World Journal of Urology

, Volume 36, Issue 9, pp 1431–1440 | Cite as

The relationship between HPV status and chemoradiotherapy in the locoregional control of penile cancer

  • Zhigang Yuan
  • Arash O. Naghavi
  • Dominic Tang
  • Youngchul Kim
  • Kamran A. Ahmed
  • Jasreman Dhillon
  • Anna R. Giuliano
  • Philippe E. Spiess
  • Peter A. Johnstone
Original Article



Penile cancer (PeCa) is a rare, aggressive malignancy often associated with the human papillomavirus (HPV). The practice of a personalized risk-adapted approach is not yet established. This study is to assess the relationship between HPV tumor status and chemoradiotherapy (CRT) in PeCa locoregional control (LRC).


We retrospectively identified patients with HPV status who were diagnosed with squamous cell carcinoma of the penis and treated with surgical resection between 1999 and 2016. The relationship between tumor/treatment characteristics and LRC were analyzed with univariate and multivariate Cox proportional hazard regression analysis (UVA and MVA, respectively). Time-to-event outcomes were estimated with Kaplan–Meier curves and compared via log-rank tests.


Fifty-one patients were identified. The median follow-up was 36.6 months. Patients were primarily HPV-negative (HPV−) (n = 28, 55%), and pathologic node positive (pN+) (55%). The 2 year LRC rate was 54%. pN+ patients had a significantly lower 2 year LRC (37 vs. 81%, p = 0.002). In the subgroup analysis of pN+ patients (n = 28), there was a LRC benefit associated with the addition of CRT (HR 0.19; 95% CI 0.05–0.70, p = 0.012) and HPV-positive (HPV+) disease (HR 0.18; 95% CI 0.039–0.80, p = 0.024) using MVA. HPV+ patients treated with CRT had improved 2 year LRC compared to HPV− patients (83 vs. 38%, p = 0.038).


Adjuvant CRT and HPV+ disease independently predicted for improved LRC in pN+ PeCa. In HPV+ PeCa, the LRC benefit was primarily observed in patients treated with adjuvant CRT. Prospective investigation of HPV+ and CRT is required to further delineate their roles in optimizing PeCa treatment.


Chemoradiation therapy HPV Penile cancer Locoregional recurrence Surgery 


Author contributions

ZGY: Project development, data collection, manuscript writing. AON: project development, data analysis, manuscript writing. DT: project development, data collection. KAA: project development, data analysis, manuscript writing. JD: data collection. PAJ, PES, and ARG: project development, manuscript writing. YC Kim: data analysis.

Compliance with ethical standards

Conflict of interest

Dr. Anna R. Giuliano is on a member of Merck’s Scientific and Global Advisory Boards and receives funding form Merck for investigator initiated studies related to HPV. The other authors declare that they have no conflict of interest.

Research involving human participants and/or animals

For this type of study formal consent is not required. This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

345_2018_2280_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 23 kb)


