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Year : 2011  |  Volume : 54  |  Issue : 1  |  Page : 59-62
Utility of p63 immunohistochemical stain in differentiating urothelial carcinomas from adenocarcinomas of prostate

1 Department of Pathology and Microbiology, Aga Khan University, Karachi, Pakistan
2 Consultant Pathologist, Shaukat Khanum Cancer Hospital, Lahore, Pakistan

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Date of Web Publication7-Mar-2011


Background: Prostatic adenocarcinoma and urothelial carcinoma of the urinary bladder are common cancers in men. High grade forms of these tumors may present ambiguous morphologic features that do not permit a definite diagnosis. This distinction between the two tumors has significant staging and therapeutic implications. Hence, an accurate diagnosis is essential for optimal patient care. p63 is a new marker which can be used in this context. It is expressed in most of the urothelial carcinomas and negative in majority of prostatic adenocarcinomas. Aim: To compare the expression of p63 in urothelial carcinomas and adenocarcinomas of prostate. Materials and Methods: Comparative cross--sectional study was carried out at a tertiary cancer hospital from 15 June 2006 to 15 December 2006. Immunohistochemical stain p63 was performed on 50 cases of urothelial carcinoma and 50 prostatic adenocarcinomas. Patients' name, age, histology numbers, grade of tumor, and expression of p63 were recorded. p63 expression was seen in 44 of 50 urothelial carcinomas (88%). None of the prostatic adenocarcinomas expressed p63. The ages of patients with prostatic adenocarcinoma ranged from 49 to 86 years with a median age of 71 years and 41 to 83 years for urothelial carcinomas with a median age of 60.5 years. Conclusion: p63 can be used as a reliable marker to distinguish prostatic adenocarcinomas from urothelial carcinomas in difficult cases in conjunction with other markers like PSA.

Keywords: p63, prostate, prostatic adenocarcinomas, urinary bladder, urothelial carcinomas

How to cite this article:
Ud Din N, Qureshi A, Mansoor S. Utility of p63 immunohistochemical stain in differentiating urothelial carcinomas from adenocarcinomas of prostate. Indian J Pathol Microbiol 2011;54:59-62

How to cite this URL:
Ud Din N, Qureshi A, Mansoor S. Utility of p63 immunohistochemical stain in differentiating urothelial carcinomas from adenocarcinomas of prostate. Indian J Pathol Microbiol [serial online] 2011 [cited 2022 Aug 11];54:59-62. Available from: https://www.ijpmonline.org/text.asp?2011/54/1/59/77326

   Introduction Top

Bladder cancer is the most common urological malignancy in Pakistan. [1] It­ is the seventh most common cancer worldwide, with an estimated 260,000 new cases occurring each year in men and 76,000 in women. [2] Approximately 98% of malignant tumors arising in the urinary bladder is of epithelial origin and of these, 90% are urothelial carcinomas. Urothelial carcinoma is a major cause of morbidity and mortality throughout the world. It is typically seen in patients over 50 years of age but is occasionally seen in younger adults; it is rare in children. Urothelial carcinoma has been of interest epidemiologically because of its association with exposure to aniline dyes. [3] More recently, an association with cigarette smoking has become well substantiated.

Carcinoma of the prostate is the most common internal malignancy among men in the United States and is responsible for 10% of all cancers. Each year in the New York State more than 11,000 men are diagnosed with prostate cancer, and more than 2300 die from it. Prostate cancer is the leading cause of new cancer in men and is second only to lung cancer as a leading cause of cancer related deaths in men. [4] Both incidence and mortality have decreased in the past few years. [5]

p63 is a nuclear protein encoded by a gene on chromosome 3q27--29 with homology to p53((a tumor suppressor gene), it has shown to regulate growth and development in epithelium of the skin, cervix, breast, and urogenital tract. Specific isotopes are expressed in basal cells of prostate, myoepithelial cells of breast, urothelium, and squamous epithelium. [6] A monoclonal antibody is active in paraffin embedded tissue following antigen retrieval. p63 has similar applications to those of high-molecular-weight cytokeratins in the diagnosis of prostatic adenocarcinoma, but with the advantages that p63 (1) stains a subset of 34betaE12 negative basal cells, (2) is less susceptible to the staining variability of 34betaE12 (particularly in transurethral resection of prostate (TURP) specimens with cautery artifact), and (3) is easier to interpret because of its strong nuclear staining intensity and low background. Prostatic adenocarcinomas have occasional p63 immunoreactive cells, most representing entrapped benign glands or intraductal spread of carcinoma with residual basal cells. [7]

   Materials and Methods Top

This study was carried out in Pathology department of a tertiary care cancer hospital and Research Centre.

