**1. Introduction**

Thyroid cancer is the most common endocrine tumor and its incidence has been raising up over the last 20 years, mostly due to the flowering diagnosis of micro thyroid carcinomas [1]. Thyroid cancer is subcategorized into follicular and non-follicular derived carcinoma (e.g., medullary thyroid carcinoma). Among the first, World Health Organization (WHO) identifies papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC) [2].

Thyroid cancer 5 year-survival is variable among the different hystotypes. According to a recent epidemiological study performed in Denmark by using a national cancer registry, the 5 year-survival rates were 91.1% and 79.9% in PTC and FTC, respectively, 63.6% in PDTC and 12.2% in ATC [3]. Unfortunately, PDTC and ATC median overall survival is 6 years and 6 months, respectively [4,5]. Although PDTC and ATC are rare, therapy for patients affected by PDTC and ATC represents an unmet clinical need that should be addressed, considering their poor survival. In addition, PDTC and ATC harbor diagnostic pitfalls that make difficult their clinical management. Although PDTC was added in WHO classification in 2004, its diagnostic criteria are not widely shared and many pathologists are following criteria of Turin consensus conference [6] and others Memorial Sloan Kettering Cancer Center ones [7]. Likewise, the wide spectrum of ATC hystotypes could challenge

**Citation:** Prete, A.; Matrone, A.; Gambale, C.; Torregrossa, L.; Minaldi, E.; Romei, C.; Ciampi, R.; Molinaro, E.; Elisei, R. Poorly Differentiated and Anaplastic Thyroid Cancer: Insights into Genomics, Microenvironment and New Drugs. *Cancers* **2021**, *13*, 3200. https://doi.org/10.3390/ cancers13133200

Academic Editors: Fabio Medas and Pier Francesco Alesina

Received: 30 May 2021 Accepted: 24 June 2021 Published: 26 June 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

the differential diagnosis with other cancers (e.g., angiomatoid variant ATC with thyroid angiosarcoma) [8] or even with benign lesions (e.g., acute thyroiditis) [9] (Figure 1).

**Figure 1.** (**A**–**C**) Anaplastic thyroid carcinoma (ATC) (hematoxylin and eosin stain); (**A**) The presence of extensive tumor necrosis is a typical aspect of ATC (see asterisk \*) (original magnification ×10); (**B**) The neoplastic cells show marked nuclear atypia with spindled and pleomorphic morphology, associated to elevated mitotic rate, simulating high-grade pleomorphic sarcoma. In the insert, focal immunostaining for cytokeratins supports the epithelial nature of ATC (original magnification ×20); (**C**) At higher magnification, the pronounced nuclear atypia and an atypical mitosis (see arrow) are shown (original magnification ×40). (**D**–**F**) Poorly differentiated thyroid carcinoma (PDTC) (hematoxylin and eosin stain); (**D**) The typical example of PDTC is the so-called "insular carcinoma". In this field, the tumor shows a small focus of tumor necrosis (see asterisk \*) (original magnification ×10); (**E**) The neoplasm exhibits a prevalent solid growth pattern (original magnification ×20); (**F**) At higher magnification, the tumor cells appear small and uniform, the nuclei are generally rounded and hyperchromatic, in absence of the typical aspects of papillary thyroid carcinoma (original magnification ×40).

In the past, many treatments were proposed to answer this aforementioned need, but with disappointing results [10]. Nowadays many clinicians are proposing genetically guided treatments for PDTC and ATC, according to the new discoveries about their genetic landscape [11,12].

In the current review, as first, we summarize the upcoming findings about genetic features of PDTC and ATC, from mutations occurring in DNA to alterations in RNA; therefore, we describe their tumor microenvironments and the interactions between tumor and other neighboring cells; finally, we recapitulate how this upcoming evidence are changing the treatment of PDTC and ATC.
