IMMUNOHISTOCHEMICAL EXPRESSION OF P63 IN UROTHELIAL CARCINOMA

Document Type : Original Article

Authors

1 Department of Pathology Faculty of Medicine, Sohag University

2 Department of Urology and Genetics Faculty of Medicine, Sohag University

Abstract

Introduction: Urothelial carcinoma is the most common histologic type of urinary bladder cancer in Egypt. Detection of high-grade urothelial carcinoma is important for modification of therapy and improving the prognosis. P63 is expressed at high levels in the basal layers of different epithelial tissues, including the urothelium. Aim of the work: to study the diagnostic and prognostic value of p63 expression in urothelial carcinoma (UC).   Materials and Methods: Fifty cases of bladder urothelial carcinoma were involved in the study; 12 cases of non-invasive UC, (3 HG & 9 LG), and 38 cases of invasive UC, (30 HG & 8 LG). Sixteen cases of UC showed Bilharziasis. All the specimens were stained with p63 using immunohistochemical technique.  Results:  P63 was expressed in 28/38 cases (73.7%) of invasive UC and in all cases of non-invasive UC, and also in 16/17 (94%) low-Grade and in 24/33 (72.7%) of high-grade UC, with a statistically significant relation between p63 expression and both invasion (p > 0.001) and the tumor grade (p> 0.034). Conclusion: P63 can be used as a diagnostic and a prognostic factor for high grade invasive UC

Keywords


1-      Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM.   Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.  Int J Cancer. 2010; 127(12): 2893-917                   
2-      Huang W, Williamson SR, Rao Q, Lopez-Beltran A, Monitroni R, Eble JN, Grignon DJ, Idrees MT, Emerson RE, Zhou XJ, Zhang S, Baldridge LA, Hahn NM, Wang M, Koch MO, Cheng L.   Novel markers of squamous differentiation in the urinary bladder.   Hum Pathol.  2013; 44: 1989-1997.
   3- Gouda I, Mokhtar N, Bilal D, El-Bolkainy T, El-bolkainy NM.   Bilharziasis and bladder cancer: a time trend analysis of 9843 patients.   J Egypt Natl Canc Inst. 2007; 19: 158-162.
4- Khaled H.   Schistosomiasis and cancer in Egypt: review. Medical Oncology, National Cancer Institute, Cairo University, Cairo 11796, Egypt.  J Advanced Res .2013; 4: 461-466.
 
5- Shariat SF, Karakiewicz PI, Palapattu GS, Lotan Y, Rogers CG, Amiel GE, Vazina A, Gupta A, Bastian PJ, Sagalowsky AI, Schoenberg MP, Lerner SP.   Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the bladder cancer Research consortium.   J Urol 2006; 176: 2414-2422.
 
6- Lee R and Droller MJ.   The natural history of bladder cancer.   Implications for therapy. Urol  Clin  North Am. 2000; 27: 1-13.
 
7- Higgins JP, Kaygusuz G, Wang L, Montgomery K, Mason V, Zhu SX, Marinelli RJ, Presti JC Jr, Van de Rijn M,
 
 
Brooks JD.   Placental S100 (S100P) and GATA3: Markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray.   Am J Surg Pathol. 2007; 31: 673-680.
 
8- Hodges KB, Lopez-Beltran A, Emerson RE, Montironi R, Cheng L.   Clinical utility of immunohistochemistry in the diagnoses of urinary bladder neoplasia.   Appl Immunohistochem Mol Morphol. 2010; 18: 401-410.
 
9- Pignon J C, Grisanzio C, Geng Y, Song J, Shivdasani RA, Signoretti S.   P63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia.  Proc Natl Acad Sci U S A. 2013; 110 (20): 8105-8110.
 
10- Joerger, AC, Rajagopalan, S, Natan, E, Veprintsev, DB, Robinson, CV and Fersht, AR Structural evolution of p53, p63, and p73: Implication for heterotetramer formation. Proc. Natl. Acad. Sci. USA 106 (2009): 17705-17710.
 
11- Gressner O, Schilling T, Lorenz K, Schulze-Schleithoff E, Koch A, Schulze-Bergkamen H, Lena AM, Candi E, Terrinoni A, Catani MV, Oren M, Melino G, Krammer PH, Stremmel W, and Muller M.   TAp63α induces apoptosis by activating signaling via death receptors and mitochondria.   EMBO J 2005; 24: 2458-2471.
 
12- Mundt HM, Stremmel W, Melino G, Krammer PH, Schilling T, and Muller M.   Dominant negative ∆Np63α induces drug resistance in hepatocellular carcinoma by interference with apoptosis signaling pathways.   Biochem Biophys Res Commun 2010; 369: 335-341.
 
13- Park, B. J., Lee SJ, Kim JI, Lee SJ, Lee CH, Chang SG, Park JH, Chi SG.   Frequent alterations of p63 expression in human primary bladder carcinomas.   Cancer Res. 2000; 60: 3370-3374.
 
14- Koga, F., Kawakami S, Kumagai J, Takizawa T, Ando N, Arai G, Kageyama Y, Kihara K.    Impaired TNp63 expression characterizes aggressive phenotypes of urothelial neoplasms. Br J Cancer 2003; 88: 740-747.
15- Hibi, K., Trink, B., Patturajan, M, Westra WH, Caballero OL, Hill DE, Ratovitski EA, Jen J, Sidransky D.   AIS are an oncogene amplified in squamous cell carcinoma. Proc  Natl  Acad  Sci. 2000; 97: 5462-5467.
 
