Medullary Carcinoma

The C cell is the cell of origin for medullary carcinoma and is at the basal portion of follicular epithelium adjacent to the basement membrane. C cells are best demonstrated by immunohistochemical stains for calcitonin and markers for neuroendocrine cells, such as neuron-specific enolase, chro-mogranin, and synaptophysin. The clinical syndromes encountered with C cells include

• C-cell hyperplasia

• Familial medullary carcinoma

• Nonfamilial or sporadic medullary carcinoma

Seventy-five percent of medullary carcinomas are sporadic and the remaining 25% are familial.

The familial forms are77

• Medullary thyroid carcinoma alone (familial MTC or FMTC).

• Multiple endocrine neoplasia type 2A (MEN 2A), characterized by medullary carcinoma of the thyroid gland, bilateral adrenal medullary hyperplasias or pheochromocytomas, primary hyperparathyroidism with parathyroid glandular hyperplasia, and congenital colonic aganglionosis (Hirschsprung disease).

• Multiple endocrine neoplasia type 2B (MEN 2B), defined by medullary carcinoma, pheochromocytomas, a marfanoid habitus with distinct facies, hyperex-tensibility of joints, hypertrophic corneal nerves, submucosal neuromas of the conjunctiva and tongue, and submucosal colonic ganglioneuromatosis.

C-cell hyperplasia is recognized as the precursor for MTCs in the familial forms.78 There are two types of hyperplasia, one associated with familial medullary carcinomas (neoplasm associated) and the second (physiologic hyperplasia) found with conditions such as autoimmune thyroiditis, occasionally with hypothyroidism, non-Hodgkin thyroidal lymphomas, and nodular and diffuse goiters with or without hyperthyroidism. Primary and secondary hyperparathyroidism has been associated with C-cell hyperplasia. The pathogenetic mechanisms for physiologic hyperplasia may be thyroid-stimulating hormone stimulation and hypercalcemia.

C-cell hyperplasia has also been described adjacent to thyroid tumors of follicular cell origin.78 No explanation for this phenomenon is available. In a few cases, mild increases in serum calcitonin have been demonstrated, and preoperative diagnoses of C-cell carcinomas have been considered.

In contrast to the familial forms of C-cell hyperplasia, physiologic hyperplasia appears to have extremely low potential for malignant change. Rare cases of small medullary carcinomas, existing with C-cell hyperplasia, have been reported in thyroid glands of patients with longstanding primary or secondary hyperparathyroidism and rarely when medullary carcinomas are found in glands affected by autoimmune thyroiditis.

Medullary carcinomas form discrete masses that are usually solid and well demarcated. They vary in size from a few millimeters to large masses that occupy an entire thyroid lobe. The neoplasms can be associated with massive metastases to regional lymph nodes.

Microscopically, the neoplasms are composed of oval and spindle cells, separated into organoid nodules by thin bands of collagen, similar to the pattern seen in carcinoids and paragangliomas (Fig. 25-4). Amyloid is present in 75% to 80% of the tumors.79 Amyloid stains pink with hematoxylin-eosin stain, and its presence is confirmed by the green birefringence

FIGURE 25-4. Medullary carcinoma: nests of ovoid cells surrounded by dense matrix (amyloid by Congo red stain) (arrow).

seen when examined by polarized light. The most dependable method for identifying C-cell carcinomas is an immunohistochemical stain for calcitonin.

The tumors are unilateral in the sporadic forms, whereas the familial tumors are usually bilateral and, when found unilaterally, are also multifocal. Only 6% of familial tumors occur unilaterally.77'79 Spread to lymph nodes is usually to the central and lateral compartments. In patients who present with no palpable tumors in the neck, metastases to lymph nodes are uncommon (10%). In contrast, patients with palpable neck masses have high rates of involvement of lymph nodes by metastases.77 79

Medullary carcinomas of all types represent approximately 7% of all thyroid carcinomas and, of these, 75% are sporadic. In sporadic cases, patients are usually in their fourth decade and present with unilateral lesions without associated endocrinopathy. The remainder occur as familial forms, inherited as autosomal dominant traits.

The most indolent and most difficult to detect is FMTC. MEN 2A may not be clinically expressed in 30% of patients by 70 years of age. Pheochromocytomas, usually bilateral, occur in approximately 50% of patients and hyperparathyroidism in approximately 20%. In MEN 2A, the thyroid carcinoma develops before the pheochromocytomas or parathyroid hyperplasia. MEN 2A can be associated with cutaneous lichen amyloidosis, Hirschsprung disease, or both.

Patients with MEN 2B have a marfanoid habitus, mucosal and intestinal neuromas, and medullary carcinoma. The patients have distinctive facies, with thick lips showing neuromas that also occur in the conjunctiva and tongue. Pheochromocytomas develop in 50% of patients, but unlike the situation in MEN 2A, parathyroid glandular hyperplasia does not. Hirschsprung disease, primarily a sporadic disease, has been described in patients with FMTC and MEN 2A with heterogeneous germline mutations of RET in some of the families.

Surgery, total thyroidectomy, is the preferred method of treatment for all medullary carcinomas, with resection of all affected lymph nodes in the central compartment. If the primary tumor is larger than 1.5 cm, the dissection is extended to include the lateral neck with removal of all affected lymph nodes. These tumors do not take up radioactive iodine, and there are no effective chemotherapeutic agents.

Preventive surgery in patients with MEN 2A and MEN 2B has become routine because of the ready availability of screening methods for the RET protooncogene.77'79 In patients with MEN 2A and FMTC, prophylactic surgery at 6 years of age is favored, and in patients with MEN 2B, thyroidectomies are recommended during infancy. The earlier operations in patients with MEN 2B are recommended because of the early development and aggressiveness of the carcinomas in these patients.

The clinical outcomes associated with the different forms of medullary carcinoma are

• All forms, 5-year survival rate, 78% to 91%; 10-year rate, 61% to 75%

• Sporadic MTC, corrected for stage, similar to MEN 2A

• FMTC, best survival rate

• MEN 2A, midway between sporadic MTC and 2B

• MEN 2B, worst survival rate

Tumors of C cells with cells in papillary and follicular patterns have been reported, and metastases with similar histologic patterns have been described.80"82 The cell of origin for such tumors has not been established. Their clinical behavior is similar to that of the usual medullary carcinomas.

C-cell adenomas have been described but have not been accepted as recognizable clinical entities.83

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