Duration of Study

15 June 2006 to 15 December 2006.

Sample Size

A total of 100 male patients of more than 40 years (50 patients each of urothelial and prostatic adenocarcinomas) were studied.

Sampling Technique

0Non--probability convenience sampling was applied.

Study Design

Comparative cross--sectional study.

Data Collection Procedure

The study was started after approval by the institutional review board (IRB) of the hospital. Transurethral resection specimens containing urothelial carcinomas and prostatic adenocarcinomas of male patients of more than 40 years of age were included in the study. Recurrent tumors and specimens subjected to neoadjuvent therapy were excluded from the study. A total of 100 cases (50 samples of prostatic adenocarcinomas and 50 samples of urothelial carcinomas) were selected and p63 immunohistochemical stain was performed.

The patient's name, age, histology number, grade of tumor, expression of p63 on urothelial, and prostatic adenocarcinomas were recorded.

Hematoxylin and eosin (H and E) stained slides were reviewed in all cases to verify the histologic findings. Representative formalin--fixed, paraffin--embedded tissue blocks were selected for p63 immunohistochemical staining.

Staining Interpretation and Reporting Criteria

The staining results of the tumor were expressed as the product of the brown nuclear staining intensity and the percentage of positive cells.

The whole section was scanned at low power in order to assess the general level of intensity throughout. The average intensity of the staining corresponds to the presence of negative, weak, moderate, and strong staining. The percentage of tumor cells was scored as follows.

0 = no reactivity; 1 = less than 10% of cancer cell nuclei positive; 2 = 10-- 25 % positive; 3 = 25--50 % positive, 4 = 50--75 % positive; 5 = 75--90% positive; and 6 = >90% of tumor cell nuclei positive.

Data Analysis

0The data entered into the computer and results were reported as frequencies and proportions by using SPSS--10. As the results were qualitative in nature, the outcome of the results was tested for significance by applying the chi--square (χ2 ) test to the observations of the positive and negative nuclear staining in urothelial carcinomas and adenocarcinomas of prostate.

   Results Top

During the study period, 100 transurethral resection specimens diagnosed as urothelial carcinomas and prostatic adenocarcinomas were studied and expression of p63 was noted.

The age of the all patients ranged from 41 years to 86 years with a median age of 66 years.

The age of the patients of urothelial carcinoma ranged from 41 to 83 years with a median age of 60.5 years. Fourteen patients (28%) are in the age group of 61--65 years.

The age of the patients of prostatic adenocarcinomas ranged from 46 to 86 years with a median age of 71 years. A significant percentage i.e. 26% and 28% of patients are in the age groups of 66--70 and 71--75 years, respectively [Table 1].
Table 1: p63 Staining in urothelial carcinomas

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Out of 50 urothelial carcinomas, 31 were low grade (62%) and 19 were high grade (38%).

The Gleason score of the patients of prostatic adenocarcinoma was between 5 and 9. Gleason score 9 was found in 22 cases (44%) and 7 in 18 cases (36%). If comparing Gleason score with age, 9 cases of score 7 were found in the age group 71 to 75 years and 8 cases of score 9 were present in the age group 66 to 70 years [Table 2].
Table 2: Test Statistics

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Out of the 50 urothelial carcinomas 44 stained with p63 (88%). Overall, 54% of cases showed strong nuclear staining in >90% of tumor cells [Table 2].

Out of 31 low grade urothelial carcinomas, 26 positively stained with p63 (83.8%) [Figure 1]a and b.
Figure 1: (a) Low grade urothelial carcinoma; (H and E, ×200). (b) (INSET) Strong p63 staining in low grade urothelial carcinoma (IHC, ×200).

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Out of 19 high grade urothelial carcinomas, 18 were positively stained with p63 (94.7%) [Figure 2]a and b.
Figure 2: (a) High grade urothelial carcinoma; (H and E, ×400).(b) (INSET) Strong p63 staining in high grade urothelial carcinoma (IHC, ×400).

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None of the 50 prostatic adenocarcinomas expressed p63 [Figure 3]a and b. Staining status was compared between urothelial carcinomas and prostatic adenocarcinomas in all 100 cases. Basal cells of benign glands of prostate were taken as positive internal controls. p63 positivity was observed in 88% of urothelial carcinomas and none of prostatic adenocarcinomas with a P value of 0.001 [Table 2].
Figure 3: (a) Prostatic adenocarcinoma, Gleason's score 4+4 with entrapped benign glands (arrows); (H and E, ×400). (b) (INSET) Negative p63 staining in prostatic adenocarcinoma, Gleason's score 4+4 with positivity of basal cells of entrapped benign glands (arrows); (IHC, ×400).

