Cyclin E plays a pivotal role in the regulation of G1-S transition and relates to malignant transformation of the cells. However, the clinical significance of cyclin E expression in patients with papillary thyroid carcinoma (PTC) remains unknown. We examined by immunohistochemistry the expression of cyclin E in 41 resected PTCs in pathologic stages from pT1a to pT4 and analyzed its relation to clinicohistopathologic factors. The positive staining was divided into 3 grades: no expression if less than 10%, expression if 11-50% and overexpression if more than 50% of the nuclei of tumor cells were stained positively. Cylin E expressions were observed in 75.6% of analyzed PTCs but only 60% of papillary microcarcinomas (PMCs) were immunopositive for cyclin E expression. However, cyclin E staining was observed in 90.4% of PTCs in a group with TNM higher than pT1a. Key words: cyclin E; papillary thyroid carcinoma; papillary thyroid microcarcinomaSeveral clinical and histopathologic factors have been shown to be important prognostic factors for survival in papillary thyroid carcinoma (PTC). These include patient age, patient gender, tumor size, extrathyroidal extension and the presence of distant metastases. 1,2 However, there is a clinical need for a prognostic marker for thyroid papillary cancer, especially considering increasing number of diagnosed papillary thyroid microcarcinomas. 3 Papillary microcarcinomas (PMCs) of the thyroid are defined as small papillary carcinomas measuring less than 1 cm in maximum dimension. The biology of these tumors is not fully understood because, although lymph node metastases from PMCs are very uncommon on rare occasions, a PMC behaves aggressively and metastasizes early, presenting with clinically evident lymph node metastases. These tumors then result in significant morbidity and mortality. 4 At present, traditional histopathologic assessment cannot distinguish between the typical PMC, which almost always remains quiescent, and the unusual PMC, which has the potential to behave aggressively.The last decade has seen an enormous expansion in our understanding of the molecular mechanisms governing cell cycle regulation. Altered expression of cell cycle regulators and the subsequent deregulation of the cell cycle may be important steps in carcinogenesis and are the most consistently found events in human malignancies, including thyroid cancer. [5][6][7][8][9][10][11] Among the G1 cyclins, cyclin D1 and cyclin E are key regulators during the G1/S cell cycle transition, and perhaps the most important checkpoint in the mammalian cell cycle. 12 Amplification of the cyclin E gene locus was observed in several cancers, including breast, 13-16 thyroid, 8,11 colorectal, 17,18 laryngeal 19 and lung cancers. 20 -22 Furthermore, cyclin E is also altered in leukemias and lymphomas. [23][24][25] Moreover, in several studies, the cyclin E expression was associated with bad prognosis. 14 -16,19 -21,26 In 1994, Keyomarsi et al. 14 proposed cyclin E as a prognostic marker for breast cancer and in the...
Purpose: Uncontrolled cell proliferation, a hallmark of cancer, may result from an increased expression of cell cycle up-regulators, and/or from a reduced expression of cell cycle down-regulators. In the present study, we analyzed, by immunohistochemistry, the expression of a panel of three proteins: cyclin E and two cell cycle inhibitors, p21Cip1/WAF1 and retinoblastoma protein (pRb) product, in different stages of papillary thyroid carcinomas (PTC). Experimental Design: We investigated immunostaining patterns of the proteins in question in 51 resected PTC in pathologic stages, ranging from pT1a to pT4, taking into consideration their relation to clinicohistopathologic factors. Results: We observed a significant, progressive loss of expression of p21Cip1/WAF1 with advancing tumor grade. The differences reached values of significance between pT1a [papillary thyroid microcarcinomas (PMC)] and pT2 and between PMC and pT4 stages of PTC. pRb presented a similar immunostaining pattern to that of p21Cip1/WAF1 and the differences reached values of significance between pT1a and pT2, and between PMC and pT4 stages of PTC. The results of cyclin E immunostaining corresponded to our recently published result, and a negative correlation was observed between the immunostaining index of cyclin E and pRb. Conclusions: The results of the present study suggest that cyclin E expression and suppression of pRb and p21Cip1/WAF1 may be characteristic patterns of immunostaining for PTC with a tendency to early metastasizing. If our results are confirmed in a larger study, the diagnostic panel, constructed of the antibodies against these proteins, may become a valuable tool in predicting the metastatic potential in PTC.
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