Clinical Outcome, Role of BRAF\(^{V600E}\), and Molecular Pathways in Papillary Thyroid Microcarcinoma: Is It an Indolent Cancer or an Early Stage of Papillary Thyroid Cancer?

Abstract

Most human thyroid cancers are differentiated papillary carcinomas (PTC). Papillary thyroid microcarcinomas (PTMC) are tumors that measure 1 cm or less. This class of small tumors has proven to be a very common clinical entity in endocrine diseases. PTMC may be present in 30–40% of human autopsies and is often identified incidentally in a thyroid removed for benign clinical nodules. Although PTMC usually has an excellent long-term prognosis, it can metastasize to neck lymph nodes; however deaths related to this type of thyroid tumor are very rare. Few data exist on molecular pathways that play a role in PTMC development; however, two molecules have been shown to be associated with aggressive PTMC. S100A4 (calcium-binding protein), which plays a role in angiogenesis, extracellular matrix remodeling, and tumor microenvironment, is over-expressed in metastatic PTMC. In addition, the BRAF(^{V600E}) mutation, the most common genetic alteration in PTC, is present in many PTMC with extra thyroidal extension and lymph node metastasis. Importantly, recently developed selective [e.g., PLX4720, PLX4032 (Vemurafenib, also called RG7204)] or non-selective (e.g., Sorafenib) inhibitors of BRAF(^{V600E}) may be an effective treatment for patients with BRAFV600E-expressing PTMCs with aggressive clinical–pathologic features. Here, we summarize the clinical outcome, cancer genetics, and molecular mechanisms of PTMC.