Altered Expression of Cyclins and Cell Cycle Inhibitors in Papillary Thyroid Cancer: Prognostic Implications

Abstract

Currently we lack biochemical or molecular markers that predict recurrence and metastases in thyroid cancer. Recent studies in a number of other human malignancies indicate that expression and/or subcellular localization of certain cell cycle regulators has prognostic utility. We have investigated the expression of cyclins D1 and E and of cyclin-dependent kinase inhibitor's p21 and p27 in papillary thyroid cancer (PTC) and correlated this with clinical/histological stage at diagnosis and with clinical outcome. PTCs were compared to normal thyroid, adenomas, and undifferentiated thyroid cancers (UTCs). Our studies indicate that PTCs and UTCs demonstrate low nuclear expression of cyclin E and p27, allowing a clear distinction between adenomas and these carcinomas (p < 0.004). A pattern of low nuclear expression of all four markers was observed in stage IV PTCs and UTCs, while stage I PTCs had low D1 and E accompanied by high p21 or p27. Expression of cytoplasmic cyclin D1 was significantly lower in stage IV PTCs and UTCs than in stage I-III PTC's (p </= 0.020), and appeared to correlate inversely with poor outcome in PTCs (p = 0.010). These studies suggest that evaluation of a panel of these markers and attention to their subcellular localization may be a useful adjunct in differentiating benign from malignant thyroid neoplasms and in predicting tumor behavior.