| Abstract|| |
Background: Urothelial carcinomas (UC) is of the most common cancers urinary bladder. Aim: The aim of the study is to assess the immunohistochemical staining differences between p63 and p53 according to the pathological stage and histological grade of the tumor in urinary bladder carcinomas. Materials and Methods: Totally 62 urinary bladder transurethral resection materials diagnosed with urothelial carcinoma in the pathology department of our hospital were included in the study. On pathological examination, cases were dichotomized as noninvasive and invasive, whereas noninvasive cases were dichotomized as low grade and high grade and invasive cases were dichotomized as pT1 and pT2. Subsequently, the cases were evaluated by means of p63 and p53 immunohistochemical staining. Statistical analyses were performed by SPSS program, and Chi-square and Fisher's exact tests. Results: When pTa was evaluated in terms of p63 immunoreactivity, no statistically significant difference was observed between LGPUC and HGPUC, noninvasive papillary UC, regarding staining percentages ( P > 0.05), whereas statistically significant relation was observed for pT1 and pT2 regarding p63 staining percentages ( P < 0.05). For pTa, no statistically significant relation was observed between LGPUC and HGPUC, noninvasive papillary UC, in terms of p53 staining percentages ( P > 0.05). However, highly significant relationship was observed for pT1 and pT2 in terms of p53 staining percentages ( P < 0.01). No significant relationship was observed between the staining percentages of p53 and p63 ( P > 0.05). Conclusion: The role of p53 and p63 immunoreactivities in the differential diagnosis and prognosis of urinary bladder carcinomas according to the pathological stage and histological grade of the tumor will be understood better with the increasing number of long term investigations performed with large series at a molecular level.
Keywords: Bladder cancer, immunohistochemistry, p53, p63
|How to cite this article:|
Koyuncuer A. Immunohistochemical expression of p63, p53 in urinary bladder carcinoma. Indian J Pathol Microbiol 2013;56:10-5
| Introduction|| |
In Europe and the United States approximately 20 new cases of bladder cancer per 100,000 persons are diagnosed each year and 5/100,000 persons die from this disease annually. The majority of these cancers are superficial urothelial cell carcinomas (UCCs). 
Urothelial carcinomas (UC) are divided into three groups: pTa, pT1, and ≥ pT2 disease, regarding the local extension. pTa bladder cancers have a variable recurrence rate and progression.  About 70% of superficial transitional cell bladder cancers recur and 10-20% progress to a higher stage, grade or metastatic disease. In comparison with superficial transitional cell carcinoma, the prognosis of muscle invasive tumors or metastatic disease is poor. 
p53 is the most frequently mutated tumor suppressor gene identified in human cancers. Tumor suppression functions of p53 stem, in part, from its capabilities to induce cell cycle arrest in late G1 and/or apoptosis in response to genotoxic stress and hypoxia, and mutational inactivation of p53 is associated with an increased risk of tumorigenesis.  Alterations in the p53 pathway contribute to bladder tumor progression and are likely to provide relevant prognostic information to assist in the management of bladder cancer patients.  The evidence shows that over-expression of p53 is a promising prognostic factor and several studies have addressed the association of p53 mutation with high grade, high stage bladder cancer, and an unfavorable prognosis.  p53, p63, and p73 are members of the p53 gene family involved in development, differentiation, and response to cellular stress. 
Both p63 and p73 encode multiple proteins with transactivation, DNA-binding, and tetramerization domains. In normal tissues, p53 levels are undetectable and only reach significant levels after genotoxic stress or mutational inactivation causing p53 protein stabilization. In contrast, p63 exhibits a strikingly varied expression pattern in normal tissues. Work from our group and others has shown that p63 is expressed at high levels in squamous epithelium and urothelium, as well as the basal cell compartment of glandular epithelium in prostate, breast, and bronchi.  The former has limited potential to progress to invasive disease and eventually provides excellent prognosis. The latter originates in carcinoma in situ and results in a high risk of the development of incurable distant metastases. Thus far, three studies have investigated the role of p63 in urothelial neoplasms. The first group of investigators proposed that over-expression of Np63 mRNA or down-regulation of TAp63 mRNA relates to carcinogenesis and tumor progression. 
