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There are few pathologic or molecular studies of penile precancerous lesions, and the majority refers to lesions associated with invasive carcinomas. Penile Intraepithelial Neoplasia (PeIN) is classified in two morphologically and distinctive molecular groups, non-HPV and HPV-related with special subtypes. The primary purpose of this international series was to classify PeIN morphologically, detect HPV genotypes and determine their distribution according to PeIN subtypes. A secondary aim was to evaluate the p16

Basaloid squamous cell carcinoma (BSCC) is a subtype of squamous cell carcinoma that characteristically occurs in the head and neck, may be related to HPV infection and is usually considered to be aggressive. We present the first description of BSCC of the breast. The tumor exhibited characteristic histologic features of BSCC, including nests of basaloid squamous cells with comedonecrosis, abrupt keratinization, and abundant hyaline basement membrane-like material deposition. The tumor showed immunohistochemical features of triple negativity, diffuse p63 positivity, p16 positivity, and Rb negativity. HPV immunogenotyping was negative. The patient was free of disease after treatment with breast conserving surgery, chemotherapy and radiotherapy. BSCC of the breast should be distinguished from basaloid adenoid cystic carcinoma, triple-negative basal-like breast cancer and nonbasaloid squamous cell carcinoma of the breast based on histology and immunohistochemistry. The prognostic implications of BSCC of the breast should be further studied in larger series.

There are at least two different etio-pathogenic pathways for the development of vulvar squamous cell carcinoma (VSCC): one associated with infection by human papillomavirus (HPV) and another independent of HPV. We aimed to describe the histological characteristics of HPV-associated and HPV-independent tumors and to determine the best strategy to identify HPV in VSCC. A single paraffin block was available for review from a series of 1594 VSCCs. In all cases HPV DNA detection was analyzed using the SPF10PCR/DEIA/LiPA25 system and p16 immunohistochemistry (IHC). A tumor was considered as unquestionably HPV-associated if both HPV DNA and p16 IHC were positive. A tumor was considered indisputably HPV-independent if both HPV DNA and p16 IHC were negative. Two groups of tumors were classified as non-conclusive: 1) HPV DNA+/p16-; and 2) HPV DNA-/p16+. WHO typing and a thorough histological evaluation were conducted in all cases. 441 tumors were HPV DNA+ with 367 cases (23.0%) being HPV DNA+/p16+. These HPV DNA+/p16+ tumors were more frequently basaloid or warty (49.8%), but 36.5% were of the keratinizing type. 1153 tumors were HPV DNA-, with 1060 cases (66.5%) being HPV DNA-/p16-. These HPV DNA-/p16- tumors were mostly keratinizing (81.2%) but were occasionally basaloid or warty (5.2%). The features of HPV DNA-/p16+ cases (n=93) were similar to those of the HPV-associated VSCC, and HPV DNA+/p16- (n=74) cases had a more diverse profile, although they were more similar to HPV-independent tumors. Several histological characteristics were more frequently associated with HPV-related VSCC (koilocytotic-like change, necrosis, moderate to marked pleomorphism, invasive front in nests; p

Background Many countries, mainly high- and upper-middle income, have implemented human papillomavirus (HPV) vaccination programs, with 47 million women receiving the full course of vaccine (three doses) in 2014. To evaluate the potential impact of HPV vaccines in the reduction of HPV-related disease, we aimed to estimate the HPV type distribution and burden of anogenital and head and neck cancers attributable to HPV types (HPVs 16/18/31/33/45/52/58/6/11) included in currently licensed HPV vaccines. Methods In all, 18 247 formalin-fixed paraffin-embedded specimens were retrieved from 50 countries. HPV DNA detection and typing were performed with the SPF-10 PCR/DEIA/LiPA25 system. With the exception of cervical cancer, HPV DNA-positive samples were additionally subjected to HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. For cervical cancer, estimates were based on HPV DNA, whereas for other sites, estimates were based on HPV DNA, E6*I mRNA, and p16INK4a biomarkers. Results The addition of HPVs 31/33/45/52/58 to HPVs 16/18/6/11 in the nonavalent HPV vaccine could prevent almost 90% of cervical cancer cases worldwide. For other sites, the nonavalent HPV vaccine could prevent 22.8% of vulvar, 24.5% of penile, 60.7% of vaginal, 79.0% of anal cancers, 21.3% of oropharyngeal, 4.0% of oral cavity, and 2.7% of laryngeal cancer cases. Conclusions Our estimations suggest a potential impact of the nonavalent HPV vaccine in reducing around 90% of cervical cancer cases and a global reduction of 50% of all the cases at HPV-related cancer sites.

