F. X. Bosch

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.

A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)‐based test which was used. The formerly HPV‐negative cases from this study have therefore been reanalysed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV‐negative and a sample of 48 of the 866 cases which were HPV‐positive in the original study. Moreover, 55 of the 66 formerly HPV‐negative biopsies were also reanalysed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR‐negative and ‐positive. Type‐specific E7 PCR for 14 high‐risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV‐negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA‐positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV‐negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0·001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99·7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV‐negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening. Copyright

The role of HPV in the etiology of cervical cancer

To assess the association between human papillomavirus (HPV) and cervical cancer we have carried out two case-control studies of cervical intraepithelial neoplasia grade III (CIN III) (525 cases and 512 matched controls) and two case-control studies of invasive squamous cell carcinoma (436 cases and 387 population controls) in Cali, Colombia and nine provinces of Spain. HPV DNA detected by polymerase chain reaction, a PCR-based hybridization assay in the exfoliated cells of the uterine cervix, was the strongest risk factor in both countries. For invasive cancer the adjusted odds ratios and 95% confidence intervals were: 46.2 (18.5-115.1) in Spain and 15.6 (6.9-34.7) in Columbia and for CIN III they were: 56.9 (24.8-130.6) in Spain and 15.5 (8.2-29.4) in Columbia. This strong association was specific for types 16, 18, 31, 33 and 35 and also for HPV types not yet characterized. Hormonal factors such as oral contraceptives and high parity appear to confer an additional risk increasing the progression from chronic HPV infection to cancer. Our overall results indicate that HPV is the main cause of cervical cancer in two countries with contrasting rates of cervical cancer, Columbia having an incidence rate about 8 times higher than Spain.

The basaloid cell is the best tissue marker for human papillomavirus in invasive penile squamous cell carcinoma: a study of 202 cases from Paraguay.

Human papillomavirus (HPV) has been reported in 12-82% of penile squamous cell carcinomas (SCC). There is an association of the virus with basaloid and warty carcinomas but the reported prevalence is variable. The causes of these variations are not clear. They may be owing to geographic differences, the use of different techniques to detect HPV, the status of the original paraffin blocks, or to variable criteria in tumor classification. The aims of the study were to determine the prevalence of HPV in penile SCC and subtypes using a sensitive technique, to investigate genotypes involved, and to search for other morphologic features associated with the virus from a series of cases from Paraguay. HPV detection was done by SPF-10 polymerase chain reaction followed by DNA enzyme-immunoassay and genotyping by LIPA 25 (version 1). Samples were tested at Catalan Institute of Oncology, Barcelona, and cross testing was carried out at the Delft Diagnostic Laboratories in The Netherlands. HPV was detected in 64 of 202 cases (32%). Thirteen tumors had multiple HPV genotypes. Most prevalent genotypes were HPV-16 (46 cases), HPV-6 (6 cases), and HPV-18 (4 cases), either in single or in multiple infections. HPV was preferentially associated with warty-basaloid (82%), basaloid (76%), and warty (39%) carcinomas and not detected in verrucous, mixed verrucous-papillary, pseudohyperplastic, and pseudoglandular SCCs. There was a strong association between HPV and higher histologic grade. Basaloid cells were more frequently found in HPV positive tumors (72%) and this association was statistically significant in univariate and multivariate analyses. Cells with koilocytotic features and keratinizing squamous cells were also present but to a much lesser degree (47% and 19%, respectively). In summary, HPV was found in a third of the cases and the most common genotype was HPV-16. Low-risk genotypes were rarely found in single infections, representing 4 cases among all analyzed (2%). There was an association between HPV presence and higher histologic grade and with basaloid, warty-basaloid, and warty carcinomas. Our results also suggest that, in penile SCC, the basaloid cell is the best tissue marker for oncogenic HPV infection.

Value of p16INK4a in the Pathology of Invasive Penile Squamous Cell Carcinomas: A Report of 202 Cases

