Papillary thyroid carcinomas. Activation of the MAP kinase pathway is a feature of most papillary carcinomas. The most common mechanisms of MAP kinase signaling are: (1) rearrangements in genes that encode the receptor tyrosine kinases RET and NTRK1 (neurotrophic tyrosine kinase receptor 1); and (2) activating point mutations in BRAF, whose product is a component of the MAP kinase pathway (see
Fig. 20.14 ). One third to one half of papillary thyroid carcinomas harbor a gain-of-function mutation in BRAF, which is the most common driver mutation in this neoplasm. Since chromosomal rearrangements of the RET or NTRK1 genes and mutations of BRAF have redundant effects, papillary thyroid carcinomas demonstrate either one or the other molecular abnormality, but not both.
Follicular thyroid carcinomas. Follicular thyroid carcinomas frequently harbor driver mutations in RAS or in components of the PI3K/AKT signaling pathway. Both gain-of-function mutation in PI3K and loss-of-function mutations in PTEN, a negative regulator of PI3K, are seen. RAS and PI3K mutations also are found in benign follicular adenomas to and anaplastic carcinomas (see next) suggesting a shared histogenesis. One third to one half of follicular carcinomas also have a unique (2;3) (q13;p25) translocation that disrupts PAX8, a paired homeobox gene that is important in thyroid development, and the peroxisome proliferator–activated receptor gene (PPARG), whose gene product is a nuclear hormone receptor implicated in terminal differentiation of cells.
Anaplastic carcinomas. These highly aggressive tumors can arise de novo or, more commonly, by progression of a well-differentiated papillary or follicular carcinoma. Molecular alterations present in anaplastic carcinomas include those also seen in well-differentiated carcinomas (e.g., RAS or PIK3CA mutations), as well as additional mutations that are specific to anaplastic carcinoma. The most common of these unique mutations are loss-of-function mutations in TP53, which are believed to have an important role in the development of anaplastic carcinomas.
Medullary thyroid carcinomas. In contrast with the subtypes described earlier, these neoplasms arise from the parafollicular C cells, rather than the follicular epithelium. Familial medullary thyroid carcinomas occur in multiple endocrine neoplasia type 2 (MEN-2) (see later) and are associated with germ line RET proto-oncogene mutations that lead to constitutive activation of the RET tyrosine kinase receptor. RET mutations are also seen in approximately one-half of nonfamilial (sporadic) medullary thyroid cancers.
Environmental Factors. The major risk factor predisposing to thyroid cancer is exposure to ionizing radiation, particularly during the first 2 decades of life. In keeping with this finding, there was a marked increase in the incidence of papillary carcinomas among children exposed to ionizing radiation after the Chernobyl nuclear disaster in 1986. Deficiency of dietary iodine (and by extension, an association with goiter) is linked with a higher frequency of follicular carcinomas.
As mentioned earlier, papillary carcinomas are the most common form of thyroid cancer. These tumors may occur at any age, and they account for the vast majority of thyroid carcinomas associated with previous exposure to ionizing radiation.
Papillary carcinomas are solitary or multifocal lesions. Some tumors may be well circumscribed and encapsulated; others infiltrate the adjacent parenchyma and have ill-defined margins. The cut surface sometimes reveals papillary foci that point to the diagnosis (