Original Study| Volume 14, ISSUE 4, P346-351, August 2016

Clinical Significance of p53 and p16ink4a Status in a Contemporary North American Penile Carcinoma Cohort

Published:December 23, 2015DOI:



      Because of the low incidence of penile carcinoma (PC), the value of p16ink4a, p53, and human papilloma virus (HPV) infection status in clinical practice remains unclear. Herein, we report our experience with potential clinical utility of these markers in men with PC treated at our institution.

      Patients and Methods

      Tissue microarrays of 57 cases of invasive penile squamous cell carcinomas were immunohistochemically stained for p16 and p53. HPV in situ hybridization (ISH) for high-risk subtypes was also performed. Association between marker status, nodal disease, overall (OS) and cancer-specific survival (CSS) were assessed.


      p16 and HPV ISH were positive in 23 (40%) and 24 (42%) of the cohort, respectively. The proportion of warty, basaloid, or mixed warty basaloid tumor subtypes were significantly greater in the p16-positive patients (48% vs. 3%; P < .01). p53 expression was negative in 31 (54%) cases. Only in p16-negative patients, positive p53 status was associated with pN+ disease (odds ratio, 4.4 [95% confidence interval (CI), 1.04-18.6]). In Kaplan–Meier analysis, the unadjusted estimated OS was insignificantly longer in p16-positive patients (median OS, 75 vs. 27 months; P = .27) and median CSS was not reached (P = .16). In a multivariable Cox proportional hazard model, when controlling for pathological nodal status and adjuvant chemotherapy, p16 status was a significant predictor for improved CSS (hazard ratio, 0.36 [95% CI, 0.13-0.99]). The worst CSS was seen in pN+ patients with double negative p16 and p53 expression (8 vs. 34 months; P = .01).


      In this current cohort, p53 and p16 status showed clinical utility in predicting nodal disease as well as survival.


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        • Mannweiler S.
        • Sygulla S.
        • Winter E.
        • et al.
        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. 2013; 69: 73-81
        • Werness B.A.
        • Levine A.J.
        • Howley P.M.
        Association of human papillomavirus types 16 and 18 E6 proteins with p53.
        Science. 1990; 248: 76-79
        • Lopes A.
        • Bezerra A.L.
        • Pinto C.A.
        • et al.
        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. 2002; 168: 81-86
        • Kayes O.
        • Ahmed H.U.
        • Arya M.
        • et al.
        Molecular and genetic pathways in penile cancer.
        Lancet Oncol. 2007; 8: 420-429
        • Gunia S.
        • Erbersdobler A.
        • Hakenberg O.W.
        • et al.
        p16(INK4a) is a marker of good prognosis for primary invasive penile squamous cell carcinoma: a multi-institutional study.
        J Urol. 2012; 187: 899-907
        • Tang D.H.
        • Clark P.E.
        • Giannico G.
        • et al.
        Lack of P16ink4a over expression in penile squamous cell carcinoma is associated with recurrence after lymph node dissection.
        J Urol. 2015; 193: 519-525
        • Kirrander P.
        • Kolaric A.
        • Helenius G.
        • et al.
        Human papillomavirus prevalence, distribution and correlation to histopathological parameters in a large Swedish cohort of men with penile carcinoma.
        BJU Int. 2011; 108: 355-359
        • Ferrandiz-Pulido C.
        • Masferrer E.
        • de Torres I.
        • et al.
        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. 2013; 68: 73-82
        • Do H.T.
        • Koriyama C.
        • Khan N.A.
        • et al.
        The etiologic role of human papillomavirus in penile cancers: a study in Vietnam.
        Br J Cancer. 2013; 108: 229-233
        • Gross G.
        • Pfister H.
        Role of human papillomavirus in penile cancer, penile intraepithelial squamous cell neoplasias and in genital warts.
        Med Microbiol Immunol. 2004; 193: 35-44
        • Djajadiningrat R.S.
        • Graafland N.M.
        • van Werkhoven E.
        • et al.
        Contemporary management of regional nodes in penile cancer-improvement of survival?.
        J Urol. 2014; 191: 68-73
        • Djajadiningrat R.S.
        • Jordanova E.S.
        • Kroon B.K.
        • et al.
        Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome.
        J Urol. 2015; 193: 526-531
        • Hakenberg O.W.
        • Comperat E.M.
        • Minhas S.
        • et al.
        EAU Guidelines on penile cancer: 2014 update.
        Eur Urol. 2015; 67: 142-150
        • Backes D.M.
        • Kurman R.J.
        • Pimenta J.M.
        • et al.
        Systematic review of human papillomavirus prevalence in invasive penile cancer.
        Cancer Causes Control. 2009; 20: 449-457
        • Camus S.
        • Menendez S.
        • Cheok C.F.
        • et al.
        Ubiquitin-independent degradation of p53 mediated by high-risk human papillomavirus protein E6.
        Oncogene. 2007; 26: 4059-4070
        • Blanton R.A.
        • Coltrera M.D.
        • Gown A.M.
        • et al.
        Expression of the HPV16 E7 gene generates proliferation in stratified squamous cell cultures which is independent of endogenous p53 levels.
        Cell Growth Differ. 1992; 3: 791-802
        • Ferreux E.
        • Lont A.P.
        • Horenblas S.
        • et al.
        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. 2003; 201: 109-118
        • Liu J.Y.
        • Li Y.H.
        • Zhang Z.L.
        • et al.
        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. 2013; 31: 1519-1524
        • Singhi A.D.
        • Westra W.H.
        Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience.
        Cancer. 2010; 116: 2166-2173
        • Huang C.C.
        • Qiu J.T.
        • Kashima M.L.
        • et al.
        Generation of type-specific probes for the detection of single-copy human papillomavirus by a novel in situ hybridization method.
        Mod Pathol. 1998; 11: 971-977