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Human papillomavirus (HPV)-induced invasive cervical squamous cell cancer (SCC) develop via high-grade squamous intraepithelial lesion (HSIL). In contrast to classic thick HSIL, thin HSIL (≤9 cell layers) are poorly documented. This study compares histology, HPV genotypes, and aberrations in 50 cancer genes of 45 thin HSIL to 45 thick HSIL, 20 pT1a SCC, and 40 ≥pT1b SCC. Thin HSIL arose from proliferating reserve cells within endocervical epithelium or immature metaplasia throughout the transformation zone after infection with high-risk HPV genotypes (36/45; 80%), and 20% non-high-risk HPV genotypes compared with 2.5% thick HSIL, pT1a SCC, and ≥pT1b SCC. Thin HSIL were multifocal proliferations with varying epithelial thickness between 1 and 2 to 9 cell layers, with occasional transitions to thick HSIL or concomitant lesions of thick HSIL. Overall, 40% thin HSIL were located distant to and most thick HSIL occurred near or at the squamocolumnar junction. Only 20% thick HSIL showed koilocytosis. All HSIL lacked somatic gene mutations, compared with 30% pT1a and 55%≥pT1b SCC. Overrepresented rare germline variants in the MET, JAK3, and FGFR3 genes occurred in all patient groups. In summary, thin and thick HSIL arose independently of somatic gene mutations. The maturation level of the squamous epithelium at the time of transforming infection determines if a thick HSIL develops directly from HPV-infected proliferating reserve cells via thin HSIL or in stratified glycogenated squamous epithelium via low-grade squamous intraepithelial lesion. These observations raise doubts about the biological relevance of separation into thin and thick HSIL. The oncogenic potential of HPV genotypes but also germline variants may influence the natural history.

A male Holstein-Friesian calf was born with multiple, cauliflower-like, pale pink cutaneous masses on the head and limbs. On histopathological examination, the cutaneous masses were diagnosed as congenital cutaneous fibropapillomatosis. Those lesions involved focal proliferation of sebaceous gland in the dermis. There were no histological findings to suggest bovine papillomavirus infection, such as the presence of intranuclear inclusion bodies, large keratohyalin granules, and koilocytosis. Furthermore, papillomaviral antigens and DNA were not detected by immunohistochemistry and polymerase chain reaction, respectively. These results suggested that there was no association between these cutaneous lesions and bovine papillomavirus infection, and the lesions were considered as harmartomatous changes.

Canine papillomatosis is mainly attributed to papillomavirus infections. Papillomavirus DNA is also frequently identified in healthy skin, and evidence of high papillomavirus diversity complicates this simplistic view of causality. The aim of this study was to determine how frequently canine papillomas contain papillomavirus DNA and express viral protein, and how these factors correlate to the histology and anatomic location. Fifty-three archived, formalin-fixed samples of canine papillomas and eight samples of other proliferative skin lesions from dogs were included. Samples were re-evaluated histologically, tested for papillomavirus L1-antigen using immunohistochemistry, and for papillomavirus DNA with PCR assays and molecular sequencing. Most papillomas from haired skin contained papillomavirus DNA (96%) and antigen (92%). Of oral papillomas, 88% were positive for both papillomavirus DNA and antigen. Approximately 50% of non-papilloma proliferations and papillomas from eyelid/conjunctiva specimens contained viral DNA, but antigen was present in only 12% of eyelid/conjunctiva papillomas and in none of the non-papilloma proliferations. The presence of viral antigen was highly correlated with histological indicators of viral infection, including intranuclear inclusions, koilocytes, cytoplasmatic vacuolation and dysplasia. The viruses found were mainly CPV1 and CPV2. CPV1 dominated in oral infections, while CPV2 dominated in cutaneous endophytic papillomas. Co-infections with CPV1 and CPV2 accounted for about 20% of all detected infections. These results support a role for papillomaviruses in canine cutaneous and oral, exophytic and endophytic papillomas and support previously raised doubts about their role in squamous papillomas from eyelid/conjunctiva specimens.

