Biomarkers in well differentiated thyroid cancer

Differentiated thyroid cancer (DTC) includes different histological subtypes [1]. DTC incidence has 3-times fold increased from 1975 to 2009 [2], accounting at present for 3.4% of all new cancer cases [3]. It has been estimated that approximately 1.2% of subjects will be diagnosed with thyroid cancer at some point during their lifetime (2012-2014 SEER data). Nonetheless, its prognosis is very good with a 5-years survival rate > 98% [3] and a 10-year relative survival rate between 76% and 93% according to the histological subtypes [4]. Small papillary thyroid carcinomas have contributed to the worldwide increased incidence of differentiated thyroid cancer observed over the past decades. Moreover, the disease-specific mortality has not changed since 1935 [5]. However, about 10% of patients develop distant metastases and two thirds of them become refractory to the treatment with radioactive iodine (RAI) [6]. Differently from the majority of DTC, metastatic patients experience a rapidly progressive disease (average interval between the first and second metastases of <15 months [7]) with an even worse prognosis when RAI refractoriness occurred (10-year survival rate < 10% with a mean life expectancy of 3-5 years [8]). The identification of tumor heterogeneity could be of great value in DTC. The identification, characterization, understanding, and, possibly, treatment of tumor heterogeneity are key challenges in oncology. Malignant cancer lesions are composed by heterogenous components (i.e., biologic features, gene expression profiles, metabolic patterns, and behavioral characteristics). Heterogeneity varies in the same cancer and has a wide spectrum even in the same stage because there are differences in properties as the growth rate, vascularity, and necrosis within the same tumor cell population [9]. Currently, DTC patients are grouped in different classes of risk (from low to high) and managed accordingly [10]. Common risk factors include histological characteristics of aggressiveness, extrathyroidal extension, vascular invasion, number and size of involved lymph nodes, and distant metastases [10]. However, none of the available risk stratification approaches is effective in distinguishing aggressive from indolent thyroid cancers and in identifying patients who will recur during their lifetime.