**1. Introduction**

Thyroid cancers are the most common endocrine malignancies and have been shown to be one of the fastest-growing malignancies worldwide over the past two decades [1–3]. More than 95% of thyroid carcinomas derive from follicular epithelial cells, and up to 90% of all cases are papillary thyroid cancer (PTC) [4,5]. PTCs usually grow slowly and in an indolent fashion, and their association with lymph node metastasis varies from 30% to 90% of cases [6,7]. Most thyroid carcinomas can be successfully treated with surgical resection and radiometabolic therapy, but a subset of them will progress to refractory/metastatic disease. A role of primary importance in the aggressive behavior of solid and hematological neoplasms has long been identified in the transformation of the tumor microenvironment into an angiogenic microenvironment [8–10]. In fact, during tumor growth and progression, angiogenesis represents a biological process uncontrolled and unlimited in time; the angiogenic switch, characterized by the formation of new vessels (i.e., the transition from the avascular to the vascular phase), induces tumor cell proliferation, local invasion, and hematogenous metastasis [8,9,11]. Identification of tumor biomarkers that might predict disease progression is a medical need. Biomarkers based on genes that appear up- or down-regulated in thyroid cancers have shown poor predictive value and cannot distinguish benign from neoplastic nodules [12]. Moreover, traditional tissue biopsies are somewhat invasive, create discomfort to the patients, and are burdened by contamination from normal tissue and sampling errors [13].

Another area where biomarkers are lacking is the identification of disease persistence after surgery/medical therapy and the ability to distinguish between complete response after treatment or recurrence of disease [13].

Angiogenesis is an essential event for the progression of solid tumors and is promoted by angiogenic cytokines released in the tumor microenvironment by tumor and stromal cells, and can also be found and measured out with a serum assay in terms of circulating angiogenic factors [14]. This is a noninvasive, inexpensive, and safe test that can be potentially used in screening, diagnosis, and follow-up of thyroid cancer patients. Here, we will review the role of angiogenesis in thyroid cancer progression, spread, and metastasis. Moreover, the potential role of proangiogenic cytokines for risk stratification of patients with thyroid cancer will be addressed, as well as the individuation of angiogenesis as a potential therapeutic target.
