Human papillomavirus is a necessary cause of invasive cervical cancer worldwide

A recent report that 93 per cent of invasive cervical cancers worldwide con tain human papillomavirus (HPV) may be an underestimate; due to sample inad equacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The form erly HPV-negative cases from this study have therefore been reanalysed for HPV serum antibodies and HPV DNA, Serology for HPV 16 VLPs, E6, and E7 anti bodies was performed on 49 of the 66 cases which were HPV-negative and a sa mple of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalysed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different NPV PCR assays targeting different open reading frames (ORF s), No significant difference was found in serology for HPV 16 proteins bet ween the cases that were originally HPV PCR-negative and -positive, Type-sp ecific E7 PCR for 14 high-risk NPV types detected HPV DNA in 38 (69 per cen t) of the 55 originally HPV-negative and amplifiable specimens. The HPV typ es detected were 16, 18, 31, 33, 39, 45, 52, and 58, Two (4 per cent) addit ional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR, Histo logical analysis of the 55 specimens revealed that 21 were qualitatively in adequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate (p < 0.001). Combining the data from this and the previous study and excluding inadequate specimen s, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent, Th e presence of HPV in virtually all cervical cancers implies the highest wor ldwide attributable fraction so far reported for a specific cause of any ma jor human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cyt ology in routine cervical screening. Copyright (C) 1999 John Wiley & Sons, Ltd.