  1. 1.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300CrossRefPubMedGoogle Scholar
  2. 2.
    Mannweiler S, Sygulla S, Winter E, Regauer S (2013) Two major pathways of penile carcinogenesis: HPV-induced penile cancers overexpress p16ink4a, HPV-negative cancers associated with dermatoses express p53, but lack p16ink4a overexpression. J Am Acad Dermatol 69:73–81CrossRefPubMedGoogle Scholar
  3. 3.
    Pow-Sang MR, Ferreira U, Pow-Sang JM, Nardi AC, Destefano V (2010) Epidemiology and natural history of penile cancer. Urology 76:S2–S6CrossRefPubMedGoogle Scholar
  4. 4.
    Srinivas V, Morse MJ, Herr HW, Sogani PC, Whitmore WF Jr (1987) Penile cancer: relation of extent of nodal metastasis to survival. J Urol 137:880–882CrossRefPubMedGoogle Scholar
  5. 5.
    Ficarra V, Akduman B, Bouchot O, Palou J, Tobias-Machado M (2010) Prognostic factors in penile cancer. Urology 76:S66–S73CrossRefPubMedGoogle Scholar
  6. 6.
    Leone A, Diorio GJ, Pettaway C, Master V, Spiess PE (2017) Contemporary management of patients with penile cancer and lymph node metastasis. Nat Rev Urol 14:335CrossRefPubMedGoogle Scholar
  7. 7.
    Ornellas AA, Kinchin EW, Nobrega BL, Wisnescky A, Koifman N, Quirino R (2008) Surgical treatment of invasive squamous cell carcinoma of the penis: Brazilian National Cancer Institute long-term experience. J Surg Oncol 97:487–495CrossRefPubMedGoogle Scholar
  8. 8.
    Chen MF, Chen WC, Wu CT, Chuang CK, Ng KF, Chang JT (2004) Contemporary management of penile cancer including surgery and adjuvant radiotherapy: an experience in Taiwan. World J Urol 22:60–66CrossRefPubMedGoogle Scholar
  9. 9.
    Franks KN, Kancherla K, Sethugavalar B, Whelan P, Eardley I, Kiltie AE (2011) Radiotherapy for node positive penile cancer: experience of the Leeds teaching hospitals. J Urol 186:524–529CrossRefPubMedGoogle Scholar
  10. 10.
    Tang DH, Djajadiningrat R, Diorio G, Chipollini J, Ma Z, Schaible BJ, Catanzaro M, Ye D, Zhu Y, Nicolai N et al (2017) Adjuvant pelvic radiation is associated with improved survival and decreased disease recurrence in pelvic node-positive penile cancer after lymph node dissection: A multi-institutional study. Urol Oncol 35:605.e617–605.e623CrossRefGoogle Scholar
  11. 11.
  12. 12.
    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 43:419–425CrossRefPubMedGoogle Scholar
  13. 13.
    Mannweiler S, Sygulla S, Beham-Schmid C, Razmara Y, Pummer K, Regauer S (2011) Penile carcinogenesis in a low-incidence area: a clinicopathologic and molecular analysis of 115 invasive carcinomas with special emphasis on chronic inflammatory skin diseases. Am J Surg Pathol 35:998–1006CrossRefPubMedGoogle Scholar
  14. 14.
    Braakhuis BJ, Snijders PJ, Keune WJ, Meijer CJ, Ruijter-Schippers HJ, Leemans CR, Brakenhoff RH (2004) Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst 96:998–1006CrossRefPubMedGoogle Scholar
  15. 15.
    Naghavi AO, Strom TJ, Ahmed KA, Echevarria MI, Abuodeh YA, Venkat PS, Frakes JM, Harrison LB, Trotti AM, Caudell JJ (2016) Management of oropharyngeal cancer in the HPV era. Cancer Control 23:197–207CrossRefPubMedGoogle Scholar
  16. 16.
    Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100:261–269CrossRefPubMedGoogle Scholar
  17. 17.
    Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, Sasaki C, Joe J, Camp RL, Rimm DL, Psyrri A (2006) Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 24:736–747CrossRefPubMedGoogle Scholar
  18. 18.
    Zargar-Shoshtari K, Spiess PE, Berglund AE, Sharma P, Powsang JM, Giuliano A, Magliocco AM, Dhillon J (2016) Clinical significance of p53 and p16(ink4a) status in a contemporary North American penile carcinoma cohort. Clin Genitourin Cancer 14:346–351CrossRefPubMedGoogle Scholar
  19. 19.
    Bezerra SM, Chaux A, Ball MW, Faraj SF, Munari E, Gonzalez-Roibon N, Sharma R, Bivalacqua TJ, Burnett AL, Netto GJ (2015) Human papillomavirus infection and immunohistochemical p16(INK4a) expression as predictors of outcome in penile squamous cell carcinomas. Hum Pathol 46:532–540CrossRefPubMedGoogle Scholar