The aim of our study was to see whether  p63, p53 expression varied according to grade and stage of bladder cancer,  expression of p63, p53 between the groups Noninvasive papillary urothelial carcinoma, low grade (LGPUC), Noninvasive papillary urothelial carcinoma, high grade (HGPUC), invasion into the subepithelial connective tissue/lamina propria/submucosa (pT1), and muscularis propria (pT2).
This retrospective study concerned 62 patients who underwent either TUR of non-invasive and invasive bladder tumors by TUR between 2005 and 2006 in our establishments. The aim of the present study is to determine whether p53 and p63 immunoreactivities are predictive of superficial bladder cancer also to compare each of these markers with the histological grade and pathological stage of tumors.
| Materials and Methods|| |
This study was approved by the local Institutional review board.
Patients and tissue samples
The study included 62 patients with primary superficial (pTa and pT1) bladder tumors who were admitted to and underwent TUR in Istanbul of Goztepe research and training hospital. The patients' mean age was 62.9 years (22-84 years) with a male: female ratio of (49/13) 3.76:1, [Table 1].
All analyses were restricted to the initial tumor tissues diagnosed from each patient. The histopathological examinations were carried out on 3-5 μm thick formalin-fixed, paraffin tissue blocks that were stained with hematoxylin-eosin (HE). Immunohistochemical staining was performed on 5 mm sections using primary antibodies directed against p53 and p63. Briefly, sections were deparaffinized in xylene and rehydrated in graded alcohols. Endogenous peroxidase activity was blocked by immersing sections in 0.3% H 2 O 2 in methanol for 30 min. Sections were placed in a microwave oven for 12 min at 500 W and were allowed to cool at room temperature for 40 min before immunostaining. The primary antibodies against p53 (ready to use liquid mouse monoclonal antibody, 7 ml, product code: RTU-p53-DO7, clone: DO-7, immunogen: recombinant human wild type p53 protein, total protein concentration: 1.0-8.0 g/L., antibody concentration: 1.26 mg/L Novocastra Laboratoires Ltd., United Kingdom) and p63 (Antihuman-p63, Clone: 4A4, mouse, 6 ml, ready to use antibody Biogenex, protein concentration: 10-15 mg/ml, Biogenex Laboratories Inc., USA) were then applied for 1 h at room temperature (20°C). Subsequently, biotinylated anti-mouse antibody was applied to the sections for 30 min. Streptavidin-biotinylated peroxidase complex was then applied and the sections incubated with diaminobenzidine as a chromogen.
Evaluation of immunohistochemical staining
After immunohistochemical staining, the sections were counterstained with hematoxylin to enhance nuclear detection. For negative controls, primary antibody was substituted with PBS in duplicate sections. A colon carcinoma tissue that was detected to be immunoreactive for p53 and a normal skin tissue that was detected as p63 used as positive controls. Only scores with at least 200 malignant cells were scored. p63 staining was considered positive if nuclear percentage between 0 (stained cells < 10%), 1 (>10% stained cells < 80%), and 2 (stained cells > 80-100%) was assessed. Regarding p53, tumors with nuclear immunoreactivity of more than 10% were considered positive according to other previous studies. ,,
The tumors were graded histologically according to the recommendations of the WHO-2004 and staged according to the TNM classification of the American Joint committee of cancer classification. The distribution of the tumors according to histological grade (G) (pTa; papillary carcinoma low-grade, papillary carcinoma high-grade), pathological stage (pT1; tumor invades subepithelial connective tissue, pT2; tumor invades muscle) ,,,,, [Table 2].
|Table 2: Distribution of cases according to histologic grades and pathologic tumor stages*|
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The p53 and p63 indices were analyzed in discrete and continuous fashions. SPSS (Statistical Package for Social Sciences) for Windows 15.0 program, Chi-square test, and Fisher's Exact was performed to compare categorical variables with the status of p63 and p53 expression. All differences associated with a chance probability of 0.05 or less were considered statistically significant. Continuous variables are presented as mean ± SD.
| Results|| |
In p53 and p63 immunohistochemical examination of all participants; p53 staining showed immunoreactivity below 10% in 37.1% (23 cases), and at or over 10% in 62.9% (39 cases) of the patients. No staining below 10% was observed with p63; in 59.7% (37 cases) of the patients staining was observed between 10 and 80%, whereas at or over 80% in 40.3% (25 cases) of the patients [Table 3].
