Assessment of RET/PTC Oncogene Activation and Clonality in Thyroid Nodules with Incomplete Morphological Evidence of Papillary Carcinoma

Abstract

Noninvasive thyroid nodules that exhibit borderline morphological signs of papillary cancer are difficult to diagnose and we do not know if they represent papillary carcinoma precursor lesions. Forty-six such nodules were analyzed for RET activation by immunohistochemistry and, in selected cases, by reverse transcriptase-polymerase chain reaction performed on RNA extracted after laser capture microdissection (LCM) of the tumor foci with and without papillary carcinoma features and positive RET immunoreactivity. RET immunoreactivity was identified, at least focally, in 30 of 46 (65.2%) of the nodules where it closely paralleled the morphological changes. Enough RNA was obtained after LCM in seven samples. RET/PTC1 or RET/PTC3 were detected in microscopic foci with papillary carcinoma features in most of the thyroid nodules (five of seven cases). No RET/PTC1 or RET/PTC3 rearrangements were detected in areas of the same tumors that lacked the cytological alterations. Analysis of clonality in the same nodules selected for LCM demonstrated that two were monoclonal and six were polyclonal. We conclude that RET activation closely parallels the morphological changes, that it is restricted to those areas of the tumor with the cytological alterations and that it is detectable in both mono- and polyclonal tumors. Although the finding of microscopic foci indicative of papillary carcinoma in a hyperplastic or adenomatous nodule does not justify the interpretation of the entire lesion as papillary carcinoma, it is possible that such foci may precede the development of invasive papillary cancer.

RET rearrangements in post-Chernobyl papillary thyroid carcinomas with a short latency analysed by interphase FISH

“…These findings on post-Chernobyl PTCs developed with short and long latency after irradiation suggest that multiple clones develop from follicular cells to form papillary cancer. This interpretation is supported by other studies on papillary cancers (Sugg et al, 1998;Tallini et al, 1998;Fusco et al, 2002) and the recent demonstration that the histology of post-Chernobyl PTCs is inhomogeneous and is changing with time after the accident (Williams et al, 2004). This is borne out in this study, as the proportion of tumours of a solidfollicular morphology is increased in those of longer latency, and those of a purely solid morphology is decreased (Figure 3).…”

“…As demonstrated in Figure 4, RT -PCR and interphase FISH results are in good agreement in control cell lines. The reported genetic heterogeneity in our study is a well-known phenomenon in solid tumours and even in thyroid lesions (FerrerRoca et al, 1998;Fusco et al, 2002) and indicates that clonal evolution in such tumours is a complex process. These findings on post-Chernobyl PTCs developed with short and long latency after irradiation suggest that multiple clones develop from follicular cells to form papillary cancer.…”

A Thyroid Tumor-Specific Antigen Formed by the Fusion of Two Self Proteins

“…Previous data have shown frequent expression of RP3 fusion gene at very early stages of cancer (38) and in thyroid tissue of patients with thyroid autoimmune disease, suggesting that this expression may underlie the coexistence of neoplasia (10,11) and autoimmunity. Studying the early stages of RP3 expression in mouse thyroid tissue will help to evaluate the inflammatory conditions within the organ observed at very early stages following thyroid transformation, but before carcinoma and/or autoimmune disease occurs.…”

An update on molecular biology of thyroid cancers

“…However, there was no significant correlation found in the occurrence of RET/PTC in patients with and without history of medical radiation [194]. Presence of RET/PTC activation may be a complementary approach in patients reported to have indeterminate cytology by FNAB and with borderline histological features of malignancy in microscopic papillary foci of thyroid nodules [195]. Most studies demonstrated that the sensitivity of molecular assays has improved by combined detection of BRAF and RET/PTC.…”