BackgroundHuman papillomavirus (HPV) is the cause of a fraction of head and neck squamous cell carcinoma. Although this relation is well-known, it is still not clear the role of HPV in premalignant oral lesions such as oral lichen planus (OLP) and dysplasia. We aimed to evaluate the HPV-DNA prevalence and type distribution in a set of oral biopsies obtained from patients diagnosed with OLP and dysplasia, as well as the role of HPV in these lesions.MethodsA retrospective cohort of all premalignant oral lesions consecutively diagnosed from March 30th 1995 to May 21st 2014 at Hospital of Bellvitge and Odontological University Hospital of Bellvitge was identified and classified in four groups: OLP (groups 1 and 2) and dysplasias (groups 3 and 4) that progressed or not to invasive cancer during follow-up. A random selection targeting 25 cases was aimed to be performed for each group. All selected cases were subjected to pathological evaluation, DNA quality control and HPV-DNA detection. HPV-DNA positive samples were further subject to p16INK4a analysis.ResultsA total of 83 cases yielded a valid HPV-DNA result. From those, 7 and 34 cases were OLP that progressed or not to invasive cancer during follow-up, whereas 24 and 18 cases were displasias that progressed or not to invasive cancer during follow-up, respectively. HPV-DNA was detected in 4 samples (3 dysplastic lesions and 1 OLP). Two samples were HPV16 positive (2%), 1 sample HPV18 positive (1%) and 1 sample (1%) was HPV indeterminate. Two out of four HPV-DNA positive cases had high p16INK4a expression and none of the HPV positive cases progressed to invasive cancer during long-term follow-up.ConclusionsWe found a low HPV-DNA attributable fraction in premalignant lesions of the oral cavity, suggesting that HPV is unlikely to play a significant role in oral carcinogenesis in our setting.

Objetivo: Evaluar el impacto de la ausencia de cribado en la incidencia de cáncer de cuello uterino durante el periodo 2000-2010 en el Principado de Asturias. Diseno: ˜ Estudio retrospectivo. Emplazamiento: Todos los hospitales públicos de Asturias. Mediciones principales: Fueron revisadas 374 historias clínicas de mujeres diagnosticadas de cáncer de cuello uterino. La información clínica, el estadio FIGO y los datos de las citologías previas fueron obtenidos de las historias clínicas e informes de anatomía patológica. Se realizó análisis bivariante utilizando el test de chi-cuadrado de Pearson y regresión logística para el cálculo de odds ratio e intervalos de confianza al 95%. Resultados: El 65,6% de las mujeres diagnosticadas de cáncer de cérvix entre los 25 y los 70 anos ˜ no habían realizado una citología en al menos los 5 anos ˜ y medio anteriores al diagnóstico. Este porcentaje se relacionó con la mayor edad al diagnóstico, la presencia de síntomas asociados y con un estadio tumoral avanzado en el momento del diagnóstico. En las mujeres diagnosticadas con una edad mayor de 70 anos ˜ se objetivó que el 83,3% no habían realizado ninguna citología con anterioridad al momento del diagnóstico. Conclusión: La implantación de un buen programa de cribado de cáncer cervicouterino y una calidad óptima del sistema en cada uno de los procedimientos que lo integran contribuiría a disminuir la incidencia y la mortalidad por cáncer de cuello uterino en Asturias.

Background: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. Methods: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16(INK4a)/pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC. Results: 788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16(INK4a), HPV-DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16(INK4a), respectively. Being nonsmoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub-sites and treatments was observed. Double positivity for HPV-DNA/p16(INK4a) showed strongest diagnostic accuracy and prognostic value. Conclusions: Double positivity for HPV-DNA/p16(INK4a), a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients' classification and handling and also suggest that not all the HPV-related OPC behave similarly.

