primary treatment for MTC is extensive and meticulous surgical resection. There is a limited role for external-beam radiotherapy (EBRT).

In cases of metastasis, the approach depends on the severity and rate of progression of disease. Metastatic MTC can be treated with limited surgical resection, EBRT in certain situations, or medical management with tyrosine kinase inhibitors (TKIs) or other agents. 

Metastatic disease

Asymptomatic metastatic tumors (generally less than 1 to 2 cm in diameter) growing in diameter less than 20% per year should be monitored for progression, with imaging every 6 to 12 months.

For other patients, first-line treatment is surgery or palliative EBRT. If they are not candidates for surgery or radiotherapy, systemic treatment as part of a clinical trial may be the best option. Other options include TKI therapy, such as with cabozantinib or vandetanib or sorafenib or sunitinib.

Cytotoxic agents are used for metastatic MTC only if the patient is unable to participate in clinical trials or experiences intolerance or failure of TKIs. Most regimens combine dacarbazine with other agents, including vincristine, 5-fluorouracil, cyclophosphamide,  streptozocin, or doxorubicin. No one combination has demonstrated a significant advantage over others. 

 Clinical trials involving injection of autologous dendritic cells are ongoing, with mixed responses.[10]

Radioimmunotherapy using anti–carcinoembryonic antigen/anti-diethylenetriamine pentaacetic acid (DTPA)–indium recombinant bispecific antibody (BsMAb), followed 4 days later by a 131I-labeled bivalent hapten, resulted in a median overall survival of 110 months compared with 60 months in a contemporaneous untreated cohort.[11]

Peptide receptor radionuclide therapy produces a cytotoxic effect through the binding of a radiolabeled ligand to its respective receptor expressed on a tumor’s surface. Phase 2 trials in patients with metastatic MTC whose tumors expressed somatostatin or cholecystokinin (CCK) receptors have demonstrated some benefit.[10]

Medical Care

In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in medullary thyroid cancer.  Activating mutations of the RET tyrosine kinase receptor in medullary thyroid carcinoma makes MTC a good model for the use of small organic molecule tyrosine kinase inhibitors for treatment of metastatic disease. Clinical trials have shown promising results and tolerable toxicity.[12]

Vandetanib (Caprelsa) and cabozantinib (Cometriq) are tyrosine kinase inhibitors approved  for progressive, metastatic medullary thyroid cancer. These agents target various tyrosine kinases including MET, RET, and VEGFR-2.

The FDA approval of vandetanib was based on the results of the ZETA study, a phase III, double-blind trial that randomized 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) or placebo (n=100). Participants randomized to vandetanib showed a statistically significant improvement in progression-free survival (PFS) when compared to those randomized to placebo (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.53; p <0.0001). This difference reflects a 65% reduction in risk for disease progression. Median progression-free survival was 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm. At the primary PFS analysis, no significant overall survival difference was noted.[13, 14, 15]

Approval for cabozantinib was based on the EXAM clinical trial, an international, multicenter, randomized study that included 330 patients with progressive, metastatic medullary thyroid carcinoma. A statistically significant prolongation in progression-free survival was seen with cabozantinib compared with placebo (11.2 vs 4.0 months; p <0.0001). Partial responses were observed only among patients in the active treatment arm (27% vs 0%; p <0.0001), and more patients in the cabozantinib group than in the placebo group were alive and free of disease progression at 1 year (47.3% vs 7.2%). Median duration of response was 14.7 months.[16]

See Thyroid Cancer Treatment Protocols for summarized information.

Surgical Care

Surgical treatment goals of medullary thyroid carcinoma (MTC) are as follows:

  • Provide local control of the cancer

  • Maintain laryngoesophageal function (speech and swallowing)

  • Tailor surgical treatment according to the type of MTC presentation (ie, sporadic, familial)

Sporadic MTC

Sporadic MTC occurring in patients presenting with a palpable thyroid nodule verified by fine-needle aspiration is treated as follows:

  • Perform a total thyroidectomy and central neck dissection for cases of symptomatic (clinically detected) MTC.

  • For patients with microscopic involvement of regional lymph nodes, advocate a central neck dissection, which involves complete dissection of structures and removal of node-bearing tissue between the hyoid bone and innominate vessels, sternothyroid resection, removal of paratracheal lymph nodes, and possible thymectomy.

  • Autograft an inferior parathyroid gland that is histologically confirmed as cancer-free into the sternocleidomastoid or forearm muscle.

  • In palpable lymph node disease, perform a modified radical neck dissection. For increasing calcitonin levels, a reoperative neck dissection may be indicated.

