Virchows Archiv

, Volume 475, Issue 4, pp 397–405 | Cite as

The molecular pathogenesis of penile carcinoma—current developments and understanding

  • Anthony EmmanuelEmail author
  • Jeremy Nettleton
  • Nick Watkin
  • Daniel M. Berney
Review and Perspectives


Penile squamous cell carcinoma is a rare malignancy with various distinct histological subtypes, each with distinct appearances, histotypic specific associations with human papillomavirus (HPV) and clinical behaviour. Despite a wealth of pathological knowledge, there still remains a limited understanding of the fundamental molecular drivers that govern penile carcinogenesis with their underlying prognostic and therapeutic importance. However, recent work has improved our fundamental understanding of the molecular pathogenesis of penile cancer: commonly divided into the HPV-dependent and HPV-independent pathways. This review aims to summarise current developments in the histopathology and the molecular pathogenesis of penile cancer, with the advent of next-generation sequencing, and the opportunities for the targeting of molecular drivers of metastatic disease.


Penile squamous cell carcinoma Human papillomavirus Penile intraepithelial neoplasia Histotype Carcinogenesis Genetics 



Literature review—AA and JN

Manuscript writing—AA

Final manuscript review—AA, JN, NW and DB

Compliance with ethical standards

This study has full adherence and compliance to ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Barski D, Georgas E, Gerullis H, Ecke T (2014) Metastatic penile carcinoma - an update on the current diagnosis and treatment options. Cent European J Urol 67(2):126–132PubMedPubMedCentralGoogle Scholar
  2. 2.
    Hakenberg OW, Comperat EM, Minhas S, Necchi A, Protzel C, Watkin N (2014) EAU guidelines on penile cancer: 2014 update. Eur Urol 67(1):142–150PubMedGoogle Scholar
  3. 3.
    Shabbir M, Minhas S, Muneer A (2011) Diagnosis and management of premalignant penile lesions. Ther Adv Urol 3(3):151–158PubMedPubMedCentralGoogle Scholar
  4. 4.
    Velazquez EF, Chaux A, Cubilla AL (2012) Histologic classification of penile intraepithelial neoplasia. Semin Diagn Pathol 29(2):96–102PubMedGoogle Scholar
  5. 5.
    Alemany L, Cubilla A, Halec G, Kasamatsu E, Quiros B, Masferrer E et al (2016) Role of human papillomavirus in penile carcinomas worldwide. Eur Urol 69(5):953–961PubMedGoogle Scholar
  6. 6.
    Longpre MJ, Lange PH, Kwon JS, Black PC (2013) Penile carcinoma: lessons learned from vulvar carcinoma. J Urol 189(1):17–24PubMedGoogle Scholar
  7. 7.
    Krustrup D, Jensen HL, van den Brule AJ, Frisch M (2009) Histological characteristics of human papilloma-virus-positive and -negative invasive and in situ squamous cell tumours of the penis. Int J Exp Pathol 90(2):182–189PubMedPubMedCentralGoogle Scholar
  8. 8.
    Christodoulidou M, Sahdev V, Houssein S, Muneer A (2015) Epidemiology of penile cancer. Curr Probl Cancer 39(3):126–136PubMedGoogle Scholar
  9. 9.
    Kayes O, Ahmed HU, Arya M, Minhas S (2007) Molecular and genetic pathways in penile cancer. Lancet Oncol 8(5):420–429PubMedGoogle Scholar
  10. 10.
    Sonpavde G, Pagliaro LC, Buonerba C, Dorff TB, Lee RJ, Di Lorenzo G (2013) Penile cancer: current therapy and future directions. Ann Oncol 24(5):1179–1189PubMedPubMedCentralGoogle Scholar
