Differential HPV16 variant distribution in squamous cell carcinoma, adenocarcinoma and adenosquamous cell carcinoma.

Human Papillomavirus 16 (HPV16) causes 70% of invasive cervical cancers (ICC) worldwide. Interaction between HPV16 genetic diversity, host genetics and target tissue largely determine the chances to trigger carcinogenesis. We have analyzed the differential prevalence of viral variants in 233 HPV16-monoinfected squamous (SCC), glandular (ADC) and mixed (ADSC) ICCs from four continents, assessing the contribution of geographical origin and cancer histology. We have further quantified the contribution of viral variants and cancer histology to differences in age at tumor diagnosis. The model fitted to the data explained 97% of the total variance: the largest explanatory factors were differential abundance among HPV16 variants (78%) and their interaction with cancer histology (9.2%) and geography (10.1%). HPV16_A1-3 variants were more prevalent in SCC while HPV16_D variants were increased in glandular ICCs. We confirm further a non-random geographical structure of the viral variants distribution. ADCs were diagnosed at younger ages than SCCs, independently of the viral variant triggering carcinogenesis. HPV16 variants are differentially associated with histological ICCs types, and ADCs are systematically diagnosed in younger women. Our results have implications for the implementation of cervical cancer screening algorithms, to ensure proper early detection of elusive ADCs.

Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV) is a causal factor in virtually all cervical and a subset of oropharyngeal squamous cell carcinoma (OP-SCC), whereas its role in laryngeal squamous cell carcinoma (L-SCC) is unclear. METHODS: Formalin-fixed paraffin-embedded (N=154) and deep-frozen tissues (N=55) of 102 L-SCC patients were analysed for the presence of 51 mucosal HPV types. HPV DNA-positive (HPV DNA+) cases were analysed for E6*I mRNA transcripts of all high risk (HR)/probably/possibly (p)HR-HPV identified, and for HPV type 16 (HPV16) viral load. Expression of p16(INK4a), pRb, cyclin D1 and p53 was analysed by immunohistochemistry. RESULTS: Ninety-two patients were valid in DNA analysis, of which 32 (35%) had at least one HPV DNA+ sample. Among the 29 single infections, 22 (76%) were HPV16, 2 (7%) HPV56 and 1 each (4%) HPV45, HPV53, HPV70, HPV11 and HPV42. Three cases harboured HPV16 with HPV33 (twice) or HPV45. Only 32% of HPV DNA+ findings were reproducible. Among HPV16 DNA+ L-SCC, 2 out of 23 (9%) had high viral loads, 5 out of 25 (21%) expressed E6*I mRNA and 3 out of 21 (14%) showed high p16(INK4a) and low pRb expression (all three HPV16 RNA-positive), immunohistochemical marker combination not identified in any other HPV DNA+ or HPV DNA-negative (HPV DNA-) L-SCC, respectively. CONCLUSION: HPV type 16 has a causative role in a small subgroup of L-SCC (<5% in this German hospital series).

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women.

BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. METHODS: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. INTERPRETATION: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. FUNDING: GlaxoSmithKline Biologicals.

Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries.

Early age at first sexual intercourse (AFSI) has long been associated with an increased risk of invasive cervical carcinoma (ICC). Age at first pregnancy (AFP) and ICC have been investigated less, although AFSI and AFP are strongly interrelated in most developing countries. A pooled analysis of case-control studies on ICC from eight developing countries with 1864 cases and 1719 controls investigated the roles of AFSI, AFP, and ICC risk. Age at first sexual intercourse, AFP and age at first marriage (AFM) were highly interrelated and had similar ICC risk estimates. Compared with women with AFSI > or = 21 years, the odds ratio (OR) of ICC was 1.80 (95% CI: 1.50-2.39) among women with AFSI 17-20 years and 2.31 (95% CI: 1.85-2.87) for AFSI < or = 16 years (P-trend <0.001). No statistical interaction was detected between AFSI and any established risk factors for ICC. The ICC risk was 2.4-fold among those who reported AFSI and AFP at < or = 16 years compared with those with AFSI and AFP at > or = 21 years. These data confirm AFSI and AFB as risk factors for ICC in eight developing countries, but any independent effects of these two events could not be distinguished.