  • In a 2009 retrospective review of elective superior mediastinal neck dissections for thyroid carcinomas, the authors concluded that "elective transcervical superior mediastinal dissection was commonly positive in patients with papillary, medullary, and anaplastic thyroid carcinomas. A transcervical approach may be safely performed without sternotomy to the level of the brachiocephalic vein." They pointed out that further studies are needed to determine the impact of elective superior mediastinal lymph node dissections on survival.[17]

Familial MTC

Prophylactic thyroidectomy is indicated for carriers of RET mutations who have no apparent disease but are at risk for aggressive MTC. Guidelines from the American Thyroid Association classify RET carriers into four risk levels, on the basis of the particular mutation involved. The age at which thyroidectomy is recommended corresponds to the level of risk and varies from as soon as possible within the first year of life (for those at highest risk) to beyond 5 years of age, provided that stringent criteria are met.[1]

Perform a total thyroidectomy with a central neck dissection or modified radial neck dissection for patients with clinically detectable disease evidenced by increased calcitonin levels, thyroid nodule on ultrasonography, or findings on physical examination. MTC is diagnosed after thyroidectomy in approximately 10-15% of cases.

Patients with persistently elevated serum calcitonin levels, positive RET findings, or nodal disease are good candidates for completion thyroidectomy and lymph node dissection.[18] However, patients with undetectable calcitonin levels, negative RET test findings, and no ultrasonography abnormalities may be conservatively monitored.

Consultations

Consultations may include the following:

  • General physician

  • Head and neck surgeon

  • Endocrinologist

  • Geneticist, for cases of inherited MTC such as in patients with MEN 2 syndromes.

  • Oncologist

 

Guidelines

Guidelines Summary

Guidelines Contributor: Kemp M Anderson Medical University of South Carolina College of Medicine

The following organizations have released guidelines for the diagnosis and/or management of thyroid cancer:

  • American Thyroid Association (ATA) [1, 19, 20]
  • National Comprehensive Cancer Network (NCCN) [21]
  • American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA)(diagnosis only) [22]

Prevention

The familial medullary thyroid carcinoma (MTC) syndromes consist of multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC. They are inherited in an autosomal dominant fashion. Children inheriting any of these syndromes have a 100% risk of developing MTC.

MEN 2A (Sipple syndrome) consists of MTC, pheochromocytoma (in 50% of patients), and hyperparathyroidism (10-20% of patients). MEN 2B consists of MTC, pheochromocytoma (in 50% of patients), marfanoid habitus, and ganglioneuromatosis. FMTC consists of MTC alone.

MTC in MEN 2B has the most aggressive biologic features. In this situation, MTC usually develops around 10 years of age, and it has a high propensity for rapid growth and metastasis. MTC in MEN 2A can appear in the first decade of life, and it almost always develops by the second decade. MTC in FMTC usually develops during adulthood.

Genetic testing is now the mainstay in the diagnosis of the familial MTC syndromes. Germline RET proto-oncogene mutations (on chromosome arm 10q) discovered in these syndromes include the following[1] :

  • MEN 2A – Majority of cases show substitutions of conserved cysteine residues in exons 10 and 11
  • MEN 2B – 95% of cases show threonine-for-methionine substitution in codon 918 of exon 16.
  • Familial MTC - Most commonly seen with mutations in exons 10, 13 & 14

Guidelines from the American Thyroid Association (ATA) recommend prophylactic thyroidectomy for individuals that have a documented RETmutation and are at risk for aggressive medullary thyroid carcinoma.[1]

The original ATA guidelines[1] stratified risk level of RET carriers into four categories, A through D, based upon the increasing aggressiveness of the particular mutation. Due to some confusion and lack of uniformity with other staging guidelines, the revised ATA guidelines[20] transition category D to “highest risk” (HST), transition category C to “high risk” (H), and combine categories B and A into “moderate risk”. The risk stratification, screening schedules, and prophylactic thyroidectomy schedules are described in the table below.

Table. Revised ATA MTC Risk Levels and Pediatric Recommendations (Open Table in a new window)

Risk Level

RETcodon Mutation

Possible Diagnoses

Prophylactic Thyroidectomy

Recommendations

Follow-up

Highest Risk (HST)

M918T+All MEN2B

MEN2B

Within the first year of life or the first months of life based upon specialist and parental discussions. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection.

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually; begin screening for pheochromocytoma at age 11 yr

High Risk (H)

C634, A883F

MEN2A

At or before age 5 yr, to be determined on the basis of serum Ctn

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually. Begin screening for pheochromocytoma at age 11.

Moderate Risk (MOD)

All other mutations

MEN2A

When serum Ctn becomes elevated or in childhood to avoid lengthy evaluation period.