When pTa was evaluated in terms of p63 immunoreactivity, no statistically significant relationship was determined between LGPUC and HGPUC, noninvasive papillary UC, regarding staining percentages (P > 0.05), whereas statistically significant relationship was observed for pT1 and pT2 in terms of p63 staining percentages (P < 0.05); 10-80% staining percentage of pT2 was determined significantly high. Of the cases that showed a staining percentage between 10 and 80%, 8 (72.7%) were LGPUC, 3 (27.3%) were HGPUC, 13 were pT1, and 13 were pT2. Six (85.7%) of seven pTa cases that showed a staining percentage over 80% were LGPUC. Fifteen (83.3%) of 18 pT1-pT2 cases that showed p63 staining percentage over 80% were pT1. Three pT2 cases (16.7%) showed a staining percentage over 80% [Figure 1], [Table 4].
|Table 4: Evaluati on of pTa PUC and pT1-pT2 according to staining percentages|
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|Figure 1: pTa Stage, p63 Staining, Nuclear staining distribution > 80% (p63, x100)|
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For pTa, no statistically significant relationship was observed between LGPUC and HGPUC, noninvasive papillary carcinomas, regarding p53 staining percentages (P > 0.05). All of the three cases that showed a p53 staining percentage below 10% were LGPUC. All of HGPUC cases showed immunoreactivity over 10%. Statistically highly significant relationship was observed for pT1 and pT2 regarding p53 staining percentages (P < 0.01); the staining percentage of pT1 below 10% and the staining percentage of pT2 by 10% or over were determined significantly high. Whereas 17 (60.7% of all pT1 cases) of 20 pT1 and pT2 cases that showed p53 staining percentage below 10% were pT1, 13 (81.3% of all pT2 cases) of 24 pT1 and pT2 cases that showed immunoreactivity over 10% were pT2 [Figure 2], [Table 5]. No statistically significant relationship was observed between the staining percentages of p53 and p63 (P > 0.05); 16 (69.6%) of 23 cases that showed p53 staining percentage below 10% also showed p63 staining between 10 and 80%. A p63 staining by 80% or over was observed in seven cases (30.4%). Concurrent p63 staining between 10 and 80% was demonstrated in 21 (53.8%) of 39 cases that showed p53 staining percentage over 10%. In 18 cases the positivity of p53 staining has been determined over 10%, a p63 staining over 80% was observed [Table 6].
|Table 5: Evaluati on of pTa PUC and pT1-pT2 p53 according to staining percentages|
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|Figure 2: pT2 Stage, p53 Staining, Nuclear staining distribution > 10% (p53, x200)|
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When the pathological tumor stages were evaluated within themselves according to p63 staining, no statistically significant difference was observed between pTa and pT1-pT2 (P > 0.05), whereas there was statistically significant difference between pTa and pT1-pT2 regarding p53 staining (P < 0.05); in pTa cases, staining percentages over 10% and in pT1-pT2 cases, staining percentages below 10% were determined significantly high. Statistically significant difference was observed between p53 staining percentages regarding the age (P < 0.05); staining percentage by 10% and over was determined significantly high among those over the age of 70 years. Whereas 21 (91.3%) of the cases that showed p53 staining positivity below 10% were under the age of 70 years, 2 cases were over the age of 70 years. Of the 39 cases with p53 immunoreactivity over 10%; 26 (66.7%) were under the age of 70 years and 13 (33.3%) were over the age of 70 years. The great majority of the patients over the age of 70 years had p53 positivity over 10%. No statistical significance was observed between p53 staining percentages regarding gender (P > 0.05).
| Discussion|| |
Urothelial (transitional cell) carcinoma of the bladder is a significant neoplasm associated with > 55,000 new cases and 12,000 cancer-related deaths per year in the United States. It is the fifth most common cancer in the United States and the fourth leading cause of cancer deaths.  Bladder cancer presents as superficial (non muscle invasive) papillary tumors in 70% of cases; two-thirds of superficial bladder tumors are confined to the mucosa (Ta) and a third invade the lamina propria (T1).  Most cases of bladder cancer are superficial at the time of diagnosis (stage Ta-T1). The recurrence rate of superficial tumors can be as high as 70%, with 10-15% progressing to muscle-invasive disease.  The T2 to T4 UCCs of the bladder are considered to belong to a prognostically homogeneous group of tumors with a poor prognosis. 