BackgroundOne third to one half of penile squamous cell carcinomas (SCCs) are related to human papillomavirus (HPV) infection. Viral detection is usually carried out by polymerase chain reaction (PCR) or other molecular methods. In this study, we evaluated p16INK4a immunohistochemical expression, which is simpler and less costly, as a potential marker of high-risk HPV (HR-HPV) infection in penile SCC. Design and MethodsWe pathologically classified 202 invasive penile carcinomas and performed HPV genotyping by short PCR fragment (SPF)10 PCR and p16INK4a immunohistochemistry. We also evaluated HPV and p16INK4a according to the histologic subtypes of penile SCC. Tumors depicting continuous p16INK4a immunostain in all neoplastic cells were considered positive. HPV and p16INK4a status were compared using classifier performances and concordance indexes. ResultsEvidence of HPV (low-risk and high-risk genotypes) was found in 63 cases (31%) by PCR. Fifty-three p16INK4a-positive cases were identified (26%). Overexpression of p16INK4a had a sensitivity of 67% and a specificity of 91% for defining the HPV status. Concordance indexes between p16INK4a and HPV status were high (≥78%) in general cases and in all histologic subtypes of penile SCC. The stain was useful in the differential diagnosis of basaloid and low-grade warty carcinomas. Low-risk HPV genotypes were found in 5 tumors, 4 of which were p16INK4a negative. Basaloid and nonbasaloid high-grade (grade 3) SCCs were more likely to be HR-HPV positive when compared with grades 1 to 2 tumors (P<0.000001 and 0.0417, respectively). Conclusionsp16INK4a overexpression was found to be a reliable marker for HR-HPV and a helpful tool in the differential diagnosis of low-grade verruciform and high-grade solid penile tumors. SCC variants depicting basaloid features were more likely to be HPV and p16INK4a positive than low-grade, keratinizing lesions. We also observed a tendency toward HPV positivity in high-grade nonbasaloid tumors. Our results indicated a concordance between HPV and p16INK4a status and this observation may have diagnostic and prognostic implications.

Type-specific human papillomavirus distribution in invasive cervical carcinomas in Paraguay. A study of 432 cases

Cervical carcinoma is the most common malignant tumor among woman in Paraguay. Cytological screening programs have not been successful and a plan for human papillomavirus (HPV) based‐screening program and/or vaccination is under evaluation. This study aimed to identify the contribution of HPV genotypes in invasive cervical cancer in Paraguay to provide essential background data to guide and assess the introduction and impact of new preventive strategies based on HPV. Four hundred thirty two histologically confirmed cases (1960–2004) were analyzed. HPV detection in paraffin blocks was performed at the Catalan Institute of Oncology using PCR with SPF‐10 broad spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridization line probe analysis. The majority of cases were squamous cell carcinoma (92.8%). Mean patients age was 48 years old. HPV DNA was detected in 73.1% of the cases and single infections were predominant (97.8%). The most common HPV single types were 16, 18, 45, 33, 31, 52, 35, and 39. 73.1% of HPV positive cases had an HPV 16, 18 as single infection. HPV16 was frequent in SCC whereas HPV 18 and 45 were prevalent in glandular tumors. Significant decrease of HPV 16 with age groups (P‐trend = 0.022) and increase in other HPV types (P‐trend > 0.001) were observed. The potential impact of HPV 16 and 18 for a vaccination program was 73.1%. The study provide a profile of the HPV situation in the country, with robust clinical, pathological and virological data which would permit a better cervical cancer screening and vaccination programs. J. Med. Virol. 84:1628–1635, 2012.

Mother to child transmission of hepatitis B virus in the Philippines

SummaryA follow-up study of mother to infant transmission of hepatitis B virus was conducted in the Philippines between 1981 and 1983. The prevalence of HBsAg among 527 mothers was 8.5%. Overall, seven out of 17 (41.2%) infants born to HBsAg carrier mothers became HBsAg positive within the first 12 months of life. The risk of becoming HBsAg positive was about 20 times higher for infants born to HBsAg positive mothers than for infants born to HBsAg negative mothers (OR=18.9, 95% Ci=2.0−86.6). The risk was even higher if the mother was a carrier of both HBsAg und HBeAg (OR=91.0, 95% Ci=49.2−164.8). However, the risk of transmission was very low if the mother was an HBsAg carrier and anti-HBe positive. It was estimated that mother to infant transmission accounts for about one third of HBsAg positivity at one year of age. The implications of these findings in the planning of vaccination campaigns to prevent HBV infections are discussed.ZusammenfassungIn den Philippinen wurde zwischen 1981 und 1983 eine Verlaufsstudie zur Mutter-Kind-Übertragung des Hepatitis-B-Virus durchgeführt. Bei 527 Müttern fand sich eine HBsAg-Prävalenz von 8,5%. Sieben von 17 Neugeborenen (41,2%) der HBsAg-Carrier-Mütter wurden im Ablauf der ersten 12 Lebensmonate HBsAg-positiv. Bei Kindern HBsAg-positiver Mütter war das Risiko einer HBsAg-Serokonversion 20mal höher als bei Kindern HBsAg-negativer Mütter (OR=18,9; 95%; Ci=2,0−86,6). Bei Müttern, die nicht nur HBsAg, sondern auch HBeAg-Carrier waren, bestand ein noch größeres Risiko für das Kind, HBsAg-positiv zu werden (OR=91,0; 95%; Ci=49,2−164,8). Bei Müttern, die HBsAg-Carrier, aber anti-HBe-positiv waren, bestand nur ein sehr geringes Übertragungsrisiko. Schätzungsweise sind ein Drittel der Fälle von HBsAg-Positivität bei einjährigen Kindern auf Mutter-Kind-Übertragung zurückzuführen. Die Bedeutung dieser Daten für die Planung von Impfaktionen zur Prävention von HBV-Infektionen wird diskutiert.