Human papillomavirus infection with particular reference to genital disease.

HPV is the commonest sexually transmitted viral infection in the United Kingdom and as such poses a major public health problem. In addition to the potential physical morbidity associated with genital warts, abnormal cervical cytology, and anogenital dysplasia and neoplasia, the associated psychological morbidity should not be forgotten. Although our knowledge of viral function and disease pathogenesis has advanced appreciably in recent years, we are still some way from developing an in vitro method of viral propagation. Vaccination against HPV infection will hopefully be achieved within the next 10 years, but a prevention and treatment strategy which is appropriate for both developed and developing nations must be our major long term goal.     

Human papillomavirus infection and cervical cancer in Latin America

To evaluate a possible association between infection with human papillomavirus (HPV) and cervical cancer, we performed a multicenter case-control study in Latin America of 759 cases of invasive cervical cancer and 1467 randomly selected age-matched controls. Demographic, sexual, behavioral, and other clinical data were obtained by interview, and HPV DNA was assayed in cervical-swab specimens with use of filter in situ hybridization. Cervical infection with HPV 16 or 18 or both was strongly associated with cervical cancer. HPV DNA was detected in 62 percent of the cases but only 32 percent of the controls, and the relative risk of cancer increased from 2.1 (95 percent confidence interval, 1.6 to 2.8) to 9.1 (6.1 to 13.6) with hybridization reactions of increasing strength. Although the number of sexual partners, age at first intercourse, number of live births, and Pap-smear history were also significant risk factors, the strong associations between infection with HPV 16 or 18 or both and cervical cancer persisted after we adjusted for these variables. These observations are consistent with the hypothesis that genital infection with HPV 16 or 18 may have a role in the pathogenesis of cervical cancer. Other well-known risk factors were also identified in the study, but they did not affect the association between HPV and cervical cancer.     

Human papillomavirus infection in non-neoplastic uterine cervical disease in Hong Kong.

The polymerase chain reaction (PCR) was used to detect and identify human papillomavirus (HPV) in 108 cases of formalin-fixed, paraffin-embedded, non-neoplastic uterine cervical biopsy tissue retrieved from the surgical pathology archives of the Department of Pathology, Caritas Medical Centre, Hong Kong. After DNA extraction, HPV L1 gene primers were used to detect the presence of HPV, and type-specific primers (to HPV types 6, 11, 16, 18, 31 and 33) were used to identify the specific HPV type on HPV L1-positive cases. PCR amplification of the beta-globin gene was used to ensure the quality of amplifiable DNA extracted. Of 94 cases that yielded sufficient good-quality DNA for PCR analysis, three (one endocervical polyp, one chronic inflammation with erosion, and a normal biopsy) had detectable HPV infection. Two of these had high-risk HPV type 16; the other had an uncommon HPV type. In view of the low incidence of HPV found in these patients, large-scale population screening of clinical samples using PCR to detect the presence of HPV and identify high-risk asymptomatic patients would not be cost-effective.     

Cytologic and morphologic characteristics of human papillomavirus infection in cervix uteri pathology]

The role of human papilloma virus (HPV) in genital cancer is not yet clear at present, but the available data testify to serious changes in cervix uteri epithelium in the process of its infection. Close correlation was demonstrated between HPV type specificity and the degree of epithelial morphological changes as well as histologic tumor variant, and its degree of differentiation. Interrelation between HPV type and level of both regression and progression of atypically changed cervix uteri epithelium is established. Cytomorphological method of the evaluation of cell koilocytotic atypia is the marker to diagnose HPV infection when screening a chosen woman population. The development and introducing of sensitive and reliable identification methods of type-specific DNA sequences of HPV infection in diagnostic material to form a low risk (HPV-6 and II types) and a high risk group (HPV-16 and 18 types) by malignancy of cervix uteri epithelium have considerable promise. It is advisable to study HPV role in the development of adenogenic tumors of uterine cervix and body.     

Human papillomavirus infection, centrosome aberration, and genetic stability in cervical lesions.