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   Discussion Top

Distinguishing poorly differentiated prostate cancer arising in the urinary bladder neck from high grade urothelial carcinoma with prostatic extension frequently can be a challenging task for surgical pathologist owing to overlapping morphologic characteristics and similar clinical manifestations in the two entities. This distinction has significant therapeutic and staging implications. For example, cystoprostatectomy, the standard surgical procedure for the treatment of bladder cancer, is inappropriate for prostatic cancer and the determination of the tumor stage, for its prognostication would require correct diagnosis as extension of bladder cancer into the prostate as well as prostate cancer into the bladder would signify pT4 disease. [8]

Distinction of poorly differentiated prostatic cancer from a high grade urothelial carcinoma in transurethral resection specimens is a relatively common problem, with the difficulty compounded by the relatively common occurrence of glandular differention in the latter and the frequently raised serum prostate-specific antigen in cases of urothelial carcinoma extending into the prostate gland. The presence of coexisting low grade papillary urothelial tumor or urothelial carcinoma in situ would favor high grade urothelial carcinoma, but the possibility of synchronous prostate cancer would have to be excluded as both tumor types occur in elderly men.

Although several markers have been analyzed to determine the prostatic or urothelial origin of poorly differentiated tumors, no marker to date has been sufficiently sensitive and/or specific. Prostate specific antigen and prostate-specific acid phosphatase traditionally have been used to confirm a prostatic origin; however, they are not expressed uniformly in poorly differentiated prostatic carcinoma and might be negative in up to 27% and 19% of cases, respectively. [9],[10] Two markers have proved useful in the diagnosis of prostatic carcinoma  alpha--methyl--acyl--coenzyme A racemase (AMACR), a positive diagnostic tissue biomarker of prostate cancer, and p63, a basal cell marker for which usefulness in the diagnosis of prostatic carcinoma is supported by its lack of staining in atypical glands. [11],[12],[13]

Cytokeratin (CK) 7, CK20, and high-molecular-weight cytokeratin (HMWCK) have been studied as potential urothelial markers. [14] Although they are useful in certain situations, they are not entirely specific for urothelial carcinoma. Recently, uroplakin, a membranous glycoprotein, has emerged as a highly specific marker of urothelial carcinoma. However it is only moderately sensitive and is expressed only in 50% to 60% of urothelial carcinomas, typically in well--differentiated tumors. [14] Therefore, its usefulness in resolving diagnostically challenging cases in day to day practice seems limited.

Our study validates the results of Kaufmann et al., [15] who performed p63 on urothelial carcinomas and prostatic adenocarcinomas. They found p63 positivity in 87% of urothelial carcinomas and 2% of prostatic adenocarcinomas and observed that staining for p63 was easily interpreted as positive or negative. They stressed that p63 is a pleasant stain to evaluate, positive and negative cases are readily distinguished and concluded that p63 can be useful marker in the differential diagnosis of urothelial carcinoma from poorly differentiated prostatic carcinoma.

Like the results of Kunju et al.[16] we found p63 positivity in 94.7% of high grade urothelial carcinomas. They performed p63 along with a panel of immunohistochemical stains on 36 cases of high grade urothelial carcinomas and 42 cases of poorly differentiated prostatic carcinomas. p63 positivity was seen in 92% of urothelial carcinomas. None of the prostatic carcinoma stained with p63. They found p63 to be a fairly sensitive and highly specific marker of urothelial carcinoma with consistent diffuse nuclear positivity in 92% of all documented cases of urothelial carcinomas.

Our study also serve to corroborate the results of Langner et al. [17] who performed p63 stain on 53 transitional cell(urothelial) carcinomas of the upper urinary tract and 188 renal cell carcinomas. Overall p63 was positive in 51(96.2%) of urothelial carcinomas and 23(92%) of high grade urothelial carcinomas. In the renal cell carcinoma group, all tumors regardless of the histologic subtype, grade, and stage were negative.

The results of p63 staining on prostatic adenocarcinoma supports the results of Signoretti et al., [18] who performed p63 on 130 cases of invasive prostate cancer and found p63 negativity in 126(97%) cases. Four cases showed p63 positivity in <1% of tumor cells.

The ages of our patients were between 41 and 86 years. The peak incidence of urothelial carcinoma was seen in 61--65 years and for prostatic adenocarcinoma in 66--75 years which supports the international data.