Expression of simple epithelial type cytokeratins in stratified epithelia as detected by immunolocalization and hybridization in situ.

Multi-layered ("stratified") epithelia differ from one-layered ("simple") polar epithelia by various architectural and functional properties as well as by their cytoskeletal complements, notably a set of cytokeratins characteristic of stratified tissue. The simple epithelial cytokeratins 8 and 18 have so far not been detected in any stratified epithelium. Using specific monoclonal antibodies we have noted, in several but not all samples of stratified epithelia, including esophagus, tongue, exocervix, and vagina, positive immunocytochemical reactions for cytokeratins 8, 18, and 19 which in some regions were selective for the basal cell layer(s) but extended into suprabasal layers in others. In situ hybridization with different probes (riboprobes, synthetic oligonucleotides) for mRNAs of cytokeratin 8 on esophageal epithelium has shown, in extended regions, relatively strong reactivity for cytokeratin 8 mRNA in the basal cell layer. In contrast, probes to cytokeratin 18 have shown much weaker hybridization which, however, was rather evenly spread over basal and suprabasal strata. These results, which emphasize the importance of in situ hybridization in studies of gene expression in complex tissues, show that the genes encoding simple epithelial cytokeratins can be expressed in stratified epithelia. This suggests that continual expression of genes coding for simple epithelial cytokeratins is compatible with the formation of squamous stratified tissues and can occur, at least in basal cell layers, simultaneously with the synthesis of certain stratification-related cytokeratins. We also emphasize differences of expression and immunoreactivity of these cytokeratins between different samples and in different regions of the same stratified epithelium and discuss the results in relation to changes of cytokeratin expression during fetal development of stratified epithelia, in response to environmental factors and during the formation of squamous cell carcinomas.

Molecular characterization and expression of the stratification-related cytokeratins 4 and 15.

A number of human cytokeratins are expressed during the development of stratified epithelia from one-layered polar epithelia and continue to be expressed in several adult epithelial tissues. For studies of the regulation of the synthesis of stratification-related cytokeratins in internal tissues, we have prepared cDNA and genomic clones encoding cytokeratin 4, as a representative of the basic (type II) cytokeratin subfamily and cytokeratin 15, as representative of the acidic (type I) subfamily, and determined their nucleotide sequences. The specific expression of mRNAs encoding these two polypeptides in certain stratified tissues and cultured cell lines is demonstrated by Northern blot hybridization. Hybridization in situ with antisense riboprobes and/or synthetic oligonucleotides shows the presence of cytokeratin 15 mRNA in all layers of esophagus, whereas cytokeratin 4 mRNA tends to be suprabasally enriched, although to degrees varying in different regions. We conclude that the expression of the genes encoding these stratification-related cytokeratins starts already in the basal cell layer and does not depend on vertical differentiation and detachment from the basal lamina. Our results also show that simple epithelial and stratification-related cytokeratins can be coexpressed in basal cell layers of certain stratified epithelia such as esophagus. Implications of these findings for epithelial differentiation and the formation of squamous cell carcinomas are discussed.

The impact of a quadrivalent human papillomavirus (types 6, 11, 16, 18) virus-like particle vaccine in European women aged 16 to 24.

BACKGROUND: Quadrivalent human papillomavirus (HPV types 6/11/16/18) L1 VLP vaccine is highly effective in preventing HPV 6/11/16/18-related cervical and external genital disease. Herein, we evaluated the impact of the quadrivalent HPV 6/11/16/18 L1 VLP vaccine on prevention of HPV-associated cervico-genital lesions in a broad population of sexually active European women. METHODS: Female subjects (N = 9265) aged 16-24 with four or fewer lifetime sexual partners were enrolled and randomized to quadrivalent HPV vaccine or placebo. Subjects underwent cervicovaginal sampling for HPV DNA detection. Papanicolaou testing and anti-HPV 6/11/16/18 serology testing was also performed. RESULTS: Vaccine efficacy against lesions representing immediate cervical cancer precursors (cervical intraepithelial neoplasia grade 2/3 or adenocarcinoma in situ) related to HPV 6/11/16/18 in the per-protocol population was 100.0%[95% confidence interval (95% CI), 89.8-100.0]. Efficacy against external genital lesions (vulvar or vaginal intraepithelial neoplasia, condyloma, vulvar or vaginal cancer) related to vaccine HPV types in the per-protocol European population was 99.0% (95% CI, 94.4-100.0). CONCLUSION: These data demonstrate that quadrivalent HPV 6/11/16/18 vaccination programs in 16- to 24-year-old European women can be beneficial. NCT0009252, NCT00092534, NCT00092495.

