HPV-negative carcinoma of the uterine cervix: a distinct type of cervical cancer with poor prognosis L Rodr  ıguez-Carunchio, a I Soveral, b RDM Steenbergen, c A Torn e, b S Martinez, b P Fust e, b J Pahisa, b L Marimon, a J Ordi, a M del Pino b a Department of Pathology, Centre de Recerca en Salut Internacional de Barcelona (CRESIB), Hospital Cl  ınic, University of Barcelona, Faculty of Medicine, Barcelona, Spain b Institute of Gynaecology, Obstetrics and Neonatology, Institut d 0 Investigacions Biom ediques August Pi I Sunyer (IDIBAPS), Hospital Cl  ınic, University of Barcelona, Faculty of Medicine, Barcelona, Spain c Unit of Molecular Pathology, Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands Correspondence: Prof. J Ordi, Department of Pathology, CRESIB, Hospital Cl  ınic, University of Barcelona, Faculty of Medicine, C/Villarroel 170, 08036 Barcelona, Spain. Email jordi@clinic.ub.es Accepted 2 July 2014. Published Online 17 September 2014. 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. Please cite this paper as: Rodr  ıguez-Carunchio L, Soveral I, Steenbergen RDM, Torn e A, Martinez S, Fust e P, Pahisa J, Marimon L, Ordi J, del Pino M. HPV-negative carcinoma of the uterine cervix: a distinct type of cervical cancer with poor prognosis. BJOG 2014; DOI: 10.1111/1471-0528.13071. Introduction Human papillomavirus (HPV) has been identified as the key causative agent for the development of cancer of the uterine cervix (CC). 1 The prevalence of HPV infection in CC has been estimated to be as high as 99%; 1,2 however, in almost all studies using highly sensitive HPV tests a small proportion of CCs are negative for HPV. 3,4 It has been sug- gested that HPV-negative CC may represent a biologically distinct subset of tumours carrying a poorer prognosis than JO and MdP are both senior authors of the article. 1 ª 2014 Royal College of Obstetricians and Gynaecologists DOI: 10.1111/1471-0528.13071 www.bjog.org