AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

MTC has a genetic association with multiple endocrine neoplasia (MEN) type 2A and 2B syndromes, but it has an inheritable non-MEN mode of transmission.

Sporadic, or isolated, MTC occurs in 75% of patients, and familial MTC comprises the rest.

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

Advances in genetic testing in the past few years have revolutionized the management of this disease.

Pathophysiology

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 MEN syndromes, it always is 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 protooncogene, a receptor protein tyrosine kinase encoded on chromosome 10, have been recently classified into discrete subtypes; prophylactic thyroidectomy can now be offered to specific types of patients with this genetic abnormality.

Frequency

United States

MTC comprises less than 10% of all thyroid cancers. This figure translates into approximately 1000 diagnoses per year.

International

International incidence is similar to that in the United States.

Mortality/Morbidity

Isolated 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 MEN syndromes may have a more aggressive course, which also depends on associated comorbidity (eg, pheochromocytoma).

Interestingly, despite advances in genetic screening for the ret protooncogene, recent evidence has yet to show a definitive impact on disease prognosis in preliminary population studies.

Age

Peak incidence of isolated MTC occurs in the fifth or sixth decade of life, and peak incidence of MTC associated with MEN 2A or 2B occurs during the second or third decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

• MTC has a genetic association with MEN syndromes types 2A and 2B; however, it is inheritable by a non-MEN mode of transmission. Sporadic MTC occurs in 75% of patients, and familial MTC comprises the rest.
• Ret has led to MTC development in cells derived from neural crest tissue.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

VIPomas

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Obtain serum calcitonin levels to detect subclinical disease in the thyroid gland, cervical lymph nodes, or at distant sites.
• Traditionally, the pentagastrin-induced rise in calcitonin secretion has been used to diagnose medullary thyroid carcinoma (MTC); however, 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 diagnosed with MEN type 2A or 2B.
• Obtain screening for the development of familial MTC in family members of patients with history of MTC or MEN 2A or 2B.
• Screen all family members for missense mutation in ret in leukocytes.
• Pentagastrin-stimulated calcitonin levels may indicate subclinical disease. If this occurs, conduct a thyroidectomy.
• A positive ret in an asymptomatic family member should lead to discussion and pursuit of a prophylactic total thyroidectomy (see Treatment).

Imaging Studies

• Preoperatively performing cervical ultrasonography can detect lymph node metastases.
• CT scanning, MRI, and bone scanning can detect distant metastases to the liver, lung, bone, and brain.

Procedures

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

Histologic Findings

Grossly, 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.
• Treat patients with MEN 2A syndrome and preclinically detected MTC (via DNA ret analysis, calcitonin levels within the reference range, normal findings on cervical ultrasonography) by simple total thyroidectomy without cervical lymph node dissection.
  • The optimal timing for prophylactic thyroidectomy is controversial. Ideally, genetic testing should be performed shortly after birth. Performing total thyroidectomy before age 5 years for disease-free carriers of the ret mutation has been recommended. However, patients with MEN 2B syndrome should have a thyroidectomy as soon as possible after the first 6 months of life.
• 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Even though Ret kinase inhibitors have been shown to inhibit Ret kinase activity in vitro, studies are still in the early experimental phase. As no standard medications to treat MTC currently exist, the standard treatment is surgical.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 indicate adjuvant radiotherapy.
• A palliative benefit in controlling symptoms from bony metastases may be derived from external beam radiotherapy.

Further Outpatient Care

• Monitor calcitonin levels postoperatively to detect possible increasing levels, indicating recurrent and/or metastatic disease.
• 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.

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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Carlomagno F, Santoro M. Identification of RET kinase inhibitors as potential new treatment for sporadic and inherited thyroid cancer. J Chemother. Nov 2004;16 Suppl 4:49-51. [Medline].
• Chi DD, Moley JF. Medullary thyroid carcinoma: genetic advances, treatment recommendations, and the approach to the patient with persistent hypercalcitoninemia. Surg Oncol Clin N Am. Oct 1998;7(4):681-706. [Medline].
• Evans DB, Fleming JB, Lee JE, et al. The surgical treatment of medullary thyroid carcinoma. Semin Surg Oncol. 1999;16:50-63. [Medline].
• Fitze G. Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg. Dec 2004;14(6):375-83. [Medline].
• Gibelin H, Essique D, Jones C, et al. Increased calcitonin level in thyroid nodules without medullary carcinoma. Br J Surg. May 2005;92(5):574-8. [Medline].
• Hyer SL, Newbold K, Harmer C. Familial medullary thyroid cancer: clinical aspects and prognosis. Eur J Surg Oncol. May 2005;31(4):415-9. [Medline].
• Kebebew E, Greenspan FS, Clark OH, et al. Extent of disease and practice patterns for medullary thyroid cancer. J Am Coll Surg. Jun 2005;200(6):890-6. [Medline].
• Moley JF. Medullary thyroid cancer. Surg Clin North Am. 1995;75:405-20.
• Quayle FJ, Moley JF. Medullary thyroid carcinoma: including MEN 2A and MEN 2B syndromes. J Surg Oncol. Mar 1 2005;89(3):122-9. [Medline].
• Rosenthal MS, Pierce HH. Inherited medullary thyroid cancer and the duty to warn: revisiting Pate v. Threlkel in light of HIPAA. Thyroid. Feb 2005;15(2):140-5. [Medline].
• Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am. 1998;31:823-31.
• Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary thyroid carcinoma. World J Surg. 1996;20:88-93. [Medline].

Article Last Updated: Apr 18, 2006