The most frequent neoplasia originating from the thyroid epithelium is Papillary thyroid carcinoma (PTC), accounting for about 80% of all thyroid cancers. Somatic chromosomal rearrangements involving prevalently RET and, to a less extent, NTRK1 loci, are implicated in the development of papillary carcinoma. These oncogenes are inappropriately expressed and participate in constitutive signaling, bypassing the need for receptor activation by growth factors. Mutant forms of RAS and BRAF can also constitutively stimulate BRAF and MEK respectively. The BRAF-MEK pathway can then activate ERK which enhances the expression of chemokines like CXCL1 and CXCL10 that promote cell proliferation and invasion.
Of all thyroid cancers, 15-20% are follicular thyroid carcinoma (FTC). The most distinctive molecular features of follicular carcinoma are aneuploidy, the high prevalence of RAS mutations and PAX8-PPAR-gamma rearrangements. The PAX8-PPAR-gamma oncoprotein inhibits the transcriptional activity of wild-type PPAR-gamma. The resultant disruption of several PPAR gamma dependent cellular pathways leads to malignant transformation.
Most poorly differentiated and undifferentiated thyroid carcinomas (UTC) are considered to derive from pre-existing well-differentiated thyroid carcinoma through additional genetic events. The nuclear accumulation of beta catenin and/or inactivation of p53 are events associated with UTC.