All Title Author
Keywords Abstract

PLOS ONE  2014 

The Expression Patterns of p53 and p16 and an Analysis of a Possible Role of HPV in Primary Adenocarcinoma of the Urinary Bladder

DOI: 10.1371/journal.pone.0095724

Full-Text   Cite this paper   Add to My Lib


Background Primary adenocarcinoma of the urinary bladder is rare. The molecular and cellular events leading to its pathogenesis are not well delineated. The goal of this study was to investigate p53 and p16 expression, as well as HPV status, in a relatively large series of primary bladder adenocarcinomas. Materials and Methods Thirty six cases of urinary bladder adenocarcinoma were chosen from participating institutions. The diagnosis and available clinical history were reviewed in each case. Immunostains for p53, p16 and HPV and high-risk and low-risk HPV-ISH were performed on all tumors. Results Patients had an average age of 61 years with a male predominance (1.5:1 male:female ratio). The average tumor size in cystectomy specimens was 4.3 cm. Of the cases managed by transurethral resection, 40% were pT2 at the time of diagnosis. In cystectomy specimens, 77% were either pT3 or pT4. Strong nuclear p16 expression was seen in 67% of all cases and p53 expression was present in 58% of the cases. Expression of both markers was seen in 33% of cases. Expression of p16 or p53 alone was present in 12 (33%) and 9 (25%) cases, respectively. Neither marker was expressed in only 3 (8%) of the tumors. No significant correlation between clinical variables and any of the markers we studied was identified. No HPV infection was detected in any case. Conclusions Expression of p53 and/or p16 is very common in urinary bladder adenocarcinoma. These findings implicate a high likelihood that alterations in these cell cycle proteins contribute to the pathogenesis of these tumors. Despite frequent immunohistochemical labeling for p16, no evidence of HPV infection was found.


