Fetal adenomas and minimally invasive follicular carcinomas of the thyroid frequently display a triploid or near triploid DNA pattern

Abstract

The ploidy pattern and the percentage of S-phase cells were investigated by means of flow cytometry using fresh or frozen samples in a series of 143 tumors and tumor-like lesions of the thyroid in an attempt to find whether there is any relationship between the histological characteristics of the lesions and their DNA content. The percentages of aneuploidy cases per category were: nodular goiter, 18.5% (15/81); fetal adenoma (including cases with trabecular/solid growth pattern), 58.3% (14/24); follicular adenoma other than fetal adenoma, 0% (0/18); papillary carcinoma, 11.1% (1/9); and minimally invasive follicular carcinoma, 57.1% (4/7). Regardless of the histological category, aneuploid lesions had a significantly higher (P < 0.001) percentage of S-phase cells (7.3%) than diploid lesions (4.1%). All the six cases with a DNA content within the triploid range were fetal adenomas, but one was a follicular carcinoma displaying a fetal adenoma-like growth pattern. The other three follicular carcinomas with an aneuploid DNA pattern also displayed foci of fetal adenoma-like growth pattern. Image cytometry of the four aneuploid follicular carcinomas showed similar DNA indexes in the peripheral, invasive foci of the lesions and in the central fetal adenoma-like areas. These results demonstrate that aneuploidy in benign tumors is restricted to adenomas displaying a fetal or fetal/embryonal growth pattern and support the concept that chromosome instability is a major pathway of tumorigenesis in thyroid follicular neoplasms.

Follicular thyroid carcinoma

“…Multifocality and recurrence in the residual parenchyma after partial thyroidectomy are uncommon. 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.…”

“…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.)…”

Molecular signatures of thyroid follicular neoplasia

“…RAS is mutated in up to half of the tumors and a recurrent PAX8-PPARg translocation has been identified in 26-56% of the cancers, but also in a number of adenomas (Nikiforova et al 2003, Delellis 2006, Fagin & Mitsiades 2008. The microFAs or fetal adenomas (FEAs) represent a subtype of follicular nodules exhibiting a high degree of aneuploidy, which renders these tumors more likely to become malignant (Castro et al 2001). A number of studies have successfully exploited global expression profiling to identify molecular markers or signatures of thyroid neoplasia (Barden et al 2003, Finley et al 2004, Mazzanti et al 2004, Lubitz et al 2005, Weber et al 2005, Fryknas et al 2006, Griffith et al 2006, Fujarewicz et al 2007, Prasad et al 2008, Hinsch et al 2009).…”

H-RAS 81 polymorphism is significantly associated with aneuploidy in follicular tumors of the thyroid

“…Follicular tumors of the thyroid are often aneuploid (Johannessen et al, 1982;Hostetter et al, 1988;Joensuu and Klemi, 1988;Schelfhout et al, 1990;Cusick et al, 1991;Castro et al, 2001). Although the presence of aneuploidy is not by itself an indicator of malignancy (Johannessen et al, 1982;Joensuu and Klemi, 1988;Hostetter et al, 1988;Schelfhout et al, 1990;Cusick et al, 1991;Castro et al, 2001), aneuploid carcinomas tend to carry a worse prognosis than diploid (or neardiploid) carcinomas of the thyroid (Joensuu and Klemi, 1988;Schelfhout et al, 1990).…”

“…Although the presence of aneuploidy is not by itself an indicator of malignancy (Johannessen et al, 1982;Joensuu and Klemi, 1988;Hostetter et al, 1988;Schelfhout et al, 1990;Cusick et al, 1991;Castro et al, 2001), aneuploid carcinomas tend to carry a worse prognosis than diploid (or neardiploid) carcinomas of the thyroid (Joensuu and Klemi, 1988;Schelfhout et al, 1990).…”