Medullary Thyroid Cancer

Thyroid Factor

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ELECTRON KEBEBEW, MD ORLO H. CLARK, MD

Medullary thyroid cancer (MTC) is a relatively rare malignancy, accounting for 3 to 8% of all thyroid cancers; however, it is responsible for up to 14% of all thyroid cancer deaths.1-3 In 1959, MTC was described as a unique clinical entity by Hazard and colleagues.4 It is distinct from other thyroid carcinomas because it originates from parafollicular cells of the thyroid gland. Furthermore, MTC has a distinct clinical behavior, hereditary occurrence, and molecular biology. The tremendous advances and application of molecular medicine to patient care parallel the advances made in understanding the pathogenesis and genetics of MTC.3 MTC has been recognized to occur in hereditary and sporadic forms because of the early contributions of Sipple. The introduction of fine-needle aspiration (FNA) cytology has allowed for accurate preoperative diagnosis of MTC, which has allowed for the selection of the appropriate initial extent of surgical resection preoperatively. Measurement of basal and stimulated serum calcitonin (a tumor marker for MTC) levels has been instrumental for screening patients at risk for hereditary MTC and remains indispensable in the surveillance of patients for persistent or recurrent MTC after initial treatment. More recently, the identification of the RET proto-onco-gene, the gene responsible for hereditary MTC, has been effectively used to identify gene carrier status in affected families.5-8 Clinically, genetic screening has allowed for the identification of at-risk individuals at a young age, leading to prophylactic treatment of these patients sometimes even before the development of any neoplasia.7-9 Owing to these advances, the diagnosis and treatment of patients with MTC have improved immensely and have translated into improved patient outcome.10

EMBRYOLOGY, PHYSIOLOGY, AND PATHOLOGY

The parafollicular or C cells in the thyroid gland have a more distinct embryologic origin, phenotype, and function than the follicular cells of the thyroid gland. The C cells are derived from the neural crest cells that migrate during embryogenesis from the neuroectoderm (ultimobranchial pouch III) to reside adjacent to but outside the thyroid follicles. In a normal thyroid gland, C cells are infrequent and dispersed with no more than one to two C cells identified per high-power field. The largest concentration of C cells exists between the junction of the upper one-third and lower two-thirds of each thyroid lobe (Figure 3-1). This is the most common location where MTC or C-cell hyperplasia (CCH) develops in patients with hereditary MTC.

Although the function of C cells remains controversial, it has been shown that C cells regulate calcium hemostasis, albeit transiently, by affecting bone metabolism. Like most cells of neuroectodermal origin, C cells have an amine precursor uptake decar-boxylase system. C cells secrete calcitonin, a small polypeptide 32 amino acids long, after post-translational modification. Calcitonin is secreted into the plasma and binds calcitonin receptors on the osteoclast cell surface to inhibit bone resorption. Cal-citonin production in C cells is regulated at several levels: gene expression, post-transcription modification, and cellular secretion. Calcitonin expression in

Figure 3-1. Distribution of parafollicular cells (C cells) in the thyroid gland. The highest concentration of C cells is in the area between the upper one-third and lower two-thirds of each thyroid lobe. This is the usual location where C-cell hyperplasia and medullary thyroid cancer (MTC) originate in patients with hereditary MTC.

Figure 3-1. Distribution of parafollicular cells (C cells) in the thyroid gland. The highest concentration of C cells is in the area between the upper one-third and lower two-thirds of each thyroid lobe. This is the usual location where C-cell hyperplasia and medullary thyroid cancer (MTC) originate in patients with hereditary MTC.

the C cells can be inhibited by 1,25-dihydroxyvitamin D or glucocorticoids.1113 It can be enhanced by activation of the protein kinase A and protein kinase C intracellular pathways.1113 Calcium is the main physiologic, extracellular substance that regulates calcitonin secretion from C cells. Pentagastrin, P-adren-ergic agonists, and growth hormone-releasing factor have also been found to regulate calcitonin secretion from C cells.14-16 The increase in calcitonin secretion from C cells that occurs with calcium and pentagas-trin stimulation (calcitonin stimulation test) has been clinically useful for screening patients at risk for hereditary MTC and for patient follow-up to detect persistent or recurrent MTC.7 816 Calcitonin also may be secreted from Kulchitsky's cells of the lung, pituitary gland, thymus, hepatoma, and lung carcinoma or in benign liver disease. Although the calcitonin secreted by cells other than the C cells is usually pro-calcitonin, it is detected by most biochemical assays (immunochemical and radioimmunoassays).3 Indeed, these other sources of calcitonin account for false-positive results of calcitonin basal and stimulated screening tests. Today, the commercial availability of genetic testing for the RET proto-oncogene mutations has eliminated some of the problems associated with biochemical calcitonin screening testing in patients at risk of developing MTC.

In sporadic MTC, a large unifocal tumor is usually found, whereas in the hereditary forms of MTC, the tumors are usually bilateral and multicentric, with or without CCH present. CCH in hereditary MTC is generally regarded as a premalignant lesion, but this is less clear for sporadic MTC (Figure 3-2). CCH is usually of monoclonal cell origin and may have a diffuse or nodular pattern. CCH usually develops where the greatest number of C cells reside in the thyroid gland. To identify CCH or microscopic MTC, it is important to take thin (1 to 5 ^m) sections of the thyroid and perform a systematic complete histologic examination of the entire thyroid gland (Figure 3-3). Microscopic MTC is distinguished from CCH by invasion through the basement membrane of the thyroid follicle. Young patients undergoing preventive thyroidectomy, based on a positive genetic screening test, may only have CCH or no pathologic abnormality.9 Nonspecific CCH may occur with chronic lymphocytic thyroiditis, multinodular goiter, follicular neoplasm, lymphomas, and papillary thyroid cancer.17-20 In such a situation, CCH does not indicate a premalignant lesion.

RET Somatic mutation (~25% of sporadic MTC)

RET Somatic mutation (~25% of sporadic MTC)

Microscopic MTC

RET germline mutation

Second genetic hit

Mitogen stimuli

Figure 3-2. Multistep model for medullary thyroid carcinogenesis (MTC). Although C-cell hyperplasia is thought to progress to MTC in hereditary cases, this is less certain in sporadic MTC. In addition to RETmuta-tions, a second genetic defect or mitogen stimuli probably contribute to the development of MTC.

Microscopic MTC

RET germline mutation

Second genetic hit

Mitogen stimuli

Parafollicular cells

Figure 3-2. Multistep model for medullary thyroid carcinogenesis (MTC). Although C-cell hyperplasia is thought to progress to MTC in hereditary cases, this is less certain in sporadic MTC. In addition to RETmuta-tions, a second genetic defect or mitogen stimuli probably contribute to the development of MTC.

Parafollicular cells

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