[1]  Cheng L, Lopez-Beltran A, Bostwick DG (2012) Bladder pathology. Hoboken, N.J.: Wiley-Blackwell. vii, 754 p. p.
[2]  Dahm P, Gschwend JE (2003) Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur Urol 44: 672–681. doi: 10.1016/s0302-2838(03)00416-0
[3]  Ploeg M, Aben KK, Kiemeney LA (2009) The present and future burden of urinary bladder cancer in the world. World J Urol 27: 289–293. doi: 10.1007/s00345-009-0383-3
[4]  Zaghloul MS, Nouh A, Nazmy M, Ramzy S, Zaghloul AS, et al. (2006) Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients. Urol Oncol 24: 13–20. doi: 10.1016/j.urolonc.2005.05.027
[5]  el-Mekresh MM, el-Baz MA, Abol-Enein H, Ghoneim MA (1998) Primary adenocarcinoma of the urinary bladder: a report of 185 cases. Br J Urol 82: 206–212. doi: 10.1046/j.1464-410x.1998.00718.x
[6]  Ploeg M, Aben KK, Hulsbergen-van de Kaa CA, Schoenberg MP, Witjes JA, et al. (2010) Clinical epidemiology of nonurothelial bladder cancer: analysis of the Netherlands Cancer Registry. J Urol 183: 915–920. doi: 10.1016/j.juro.2009.11.018
[7]  Rao Q, Williamson SR, Lopez-Beltran A, Montironi R, Huang W, et al. (2013) Distinguishing primary adenocarcinoma of the urinary bladder from secondary involvement by colorectal adenocarcinoma: extended immunohistochemical profiles emphasizing novel markers. Mod Pathol 26: 725–732. doi: 10.1038/modpathol.2012.229
[8]  Levine AJ, Momand J, Finlay CA (1991) The p53 tumour suppressor gene. Nature 351: 453–456. doi: 10.1038/351453a0
[9]  Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253: 49–53. doi: 10.1126/science.1905840
[10]  Ruas M, Peters G (1998) The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1378: F115–177. doi: 10.1016/s0304-419x(98)00017-1
[11]  Alexander RE, Hu Y, Kum JB, Montironi R, Lopez-Beltran A, et al. (2012) p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma. Mod Pathol 25: 1526–1533. doi: 10.1038/modpathol.2012.103
[12]  Tzai TS, Tsai YS, Chow NH (2004) The prevalence and clinicopathologic correlate of p16INK4a, retinoblastoma and p53 immunoreactivity in locally advanced urinary bladder cancer. Urol Oncol 22: 112–118. doi: 10.1016/s1078-1439(03)00176-5
[13]  Shariat SF, Tokunaga H, Zhou J, Kim J, Ayala GE, et al. (2004) p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol 22: 1014–1024. doi: 10.1200/jco.2004.03.118
[14]  Kapur P, Lotan Y, King E, Kabbani W, Mitra AP, et al. (2011) Primary adenocarcinoma of the urinary bladder: value of cell cycle biomarkers. Am J Clin Pathol 135: 822–830. doi: 10.1309/ajcp76kuvotbkqry
[15]  Benevolo M, Mottolese M, Marandino F, Vocaturo G, Sindico R, et al. (2006) Immunohistochemical expression of p16(INK4a) is predictive of HR-HPV infection in cervical low-grade lesions. Mod Pathol 19: 384–391. doi: 10.1038/modpathol.3800551
[16]  Doxtader EE, Katzenstein AL (2012) The relationship between p16 expression and high-risk human papillomavirus infection in squamous cell carcinomas from sites other than uterine cervix: a study of 137 cases. Hum Pathol 43: 327–332.
[17]  Keating JT, Cviko A, Riethdorf S, Riethdorf L, Quade BJ, et al. (2001) Ki-67, cyclin E, and p16INK4 are complimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia. Am J Surg Pathol 25: 884–891. doi: 10.1097/00000478-200107000-00006
[18]  Klaes R, Benner A, Friedrich T, Ridder R, Herrington S, et al. (2002) p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol 26: 1389–1399. doi: 10.1097/00000478-200211000-00001
[19]  Klaes R, Friedrich T, Spitkovsky D, Ridder R, Rudy W, et al. (2001) Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92: 276–284. doi: 10.1002/ijc.1174
[20]  Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408: 307–310. doi: 10.1038/35042675
[21]  Slaton JW, Benedict WF, Dinney CP (2001) P53 in bladder cancer: mechanism of action, prognostic value, and target for therapy. Urology 57: 852–859. doi: 10.1016/s0090-4295(01)00968-2
[22]  Kakehi Y, Ozdemir E, Habuchi T, Yamabe H, Hashimura T, et al. (1998) Absence of p53 overexpression and favorable response to cisplatin-based neoadjuvant chemotherapy in urothelial carcinomas. Jpn J Cancer Res 89: 214–220. doi: 10.1111/j.1349-7006.1998.tb00551.x
[23]  He F, Mo L, Zheng XY, Hu C, Lepor H, et al. (2009) Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis. Cancer Res 69: 9413–9421. doi: 10.1158/0008-5472.can-09-2158
[24]  Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, et al. (2003) Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 348: 518–527. doi: 10.1056/nejmoa021641
[25]  zur Hausen H (1994) Molecular pathogenesis of cancer of the cervix and its causation by specific human papillomavirus types. Curr Top Microbiol Immunol 186: 131–156. doi: 10.1007/978-3-642-78487-3_8
[26]  Rayess H, Wang MB, Srivatsan ES (2012) Cellular senescence and tumor suppressor gene p16. Int J Cancer 130: 1715–1725. doi: 10.1002/ijc.27316
[27]  Romagosa C, Simonetti S, Lopez-Vicente L, Mazo A, Lleonart ME, et al. (2011) p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene 30: 2087–2097. doi: 10.1038/onc.2010.614
[28]  Zhao W, Huang CC, Otterson GA, Leon ME, Tang Y, et al. (2012) Altered p16(INK4) and RB1 Expressions Are Associated with Poor Prognosis in Patients with Nonsmall Cell Lung Cancer. J Oncol 2012: 957437. doi: 10.1155/2012/957437
[29]  Steinestel J, Cronauer MV, Muller J, Al Ghazal A, Skowronek P, et al. (2013) Overexpression of p16(INK4a) in urothelial carcinoma in situ is a marker for MAPK-mediated epithelial-mesenchymal transition but is not related to human papillomavirus infection. PLoS One 8: e65189. doi: 10.1371/journal.pone.0065189
[30]  Pientong C, Ekalaksananan T, Kongyingyoes B, Kritpetcharat O, Swadpanich U, et al. (2004) Immunocytochemical staining of p16INK4a protein from conventional Pap test and its association with human papillomavirus infection. Diagn Cytopathol 31: 235–242. doi: 10.1002/dc.20122
[31]  Jordan RC, Lingen MW, Perez-Ordonez B, He X, Pickard R, et al. (2012) Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol 36: 945–954. doi: 10.1097/pas.0b013e318253a2d1
[32]  Lewis JS Jr, Chernock RD, Ma XJ, Flanagan JJ, Luo Y, et al. (2012) Partial p16 staining in oropharyngeal squamous cell carcinoma: extent and pattern correlate with human papillomavirus RNA status. Mod Pathol 25: 1212–1220. doi: 10.1038/modpathol.2012.79
[33]  Woo SB, Cashman EC, Lerman MA (2013) Human papillomavirus-associated oral intraepithelial neoplasia. Mod Pathol 26: 1288–1297. doi: 10.1038/modpathol.2013.70
[34]  Samarawardana P, Dehn DL, Singh M, Franquemont D, Thompson C, et al. (2010) p16(INK4a) is superior to high-risk human papillomavirus testing in cervical cytology for the prediction of underlying high-grade dysplasia. Cancer Cytopathol 118: 146–156. doi: 10.1002/cncy.20078
[35]  Shaker OG, Hammam OA, Wishahi MM (2013) Is there a correlation between HPV and urinary bladder carcinoma? Biomed Pharmacother 67: 183–191. doi: 10.1016/j.biopha.2012.10.019
[36]  Westenend PJ, Stoop JA, Hendriks JG (2001) Human papillomaviruses 6/11, 16/18 and 31/33/51 are not associated with squamous cell carcinoma of the urinary bladder. BJU Int 88: 198–201. doi: 10.1046/j.1464-410x.2001.02230.x
[37]  Ben Selma W, Ziadi S, Ben Gacem R, Amara K, Ksiaa F, et al. (2010) Investigation of human papillomavirus in bladder cancer in a series of Tunisian patients. Pathol Res Pract 206: 740–743. doi: 10.1016/j.prp.2010.06.005


comments powered by Disqus