Der Urologe

, Volume 57, Issue 4, pp 398–407 | Cite as

Die molekulare Charakterisierung des Peniskarzinoms

Literaturreview zu neuen Prognosemarkern und potentiellen Therapietargets
  • M. May
  • S. D. Brookman-May
  • T. H. Ecke
  • M. Burger
Leitthema
  • 69 Downloads

Zusammenfassung

Das Plattenepithelkarzinom des Penis („squamous cell carcinoma of the penis“, SCCP) ist in den westlichen Industrienationen zwar selten, weist jedoch in den fortgeschrittenen Tumorstadien einen aggressiven Erkrankungsverlauf auf mit einer dann hohen rezidiv- und karzinombedingten Mortalitätsrate. Aktuell sind keine molekularen Biomarker in der klinischen Routine bei SCCP-Patienten etabliert. Der diesbezügliche Bedarf ist jedoch immens, da geeignete Biomarker in der Prognosedeterminierung, der Festlegung von Art und Ausmaß der Primärtherapie, der Indikationsstellung zur inguinalen Lymphadenektomie bzw. adjuvanten Therapie und auch als Targets für eine gerichtete systemische Therapie sinnvoll einzusetzen wären. Das SCCP entwickelt sich aus der Progression einer Precursor-Läsion und hierbei ist ein HPV-abhängiger (HPV: humane Papillomaviren) von einem HPV-unabhängigen Pathway zu unterscheiden. In der Entschlüsselung der genetischen und epigenetischen Signaturen der distinkten molekularen Pathways liegt das Potential für eine jeweilige erfolgversprechende gerichtete Therapie. Hierzu ist eine Zunahme der translationalen Forschung in großen multiinstitutionalen Kollaborationen zu fordern, um nachfolgend auf dieser Basis effektive gerichtete (personalisierte) Therapiestrategien entwickeln zu können. Der hier vorliegende Reviewartikel soll konzis den gegenwärtigen Forschungsstand zu den molekularen Veränderungen des SCCP unter separater Berücksichtigung der zur Prognose untersuchten molekularen Marker einerseits und der als erfolgversprechende Therapietargets erscheinenden Biomarker andererseits abbilden. Zudem werden kurz die bisherigen Forschungsaktivitäten der eigenen Arbeitsgruppe zu diesem Thema dargestellt.

Schlüsselwörter

Plattenepithelkarzinom Karzinogenese Biomarker Tumorsuppressorgen Lymphknoten 

Molecular characterization of penile cancer

Literature review of new prognostic markers and potential therapeutic targets

Abstract

Squamous cell carcinoma of the penis (SCCP) is a rare cancer type in Western industrialized nations; nevertheless, it shows an aggressive course of disease in advanced tumor stages with accordantly high recurrence and progression rates. While molecular biomarkers are not established in clinical routine for the management of SCCP patients yet, the accordant unmet need is enormous, as adequate biomarkers would be meaningful for prognostic determination, planning of modality and extent of primary therapy, indication for inguinal lymph node resection, adjuvant treatment, and as potential targets for specific systemic treatment. SCCP regularly develops from a precursor lesion. In this regard, human papillomavirus (HPV)-dependent and -independent pathways are differentiated. The potential for specific target therapy options is mainly based on the decoding of genetic and epigenetic signatures of distinct molecular pathways. In order to develop targeted and personalized treatment strategies based on molecular pathways, an increase in translational research in large multi-institutional collaborations must be promoted. This review article aims to summarize the current status of research concerning molecular changes related to SCCP under separate consideration of prognostic molecular markers, on the one hand, and biomarkers considered potential therapeutic targets, on the other hand. In addition, previous research activities of our own working group on this topic are briefly described.

Keywords

Squamous cell carcinoma Carcinogenesis Biomarkers Tumor suppressor genes Lymph nodes 

Notes

Danksagung

Die Autoren bedanken sich ganz herzlich bei Herrn Prof. Dr. med. Stefan Koch, Direktor des Pathologischen Instituts im Helios-Klinikum Bad Saarow, für seine Anmerkungen zu der vorliegenden Arbeit und bei Herrn Dr. med. Sven Gunia, Oberarzt des Pathologischen Instituts im Vivantes-Humboldt-Klinikum Berlin, für die Anfertigung der aussagekräftigen Abbildungen.

