Pathogenetic mechanisms in thyroid follicular-cell neoplasia

Key Points Thyroid tumours are the most common malignancy of endocrine organs, and incidence rates have steadily increased over recent decades. Most carcinomas that are derived from follicular epithelial cells are indolent tumours that can be effectively managed. However, a subset of these tumours can behave aggressively, and there is currently no effective form of treatment. Radiation exposure, iodine intake, lymphocytic thyroiditis, hormonal factors and family history all alter the risk of thyroid carcinoma. Alterations in key signalling effectors seem to be the hallmark of distinct forms of thyroid neoplasia. Mutations or rearrangements that involve mitogen-activated protein kinase (MAPK)-pathway effectors seem to be required for transformation. Signalling through growth factors and their receptors is considered essential for cancer progression, and some of these growth factors have been identified as modifiers of the behaviour of transformed thyroid cells. Cell-cycle regulators and adhesion molecules are altered in thyroid carcinomas, typically through epigenetic mechanisms that indicate progression to poorly differentiated or undifferentiated forms. Several molecules that are involved in the pathogenesis of thyroid cancers are emerging as diagnostic and/or prognostic tools for patient management. This paper examines recent advances in our understanding of the pathogenesis of thyroid cancer. This will help the diagnosis and therapy of what is one of the few malignancies whose incidence is increasing. Thyroid cancer is one of the few malignancies that are increasing in incidence. Recent advances have improved our understanding of its pathogenesis; these include the identification of genetic alterations that activate a common effector pathway involving the RET–Ras–BRAF signalling cascade, and other unique chromosomal rearrangements. Some of these have been associated with radiation exposure as a pathogenetic mechanism. Defects in transcriptional and post-transcriptional regulation of adhesion molecules and cell-cycle control elements seem to affect tumour progression. This information can provide powerful ancillary diagnostic tools and can also be used to identify new therapeutic targets.