The diagnosis of bladder cancer ultimately depends on both cystoscopic examination of bladder, and the pathologic evaluation of samples. TUR of the tumor should be done so as to maximize the preservation of architectural detail and the relation of the tumor to the various layers of the bladder wall. 
In the present study, when the cases were classified according to the pathological tumor stage, 28 of 62 cases were determined to be in stage pT1. It was conspicuous that the majority of the cases were in this stage. This result seems to be either close to or in line with study results of Hrouda et al.,  which was conducted on 54 cases with superficial transitional cell carcinoma and 39 were pT1; and that of Erill et al.  which was conducted on 76 cases and 23 of them were pT1 and 16 were pT2-4 (endoscopic resection, cystectomy, and TUR were performed) and the study of Gumus et al.  which was conducted on 76 cases with urinary bladder carcinoma and 30 cases were pT1.
The positivity of p53 immunostaining over 10% in those over the age of 70 years participated in the present study was observed to be statistically significantly different ( P < 0.05). Of the 39 cases in which p53 was positive over 10%, 26 (66.7%) were under the age of 70 years, whereas 13 were over the age of 70 years. Nevertheless, we observed a p53 expression below 10% in 2 of 15 cases over the age of 70 years. We are of the opinion that these data are needed to be corroborated with the studies on large series. Different results have been reported in the literature. Gumus et al.  determined the p53 positivity in 21 of 41 cases over the age of 60; however, it was not found to be statistically significant. Toulopidis et al. determined the p53 to be negative in 16 and positive in 12 of 28 cases over the age of 70 years (totally 58 cases), but they were not statistically significant. In the mentioned study, 52% of 25 patients with p53 positivity were under the age of 70 years, whereas 48% were over the age of 70 years. In the same study, it was also reported that recurrence rates were 2.6 times more common in female patients than in male patients, 2 times more common in grade 3 tumors than grade 2 ones, and young patients showed statistically significant recurrence rates (patients over the age of 70 showed the lower recurrence rate by 38% compared to those 60 years of age). In addition, they demonstrated no relationship was present between p53 and other prognostic factors.  In the present study, we observed no statistically significant difference between p53 immunoreactivities according to gender difference ( P > 0.05). Samples from 6 of the 13 female patients participated in the present study were stained p53 positive below 10%, whereas 7 were stained p53 positive over 10%. It was determined in the study by Ozgoz et al.  that p53 mutation was determined in all of the three female patients; they reported that this might suggest that p53 mutation rates in urinary bladder cancers seen in females might be higher than those seen in males, but it was hard to say so, because of the limited number of female patients in the group.
In the present study, observing a p53 positivity below 10% in 60.7% of pT1 cases and over 10% in 81.3% of pT2 tumors revealed a statistically highly significant relation ( P < 0.01). There are numbers of studies in the literature conducted on p53, tumor grade and tumor stage.  Different results have been obtained as the consequence of these studies. We thought that these differences emerge from heterogeneity within the tumors. In the present study, it was conspicuous that all of the HGPUC cases in pTa stage were positive over 10%, despite their limited number. The positivity over 10% in 81.3% of the tumors in pT2 stage indicates that the tumors that invade the muscles are more reactive for p53 as compared to the tumors that invade lamina propria. Similarly, when pTa and pT1-pT2 stage tumors were compared in total, statistically significant difference was determined between pTa and pT1-pT2 regarding p53 staining (P < 0.05); staining over 10% in pTa cases and staining below 10% in pT1-pT2 cases were determined to be significantly high. a p53 staining over 10% was observed in 83.3% (15 cases) of pTa stage tumors and in 54.5% (24 cases) of pT1-pT2 stage tumors. In the study conducted by Compérat et al.  observed that 7 of 22 cases with papillary urothelial neoplasm low malign potential, 10 noninvasive LGPUC (total 26 cases), and 6 noninvasive HGPUC cases (total 8 cases) with tumor cell reactivity of 20-80% with p53. p53 expression was reported in 84% of pT1 cases and in 72% of cases in pT2 stage or over. Statistically significant difference was observed between the staining of pTa and pT1-pT2. In the same study, staining of noninvasive HGPUC and pT1 were 75 and 84%, respectively, and was statistically highly significant. 