Background The presence of human papilloma virus in benign oral lesions has been studied by different techniques obtaining extremely variable results. The objective of this study was to determine the presence of human papillomavirus in 83 cases of benign hyperplastic epithelial oral lesions. Material and Methods Eighty-three oral lesions with clinical or histopathological features suggestive of HPV infection were retrieved from the files of four oral pathology services. Demographic data were obtained from patient´s medical charts. All cases had available clinical image, H&E preparations and paraffin blocks with enough tissue for HPV detection by in situ hybridization, and immunohistochemical reactions for Ki67. Results Episomal positivity for wide spectrum HPV was observed in 24% of the cases; most of them (70%) HPV 6/11 positive. HPV 16/18 was not detected. Condyloma acuminatum was the most common lesion associated with HPV (75%), followed by verruca vulgaris (15%), squamous papilloma and multifocal epithelial hyperplasia, 5% each. Koilocytes were identified in all the HPV positive cases. Ki67 showed an abnormal proliferation pattern in 90% of the HPV positive cases; most of them (70%) showing groups of proliferating cells in focal superficial regions, and in 20% positivity was seen almost in the whole thickness of the epithelium. HPV negative cases showed Ki67 positive cells restricted to the basal layer. Conclusions Regarding oral lesions associated with HPV, condyloma is the most common lesion expressing low-risk subtypes. The etiology of squamous papilloma remains controversial as HPV was found in 1.9% of the cases. The identification of koilocytes and the pattern of expression of Ki67 reflect HPV infection and are helpful for classification. Papillary oral lesions not associated to HPV deserve further studies to better clarify its etiology. Key words:Human papillomavirus, condyloma, papilloma.

Psychological stress is an important factor involved in disease manifestations of human papillomavirus (HPV) infection, and it can participate in HPV-associated carcinogenesis. The impact or effect which stress can have (exert) depends on a person’s genetic pool, experiences and behaviors. Due to inconsistencies in some study results, this issue remains a subject of research. Concerning the course of HPV manifestations, it has been observed that a higher number of life stressors in at least the previous 6 months, the absence of social support and the types of personal coping mechanisms employed, all influence HPV progression. In women with cervical dysplasia, a connection between greater stress experiences and dysregulation of specific immune responses has been observed. Once HPV enters a cell via the α6 integrin there are three possible sequences: latent infection, subclinical infection, and clinically manifest disease. HPV proliferation in differentiated epithelial cells induces morphologically cytopathic changes (koilocytosis, epidermal thickening, hyperplasia, hyperkeratosis). Oncogenic transformation requires the integration of the virus genome into the host genome. In doing so, DNA in the E1 region of E2 breaks down, leading to transcription disorders of E6 and E7. For the formation of irreversible malignancy, the following sequence is necessary: initial expression of E6 and E7 genes followed by suppression of apoptosis and the stabile expression of E6 and E7 proteins that protect transformed cells from apoptosis. A successful immune response is characterized by a strong, local cell-mediated immune response. Several factors are important for the regression of HPV manifestation/infection, among which is psychological stress which can prolong the duration and severity of HPV disease. Stress hormones may reactivate latent tumor viruses, stimulate viral oncogene expression, and inhibit antiviral host responses. In the regression of HPV infection, increased activity of Th1 cells was observed. However, during psychosocial stress, a decrease in the Th1 type of immune response is seen, and there is a shift towards a Th2 response. Understanding perceived stress and biological changes in stress, as well as the evaluation of immune parameters, gives researchers a better picture of how stress influences HPV infections and how to improve disease management and outcomes.

Papillomaviruses (PVs) are circular double-stranded DNA virus belonging to Papillomaviridae family. During the infection cycle, PVs translate proteins that can influence cell growth and differentiation, leading to epidermal hyperplasia and papillomas (warts) or malignant neoplasms. Canis familiaris papillomaviruses (CPVs) have been associated with different lesions, such as oral and cutaneous papillomatosis, pigmented plaques, and squamous cell carcinomas (SCCs). Here, we report a clinical case of a mixed bred female dog with pigmented plaques induced by CPV16 (Chipapillomavirus 2) that progressed to in situ and invasive SCCs. Gross and histological findings were characterized, and the lesions were mainly observed in ventral abdominal region and medial face of the limbs. In situ hybridization (ISH) revealed strong nuclear hybridization signals in the neoplastic epithelial cells, as well as in the keratinocytes and koilocytes of the pigmented viral plaques. The full genome of the CPV16 recovered directly from the lesions was characterized, and the phylogenetic relationships were determined. The identification of oncoprotein genes (E5, E6, and E7) by high throughput sequencing (HTS) and their expected domains are suggestive of the malignant transformation by CPV16.

