Demonstration of human papillomavirus DNA and the increased proliferating cell nuclear antigen (PCNA) in skin biopsies of patients with severe, treatment-resistant atopic dermatitis

Y Niwa MD PhD^a, H Sumi MD^b, T Terashima MD^a, T Nakamura MD^a, H Akamatsu MD^c

^aNiwa Institute for Immunology, Tosashimizu, Kochi, Japan, ^bDepartment of Internal Medicine, National Cancer Center Hospital East, Kashiwa, Japan, ^cDepartment of Dermatology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

AIM: The incidence of atopic dermatitis has increased in Japan, along with the number of patients with severe and treatment-resistant atopic dermatitis especially in urban and industrial areas (Arch Dermatol 130: 1387, 1994; Br J Dermatol 132: 772, 1995). We have reported that these changes could be due to increased reactive oxygen species (ROS) generated from environmental pollution including nitrogen oxide mainly produced from industrial petroleum and by exhaust from automobiles and solar radiation increased by breaks in the earth’s ozone layer: increased exposure to high concentrations of environmental ROS produces excessive epidermal lipid peroxides by reacting with unsaturated fatty acids, promoting loss of skin moisturization, which is one of the hallmarks of atopic dermatitis (Arch Dermatol 130: 1387, 1994). We have further described that environmentally generated ROS induced oxidative protein damage in the stratum corneum, leading to the disruption of barrier function and exacerbation of atopic dermatitis (Br J Dermatol 149: 248, 2003). Among 4,738 patients with severe, corticosteroid-resistant atopic dermatitis treated in our hospital during these five years, five patients developed skin malignancy. Because atopic dermatitis patients are known to be susceptible to cutaneous viral infections, we suspected that an oncogenic viral infection may account for this case clustering. METHODS: We examined the presence of oncogene DNA from human papillomavirus (HPV) using polymerase chain reaction (PCR), and the potentiation of DNA production using monoclonal antibody against proliferating cell nuclear antigen (PCNA) in skin biopsies of 110 patients with the most severe and treatment-resistant atopic dermatitis. RESULTS: In 26 of these cases, oncogene of DNA from the E6 and/or E7 regions of HPV types 16 and/or 18 was demonstrated. Labeling index (LI) of PCNA-positive cells was 32.2% in these biopsies, compared with 8.9% in normal skin from healthy controls. CONCLUSIONS: Since the LI of staining for PCNA, which is a cofactor of DNA polymerase-delta and is essential for cell proliferation can be helpful in the early diagnosis of skin malignancies (Arch Dermatol Res 291: 413, 1999), the patients with severe atopic dermatitis appear to be at increased risk for skin malignancy through several mechanisms including high exposure to environmentally produced ROS which can be good candidates for both the cause for severe and treatment-resistant atopic dermatitis, and initiator and promoter of malignancy.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 996 (Genetic & environmental interactions).