Einhaltung ethischer Richtlinien

Interessenkonflikt

M. May, S.D. Brookman-May, T.H. Ecke und M. Burger geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Roiner M, Maurer O, Lebentrau S et al (2018) Management of penile cancer patients – new aspects of a rare tumor entity. Aktuelle Urol.  https://doi.org/10.1055/s-0043-121223 Google Scholar
  2. 2.
    Verhoeven RH, Janssen-Heijnen ML, Saum KU et al (2013) Population-based survival of penile cancer patients in Europe and the United States of America: no improvement since 1990. Eur J Cancer 49(6):1414–1421CrossRefPubMedGoogle Scholar
  3. 3.
    Hakenberg OW, Compérat EM, Minhas S et al (2014) EAU guidelines on penile cancer: 2014 update. Eur Urol 67(1):142–150CrossRefPubMedGoogle Scholar
  4. 4.
    Chipollini J, Chaing S, Azizi M, Kidd LC, Kim P, Spiess PE (2017) Advances in understanding of penile carcinogenesis: the search for actionable targets. Int J Mol Sci.  https://doi.org/10.3390/ijms18081777 PubMedPubMedCentralGoogle Scholar
  5. 5.
    Vuichoud C, Klap J, Loughlin KR (2016) The emerging role and promise of biomarkers in penile cancer. Urol Clin North Am 43(1):135–143CrossRefPubMedGoogle Scholar
  6. 6.
    Diorio GJ, Giuliano AR (2016) The role of human papilloma virus in penile carcinogenesis and preneoplastic lesions: a potential target for vaccination and treatment strategies. Urol Clin North Am 43(4):419–425CrossRefPubMedGoogle Scholar
  7. 7.
    Spiess PE, Dhillon J, Baumgarten AS, Johnstone PA, Giuliano AR (2016) Pathophysiological basis of human papillomavirus in penile cancer: key to prevention and delivery of more effective therapies. CA Cancer J Clin.  https://doi.org/10.3322/caac.21354 PubMedGoogle Scholar
  8. 8.
    Schneede P, Schlenker B (2018) Humane Papillomaviren und Peniskarzinom. Urologe.  https://doi.org/10.1007/s00120-018-0597-3 Google Scholar
  9. 9.
    Aziz A et al (2018) Lymphknotenpositives Peniskarzinom. Urologe.  https://doi.org/10.1007/s00120-018-0601-y Google Scholar
  10. 10.
    Berdjis N, Meye A, Nippgen J et al (2005) Expression of Ki-67 in squamous cell carcinoma of the penis. BJU Int 96(1):146–148CrossRefPubMedGoogle Scholar
  11. 11.
    Stankiewicz E, Ng M, Cuzick J et al (2012) The prognostic value of Ki-67 expression in penile squamous cell carcinoma. J Clin Pathol 65(6):534–537CrossRefPubMedGoogle Scholar
  12. 12.
    Protzel C, Knoedel J, Zimmermann U, Woenckhaus C, Poetsch M, Giebel J (2007) Expression of proliferation marker Ki67 correlates to occurrence of metastasis and prognosis, histological subtypes and HPV DNA detection in penile carcinomas. Histol Histopathol 22(11):1197–1204PubMedGoogle Scholar
  13. 13.
    Kayes OJ, Loddo M, Patel N et al (2009) DNA replication licensing factors and aneuploidy are linked to tumor cell cycle state and clinical outcome in penile carcinoma. Clin Cancer Res 15(23):7335–7344CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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):89–92CrossRefPubMedGoogle Scholar
  15. 15.
    Guimarães GC, Leal ML, Campos RS et al (2007) Do proliferating cell nuclear antigen and MIB-1/Ki-67 have prognostic value in penile squamous cell carcinoma? Urology 70(1):137–142CrossRefPubMedGoogle Scholar
  16. 16.
    Ferrándiz-Pulido C, Masferrer E, de Torres I 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):73–82CrossRefPubMedGoogle Scholar
  17. 17.
    Bethune G, Campbell J, Rocker A, Bell D, Rendon R, Merrimen J (2012) Clinical and pathologic factors of prognostic significance in penile squamous cell carcinoma in a North American population. Urology 79(5):1092–1097CrossRefPubMedGoogle Scholar
