Distinctive Association of p16INK4a Overexpression With Penile Intraepithelial Neoplasia Depicting Warty and/or Basaloid Features: A Study of 141 Cases Evaluating a New Nomenclature

From the pathogenic point of view, penile cancers may be grouped in human papillomavirus-related and unrelated tumors, each one of them with distinctive morphologic features. The former are predominantly composed of small, undifferentiated basaloid cells, with more or less prominent koilocytic changes, and the latter of keratinizing differentiated squamous cells. The same cellular types are observed in precancerous lesions. On the basis of these observations, we constructed a novel nomenclature for penile precancerous lesions and classified them as penile intraepithelial neoplasia (PeIN) of differentiated, warty, basaloid, and warty-basaloid types. The aim of this study was to test the usefulness of immunohistochemical p16INK4a overexpression, considered as a surrogate for high-risk human papillomavirus infection, using this classification system. We pathologically evaluated 141 patients with PeIN, associated (123 cases) and unassociated (18 cases) with invasive cancer. Distribution of PeIN types was: differentiated, 72%; basaloid, 9%; warty-basaloid, 7%; warty, 4%; and mixed, 7%. There was a striking similarity in the morphology of in situ and invasive squamous cell carcinomas. Differentiated PeIN was commonly associated with usual, verrucous, papillary, and other low-grade keratinizing variants of squamous cell carcinoma whereas in basaloid and warty carcinomas the presence of in situ lesions with similar morphology was habitual. We evaluated p16INK4a overexpression using a 4-tiered (0, 1, 2, and 3) pattern-based system. To properly distinguish differentiated PeIN from in situ lesions with warty and/or basaloid features only pattern 3, which requires full-thickness staining in all epithelial cells, was considered positive. Using this approach, there was a significant association of the negative patterns and differentiated PeIN and of the positive pattern and warty, basaloid, and warty-basaloid PeIN (P<0.0001). Basaloid variant had the strongest association. The sensitivity rate of p16INK4a positivity for discriminating types of PeIN was of 82%, with a specificity of 100% and an accuracy of 95%. Lichen sclerosus was identified in 42 cases and their epithelial component was p16INK4a negative in all cases. Although more studies are necessary to confirm these observations, p16INK4a overexpression seems to be a useful tool for discriminating differentiated from warty, basaloid, and warty-basaloid PeIN.

[1]  B. Lloveras,et al.  HPV-negative Vulvar Intraepithelial Neoplasia (VIN) With Basaloid Histologic Pattern: An Unrecognized Variant of Simplex (Differentiated) VIN , 2009, The American journal of surgical pathology.

[2]  J. Cuzick,et al.  HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis , 2009, Modern Pathology.

[3]  P. Martin-Hirsch,et al.  p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. , 2009, Cancer treatment reviews.

[4]  D. Haidopoulos,et al.  p16 INK4A Is a Strong Biomarker for Cervical Intraepithelial Neoplasia and Invasive Cervical Carcinoma: A Reappraisal , 2009, Reproductive sciences.

[5]  M. Frisch,et al.  Histological characteristics of human papilloma‐virus‐positive and ‐negative invasive and in situ squamous cell tumours of the penis , 2009, International journal of experimental pathology.

[6]  A. Cubilla The role of pathologic prognostic factors in squamous cell carcinoma of the penis , 2009, World Journal of Urology.

[7]  P. D. de Wilde,et al.  A panel of p16INK4A, MIB1 and p53 proteins can distinguish between the 2 pathways leading to vulvar squamous cell carcinoma , 2008, International journal of cancer.

[8]  A. Usubutun,et al.  Staining characteristics of p16INK4a: Is there a correlation with lesion grade or high‐risk human papilloma virus positivity? , 2008, The journal of obstetrics and gynaecology research.

[9]  M. Jirásek,et al.  High-risk human papillomavirus infection and p16INK4a protein expression in laryngeal lesions. , 2008, Pathology, research and practice.

