Medullary Thyroid Carcinoma Workup

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

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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.

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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.

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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.

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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.

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Other Tests

 

 

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