Expression of p16 protein in lesional and perilesional condyloma acuminata and bowenoid papulosis: Clinical significance and diagnostic implications


      The histopathological and clinical overlapping features between condyloma acuminata and bowenoid papulosis can present a diagnostic challenge and we sought to determine if immunochemistry can be helpful in this setting.


      In this study, we evaluate the specificity and sensitivity of p16 immunohistochemistry in condyloma and bowenoid papulosis lesions compared with uninvolved perilesional skin and discuss the possible clinical implications.


      A total of 36 skin biopsy specimens (24 samples of condyloma and 12 samples of bowenoid papulosis with adjacent uninvolved perilesional skin) were stained with an antibody to p16 protein.


      In all, 75% of condyloma lesions showed sporadic and focal positive staining for p16 protein. All cases of bowenoid papulosis showed diffuse positive staining with p16 protein. Normal-appearing adjacent skin was negative in all cases.


      Studies with a larger number of cases are needed to confirm our data.


      This immunostain has high sensitivity and specificity for the detection of bowenoid papulosis. Although p16 is expressed in both conditions, the staining pattern in bowenoid papulosis is strongly and diffusely positive involving the full thickness of the epidermis compared with the mostly focal or sporadic pattern observed in condyloma.

      Key words

      Abbreviations used:

