Molecular pathology of well-differentiated thyroid carcinomas

Abstract

The newly discovered molecular features of well-differentiated thyroid carcinomas derived from follicular cells are reviewed, within the frame of the 2004 WHO classification of thyroid tumours, under the following headings: "Follicular carcinoma", "Papillary carcinoma", "Follicular variant of papillary carcinoma" and "Hürthle cell tumours". A particular emphasis is put on the meaning of PAX8-PPARgamma rearrangements, RAS and BRAF mutations, and deletions and mutations of mitochondrial genes and of nuclear genes encoding for mitochondrial enzymes, for thyroid tumorigenesis.

Follicular thyroid carcinoma

“…The aneuploid pattern and the various molecular alterations detected in FA and FTC [12][13][14][15] support the assumption that the development of such tumors is the end product of multiple oncogenic steps, thus justifying their usual appearance as single (unicentric) neoplasms. 15 At variance with FTCs, PTCs occur frequently as multicentric neoplasms, which may be clonally independent from each other; 15 taking this together with the fact that almost every PTC is diploid or quasi-diploid and display microsatellite stability, it is tempting to advance that, in contrast to FTC, PTC tumorigenesis reflects the end product of a few oncogenic steps. [15][16][17] The classification of FTCs in two categoriesminimally and widely invasive-has always created a sense of a 'pathological' gap: what about tumors that are 'simply' invasive?…”

“…15 At variance with FTCs, PTCs occur frequently as multicentric neoplasms, which may be clonally independent from each other; 15 taking this together with the fact that almost every PTC is diploid or quasi-diploid and display microsatellite stability, it is tempting to advance that, in contrast to FTC, PTC tumorigenesis reflects the end product of a few oncogenic steps. [15][16][17] The classification of FTCs in two categoriesminimally and widely invasive-has always created a sense of a 'pathological' gap: what about tumors that are 'simply' invasive? This gap has been filled with the creation of a third group of FTCs, the angioinvasive carcinomas.…”

“…[1][2][3]7,24 This and the need to identify unequivocal signs of invasion to make a diagnosis of FTC, renders fineneedle aspiration cytology and frozen sections useless or almost useless in these settings. [1][2][3]7 Differential Diagnosis between FA/Adenomatous Nodule and Minimally Invasive FTC Despite the huge amount of information on proliferation, apoptosis, cell-cycle differentiation and stromal markers obtained at the immunohistochemical level, 1,15,[25][26][27][28][29][30][31] the differential diagnosis between FA/adenomatous nodule and minimally invasive FTC still depends on the identification of histological signs of invasiveness. [1][2][3]7,24 The search for such signs should be made in numerous H&E-stained sections involving the capsule of the tumor.…”

“…All the aforementioned molecular features (such as aneuploidy, RAS mutations, PAX8-PPARg rearrangements, etc.) are also frequently observed in FA, [12][13][14][15]22,23,[32][33][34][35] and are therefore almost useless for diagnostic purposes. In addition, the molecular approaches for diagnosing malignancy in follicular tumors using high-throughput technologies (DNA microarrays, massive sequencing, etc.)…”

Foci formation of P53‐binding protein 1 in thyroid tumors: Activation of genomic instability during thyroid carcinogenesis

“…1 It has been proposed that GIN has a crucial role in the progression of thyroid neoplasms. 2 Thus, transfection of mutant HRAS V12 or mutant BRAF V600E induced GIN in a rat thyroid cell line, manifesting as loss of chromosomal material, mitotic bridge formation and misaligned chromosomes. [3][4][5] Recently, we found RET oncogene amplification in human thyroid cancers.…”