Abstract
We assessed the prevalence of HPV DNA in a large series of Chinese penile cancer and examine its association with the histological subtype, p16INK4a expression, and prognosis. We pathologically categorized 226 invasive penile squamous cell carcinomas and assessed HPV genoty** by real-time PCR and p16INK4a immunohistochemistry. The results were correlated with histopathological and clinical parameters and disease-specific survival (DSS). HPV DNA was detected in 32.7% (74/226) of penile cancer cases. The most frequent genotype was HPV 16 (64/74, 86.5%), followed by HPV 18 (6/74, 8.1%). Fifty-nine (26.1%) cases were positive for the p16INK4a expression, and p16INK4a expression had a sensitivity of 56.8% (95% CI, 45.2–68.3%) and a specificity of 88.8% (95% CI, 83.8–93.9%) for defining HPV status. HPV DNA (P = 0.019), p16INK4a (P = 0.038), age (P = 0.018), grade of differentiation (P = 0.001), lymph nodes (P < 0.001), T stage (P < 0.001), M stage (P < 0.001), and lymphovascular invasion (LVI, P = 0.001) were prognostic factors for DSS. HPV-positivity (HR 0.334; 95% CI, 0.158–0.705, P = 0.004) was still a significant prognostic factor for DSS in the multivariate Cox regression model. HPV DNA was observed in one third of Chinese penile carcinoma cases. The p16INK4a expression can indicate high-risk human papillomavirus (HR-HPV). HPV-positive penile tumors confer a survival benefit over HPV-negative tumors.
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Alemany L, Cubilla A, Halec G, Kasamatsu E, Quirós B, Masferrer E, Tous S, Lloveras B, Hernández-Suarez G, Lonsdale R, Tinoco L, Alejo M, Alvarado-Cabrero I, Laco J, Guimerà N, Poblet E, Lombardi LE, Bergeron C, Clavero O, Shin H-R, Ferrera A, Felix A, Germar J, Mandys V, Clavel C, Tzardi M, Pons LE, Wain V, Cruz E, Molina C, Mota JD, Jach R, Velasco J, Carrilho C, López-Revilla R, Goodman MT, Quint WG, Castellsagué X, Bravo I, Pawlita M, Muñoz N, Bosch FX, de Sanjosé S, group HVs (2016) Role of human papillomavirus in penile carcinomas worldwide. Eur Urol 69:953–961. https://doi.org/10.1016/j.eururo.2015.12.007
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24–35. https://doi.org/10.1056/NEJMoa0912217
Backes DM, Kurman RJ, Pimenta JM, Smith JS (2009) Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control 20:449–457. https://doi.org/10.1007/s10552-008-9276-9
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 46:532–540. https://doi.org/10.1016/j.humpath.2014.12.004
Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ (2009) Penile cancer: epidemiology, pathogenesis and prevention. World J Urol 27:141–150. https://doi.org/10.1007/s00345-008-0302-z
Branca M, Ciotti M, Santini D, Di Bonito L, Giorgi C, Benedetto A, Paba P, Favalli C, Costa S, Agarossi A, Alderisio M, Syrjanen K (2004) p16(INK4a) expression is related to grade of CIN and high-risk human papillomavirus but does not predict virus clearance after conization or disease outcome Int. J Gynecol Pathol 23:354–365. https://doi.org/10.1097/01.pgp.0000139639.79105.40
Chaux A, Pfannl R, Lloveras B, Alejo M, Clavero O, Lezcano C, Muñoz N, de Sanjosé S, Bosch X, Hernández-Pérez M, Velazquez EF, Cubilla AL (2010) Distinctive association of p16INK4a overexpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature. Am J Surg Pathol 34:385–392. https://doi.org/10.1097/PAS.0b013e3181cdad23
Compérat E (2018) Pathology of penile cancer. Eur Urol Suppl 17:132–137. https://doi.org/10.1016/j.eursup.2017.08.005