  11. 11.
    Pagliaro LC, Williams DL, Daliani D, Williams MB, Osai W, Kincaid M, Wen S, Thall PF, Pettaway CA (2010) Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol 28(24):3851–3857PubMedPubMedCentralGoogle Scholar
  12. 12.
    Nicholson S, Hall E, Harland SJ, Chester JD, Pickering L, Barber J, Elliott T, Thomson A, Burnett S, Cruickshank C, Carrington B, Waters R, Bahl A (2013) Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001). Br J Cancer 109(10):2554–2559PubMedPubMedCentralGoogle Scholar
  13. 13.
    Necchi A, Giannatempo P, Lo Vullo S, Raggi D, Nicolai N, Colecchia M et al (2015) Panitumumab treatment for advanced penile squamous cell carcinoma when surgery and chemotherapy have failed. Clin Genitourin Cancer 14(3):231–236PubMedGoogle Scholar
  14. 14.
    Zhu Y, Li H, Yao X-D, Zhang S-L, Zhang H-L, Shi G-H et al (2014) Feasibility and activity of sorafenib and sunitinib in advanced penile cancer: a preliminary report. Urol Int 85(3):334–340Google Scholar
  15. 15.
    Canete-Portillo S, Clavero O, Sanchez DF, Silvero A, Abed F, Rodriquez IM et al (2017) Medullary carcinoma of the penis: a distinctive HPV-related neoplasm: a report of 12 cases. Am J Surg Pathol 41(4):535–540PubMedGoogle Scholar
  16. 16.
    Cubilla AL, Velazquez EF, Amin MB, Epstein J, Berney DM, Corbishley CM, Members of the ISUP Penile Tumor Panel (2018) The World Health Organisation 2016 classification of penile carcinomas: a review and update from the International Society of Urological Pathology Expert-Driven Recommendations. Histopathology. 72(6):893–904PubMedGoogle Scholar
  17. 17.
    Sanchez DF, Canete S, Fernandez-Nestora MJ, Lezcano C, Rodriquez I, Barreto J, Alvarado-Cabrero I et al (2015) HPV-and non-HPB related subtypes of penile squamous cell carcinoma (SCC): morphological features and differential diagnosis according to the new WHO classification (2015). Semin Diagn Pathol 32(3):198–221PubMedGoogle Scholar
  18. 18.
    Chaux A, Cubilla AL (2012) Advances in the pathology of penile carcinomas. Hum Pathol 43(6):771–789PubMedGoogle Scholar
  19. 19.
    Chaux A, Velazquez EF, Algaba F, Ayala G, Cubilla AL (2010) Developments in the pathology of penile squamous cell carcinomas. Urology. 76(2 Suppl 1):S7–s14PubMedGoogle Scholar
  20. 20.
    Stankiewicz E, Prowse DM, Ktori E, Cuzick J, Ambroisine L, Zhang X, Kudahetti S, Watkin N, Corbishley C, Berney DM (2011) The retinoblastoma protein/p16 INK4A pathway but not p53 is disrupted by human papillomavirus in penile squamous cell carcinoma. Histopathology. 58(3):433–439PubMedGoogle Scholar
  21. 21.
    Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ (2009) Penile cancer: epidemiology, pathogenesis and prevention. World J Urol 27(2):141–150PubMedGoogle Scholar
  22. 22.
    Cubilla AL, Lloveras B, Alejo M, Clavero O, Chaux A, Kasamatsu E, Monfulleda N, Tous S, Alemany L, Klaustermeier J, Muñoz N, Quint W, de Sanjose S, Bosch FX (2011) Value of p16(INK)(4)(a) in the pathology of invasive penile squamous cell carcinomas: a report of 202 cases. Am J Surg Pathol 35(2):253–261PubMedGoogle Scholar
  23. 23.
    Ferrandiz-Pulido C, Masferrer E, de Torres I, Lloveras B, Hernandez-Losa J, Mojal S et al (2013) Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: correlation with pathologic subtypes, p16(INK4a) expression, and prognosis. J Am Acad Dermatol 68(1):73–82PubMedGoogle Scholar
