Immunohistochemical Evaluation of Cell Cycle Regulators: Impact on Predicting Prognosis in Stage T1 Urinary Bladder Cancer

Abstract

Background and Objective. The cell cycle is regulated by proteins at different checkpoints, and dysregulation of this cycle plays a role in carcinogenesis. Matrix metalloproteinases (MMPs) are enzymes that degrade collagen and promote tumour infiltration. The aim of this study was to evaluate the expression of various cell cycle regulators and MMPs and to correlate such expression with progression and recurrence in patients with stage T1 urothelial carcinoma of the bladder (UCB). Patients and Methods. This population-based cohort study comprised 201 well-characterized patients with primary stage T1 urothelial carcinoma of the bladder. Immunohistochemistry was performed on formalin-fixed material to quantify expression of cell cycle regulators and two MMPs. Results. Normal expression of p53 and abnormal expression of MMP9 were associated with greater risk of tumour recurrence. Also, normal p16 expression was related to a lower risk of tumour progression. MMP2, p21, cyclin D1, and pRb showed no significant results that could estimate progression or recurrence. Conclusions. Normal p16 expression is associated with a lower risk of tumour progression, but immunohistochemistry on cell cycle regulators and MMPs has little value in predicting the prognosis in stage T1 UCB.

CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response

“…However, data were inconsistent showing CyclinD1 expression as a marker of adverse [20][21][22] or favorable [23][24][25][26][27] prognosis or without prognostic impact. 28 Only two studies investigated the prognostic relevance of CCND1 amplification in bladder cancer: while CCND1 amplification was an adverse risk factor in non-muscle invasive bladder cancers, 29 it failed to predict survival in muscle invasive tumors. 30 Finally, CyclinD1 expression has been shown to predict response to chemotherapies in cancers of the head and neck; 10,11 however, this potential has never been tested in bladder cancer.…”

Evaluation of different p16 immunostaining methods and the prognostic role of p16/Ki-67 combined expression in non-muscle invasive bladder cancers

“…Another study interpreted p16 expression below 5% as negative staining for p16 [1]. Some authors regarded expression loss (no staining) and overexpression (staining > 50%) as abnormal and moderate staining as normal [21][22][23][24]. Four of the scoring methods employed in these studies were also used in our work for comparison.…”

“…In our study, there was a statistically significant association between recurrence and p16 expression only when the p16d scoring system was used. Olsson et al [23] also used the same staining pattern (p16d) in stage T1 urinary bladder cancers and they detected normal p16 expression was related to a lower risk of tumor progression. Similar to our study, Lee et al [21] investigated four cell cycle proteins (p16, pRb, p53, cyclin D1) and found no correlation between progression and p16 (p16d method) expression; their results suggested that multiple genetic defects affected the clinical course and metastatic capacity of bladder carcinomas.…”

“…However, the functional and biological importance of cytoplasmic staining is not yet understood [35]. Some studies on p16 expression take into account only nuclear staining [1,24,36], while others consider both nuclear and cytoplasmic staining [18,19,23]. Han et al compared endocervical carcinomas and endometrial adenocarcinomas in terms of p16 expression.…”

P53 is still a reliable marker in prognosis of non muscle invasive tumors.

“…Approximately 15-70% of pT1 tumors relapse within a year after transurethral resection and 7-44% of these tumors are likely to progress into muscle in five years (2).…”