      CDK (cyclin-dependent kinase), HPV (human papillomavirus), SCC (squamous cell carcinoma)
      To read this article in full you will need to make a payment
      AAD Member Login
      AAD Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Majewski S.
        • Jablonska S.
        Human papillomavirus-associated tumors of the skin and mucosa.
        J Am Acad Dermatol. 1997; 36: 659-685
        • Darragh T.M.
        • Colgan T.J.
        • Thomas Cox J.
        • Heller D.S.
        • Henry M.R.
        • Luff R.D.
        • et al.
        The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.
        Int J Gynecol Pathol. 2013; 32: 76-115
        • Samama B.
        • Lipsker D.
        • Boehm N.
        p16 Expression in relation to human papillomavirus in anogenital lesions.
        Hum Pathol. 2006; 37: 513-519
        • Su X.Y.
        • Lai W.
        • Zhu H.L.
        • Su Z.L.
        • Guo S.Z.
        • Lin S.X.
        Predicting cancerization of condyloma acuminatum by testing expression of p16.
        Ai Zheng. 2004; 23: 1346-1349
        • Klaes R.
        • Friedrich T.
        • Spitkovsky D.
        • Ridder R.
        • Rudy W.
        • Petry U.
        • et al.
        Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri.
        Int J Cancer. 2001; 92: 276-284
        • Dunne E.F.
        • Unger E.R.
        • Sternberg M.
        • McQuillan G.
        • Swan D.C.
        • Patel S.S.
        • et al.
        Prevalence of HPV infection among females in the United States.
        JAMA. 2007; 297: 813-819
        • Dunne E.F.
        • Nielson C.M.
        • Stone K.M.
        • Markowitz L.E.
        • Giuliano A.R.
        Prevalence of HPV infection among men: a systematic review of the literature.
        J Infect Dis. 2006; 194: 1044-1057
        • Bergeron C.
        • Naghashfar Z.
        • Canaan C.
        • Shah K.
        • Fu Y.
        • Ferenczy A.
        Human papillomavirus type 16 in intraepithelial neoplasia (bowenoid papulosis) and coexistent invasive carcinoma of the vulva.
        Int J Gynecol Pathol. 1987; 6: 1-11
        • Kato T.
        • Saijyo S.
        • Hatchome N.
        • Tagami H.
        • Kawashima M.
        Detection of human papillomavirus type 16 in bowenoid papulosis and invasive carcinoma occurring in the same patient with a history of cervical carcinoma.
        Arch Dermatol. 1988; 124: 851-852
        • Della Tore G.
        • Donghi R.
        • Longoni A.
        • Pilotti S.
        • Pasquini G.
        • De Palo G.
        • et al.
        HPV DNA in intraepithelial neoplasia and carcinoma of the vulva and penis.
        Diagn Mol Pathol. 1992; 1: 25-30
        • Rogozinski T.T.
        • Janniger C.K.
        Bowenoid papulosis.
        Am Fam Physician. 1988; 38: 161-164
        • Nobori T.
        • Miura K.
        • Wu D.J.
        • Lois A.
        • Takabayashi K.
        • Carson D.A.
        Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.
        Nature. 1994; 21: 753-756
        • Kamb A.
        • Gruis N.A.
        • Weaver-Feldhaus J.
        • Liu Q.
        • Harshman K.
        • Tavtigian S.V.
        • et al.
        A cell cycle regulator potentially involved in genesis of many tumor types.
        Science. 1994; 264: 436-440
        • Spruck III, C.H.
        • Gonzalez-Zulueta M.
        • Shibata A.
        • Simoneau A.R.
        • Lin M.F.
        • Gonzales F.
        • et al.
        p16 Gene in uncultured tumors.
        Nature. 1994; 21: 183-184
        • Sherr C.J.
        • McCormick F.
        The RB and p53 pathways in cancer.
        Cancer Cell. 2002; 2: 103-112
        • Serrano M.
        • Hannon G.J.
        • Beach D.
        A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
        Nature. 1993; 366: 704-707
        • Parry D.
        • Bates S.
        • Mann D.J.
        • Peters G.
        Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumor suppressor gene product.
        EMBO J. 1995; 14: 503-511
        • Ohtani N.
        • Yamakoshi K.
        • Takahashi A.
        • Hara E.
        The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression.
        J Med Invest. 2004; 51: 146-153
        • Ponti G.
        • Luppi G.
        • Losi L.
        • Cesinaro A.M.
        • Sartori G.
        • Maiorana A.
        • et al.
        p16 Immunohistochemistry of multiple primary melanomas as screening to identify familial melanoma syndrome.
        Int J Dermatol. 2012; 51: 488-492
        • Mäkitie A.A.
        • MacMillan C.
        • Ho J.
        • Shi W.
        • Lee A.
        • O’Sullivan B.
        • et al.
        Loss of p16 expression has prognostic significance in human nasopharyngeal carcinoma.
        Clin Cancer Res. 2003; 9: 2177-2184
        • Schneider-Stock R.
        • Boltze C.
        • Lasota J.
        • Peters B.
        • Corless C.L.
        • Ruemmele P.
        • et al.
        Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study.
        Clin Cancer Res. 2005; 11: 638-645
        • Lundberg M.
        • Leivo I.
        • Saarilahti K.
        • Mäkitie A.A.
        • Mattila P.S.
        Transforming growth factor beta 1 genotype and p16 as prognostic factors in head and neck squamous cell carcinoma.
        Acta Otolaryngol. 2012; 132: 1006-1012
        • Hodges A.
        • Smoller B.R.
        Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin.
        Mod Pathol. 2002; 15: 1121-1125
        • Willman J.H.
        • Heinz D.
        • Golitz L.E.
        • Shroyer K.R.
        Correlation of p16 and pRb expression with HPV detection in Bowen’s disease.
        J Cutan Pathol. 2006; 33: 629-633
        • Lu D.W.
        • El-Mofty S.K.
        • Wang H.L.
        Expression of p16, Rb, and p53 proteins in squamous cell carcinomas of the anorectal region harboring human papillomavirus DNA.
        Mod Pathol. 2003; 16: 692-699
        • Santos M.
        • Montagut C.
        • Mellado B.
        • García Á.
        • Ramón y Cajal S.
        • Cardesa A.
        • et al.
        Immunohistochemical staining for p16 and p53 in premalignant and malignant epithelial lesions of the vulva.
        Int J Gynecol Pathol. 2004; 23: 206-214
        • Auepemkiate S.
        • Thongsuksai P.
        • Boonyaphiphat P.
        p16 Expression in Bowen’s disease and bowenoid papulosis.
        J Med Assoc Thai. 2006; 89: 1460-1465
        • Pirog E.C.
        • Quint K.D.
        • Yantiss R.K.
        p16/CDKN2A and Ki-67 enhance the detection of anal intraepithelial neoplasia and condyloma and correlate with human papillomavirus detection by polymerase chain reaction.
        Am J Surg Pathol. 2010; 34: 1449-1455
        • Riethdorf S.
        • Neffen E.F.
        • Cviko A.
        • Löning T.
        • Crum C.P.
        • Riethdorf L.
        p16INK4A expression as biomarker for HPV 16-related vulvar neoplasias.
        Hum Pathol. 2004; 35: 1477
        • Sano T.
        • Oyama T.
        • Kashiwabara K.
        • Fukuda T.
        • Nakajima T.
        Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions.
        Am J Pathol. 1998; 153: 1741-1748
        • Gage J.R.
        • Meyers C.
        • Wettstein F.O.
        The E7 proteins of the nononcogenic human papillomavirus type 6b (HPV-6b) and of the oncogenic HPV-16 differ in retinoblastoma protein binding and other properties.
        J Virol. 1990; 64: 723-730
        • van der Avoort I.A.
        • Shirango H.
        • Hoevenaars B.M.
        • Grefte J.M.
        • de Hullu J.A.
        • de Wilde P.C.
        • et al.
        Vulvar squamous cell carcinoma is a multifactorial disease following 2 separate and independent pathways.
        Int J Gynecol Pathol. 2006; 25: 22-29