  24. 24.
    Chaux A, Pfanni R, Lloveras B, Alejo M, Clavero O, Lezcano C et al (2010) Distinctive association of p16ink4a overpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature. Am J Surg Pathol 34(3):385–392PubMedGoogle Scholar
  25. 25.
    Kristiansen S, Svensson A, Drevin L, Forslund O, Torbrand C, Biartling C (2018) Risk factors for penile intraepithelial neoplasia: a population-based registry study in Sweden, 2000-2012. Acta Derm Venereol 99(3):315–320Google Scholar
  26. 26.
    Yugawa T, Kiyono T (2009) Molecular mechanisms of cervical carcinogenesis by high-risk human papillomaviruses: novel functions of E6 and E7 oncoproteins. Rev Med Virol 19(2):97–113PubMedGoogle Scholar
  27. 27.
    Guimera N, Lloveras B, Lindeman J, Alemany L, van de Sandt M, Alejo M et al (2013) The occasional role of low-risk human papillomaviruses 6, 11, 42, 44, and 70 in anogenital carcinoma defined by laser capture microdissection/PCR methodology: results from a global study. Am J Surg Pathol 37(9):1299–1310PubMedGoogle Scholar
  28. 28.
    Yoon CS, Kim KD, Park SN, Cheong SW (2001) alpha(6) Integrin is the main receptor of human papillomavirus type 16 VLP. Biochem Biophys Res Commun 283(3):668–673PubMedGoogle Scholar
  29. 29.
    Boyer SN, Wazer DE, Band V (1996) E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res 56(20):4620–4624PubMedGoogle Scholar
  30. 30.
    Ferreux E, Lont AP, Horenblas S, Gallee MP, Raaphorst FM, von Knebel Doeberitz M 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):109–118PubMedGoogle Scholar
  31. 31.
    Steinestel J, Al Ghazal A, Arndt A, Schnoeller TJ, Schrader AJ, Moeller P et al (2015) The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma. BMC Cancer 15:220PubMedPubMedCentralGoogle Scholar
  32. 32.
    Klingelhutz AJ, Foster SA, McDougall JK (1996) Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature. 380(6569):79–82PubMedGoogle Scholar
  33. 33.
    Gewin L, Myers H, Kiyono T, Galloway DA (2004) Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes Dev 18(18):2269–2282PubMedPubMedCentralGoogle Scholar
  34. 34.
    De Paula AA, Motta ED, Alencar Rde C, Saddi VA, da Silva RC, Caixeta GN et al (2012) The impact of cyclooxygenase-2 and vascular endothelial growth factor C immunoexpression on the prognosis of penile carcinoma. J Urol 187(1):134–140PubMedGoogle Scholar
  35. 35.
    Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C et al (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 30(3):377–386PubMedGoogle Scholar
  36. 36.
    Poetsch M, Hemmerich M, Kakies C, Kleist B, Wolf E, vom Dorp F, Hakenberg OW, Protzel C (2011) Alterations in the tumor suppressor gene p16(INK4A) are associated with aggressive behavior of penile carcinomas. Virchows Arch 458(2):221–229PubMedGoogle Scholar
  37. 37.
    Afonso LA, Carestiato FN, Ornellas AA, Ornellas P, Rocha WM, Cordeiro TI, Lisboa DC, Alves GB, Cavalcanti SMB (2017) Human papillomavirus, Epstein-Barr virus and methylation status of p16ink4a in penile cancer. J Med Virol 89(10):1837–1843PubMedGoogle Scholar
  38. 38.
    Ouban A, Dellis J, Salup R, Morgan M (2003) Immunohistochemical expression of Mdm2 and p53 in penile verrucous carcinoma. Ann Clin Lab Sci 33(1):101–106PubMedGoogle Scholar