The role of vegetable and fruit consumption and other habits on survival following the diagnosis of oral cancer: a prospective study in Spain.

The authors carried out a hospital-based prospective study to evaluate the role of behavioral and clinical risk factors, occurring before and after diagnosis, on the prognosis of 146 patients with newly diagnosed oral cancer using Cox models. High weekly intake of vegetables before and after diagnosis were both associated with lower recurrence rates, longer overall survival and longer oral cancer survival. Diagnostic delay was associated with an increased risk of recurrence and oral cancer mortality. Patients presenting with pharyngeal pain or a mucosal lesion had a longer oral cancer survival than patients presenting with other symptoms. Quitting tobacco and alcohol consumption before and after diagnosis were both associated with a lower recurrence and/or better survival, but the effects were not statistically significant. This study suggests that high consumption of vegetables before and after diagnosis of oral cancer may reduce the risk of recurrence, overall mortality and cancer mortality in oral cancer patients.

Proteomic analysis reveals successive aberrations in protein expression from healthy mucosa to invasive head and neck cancer.

Development of head and neck squamous cell carcinoma (HNSCC) is a multistep process and in many cases involves a phenomenon coined 'field cancerization'. In order to identify changes in protein expression occurring at different stages of tumorigenesis and field cancerization, we analysed 113 HNSCCs and 73 healthy, 99 tumor-distant and 18 tumor-adjacent squamous mucosae by SELDI-TOF-MS on IMAC30 ProteinChip Arrays. Forty-eight protein peaks were differentially expressed between healthy mucosa and HNSCC. Calgizarrin (S100A11), the Cystein proteinase inhibitor Cystatin A, Acyl-CoA-binding protein, Stratifin (14-3-3 sigma), Histone H4, alpha- and beta-Hemoglobin, a C-terminal fragment of beta-hemoglobin and the alpha-defensins 1-3 were identified by mass spectrometry. The alpha-defensins showed various alterations in expression as validated by immunohistochemistry (IHC). Supervised prediction analysis revealed excellent classification of healthy mucosa (94.5% correctly classified) and tumor samples (92.9% correctly classified). Application of this classifier to the tumor-adjacent and tumor-distant mucosa samples disclosed dramatic changes: only 59.6% of the tumor-distant biopsies were classified as normal, 27.3% were predicted as aberrant or HNSCC. Strikingly, 72% of the tumor-adjacent mucosae were predicted as aberrant. These data provide evidence for the existence of genetically altered fields with inconspicuous histology. Comparison of the protein profiles in the tumor-distant-samples with clinical outcome of 32 patients revealed a significant association between aberrant profiles with tumor relapse events (P=0.018; Fisher's exact test, two-tailed). We conclude that proteomic profiling in conjunction with protein identification greatly outperforms histopathological diagnosis and may have significant predictive power for clinical outcome and personalized risk assessment.

Health and economic impact of HPV 16 and 18 vaccination and cervical cancer screening in India.