16- Nekulova M, Holcakova J, Coates P, Vojtesek B.   The role of p63 in cancer, stem cells and cancer stem cells. Cell Mol Biol Lett. 2011; 16: 296-327.
 
17- Lopez-Beltran A, Sauter G, Gasser T, Hartmann A, Schmitz-Drager BJ, Helpap B, Ayala AG, Tamboli P, Knowles MA, Sidransky D, Cordon-Cardo C, Jones PA, Cairns P, Simon R, Amin MB, Tyczynski JE. Infiltrating urothelial carcinoma: In World Health Organization classification of tumors. Pathology and Genetics of tumors of the urinary system and male genital organs. Lyon, IARCC Press. 2004; PP: 91-94.
 
18- Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, and Trotti A.   AJCC cancer staging manual (7th ed). New York, NY: Springer 2010.
 
19- Chan WY, Cheung KK, Schorge JO, Huang LW, Welch WR, Bell DA, Berkowitz RS, Mok SC. Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers.   Am J Pathol. 2000; 156: 409-417.
 
20- Melino G.   P63 is a suppressor of tumergenesis and metastasis interacting with mutant P53.   Cell Death Differe. 2011; 18 (9): 1487-1499.
 
21- Craig AL, Holcakova J, Finlan LE, Nekulova M, Hrstka R, Gueven N, DiRenzo J, Smith G, Hupp TR, and Vojtesek B.   Delta Np63 transcriptionally regulates ATM to control p53 serin-15-phosphorylation.  Mol Cancer 2010; 9: 195.
22- Stefanou D, Batistatu A, Nonni A, Arkoumani E, Agnantis NJ.   P63 expression in benign and malignant breast lesions.   Histol Histopathol 2004; 19(2): 465-471.
 
23- Wang X, Mori I, Tang W, Nakamura M, Nakamura Y, Sato M, Sakurai T, and Kakudo K.   P63 expression in normal, hyperplastic and malignant breast tissues.   Breast Cancer 2002; 9(3): 216: 219. 
 
24- Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, Federman S, Miller JR 3rd, Allen RE, Singer MI, Leong SP, Ljung BM, Saqebiel RW, Kashani-Sabet M.   The gene expression signatures of melanoma progression.   Proc Natl Acad Sci USA 2055; 102(7): 6092-6097.
 
25- Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, Ponzin D, McKeon F and DeLuca M.   P63 identifies keratinocytes stem cells.   Pro Natl Acad Sci USA 2001; 98: 3156-3161.
 
26- Stepan A, Margaritescu CL, Simionescu C, Ciurea R.   E-cadherin and P63 immunoexpression in dysplastic lesions and urothelial carcinoma of the bladder.   Romanian J of Morphology and Embryology 2009; 50 (3): 461-465.
 
27- Barbieri CE, Tang LJ, Brown KA, and Pietenpol JA.   Loss of p63 leads to increased cell migration and upregulation of genes involved in invasion and metastasis.   Cancer Res 2006; (66): 7589-7597.
 
28- Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB, Wistuba I and Flores ER.   TAp63 suppresses metastasis through coordinate regulationof Dicer and mi RNAs.   Nature 2010; 467: 986-990. 
29- Raheem SA, Saied AN, Al Shaer R, Mustafa O, Ali AH.   The role of CK20, P53 and P63 in differentiation of some urothelial lesions of urinary bladder, immunohistochemical study.  Open Journal Of Pathology 2014; 4: 181-193.
 
30-Koyuncuer A.   Immunohistochemical expression of P63 and P53 in urinary bladder carcinoma.   Indian J Pathology & Microbiology 2013; 56 (1): 10-15.
 
31- Urist MJ, Di Como CJ, Lu ML, Charytonowicz E, Verbel D, Crum CP, Ince TA, Mckeon FD, Cordon-Cardo C.   Loss of P63 expression is associated with tumour progression in bladder cancer.   Am J Patholo 2002; 16 (4): 1199-1206.
 
32- Koga F, Kawakami S, Fuji Y, Sato K, Ohtsuka Y, Iwai A, Ando N, Takizawa T, Kaqeyama Y, Kihara K.   Impaired p63 expression associated with poor prognosis and Uroplakin III expression in invasive urothelial carcinoma of the bladder.   Clin Cancer Res 2003; 9(15): 5501-5507.
 
33- Choi W, Shah JB, Tran M, Svatek R, Marquis L, Lee L, Yu D, Adam L, Wen S, Shen Y, Dinney C, McConkey DJ, Siefker-Radtke A.   P63 expression defines lethal subsets of muscle-invasive bladder cancer.   Plosone 2012; 7 (1): e30206.
 
34- Karni-Schmidt O, Castillo-Martin M, Hvai Shon T, Gladoun N, Domingo-Domenech J, Sanchez-Carbayo M, Li Y, Lowe S, Prives C, Cordon-Cardo C.   Distinct expression profile of P63 variants during urothelial development and bladder cancer progression.   Am J Patholo 2011; 178: 159-165.
 
35- Mursi K, Agag A, Hammam O, Riad A and Daw M.   The expression of p63 in bladder cancer vs chronic bilharzial bladder.   Arab J Urol 2013; 11(1): 106-112.