Type 2 Multiple Endocrine Neoplasia Workup

Perform genetic screening for RET mutations in all index patients. If a mutation is identified, also screen family members who are at risk.

For individuals identified with a mutation or for persons who are at risk, biochemical screening consists of ascertainment of baseline calcitonin levels and of serum calcium and parathyroid hormone (PTH) levels, along with urine collection for catecholamines and metanephrine concentrations. (However, a plasma metanephrine level can be used for screening.)

If a patient's calcitonin level is within reference ranges, a pentagastrin and/or Ca⁺⁺ stimulation test may be used as a guide to assess the necessity of a central compartment or modified neck dissection.

Patients who have been diagnosed with medullary thyroid carcinoma require serial calcitonin (+/- provocative testing) and carcinoembryonic antigen (CEA) testing to assess for persistent or recurrent disease.

Fine-needle aspiration

Avoid the removal of cells from thyroid masses for cytology in patients with type 2 multiple endocrine neoplasia (MEN 2) who have had their diagnosis previously confirmed by either genetic analysis or elevated calcitonin levels. These patients have an established diagnosis, and a biopsy increases the possibility of tumor spread. A fine-needle aspiration biopsy is primarily used in an index patient who presents with a thyroid nodule when the clinician considers the presence of medullary thyroid carcinoma to be unlikely.

Screening for medullary thyroid carcinoma is done with the pentagastrin stimulation test, with serum calcitonin measured at baseline and at 2, 5, and 10 minutes. False-positive and false-negative results have been reported.

Urinary catecholamines and metanephrines screen for pheochromocytomas. (If these are elevated, imaging studies of the adrenals are recommended.)

Serum calcium level and PTH levels screen for hyperparathyroidism. An inappropriately elevated PTH level in relation to the serum calcium is consistent with primary hyperparathyroidism. If the 24-hour urine calcium level is low, the presence of familial hypocalciuric hypercalcemic syndrome should be considered.

Perform computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the adrenals. A metaiodobenzylguanidine (MIBG) scan is useful for localizing pheochromocytomas.^{[8, 9, 10]}

If calcitonin levels are elevated at either baseline or with provocative testing, evaluate the chest and abdomen for metastatic disease. Available modalities include CT scanning, MRI, octreotide scanning, and, in some instances, laparoscopy.

Radionuclide scanning may reveal the extent of metastasis. OctreoScan provides a whole-body examination and is used to examine the spread of medullary thyroid carcinoma. The somatostatin analogue octreotide, which is used for the treatment of hormone-related symptoms, is labeled with the isotope indium-111 (¹¹¹ In) and injected intravenously. The next day, the patient is examined with a gamma camera, which can detect the accumulation of radioactivity.

The tumor in medullary thyroid carcinoma is well demarcated, firm, and grayish white. Polygonal cells are uniform, with finely granular eosinophilic cytoplasm with central nuclei. Amyloid formed from calcitonin molecules is often found. Other findings include the following:

• C-cell hyperplasia - Frequently found; is a precursor in the malignant transformation to medullary thyroid carcinoma.
• Pheochromocytomas - Benign tumors, often bilateral and multifocal, that arise from diffuse hyperplasia of the adrenal medulla
• Parathyroid hyperplasia - In this, overgrowth is the most common finding, although adenomatous changes occur in a small percentage of cases

TNM classification is used for postoperative staging. (T = the size of the primary lesion, N = the presence or absence of regional lymph node metastatic involvement, and M = the presence or absence of distant metastatic lesions.)

Primary lesions are designated as follows:

• T1 - Tumor 2cm or less in greatest dimension, limited to the thyroid
• T2 - Tumor greater than 2 cm but less than or equal to 4 cm; limited to the thyroid
• T3 - Tumor greater than 4 cm; limited to the thyroid
• T4a - Tumor of any size that extends extrathyroidally and invades subcutaneous soft tissues
• T4b - Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels

Regional lymph node metastatic involvement is designated as follows:

• N0 - No evidence of lymph node metastases
• N1 - Regional lymph node metastasis
• N1a - Metastasis to level VI (central compartment) cervical lymph node(s)
• N1b - Metastasis to unilateral or bilateral cervical nodes or to superior mediastinal lymph node(s)

Occurrence of distant metastatic lesions is designated as follows:

• M0 – No evidence of distant metastases exists
• M1 – Distant metastatic lesions exist

Postoperative staging is as follows:

• Stage 1 - T1,N0,M0
• Stage II - T2,N0,M0
• Stage III – (T3,N0,M0), (T1,N1a,M0), (T2,N1a,M0), (T3,N1a,M0)
• Stage IVA - (T4a,N0,M0), (T4a,N1a,M0), (T1,N1b,M0), (T2,N1b,M0), (T3,N1b,M0), (T4a,N1b,M0)
• Stage IVB - T4b, any N, M0
• Stage IVC - Any T, any N, and M1