title: The overexpression of p16 is not a surrogate marker for high-risk human papilloma virus genotypes and predicts clinical outcomes for vulvar cancer.
abstract: We aimed to evaluate the correlation between p16(ink4a)-overexpression and high risk (hr)HPV-DNA in vulvar squamous cell carcinoma (vSCC) tumors as well as the impact of both biomarkers on the prognosis of vSCC patients.
  
  
  
  PCR-detection of (hr)HPV-DNA and immunohistochemical staining for p16(ink4a) were conducted in 85 vSCC tumors. Survival analyses included the Kaplan-Meier method, log-rank test and Cox proportional hazards model.
  
  
  
  p16(ink4a)-overexpression and (hr)HPV-DNA were detected in 35 and 37 of the 85 tumors, respectively. Among the 35 p16(ink4a)-positive tumors, 10 lacked (hr)HPV-DNA (29 %). Among the 50 p16(ink4a)-negative tumors, (hr)HPV-DNA was detected in 12 cases (24 %). The median follow-up was 89.20 months (range 1.7-189.5 months). P16(ink4a)-overexpression, but not (hr)HPV-DNA positivity of the primary tumor, was correlated with prolonged overall survival (OS) (p = 0.009). P16(ink4a)-overexpression predicted a better response to radiotherapy (p < 0.001). Univariate analysis has demonstrated that age (p = 0.025), tumor grade (p = 0.001), lymph node metastasis (p < 0.001), FIGO stage (p < 0.001), p16(ink4a)-overexpression (p = 0.022), and adjuvant RTX (p < 0.001) were prognostic factors for OS. Multivariate analysis has demonstrated that lymph node metastasis (HR 1-2.74, 95 % CI 1.50-5.02, p = 0.019), tumor grade (HR 1-2.80, 95 % CI 1.33-5.90, p = 0.007) and p16(ink4a)-overexpression (HR 1-2.11, 95 % CI 1.13-3.95, p = 0.001) are independent prognostic factors.
  
  
  
  The discovered overlap suggests the use of p16(ink4a) in combination with HPV-DNA detection as an ancillary test for future research and clinical studies in vSCC. The prognostic and predictive value of p16(ink4a)-overexpression should be tested in larger cohort studies.
authors.affiliation: Department of Surgical Oncology, The Medical University of Gdańsk, ul. Smoluchowskiego 17, 80-214, Gdańsk, Poland. jacek.sznurkowski@gumed.edu.pl.
authors.forename: Jacek J
authors.initials: JJ
authors.lastname: Sznurkowski
authors.affiliation: Department of Pathology, The Medical University of Gdańsk, ul. Smoluchowskiego 17, 80-214, Gdańsk, Poland.
authors.forename: Anton
authors.initials: A
authors.lastname: Żawrocki
authors.affiliation: Department of Pathology, The Medical University of Gdańsk, ul. Smoluchowskiego 17, 80-214, Gdańsk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000473:pathology* / Q000628:therapy / Q000821:virology*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000032:analysis*; D004279:DNA, Viral / Q000302:isolation & purification; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000401:mortality / Q000473:pathology* / Q000628:therapy / Q000821:virology*; D011379:Prognosis; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D014846:Vulvar Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy / Q000821:virology*
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004279:DNA, Viral
keywords: HPV; Prognosis; Vulvar cancer; p16; vSCC