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.

Expression of p21cip1, p27kip1, and p16INk4a Cyclin-Dependent Kinase Inhibitors in Papillary Thyroid Carcinoma: Correlation with Clinicopathological Factors

“…However, clinical significance of p21 cip1 positivity remains contradictory. Some authors failed to demonstrate any correlation between protein staining and clinicopathological tumor behavior [4,11]. On the other hand, others have found that p21 cip1 expression was higher in dedifferentiated [5,6], in larger tumors, or in tumors extended beyond the thyroid capsule [12].…”

“…CIP/KIP members have been broadly studied in several human tumors. It has been reported that more than 30-50% of PTC show positive p21 cip1 expression [4][5][6][8][9][10][11][12]. However, clinical significance of p21 cip1 positivity remains contradictory.…”

“…Furthermore, some of those reports have found higher expression in anaplastic and poorly differentiated tumors [5,6], whereas others failed to demonstrate this correlation [4,11]. On the other hand, some authors have shown that p27 kip1 protein expression, another CIP/ KIP family member, is decreased in papillary thyroid carcinoma (PTC) in comparison with follicular carcinoma and benign thyroid lesions [11,[13][14][15][16][17][18][19][20][21]. Moreover, p27 kip1 underexpression could predict lymph node metastasis [18][19][20] and more aggressive tumors [16] in PTC.…”

“…However, few works have been addressed in differentiated thyroid carcinoma (DTC). Some of them have reported that more than 30-50% of DTC show positive p21 cip1 immunoreactivity [4][5][6][7][8][9][10][11][12]. Furthermore, some of those reports have found higher expression in anaplastic and poorly differentiated tumors [5,6], whereas others failed to demonstrate this correlation [4,11].…”

“…Some of them have reported that more than 30-50% of DTC show positive p21 cip1 immunoreactivity [4][5][6][7][8][9][10][11][12]. Furthermore, some of those reports have found higher expression in anaplastic and poorly differentiated tumors [5,6], whereas others failed to demonstrate this correlation [4,11]. On the other hand, some authors have shown that p27 kip1 protein expression, another CIP/ KIP family member, is decreased in papillary thyroid carcinoma (PTC) in comparison with follicular carcinoma and benign thyroid lesions [11,[13][14][15][16][17][18][19][20][21].…”