  39. 39.
    Yanagawa N, Osakabe M, Hayashi M, Tamura G, Motoyama T (2008) Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas. Virchows Arch 452(4):377–382PubMedGoogle Scholar
  40. 40.
    Faraj SF, Gonzalez-Roibon N, Munari E, Sharma R, Burnett AL, CUbilla AL et al (2017) Strong association of insulin-like growth factor 1 receptor expression with histologic grade, subtype, and HPV status in penile squamous cell carcinomas: a tissue microarray study of 112 cases. Virchows Arch 470(6):695–701PubMedGoogle Scholar
  41. 41.
    Stankiewicz E, Prowse DM, Ng M, Cuzick J, Mesher D, Hiscock F, Lu YJ, Watkin N, Corbishley C, Lam W, Berney DM (2011) Alternative HER/PTEN/Akt pathway activation in HPV positive and negative penile carcinomas. PLoS One 6(3):e17517PubMedPubMedCentralGoogle Scholar
  42. 42.
    Carthon BC, Ng CS, Pettaway CA, Pagliaro LC (2014) Epidermal growth factor receptor-targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis. BJU Int 113(6):871–877PubMedPubMedCentralGoogle Scholar
  43. 43.
    Silva Amancio AM, Cunha IW, Neves JI, Quetz JD, Carraro DM, Rocha RM et al (2017) Epidermal growth factor receptor as an adverse survival predictor in squamous cell carcinoma of the penis. Hum Pathol 61:97–104PubMedGoogle Scholar
  44. 44.
    Adimonye A, Stankiewicz E, Kudahetti S, Trevisan G, Tinwell B, Corbishley C, Lu YJ, Watkin N, Berney D (2018) Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway. Oncotarget 9(22):16074–16086PubMedPubMedCentralGoogle Scholar
  45. 45.
    Ferrandiz-Pulido C, Hernandez-Losa J, Masferrer E, Vivancos A, Somoza R, Mares R et al (2015) Identification of somatic gene mutations in penile squamous cell carcinoma. Genes Chromosom Cancer 54(10):629–637PubMedGoogle Scholar
  46. 46.
    Andersson P, Kolaric A, Windahl T, Kirrander P, Soderkvist P, Karlsson MG (2008) PIK3CA, HRAS and KRAS gene mutations in human penile cancer. J Urol 179(5):2030–2034PubMedGoogle Scholar
  47. 47.
    Gou HF, Li X, Qiu M, Cheng K, Li LH, Dong H, Chen Y, Tang Y, Gao F, Zhao F, Men HT, Ge J, Su JM, Xu F, Bi F, Gao JJ, Liu JY (2013) Epidermal growth factor receptor (EGFR)-RAS signaling pathway in penile squamous cell carcinoma. PLoS One 8(4):e62175PubMedPubMedCentralGoogle Scholar
  48. 48.
    Ferrandiz-Pulido C, Masferrer E, Toll A, Hernandez-Losa J, Mojal S, Pujol RM, Ramon y Cajal S, de Torres I, Garcia-Patos V (2013) mTOR signaling pathway in penile squamous cell carcinoma: pmTOR and peIF4E over expression correlate with aggressive tumor behavior. J Urol 190(6):2288–2295PubMedGoogle Scholar
  49. 49.
    Chaux A, Munari E, Cubilla AL, Hicks J, Lecksell K, Burnett AL, Netto GJ (2014) Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases. Histopathology. 64(6):863–871PubMedGoogle Scholar
  50. 50.
    Feber A, Worth DC, Chakravarthy A, de Winter P, Shah K, Arya M, Saqib M, Nigam R, Malone PR, Tan WS, Rodney S, Freeman A, Jameson C, Wilson GA, Powles T, Beck S, Fenton T, Sharp TV, Muneer A, Kelly JD (2016) CSN1 somatic mutations in penile squamous cell carcinoma. Cancer Res 76(16):4720–4727PubMedPubMedCentralGoogle Scholar
  51. 51.
    La-Touche S, Lemetre C, Lambros M, Stankiewicz E, Ng CK, Weigelt B et al (2016) DNA copy number aberrations, and human papillomavirus status in penile carcinoma. Clinico-pathological correlations and potential driver genes. PLoS One 11(2):e0146740PubMedPubMedCentralGoogle Scholar