[10]  L. B. Moura,et al.  p16INK4 expression in precursor lesions of squamous cell cervical cancer related to the presence of HPV-DNA. , 2008, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[11]  N. Mulvany,et al.  Diagnostic utility of p16INK4a: a reappraisal of its use in cervical biopsies , 2008, Pathology.

[12]  C. Zettler,et al.  Immunohistochemical expression of p16 and p53 in vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva , 2008, Pathology & Oncology Research.

[13]  S. Bean,et al.  Immunohistochemical Expression of p16 and Ki-67 Correlates With Degree of Anal Intraepithelial Neoplasia , 2007, The American journal of surgical pathology.

[14]  K. Shroyer,et al.  Human papillomavirus testing and molecular markers of cervical dysplasia and carcinoma , 2007, Cancer.

[15]  M. Troxell,et al.  p16INK4A Immunohistochemistry is Superior to HPV In Situ Hybridization for the Detection of High-risk HPV in Atypical Squamous Metaplasia , 2007, The American journal of surgical pathology.

[16]  E. Campo,et al.  p16 Overexpression Identifies HPV-positive Vulvar Squamous Cell Carcinomas , 2006, The American journal of surgical pathology.

[17]  K. Shroyer,et al.  Correlation of p16 and pRb expression with HPV detection in Bowen’s disease , 2006, Journal of cutaneous pathology.

[18]  S. Lele,et al.  Overexpression of p16INK4 is a reliable marker of human papillomavirus-induced oral high-grade squamous dysplasia. , 2006, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[19]  K. Cooper,et al.  p16INK4a Immunoexpression: Surrogate Marker of High-risk HPV and High-grade Cervical Intraepithelial Neoplasia , 2006, Advances in anatomic pathology.

[20]  E. Wilkinson,et al.  Review of Terminology of Precursors of Vulvar Squamous Cell Carcinoma , 2006, Journal of lower genital tract disease.

[21]  G. Micali,et al.  Association of penile lichen sclerosus and oncogenic human papillomavirus infection , 2006, International journal of dermatology.

[22]  Tom Fawcett,et al.  An introduction to ROC analysis , 2006, Pattern Recognit. Lett..

[23]  D. Lipsker,et al.  p16 expression in relation to human papillomavirus in anogenital lesions. , 2006, Human pathology.

[24]  A. Tannapfel,et al.  p16, p14, p53, and Cyclin D1 Expression and HPV Analysis in Small Cell Carcinomas of the Uterine Cervix , 2006, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[25]  L. Mariani,et al.  Immunohistochemical expression of p16INK4a is predictive of HR-HPV infection in cervical low-grade lesions , 2006, Modern Pathology.

[26]  W. McCluggage,et al.  p16 Expression in the Female Genital Tract and Its Value in Diagnosis , 2006, Advances in anatomic pathology.

[27]  P. D. de Wilde,et al.  Vulvar Squamous Cell Carcinoma is a Multifactorial Disease Following Two Separate and Independent Pathways , 2006, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[28]  G. Elmberger,et al.  P16(INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma. , 2005, Anticancer research.

[29]  M. Sideri,et al.  Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. , 2005, The Journal of reproductive medicine.

[30]  C. Sung,et al.  Simplex (differentiated) type VIN: absence of p16INK4 supports its weak association with HPV and its probable precursor role in non‐HPV related vulvar squamous cancers , 2005, Histopathology.

[31]  M. Lindström,et al.  p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia , 2005, Modern Pathology.

[32]  E. Wilkinson,et al.  Human Papillomavirus Infection and p16INK4a Protein Expression in Vulvar Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma , 2005 .

[33]  H. Lai,et al.  Is p16(INK4A) expression more useful than human papillomavirus test to determine the outcome of atypical squamous cells of undetermined significance-categorized Pap smear? A comparative analysis using abnormal cervical smears with follow-up biopsies. , 2005, Gynecologic oncology.

[34]  H. Dienes,et al.  Expression of p16 protein is associated with human papillomavirus status in tonsillar carcinomas and has implications on survival. , 2005, Advances in oto-rhino-laryngology.

