Infection with high-risk human papillomavirus (HPV) is necessary for the development of a cervical lesion, but only a fraction of precursor lesions progress to cancer. Additional factors, other than HPV type per se, are likely to increase the probability for progression. Intratype genome variations have been reported to be associated with viral persistence and the development of a major cervical disease. We have recently shown that the prevalence of specific HPV16-E6 variants in invasive cervical cancer (ICC) varies between Italian and Swedish women. To extend our initial study we have analyzed E6 variants in cervical lesions from Czech women, ranging from low-grade cervical intraepithelial neoplasia (LCIN) to ICC and scaled up the sample size of our initial study of Swedish and Italian women. In addition, we have correlated the cases of cancers with human leukocyte antigen (HLA) class II haplotypes. In line with our earlier observation, the distribution of specific HPV16-E6 genotypes in CIN and ICC varied in the 3 cohorts. For instance, the HPV16-E6 L83V variant, which has been found to be positively associated with ICC in Swedish women (p ‫؍‬ 0.002), was more prevalent in LCIN than in ICC in Italian and Czech women (p ‫؍‬ 0.01 and ‫؍‬ 0.03, respectively). These data indicate that host genetic factors, such as HLA polymorphism, may determine the potential oncogenicity of the HPV16-E6 L83V variant. Indeed, the DR04-DQ03 haplotype, which is approximately 3-fold more abundant in the normal Swedish population than in those in Italy and the Czech Republic, was found to be positively associated with HPV16-E6 L83V in the 3 cohorts investigated (p ‫؍‬ 0.01). This observation may explain why L83V is a risk factor more in Sweden than in the other 2 countries. © 2001 Wiley-Liss, Inc. Key words: HPV16; E6 and E7 genotypes; polymorphism; cervical lesion; human leukocyte antigenCertain human papillomavirus (HPV) genotypes are etiologic agents for cervical cancer development. 1 HPV16 is the most frequently detected genotype in cervical carcinoma and its precursors. [2][3][4][5] Biochemical data have demonstrated that the products of 2 early genes, E6 and E7, are the major oncoproteins of HPV16. 6 HPV16 E6 and E7 associate with and inactivate the biologic function of several cellular proteins, including the regulators of cell cycle checkpoints, p53 and pRb. 7 Infection with high-risk HPV is the principal risk factor for the development of an invasive lesion. However, most HPV infections regress spontaneously and, for the cases that do progress to cancer, a long period of latency is normally required. It is clear that additional risk factors play a role in disease progression. Recently, independent studies have provided evidence that specific intratype HPV genome variations may influence the persistence of the infection and the progression of a precursor lesion to cancer. 8 -10 Several North American and South American studies have shown that nonprototype-like HPV16 variants, which harbor several nucleotide changes within the...

Because the biological spectrum of human papillomavirus (HPV) genotypes present in cervical cancer lesions varies according to the geographical region studied, and because little genotype information is available for Central and Eastern European countries, we studied the endemic HPV-genotype spectrum in cervical samples collected from women visiting gynaecological departments of selected hospitals in the Czech Republic. In a series of 389 samples, 171 (44.0%) were positive for HPV DNA using a consensus-primer polymerase chain reaction (PCR). Genotyping of the HPV PCR products was done using dot-blot hybridisation with type-specific oligonucleotide probes and thermocycle DNA sequencing. Twenty-two different HPV types were detected, HPV-16 being the most prevalent type irrespective of severity of the lesions (55.0%). Multiple HPV types were found in 16.4% of our HPV-DNA-positive samples. The prevalence of HPV infection was 23.0% in women with normal findings and 59.4% in patients with cervical neoplasia, and increased significantly with the severity of the disease: 52.9% in low-grade lesions, 58.0% in high-grade lesions, and 73.5% in cervical carcinomas (P for trend < .00001). In the sera of 191 subjects, 89 with normal findings and 102 with different forms of cervical neoplasia, the prevalence of HPV-specific IgG antibodies was tested by an enzyme-linked immunosorbent assay (ELISA) using virus-like particles (VLPs) of HPV-16, -18, and -33. Antibodies were significantly more prevalent in HPV-DNA-positive than in HPV-DNA-negative women and there was no association with age. In agreement with the results of HPV genotyping, antibodies reactive with HPV-16 VLPs were the most frequent and, moreover, their prevalence increased with the cervical lesion severity. About half of the subjects with smears in which either HPV-16 or HPV-33 DNA had been detected possessed antibodies reactive with homotypic VLPs. With HPV-18-DNA-positive subjects, however, fewer than 25% displayed homotypic antibodies. In general, subjects older than 30 years of age had antibodies reactive to HPV-specific VLPs more often than subjects younger than 30 years of age. In women with benign findings, the seropositivity to HPV-16, -18, and -33 VLPs increased with age, whereas in women with cervical neoplasia the seropositivity decreased with age.