DNA replication and centrosome duplication have to be strictly synchronized to guarantee genomic stability. p53, pRb, cyclin E, and cyclin A are reported to be involved in the synchronizing process. We investigated the relationship between papillomavirus infection, centrosome aberration and aneuploidy during genesis of cervical carcinoma. The number of centrosomes found in cells from normal cervical epithelium (n = 5), condyloma acuminata (n = 5), cervical intraepithelial neoplasia (CIN) I, II, and III (n = 14) and invasive cervical carcinoma (n = 5) was analyzed by gamma tubulin immunofluorescence staining. The nuclear DNA content was investigated by image cytometry and human papillomavirus (HPV) infection was determined by polymerase chain reaction. Normal epithelia and condyloma acuminata showed cells with one or two centrosomes, whereas CIN lesions showed cells with an increasing number of centrosomes. This abnormality was found to be lowest in CIN I lesions, increased with advancing grade of CIN and was highest in lesions of invasive carcinomas. In parallel, an increasing number of cells with aberrant DNA content was seen. All carcinomas and all except one of the CIN III lesions showed aneuploidy. Three CIN II cases were aneuploid and two cases with CIN I were tetraploid. Normal epithelia and condyloma acuminata showed diploidy. All invasive carcinomas and lesions with CIN were positive for high-risk HPV types 16, 18, or 31, except one invasive carcinoma and one CIN II lesion positive for universal primers only. Three condyloma acuminata were HPV 16-positive and one HPV 6-positive. The results suggest that high-risk HPV infection is correlated to a progressive numerical disturbance of centrosome replication followed by progressive chromosomal aberrations in CIN lesions and invasive carcinomas.     

Human papillomavirus infection of the uterine cervix. Tissue sampling and laboratory methods affect correlations between infection rates and dysplasia.

Two common tissue sampling techniques--colposcopic biopsy and cervical scrape--and two common human papillomavirus (HPV) detection techniques--Southern blot and dot blot (SB and ViraPap [VP])--were compared to determine whether differences in these techniques alter correlations between "oncogenic" HPVs and cervical neoplasia. In 87 women with persistently abnormal Papanicolaou (Pap) smears, concurrent biopsy and scrape specimens contained HPV in 21 (24%) and contained no HPV in 26 (30%); 30 scrape specimens (34.5%) tested positive when the biopsy tested negative and 10 (11.5%) scrape specimens tested negative when the biopsy tested positive (overall concordance, 54%). Concordance for the most prevalent HPVs (16/18) was 59%. In carcinoma in situ, HPV was found in biopsy samples significantly more frequently than in scrape specimens: 17 of 23 (75%) biopsy samples versus 9 of 23 (39%) scrape specimens (P = 0.018). Conversely, in mild or no dysplasia, 0 of 42 biopsy samples tested positive for HPV 16/18 compared with 12 of 42 scrape specimens (29%; P = 0.0001). Of 229 specimens analyzed by SB and VP, 43 (19%) tested positive and 148 (65%) tested negative for HPV by both methods (concordance, 84%). Corroborative results indicated that 29 of 35 (83%) VP-positive SB-negative results were truly positive compared with none of three SB-positive VP-negative results. Both the cervical sampling technique and the method for HPV detection can significantly affect statistical correlations between cervical dysplasia and HPV type.     

Human papillomavirus infection and gastric cancer risk: A meta-epidemiological review

Gastric cancer (GC) is a multifactorial disease, and several modifiable risk factors have been reported. This review summarizes and interprets two previous quantitative systematic reviews evaluating the association between human papillomavirus (HPV) infection and GC risk. The results of two systematic reviews evaluating the same hypothesis showed a statistically significant difference in summary odds ratios and their 95% confidence intervals. Thus, it is necessary to conduct a subgroup analysis of Chinese and non-Chinese studies. Additional meta-analyses that control for heterogeneity are required. Reanalysis showed that all the Chinese studies had statistical significance, whereas the non-national studies did not. The funnel plot asymmetry and Egger's test confirmed publication bias in the Chinese studies. In addition, the proportion of HPV-positive cases in Chinese studies was 1.43 times higher than that in non-Chinese studies and 2.81 times lower in controls. Therefore, the deduced evidence is currently insufficient to conclude that HPV infection is associated with GC risk.     

Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals

The role of human papillomavirus (HPV) in anogenital carcinogenesis is established firmly, but a similar role in non-melanoma skin cancer remains speculative. Certain immunosuppressed individuals have an increased incidence of both viral warts and non-melanoma skin cancer, that has prompted the suggestion that HPV may play a pathogenic role. Differences in the techniques used to detect HPV DNA in skin, however, have led to discrepancies in the prevalence and spectrum of HPV types reported in these malignancies. This study describes the use of a comprehensive degenerate PCR technique to compare the HPV status of 148 Non-melanoma skin cancers from immunosuppressed and immunocompetent individuals. HPV DNA was detected in 37/44 (84.1%) squamous cell carcinomas, 18/24 (75%) basal cell carcinomas and 15/17 (88.2%) premalignant skin lesions from the immunosuppressed group compared with 6/22 (27.2%) squamous cell carcinomas, 11/30 (36.7%) basal cell carcinomas and 6/11 (54. 4%) premalignancies in the immunocompetent group. Epidermodysplasia verruciformis HPV types prevailed in all lesion types from both groups of patients. In immunosuppressed individuals, cutaneous HPV types were also identified at high frequency, and co-detection of multiple HPV types within single tumours was commonly observed. This study represents the largest and most comprehensive analysis of the HPV status of non-melanoma skin cancers yet undertaken; whereas there are clearly significant differences in non-melanoma skin cancers from immunosuppressed and immunocompetent populations, we provide evidence that the prevalence and spectrum of HPV types does not differ in squamous cell carcinomas, basal cell carcinomas or premalignancies within the two populations. These data have important implications for future investigation of the role of HPV in cutaneous carcinogenesis at a functional level.     