Evaluate every 6 months for 1 year. Annual follow-ups thereafter if serum Ctn is normal or undetectable. Begin screening for pheochromocytoma at age 16 yr

CEA=carcinoembryonic antigen;  Ctn=calcitonin; MEN=multiple endocrine neoplasia; US=ultrasound

Diagnosis

All the guidelines advocate ultrasound evaluation of thyroid nodules along with measurement of serum thyroid-stimulating hormone (TSH) levels to determine whether a fine needle aspiration biopsy (FNAB) is indicated. A routine measurement of serum thyroglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended because Tg levels are elevated in most benign thyroid conditions.[19, 21, 22]

Although all the guidelines recommend FNAB as the procedure of choice in the evaluation of solid thyroid nodules, there is variance in the size of the nodule as an indication for FNAB, as follows[19, 21, 22] :

  • >0.5 cm in diameter (ATA) [19]
  • >1 cm, in the absence of suspicious sonographic features (AACE/AME/ETA) [22]
  • >1 cm if suspicious sonographic features are present; >1.5 cm if no suspicious sonographic features are present (NCCN) [21]

AACE/AME/ETA and NCCN suggest a serum calcitonin assay as an optional test, 56 but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence. 1 All three guidelines recommend radionuclide imaging in patients with a low TSH level.[19, 21, 22]

Patients with medullary thyroid carcinoma (MTC) can be identified by pathologic diagnosis or by prospective genetic screening. According to the revised ATA guidelines, an FNAB result suspicious for MTC should prompt the following[19] :

  • Ultrasound of the neck
  • Serum calcitonin assay
  • Serum carcinoembryonic antigen (CEA) measurement
  • DNA analysis for  RET germline mutation

According to 2009 ATA guidelines, a calcitonin level >100 pg/mL should be considered suspicious of MTC [1] . Although calcitonin is a valuable tumor marker in patients with MTC, the 2015 Revised ATA guidelines note that clinical judgment should be exercised in the interpretation of calcitonin test results. Serum levels can be falsely high or low in a variety of clinical diseases, can be elevated in children under 3 years of age, and can be higher in males than females.[20]

The NCCN recommends the following diagnostic procedures when FNAB results indicate MTC5:

  • Basal serum calcitonin level
  • CEA level
  • Pheochromocytoma screening
  • Serum calcium assay
  • Consider genetic counseling
  • Screen for  RET proto-oncogene mutations (exons 10, 11, 13-16)
  • Thyroid and neck ultrasound (including central and lateral compartments), if not previously done
  • Consider evaluation of vocal cord mobility
  • Consider contrast-enhanced CT of chest and mediastinum or MRI if N1 disease or calcitonin >400 pg/mL

Treatment

The National Comprehensive Cancer Network (NCCN) guidelines recommend total thyroidectomy and bilateral central neck dissection (level VI) for all patients with medullary thyroid carcinoma (MTC) whose tumor is ≥1 cm or who have bilateral thyroid disease, as well as the following[21] :

  • Therapeutic ipsilateral or bilateral modified neck dissection for clinically or radiologically identifiable disease (levels II–V)
  • Prophylactic ipsilateral modified neck dissection for high volume or gross disease in the adjacent central neck may be considered

External beam radiation therapy (EBRT) is an option for treatment of incomplete tumor resection when further surgical resection is no longer possible. EBRT can also be considered for adjuvant treatment for extrathyroidal extension (T4a or T4b) with positive margins

Other therapy considerations are as follows:

  • Total thyroidectomy is recommended and neck dissection can be considered for those whose tumor is <1 cm and for unilateral thyroid disease
  • Radioiodine (131I) therapy is not effective

Suppression of thyroid-stimulating hormone (TSH) is not appropriate; TSH is kept in the normal range by adjusting levothyroxine dose.

  • Pheochromocytoma removal prior to thyroid surgery by laparoscopic adrenalectomy, and treatment preoperatively with alpha-adrenergic blockade (phenoxybenzamine) or with alpha-methyltyrosine to avoid a hypertensive crisis during surgery
 

Medication

Medication Summary

Although surgery remains the standard treatment for medullary thyroid carcinoma (MTC), several medications have entered clinical trials. For the most part, these are tyrosine kinase inhibitors that target vascular endothelial growth factor receptors. Partial response rates of up to 30% have been reported in single-agent studies, but prolonged disease stabilization is more common.[23] For example, a phase II study of motesanib—a highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit—has been conducted in 91 patients with MTC. The objective response rate was low, but 81% of patients achieved stable disease during treatment.[24] In addition, sorafenib and sunitinib, which are approved for other malignancies, are being used selectively for patients who do not qualify for clinical trials.[23]

Vandetanib and cabozantinib are tyrosine kinase inhibitors approved by the FDA for treatment of symptomatic or progressive, metastatic medullary thyroid cancer.

Tyrosine Kinase Inhibitors

Class Summary

These agents target various tyrosine kinases including MET, RET, and VEGFR-2.