In their study performed on 260 cases with urothelial cell carcinoma, Van et al.  determined p53 positivity in 11% of pTa cases, in 51% of pT1 cases, and in 56% of pT2 cases.  In the study conducted by Kilicli et al.  on 188 patients with primary superficial (pTa and pT1) urinary bladder tumor, mean p53 positivity was determined by 58.5%. As the result of the mentioned study, they showed that p53 and Ki-67 have high sensitivity for the predictive risk for the recurrence and progression in superficial UC. 
In the present study, p63 immunoreactivity was observed by 10 to 80% in 59.7% of the participants and over 80% in 40.3% of the participants. No significant relation was determined between the p63 staining of pTa cases (P > 0.05). However, the facts that 83.3% of pT1-pT2 stage with staining over 80% were pT1, and 13 of 16 pT2 cases showed reactivity between 10 and 80% with p63, indicating that the staining percentage of pT2 between 10 and 80% is significantly high (P < 0.05). This result corroborates the opinion that there is a negative correlation between the increase in tumor stage and p63 positivity. However, the present study differs from certain studies also in the way that none of the cases in the present study has showed p63 staining below 10% regardless of the grade and the stage of the tumor. When pTa and pT1-pT2 staining was compared in total, we determined a p63 positivity 10-80% in 61.1% of pTa cases, and in 59.1% of pT1-2 cases, although any statistical significant difference was not observed (P > 0.05). We observed p63 immunoreactivity over 80% in 7 pTa and in 18 pT1-2 cases. It is conspicuous that six (85.7%) of the pTa cases that has showed a staining over 80% were LGPUC and HGPUC cases and were stained at a lower rate. We believe that these data require to be further studied and are confirmed in larger series. In their p63 study conducted on 160 patients with transitional cell carcinoma, of whom 54 had papillary superficial (pTa) tumor and 104 had invasive (pT2-pT4) tumor, Urist et al. reported that tumor cells in low grade papillary superficial urinary bladder tumors showed staining by 93%, whereas moderate or high grade tumors showed 68% positivity and invasive tumors showed 16% reactivity. In that study, they have demonstrated that inverse to the increase in pathological grade of superficial stage tumors, p63 immunoreactivity has been decreased by statistically significant rates.  In their study conducted on 49 patients with urinary bladder tumor, Comperat et al. observed an immunoreactivity by 10-80% for p63 in 17% of cases, and a staining rate of 80% and over in 83% of 18 pTa cases (12 high grade pTa and 6 microinvasive high grade pT1). In the same study, staining was observed by 10-80% in 20% of tumors, and a staining rate of 80% and over in 60% of the cases with pT1 (5 cases) tumor. They observed immunoreactivity by 10-80% in 48% of tumors, and a staining rate of 80% and over in 22% of the cases with pT2/T3/T4 tumors (31 cases). The most conspicuous aspect of this study was the strong deregulation of the genes in urothelial carcinoma and abnormal p63 expression at early stages. 
In this present study, no statistically significant correlation was observed between the staining percentages of p53 and p63 (P > 0.05); we have attributed this result to the fact that p63 and p53 affect urinary bladder carcinogenesis in different ways. The absence of correlation has been confirmed by other studies conducted on different organ cancers.
| Conclusion|| |
The place of p53 and p63 immunoreactivities in predicting the prognosis of the tumor with regard to the grade and the stage, which is still controversial, will be understood better with the increase in the studies performed on larger series with a long term follow-up and at a molecular level.
| Acknowledgments|| |
We thank the M. Murat Naki, MD, Dr. Lutfi Kirdar Kartal Education, and Research Hospital Department of Obstetrics and Gynecology Istanbul/Turkey for their assistance in the measurement phase of this study.
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Zaman Sokak, No: 37, Balkanci Apartmani C Blok 5/18, Merdivenköy, Kadiköy, Istanbul
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]