Effect of Anal Epidermoid Cancer-related Viruses on the Dendritic (Langerhans’) Cells of the Human Anal Mucosa 1 Iradj Sobhani, 2 Francine Walker, Thomas Aparicio, Laurent Abramowitz, Dominique Henin, Anne C. Cremieux, and Jean Claude Soule Department of Gastroenterology and Oncology [I. S., F. W., T. A., L. A., D. H., J. C. S.]; INSERM Unite ´ 410 [I. S., F. W., T. A., J. C. S.]; and Centre de Diagnostic Anonyme et Gratuit [A. C. C.], Ho ˆpital Bichat-Claude Bernard 75877 Paris Cedex 18, France ABSTRACT Purpose: The incidence of anal cancer is high in patients with anal condyloma. HIV increases this risk. We analyzed anal mucosa from normal individuals and individuals with condyloma. Experimental Design: Normal anal mucosa from 155 consecutively recruited patients (102 HIV-positive and 53 HIV-negative) with anal condyloma was compared with that obtained from 30 HIV-negative patients after hemorrhoid surgery (controls). Langerhans’ cells (LCs), T lymphocytes, and viruses [EBV, cytomegalovirus, herpes simplex virus 1, and human papillomavirus (HPV) types] in anal mucosa and HIV load and CD4 T-lymphocyte counts in the serum were characterized. Results: None of the control individuals had anal squa- mous intraepithelial lesion or HPV versus 19 HIV-positive and 4 HIV-negative patients with anal condyloma (P  0.07). The number of LCs/mm in anal tissue was signifi- cantly higher in HIV-negative patients with condylomata (median, 30; range, 2–130) than in HIV-positive patients (median, 15; range, 0 –100) or in controls (median, 17; range, 4 –35). In HIV-negative individuals, the occurrence of condylomata was linked with a higher number of LCs. Significant differences were observed between HIV-positive and HIV-negative patients with anal condylomata:number of LCs/mm anal tissue, oncogenic HPV (26% versus 8%), other current infections (35.6% versus 5%), being male (93% versus 74%). Multivariate regression analysis found HIV as the only risk factor for a decrease in the number of LCs (odds ratio, 6; 95% confidence interval, 2.28 –16.1; P < 0.001) and the serum HIV load (odds ratio, 4.9; 95% confi- dence interval, 1.1–21.4 log/ml; P < 0.03) but not the serum CD4 T-lymphocyte rate as a predictive risk factor for having <17 LCs/mm tissue. Conclusion: HPV increases the number of LCs in anal mucosa in HIV-negative individuals. HIV alters anal den- dritic cells, likely leading to an increase in anal cancer risk. INTRODUCTION HPV 3 is widespread in the homosexual population and causes anal condyloma. This lesion is considered to be a major epidemiological marker of individual risk for anal cancer (1– 6). Indeed, squamous cell carcinoma is a rare neoplasm of the anal mucosa in the general population, and its incidence in homo- sexual, HIV-infected, and immunocompromised individuals is increasing (7–9). Anal condylomata increases the relative risk of anal carcinomas by 11.7 in women and by 8 in men (3). HIV is another widespread infection in the homosexual population. It increases the relative risk of anal carcinoma by 1.7 in women and 3.1 in men (3). Furthermore, the frequency of relapses is significantly higher in HIV-positive patients than in HIV-negative individuals (10, 11). The mechanism by which these two viruses induce anal carcinoma is unknown. HPV seems to induce high-grade dys- plasia (HGSIL), probably by integrating into host DNA and/or inhibiting the p53 protein (12). HIV is thought to cause anal carcinoma by increasing the activity of HPV, particularly onco- genic types, by inducing acquired immunodeficiency syndrome (11). It is not clear whether and how the tissue immunity of the anal mucosa is altered in individuals infected with HIV and HPV. We addressed these issues by conducting a comparative study in consecutively recruited patients with anal condyloma. The anal lesions were resected in all cases and histologically analyzed. We also compared the number of immune cells, specially dendritic cells (also called LCs) in samples of normal anal mucosa from these patients with the number of immune cells in anal mucosa taken from healthy individuals undergoing surgery for hemorrhoids. We used statistical analyses to look at the effect of HIV status, HPV status, HPV oncogenic type, and systemic and anal mucosal immunity in the different groups. PATIENTS AND METHODS Patients and Study Design All patients referred to the Departments of Coloproctology, Dermatology, or Sexually Transmitted Diseases of Bichat Hos- Received 12/19/01; revised 5/10/02; accepted 5/17/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by Agence Nationale de Recherche sur le SIDA, Project 94056, Promotion AP 940422, and Socie ´te ´ Nationale Franc ¸aise de Gastro-Ente ´rologie. 2 To whom requests for reprints should be addressed, at Service de Gastroenterologie, 46 Rue H. Huchard, 75877 Paris Cedex 18, France. Phone: 33-1-40-25-72-01; Fax: 33-1-40-25-87-83; E-mail: iradj.sobhani@ bch.ap-hop-paris.fr. 3 The abbreviations used are: HPV, human papillomavirus; HGSIL, high-grade squamous intraepithelial lesion; LC, Langerhans’ cells; BMI, body mass index; CMV, cytomegalovirus; ASIL, anal squamous intra- epithelial lesion; HSV, human simplex virus; ISH, in situ hybridization; OR, odds ratio; CI, confidence interval. 2862 Vol. 8, 2862–2869, September 2002 Clinical Cancer Research