Time trends of human papillomavirus types in invasive cervical cancer, from 1940 to 2007.

Contribution over time of human papillomavirus (HPV) types in human cancers has been poorly documented. Such data is fundamental to measure current HPV vaccines impact in the years to come. We estimated the HPV type-specific distribution in a large international series of invasive cervical cancer (ICC) over 70 years prior to vaccination. Paraffin embedded ICC cases diagnosed between 1940 and 2007 were retrieved from eleven countries in Central-South America, Asia and Europe. Included countries reported to have low-medium cervical cancer screening uptake. Information on age at and year of diagnosis was collected from medical records. After histological confirmation, HPV DNA detection was performed by SPF-10/DEIA/LiPA25 (version1). Logistic regression models were used for estimating the adjusted relative contributions (RC) of HPV16 and of HPV18 over time. Among 4,771 HPV DNA positive ICC cases, HPV16 and HPV18 were the two most common HPVs in all the decades with no statistically significant variations of their adjusted-RC from 1940-59 to 2000-07 (HPV16-from 61.5 to 62.1%, and HPV18-from 6.9 to 7.2%). As well, the RC of other HPV types did not varied over time. In the stratified analysis by histology, HPV16 adjusted-RC significantly increased across decades in adenocarcinomas. Regarding age, cases associated to either HPV16, 18 or 45 were younger than those with other HPV types in all the evaluated decades. The observed stability on the HPV type distribution predicts a high and stable impact of HPV vaccination in reducing the cervical cancer burden in future vaccinated generations.

The occasional role of low-risk human papillomaviruses 6, 11, 42, 44, and 70 in anogenital carcinoma defined by laser capture microdissection/PCR methodology: results from a global study.

Low-risk human papillomaviruses (LR-HPVs) have been associated occasionally with clinically and pathologically unusual anogenital malignancies. The relation between clinicopathologic features and any pathogenetic role of LR-HPV remains unclear. From a global study of 13,328 anogenital carcinomas, we identified 57 cases in which whole-tissue polymerase chain reaction using SPF10-LiPA25 showed single LR-HPV infection. In 43/46 (93.5%) available carcinomas, multiple polymerase chain reaction assays confirmed single detection of HPV6, 11, 42, 44, or 70 DNA. In 75% (n=32) of these, LR-HPV DNA was confirmed in tumor cells by laser capture microdissection. In 2 cases, including 1 adenocarcinoma, viral DNA was only found outside the tumor. All anogenital tumors with confirmed HPV6/11 showed a distinctive range of papillary, warty or warty-basaloid, squamous, or transitional histology with patchy or negative p16 expression. HPV6-associated cervical tumors occurred at a low median age. HPV42/70 was associated with typical squamous cell carcinoma showing diffuse p16 staining like high-risk HPV-related malignancies. HPV44 was found in malignant cells in 1 case. Viral taxonomy and theoretical analysis show that HPV6/11 belong to a different genus from HPV42/70 with E6/E7 gene products that would not bind pRb or p53, whereas HPV42/70 could bind pRb. Our data support the causal involvement of LR-HPVs in the carcinogenesis of <2% of anogenital malignancies of 2 distinct clinicopathologic patterns related to the genetic structure of the HPV types 6/11 and 70/42. HPV42/70 was associated with typical squamous carcinomas. Importantly all carcinomas associated with HPV6/11 globally showed verruco-papillary, well-differentiated, squamous, or transitional histology without p16 expression.

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.

Basaloid squamous cell carcinoma of the penis with papillary features: a clinicopathologic study of 12 cases.

There are 3 distinct variants of penile squamous cell carcinoma frequently associated with human papillomavirus (HPV): basaloid, warty-basaloid, and warty carcinomas. Considering the high incidence rates of penile cancer in some countries, a large international study was designed to evaluate the presence of HPV, its genotype distribution, and its association with histologic types of penile cancer. In this international review of >900 cases, we found a group of highly distinct papillary neoplasms composed of basophilic cells resembling urothelial tumors but frequently associated with HPV. Macroscopically, tumors were exophytic or exoendophytic. Microscopically, there was a papillomatous pattern of growth with a central fibrovascular core and small basophilic cells lining the papillae. Positivity for HPV was present in 11 of 12 tumors (92%). Single genotypes found were HPV-16 in 9 tumors and HPV-51 in 1 tumor. Multiple genotypes (HPV-16 and HPV-45) were present in another case. Overexpression of p16 was observed in all cases. Uroplakin-III was negative in all cases. The differential diagnosis was with basaloid, warty-basaloid, warty, and papillary squamous cell carcinoma and with urothelial carcinomas. Local excision (4 cases), circumcision (3 cases), or partial penectomy (5 cases) were preferred treatment choices. Tumor thickness ranged from 1 to 15 mm (average, 7 mm). Two patients with tumors invading 11 and 15 mm into the corpus spongiosum developed inguinal nodal metastasis. Of 11 patients followed up (median 48 mo), 7 were alive with no evidence of metastatic disease, 3 died from causes other than penile cancer, and another died postoperatively. This morphologically distinct tumor probably represents a papillary variant of basaloid carcinomas (papillary-basaloid carcinomas). Unlike typical basaloid carcinomas, the overall prognosis was excellent. However, deeply invasive tumors were associated with regional nodal metastasis indicating a potential for tumor-related death.

