Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva
Introduction
Vulvar cancer is a rare entity with incidence rates ranging from 0.5 to 1.5 per 100,000 women, representing about 4% of all gynaecological malignancies.1 Lower rates are observed in Asia and Africa than in other parts of the world. Over the past few decades, the incidence rates of invasive vulvar cancer (IVC) and vulvar intraepithelial neoplasia (VIN) have both been reported to increase, particularly amongst younger women.2, 3, 4, 5 Squamous cell carcinoma accounts for more than 90% of the malignant tumours of the vulva and several morphological variants have been described including keratinising, basaloid, warty and verrucous carcinoma. Basaloid and warty variants representing about 1/3 of cases, are commoner in younger women, and are often associated with human papillomavirus (HPV) DNA detection. These tumours share many risk factors with cervical cancer. By contrast, keratinising variants arise from chronic vulvar dermatosis, such as lichen sclerosus, are not associated with HPV and tend to occur in older women. HPV associated vulvar cancers do not seem to differ in prognosis from HPV negative cases although data are scanty and based on few observations.6
HPV-DNA is currently identified in the majority of VIN lesions (>80%), while HPV detection amongst invasive vulvar carcinomas is generally estimated to be around 40% for overall histological variants. Data derived from meta-analysis show that HPV-DNA detection in invasive warty/basaloid tumours is more frequent (69.4%) than in invasive keratinising types (13.3%).7 HPV related vulvar neoplasia is mainly associated to HPV 16 contributing to a larger proportion compared to that observed for cervical cancer.7, 8, 9, 10 Previous reports have however been limited by the wide range of HPV assays used and by a potential publication bias towards HPV positive cases. A recent study on formalin fixed paraffin embedded cases (FFPE) retrieved from an archival in the US has reported a 36% HPV detection in IVC and 76% in VIN lesions.11
The objective of this international collaborative study was to evaluate the HPV contribution and genotype distribution in IVC and VIN lesions from pathological archives in 39 countries from five continents. The consortium included a common standard protocol and a sensitive assay was used for HPV-DNA detection (SPF10/DEIA/LiPA25 system). IVC cases were further largely tested for the cyclin-dependent kinase-4 inhibitor (p16INK4a) which has shown to be overexpressed in at least 90% of VIN and HPV related IVC cases.12, 13, 14 Cases in which HPV-DNA is detected but with no overexpression of p16INK4a could represent a transient infection with no role in carcinogenesis. The use of p16INK4a in combination with HPV-DNA detection is becoming a common recommended ancillary test for research and clinical studies when HPV is not a necessary cause.15, 16, 17
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Study design and materials
The project was designed and coordinated by the Catalan Institute of Oncology (ICO) in Barcelona, Spain in collaboration with DDL Diagnostic Laboratory in Rijswijk, The Netherlands. The study started in 2007 as a retrospective cross-sectional survey to estimate the prevalence of HPV-DNA and type distribution in vulvar cancers and high grade pre-neoplastic lesions for the 30-year period 1980–2011. Case recruitment protocols were similar to the previously described in a similar study for cervical
Results
Table 1 describes the cases included in the study by histology categories. A total of 587 VIN cases and of 1709 IVC cases were included in the study. The majority of VIN was WB type (91.1%) and IVC cases were largely SCC keratinising (72.2%). IVC SCC_WB accounted for 19.1% of the cases (Table 1). IVC patients were, on average, significantly older than VIN cases (68.5 versus 49.5 years, p < 0.05).
VIN cases were more likely to originate from Europe, America and Australia and to be diagnosed in the
Discussion
This is the largest study on HPV contribution and type distribution in IVC using standardised protocols and highly sensitive HPV testing technology. It provides a robust HPV genotype worldwide reference data and, probably, the best available HPV driven estimates for this relatively rare cancer. This analysis confirms the predominant contribution of HPV 16 to the aetiology of HPV related vulvar cancer and VIN and suggests that other HPV types, such as HPV 33, HPV 18 and HPV 45, which are common
Sponsorship
The study has been partially supported by grants from the Instituto de Salud Carlos III (Spanish Government, Grants RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056, and CIBERESP), from the Agència de Gestió d’Ajuts Universitaris i de Recerca (Catalan Government, Grants AGAUR 2005SGR 00695 and 2009SGR126), Stiching Pathologie Ontwikkeling en Onderzoek (SPOO) foundation (The Netherlands), NHS Cervical Screening Programme (United Kingdom) and the Lilly Foundation (Premio de
Role of the funding source
The sponsors did not have any role in the study design and collection, analysis or interpretation of the data. None of the sponsors had access to the row data. The corresponding author had full access to all the data, and had the final responsibility to submit for publication.
Contribution
Study concept: Silvia de Sanjosé, Laia Alemany, Belén Lloveras, Wim G.V. Quint, Nubia Muñoz, F. Xavier Bosch.
Study design: Silvia de Sanjosé, Laia Alemany, Belén Lloveras, Wim G.V. Quint, Nubia Muñoz, F. Xavier Bosch.
Data acquisition: Maria Alejo, Susan M. Bigby, Elmar Armin Joura, Paula Maldonado, Jan Laco, Ignacio G. Bravo, August Vidal, Núria Guimerà, Paul Cross, Gerard V. Wain, Karl Ulrich Petry, Mariani Luciano, Christine Bergeron, Václav Mandys, Adela Rosa Sica, Ana Félix, Alp Usubutun,
Conflict of interest statement
The corresponding author has received occasional travel grants from Merck and Qiagen and holds a restricted grant from Qiagen and from Merck not related to the study presented. The senior author F. Xavier Bosch is in the Advisory Board (Merck and Co., Inc.); Speakers Bureau (GlaxoSmithKline); has received Institutional Research Grants (Merck and Co., Inc., Sanofi Pasteur MSD, GlaxoSmithKline).
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See Appendix for ‘HPV VVAP study group for vulvar site’.