Cervical cancer is a leading cause of cancer death among women in low-income countries, with approximately 25% of cases worldwide occurring in India. We estimated the potential health and economic impact of different cervical cancer prevention strategies. After empirically calibrating a cervical cancer model to country-specific epidemiologic data, we projected cancer incidence, life expectancy, and lifetime costs (I$2005), and calculated incremental cost-effectiveness ratios (I$/YLS) for the following strategies: pre-adolescent vaccination of girls before age 12, screening of women over age 30, and combined vaccination and screening. Screening differed by test (cytology, visual inspection, HPV DNA testing), number of clinical visits (1, 2 or 3), frequency (1 x , 2 x , 3 x per lifetime), and age range (35-45). Vaccine efficacy, coverage, and costs were varied in sensitivity analyses. Assuming 70% coverage, mean reduction in lifetime cancer risk was 44% (range, 28-57%) with HPV 16,18 vaccination alone, and 21-33% with screening three times per lifetime. Combining vaccination and screening three times per lifetime provided a mean reduction of 56% (vaccination plus 3-visit conventional cytology) to 63% (vaccination plus 2-visit HPV DNA testing). At a cost per vaccinated girl of I$10 (per dose cost of $2), pre-adolescent vaccination followed by screening three times per lifetime using either VIA or HPV DNA testing, would be considered cost-effective using the country's per capita gross domestic product (I$3452) as a threshold. In India, if high coverage of pre-adolescent girls with a low-cost HPV vaccine that provides long-term protection is achievable, vaccination followed by screening three times per lifetime is expected to reduce cancer deaths by half, and be cost-effective.

[Human papillomavirus nonavalent vaccine. Update 2017]. / Vacuna nonavalente frente al virus del papiloma humano. Actualización 2017.

Human papillomavirus (HPV) is the causative agent of 5% of human cancers. HPV infection is necessary for the development of cervical cancer and is responsible of a variable percentage of cancers of anus, vulva, vagina, penis, and oropharynx. Since 2007, 2 vaccines against HPV have been commercially available in Spain: bivalent (HPV types 16/18), and tetravalent (HPV types 6/11/16/18). In order to extend the protection afforded by HPV vaccines, a clinical program was launched in 2006 for the new nonavalent vaccine, including 9 HPV types (6/11/16/18/31/33/45/52/58). These types are responsible for 90% of cervical cancers, 82% of high-grade ano-genital pre-cancerous lesions, and 90% of genital warts. The purpose of this publication is to provide healthcare professionals with the scientific evidence that supports the new vaccine, as well as the clinical value that it offers in our environment.

Effect of riboflavin, retinol, and zinc on micronuclei of buccal mucosa and of esophagus: a randomized double-blind intervention study in China.

A randomized double-blind intervention trial was done in Huixian, People's Republic of China, a population with a high incidence of esophageal cancer. The aim of the trial was to determine whether a once-a-week treatment with retinol (15 mg or 50,000 IU), riboflavin (200 mg), and zinc (50 mg) could result, after 1 year, in a lower prevalence of precancerous lesions of the esophagus in the group receiving the active treatment as compared with the prevalence in the group receiving a placebo. The results of the trial, published elsewhere, indicated that the treatment had no effect on the prevalence of precancerous lesions of the esophagus. In determining whether an effect could be detected when earlier end points are used, the prevalence of micronuclei was evaluated in exfoliated cells from the esophagus and from the buccal mucosa in the present study. In a subsample of 200 out of the original 610 study subjects, smears were taken from the buccal mucosa before and after treatment, and in 170 subjects esophageal smears were obtained during endoscopy only after treatment. The smears were fixed and kept at room temperature over 1 year before being evaluated for the presence of micronuclei by means of 4'-6-diamidino-2-phenylindole fluorescent staining. Smears from approximately half of the subjects were considered suitable for evaluation. No statistically significant difference in the prevalence of micronuclei in the buccal mucosa cells was observed before and after treatment (the mean percentage of micronucleated cells in the vitamin group upon first examination, before treatment started, 0.35%; 1 year after treatment, 0.31%) or between the treatment and the placebo group at the final examination. (The mean percentage of micronucleated cells in the vitamin-treated group was 0.31 and 0.39% in the placebo group.) However, a statistically significant reduction (P = .04) was observed in the prevalence of micronuclei in esophageal cells in the treatment group as compared to the placebo. (The mean percentage of micronucleated cells in the vitamin-treated group was 0.19%; it was 0.31% in the placebo group.

Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group.