人乳头瘤病毒16型内变异株与宫颈病变

目的 研究患宫颈上皮内瘤变（Cervical intraepithelial neoplasia,CIN）的汉族妇女中人乳头瘤病毒（Human papillomavirus,HPV）16型内变异株的类型及其在临床上的意义.方法 随机收集中日友好医院妇科门诊就诊的77例感染HPV16的汉族患者的宫颈脱落细胞DNA,用PCR法扩增HPV16型包含E6和E7基因的DNA片段并测序.通过对测序得到的E6基因序列与GenBank下载的参考株的比对,研究77例汉族患者中HPV16变异株的类型并探讨其与CIN的关系.结果 纳入研究的77例患者中,最小年龄21岁,最大年龄56岁,平均年龄36.39±6.86岁.其中,CIN Ⅱ级以下病变16例（占比20.8%）,CIN Ⅱ级及以上病变61例（占比79.2%）.HPV16型内变异株只有亚洲株和欧洲株两种,亚洲株38例,欧洲株39例.经χ^2检验,χ^2=0.0034,P〉0.05,尚不支持亚洲株与欧洲株的致癌作用不同.结论 虽然本研究未发现HPV16型亚洲株与欧洲株的致癌作用不同,但本研究发现77例汉族患者感染的HPV16型内变异株以亚洲株和欧洲株为主,故我们有理由推测,HPV16型内变异株在我国汉族妇女中的分布以亚洲株和欧洲株为主,而其他变异株,特别是高致癌的亚美株并不常见.     

Melanosis of the vagina and human papillomavirus infection, an uncommon pathology: case report

Benign melanotic lesions of the vagina are uncommon and only a few cases have been reported in the literature. A 34-year-old woman was referred because of a Vaginal Intraepithelial Neoplasia 1 biopsy result. On the gynecological examination, two different hyperpigmented areas were noted in the vagina. The colposcopic visualization of the cervix and vagina found an aceto-white lesion at the right lateral wall of the upper third of the vagina. Biopsies from three areas were taken. Histological study reported a melanosis of the vagina and HPV infection. An immunohistochemical panel of epithelial markers was performed in vaginal samples, such as Cytokeratin AE1/AE3 and epithelial membrane antigen, mesenchymal marker: vimentin; melanocytic makers: protein S-100 and HMB45 (Human Melanoma Black); proliferating cell marker: proliferating cell nuclear antigen (PCNA), and P-53 oncoprotein. High Risk (16, 18, 31, 45) and Low Risk (6, 11) HPV types were studied by In Situ Hybridization using the same vaginal samples. CK, EMA and Vimentin were 2+. Melanocytic markers, HMB45 and S100, and PCNA were 1+ in basal cell layer. P-53 was negative. The melanotic tissue and acetowhite lesion were positives to HPV Types 6,11. In conclusion, melanosis of the vagina is a uncommon benign pathology. Usually, melanosis is present in women over 40 years old. We present a case of melanosis of the vagina in a young woman infected with low-risk HPV types and review the literature.     

Human papillomavirus and schistosomiasis associated bladder cancer.

AIMS: To determine the human papillomavirus DNA status of schistosomal associated squamous cell carcinoma of the urinary bladder in South Africa. METHODS: Twenty five archival samples of bladder squamous cell carcinoma associated with Schistosoma haematobium were subjected to non-isotopic in situ hybridisation and the polymerase chain reaction for the detection of human papillomavirus 6, 11, 16, 18, 31, and 33 genotypes. RESULTS: Using these two techniques, none of the 25 cases was shown to harbour human papillomavirus DNA. CONCLUSIONS: This study abrogates the role of human papillomavirus in schistosoma associated bladder carcinoma in South Africa. It is suggested that other factors including nitrosamine exposure, p53 mutation, and additional unknown chromosomal events play a major role in the development of this parasite associated neoplasm.     

Human papillomavirus infection and anal carcinoma. Retrospective analysis by in situ hybridization and the polymerase chain reaction.

