Medullary Thyroid Carcinoma

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Twenty-five percent of all MTC cases are familial in origin. MTC originates from the parafollicular cells, or C cells, of the thyroid. These cells comprise 1% of the total thyroid mass and are dispersed throughout the gland, with the highest concentration in the upper poles. The C cells produce, store, and secrete calci-

Figure 17-1. Features of patients with hereditary MTC. A, Bisected thyroid gland from a patient with multiple endocrine neoplasia (MEN) type 11A showing multicentric, bilateral foci of medullary thyroid carcinoma. B, Adrenalectomy specimen from patient with MEN type IIB demonstrating pheochromocytoma. C, Megacolon in patient with MEN type IIB. D, Midface and tongue of patient with MEN type IIB showing characteristic tongue notching secondary to plexiform neuromas. A courtesy of Dr. S. A. Wells. B, C, and D courtesy of Dr. R. Thompson. Reproduced with permission from Moley JF. Medullary thyroid cancer. In: Clark OH, Duh QY, editors. Textbook of endocrine surgery. Philadelphia: WB Saunders; 1997.

Figure 17-1. Features of patients with hereditary MTC. A, Bisected thyroid gland from a patient with multiple endocrine neoplasia (MEN) type 11A showing multicentric, bilateral foci of medullary thyroid carcinoma. B, Adrenalectomy specimen from patient with MEN type IIB demonstrating pheochromocytoma. C, Megacolon in patient with MEN type IIB. D, Midface and tongue of patient with MEN type IIB showing characteristic tongue notching secondary to plexiform neuromas. A courtesy of Dr. S. A. Wells. B, C, and D courtesy of Dr. R. Thompson. Reproduced with permission from Moley JF. Medullary thyroid cancer. In: Clark OH, Duh QY, editors. Textbook of endocrine surgery. Philadelphia: WB Saunders; 1997.

Figure 17-2. Abdominal radiographs from a 1-month-old child with multiple endocrine neoplasia type IIA and Hirschsprung's disease. Note narrowing of rectosigmoid with proximal dilatation (left) and multiple dilated loops of small bowel with air-fluid levels (right). Reproduced with permission from Cohen MS et al.1

tonin. Although calcitonin has been shown to be integral in calcium homeostasis in other vertebrate species, its role in humans is unclear. C-cell hyperplasia is the first histologic abnormality in the progression toward development of MTC. In MEN type II, C-cell hyperplasia progresses from multifocal to diffuse hyperplasia to carcinoma. A lesion can be characterized as MTC by evidence of invasion through the follicular basement membrane. MTCs are well-demarcated, firm, gray-white tumors that may have a gritty consistency owing to calcification. His-tologically, MTC can be identified by calcitonin staining and by the presence of amyloid within the tumors (Figure 17-3). Hereditary MTC is often multifocal and develops within areas of C-cell hyperplasia. The hormone calcitonin is a specific tumor marker for MTC. Basal and stimulated serum calcitonin levels correspond to tumor load and are almost always elevated in patients with palpable thyroid tumors. MTCs may also secrete other hormones, including carci-noembryonic antigen. Secretory diarrhea and flushing, most often attributed to elevated calcitonin, are the main paraneoplastic manifestations of advanced MTC. These systemic symptoms have been identified in approximately 30% of patients with MTC and markedly elevated calcitonin levels.

Early diagnosis in MTC is critical as metastases occur in the early stages of disease. Lymph node metastases are rarely present in patients in whom MTC is discovered by genetic screening or by biochemical testing, without a palpable mass in the thyroid. In contrast, most cases of sporadic MTC and cases of hereditary MTC not detected by genetic screening present as a neck mass detected on physical examination. Diagnosis is made by biopsy (fine-needle aspiration cytology) and measurement of calcitonin levels.

MTC spreads within the central compartment to perithyroidal and peritracheal lymph nodes (level VI nodes) (Figure 17-4). The central compartment includes tissue on the trachea, extending laterally to the carotid sheath and from the hyoid bone to the innominate vein. Within this compartment, spread is commonly bilateral. Upper mediastinal nodes (level VII) are also frequently involved. Further lymphatic spread can also occur to the lateral neck compartment, including jugular (levels II, III, and IV), posterior triangle (level V), and supraclavicular nodes (Figure 17-5). Spread to the lower tracheobronchial lymph

Figure 17-3. Photomicrograph of medullary thyroid carcinoma. The photomicrograph shows nests and sheets of small, uniform cells with scant to moderate amounts of amphophilic cytoplasm infiltrating around normal thyroid follicles. Reproduced with permission from Moley JF, Lairmore TC, Phay JE. Hereditary endocrinopathies. Curr Prob Surg 1999;36:653-764.