BACKGROUND: Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation. PURPOSE: Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types. METHODS: More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity. RESULTS: HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors). CONCLUSIONS: Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally. IMPLICATION: The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.

Difficulty in elucidating the male role in cervical cancer in Colombia, a high-risk area for the disease.

BACKGROUND: Epidemiologic evidence has been inconclusive in linking men's sexual behavior and genital human papillomaviruses (HPVs) with cervical cancer risk in their sexual partners in areas with a high incidence of cervical cancer. PURPOSE: This study assesses the role of men's sexual behavior and the presence of penile HPV DNA on the risk of their wives' developing cervical neoplasia in an area in Colombia with a high incidence of cervical cancer. METHODS: A total of 210 husbands of women with cervical intraepithelial neoplasia grade III (n = 118) or invasive squamous cell carcinoma of the cervix (n = 92) and a total of 262 husbands of women recruited as control subjects (173 and 89, respectively) were interviewed. Questionnaires included detailed information on sexual behavior. Exfoliated cells were obtained from the glans penis and from the distal urethra of the penis. The specimens were analyzed for HPV DNA by use of a polymerase chain reaction-based assay that included a generic probe and 25 type-specific probes. Serum specimens were collected and analyzed for antibodies to Chlamydia trachomatis, Treponema pallidum, herpes simplex virus type II, and Neisseria gonorrhoeae. RESULTS: Limited education (adjusted odds ratio [OR] = 4.4; 95% confidence interval [CI] = 1.9-9.8; for no schooling versus secondary or higher education) and presence of antibodies to C. trachomatis (adjusted OR = 2.5; 95% CI = 1.5-4.4) in husbands were the only identified risk factors for cervical neoplasia in their wives. The prevalence of HPV DNA in the penis was 25.7% among husbands of case women and 18.9% among husbands of control women (adjusted OR = 1.2; 95% CI = 0.6-2.3). Neither the lifetime number of female sexual partners (adjusted OR = 1.0; 95% CI = 0.4-2.6; for > 50 partners versus one to five) nor the lifetime number of female prostitutes as sexual partners (adjusted OR = 1.2; 95% CI = 0.7-2.0; for > or = 21 prostitutes versus one to five) was associated with the risk of cervical cancer. CONCLUSIONS: Our results are compatible with the hypothesis that in the population of Cali, whose women are at high risk of developing cervical cancer, exposure to HPV among young men is a common occurrence and is mediated by contacts with large numbers of female sexual partners and prostitutes. These widespread sexual practices limit the power of case-control studies to detect significant associations between men's sexual behavior and the cervical cancer risk in their sexual partners. HPV DNA detection in the penis of adult men is a poor reflection of lifetime exposure or of etiologically relevant exposure to HPV. The role of C. trachomatis in cervical carcinogenesis deserves further investigation. IMPLICATIONS: Further research is needed to elucidate the male's role in cervical carcinogenesis in populations at high risk for cervical cancer. HPV DNA prevalence surveys and studies of the natural history of HPV in young men will be of great value.

Causes of cervical cancer in the Philippines: a case-control study.

BACKGROUND: Among the numerous human papillomavirus (HPV) types, only types 16 and 18 have been formally classified as human carcinogens. To evaluate the associations of 33 HPV types and other risk factors with squamous cell carcinoma and adenocarcinoma of the cervix, we performed a hospital-based, case-control study in the Philippines. METHODS: The study included 356 case subjects who had histologically confirmed cervical cancer (323 incident cases of squamous cell carcinoma and 33 incident cases of adenocarcinoma/adenosquamous carcinoma) and 381 control subjects. Information on risk factors was obtained by personal interview. HPV DNA was detected in exfoliated cervical cells and biopsy specimens by use of a polymerase chain reaction assay. RESULTS: HPV DNA was detected in 93.8% of case subjects with squamous cell carcinoma and in 90.9% of case subjects with adenocarcinoma/adenosquamous carcinoma compared with 9.2% of control subjects, giving age-adjusted odds ratios of 156 (95% confidence interval [CI] = 87-280) for squamous cell carcinoma and 111 (95% CI = 31-392) for adenocarcinoma/adenosquamous carcinoma. Fifteen different HPV types were detected in squamous cell carcinoma, and six different HPV types were detected in adenocarcinoma/adenosquamous carcinoma. Among HPV types other than types 16 and 18, the associations of HPV with risk of squamous cell carcinoma were strongest for HPV45. In addition to HPV, high parity, low socioeconomic status, and smoking were also associated with both types of cervical cancer. CONCLUSIONS: As has been shown for squamous cell carcinoma, HPV is the central cause of adenocarcinoma/adenosquamous carcinoma of the uterine cervix. The observed associations of less prevalent HPV types with cervical cancer have important implications for cervical cancer prevention strategies.

