World Journal of Urology

, Volume 27, Issue 2, pp 161–167

Molecular prognostic factors in penile cancer

  • Asif Muneer
  • O. Kayes
  • Hashim U. Ahmed
  • Manit Arya
  • Suks Minhas
Topic Paper

Abstract

Objectives

Penile cancer is a rare tumour in developed countries but more common in South America and East Africa. Although pathological prognostic factors have been established, there is great interest in evaluating molecular markers which correlate with prognosis and outcome.

Methods

We have reviewed the current status of our understanding of the molecular biology of penile cancer in order to identify established and potential prognostic factors in penile cancer. We have conducted an extensive literature search to review the current understanding of the role of prognostic markers in penile cancer.

Results

Although several markers have been evaluated, currently the clinical application of these markers is limited. HPV positive tumours show a variable prognostic outcome. P53 status may correlate with survival in T1 disease but further studies are required to establish the link to lymph node spread.

Conclusions

Pathological variables are well-established but further work is required to investigate the role of molecular markers. The development of molecular prognostic markers is important for the surveillance of patients and prediction of lymph node involvement as well as a prognostic marker for survival.

Keywords

Prognostics Squamous cell carcinoma Penile Molecular 

References

  1. 1.
    Burgers JK, Badalament RA, Drago JR (1992) Penile cancer. Clinical presentation, diagnosis, and staging. Urol Clin North Am 19(2):247–256PubMedGoogle Scholar
  2. 2.
    Pietrzak P, Hadway P, Corbishley CM, Watkin NA (2006) Is the association between balanitis xerotica obliterans and penile carcinoma underestimated? BJU Int 98(1):74–76PubMedCrossRefGoogle Scholar
  3. 3.
    Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV, de Sanjose S et al (2002) Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 346(15):1105–1112PubMedCrossRefGoogle Scholar
  4. 4.
    Franceschi S, Castellsague X, Dal Maso L, Smith JS, Plummer M, Ngelangel C et al (2002) Prevalence and determinants of human papillomavirus genital infection in men. Br J Cancer 86(5):705–711PubMedCrossRefGoogle Scholar
  5. 5.
    Lopes A, Hidalgo GS, Kowalski LP, Torloni H, Rossi BM, Fonseca FP (1996) Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy. J Urol 156(5):1637–1642PubMedCrossRefGoogle Scholar
  6. 6.
    Ficarra V, Zattoni F, Artibani W, Fandella A, Martignoni G, Novara G et al (2006) Nomogram predictive of pathological inguinal lymph node involvement in patients with squamous cell carcinoma of the penis. J Urol 175(5):1700–1704PubMedCrossRefGoogle Scholar
  7. 7.
    Rubin MA, Kleter B, Zhou M, Ayala G, Cubilla AL, Quint WG et al (2001) Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol 159(4):1211–1218PubMedGoogle Scholar
  8. 8.
    Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA et al (2005) Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 116(4):606–616PubMedCrossRefGoogle Scholar
  9. 9.
    Picconi MA, Eijan AM, Distefano AL, Pueyo S, Alonio LV, Gorostidi S et al (2000) Human papillomavirus (HPV) DNA in penile carcinomas in Argentina: analysis of primary tumors and lymph nodes. J Med Virol 61(1):65–69PubMedCrossRefGoogle Scholar
  10. 10.
    Senba M, Kumatori A, Fujita S, Jutavijittum P, Yousukh A, Moriuchi T et al (2006) The prevalence of human papillomavirus genotypes in penile cancers from northern Thailand. J Med Virol 78(10):1341–1346PubMedCrossRefGoogle Scholar