   Conclusion Top

Our results proved our hypothesis correct that majority of the prostatic adenocarcinomas are p63 negative and most of the urothelial carcinomas are p63 positive. Hence we conclude that p63 is a reliable marker of urothelial differentiation and can be used along with other markers in morphologically difficult cases when the differential diagnosis is between poorly differentiated adenocarcinoma of prostate and high grade urothelial carcinoma of urinary bladder.

   References Top

1.Rafique M, Javed AA. Clinico-pathological features of bladder carcinoma: Experience from a tertiary care hospital of Pakistan. Int Urol Nephrol 2006;38:247-50.  Back to cited text no. 1
2.Parkin DM, Bray F, Ferlay J, Pisani P. Esimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-6.   Back to cited text no. 2
3.Wallace DM. Occupational urothelial cancer. Br J Urol 1988;61:175-82.  Back to cited text no. 3
4.Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer Statistics 2000. CA Cancer J Clin 2000;50:7-33.  Back to cited text no. 4
5.Hankey BF, Feuer EJ, Clegg LX, Hayes RB, Legler JM, Prorok PC. Cancer surveillance series: Interpreting trends in prostate cancer-- part 1: Evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J Natl Cancer Inst 1999;91:1017-24.  Back to cited text no. 5
6.Ordonez NG. Thrombomodulin expression in transitional cell carcinoma. Am J Clin Pathol 1998;110:385-90.  Back to cited text no. 6
7.Higgins JP, Kaygusuz G, Wang L, Montgomery K, Mason V, Zhu SX, et al. Placental S100 (S100P) and GATA3: Markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray. Am J Surg Pathol 2007;31:673-80.  Back to cited text no. 7
8.Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L, et al. p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000;157:1759-75.  Back to cited text no. 8
9.Varma M, Jasani B. Diagnostic utility of immunohistochemistry in morphologically difficult prostate cancer: Review of current literature. Histopathology 2005;47:1-16.  Back to cited text no. 9
10.Varma M, Morgan M, Jasani B, Tamboli P, Amin MB. Polyclonal anti-PSA is more sensitive but less specific than monoclonal anti-PSA: Implications for diagnostic prostatic pathology. Am J Clin Pathol 2002;118:202-7.  Back to cited text no. 10
11.Varma M, Berney DM, Jasani B, Rhodes A. Technical variations in prostatic immunohistochemistry: Need for standardisation and stringent quality assurance in PSA and PSAP Immunostaining. J Clin Pathol 2004;57:687-90.  Back to cited text no. 11
12.Jiang Z, Woda BA, Rock KL, Xu Y, Savas L, Khan A. P504S: A new molecular marker for the detection of prostate carcinoma. Am J Surg Pathol 2001;25:1397-404.  Back to cited text no. 12
13.Zhou M, Shah R, Shen R, Rubin MA. Basal cell cocktail (34betaE12+ p63) improves the detection of prostate basal cells. Am J Surg Pathol 2003;27:365-71.  Back to cited text no. 13
14.Bassily NH, Vallorosi CJ, Akdas G, Montie JE, Rubin MA. Coordinate expression of cytokeratins 7 and 20 in prostate adenocarcinoma and bladder urothelial carcinoma. Am J Clin Pathol 2000;113:383-8.  Back to cited text no. 14
15.Kaufmann O, Volmerig J, Dietel M. Uroplakin 3 rd is a highly specific and moderately sensitive immunohistochemical marker for primary and metastatic urothelial carcinomas. Am J Clin Pathol 2000;113:683-7.  Back to cited text no. 15
16.Kunju LP, Mehra R, Snyder M, Shah R. Prostate--specific antigen, high--molecular--weight cytokeratin (clone 34betaE12), and/ or p63: An optimal immunohistochemical panel to distinguish poorly differentiated prostate adenocarcinoma from urothelial carcinoma. Am J Clin Pathol 2006;125:675-81.  Back to cited text no. 16
17.Langner C, Ratschek M, Tsybrovskyy O, Schips L, Zigeuner R. p63 immunoreactivity distinguishes upper urinary tract transitional-cell carcinoma and renal-cell carcinoma even in poorly differentiated tumors. J Histochem Cytochem 2003;51:1097-9.  Back to cited text no. 17
18.Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L. p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000;157:1769-75.  Back to cited text no. 18

Correspondence Address:
Asim Qureshi
Consultant Pathologist, Shaukat khanum cancer hospital, Lahore
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.77326

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