  18. 18.
    Steinestel J, Al Ghazal A, Arndt A et al (2015) The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma. BMC Cancer.  https://doi.org/10.1186/s12885-015-1268-z PubMedPubMedCentralGoogle Scholar
  19. 19.
    Poetsch M, Hemmerich M, Kakies C et al (2011) Alterations in the tumor suppressor gene p16(INK4A) are associated with aggressive behavior of penile carcinomas. Virchows Arch 458(2):221–229CrossRefPubMedGoogle Scholar
  20. 20.
    Tang DH, Clark PE, Giannico G, Hameed O, Chang SS, Gellert LL (2015) Lack of P16ink4a over expression in penile squamous cell carcinoma is associated with recurrence after lymph node dissection. J Urol 193(2):519–525CrossRefPubMedGoogle Scholar
  21. 21.
    Morshaeuser L, May M, Burger M et al (2017) p53-expression in patients with renal cell carcinoma correlates with a higher probability of disease progression and increased cancer-specific mortality after surgery but does not enhance the predictive accuracy of robust outcome models. Urol Oncol. pii: S1078-1439(17)30596-3.  https://doi.org/10.1016/j.urolonc.2017.11.011 Google Scholar
  22. 22.
    Lopes A, Bezerra AL, Pinto CA, Serrano SV, de Mell OCA, 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):81–86CrossRefPubMedGoogle Scholar
  23. 23.
    Zhu Y, Zhang HL, Yao XD et al (2010) Development and evaluation of a nomogram to predict inguinal lymph node metastasis in patients with penile cancer and clinically negative lymph nodes. J Urol 184(2):539–545CrossRefPubMedGoogle Scholar
  24. 24.
    Alves G, Heller A, Fiedler W et al (2001) Genetic imbalances in 26 cases of penile squamous cell carcinoma. Genes Chromosomes Cancer 31(1):48–53CrossRefPubMedGoogle Scholar
  25. 25.
    Busso-Lopes AF, Marchi FA, Kuasne H et al (2015) Genomic profiling of human penile carcinoma predicts worse prognosis and survival. Cancer Prev Res (Phila) 8(2):149–156CrossRefGoogle Scholar
  26. 26.
    McDaniel AS, Hovelson DH, Cani AK et al (2015) Genomic profiling of penile squamous cell carcinoma reveals new opportunities for targeted therapy. Cancer Res 75(24):5219–5227CrossRefPubMedGoogle Scholar
  27. 27.
    Kuasne H, Marchi FA, Rogatto SR, de Syllos Cólus IM (2013) Epigenetic mechanisms in penile carcinoma. Int J Mol Sci 14(6):10791–10808CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Masferrer E, Ferrándiz-Pulido C, Lloveras B et al (2012) MYC copy number gains are associated with poor outcome in penile squamous cell carcinoma. J Urol 188(5):1965–1971CrossRefPubMedGoogle Scholar
  29. 29.
    Guerrero D, Guarch R, Ojer A et al (2008) Hypermethylation of the thrombospondin-1 gene is associated with poor prognosis in penile squamous cell carcinoma. BJU Int 102(6):747–755CrossRefPubMedGoogle Scholar
  30. 30.
    Feber A, Arya M, de Winter P et al (2015) Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer. Clin Cancer Res 21(5):1196–1206CrossRefPubMedGoogle Scholar
  31. 31.
    Udager AM, Liu TY, Skala SL et al (2016) Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. Ann Oncol 27(9):1706–1712CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    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):690–697CrossRefPubMedGoogle Scholar
  33. 33.
    Stankiewicz E, Prowse DM, Ng M et al (2011) Alternative HER/PTEN/Akt pathway activation in HPV positive and negative penile carcinomas. PLoS ONE 6(3):e17517CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Di Lorenzo G, Perdonà S, Buonerba C et al (2013) Cytosolic phosphorylated EGFR is predictive of recurrence in early stage penile cancer patients: a retropective study. J Transl Med 11:161CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Di Lorenzo G, Buonerba C, Ferro M et al (2015) The epidermal growth factor receptors as biological targets in penile cancer. Expert Opin Biol Ther 15(4):473–476CrossRefPubMedGoogle Scholar
