eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Thyroid, Medullary Carcinoma

Anastasios K Konstantakos, MD, Clinical Associate Surgeon, Department of Cardiovascular Surgery, Billings Clinic, Billings, Montana

Updated: Sep 29, 2009

Introduction

Background

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.

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. 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 risk¹ ; prophylactic thyroidectomy can now be offered to specific types of patients with this genetic abnormality (see Prevention).

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.

Clinical

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 produce symptoms of weight loss, lethargy, and bone pain.

Physical

• 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.

Causes

• Medullary carcinoma of the thyroid (MTC) has a genetic association with multiple endocrine neoplasia (MEN) 2A and 2B; however, it is heritable 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.

Differential Diagnoses

Other Problems to Be Considered

VIPomas

Workup

Laboratory Studies

• According to the American Thyroid Association, preoperative laboratory testing in patients with possible medullary thyroid carcinoma (MTC) has 3 purposes¹ :
  • 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, identify primary hyperparathyroidism and/or pheochromocytoma —comorbid conditions that alter the surgical approach and surgical priorities.
  • Identify RET mutation carriers so that testing of appropriate family members can allow for early diagnosis and treatment of affected individuals.
• 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.
  • 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.⁵ 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 many other countries, and DNA testing for RET has replaced this diagnostic method in familial cases.
• 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
• Patients with regional lymph node involvement or calcitonin levels >400 pg/mL should undergo preoperative CT scanning of the chest and neck, as well as 3-phase, contrast-enhanced, multidetector liver CT or contrast-enhanced MRI to detect metastatic disease.¹

Procedures

• Fine-needle aspiration yields cytologic information, allowing diagnosis of MTC.⁶

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. 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

Treatment

Medical Care

In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in medullary thyroid cancer. They explained that the discovery of particular genetic abnormalities in genetic tumors reveals specific targets for therapy. In particular, 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. However, these studies are still in the early stages, and these therapies are not yet FDA approved.⁸

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 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.⁹
• 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 4 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.

Consultations

• Consult a general physician.
• Consult a head and neck surgeon.
• Consult an endocrinologist.
• Consult a geneticist for cases of inherited MTC such as in patients with MEN 2 syndromes.
• Consult an oncologist.

Medication

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.¹⁰ 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.¹¹ In addition, sorafenib and sunitinib, which are approved for other malignancies, are being used selectively for patients who do not qualify for clinical trials.¹⁰

Follow-up

Further Inpatient Care

• Role of adjuvant therapy
  • Thyroid hormone therapy and radiotherapy are not as effective as surgical treatment for medullary thyroid carcinoma (MTC).
  • Positive surgical margins or mediastinal extension may be an indication for adjuvant radiotherapy.
• A palliative benefit in controlling symptoms from bony metastases may be derived from external beam radiotherapy.

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 levels after total thyroidectomy, or above-normal levels after hemithyroidectomy, mandate further assessment with imaging studies, as per American Thyroid Association guidelines.
  • I f 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.¹²
• Perform reoperative cervical exploration for isolated recurrent cervical disease (without distant metastases) as demonstrated by ultrasonography or CT scanning.
• Identification of distant metastatic disease may depend on 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 the presence of elevated plasma calcitonin levels, elective cervical lymph node dissection or modified radial neck dissection may be performed.

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; however, 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.

Patient Education

• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education articles Thyroid Problems and Anatomy of the Endocrine System.

Miscellaneous

Medicolegal Pitfalls

• Failure to adequately pursue diagnosis of other diseases (particularly pheochromocytoma) because of the association with MEN syndromes prior to embarking on surgical treatment for MTC is a potential pitfall.
• Failure to diagnose pheochromocytoma before operating on a patient for MTC can be fatal.
• Failure to diagnose RET -positive family members via genetic screening has recently become a unique source of medicolegal concern.

References

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Keywords

medullary thyroid carcinoma, MTC, thyroid cancer, thyroid cancer symptoms, thyroid cancer diagnosis, thyroid cancer treatment, thyroid tumor, multiple endocrine neoplasia, MEN, thyroidectomy, hypothyroidism

Contributor Information and Disclosures

Author

Anastasios K Konstantakos, MD, Clinical Associate Surgeon, Department of Cardiovascular Surgery, Billings Clinic, Billings, Montana
Disclosure: Nothing to disclose.

Medical Editor

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

eMedicine gratefully acknowledges the contributions of Debra J Graham, MD, to previous versions of this article.

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