  20. 20.
    Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J (2009) Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 27:1992–1998CrossRefPubMedGoogle Scholar
  21. 21.
    Lewis JS Jr, Thorstad WL, Chernock RD, Haughey BH, Yip JH, Zhang Q, El-Mofty SK (2010) p16 positive oropharyngeal squamous cell carcinoma:an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol 34:1088–1096CrossRefPubMedGoogle Scholar
  22. 22.
    Sharma P, Djajadiningrat R, Zargar-Shoshtari K, Catanzaro M, Zhu Y, Nicolai N, Horenblas S, Spiess PE (2015) Adjuvant chemotherapy is associated with improved overall survival in pelvic node-positive penile cancer after lymph node dissection: a multi-institutional study. Urol Oncol 33(496):e417–e423Google Scholar
  23. 23.
    Sonpavde G, Pagliaro LC, Buonerba C, Dorff TB, Lee RJ, Di Lorenzo G (2013) Penile cancer: current therapy and future directions. Ann Oncol 24:1179–1189CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Liu JY, Li YH, Zhang ZL, Yao K, Ye YL, Xie D, Han H, Liu ZW, Qin ZK, Zhou FJ (2013) The risk factors for the presence of pelvic lymph node metastasis in penile squamous cell carcinoma patients with inguinal lymph node dissection. World J Urol 31:1519–1524CrossRefPubMedGoogle Scholar
  25. 25.
    Nicolai N, Sangalli LM, Necchi A, Giannatempo P, Paganoni AM, Colecchia M, Piva L, Catanzaro MA, Biasoni D, Stagni S et al (2016) A combination of cisplatin and 5-fluorouracil with a taxane in patients who underwent lymph node dissection for nodal metastases from squamous cell carcinoma of the penis: treatment outcome and survival analyses in neoadjuvant and adjuvant settings. Clin Genitourin Cancer 14:323–330CrossRefPubMedGoogle Scholar
  26. 26.
    Necchi A, Pond GR, Raggi D, Ottenhof SR, Djajadiningrat RS, Horenblas S, Khoo V, Hakenberg OW, Draeger D, Protzel C et al (2017) Clinical outcomes of perioperative chemotherapy in patients with locally advanced penile squamous-cell carcinoma: results of a multicenter analysis. Clin Genitourin Cancer 15(548–555):e543Google Scholar
  27. 27.
    Lapierre A, Riou O, Flechon A, Mottet N, Azria D (2017) Advanced penile cancer with iliac lymph node involvement treated with radiation and concurrent gemcitabine. Cancer Radiother 21:134–137CrossRefPubMedGoogle Scholar
  28. 28.
    Nicholson S, Kayes O, Minhas S (2014) Clinical trial strategy for penis cancer. BJU Int 113:852–853CrossRefPubMedGoogle Scholar
  29. 29.
    Lassen P, Lacas B, Pignon JP, Trotti A, Zackrisson B, Zhang Q, Overgaard J, Blanchard P (2018) Prognostic impact of HPV-associated p16-expression and smoking status on outcomes following radiotherapy for oropharyngeal cancer: the MARCH-HPV project. Radiother Oncol 126:107–115CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang D, Zhang W, Liu W, Mao Y, Fu Z, Liu J, Huang W, Zhang Z, An D, Li B (2017) Human papillomavirus infection increases the chemoradiation response of esophageal squamous cell carcinoma based on P53 mutation. Radiother Oncol 124:155–160CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Zhigang Yuan
    • 1
  • Arash O. Naghavi
    • 1
  • Dominic Tang
    • 2
  • Youngchul Kim
    • 3
  • Kamran A. Ahmed
    • 1
  • Jasreman Dhillon
    • 4
  • Anna R. Giuliano
    • 5
  • Philippe E. Spiess
    • 2
  • Peter A. Johnstone
    • 1
  1. 1.Department of Radiation OncologyH Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.Department of Genitourinary OncologyH Lee Moffitt Cancer Center and Research InstituteTampaUSA
  3. 3.Department of Biostatistics and BioinformaticsH Lee Moffitt Cancer Center and Research InstituteTampaUSA
  4. 4.Department of Anatomic PathologyH Lee Moffitt Cancer Center and Research InstituteTampaUSA
  5. 5.Department of Cancer EpidemiologyH Lee Moffitt Cancer Center and Research InstituteTampaUSA

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