Identifying Genetic Alterations in Poorly Differentiated Thyroid Cancer: A Rewarding Pursuit

The concept of \u93poorly differentiated thyroid carcinoma\u94 (PDTC) was initially proposed more than 25 yr ago ( 1, 2). It described a subgroup of thyroid carcinomas that seemed to fall, in terms of clinicopathological behaviors and aggressiveness, between the classically defined differentiated papillary thyroid carcinomas (PTC)/follicular thyroid carcinomas (FTC) and the undifferentiated anaplastic thyroid carcinomas (ATC). Over the next 20 yr of research, numerous studies supported the existence of such a clinicopathological entity of thyroid carcinoma, leading to the official inclusion of PDTC as a separate tumor entity in the World Health Organization (WHO) classification of thyroid tumors several years ago ( 3). In recent years, much effort has been made to identify genetic alterations in PDTC. Most of the studies have been focused particularly on identifying genetic alterations in the MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, two major signaling pathways that have been extensively studied for their fundamental roles in thyroid tumorigenesis ( 4, 5). Examples of these genetic alterations include the BRAF mutation and RET/PTC rearrangements in the former pathway and Ras mutations in the latter pathway. Less studied genetic alterations include PAX8/PPAR? rearrangement, f-catenin mutation, and a few others. A somewhat disturbing issue regarding the actual role of these genetic alterations in PDTC is the large variation of their prevalences and types in PDTC reported by different investigators. A possible reason for this is that, unlike PTC, FTC, and ATC, the diagnostic criteria used for PDTC varied considerably among different investigators. This may not be surprising because PDTC or PDTC-like tumors may display an intermediate spectrum of clinicopathological behaviors between differentiated and undifferentiated thyroid carcinomas. It is often, therefore, not a straightforward task to clearly define PDTC based on clinicopathological grounds, particularly when the classical WHO criteria are not uniformly followed. It is also likely that ..