Risk factors for cervical cancer in Thailand: a case-control study.

BACKGROUND: Human papillomaviruses (HPV) types 16 and 18 are clearly involved in the etiology of cervical cancer, but the evidence for the carcinogenicity of other HPV types is limited. Cofactors involved in the progression from infection with HPV to high-grade precursors and cancer have not been clearly defined by the results of previous studies. METHODS: We conducted a hospital-based, case-control study of invasive cervical cancer to investigate risk in relation to HPV infection and its epidemiologic cofactors in Hat-Yai, Thailand. A total of 338 patients with squamous cell carcinoma, 39 patients with adenocarcinoma/adenosquamous carcinoma, and 261 control subjects were included in the study and were interviewed to obtain information with regard to cervical cancer risk factors. HPV DNA presence in cervical exfoliated cells or frozen biopsy specimens was determined by a polymerase chain reaction assay. RESULTS: HPV DNA was detected in 95% of patients with squamous cell carcinoma, 90% of those with adenocarcinoma/adenosquamous carcinoma, and 16% of control subjects. For patients with squamous cell carcinoma, the most common types of HPV found were type 16 (60% of the positives), type 18 (18%), type 58 (3%), type 52 (3%), and type 31 (2%). For patients with adenocarcinoma/adenosquamous carcinoma, the most common HPV types found were type 18 (60% of the positives), type 16 (37%), and type 45 (3%). The risk factors that remained associated with risk of both histologic types after adjustment for HPV and their mutual confounding effects were limited education, increasing number of sexual partners, history of venereal diseases, and interval since last Pap smear (i.e., cytologic) test. Among patients with squamous cell carcinoma, some association with smoking was also observed. CONCLUSION: New preventive strategies for cervical cancer will require the consideration of multiple HPV types.

Male sexual behavior and human papillomavirus DNA: key risk factors for cervical cancer in Spain.

BACKGROUND: It is now established that certain types of human papillomaviruses (HPVs) are the sexually transmitted agents etiologically linked to cervical cancer. Studies assessing the contribution of the male's sexual behavior and genital HPV DNA status to the risk of development of cervical neoplasia in sexual partners have yielded inconsistent results. PURPOSE: This study evaluates the role of men's sexual behavior and the presence of HPV DNA in the penis on the development of cervical cancer in their sexual partners in Spain, a low-risk area for cervical neoplasia. METHODS: Husbands (n = 633) of women participating in two case-control studies of cervical neoplasia were interviewed to obtain information on lifestyle habits, including sexual practices. Cytologic samples were taken from the distal urethra and the surface of the glans penis of 183 husbands of case women and of 171 husbands of control women. These samples were analyzed by a polymerase chain reaction-based system using a generic probe and 25 type-specific probes for the detection and typing of HPV DNA. Serologic specimens were also obtained and analyzed for antibodies to Chlamydia trachomatis, Treponema pallidum, herpes simplex virus type II, and Neisseria gonorrhoeae. RESULTS: The presence of HPV DNA in the husbands' penis conveyed a fivefold risk of cervical cancer to their wives (adjusted odds ratio [OR] for HPV DNA positivity = 4.9; 95% confidence interval [CI] = 1.9-12.6). The risk of cervical cancer was strongly related to HPV type (adjusted OR for HPV type 16 = 9.0; 95% CI = 1.1-77.5), to the husbands' number of extramarital partners (adjusted OR = 11.0; 95% CI = 3.0-40.0; for > or = 21 women versus one), and to the number of prostitutes as extramarital sexual partners (adjusted OR = 8.0; 95% CI = 2.9-22.2; for > or = 10 women versus none). Presence of antibodies to C. trachomatis (adjusted OR = 2.6; 95% CI = 1.4-4.6) and an early age at first sexual intercourse of the husband (adjusted OR = 3.2; 95% CI = 1.7-5.9; for < or = 15 years versus > or = 21 years) were also associated with cervical neoplasia in the wife. After adjustment for these variables and for the wife's pack-years of smoking, the husband's smoking was moderately associated with cervical cancer in his wife (adjusted OR = 2.5; 95% CI = 1.4-4.4; for > or = 26.2 pack-years versus none). CONCLUSIONS: The study supports the role of men as vectors of the HPV types that are related to cervical cancer. Life-time number of female sexual partners, number of female prostitutes as sexual partners, and detection of HPV DNA in the penis of husbands are all surrogate markers of exposure to HPV during marriage. IMPLICATIONS: Men who report multiple sexual partners or who are carriers of HPV DNA may be vectors of high-risk HPV types and may place their wives at high risk of developing cervical cancer. Prostitutes are an important reservoir of high-risk HPVs.