Objective The Netherlands converted to high-risk (hr)HPV-based screening in 2017. An increase in referral of hrHPV-positive women with low risk for cervical intraepithelial neoplasia grade 3 or more (CIN3+) is anticipated and reduction of unjustified referrals will have priority. The relevance of koilocytosis in relation to the underlying risk of high-grade CIN in a primary HPV screening setting is unclear. The aim was to investigate whether the risk for CIN3+ differs between hrHPV-positive atypical squamous cells of undetermined significance (ASC-US)/low-grade squamous intraepithelial lesion (LSIL) with or without koilocytosis. Methods Retrospective cohort study, using data from the Dutch national pathology database (PALGA). The population was 1201 hrHPV-positive women with cytological diagnosis of ASC-US/LSIL. Reporting of koilocytosis was assessed as well as detection rates of CIN1 or less, CIN2 and CIN3+ for ASC-US/LSIL cytology stratified by presence or absence of koilocytosis. Crude and adjusted odds ratios were determined. Results Koilocytosis was present in 40.1% of ASC-US and 45.9% of LSIL cases. CIN3+ is significantly less often found when koilocytosis is present (7.8% for hrHPV-positive ASC-US with- vs 15.8% without koilocytosis). For hrHPV-positive LSIL this was 11.7% vs 20.2%. The crude and adjusted odds ratios for CIN3+ was 0.45 for hrHPV-positive ASC-US and 0.52 for hrHPV-positive LSIL. Conclusions The presence of koilocytosis is a negative predictor of CIN3+. The risk of hrHPV-positive ASC-US with koilocytosis is in the same range as hrHPV-positive/cytology negative cases and in a setting of primary hrHPV screening these cases could be followed conservatively by repeat cytology. The results should be confirmed by the first data from the Dutch HPV-based screening programme.

Our aim was to estimate the risk of disease incidence in women with atypical squamous cell of undetermined significance (ASC-US) without histology-proven cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by human papillomavirus (HPV) genotype.Between January 2002 and September 2010, incidence of CIN2+ in 2880 women including 2172 with ASC-US and histology-proven negative and 708 with ASC-US with histology-proven CIN1 was investigated. Baseline HR-HPV status was determined by the hybrid capture II assay (HC2) and HR-HPV genotype by the HPV DNA chip test (HDC). Cumulative incidence and hazard ratios were estimated to explore differences between index data and associations with CIN2+.Of the 2880 women, the HC2 was positive in 1509 women (52.4%) and the HDC was positive in 1563 women (54.3%). The overall agreement between the HDC and HC2 was 97.4%. One hundred ninety (6.6%) patients developed CIN2+. The 5-year cumulative incidence rate of CIN2+ in HPV-16, HPV-31, HPV-52, and HPV-58 were 16.7%, 15.1%, 12.6%, and 12.9%, respectively. On multivariate analysis, being positive in HPV-16 (hazards ratio [HR]=2.431; 95% CI, 1.789-3.332; P0.01), HPV-31 (HR=2.335; 95% CI, 1.373-3.971; P0.01), HPV-52 (HR=1.592; 95% CI, 1.031-2.458; P=0.03), and HPV-58 (HR=1.650; 95% CI, 1.132-2.407; P0.01) were significantly associated with developing CIN2+ compared to being negative for that type.Among women with ASC-US, HPV-16, HPV-31, HPV-52, or HPV-58 positive women may need intensified follow-up as they have the highest risk of becoming CIN2+.

The aim of this study was to investigate the clinical performance of high risk (HR) HPV E6/E7 mRNA assay in detecting cervical high-grade intraepithelial neoplasia and cancer among women with atypical squamous cells of undetermined significance (ASCUS) Papanicolaou (Pap) smears. A total of 160 patients with ASCUS who underwent HR-HPV DNA assay, HR-HPV E6/E7 mRNA assay and colposcopy biopsy at Third Affiliated Hospital of Zhengzhou University, China, from December 2015 to March 2017, were enrolled. Logistic regression analysis was used to evaluate the relationship between pathological results with clinical biologic factors. Univariate analysis showed that the qualitative results of HR-HPV DNA, qualitative results of HR-HPV E6/E7 mRNA and expression levels of HR-HPV E6/E7 mRNA were risk factors of high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer (all P