Figure 17-3. Photomicrograph of medullary thyroid carcinoma. The photomicrograph shows nests and sheets of small, uniform cells with scant to moderate amounts of amphophilic cytoplasm infiltrating around normal thyroid follicles. Reproduced with permission from Moley JF, Lairmore TC, Phay JE. Hereditary endocrinopathies. Curr Prob Surg 1999;36:653-764.

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Figure 17-4. Schematic representation of the anatomic landmarks and lymph node compartments in the neck and upper mediastinum encountered in surgical reinterventions in medullary thyroid carcinoma. The central compartment is delimited inferiorly by the innominate vein, superiorly by the hyoid bone, laterally by the carotid sheaths, and dorsally by the prevertebral fascia. It comprises lymphatic and soft tissues around the esophagus as well as pretracheal and paratracheal lymph nodes, which drain the thyroid bed (level VI). The submandibular nodal group (level I) is subsumed in the central compartment by some classifications. The lateral compartments span the area between the carotid sheath, sternocleidomastoid muscle, and trapezius muscle. The inferior border is defined by the subclavian vein, and the hypoglossal nerve determines the superior boundary. The lymph node chain adjacent to the jugular vein is divided cranially to caudally in superior jugular nodes (level II), midjugular nodes (level III), and inferior jugular nodes (level IV). Lymph nodes situated in the posterior triangle between the dorsolateral sternocleidomastoid muscle, trapezius muscle, and subclavian vein are classified as level V nodes. Mediastinal lymphatic tissue is referred to as level VII lymph nodes. Reproduced with permission from Musholt TJ, Moley JF. Management of persistent or recurrent medullary thyroid carcinoma. Probl Gen Surg 1997;14:89-109.

Figure 17-4. Schematic representation of the anatomic landmarks and lymph node compartments in the neck and upper mediastinum encountered in surgical reinterventions in medullary thyroid carcinoma. The central compartment is delimited inferiorly by the innominate vein, superiorly by the hyoid bone, laterally by the carotid sheaths, and dorsally by the prevertebral fascia. It comprises lymphatic and soft tissues around the esophagus as well as pretracheal and paratracheal lymph nodes, which drain the thyroid bed (level VI). The submandibular nodal group (level I) is subsumed in the central compartment by some classifications. The lateral compartments span the area between the carotid sheath, sternocleidomastoid muscle, and trapezius muscle. The inferior border is defined by the subclavian vein, and the hypoglossal nerve determines the superior boundary. The lymph node chain adjacent to the jugular vein is divided cranially to caudally in superior jugular nodes (level II), midjugular nodes (level III), and inferior jugular nodes (level IV). Lymph nodes situated in the posterior triangle between the dorsolateral sternocleidomastoid muscle, trapezius muscle, and subclavian vein are classified as level V nodes. Mediastinal lymphatic tissue is referred to as level VII lymph nodes. Reproduced with permission from Musholt TJ, Moley JF. Management of persistent or recurrent medullary thyroid carcinoma. Probl Gen Surg 1997;14:89-109.

nodes is equivalent to distant metastases. In a recent report, we analyzed the distribution of nodal metastases in a series of MTCs that presented as a palpable neck mass and in which central and bilateral cervical nodes were removed and examined histologically. We found that the incidence of central (levels VI and VII) node involvement was extremely high (79%), regardless of the size of the primary tumor. There was also frequent involvement of ipsilateral (75%) and contralateral (47%) level II, III, and IV nodes.2

Primary MTC and tumor in lymph node metastases may involve adjacent structures by direct invasion or compression. Structures most commonly affected include the trachea, recurrent laryngeal nerve, jugular veins, and carotid arteries. Invasion of these structures may result in stridor, upper airway obstruction, hoarseness, dysphagia, and bleeding or arterial stenosis or occlusion. MTC in the thyroid or in cervical metastases may cause localized pain.

Distant metastases to the liver, lung, adrenal glands, and bone occur with large primary lesions. In a study from a Swedish registry, it was noted that MTC patients with a palpable mass in the neck had distant metastatic disease in 20% of cases, regardless of heritability.3 Furthermore, occult remote micrometastases are most likely the cause of most cases of persistent hypercalcitoninemia after extensive lymph node dissection.

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