The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value.We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16Double positivity for HPV-DNA/p16

Background Human papillomavirus (HPV)-related anal cancer lesions are often found adjacent to the squamocolumnar junction (SCJ). We have assessed the histopathology and associated HPV genotypes in anal SCJ lesions in surgically excised anal warts in HIV-negative and –positive patients. Methods Histopathology identified 47 squamous intraepithelial lesions (SILs) adjacent to the SCJ amongst a total of 145 cases of clinically diagnosed anal condylomata. The anal SCJ lesions were further analyzed with p16, CK7 and p63 immunohistochemistry and HPV genotyping. Results Sixteen (16/47) of the excised anal wart lesions contained HSIL; Three were HSIL and exclusively associated with oncogenic HPVs. A further thirteen (13/47) were mixed lesions. Of these eight were HSILs with LSIL and six were HSILs with papillary immature metaplasia (PIM); Ten of the mixed lesions were associated with one or more oncogenic HPVs, while three cases were exclusively associated with HPV6. Conclusions Clinically diagnosed anal warts cannot be assumed to be limited to low-grade lesions as anal warts of the SCJ often show heterogeneous lesions, with coexistence of LSIL, PIM, and HSIL. Lesions showing PIM, however, may mimic HSIL, because they are hypercellular, but lack the nuclear atypia and conspicuous mitotic activity of HSIL; and are p16 negative., Highlights • Anal warts of the SCJ are often heterogeneous; with LSIL, including PIM and HSIL. • Anal HSILs only with HPV6 may indicate that LR-HPVs have some role in oncogenesis. • Recognition of PIM is important given its potential for being confused with HSIL. • Clinical diagnosis of anal warts cannot be assumed to be limited to LSIL. • Microscopic examination of anal warts is encouraged with appropriate immunostains.

There are at least two different etio-pathogenic pathways for the development of vulvar squamous cell carcinoma (VSCC): one associated with infection by human papillomavirus (HPV) and another independent of HPV. We aimed to describe the histological characteristics of HPV-associated and -independent tumors and to determine the best strategy to identify HPV in VSCC. A single paraffin block was available for review from a series of 1,594 VSCCs. In all cases HPV DNA detection was analyzed using the SPF10PCR/DEIA/LiPA25 system and p16 immunohistochemistry (IHC). A tumor was considered as unquestionably HPV-associated if both HPV DNA and p16 IHC were positive. A tumor was considered indisputably HPV-independent if both HPV DNA and p16 IHC were negative. Two groups of tumors were classified as non-conclusive: (1) HPV DNA+/p16- and (2) HPV DNA-/p16+. WHO typing and a thorough histological evaluation were conducted in all cases. Four hundred and forty-one tumors were HPV DNA+ with 367 cases (23.0%) being HPV DNA+/p16+. The latter tumors were more frequently basaloid or warty (49.8%), but 36.5% were of the keratinizing type; 1,153 tumors were HPV DNA-, with 1,060 cases (66.5%) being HPV DNA-/p16-. These HPV DNA-/p16- tumors were mostly keratinizing (81.2%) but were occasionally basaloid or warty (5.2%). The features of HPV DNA-/p16+ cases (n = 93) were similar to those of the HPV-associated VSCC, and HPV DNA+/p16- (n = 74) cases had a more diverse profile, although they were more similar to HPV-independent tumors. Several histological characteristics were more frequently associated with HPV-related VSCC (koilocytotic-like change, necrosis, moderate to marked pleomorphism, invasive front in nests; p 0.001), however, none of these characteristics allowed differentiation between HPV-associated and -independent VSCC. In conclusion, histological criteria do not allow differentiation between HPV-associated and -independent VSCC. p16 Alone is a clinically easy strategy to determine HPV status in VSCC.

Resumen Objetivo Evaluar el impacto de la ausencia de cribado en la incidencia de cáncer de cuello uterino durante el periodo 2000-2010 en el Principado de Asturias. Diseño Estudio retrospectivo. Emplazamiento Todos los hospitales públicos de Asturias. Mediciones principales Fueron revisadas 374 historias clínicas de mujeres diagnosticadas de cáncer de cuello uterino. La información clínica, el estadio FIGO y los datos de las citologías previas fueron obtenidos de las historias clínicas e informes de anatomía patológica. Se realizó análisis bivariante utilizando el test de chi-cuadrado de Pearson y regresión logística para el cálculo de odds ratio e intervalos de confianza al 95%. Resultados El 65,6% de las mujeres diagnosticadas de cáncer de cérvix entre los 25 y los 70 años no habían realizado una citología en al menos los 5 años y medio anteriores al diagnóstico. Este porcentaje se relacionó con la mayor edad al diagnóstico, la presencia de síntomas asociados y con un estadio tumoral avanzado en el momento del diagnóstico. En las mujeres diagnosticadas con una edad mayor de 70 años se objetivó que el 83,3% no habían realizado ninguna citología con anterioridad al momento del diagnóstico. Conclusión La implantación de un buen programa de cribado de cáncer cervicouterino y una calidad óptima del sistema en cada uno de los procedimientos que lo integran contribuiría a disminuir la incidencia y la mortalidad por cáncer de cuello uterino en Asturias.