Cubilla AL, Reuter VE, Gregoire L, Ayala G, Ocampos S, Lancaster WD, Fair W (1998) Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol 22:755–761. https://doi.org/10.1097/00000478-199806000-00014
Cubilla AL, Lloveras B, Alejo M, Clavero O, Chaux A, Kasamatsu E, Monfulleda N, Tous S, Alemany L, Klaustermeier J, Munoz 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 35:253–261. https://doi.org/10.1097/PAS.0b013e318203cdba
Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA, Carter JJ, Porter PL, Galloway DA, McDougall JK, Krieger JN (2005) Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 116:606–616. https://doi.org/10.1002/ijc.21009
de Araujo LA, De Paula AAP, de Paula H, Ramos JEP, de Oliveira BR, De Carvalho KPA, Guimaraes RA, de Alencar RCG, Duarte ECB, Rabelo Santos SH, Saddi VA, Carneiro M (2018) Human papillomavirus (HPV) genotype distribution in penile carcinoma: association with clinic pathological factors. PloS one 13:e0199557. https://doi.org/10.1371/journal.pone.0199557
Djajadiningrat RS, Jordanova ES, Kroon BK, van Werkhoven E, de Jong J, Pronk DT, Snijders PJ, Horenblas S, Heideman DA (2015) Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol 193:526–531. https://doi.org/10.1016/j.juro.2014.08.087
Ferrándiz-Pulido C, Masferrer E, de Torres I, Lloveras B, Hernandez-Losa J, Mojal S, Salvador C, Morote J, Ramon y Cajal S, Pujol RM, Garcia-Patos V, Toll A (2013) Identification and genoty** 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 68:73–82. https://doi.org/10.1016/j.jaad.2012.05.029
Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, Vignat J, Ferlay J, Bray F, Plummer M, Franceschi S (2012) Global burden of human papillomavirus and related diseases. Vaccine 30(Suppl 5):F12–F23. https://doi.org/10.1016/j.vaccine.2012.07.055
Gregoire L, Cubilla AL, Reuter VE, Haas GP, Lancaster WD (1995) Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma. J Natl Cancer Inst 87:1705–1709. https://doi.org/10.1093/jnci/87.22.1705
Hakenberg OW, Comperat EM, Minhas S, Necchi A, Protzel C, Watkin N (2015) EAU guidelines on penile cancer: 2014 update. Eur Urol 67:142–150. https://doi.org/10.1016/j.eururo.2014.10.017
Hakenberg OW, Minhas ES, Necchi A, Protzel C, Watkin N, Compérat E (2018) EAU Guidelines on Penile Cancer 2018European Association of Urology Guidelines. 2018 Edition. European Association of Urology Guidelines Office, Arnhem, The Netherlands, pp
Lont AP, Kroon BK, Horenblas S, Gallee MP, Berkhof J, Meijer CJ, Snijders PJ (2006) Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 119:1078–1081. https://doi.org/10.1002/ijc.21961
Martins VA, Pinho JD, Teixeira Junior AAL, Nogueira LR, Silva FF, Maulen VE, Khayat AS, Calixto JRR, Costa HA, Ramalho LNZ, Silva GEB (2018) P16INK4a expression in patients with penile cancer. PLoS One 13:e0205350. https://doi.org/10.1371/journal.pone.0205350
McAlpine JN, Kim SY, Akbari A, Eshragh S, Reuschenbach M, von Knebel DM, Prigge ES, Jordan S, Singh N, Miller DM, Gilks CB (2017) HPV-independent differentiated vulvar intraepithelial neoplasia (dVIN) is associated with an aggressive clinical course. Int J Gynecol Pathol 36:507–516. https://doi.org/10.1097/pgp.0000000000000375
Miralles-Guri C, Bruni L, Cubilla AL, Castellsagué X, Bosch FX, de Sanjosé S (2009) Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol 62:870–878. https://doi.org/10.1136/jcp.2008.063149
Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM (2016) The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol 70:93–105. https://doi.org/10.1016/j.eururo.2016.02.029
