Review Histopathological-molecular classifications of papillary thyroid cancers: Challenges in genetic practice settings

Abstract

Thyroid cancer is a relatively rare disease. A literature review concerning frequencies and successive histopathological and molecular classifications of thyroid cancer was conducted to highlight new guidelines for molecular diagnostics to be implemented in practice for managing the most prevalent form of differentiated thyroid carcinomas, namely papillary thyroid cancer. Our study has shown that the frequency of thyroid cancer varies among countries, with its incidence rising faster than any other malignancy in recent decades, mainly owing to the increasing rate of detection of small cancers. Furthermore, the histopathological types of thyroid cancer have been redefined along successive WHO classifications. Indeed, to better stratify the prognosis and patient management, continuous improvements have been made to the classifications based on increasingly relevant criteria, ranging from histological structure to genetic signatures, and including cellular criteria of malignancy. In 1974, during the first edition of the WHO classifications, papillary thyroid cancer was defined as a malignant epithelial tumor containing a papillary structure. Faced with numerous issues of plethoric diagnosis and unnecessary treatments resulting from the binary distinction of thyroid proliferations into benign or malignant (in subsequent editions in 1988 and 2004), the fourth edition in 2017 added a third category, that of borderline thyroid tumors (uncertain malignant potential), with the introduction of nuclear features as major classification criteria. In the fifth edition (WHO 2022 classification), nuclear features and molecular signatures have become essential criteria, distinguishing thyroid neoplasms based on the signaling pathways involved. Thus, three groups of thyroid cancers have been separated based on mutational profiles and gene expression: 1/ the BRAFV600E-like cancer group involving BRAF V600E mutation and gene fusions involving BRAF, RET, NTRK1/3,ALK and MET; 2/ the RAS-like cancer group including NRAS, HRAS, KRAS, EIF1AX, DICER1, BRAF K601E mutations, and gene fusions involving PPARG and THADA; and 3/ the no-BRAF V600E/no-RAS-like neoplasms group involving PAX8/PPARG gene fusion and mutations in EZH1, IDH1, SOS1, SPOP, DICER1, and PTEN.