HPV-negative carcinoma of the uterine cervix: a distinct type of cervical cancer with poor prognosis

BJOG. 2015 Jan;122(1):119-27. doi: 10.1111/1471-0528.13071. Epub 2014 Sep 17.


Objective: Using highly sensitive polymerase chain reaction (PCR) techniques, we reanalysed all cervical carcinomas (CCs) found to be human papillomavirus (HPV)-negative by Hybrid Capture 2 (HC2) to determine the prevalence of true HPV-negativity. We also evaluated the characteristics of the patients with tumours with confirmed HPV-negativity.

Design: Observational study.

Setting: Barcelona, Spain.

Population: A cohort of 136 women with CC (32 adenocarcinomas, 104 squamous cell carcinomas) who had pre-treatment HC2 testing.

Methods: All negative cases were reanalysed and genotyped for HPV using three PCR assays (SPF10, GP5+/6+ and E7-specific assay).

Main outcome measures: Percentage of confirmed HPV-negative and HPV-positive tumours. Clinicopathological features and disease-free survival (DFS) and overall survival (OS) of both groups.

Results: Fourteen of 136 women (10.2%) were negative for HPV by HC2. After reanalysis by PCR-based techniques only 8/136 (5.8%) tumours were confirmed as HPV-negative, whereas in six cases different HPVs were identified [HPV-11, -16 (two tumours), -18, -45, and -68]. Confirmed HPV-negativity was more frequent in adenocarcinomas than in squamous cell carcinomas (5/32, 15.6% versus 3/104, 2.9%, respectively; P = 0.017). Patients with CCs with confirmed HPV-negativity had significantly worse DFS than women with HPV-positive tumours [51.9 months (95% CI 12.2-91.7 months) versus 109.9 months (95% CI 98.2-121.5 months); P = 0.010]. In the multivariate analysis HPV-negativity and International Federation of Gynecology and Obstetrics (FIGO) staging were associated with increased risk of progression and mortality.

Conclusions: An HC2-negative result is an uncommon finding in women with CC, but in almost half of these cases HPVs are identified by more sensitive techniques. CCs with confirmed HPV-negativity are more frequently adenocarcinomas, and seem to be associated with worse DFS.

Keywords: Cervical cancer; human papillomavirus; p16; p53; prognosis; uterine cervix.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology
  • Adenocarcinoma / virology
  • Adenocarcinoma, Mucinous / pathology*
  • Adenocarcinoma, Mucinous / virology
  • Adult
  • Aged
  • Carcinoma, Adenosquamous / pathology*
  • Carcinoma, Adenosquamous / virology
  • Carcinoma, Squamous Cell / pathology*
  • Carcinoma, Squamous Cell / virology
  • Cohort Studies
  • DNA, Viral / genetics*
  • Female
  • Humans
  • Middle Aged
  • Papillomaviridae / genetics*
  • Papillomavirus Infections / diagnosis
  • Papillomavirus Infections / genetics*
  • Polymerase Chain Reaction
  • Prognosis
  • Uterine Cervical Neoplasms / pathology*
  • Uterine Cervical Neoplasms / virology


  • DNA, Viral