In Iran, human papillomavirus (HPV) vaccination is not currently included in the national vaccination program and there are no comprehensive approaches to cervical screening program. Regional data on distribution of HPV types in women is important to predict the impact of current HPV vaccines. Although several studies on distribution of HPV types in cervical precancer and cancer have been conducted in Iran, in most of them HPV positive samples were subjected to specific-primer genotyping (mainly 16 and 18), and leaving the other HPV genotypes almost undetermined. Therefore, the present study aimed to investigate the distribution of HPV types in cervical neoplasia from West and Northwest of Iran. A total of 112 women with atypia, cervical intraepithelial neoplasia, and invasive cervical cancer were included. A PCR assay was performed in all samples to detect the presence of the HPV genome using the GP5+/6+ L1 consensus primer set. All HPV positive samples were subjected for sequencing. In overall, HPV prevalence was 20% in atypica, 44.5% in cervical intraepithelial neoplasia I, 92.3% in cervical intraepithelial neoplasia II-III, and 98.2% in invasive cervical cancer. The most frequent HPV type was HPV 16 (79.2%), which was followed by HPV types 18, 6, and 33 at the frequencies of 6.5%, 5.1%, and 2.7%, respectively. The least HPV types were found to be 31, 45, 53, 58, and 66. In conclusion, this study shows that the current HPV vaccines could have great impact to reduce the burden of cervical cancer in Iran.

Although Human Papillomavirus (HPV) exerts a vital influence on cervical carcinogenesis, other factors influence the development of a squamous intraepithelial lesion (SIL) that may or not progress to cervical cancer. Among several cytokines, Interleukin 10 (IL-10) stands out as an important anti-inflammatory factor, leading to immune system evasion through an immunosuppressive state. In the cervical microenvironment, during different stages of HPV infection, IL-10 production can be induced and maintained by different cell sources, including infected keratinocytes, some subsets of dendritic cells (DC), tumor associated macrophages (TAM), T regulatory cells (Treg) and tumor cells. Further, a wide range of effects can be exerted by IL-10 on different cell populations, such as inhibiting proinflammatory cytokine production, DCs differentiation, antigen presenting function and T-helper 1 (Th1) polarization. IL-10 is one of several cytokines involved in cancer development and sustenance, although its role in cancer is still controversial and poorly understood. However, cervical IL-10 levels tend to increase in parallel to SIL development and are even higher within cervical tumors. Accumulating data have shown that after HPV infection, IL-10 levels are enhanced as a result of HPV E2, E6 and E7 proteins action over IL-10 gene transcription, while IL-10 stimulates HPV E6 and E7 expression. Therefore, this interplay between HPV and IL-10 creates a vicious cycle that could favor an immunosuppressive microenvironment in the cervix, facilitating the progression of a simple HPV infection to SIL or cervical cancer.

Human papillomaviruses are small DNA viruses with a tropism for squamous epithelia. A unique aspect of human papillomavirus molecular biology involves dependence on the differentiation status of the host epithelial cell to complete the viral lifecycle. A small group of these viruses are the etiologic agents of several types of human cancers, including oral and anogenital tract carcinomas. This review focuses on the basic molecular biology of human papillomaviruses.

Objective Much of what is known about the significance of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma is derived from single-institution retrospective studies, post hoc analyses of tissue specimens from clinical trials, and tissue bank studies with a small sample size. The objective of this study is to investigate the impact of HPV on the frequency and clinical presentation of oropharyngeal carcinoma in a large, national sample with information from patients who underwent HPV testing. Study Design Retrospective, cross-sectional study. Methods We identified a comprehensive national sample of 8,359 patients with oropharyngeal carcinoma and known HPV status diagnosed between 2010 and 2011 within the National Cancer Database. Multivariable logistic regression was used to assess correlates of patient and tumor characteristics on HPV status. Results Among patients with oropharyngeal carcinoma, the frequency of HPV-related squamous cell carcinoma in the United States was 65.4%. HPV-related oropharyngeal carcinoma was associated with younger age, male sex, and white race (P < 0.001). Advanced primary tumor stage was associated with HPV-negative disease (P < 0.001), whereas increasing nodal burden was associated with HPV-positive disease (P < 0.001). Despite less-advanced nodal disease, HPV-negative tumors were associated with a higher likelihood of metastasis at presentation (P < 0.001). Conclusion HPV now accounts for the majority of newly diagnosed oropharyngeal carcinoma in the United States and is associated with a distinct clinical profile, supporting efforts to re-evaluate the staging and treatment paradigm for HPV-associated oropharyngeal cancer. Level of Evidence 4. Laryngoscope, 127:2270–2278, 2017

