Medullary Carcinoma

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Medullary carcinoma of the thyroid comprises 5-10% of all thyroid carcinomas (5). This lesion is usually readily recognised because of its unusual cytologic and histologic features but sometimes special investigation is required to distinguish it from follicular lesions or other tumours, including lymphomas and/or anaplastic carcinomas.

The aspirate from medullary carcinoma has a variable appearance. The cells may be spindle-shaped, columnar or plasmacytoid; they may even exhibit oncocytic or clear cell morphology. Nucleoli and nuclear pseudoinclusions are often seen. Amyloid is identified in up to 60% of cases as homogeneous, spherical or rod-shaped extracellular material which polarises with the Pap stain or the Congo Red stain. The diagnosis is confirmed by immunostaining for calcitonin or the demonstration of secretory granules on electron microscopy.

Figure 20. Medullary carcinoma of thyroid is derived from the calcitonin-producing C cells that are neuroendocrine cells. These lesions are composed of solid nests of epithelial cells with poorly defined cell borders. They often have stromal fibrosis and occasionally there is deposition of intensely eosinophilic material, amyloid, derived from the calcitonin precursor molecule.

Figure 20. Medullary carcinoma of thyroid is derived from the calcitonin-producing C cells that are neuroendocrine cells. These lesions are composed of solid nests of epithelial cells with poorly defined cell borders. They often have stromal fibrosis and occasionally there is deposition of intensely eosinophilic material, amyloid, derived from the calcitonin precursor molecule.

Medullary carcinoma has a wide range of histologic appearances (2,221). Typically, the tumors are composed of sheets or more usually nests of round, polyhedral or spindle-shaped cells which may exhibit palisading at the periphery (Figure 20). The stroma is vascular. There may be prominent amyloid in the stroma, which, when present, provides a helpful diagnostic marker. However, although amyloid is present in more than half of these tumours, it may be intracytoplasmic and difficult to identify without a high index of suspicion. In addition, amyloid may also be present in occasional non-medullary thyroid carcinomas (222).

Sometimes, fixation artefact produces a pseudopapillary appearance; areas of true papillary architecture may also be found and the distinction of such lesions from papillary carcinoma can be difficult (223). A pseudofollicular appearance frequently results from entrapped nonneoplastic thyroid follicles or rounded masses of amyloid and true glandular variants have been described. Dedifferentiation results in a small cell tumour morphology, which can mimic lymphoma. Oncocytic features may predominate and make the distinction of medullary from oncocytic follicular carcinoma difficult.

Foreign body giant cells may be associated with amyloid deposits and calcification may be identified. These features may result in difficult differential diagnosis. True psammoma bodies are generally not seen in these tumours but have been reported.

Staining for amyloid can be helpful. Congo Red staining is typical and the apple-green birefringence with polarised light is diagnostic. Nevertheless, as indicated, some follicular tumors may also contain amyloid stroma.

Immunohistochemical staining represents the gold standard for the diagnosis of medullary thyroid carcinoma. These tumours express cytokeratins, chromogranin A, and NSE, but the most specific diagnostic marker is calcitonin. The number of calcitonin-positive cells varies from case to case, but the diagnosis should be questioned in the absence of calcitonin staining. The amyloid in these tumours often stains for calcitonin, likely because the amyloid protein represents deposition of a precursor of the calcitonin molecule.

These tumours also stain for carcinoembryonic antigen (CEA) and the inverse relationship between the intensity of staining for calcitonin and that for CEA may be prognostically significant: tumors containing few calcitonin-positive cells and abundant CEA immunoreactivity are said to have a worse prognosis than the well differentiated tumours with strong calcitonin immunoreactivity (224,225). CEA is not identified in follicular thyroid tumors; occasional reports of positivity are attributable to use of antibodies that react with non-specific cross-reacting antigens (226). Therefore CEA positivity indicates the presence of medullary thyroid carcinoma or other lesions such as metastatic carcinomas or thymic carcinomas.