[35]  E. Wilkinson,et al.  Human papillomavirus infection and p16(INK4a) protein expression in vulvar intraepithelial neoplasia and invasive squamous cell carcinoma. , 2005, Journal of lower genital tract disease.

[36]  S. Riethdorf,et al.  p16INK4A expression as biomarker for HPV 16-related vulvar neoplasias. , 2004, Human pathology.

[37]  T. Ekalaksananan,et al.  Immunocytochemical staining of p16INK4a protein from conventional Pap test and its association with human papillomavirus infection , 2004, Diagnostic cytopathology.

[38]  S. Cajal,et al.  Immunohistochemical Staining for p16 and p53 in Premalignant and Malignant Epithelial Lesions of the Vulva , 2004, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[39]  Hanlin L. Wang,et al.  Detection of Human Papillomavirus DNA and Expression of p16, Rb, and p53 Proteins in Small Cell Carcinomas of the Uterine Cervix , 2004, The American journal of surgical pathology.

[40]  K. Shah,et al.  Distinction of Endocervical and Endometrial Adenocarcinomas: Immunohistochemical p16 Expression Correlated With Human Papillomavirus (HPV) DNA Detection , 2004, The American journal of surgical pathology.

[41]  N. Rosenblum,et al.  p16 Expression in Squamous Lesions of the Female Genital Tract , 2003, Journal of Molecular Histology.

[42]  W. Dinjens,et al.  A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5–8 , 2003, International journal of cancer.

[43]  E. Velazquez,et al.  Lichen Sclerosus in 68 Patients With Squamous Cell Carcinoma of the Penis: Frequent Atypias and Correlation With Special Carcinoma Variants Suggests a Precancerous Role , 2003, The American journal of surgical pathology.

[44]  E. Pirog,et al.  Low-Grade Vulvar and Vaginal Intraepithelial Neoplasia: Correlation of Histologic Features with Human Papillomavirus DNA Detection and MIB-1 Immunostaining , 2003, Modern Pathology.

[45]  Hanlin L. Wang,et al.  Expression of p16, Rb, and p53 Proteins in Squamous Cell Carcinomas of the Anorectal Region Harboring Human Papillomavirus DNA , 2003, Modern Pathology.

[46]  N. Kiviat,et al.  p16INK4a Expression Correlates with Degree of Cervical Neoplasia: A Comparison with Ki-67 Expression and Detection of High-Risk HPV Types , 2003, Modern Pathology.

[47]  H. Dienes,et al.  Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. , 2003, The American journal of pathology.

[48]  F. X. Bosch,et al.  Epidemiologic classification of human papillomavirus types associated with cervical cancer. , 2003, The New England journal of medicine.

[49]  M. Rubin,et al.  Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. , 2001, The American journal of pathology.

[50]  B. Quade,et al.  Ki-67, Cyclin E, and p16 INK4 Are Complimentary Surrogate Biomarkers for Human Papilloma Virus-Related Cervical Neoplasia , 2001, The American journal of surgical pathology.

[51]  T. Ince,et al.  Surrogate Biomarkers of HPV Infection in Cervical Neoplasia Screening and Diagnosis , 2001, Advances in anatomic pathology.

[52]  C. Meijer,et al.  Morphological Features of Epithelial Abnormalities and Precancerous Lesions of the Penis , 2000, Scandinavian journal of urology and nephrology. Supplementum.

[53]  G. Micali,et al.  Penile cancer among patients with genital lichen sclerosus. , 1999, Journal of the American Academy of Dermatology.

[54]  R West,et al.  Of bombers, radiologists, and cardiologists: time to ROC , 1999, Heart.

[55]  M. Chan,et al.  Expression of p16INK4 and retinoblastoma protein Rb in vulvar lesions of Chinese women. , 1998, Gynecologic oncology.

[56]  G. Haas,et al.  Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma. , 1995, Journal of the National Cancer Institute.

[57]  W. Catalona,et al.  Tumors of the Prostate Gland , 1985 .

[58]  Gilmore Hr,et al.  Armed Forces Institute of Pathology. , 1968, Oral surgery, oral medicine, and oral pathology.