The principal aims of this study were to test whether persistence of human papillomavirus (HPV) DNA is predictive of recurrent disease in women after surgical treatment for cervical lesions, to distinguish between persistent and newly acquired HPV infection, and to observe the effect of surgical treatment on levels of HPV-specific antibodies. A group of 198 patients surgically treated for low-grade and high-grade squamous intraepithelial lesions and 35 age-matched controls were monitored for 18 months at 6-month intervals. The presence of HPV DNA in cervical smears was detected by means of consensus polymerase chain reaction, and serum levels of HPV-specific antibodies to HPV types 16, 18, 31, 33, and 45 were measured. In ten patients positive for HPV type 16 in consecutive samples, the HPV 16 variants were identified using a polymerase chain reaction specific for the long control region. Data regarding demographics, risk factors for cervical cancer, and risks related to HPV exposure were collected through a patient questionnaire. Subjects persistently positive for HPV DNA were more likely to present with cytological and/or colposcopical abnormalities. A higher reactivity to HPV-specific antibodies was observed in these women at the 18-month follow-up visit. All ten patients with HPV 16 infection detected in consecutive samples showed persistence of either the same prototype or the same variant during the follow-up period. Risky sexual behavior and smoking were more common in patients than in controls. Persistent HPV infection as demonstrated by both HPV DNA detection and antibody detection appears to be a risk factor for the recurrence of pathological findings in women after surgery. An individually based approach to surgical treatment is an important factor in the outcome of disease at follow-up.

We report a case of reactive syringofibroadenomatous hyperplasia in peristomal skin. The patient was a 62-year-old woman who had undergone abdominoperineal resection of the rectum for rectal adenocarcinoma with subsequent colostomy 2 years earlier. Clinically, a nodule and small, whitish, warty lesions developed at the outer margin of the stoma extending onto the adjacent skin. Following a clinical suspicion of adenocarcinoma, recurrent at the colostomy site, a 5 x 4 x 3-cm excision of the peristomal skin and the affected portion of the stoma was performed and submitted for histologic examination. The biopsy revealed a peculiar composite lesion of reactive syringofibroadenomatous hyperplasia and the excised part of the stoma. Several unusual histopathological features were detected in the syringofibroadenomatous part of the lesion such as the formation of plentiful hybrid epidermal-colonic mucosa glandular structures, intraepidermal areas of sebaceous differentiation, koilocytic changes, induction of rudimentary hair follicles, and intradermal mucinous lakes. The cellular composition of the glandular structures was mainly similar to that seen in a normal colonic mucosa epithelium. They also contained occasional Paneth cells. Being located at a distance from the stoma, these accentuated colonic mucosa epithelial glands reaching the epidermis may be a diagnostic pitfall prompting the consideration of adenocarcinoma involving the stoma. The rudimentary follicles and sebaceous differentiation were probably induced by an altered stroma and/or human papillomavirus (HPV): HPV, type 36 was identified by PCR using consensus primers followed by sequencing of the PCR products.

High-risk mucosal human papillomaviruses encode an E6 oncoprotein, which binds the cellular p53 tumor suppressor protein, thereby marking it for degradation through the ubiquitin-mediated pathway. A common p53 polymorphism at codon-72 of exon 4 results in translation to either arginine or proline. Recently reported data suggested an increased susceptibility to E6/ubiquitin-mediated degradation of the Arg72-p53 isoform and an over-representation of the homozygous Arg72-p53 genotype in cervical cancer patients. We have analyzed this polymorphism in a larger series of patients with cervical cancer and in controls in the Czech Republic. We found no statistically significant differences between the codon-72 p53 genotypes of cervical cancer patients and the control women. Based on these results, it is unlikely that Arg72-p53 is associated with an increased risk for human papillomavirus-associated cervical tumor development in Czech women.