  11. 11.
    Gross G, Pfister H (2004) Role of human papillomavirus in penile cancer, penile intraepithelial squamous cell neoplasias and in genital warts. Med Microbiol Immunol 193(1):35–44PubMedCrossRefGoogle Scholar
  12. 12.
    Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM et al (2006) Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 367(9518):1247–1255PubMedCrossRefGoogle Scholar
  13. 13.
    Heideman DA, Waterboer T, Pawlita M, Delis-van Diemen P, Nindl I, Leijte JA et al (2007) Human papillomavirus-16 is the predominant type etiologically involved in penile squamous cell carcinoma. J Clin Oncol 25(29):4550–4556PubMedCrossRefGoogle Scholar
  14. 14.
    zur Hausen H (2002) Papillomavirus and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350PubMedCrossRefGoogle Scholar
  15. 15.
    Snijders PJ, van den Brule AJ, Meijer CJ (2003) The clinical relevance of human papillomavirus testing: relationship between analytical and clinical sensitivity. J Pathol 201(1):1–6PubMedCrossRefGoogle Scholar
  16. 16.
    Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR, Villa LL (2001) Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer 91(12):2315–2321PubMedCrossRefGoogle Scholar
  17. 17.
    Wiener JS, Effert PJ, Humphrey PA, Yu L, Liu ET, Walther PJ (1992) Prevalence of human papillomavirus types 16 and 18 in squamous-cell carcinoma of the penis: a retrospective analysis of primary and metastatic lesions by differential polymerase chain reaction. Int J Cancer 50(5):694–701PubMedCrossRefGoogle Scholar
  18. 18.
    Lont AP, Kroon BK, Horenblas S, Gallee MP, Berkhof J, Meijer CJ et al (2006) Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 119(5):1078–1081PubMedCrossRefGoogle Scholar
  19. 19.
    Ornellas AA, Ornellas MH, Otero L, Simoes F, Campos MM, Harab RC et al (1999) Karyotypic findings in two cases of moderately differentiated squamous cell carcinomas of the penis. Cancer Genet Cytogenet 115(1):77–79PubMedCrossRefGoogle Scholar
  20. 20.
    Ornellas AA, Ornellas MH, Simoes F, Soares R, Campos MM, Harab RC et al (1998) Cytogenetic analysis of an invasive, poorly differentiated squamous cell carcinoma of the penis. Cancer Genet Cytogenet 101(1):78–79PubMedCrossRefGoogle Scholar
  21. 21.
    Alves G, Heller A, Fiedler W, Campos MM, Claussen U, Ornellas AA et al (2001) Genetic imbalances in 26 cases of penile squamous cell carcinoma. Genes Chromosomes Cancer 31(1):48–53PubMedCrossRefGoogle Scholar
  22. 22.
    Hall MC, Sanders JS, Vuitch F, Ramirez E, Pettaway CA (1998) Deoxyribonucleic acid flow cytometry and traditional pathologic variables in invasive penile carcinoma: assessment of prognostic significance. Urology 52(1):111–116PubMedCrossRefGoogle Scholar
  23. 23.
    Masih AS, Stoler MH, Farrow GM, Wooldridge TN, Johansson SL (1992) Penile verrucous carcinoma: a clinicopathologic, human papillomavirus typing and flow cytometric analysis. Mod Pathol 5(1):48–55PubMedGoogle Scholar
  24. 24.
    Ornellas AA, Mendes CM, Ornellas MH, Wisnescky A, Koifman N, Cabral HR (2000) Penile cancer: flow cytometry study of ploidies in 90 patients. Prog Urol 10(1):72–77PubMedGoogle Scholar
  25. 25.
    Alves G, Fiedler W, Guenther E, Nascimento P, Campos MM, Ornellas AA (2001) Determination of telomerase activity in squamous cell carcinoma of the penis. Int J Oncol 18(1):67–70PubMedGoogle Scholar
  26. 26.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253(5015):49–53PubMedCrossRefGoogle Scholar