Value of p16(INK)4(a) in the pathology of invasive penile squamous cell carcinomas: A report of 202 cases.

BACKGROUND: One 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 p16(INK)4(a) immunohistochemical expression, which is simpler and less costly, as a potential marker of high-risk HPV (HR-HPV) infection in penile SCC. DESIGN AND METHODS: We pathologically classified 202 invasive penile carcinomas and performed HPV genotyping by short PCR fragment (SPF)10 PCR and p16(INK)4(a) immunohistochemistry. We also evaluated HPV and p16(INK)4(a) according to the histologic subtypes of penile SCC. Tumors depicting continuous p16(INK)4(a) immunostain in all neoplastic cells were considered positive. HPV and p16(INK)4(a) status were compared using classifier performances and concordance indexes. RESULTS: Evidence of HPV (low-risk and high-risk genotypes) was found in 63 cases (31%) by PCR. Fifty-three p16(INK)4(a)-positive cases were identified (26%). Overexpression of p16(INK)4(a) had a sensitivity of 67% and a specificity of 91% for defining the HPV status. Concordance indexes between p16(INK)4(a) 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 p16(INK)4(a) 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). CONCLUSIONS: p16(INK)4(a) 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 p16(INK)4(a) 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 p16(INK)4(a) status and this observation may have diagnostic and prognostic implications.

Distinctive association of p16INK4a overexpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature.

From the pathogenic point of view, penile cancers may be grouped in human papillomavirus-related and unrelated tumors, each one of them with distinctive morphologic features. The former are predominantly composed of small, undifferentiated basaloid cells, with more or less prominent koilocytic changes, and the latter of keratinizing differentiated squamous cells. The same cellular types are observed in precancerous lesions. On the basis of these observations, we constructed a novel nomenclature for penile precancerous lesions and classified them as penile intraepithelial neoplasia (PeIN) of differentiated, warty, basaloid, and warty-basaloid types. The aim of this study was to test the usefulness of immunohistochemical p16 overexpression, considered as a surrogate for high-risk human papillomavirus infection, using this classification system. We pathologically evaluated 141 patients with PeIN, associated (123 cases) and unassociated (18 cases) with invasive cancer. Distribution of PeIN types was: differentiated, 72%; basaloid, 9%; warty-basaloid, 7%; warty, 4%; and mixed, 7%. There was a striking similarity in the morphology of in situ and invasive squamous cell carcinomas. Differentiated PeIN was commonly associated with usual, verrucous, papillary, and other low-grade keratinizing variants of squamous cell carcinoma whereas in basaloid and warty carcinomas the presence of in situ lesions with similar morphology was habitual. We evaluated p16 overexpression using a 4-tiered (0, 1, 2, and 3) pattern-based system. To properly distinguish differentiated PeIN from in situ lesions with warty and/or basaloid features only pattern 3, which requires full-thickness staining in all epithelial cells, was considered positive. Using this approach, there was a significant association of the negative patterns and differentiated PeIN and of the positive pattern and warty, basaloid, and warty-basaloid PeIN (P<0.0001). Basaloid variant had the strongest association. The sensitivity rate of p16 positivity for discriminating types of PeIN was of 82%, with a specificity of 100% and an accuracy of 95%. Lichen sclerosus was identified in 42 cases and their epithelial component was p16 negative in all cases. Although more studies are necessary to confirm these observations, p16 overexpression seems to be a useful tool for discriminating differentiated from warty, basaloid, and warty-basaloid PeIN.

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.

High prevalence of human papillomavirus infection in the female population of Guatemala.

