Thyroid carcinoma is the most common endocrine
neoplasm and the seventh most frequent human
malignancy. It can be distinguished into differentiated and undifferentiated. Differentiated
tumors include those arising from thyrocytes, i.e. papillary and follicular
carcinoma, while
medullary carcinoma originates from parafollicular or C cells.
Anaplastic carcinoma comprises undifferentiated
tumors. The factors inducing
thyroid carcinoma development are not fully understood despite some well-established associations, such as the one between ionizing radiation and
papillary carcinoma and that between
iodine deficiency and follicular
carcinoma. Genetic investigations of differentiated thyroid
tumors have documented mutation of genes involved in the regulation of MAP
kinase pathway activation in
papillary carcinoma, and of genes involved in the regulation of the
PI3 kinase pathway in follicular
carcinoma. Analysis of their
clinical course and of positivity for mutations has demonstrated that prognosis is greatly affected by the type of mutated gene. Genetic investigations therefore have the potential to direct diagnosis, but especially to tailor
therapy and follow-up to the individual patient and even the individual gene.
Anaplastic carcinoma, a highly aggressive, undifferentiated form, can arise as such or else be the de-differentiated progression of a papillary or a follicular
carcinoma. It displays a mutated tumor suppressor gene (p53), which is crucial in the regulation of cell apoptosis, in addition to the mutations found in papillary and follicular forms.
Medullary carcinoma is a
malignant neoplasm with an intermediate
clinical course between differentiated and undifferentiated forms. It manifests more frequently as a sporadic
neoplasm or as a familial MEN. The latter is a high-penetrance, autosomal dominant hereditary disorder. Identification of the gene responsible for
medullary carcinoma has radically changed the diagnostic approach to the familial forms, enabling early neonatal diagnosis of mutation carriers and of the disease, and early surgical approach by prophylactic
thyroidectomy. Genetic studies have significantly affected the endocrinologist's diagnostic approach, as in the case of
medullary carcinoma; over the next few years they are expected to provide further information to tackle papillary and
follicular thyroid carcinoma. This review addresses the main genetic mutations responsible for neoplastic transformation in thyroid disorders.