Olesen TB, Sand FL, Rasmussen CL, Albieri V, Toft BG, Norrild B, Munk C, Kjær SK (2019) Prevalence of human papillomavirus DNA and p16(INK4a) in penile cancer and penile intraepithelial neoplasia: a systematic review and meta-analysis. Lancet Oncol 20:145–158. https://doi.org/10.1016/s1470-2045(18)30682-x
Paner GP, Stadler WM, Hansel DE, Montironi R, Lin DW, Amin MB (2018) Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers. Eur Urol 73:560–569. https://doi.org/10.1016/j.eururo.2017.12.018
Pang C, Guan Y, Li H, Chen W, Zhu G (2016) Urologic cancer in China. Jpn J Clin Oncol 46:497–501. https://doi.org/10.1093/jjco/hyw034
Rasmussen CL, Sand FL, Hoffmann Frederiksen M, Kaae Andersen K, Kjaer SK (2018) Does HPV status influence survival after vulvar cancer? Int J Cancer 142:1158–1165. https://doi.org/10.1002/ijc.31139
Rietbergen MM, Snijders PJ, Beekzada D, Braakhuis BJ, Brink A, Heideman DA, Hesselink AT, Witte BI, Bloemena E, Baatenburg-De Jong RJ, Leemans CR, Brakenhoff RH (2014) Molecular characterization of p16-immunopositive but HPV DNA-negative oropharyngeal carcinomas. Int J Cancer 134:2366–2372. https://doi.org/10.1002/ijc.28580
Sakamoto J, Shigehara K, Nakashima K, Kawaguchi S, Nakashima T, Shimamura M, Yasuda M, Kato T, Hasegawa T, Kobori Y, Okada H, Deguchi T, Izumi K, Kadono Y, Mizokami A (2019) Etiological role of human papillomavirus infection in the development of penile cancer. Int J Infect Dis 78:148–154. https://doi.org/10.1016/j.ijid.2018.11.003
Sand FL, Rasmussen CL, Frederiksen MH, Andersen KK, Kjaer SK (2018) Prognostic significance of HPV and p16 status in men diagnosed with penile cancer: a systematic review and meta-analysis cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive. Oncology 27:1123–1132. https://doi.org/10.1158/1055-9965.epi-18-0322
Sinno AK, Saraiya M, Thompson TD, Hernandez BY, Goodman MT, Steinau M, Lynch CF, Cozen W, Saber MS, Peters ES, Wilkinson EJ, Copeland G, Hopenhayn C, Watson M, Lyu C, Unger ER (2014) Human papillomavirus genotype prevalence in invasive vaginal cancer from a registry-based population. Obstet Gynecol 123:817–821. https://doi.org/10.1097/aog.0000000000000171
Steinestel J, Al Ghazal A, Arndt A, Schnoeller TJ, Schrader AJ, Moeller P, Steinestel K (2015) The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma. BMC Cancer 15:220. https://doi.org/10.1186/s12885-015-1268-z
Zhai JP, Wang QY, Wei D, Xu KX, Man LB (2013) Association between HPV DNA and disease specific survival in patients with penile cancer. Zhonghua Yi Xue Za Zhi 93:2719–2722
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This study was supported by the grant from the Nature Science Foundation of China (No. 81872085) and Sun Yat-sen University Cancer Center Medical scientist training program (No.14zxqk08).
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Conceptualization: Chengbiao Chu, Kai Yao, Yun Cao; Methodology: Chengbiao Chu, Keming Chen, **ngliang Tan, Jiangli Lu, Yuanzhong Yang, YiJun Zhang; Formal analysis and investigation: Chengbiao Chu, Keming Chen; Writing, original draft preparation: Chengbiao Chu; Writing, review and editing: Chengbiao Chu, Kai Yao, Yun Cao; Funding acquisition: Kai Yao, Yun Cao; Resources: Chengbiao Chu, **ngliang Tan, Kai Yao, Yun Cao; all authors read and approved the final manuscript.
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Chu, C., Chen, K., Tan, X. et al. Prevalence of human papillomavirus and implication on survival in Chinese penile cancer. Virchows Arch 477, 667–675 (2020). https://doi.org/10.1007/s00428-020-02831-7
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DOI: https://doi.org/10.1007/s00428-020-02831-7