Long-term outcome related to epidermal growth factor receptor status in bladder cancer.

For bladder cancer we currently lack accurate methods of predicting outcome, although clinical stage and histological grade are broad determinants of prognosis. Preliminary data have indicated that assessment of epidermal growth factor receptor status is a method of further subclassifying bladder cancer. We assessed prospectively the clinical significance of determining epidermal growth factor receptor status in 212 patients with newly diagnosed bladder cancer who were followed for 1 to 96 months (mean 26.5). In multivariate analyses epidermal growth factor receptor was confirmed to be an independent predictor of survival (p = 0.004) and stage progression (p = 0.0004). Most importantly, epidermal growth factor receptor status was found to be 80% sensitive and 93% specific in predicting stage progression in T1, grade 3 bladder cancer. We conclude that epidermal growth factor receptor status is a useful molecular marker in patients with bladder cancer, especially those without infiltration of the detrusor muscle at presentation.

Expression of retinoblastoma gene product and p53 protein in bladder carcinoma: correlation with Ki67 index.

OBJECTIVES: To determine whether loss of the tumour suppressor gene retinoblastoma (Rb) and increased expression of the p53 protein were associated with increased tumour cell growth fraction. PATIENTS AND METHODS: Tumours from 105 patients (72 men, 33 women; median age 69 years, range 35-89) with newly diagnosed primary transitional cell bladder carcinoma were studied. Tumour samples were taken by means of cystoscopic resection. Expression of the retinoblastoma (Rb) and p53 gene products was assessed immunohistochemically in 98 of the carcinomas. The proportion of cells expressing the Ki67 antigen (Ki67 index which is a measure of growth fraction) was determined in 64 cases. RESULTS: p53 protein was detectable in 50% and Rb protein in 82% of the tumours. Staining for p53 and lack of staining for Rb protein were associated with muscle-invasive growth and high tumour grade (G3). The Ki67 index varied over a wide range (1-47%), but there were significant differences between mean indices for poorly differentiated (G3) and well or moderately differentiated (G1/G2) tumours, and between indices for muscle-invasive and the remaining tumours. The mean Ki67 indices for Rb-negative tumours and p53-positive tumours were approximately twice those for Rb-positive and p53-negative tumours. Only 10% of the tumours expressed high levels of p53 protein and failed to express Rb. CONCLUSION: These observations are consistent with the hypothesis that loss of Rb and mutation and overexpression of p53 are associated with an increased tumour cell growth fraction and that such changes may play a role in the de-regulation of cell proliferation in transitional cell carcinoma of the bladder.

c-jun oncogene expression in transitional cell carcinoma of the urinary bladder.

OBJECTIVE: To investigate c-jun oncoprotein expression in transitional cell carcinomas (TCCs) of the urinary bladder and to determine its relationship to tumour grade and stage, and to the expression of epidermal growth factor receptor (EGFR), c-erbB-2 and p53 oncoproteins. MATERIALS AND METHODS: The expression of c-jun was studied using immunohistochemistry in a series of 48 TCCs of known EGFR, c-erbB-2 and p53 status. RESULTS: Forty-four of 48 (92%) tumours showed c-jun specific nuclear immunoreactivity of variable intensity. The intensity of c-jun immunostaining was significantly related to tumour stage (P = 0.009) and EGFR status (P = 0.01). There was no correlation between c-jun oncoprotein expression and c-erbB-2 or p53 immunoreactivity. c-jun expression was not related to clinical outcome in terms of patient survival or rate of tumour recurrence. CONCLUSION: The c-jun oncoprotein is expressed in the majority of TCCs of the urinary bladder. There is a positive association between intense c-jun immunoreactivity and muscle invasive growth, and EGFR positivity in TCCs.

Abnormalities in p53 and DNA content in transitional cell carcinoma of the bladder.

OBJECTIVE: To determine if transitional cell tumours of the bladder which contain mutations in the p53 gene have alterations in their DNA content. MATERIALS AND METHODS: In 33 transitional cell tumours of the bladder, DNA content was determined by flow cytometry and compared with expression of mutant p53 as assessed by immuno-histochemistry. RESULTS: Abnormal DNA content was associated with increased staining for p53 (P < 0.05), high tumour stage (P < 0.001) and increased histological grade (P < 0.01). Although positive staining for p53 was frequently associated with abnormal DNA content, a significant number of non-diploid tumours stained negatively for mutant p53. CONCLUSION: These data demonstrate that increased staining for p53 is associated with abnormalities in DNA content suggesting that mutation of the p53 gene is associated with an increased rate of chromosomal abnormalities and an increased rate of cell proliferation.

P53 and Ki-67 immunoreactivity in human prostate cancer and benign hyperplasia.

