Intratumoral Heterogeneity in Differentiated Thyroid Tumors: An Intriguing Reappraisal in the Era of Personalized Medicine

Differentiated thyroid tumors (DTTs) are characterized by significant molecular variability in both spatial and temporal intra-tumoral heterogeneity (ITH), that could influence the therapeutic management. ITH phenomenon appears to have a relevant role in tumor growth, aggressive behavior and drug resistance. Accordingly, characteristics and consequences of ITH in DTTs should be better analyzed and understood in order to guide clinical practice, improving survival. Consequently, in the present review, we investigated morphological and molecular ITH of DTTs in benign, borderline neoplasms and in malignant entities, summarizing the most significant data. Molecular testing in DTTs documents a high risk for recurrence of cancer associated with BRAF(V600E), RET/PTC 1/3, ALK and NTRK fusions, while the intermediate risk may be related to BRAF(K601E), H/K/N RAS and PAX8/PPARγ. In addition, it may be suggested that tumor genotype is associated with peculiar phenotype.