International audience; BACKGROUND:The careHPV assay is a test for high-risk (HR) human papillomaviruses (HPV) detection designed to be affordable in resource-poor settings. We evaluated the performance of careHPV screening among 1052 women living with HIV/AIDS included in the HARP (HPV in Africa Research Partnership) study in Burkina Faso (BF) and South Africa (SA).METHODS:Cervical samples were tested for HR-HPV by the careHPV and the INNO-LiPA HPV genotyping Extra assays. All women had Pap smear testing, visual inspection with acetic acid/Lugol's iodine (VIA/VILI) and colposcopy. Cervical biopsies were obtained for participants who were HR-HPV DNA positive by careHPV or who had abnormalities detected on cytology, VIA/VILI or colposcopy.RESULTS:Overall, 45.1% of women had a positive careHPV test (46.5% in BF, 43.8% in SA). The careHPV positivity rate increased with the grade of cytological lesions. Sensitivity and specificity of careHPV for the diagnosis of CIN2+ (n=60, both countries combined) were 93.3% (95% confidence interval (CI): 83.8-98.2) and 57.9% (95% CI: 54.5-61.2), respectively. Specificity increased with CD4 count. careHPV had a similar clinical sensitivity but higher specificity than the INNO-LiPA assay for detection of CIN2+.CONCLUSIONS:Our results suggest that careHPV testing is a reliable tool for cervical cancer screening in HIV-1-infected women in sub-Saharan Africa.

The carcinogenic role of high-risk human papillomavirus (HR-HPV) types in the increasing subset of vulvar intraepithelial neoplasia and vulvar cancer in young women has been established. However, the actual number of vulvar cancer cases attributed to HPV is still imprecisely defined. In an attempt to provide a more precise definition of HPV-driven vulvar cancer, we performed HPV-type-specific E6*I mRNA analyses available for 20 HR-/possible HR (pHR)-HPV types, on tissue samples from 447 cases of vulvar cancer. HPV DNA genotyping was performed using SPF10-LiPA25 assay due to its high sensitivity in formalin-fixed paraffin-embedded tissues. Data on p16INK4a expression was available for comparative analysis via kappa statistics. The use of highly sensitive assays covering the detection of HPV mRNA in a broad spectrum of mucosal HPV types resulted in the detection of viral transcripts in 87% of HPV DNA+ vulvar cancers. Overall concordance between HPV mRNA+ and p16INK4a upregulation (strong, diffuse immunostaining in >25% of tumor cells) was 92% (K=0.625, 95% confidence interval (CI)=0.531-0.719). Among these cases, 83% were concordant pairs of HPV mRNA+ and p16INK4a+ and 9% were concordant pairs of HPV mRNA- and p16INK4a-. Our data confirm the biological role of HR-/pHR-HPV types in the great majority of HPV DNA+ vulvar cancers, resulting in an HPV-attributable fraction of at least 21% worldwide. Most HPV DNA+ vulvar cancers were associated with HPV16 (85%), but a causative role for other, less frequently occurring mucosal HPV types (HPV26, 66, 67, 68, 70 and 73) was also confirmed at the mRNA level for the first time. These findings should be taken into consideration for future screening options as HPV-associated vulvar preneoplastic lesions have increased in incidence in younger women and require different treatment than vulvar lesions that develop from rare autoimmune-related mechanisms in older women.