To examine the association of human papillomavirus (HPV) infection with anal squamous cell carcinoma, the authors applied the highly sensitive polymerase chain reaction (PCR) and in situ hybridization (ISH) techniques to detect HPV DNA in formalin-fixed, paraffin-embedded tissues from 18 patients. The presence of HPV types 16/18 in 3 (16.7%) of 18 patients with anal carcinoma was found, using a colorimetric ISH technique for HPV types 6, 11, 16, 18, 31, 35, and 51. Results from one of these three patients were also positive for HPV 31, 35, 51 by ISH techniques. When the same series was analyzed using the PCR and consensus primers to the L1 open reading frame of the HPV genomes, the frequency of positive patients rose to 14 (77.8%) of 18. PCR analysis of the 14 lesions containing HPV DNA, using type-specific primers and probes for HPV 6, 11, 16, 18, and 33, showed that 1 contained HPV 6, 1 contained HPV 11, 4 contained HPV 16, 1 contained HPV 18, 1 contained HPV 33, 5 contained HPV of unclassified type(s), and 1 contained a mixture of three HPV types. There was concordance between typing of cases that were positive by ISH and PCR methods. These data agree with the concept that HPV, in particular type 16, is implicated in the pathogenesis of anal cancer.     

Human papillomavirus infection in urine samples from male renal transplant patients

Renal allograft recipients have a well‐documented increased incidence of human papillomavirus (HPV)‐related malignancies and preventive strategies should be specifically implemented. While in females the use of the Papanicolau test and HPV detection assay are used currently as a screening test for cervical cancer, no diagnostic procedures have been implemented to monitor HPV infection in males. The aim of this study was to test for HPV infection and to determine the spectrum of viral genotypes in urine samples of men with renal transplants. The study included 88 patients who underwent kidney transplantation between 1999 and 2005. HPV sequences were detected by nested PCR, using the broad‐spectrum consensus‐primer pairs MY09/MY11 and the new MGP system, and characterized by nucleotide sequence analysis. Overall, 43 (48.9%) samples were found positive for HPV sequences and the most common genotypes were HPV 16 (53.5%) and HPV 54 (9.3%) followed by HPV 6, 53, 56, 58, 66, 11, 12, 20, 45, 62, and 71, in descending order of prevalence. The majority of HPV 16 isolates were classified as European and only one as African‐1 variant on the basis of nucleotide signature present within the MGP L1 region. The high prevalence of HPV 16 among renal allograft recipients suggests that an HPV‐16‐based preventive or therapeutic vaccine may be effective for prevention or treatment of HPV‐related neoplasia in this group of immune compromised patients. J. Med. Virol. 82:1179–1185, 2010. © 2010 Wiley‐Liss, Inc.     

Human papillomavirus type 58 DNA sequence.

The complete nucleotide sequence of human papillomavirus type 58 (HPV 58) DNA cloned from an invasive cervical carcinoma was determined. The HPV 58 genome consists of 7824 nucleotides, containing 37.9% of GC residues, and has a similar genome organization of other HPVs. On the nucleotide sequence level, it conserves the signal sequences for regulation of gene expression as with other genital HPVs and exhibits an extensive homology with HPV 33 (77%). Comparative analysis of amino acid sequences reveals that HPV 58 is closely related with HPVs 16, 31, and 33, and is more distantly related with HPVs 6, 11, 18, and 39. HPVs 58, 16, 31, and 33 can be regarded as a group in HPV.     

Human papillomavirus infection, risk for subsequent development of cervical neoplasia and associated population attributable fraction.

BACKGROUND: Human papillomavirus (HPV) is the major cause of cervical neoplasia but estimates of the population attributable fraction (PAR%), of HPV vary. PAR% has not been derived from longitudinal studies although assessment of HPV exposure prior to the neoplasia diagnosis should increase validity of such estimates. AIMS: Systematic review and meta-analysis of longitudinal studies on HPV associated relative risk (RR) for and PAR% of HPV16 in cervical neoplasia. METHODS: Pertinent data from longitudinal studies was made available through Medline and substituted by various hand searches. HPV associated weighted mean RR, with 95% confidence interval (CI) of cervical neoplasia, and the PAR% of HPV16 in cervical carcinoma were estimated both for unselected and low HPV prevalence populations. RESULTS: HPV associated RR of cervical carcinoma in PCR-based studies was 17 (95% CI 8.2-33). HPV16 associated RRs in seroepidemiological studies were 3.3 (95% CI 2.2-4.9) for the unselected population, HPV16 seroprevalence 11.0%, and 12.5 (95% CI 5.5-29) for a population with low HPV16 seroprevalence of 5.3%. Corresponding PAR% estimates of HPV16 were 27 and 44%, respectively. CONCLUSION: Protective vaccination against HPV16 infection would prevent up to 44% of cervical carcinoma.