Mutation of the p53 gene is one of the commonest genetic abnormalities found in solid human tumours. This gene is probably concerned with the control of cellular proliferation and in view of this we carried out a study of human prostate cancer and benign prostatic hyperplasia, comparing the expression of mutated p53 with measurement of growth fractions as assessed by staining with Ki-67. A series of 29 patients with prostate cancer (CaP) were compared with 34 men with benign hyperplasia (BPH); 22 of 29 prostate cancers (76%) contained Ki-67 immunoreactivity compared with 10 of 34 (29%) BPH. With respect to p53 staining, significantly more prostate cancers (17%) were stained than BPH (0%). The mean Ki-67 score in cancers positive for p53 (4.3%) was greater than that found in cancers negative for p53 (1.2%), but no statistically significant relationship was found between tumour grade and Ki-67 staining. The use of Ki-67 and p53 staining may allow identification of tumours with a higher rate of cell growth and may permit development of prognostic factors.

p53, c-erbB-2 and the epidermal growth factor receptor in the benign and malignant prostate.

Expression of the p53, the epidermal growth factor receptor (c-erbB-1) and c-erbB-2 protein was studied in 34 men with benign prostatic hyperplasia and 29 men with locally advanced prostate cancer by means of an immuno-histochemical method. Strong staining for p53 was found in five of 29 prostate cancers (17%; mean 21% +/- 7% of malignant cells stained in the positive tumours), but no staining was found in benign prostatic hyperplasia (p less than 0.05). On the other hand, the epithelium in benign glands was stained positively for c-erbB-2 in 18% (6/34) and for the epidermal growth factor receptor in 88% (30/34); whereas malignant epithelium stained strongly for c-erbB-2 in 21% (6/29) and for the epidermal growth factor receptor in only 17% (5/29). Prostate cancer was associated with a significant decrease in epidermal growth factor receptor staining (p less than 0.0001) and a significant increase in p53 staining (p less than 0.05). Most of the tumours were advanced and no significant relationship was observed between tumour stage and grade and expression of p53, the epidermal growth factor receptor or c-erbB-2. These findings demonstrate that altered expression of the epidermal growth factor receptor and p53 protein occurs in prostate cancer, but were not associated with other features of prognostic importance such as stage or grade.

Epidermal growth factor receptor and bladder cancer: a review.

Recently, expectations have been raised that molecular biological studies of human tumours may be of value in helping to predict future clinical behaviour, in terms of therapeutic response and long-term survival. The epidermal growth factor receptor (EGFr) is a cell surface receptor for EGF and transforming growth factor-alpha which is overexpressed by a number of human tumours. This article principally reviews previous investigations of the role of the epidermal growth factor receptor in bladder cancer and examines methods of detection, the correlation between EGFr status and known prognostic indicators and the value of assessing EGFr status in predicting clinical outcome in patients with bladder cancer. Recent studies of the c-erbB-2 proto-oncogene in bladder cancer and of cell cycling using Ki-67 are included.

Immunohistochemical detection of the epidermal growth factor receptor in paraffin-embedded human tissues.

Expression of the epidermal growth factor (EGF) receptor was evaluated by immunohistochemical staining of formalin-fixed, paraffin-embedded tumour tissues employing two antibodies raised to short synthetic peptides from the cytoplasmic domain of the molecule. Both antibodies gave concordant staining of a series of bladder cancers known to express or lack EGF receptors. There was no cross-reaction with the related c-erbB-2 protein, which was also over-expressed in some cases. Cancers with EGF receptor expression also expressed high levels of TGF-alpha, a receptor agonist.

Expression of mutant p53, c-erbB-2 and the epidermal growth factor receptor in transitional cell carcinoma of the human urinary bladder.

Expression of the p53, the epidermal growth factor receptor (EGFr; c-erbB-1) and c-erbB-2 proteins was studied in 82 patients with primary transitional cell carcinoma of the bladder using an immuno-histochemical method. Strong or moderate staining was found in 18% of tumours for p53 with weaker staining in a further 36% giving a total of 54% of tumours stained for p53. Strong staining was found in 15% of tumours for c-erbB-2 and in 31% for the EGFr. Tumours invading the bladder muscle were significantly more likely to be strongly stained positively for p53 and/or EGFr compared with superficial tumours: only 15% of invasive tumours were stained negatively for both p53 and EGFr. No statistical association was found between p53 and EGFr expression. Weakly positive associations were found between the expression of c-erbB-2 and p53 and between muscle invasive tumours and increased expression of c-erbB-2. Alterations in the expression of p53, c-erbB-1 and c-erbB-2 were found frequently in human transitional cell carcinoma of the urinary bladder and may be of clinical use in defining patient sub-groups of differing prognosis.