Background Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The incidence is higher in less developed countries, where penile cancer can account for up to 10% of cancers among men in some parts of Africa, South America, and Asia. Objective To describe the human papillomavirus (HPV) DNA prevalence, HPV type distribution, and detection of markers of viral activity (ie, E6*I mRNA and p16 INK4a ) in a series of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 countries. A total of 85 penile HGSILs and 1010 penile invasive cancers diagnosed from 1983 to 2011 were included. Design, setting, and participants After histopathologic evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping were performed using the SPF-10/DEIA/LiPA 25 system, v.1 (Laboratory Biomedical Products, Rijswijk, The Netherlands). HPV DNA–positive cases were additionally tested for oncogene E6*I mRNA and all cases for p16 INK4a expression, a surrogate marker of oncogenic HPV activity. Outcome measurements and statistical analysis HPV DNA prevalence and type distributions were estimated. Results and limitations HPV DNA was detected in 33.1% of penile cancers (95% confidence interval [CI], 30.2–36.1) and in 87.1% of HGSILs (95% CI, 78.0–93.4). The warty-basaloid histologic subtype showed the highest HPV DNA prevalence. Among cancers, statistically significant differences in prevalence were observed only by geographic region and not by period or by age at diagnosis. HPV16 was the most frequent HPV type detected in both HPV-positive cancers (68.7%) and HGSILs (79.6%). HPV6 was the second most common type in invasive cancers (3.7%). The p16 INK4a upregulation and mRNA detection in addition to HPV DNA positivity were observed in 69.3% of HGSILs, and at least one of these HPV activity markers was detected in 85.3% of cases. In penile cancers, these figures were 22.0% and 27.1%, respectively. Conclusions About a third to a fourth of penile cancers were related to HPV when considering HPV DNA detection alone or adding an HPV activity marker, respectively. The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines in the reduction of HPV-related penile neoplastic lesions. Patient summary About one-third to one-quarter of penile cancers were related to human papillomavirus (HPV). The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines to prevent HPV-related penile neoplastic lesions.

Objective The objective of this study was to describe prior negative screening history and symptoms around the time of diagnosis of incident cervical cancer (CC) cases diagnosed between 2000 and 2010 within the Asturias public health system. Methods Records from 374 women diagnosed with CC between 2000 and 2010 from all public hospitals in Asturias were retrieved. Clinical information, FIGO stage and all previous cytological data were extracted from clinical and histopathological records. Proportional differences were assessed using chi-square tests. Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Inter-observer agreement in cytology was checked by comparing concordance values using k-statistics. Results No prior screening history was recorded in 60.7% of CC cases and its absence increased with age and advanced stage. Advanced stage (e.g., ≥ II) at diagnosis was associated with age (>50 years) and adenocarcinoma (ADC) compared to younger women and those with a squamous cell carcinoma (SCC). False negative smears were identified in 27.1% of women with CC (ADC 52.6% vs. SCC 16.2%, p

Few studies have assessed the burden of human papillomavirus (HPV) infection in Pakistan. We aim to provide specific information on HPV-type distribution in invasive cervical cancer (ICC) in the country. A total of 280 formalin-fixed paraffin-embedded tissue blocks were consecutively selected from Shaukat Khanum Memorial Cancer Hospital and Research Centre (Lahore, Pakistan). HPV-DNA was detected by SPF10 broad-spectrum PCR followed by DNA enzyme immunoassay and genotyping by LiPA25. HPV-DNA prevalence was 87.5% (95%CI: 83.0-91.1), with 96.1% of cases histologically classified as squamous cell carcinoma. Most of the HPV-DNA positive cases presented single infections (95.9%). HPV16 was the most common type followed by HPV18 and 45. Among HPV-DNA positive, a significantly higher contribution of HPV16/18 was detected in Pakistan (78.4%; 72.7-83.3), compared to Asia (71.6%; 69.9-73.4) and worldwide (70.8%; 69.9-71.8) and a lower contribution of HPVs31/33/45/52/58 (11.1%; 7.9-15.7 vs. 19.8%; 18.3-21.3 and 18.5%; 17.7-19.3). HPV18 or HPV45 positive ICC cases were significantly younger than cases infected by HPV16 (mean age: 43.3, 44.4, 50.5 years, respectively). A routine cervical cancer screening and HPV vaccination program does not yet exist in Pakistan; however, the country could benefit from national integrated efforts for cervical cancer prevention and control. Calculated estimations based on our results show that current HPV vaccine could potentially prevent new ICC cases.

Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM). Generally attributable to infection by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade squamous intraepithelial lesions (SILs). However, anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of intraepithelial lesions and of the associated HPVs in heterosexual men and women and MSM. Perianal and anal condylomata were collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV-positive MSM). We assessed lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV infection status, MSM showed a higher proportion of condylomata as high-grade SILs compared to heterosexual men/women. High-grade SILs were also more prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio (4.6; 95% confidence interval 2.1–10.0) of perianal low-grade SILs containing only high-risk HPVs compared to HIV-negative MSM. In addition, more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low-risk HPVs. Particularly, low-grade perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high-grade SILs were common in both MSM groups. Our findings sound a note of caution for the common clinical practice for the treatment of anal condylomata as benign lesions in MSM and HIV-positive patients.