Medullary thyroid carcinomas also produce a number of other peptides including somatostatin, derivatives of the proopiomelanocortin molecule (ACTH, MSH, B-endorphin and enkephalin), serotonin, glucagon, gastrin, cholecystokinin, VIP, bombesin, and (5,227-229). Calcitonin gene-related peptide (CGRP) is also identified in normal C-cells as well as medullary thyroid carcinomas. Individual tumours may express a variety of these various hormones but none have been shown to correlate with altered prognosis (230).

Ultrastructural examination confirms the presence of cells that do not form desmo-somes but do show complex interdigitations of cell membranes. The cytoplasm contains characteristic membrane-bound secretory granules which usually are numerous and variable in size.

The importance of distinguishing this tumour from follicular lesions is two-fold. The first is for diagnostic classification and management considerations in the individual patient. These tumors do not preferentially take up iodine and therapy with radioactive iodine is not indicated; in contrast, expression of somatostatin receptors by some of these tumors (231) makes the octreoscan a feasible diagnostic tool to localise the primary lesion and to identify metastatic deposits (232) and somatostatin analoges may have applications in the management of disseminated disease (233). The other aspect of management involves the implications for both the patient and members of his/her family, since many of these tumours are hereditary (234).

The inherited forms of medullary carcinoma are of three types: familial medullary thyroid carcinoma alone (FMTC), multiple endocrine neoplasia (MEN) type IIA in which MTC is associated with pheochromocytomas, and MEN IIB in which the thyroid and adrenal proliferative disorders are associated with mucosal ganglioneuromas and a Marfanoid habitus. The inheritance of all three syndromes was mapped to the pericentromeric region of chromosome 10 by linkage analysis (235-237). Subsequently, mutations in exons 10 and 11 of the ret proto-oncogene in patients with FMTC or MEN IIA and at codon 918 in MEN IIB (238,239) have provided a more accurate marker of germline mutation and predisposition to this disease (240). Current recommendations suggest that family members of FMTC and MEN IIA kindreds have genetic screening early in life and affected members should undergo total thyroidec-tomy at around the age of 5 years. This age was chosen because of the early onset of medullary thyroid carcinoma in these familial forms of the disease; metastatic tumour has been found in patients as young as 6 years of age. Affected children with MEN IIB undergo surgery even earlier (241, Chapter 24).

Sporadic medullary carcinomas also may have mutations of ret in the same codons as the familial disorders (239,242); the mutation involved may have prognostic value (243). The presence of ret mutations in sporadic tumours indicates the importance of analysing DNA from white blood cells to establish that a mutation is germ line, therefore potentially hereditary. Other oncogenes and tumor suppressor genes have not been implicated in the pathogenesis of MCT: ras mutations are rare, c-myc, and c-erbB are not amplified (244,245), and p53 mutations are not found in these tumors (246).

Familial forms of medullary thyroid carcinoma usually result in multicentric disease as well as multicentric C-cell hyperplasia (247). Many definitions of C-cell hyperplasia have been offered, all requiring immunohistochemistry since C cells cannot be reliably recognised with routine histologic stains. Quantitation of C cells as well as geographic mapping throughout the gland must be performed (247,248). C cells are usually limited to the central portion of the junction between the upper and middle thirds of the lateral lobes where they are generally distributed singly rather than in clusters. Increased numbers of C cells (>7 cells per cluster), complete follicles surrounded by C cells, and distribution of cells beyond this geographic location are indicative of C-cell hyperplasia. The presence of C-cell hyperplasia usually indicates an inherited disorder rather than a sporadic lesion, however, C-cell hyperplasia can also be associated with chronic hypercalcemia, thyroid follicular nodular disease, and thyroiditis (249252).

The identification of oncogenic activation of ret in familial C cell disease has raised questions about the term "C cell hyperplasia". In this disorder, unlike other familial cancer syndromes that result from inactivation of tumour suppressor genes, each affected member is born with an activated oncogene. Theoretically, then, every C cell has already undergone transformation, since it does not appear to require a second hit to knock out protective mechanisms. If this proves to be true, it will suggest that the term "C cell hyperplasia" is a misnomer, since each C cell with its activated oncogene is a transformed cell that represents a site of neoplastic potential. This remains to be proven, however, and the mechanism of tumorigenesis in C cells of the thyroid, as it unfolds, will shed further light on the biology of neoplasia.

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