Poorly Differentiated and Anaplastic Thyroid Carcinomas

Poorly differentiated carcinoma is a rare thyroid tumor that arises from follicular cells and is characterized by a partial loss of thyroid differentiation and less favorable prognosis in comparison with well-differentiated papillary or follicular carcinomas.

Anaplastic (undifferentiated) carcinoma represents the most undifferentiated type of thyroid tumors. In thyroidectomy samples of poorly differentiated and anaplastic thyroid carcinomas, it is not infrequent to find areas of well-differentiated papillary, conventional follicular or oncocytic carcinoma. This suggests that these tumors may represent distinct steps in the step-wise progression: well-differentiated carcinoma derived from follicular cells → poorly differentiated carcinoma → anaplastic carcinoma.

In agreement with such a progression, some molecular alterations, considered to be early events in thyroid carcinogenesis (i.e., mutations of RAS and BRAF), are found in tumors with all levels of dedifferentiation, whereas other, late events (i.e., TP53 mutations) occur with increasing frequency in tumors that progressively loose thyroid differentiation.

Inactivating point mutations of the TP53 tumor suppressor gene are among the most common mutations found in human cancer.

In thyroid tumors, point mutations of TP53 are a late event, reported in 60% to 80% of anaplastic thyroid carcinomas and 15% to 30% of poorly differentiated carcinomas, but only in single cases of follicular and papillary carcinomas.

Most of them involve exons 5 to 8 of the gene and alter its DNA binding properties.

p53 inactivation in thyroid cells is not only responsible for accelerated tumor growth, but is also associated with the progressive loss of differentiated markers.

Indeed, the recovery of wild-type p53 expression in cultured thyroid anaplastic carcinoma cells leads to the reduction in proliferation rate, re-expression of thyroid-specific genes (e.g., TPO, PAX-8), and re-acquisition the ability to respond to thyroid-stimulating hormone stimulation. This suggests that the progressive loss of differentiation in poorly differentiated and anaplastic carcinomas is mediated, at least in part, by inactivation of the p53 gene.

It also points to the restoration of TP53 function as a possible therapeutic approach for these highly aggressive tumors. Indeed, viral TP53 gene therapy has been tested in preclinical and clinical trials for various cancer types, and is under evaluation for anaplastic thyroid carcinoma.

β-catenin is a cytoplasmic protein, which is encoded by the CTNNB1 gene and is an important intermediate in the wingless (Wnt) signaling pathway. In thyroid tumors, point mutations in exon 3 of CTNNB1 have been found in 25% of poorly differentiated carcinomas and 66% of anaplastic thyroid carcinomas, but not in well-differentiated carcinomas.

Most of the tumors carrying the mutation also demonstrated an aberrant nuclear expression of the protein determined by immunohistochemical analysis, although there was no full correlation between these findings.

Point mutations of the RAS genes have been reported in 18% to 27% of poorly differentiated carcinomas and in 50% to 60% of anaplastic thyroid carcinomas. It is likely that mutant RAS stimulates genomic instability in the affected cells and predisposes them to accumulation of additional genetic abnormalities, such as mutations of the TP53gene. This can be illustrated by a case report of an anaplastic carcinoma developed in a well-differentiated follicular carcinoma, where RAS mutation was found in both tumor components, whereas TP53 was only found in the anaplastic carcinoma.

BRAF mutations occur in approximately 15% of poorly differentiated carcinomas and approximately 20% of anaplastic carcinomas, typically in those tumors that also contain areas of well-differentiated papillary thyroid carcinoma. In these tumors, BRAF mutation is detectable in both well-differentiated and poorly differentiated or anaplastic tumor areas, providing evidence that it occurs early in tumorigenesis.

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