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Variants of Squamous Cell Carcinoma of the Anal Canal and Perianal Skin and Their Relation to Human Papillomaviruses¹

Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institut, DK-2300 Copenhagen S, Denmark [M. F., P. S., M. M.]; Department of Pathology, Odense University Hospital, DK-5000 Odense, Denmark [C. F.]; Department of Pathology, Section for Molecular Pathology, University Hospital Vrije Universiteit, 1081 HV Amsterdam, the Netherlands [A. J. C. v. d. B., C. J. L. M. M., J. M. M. W.]; Department of Medical Epidemiology, Karolinska Institute, S-17177 Stockholm, Sweden [H-O. A.]; Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard University, Boston, Massachusetts 02115 [H-O. A.]; and Department of Oncology, Radiology and Clinical Immunology, University Hospital, 5-75185 Uppsala, Sweden [B. G.]

High-risk types of human papillomaviruses (hrHPVs) may be a necessary cause in cervical cancer and in some subtype of anal, vulvar, and penile cancers. Large studies aimed at characterizing hrHPV-associated and non-hrHPV-associated subtypes of anal carcinomas are, however, lacking. We searched for human papillomavirus type 16 and 13 other hrHPVs in tumor tissue by PCR and performed a systematic histological evaluation of specimens from 386 patients with anal cancer (86% invasive; 302 women and 84 men). Cancers in women and homosexual men were more often hrHPV positive (P < 0.01) and located in the anal canal (P 0.01) than were cancers in heterosexual men. In both women and men, anal canal cancers contained hrHPV clearly more often than did perianal skin cancers, and increasing hrHPV positivity was seen with higher localization in the anal canal. Indeed, 95 and 83% of cancers involving the anal canal in women and men, respectively, were hrHPV positive versus 80 and 28% of perianal skin cancers (P-trend < 0.001). Basaloid feature, adjacent anal intraepithelial neoplasia, poor or absent keratinization, and a predominance of small or medium neoplastic cells were all strongly positively associated with hrHPV status. Like cancer of the uterine cervix, the development of cancer of the anal canal may require infection with hrHPV, whereas a dual etiology of perianal skin cancers bears parallels to vulvar and penile cancers.

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