  27. 27.
    Lopes A, Bezerra AL, Pinto CA, Serrano SV, de MellO CA, Villa LL (2002) p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol 168(1):81–86PubMedCrossRefGoogle Scholar
  28. 28.
    Lam KY, Chan KW (1999) Molecular pathology and clinicopathologic features of penile tumors: with special reference to analyses of p21 and p53 expression and unusual histologic features. Arch Pathol Lab Med 123(10):895–904PubMedGoogle Scholar
  29. 29.
    Humbey O, Cairey-Remonnay S, Guerrini JS, Algros MP, Mougin C, Bittard H et al (2003) Detection of the human papillomavirus and analysis of the TP53 polymorphism of exon 4 at codon 72 in penile squamous cell carcinomas. Eur J Cancer 39(5):684–690PubMedCrossRefGoogle Scholar
  30. 30.
    Pilotti S, Donghi R, D’Amato L, Giarola M, Longoni A, Della TG et al (1993) HPV detection and p53 alteration in squamous cell verrucous malignancies of the lower genital tract. Diagn Mol Pathol 2(4):248–256PubMedGoogle Scholar
  31. 31.
    Levi JE, Rahal P, Sarkis AS, Villa L (1998) Human papillomavirus DNA and p53 status in penile carcinomas. Int J Cancer 76(6):779–783PubMedCrossRefGoogle Scholar
  32. 32.
    Camus S, Menendez S, Cheok CF, Stevenson LF, Lain S, Lane DP (2007) Ubiquitin-independent degradation of p53 mediated by high-risk human papillomavirus protein E6. Oncogene 26(28):4059–4070PubMedCrossRefGoogle Scholar
  33. 33.
    Martins AC, Faria SM, Cologna AJ, Suaid HJ, Tucci S Jr (2002) Immunoexpression of p53 protein and proliferating cell nuclear antigen in penile carcinoma. J Urol 167(1):89–92PubMedCrossRefGoogle Scholar
  34. 34.
    Zhu Y, Zhou XY, Yao XD, Dai B, Ye DW (2007) The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int 100(1):204–208PubMedCrossRefGoogle Scholar
  35. 35.
    Prowse DM, Ktori EN, Chandrasekaran D, Prapa A, Baithun S (2008) Human papillomavirus-associated increase in p16(INK4A) expression in penile lichen sclerosus and squamous cell carcinoma. Br J Dermatol 158(2):261–265PubMedCrossRefGoogle Scholar
  36. 36.
    Ferreux E, Lont AP, Horenblas S, Gallee MP, Raaphorst FM, von Knebel DM et al (2003) Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus. J Pathol 201(1):109–118PubMedCrossRefGoogle Scholar
  37. 37.
    Senekjian EK, Young JM, Weiser PA, Spencer CE, Magic SE, Herbst AL (1987) An evaluation of squamous cell carcinoma antigen in patients with cervical squamous cell carcinoma. Am J Obstet Gynecol 157(2):433–439PubMedGoogle Scholar
  38. 38.
    Mino N, Iio A, Hamamoto K (1988) Availability of tumor-antigen 4 as a marker of squamous cell carcinoma of the lung and other organs. Cancer 62(4):730–734PubMedCrossRefGoogle Scholar
  39. 39.
    Wishnow KI, Johnson DE, Fritsche H (1990) Squamous cell carcinoma antigen (TA-4) in penile carcinoma. Urology 36(4):315–317PubMedCrossRefGoogle Scholar
  40. 40.
    Laniado ME, Lowdell C, Mitchell H, Christmas TJ (2003) Squamous cell carcinoma antigen: a role in the early identification of nodal metastases in men with squamous cell carcinoma of the penis. BJU Int 92(3):248–250PubMedCrossRefGoogle Scholar
  41. 41.
    Touloupidis S, Zisimopoulos A, Giannakopoulos S, Papatsoris AG, Kalaitzis C, Thanos A (2007) Clinical usage of the squamous cell carcinoma antigen in patients with penile cancer. Int J Urol 14(2):174–176PubMedCrossRefGoogle Scholar
  42. 42.
    Hungerhuber E, Schlenker B, Schneede P, Stief CG, Karl A (2007) Squamous cell carcinoma antigen correlates with tumor burden but lacks prognostic potential for occult lymph node metastases in penile cancer. Urology 70(5):975–979PubMedCrossRefGoogle Scholar