Blood, retinol and zinc riboflavin status in relation to precancerous lesions of the esophagus: findings from a vitamin intervention trial in the People's Republic of China.

Data from a double-blind intervention trial in China are reanalyzed to explore auxiliary information. The trial had shown that in a high-risk area for esophageal cancer the dietary supplementation of apparently healthy individuals with a combination of retinol, riboflavin, and zinc did not lead to a different prevalence of precancerous lesions of the esophagus among those receiving the active treatment compared to a placebo group. However, improvement of blood retinol and zinc levels were also observed in the placebo group. The logistic regression analysis presented in this paper illustrates that those individuals who showed large increases in retinol, riboflavin, and zinc blood levels were more likely to have a histologically normal esophagus at the end of the trial. This effect is clearer for retinol than for riboflavin and zinc and it is independent of whether the change was caused by the active treatment or occurred otherwise.

Distinct nonrandom patterns of chromosomal aberrations in the progression of squamous cell carcinomas of the head and neck.

Fifty-one randomly selected primary squamous cell carcinomas of the head and neck, derived from the larynx (n = 18) and pharynx (oropharynx, n = 18, and hypopharynx, n = 15) were analyzed with centromeric probes for chromosomes 1, 7, 9, 11, 17, and 18 to study numerical aberrations, chromosome imbalances, and aneuploidy by fluorescence in situ hybridization. The tumors were grouped into nonmetastasizing (N0) tumors (from patients clinically free of lymph node metastases for at least 18 months after surgery, n = 25) and metastasizing (N1-3) tumors (n = 26). We found a significant association between the tumor ploidy and the nodal status; in the N0 group, diploidy prevailed, and the most common aberration was loss to monosomy for chromosome 9 (44%), whereas in the N1-3 group, aneuploidy predominated (P = 0.002). Specifically, these genomic changes associated with progression to metastasis were: (a) tetrasomic or polysomic chromosomes were detected in 17 of 26 N1-3 tumors but in none of the 25 N0 tumors (P < 0.0001); (b) heterogeneous chromosomal copy numbers (i.e., extensive chromosomal imbalances) were also much more frequent in the N1-3 tumors (69.2% versus 24.0% in the N0 group; P = 0.018); and (c) loss of chromosome 9 (73%) and gains of chromosomes 7 (35%) and 17 (31%) persisted, but in addition, loss of chromosome 18 occurred in 31%. Overexpression of the p53 protein correlated with an increased incidence of chromosomal imbalances and aneuploidy (P < 0.001) and, hence, constituted an additional risk factor. The lower metastatic potential of larynx tumors as compared with tumors from the pharynx was reflected by a lower incidence of these genomic changes. These specific patterns of chromosomal aberrations can characterize and distinguish different stages of tumor progression of squamous cell carcinomas of the head and neck and should be valuable diagnostic and prognostic markers.