Key points The relative carcinogenicity of human papillomavirus (HPV) types is broadly consistent in women with or without human immunodeficiency virus (HIV) infection. HPV-16 and HPV-18 are important worldwide, and HPV-45 at least in Africa, warranting particular attention in HPV-based screening programs., Background. Data on the relative carcinogenic potential of human papillomavirus (HPV) types among women infected with human immunodeficiency virus (HIV) (WHIV) are needed to inform prevention programs for this population. Methods. A systematic literature review and meta-analysis of high-risk HPV-type distribution in 19883 HIV-positive women was performed. The women, from 86 studies worldwide, included 11739 with normal cytological findings; 1784 with atypical squamous cells of undetermined significance (ASCUS); 2173 with low-grade and 1282 with high-grade squamous intraepithelial lesions (HSILs) diagnosed cytologically; 1198 with cervical intraepithelial neoplasia grade 1 (CIN1), 456 with CIN2, and 455 with CIN3 diagnosed histologically; and 796 with invasive cervical cancers (ICCs). A large proportion of WHIV, and almost all with ICCs, were from Africa. Results. In Africa, HPV 16 accounted for 13% of HPV-positive WHIV with normal cytological findings, but this proportion increased through ASCUS, low-grade squamous intraepithelial lesions, CIN1, and CIN2 (18%–25%), up to 41%–47% for CIN3 and ICCs. Only HPV 16, HPV 18, and HPV 45 accounted for a greater proportion of HPV infections in ICCs compared with normal cytological findings (ICC:normal ratios, 3.68, 2.47, and 2.55, respectively). Other high-risk types accounted for important proportions of low- and/or high-grade lesions, but their contribution dropped in ICCs, with ICC:normal ratios in Africa ranging from 0.79 for HPV 33 down to 0.38 for HPV 56. Findings for HPV 16 and HPV 18 in Europe/North America, Asia, and Latin America were compatible with those from Africa. Conclusions. HPV 16 and HPV 18 in particular, but also HPV 45, at least in Africa, warrant special attention in WHIV. Broad consistency of findings with those in HIV-uninfected population would suggest that the risk stratification offered by partial HPV genotyping tests also have relevance for HIV-positive women.

Prevalence and type distribution of human papillomavirus (HPV) in squamous cell carcinoma (SCC) and cervical intraepithelial neoplasia (CIN) were investigated in Jiangsu Province, China. A total of 344 tissue sample cases with cervical squamous-cell carcinoma (SCC) and 135 with CIN I, 117 with CIN II, and 220 with CIN III were obtained from women undergoing biopsy or surgery. 33 samples of normal cervical tissue were collected with biopsy in inspected women. HPV detection and typing were examined by polymerase chain reaction (PCR) and gene-chip. Results showed that about 15.99% of cervical squamous-cell carcinoma, 34.09% of CIN III, 27.35% of CIN II and 10.37% of CIN I specimens exhibited multiple infections. Moreover, all total positive rate, single infection and multiple infection rates for the CIN I, CIN II, CIN III and SCC groups had significant difference (P < 0.05) when compared with the normal tissue group. The total positive rate, single infection and multiple infection rates for the CIN I, CIN II and CIN III groups showed significant difference (P < 0.05) when compared with the SCC group. All the CIN II, CIN III and SCC had intimate relationship with HPV infection. The high prevalence of HPV type 16, 18, 31, 33, 52, 58 and 59 in the cervical SCC deserves more attention in Jiangsu province.

Koilocytes are the hallmark of human papillomavirus (HPV) infection and can be observed during routine cytology tests stained by Papanicolaou. However, the test is not part of the routine urinalysis report. Here we describe a case on HPV subtype 6 infection diagnosed after finding koilocytes in fresh and unstained urine sediment of a kidney allograft recipient male patient.

Papillomas caused by viral infection are well-known tumors in animals. Microscopic features typically include neoplastic epithelium with hyperkeratosis and koilocytes. An 8-y-old castrated male Shih Tzu dog was presented with a small exophytic mass on the external upper lip. The mass was diagnosed as a viral papilloma based on microscopic and immunohistochemical examination. Sebaceous cell differentiation was found in the neoplastic epithelium of the tumor, which is a rare finding in humans or animals.