  43. 43.
    Medina PM, Valero PJ, Martinez Igarzabal MJ (1999) Verrucous carcinoma of the penis with intense basal expression of Ki 67. Arch Esp Urol 52(9):983–985Google Scholar
  44. 44.
    Gentile V, Vicini P, Giacomelli L, Cardillo MR, Pierangeli A, Degener AM (2006) Detection of human papillomavirus DNA, p53 and ki67 expression in penile carcinomas. Int J Immunopathol Pharmacol 19(1):209–215PubMedGoogle Scholar
  45. 45.
    Berdjis N, Meye A, Nippgen J, Dittert D, Hakenberg O, Baretton GB et al (2005) Expression of Ki-67 in squamous cell carcinoma of the penis. BJU Int 96(1):146–148PubMedCrossRefGoogle Scholar
  46. 46.
    Guimaraes GC, Leal ML, Campos RS, Zequi SC, da Fonseca FP, da Cunha IW et al (2007) Do proliferating cell nuclear antigen and MIB-1/Ki-67 have prognostic value in penile squamous cell carcinoma? Urology 70(1):137–142PubMedCrossRefGoogle Scholar
  47. 47.
    Dervan PA, Magee HM, Buckley C, Carney DN (1992) Proliferating cell nuclear antigen counts in formalin-fixed paraffin-embedded tissue correlate with Ki-67 in fresh tissue. Am J Clin Pathol 97(5 Suppl 1):S21–S28PubMedGoogle Scholar
  48. 48.
    Waseem NH, Lane DP (1990) Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA). Structural conservation and the detection of a nucleolar form. J Cell Sci 96(Pt 1):121–129PubMedGoogle Scholar
  49. 49.
    Martins AC, Faria SM, Velludo MAL (2000) Carcinoma of the penis: value of proliferating cell nuclear antigen (PCNA). Int Braz J Urol 26:38–42Google Scholar
  50. 50.
    Campos RS, Lopes A, Guimaraes GC, Carvalho AL, Soares FA (2006) E-cadherin, MMP-2, and MMP-9 as prognostic markers in penile cancer: analysis of 125 patients. Urology 67(4):797–802PubMedCrossRefGoogle Scholar
  51. 51.
    Kusukawa J, Sasaguri Y, Shima I, Kameyama T, Morimatsu M (1993) Expression of matrix metalloproteinase-2 related to lymph node metastasis of oral squamous cell carcinoma. A clinicopathologic study. Am J Clin Pathol 99(1):18–23PubMedGoogle Scholar
  52. 52.
    Vihinen P, Kahari VM (2002) Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer 99(2):157–166PubMedCrossRefGoogle Scholar
  53. 53.
    Couturier J, Sastre-Garau X, Schneider-Maunoury S, Labib A, Orth G (1991) Integration of papillomavirus DNA near myc genes in genital carcinomas and its consequences for proto-oncogene expression. J Virol 65(8):4534–4538PubMedGoogle Scholar
  54. 54.
    Sastre-Garau X, Favre M, Couturier J, Orth G (2000) Distinct patterns of alteration of myc genes associated with integration of human papillomavirus type 16 or type 45 DNA in two genital tumours. J Gen Virol 81(Pt 8):1983–1993PubMedGoogle Scholar
  55. 55.
    Leis PF, Stevens KR, Baer SC, Kadmon D, Goldberg LH, Wang XJ (1998) A c-rasHa mutation in the metastasis of a human papillomavirus (HPV)-18 positive penile squamous cell carcinoma suggests a cooperative effect between HPV-18 and c-rasHa activation in malignant progression. Cancer 83(1):122–129PubMedCrossRefGoogle Scholar
  56. 56.
    Golijanin D, Tan JY, Kazior A, Cohen EG, Russo P, Dalbagni G et al (2004) Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 are overexpressed in squamous cell carcinoma of the penis. Clin Cancer Res 10(3):1024–1031PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Asif Muneer
    • 1
  • O. Kayes
    • 1
  • Hashim U. Ahmed
    • 1
  • Manit Arya
    • 1
  • Suks Minhas
    • 1
  1. 1.Department of UrologyUniversity College London HospitalLondonUK

Personalised recommendations