Anaplastic or undifferentiated carcinoma accounts for 5% to 10% of all primary malignant tumors of the thyroid (192) but in many centres this is decreasing with earlier detection of disease. These tumors are rapidly growing, with massive local invasion that usually overshadows the early metastases, most frequently to lung, adrenals and bone (4,5). They are highly lethal with a 5 year survival rate of 7.1% (193) and a mean survival period of 6.2 to 7.2 months (193,194).
Microscopically, anaplastic carcinomas exhibit wide variation. Three general patterns are recognised but most tumours manifest mixed morphology:
The most common type is the giant cell variant; as the name suggests, these tumors are composed predominantly of large cells with abundant amphophilic or eosinop-hilic, often granular cytoplasm and bizarre, often multiple, hyperchromatic nuclei (Figure 18). Some have round, densely acidophilic intracytoplasmic hyaline globules. These tumors grow in solid sheets; artefactual tissue fragmentation may simulate an alveolar pattern.
The squamoid variant is composed of large, moderately pleomorphic epithelial cells that form nests, resembling squamous carcinoma (Figure 19). They may even form keratin pearls.
Spindle cell anaplastic carcinomas have a fascicular architecture and dense stromal collagen with spindle-shaped tumor cells. They may resemble fibrosarcoma; the presence of scattered atypical cells and inflammatory infiltrates may suggest malignant fibrous his-tiocytoma. Prominent vascularization may suggest hemangioendothelioma (3,5,195).
In all three variants, mitotic figures and atypical mitoses are frequent. There is usually extensive necrosis and in some cases, necrosis may be so extensive that the only viable tumour is around blood vessels. Inflammatory infiltrates are associated with necrosis and the osteoclast-like giant cells that are occasionally found in these tumors have been shown by immunohistochemical studies to be reactive cells of monocytic/histiocytic lineage (196,197).
Anaplastic carcinomas are highly infiltrative. Malignant cells usually grow between residual thyroid follicles and invade skeletal muscle, adipose tissue and other perithy-roidal structures. Blood vessel invasion and thrombosis with or without tumour cell involvement is frequent.
The appearances of anaplastic carcinoma on FNA are quite varied and reflect the histologic type with giant cells or squamoid cells or spindle cells. There is high cellu-larity, with necrosis, acute inflammation and marked cellular pleomorphism. Mitoses are often atypical and no colloid is seen.
Immunohistochemistry is useful in only a limited fashion in the diagnosis of these lesions. Most anaplastic carcinomas do not contain convincing reactivity for thyroglob-ulin and the few that are positive have only a weak or focal reaction (194, 197-201). This staining must be interpreted carefully, since it may reflect trapped nontumorous follicles or follicular cells, and since thyroglobulin is known to diffuse into non-follicular cells (5). The epithelial nature of the tumor cells can be verified with stains for cytokeratins but again most undifferentiated lesions are negative for this marker. Squamoid areas may exhibit reactivity for high molecular weight keratins and/or epithelial membrane antigen (EMA) (194, 197-199). CEA reactivity may be found in the centre of squamous
nests (194,197). Anaplastic tumours have been reported to be positive for calcitonin, but this finding should alter the diagnosis to that of medullary carcinoma (5).
p53 mutations are common in anaplastic thyroid carcinomas (202-208); since mutated forms of this tumour suppressor gene have prolonged half lives, the application of immunohistochemistry has yielded positive results in these tumours (209,210). (Chapter 8).
By electron microscopy (196,198,201,211,212), there may be formation of intercellular junctions, microvilli, and basal lamina, providing evidence of epithelial differentiation. However, many tumors do not exhibit evidence of any differentiation. Their large nuclei have prominent nucleoli and clumped chromatin; usually the cytoplasm contains only poorly developed rough endoplasmic reticulum, scattered dense bodies, lipid droplets, numerous free ribosomes, mitochondria and lysosomes. Intermediate filaments (keratin or vimentin) may form filamentous whorls that correspond to the acidophilic hyaline globules seen by light microscopy. Secretory granules are not seen in these tumours.
Most anaplastic thyroid carcinomas are aneuploid on flow cytometry; this abnormality correlates with poor outcome (162).
Some tumors do not exhibit immunohistochemical or ultrastructural markers that allow classification as epithelial malignancies. Nevertheless, the diagnosis of anaplastic carcinoma should be favoured for pleomorphic lesions in older patients if they arise in the thyroid.
Small cell carcinomas and lymphomas constitute a common source of diagnostic error, often misclassified as anaplastic carcinomas (3,5,195,198). The former are usually poorly differentiated medullary carcinomas, which can also mimic giant cell or spindle cell anaplastic carcinomas; the latter are readily identified by staining for leukocyte common antigen (LCA) and other markers of lymphoid cells. Rarely, primary intrathyroidal thymoma may be mistaken for anaplastic carcinoma (213,214).
The reported association between well-differentiated thyroid carcinoma and anaplas-tic carcinoma ranges from 7% to 89% of cases, however, the lower figures are likely underestimates, attributable to inadequate sampling (3,193,194,198,215-217). The data suggest that anaplastic carcinoma originates most often in an abnormal thyroid; the tumor has a higher incidence in regions of endemic goitre and a history of goitre is reported in over 80% of cases (3,193). As stated above, nodular goitre is often the site of monoclonal proliferation, the first step in the hyperplasia-neoplasia sequence. However, it is difficult to document transformation of a benign lesion to a malignant tumor. Insular carcinoma appears to be intermediate in the spectrum, and may represent a transition form (190,217). The association of papillary carcinoma, particularly the more aggressive tall cell variant, with anaplastic tumors has also been described (3,217,218). Thyroid carcinomas can exhibit an entire spectrum of differentiation through insular to anaplastic foci. The significance of microscopic insular or anaplastic change is controversial; some people have suggested that focal microscopic dedifferentiation does not alter prognosis but others have shown that this finding alone is statistically significant as a marker of aggressive behaviour.
The factors underlying dedifferentiation in thyroid tumors remain to be established; age and radiation have been implicated (219,220). Clearly, the vast majority of well differentiated thyroid lesions do not undergo such transformation. A pattern of genetic mutations resulting in oncogene activation or loss of tumour suppressor gene activity has been proposed to correlate with the stepwise progression from adenoma to carcinoma and through the dedifferentiation process in thyroid (202,203).
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