Vandetanib (Caprelsa)

Tyrosine kinase inhibitor (TKI) with selective activity against RET, VEGFR-2, and EGFR. Indicated for treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Cabozantinib (Cometriq)

Cabozantinib is a tyrosine kinase inhibitor that targets RET, MET, VEGFR-1, -2, and -3, KIT, TrkB, FLT-3, AXL, and TIE-2 pathways; these tyrosine kinases are involved in both normal cellular function and pathologic processes (eg, oncogenesis, metastasis, tumor angiogenesis, and maintenance of tumor microenvironment). It is indicated for treatment of progressive, metastatic medullary thyroid cancer.

 

Follow-up

Further Outpatient Care

Measure calcitonin and carcinoembryonic antigen (CEA) levels after thyroidectomy. Patients with undetectable calcitonin—or, in patients with sporadic MTC who have undergone hemithyroidectomy, calcitonin levels within the normal reference range—should have follow-up testing every 6-12 months.

Detectable CEA levels after total thyroidectomy, or above-normal levels after hemithyroidectomy, mandate further assessment with imaging studies, as per American Thyroid Association guidelines. If calcitonin becomes detectable after total thyroidectomy but imaging studies do not identify disease or if calcitonin levels rise after hemithyroidectomy, doubling time of calcitonin and CEA levels may be used to assess tumor progression.[1] In one study, 94% of patients with doubling times shorter than 25 months had progressive disease and 86% of patients with doubling times longer than 24 months had stable disease.[25]

Further intervention may include the following:

  • Perform reoperative cervical exploration for isolated recurrent cervical disease (without distant metastases) identified by ultrasonography or CT scanning
  • Identification of distant metastatic disease may require laparoscopy with probe ultrasonography to detect liver surface lesions and bone scanning to detect osseous disease
  • Selective hepatic venous sampling for liver metastases is an experimental procedure that is used to detect intrahepatic lesions with greater sensitivity
  • If metastatic workup findings are negative in a patient with elevated plasma calcitonin levels, elective cervical lymph node dissection or modified radial neck dissection may be performed.

For patients with undetectable calcitonin and normal CEA levels, post-surgical followup may include the following:

  • Physical examination twice yearly for 2 years and then yearly thereafter
  • Measurement of serum calcitonin and CEA levels twice yearly for 2 years and then yearly thereafter
  • Neck ultrasound 3 to 12 months postoperatively (depending on the extent of lymph node involvement prior to surgery) to establish a baseline; additional imaging is not required unless the calcitonin or CEA values rise during follow-up

Calcitonin values that remain ≥150 pg/mL 2 to 6 months after surgery increase the likelihood that the patient may have distant metastases. These patients should undergo neck ultrasound and additional imaging (eg, CT or MRI of neck, chest, and abdomen; bone scan or bone MRI in patients suspected of having skeletal metastases) to identify possible distant metastases. Adjuvant radiation has not been shown to influence 10 yr survival rates, however.

Further Inpatient Care

Thyroid hormone therapy and radiotherapy are not as effective as surgical treatment for medullary thyroid carcinoma (MTC). However, positive surgical margins or mediastinal extension may be an indication for adjuvant radiotherapy.

External beam radiotherapy may provide a palliative benefit in controlling symptoms from bony metastases.

Deterrence/Prevention

Management guidelines from the American Thyroid Association (ATA) recommend prophylactic thyroidectomy for individuals with documented RET mutation who are at risk for aggressive medullary thyroid carcinoma.[1] The ATA has proposed schedules for the recommended age of RET testing, first ultrasound, serum calcitonin level, and prophylactic surgery, depending on the level of risk; in those at highest risk, surgery is recommended within the first year of life.

Complications

Permanent hypoparathyroidism and recurrent laryngeal nerve palsy reportedly occur in less than 2% of virgin neck dissections. Reoperation is associated with a considerably higher risk of these injuries.

Prognosis

Prognosis depends on patient age, histologic grade, and status of surgical resection. Patients with a worse prognosis tend to be older, have higher-grade lesions, and have undergone incomplete surgical resection of the lesion.

A study by Rohmer et al concluded that disease-free survival (DFS) in younger patients (>21 y) with hereditary MTC was best predicted by TNM staging and preoperative basal CT level of less than 30 pg/mL.[26] Basal CT findings, class D genotype, and age were the key factors in deciding peroperatively timely surgery.

In a meta-analysis of 27 studies involving 984 MTC patients who underwent reoperation, Rowland and colleagues found that normalization of calcitonin after reoperation occurred in 16.2% of patients overall. Patients who underwent targeted selective lymph node removal procedures showed normalization of calcitonin in 10.5% of cases, while normalization was seen in 18.6% of those who underwent compartment-oriented procedures.[27]

Patient Education

For patient education resources, see the Endocrine System Center, as well as Thyroid Problems and Anatomy of the Endocrine System.