Low-risk human papillomaviruses (LR-HPVs) have been associated occasionally with clinically and pathologically unusual anogenital malignancies. The relation between clinicopathologic features and any pathogenetic role of LR-HPV remains unclear. From a global study of 13,328 anogenital carcinomas, we identified 57 cases in which whole-tissue polymerase chain reaction using SPF10-LiPA25 showed single LR-HPV infection. In 43/46 (93.5%) available carcinomas, multiple polymerase chain reaction assays confirmed single detection of HPV6, 11, 42, 44, or 70 DNA. In 75% (n=32) of these, LR-HPV DNA was confirmed in tumor cells by laser capture microdissection. In 2 cases, including 1 adenocarcinoma, viral DNA was only found outside the tumor. All anogenital tumors with confirmed HPV6/11 showed a distinctive range of papillary, warty or warty-basaloid, squamous, or transitional histology with patchy or negative p16INK4a expression. HPV6-associated cervical tumors occurred at a low median age. HPV42/70 was associated with typical squamous cell carcinoma showing diffuse p16INK4a staining like high-risk HPV–related malignancies. HPV44 was found in malignant cells in 1 case. Viral taxonomy and theoretical analysis show that HPV6/11 belong to a different genus from HPV42/70 with E6/E7 gene products that would not bind pRb or p53, whereas HPV42/70 could bind pRb. Our data support the causal involvement of LR-HPVs in the carcinogenesis of <2% of anogenital malignancies of 2 distinct clinicopathologic patterns related to the genetic structure of the HPV types 6/11 and 70/42. HPV42/70 was associated with typical squamous carcinomas. Importantly all carcinomas associated with HPV6/11 globally showed verruco-papillary, well-differentiated, squamous, or transitional histology without p16INK4a expression.
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*IDIBELL, Institut Català d’Oncologia, L’Hospitalet de Llobregat (Barcelona), Spain
†DDL Diagnostic Laboratory, Rijswijk, The Netherlands
‡Hospital del Mar, Barcelona, Spain
§CIBER en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
∥Consorci Sanitari Integral, Hospital General de l’Hospitalet, L’Hospitalet de Llobregat, (Barcelona), Spain
¶Instituto Nacional de Cancerología, Bogotá, Colombia
#Instituto de Patología e Investigación, Universidad Nacional de Asunción, Paraguay
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RIS HPV TT/HPV VVAPO study group is in supplementary data.
Author contributions: N.G., B.L., J.L., L.A., and W.Q. participated in the study design, data collection and analysis, interpretation of the results, and writing the report. N.M., S.d.S., F.X.B. participated in the study design, data collection, interpretation of the results, and writing the report. M.v.d.S., M.A., A.C., D.J., IG.B., and A.M. participated in the analysis, interpretation of the results, and writing the report. G.H-S. was involved in data collection and interpretation of the results. All authors provided approval of the final draft of the report.
Conflicts of Interest and Source of Funding: Partly supported by Spanish public grants from the Instituto de Salud Carlos III (grant numbers FIS PI030240, FIS PI061246, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095, RD12/0036/0056, and CIBERESP), Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR 2005SGR 00695 and 2009SGR126), Marató de TV3 Foundation (051530), Fundación Lilly, Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) foundation (The Netherlands) and GlaxoSmithKline Biologicals, Sanofi Pasteur MSD, and Merck & Co. Inc. The funders had no role in the data collection, analysis, or interpretation of the results. N.G. has received support for occasional travel by GlaxoSmithKline, Merck, and Qiagen. B.L. has received payment for lectures including service on speaker’s bureaus (personal) from Roche and Qiagen. J.L. has received grants from GlaxoSmithKline. L.A. has received support for travel to meetings for the study or other purposes (institutional) from Sanofi Pasteur MSD. M.v.d.S. has received grants from GlaxoSmithKline. M.A. has received support for occasional travel by Dako. G.H-S. has received an independent grant from MSD for epidemiological study related to genital warts in Colombia and payments from MSD for travel accommodation at the International HPV conference in Canada, 2011. A.M. has received grants from GlaxoSmithKline. D.J. has been previously an employee of GlaxoSmithKline and has received payment for consultancy from GlaxoSmithKline and MSD and grants from MSD. N.M. has received honoraria as member of Steering committees and HPV Global Advisory Board from Merck and Sanofi Pasteur MSD. S.d.S. has declared that her research unit is involved in vaccine trials organized by GlaxoSmithKline and Merck/Sanofi Pasteur MSD and investigator-driven research partially sponsored by GlaxoSmithKline and Merck/Sanofi Pasteur MSD. Travel fund to conferences/symposia/meetings are occasionally granted by either GlaxoSmithKline, Sanofi Pasteur MSD, or Qiagen. F.X.B. has received payment for Advisory Board (GlaxoSmithKline, Merck Sharp & Dohme, Sanofi Pasteur MSD); Speakers Bureau (GlaxoSmithKline); Research Grants (Merck Sharp & Dohme, Sanofi Pasteur MSD). My research unit is involved in vaccine trials organized by GlaxoSmithKline and Merck/Sanofi Pasteur MSD. Travel fund to conferences/symposia/meetings and honorarium are occasionally granted by GlaxoSmithKline, Merck, Sanofi Pasteur MSD, MTM, or Qiagen. W.Q. has received grants from GlaxoSmithKline. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Correspondence: Núria Guimerà, BSc, Unit of Infections and Cancer, Cancer Epidemiology Research Program, IDIBELL, Catalan Institute of Oncology, Av. Gran Via de l’Hospitalet, 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain (e-mail: email@example.com; firstname.lastname@example.org).