  36. 36.
    Buonerba C, Di Lorenzo G, Pond G et al (2016) Prognostic and predictive factors in patients with advanced penile cancer receiving salvage (2nd or later line) systemic treatment: a retrospective, multi-center study. Front Pharmacol 7:487CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Fenner F, Goody D, Protzel C et al (2017) E2F1 signalling is predictive of chemoresistance and lymphogenic metastasis in penile cancer: a pilot functional study reveals new prognostic biomarkers. Eur Urol Focus.  https://doi.org/10.1016/j.euf.2017.02.009 PubMedGoogle Scholar
  38. 38.
    Gunia S, Jain A, Koch S et al (2013) Periostin expression correlates with pT-stage, grading and tumour size, and independently predicts cancer-specific survival in surgically treated penile squamous cell carcinomas. J Clin Pathol 66(4):297–301CrossRefPubMedGoogle Scholar
  39. 39.
    Gunia S, Kakies C, Erbersdobler A, Hakenberg OW, Koch S, May M (2012) Expression of p53, p21 and cyclin D1 in penile cancer: p53 predicts poor prognosis. J Clin Pathol 65(3):232–236CrossRefPubMedGoogle Scholar
  40. 40.
    Gunia S, Erbersdobler A, Hakenberg OW, Koch S, May M (2012) p16(INK4a) is a marker of good prognosis for primary invasive penile squamous cell carcinoma: a multi-institutional study. J Urol 187(3):899–907CrossRefPubMedGoogle Scholar
  41. 41.
    May M, Burger M, Otto W et al (2013) Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin have no independent prognostic relevance for cancer-specific survival in surgically treated squamous cell carcinoma of the penis. BJU Int 112(4):E383–E390CrossRefPubMedGoogle Scholar
  42. 42.
    Gunia S, Erbersdobler A, Hakenberg OW, Koch S, May M (2013) C‑MET is expressed in the majority of penile squamous cell carcinomas and correlates with polysomy-7 but is not associated with MET oncogene amplification, pertinent histopathologic parameters, or with cancer-specific survival. Pathol Res Pract 209(4):215–220CrossRefPubMedGoogle Scholar
  43. 43.
    Gunia S, Jain A, Albrecht K et al (2014) Diagnostic and prognostic impact of peritumoral stromal remodeling in patients with surgically treated invasive penile squamous cell cancer. Hum Pathol 45(6):1169–1176CrossRefPubMedGoogle Scholar
  44. 44.
    May M, Brookman-May S, Burger M et al (2015) A switch from epithelial to mesenchymal properties correlates with lymphovascular invasion in squamous cell carcinoma of the penis. Pathol Res Pract 211(9):641–645CrossRefPubMedGoogle Scholar
  45. 45.
    Gunia S, Koch S, May M (2013) Is CDX2 immunostaining useful for delineating anorectal from penile/vulvar squamous cancer in the setting of squamous cell carcinoma with clinically unknown primary site presenting with histologically confirmed inguinal lymph node metastasis? J Clin Pathol 66(2):109–112CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  • M. May
    • 1
  • S. D. Brookman-May
    • 2
  • T. H. Ecke
    • 3
  • M. Burger
    • 4
  1. 1.Urologische KlinikKlinikum St. Elisabeth StraubingStraubingDeutschland
  2. 2.Urologische KlinikLudwigs-Maximilians-Universität (LMU) MünchenMünchenDeutschland
  3. 3.Urologische KlinikHelios-Klinikum Bad SaarowBad SaarowDeutschland
  4. 4.Urologische KlinikCaritas-Krankenhaus St. Josef, Universität RegensburgRegensburgDeutschland

Personalised recommendations