"Histological characteristics of HPV-associated and -independent squamous cell carcinomas of the vulva: A study of 1,594 cases"

Int J Cancer. 2017 Dec 15;141(12):2517-2527. doi: 10.1002/ijc.31006. Epub 2017 Aug 31.


There are at least two different etio-pathogenic pathways for the development of vulvar squamous cell carcinoma (VSCC): one associated with infection by human papillomavirus (HPV) and another independent of HPV. We aimed to describe the histological characteristics of HPV-associated and -independent tumors and to determine the best strategy to identify HPV in VSCC. A single paraffin block was available for review from a series of 1,594 VSCCs. In all cases HPV DNA detection was analyzed using the SPF10PCR/DEIA/LiPA25 system and p16 immunohistochemistry (IHC). A tumor was considered as unquestionably HPV-associated if both HPV DNA and p16 IHC were positive. A tumor was considered indisputably HPV-independent if both HPV DNA and p16 IHC were negative. Two groups of tumors were classified as non-conclusive: (1) HPV DNA+/p16- and (2) HPV DNA-/p16+. WHO typing and a thorough histological evaluation were conducted in all cases. Four hundred and forty-one tumors were HPV DNA+ with 367 cases (23.0%) being HPV DNA+/p16+. The latter tumors were more frequently basaloid or warty (49.8%), but 36.5% were of the keratinizing type; 1,153 tumors were HPV DNA-, with 1,060 cases (66.5%) being HPV DNA-/p16-. These HPV DNA-/p16- tumors were mostly keratinizing (81.2%) but were occasionally basaloid or warty (5.2%). The features of HPV DNA-/p16+ cases (n = 93) were similar to those of the HPV-associated VSCC, and HPV DNA+/p16- (n = 74) cases had a more diverse profile, although they were more similar to HPV-independent tumors. Several histological characteristics were more frequently associated with HPV-related VSCC (koilocytotic-like change, necrosis, moderate to marked pleomorphism, invasive front in nests; p < 0.001), however, none of these characteristics allowed differentiation between HPV-associated and -independent VSCC. In conclusion, histological criteria do not allow differentiation between HPV-associated and -independent VSCC. p16 Alone is a clinically easy strategy to determine HPV status in VSCC.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Carcinoma, Squamous Cell / virology
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • DNA, Viral / genetics
  • Female
  • Humans
  • Middle Aged
  • Papillomaviridae / genetics
  • Papillomaviridae / isolation & purification
  • Papillomavirus Infections / diagnosis*
  • Papillomavirus Infections / epidemiology
  • Retrospective Studies
  • Vulvar Neoplasms / metabolism
  • Vulvar Neoplasms / pathology*
  • Vulvar Neoplasms / virology


  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Viral