The potential introduction of the newly licensed HPV-vaccines at affordable prices could play a central role in preventing cervical cancer in middle and low-income countries, where most of the cases occur. In spite of this, basic epidemiological data about HPV and HPV-related lesions are still scarce. To determine the prevalence of cervical abnormalities, HPV prevalence, genotype distribution and related risk factors, we carried out a cross-sectional study in a population from Guatemala that included 297 women from the general population (GP women) and 297 sex workers (SW). All participating women were interviewed and underwent a complete gynecological examination that included collection of cervical cells for cytological diagnosis, HPV DNA detection and typing by PCR methods. Cervical HPV DNA prevalence among GP women and from SW was 38.1% (95% CI: 32.5-43.8) and 67.3% (95% CI: 61.7-72.6), respectively. The prevalence of abnormal cytology among GP women was 7.7% (ASCUS = 1.4%, LSIL = 4.7%, ASC-H = 0.3% and HSIL = 1.4%) and among SW was 21.6% (ASCUS = 7.5%, LSIL = 10.6%, ASC-H = 1.4% and HSIL = 2.1%). The most prevalent HPV types among women with normal cytology were HPVs 51 (n = 30), 66 (n = 25) and 16 (n = 25), and among women with HSIL or ASC-H (n = 14) HPVs 58 (n = 5) and 16 (n = 5). Determinants associated with HPV DNA detection were having had an occasional partner during the last 6 months and smoking habit among GP women, and being a minor among SW. HPV and abnormal cytology prevalence is high among women in Guatemala. The introduction of a HPV vaccination program would prevent an important fraction of HPV-related disease burden.

[Assessment of HPV detection assays for use in cervical cancer screening programs]. / Evaluación de las técnicas de detección del VPH en los programas de cribado para cáncer de cuello uterino.

OBJECTIVE: Detection of high-risk human papillomavirus types (HPV) infection is an important tool in the screening of cervical cancer and triage of cytological abnormalities. The different techniques for detection of this cancer need to be contrasted and validated for use in population screening. MATERIAL AND METHODS: Cervical cell samples were collected from 166 women attending a dermatology clinic in Oviedo (Spain). We evaluated the performance of three different assays for VPH detection. The methods utilized were 1) In-house PCR-EIA using LI consensus primers MY09/ MY11, 2) A PCR-reverse line blot hybridization (PCR-LBH) that uses LI consensus PGMY primers. 3) Hybrid Capture 2. All assays were performed blinded. The kappa statistic was used to test for global agreement between assay pairs. RESULTS: HPV DNA was detected in 24,7%, 25,3% and 29,5% of the women, respective to the assay. The overall agreement between the in-house PCR, PCR-LBH and HC2 was (73.5%) with all kappa values between assay pairs exceeding 0.56 (p<0.001). CONCLUSION: The three HPV assays were equally accurate in estimating high-risk HPV prevalence and HPV-related lesions. The method for HPV detection must be decided depending on the goals of the search (screening, follow-up or molecular studies).

Evaluación de las técnicas de detección del VPH en los programas de cribado para cáncer de cuello uterino / Assessment of hpv detection assays for use in cervical cancer screening programs

OBJETIVO: La identificación de la infección por tipos de alto riesgo del virus del papiloma humano (VPH) es una herramienta útil para el cribado de cáncer del cuello uterino. Las distintas técnicas aplicadas para su detección deben contrastarse y validarse para su empleo en la tamización poblacional. MATERIAL Y MÉTODOS: Se evalúan tres técnicas para la detección del VPH en 166 muestras cervicales procedentes de mujeres atendidas en una clínica de dermatología en Oviedo (España): a) PCR-EIA mediante consensos MY09/MY011; b) PCR con line blot hybridization (PCR-LBH) con consensos PGMY; y c) hybrid capture 2. RESULTADOS: El ADN-VPH se reconoció en 29.5 por ciento, 25.3 por ciento y 24.7 por ciento, de acuerdo con el ensayo. La concordancia global entre PCR-EIA, PCR-LBH y HC2 fue de 73.5 por ciento con los valores de kappa superiores a 0.56 entre los ensayos (p<0.001). CONCLUSIONES: La prevalencia de tipos de alto riesgo oncogénico así como de las lesiones fue similar en los tres ensayos. En virtud de que las técnicas son comparables, su elección debe basarse en las condiciones individuales de cada laboratorio y el volumen de muestras por procesar.

OBJECTIVE: Detection of high-risk human papillomavirus types (HPV) infection is an important tool in the screening of cervical cancer and triage of cytological abnormalities. The different techniques for detection of this cancer need to be contrasted and validated for use in population screening. MATERIAL AND METHODS: Cervical cell samples were collected from 166 women attending a dermatology clinic in Oviedo (Spain). We evaluated the performance of three different assays for VPH detection. The methods utilized were 1) In-house PCR-EIA using L1 consensus primers MY09/MY11, 2) A PCR-reverse line blot hybridization (PCR-LBH) that uses L1 consensus PGMY primers. 3) Hybrid Capture 2. All assays were performed blinded. The kappa statistic was used to test for global agreement between assay pairs. RESULTS: HPV DNA was detected in 24,7 percent, 25,3 percent and 29,5 percent of the women, respective to the assay. The overall agreement between the in-house PCR, PCR-LBH and HC2 was (73.5 percent) with all kappa values between assay pairs exceeding 0.56 (p<0.001). CONCLUSION: The three HPV assays were equally accurate in estimating high-risk HPV prevalence and HPV-related lesions. The method for HPV detection must be decided depending on the goals of the search (screening, follow-up or molecular studies).