  52. 52.
    Busso-Lopes AF, Marchi FA, Kuasne H, Scapulatempo-Neto C, Trindade-Filho JC, de Jesus CM et al (2015) Genomic profiling of human penile carcinoma predicts worse prognosis and survival. Cancer Prev Res (Phila) 8. United States: 2014 American Association for Cancer Research.:149–156Google Scholar
  53. 53.
    Hartz JM, Engelmann D, Furst K, Marquardt S, Spitschak A, Goody D et al (2016) Integrated loss of miR-1/miR-101/miR-204 discriminates metastatic from nonmetastatic penile carcinomas and can predict patient outcome. J Urol 196(2):570–578PubMedGoogle Scholar
  54. 54.
    Munoz JJ, Drigo SA, Barros-Filho MC, March FA, Scapulatempo-Neto C, Pessoa GS et al (2015) Down-regulation of SLC8A1 as a putative apoptosis mechanism by modulation of calcium levels in penile carcinoma. J Urol 194(1):245–251PubMedGoogle Scholar
  55. 55.
    Zhang L, Wei P, Shen X, Zhang Y, Xu B, Zhou J, Fan S, Hao Z, Shi H, Zhang X, Kong R, Xu L, Gao J, Zou D, Liang C (2015) MicroRNA expression profile in penile cancer revealed by next generation small RNA sequencing. PLoS One 10(7):e0131336PubMedPubMedCentralGoogle Scholar
  56. 56.
    Kuasne H, Barros-Filho MC, Busso-Lopes A, Marchi FA, Pinheiro M, Munoz JJ et al (2017) Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact. Oncotarget 8(9):15294–15306PubMedPubMedCentralGoogle Scholar
  57. 57.
    Udager AM, Liu TY, Skala SL, Mager MJ, McDaniel AS, Spratt DE et al (2016) Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. Ann Oncol 27(9):1706–1712PubMedPubMedCentralGoogle Scholar
  58. 58.
    Ottenhof SR, Djajadiningrat RS, de Jong J, Thygesen HH, Horenblas S, Jordanova ES (2017) Expression of programmed death ligand 1 in penile cancer is of prognostic value and associated with HPV status. J Urol 197(3 Pt 1):690–697PubMedGoogle Scholar
  59. 59.
    McDaniel AS, Hovelson DH, Cani AK, Liu CJ, Zhai Y, Zhang Y et al (2015) Genomic profiling of penile squamous cell carcinoma reveals new opportunities for targeted therapy. Cancer Res 75(24):5219–5227PubMedGoogle Scholar
  60. 60.
    Araujo LF, Terra AT Jr, Sares CTG, Sobreira CFR, Faria EF, Machado RD (2018) Mitochondrial genome analysis in penile carcinoma. Mol Biol Rep 45(4):591–600PubMedGoogle Scholar
  61. 61.
    Yang ES, Willey CD, Mehta A, Crowley MR, Crossman DK, Chen D, Anderson JC, Naik G, Della Manna DL, Cooper TS, Sonpavde G (2017) Kinase analysis of penile squamous cell carcinoma on multiple platforms to identify potential therapeutic targets. Oncotarget 8(13):21710–21718PubMedPubMedCentralGoogle Scholar
  62. 62.
    Marchi FA, Martins DC, Barros-Filho MC, Kuasne H, Busso Lopes AF, Brentani H, Trindade Filho JCS, Guimarães GC, Faria EF, Scapulatempo-Neto C, Lopes A, Rogatto SR (2017) Multidimensional integrative analysis uncovers driver candidates and biomarkers in penile carcinoma. Sci Rep 7(1):6707PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Barts Cancer Institute, Centre for Molecular OncologyBarts and The London School of Medicine and Dentistry, QMULLondonUK
  2. 2.Department of UrologyCheltenham General HospitalGloucestershireUK
  3. 3.Department of UrologySt George’s HospitalLondonUK

Personalised recommendations