Background The causal association between human papillomavirus (HPV) and oral squamous cell carcinoma (OSCC) remains controversial. Most of previous studies did not consider the potential modification effect of sexual behaviors when evaluating the role of HPV infection in OSCC risk. Objectives To explore the independent and joint effects of oral HPV infection and sexual behaviors on OSCC in Chinese population. Study design A case-control study was conducted from September 2012 to September 2015 in Fujian, China. HPV DNA genotypes were detected in tumor tissues of 178 OSCC patients and oral exfoliated cells of 189 frequency-matched controls using flow-through hybridization and gene chip. Epidemiologic data were collected with a structured questionnaire by face-to-face interviews. Odds ratios (ORs) and 95% confidence interval (CI) were estimated with unconditional logistic regression models. Results The overall HPV prevalence was 14.04% in OSCC patients and 3.17% in controls. HPV-18 was the most prevalent type in cases and controls (10.67% vs. 2.12%). Oral HPV infection was strongly associated with an increased risk of OSCC: the ORs were 7.21 (95% CI: 2.61–19.88) for HPV16/18 and 7.59 (95% CI: 2.34–24.64) for HPV-18. Moreover, the significant associations were only observed in females, young adults, married population, merchants, non-smokers, non-alcohol drinkers and non-tea drinkers. Additionally, the first intercourse below 22 years of age and oral sex practice did not show an association with OSCC. But there was a significantly multiplicative interaction between HPV 16/18 and age at first intercourse for OSCC (Pinteraction Conclusions Oral HPV infection (specifically type 18) is an independent risk factor for OSCC in Fujian area. Furthermore, there might be a combined effect of HPV 16/18 and age at first intercourse on OSCC.

Background Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) are clinically, epidemiologically and prognostically distinct from other OPSCCs. The incidence of HPV-related OPSCCs has increased significantly worldwide over the past few decades. However, no studies of OPSCC with direct molecular HPV testing has been conducted in New Zealand. Aims To estimate the proportion of OPSCCs attributable to HPV infections in a New Zealand population with a validated HPV testing algorithm. Methods HPV-status was determined by p16 immunohistochemistry and polymerase chain reaction (PCR) of both L1 and E6/7 genes on 55 OPSCCs diagnosed in 2010 and 2011 in Central and South Auckland. Baseline and survival analyses were performed according to HPV status. Results Forty-one (75%) of OPSCC tumours had HPV infections. There was 98% concordance between p16 immunohistochemistry and real-time E6/E7 PCR. After a median follow-up period of 2.6 years, patients with OPSCC of HPV aetiology had more favourable outcomes compared to patients with HPV-negative OPSCC (hazard ratio 0.14, P = 0.02) after adjustment for other variables. Conclusion This study highlights the significant role that HPV plays in the aetiology of OPSCC in New Zealand, and confirms the high rate of accuracy of p16 immunostaining.

Background Cancer of the head and neck comprises a group of neoplasms that share a similar anatomical origin. Most originate from the epithelium of the aerodigestive tract and 90% correspond to squamous cell carcinoma. In the last 15 years, an increase in the incidence of squamous cell carcinoma induced by human papillomavirus (HPV) has been seen, mainly types 16 and 18, which are the most frequent found in cancers of the oral cavity and oropharynx, and types 6 and 11 in laryngeal cancer. There are reports in the literature that show HPV as the leading cause of oropharyngeal squamous cell carcinoma. Objective Determine the prevalence of infection with high-risk HPV in patients diagnosed with squamous cell carcinoma of the oral cavity, oropharynx and larynx. Material and methods An observational, cross-sectional, descriptive, unblinded study was performed. Prevalence of HPV infection was determined by polymerase chain reaction (PCR) in DNA samples from tumour tissue of patients with squamous cell carcinoma of the oral cavity, oropharynx and larynx. Typing was subsequently performed in HPV positive samples in order to detect types 18, 16, 11 and 6, using custom primers. Results A total of 45 patients were included. The association between laryngeal squamous cell carcinoma and HPV was established in two patients, which represented an overall prevalence of 4.4% in our population, and 10% for laringeal tumours. Conclusions There is a low prevalence of HPV infection in squamous cell carcinoma of the oral cavity, oropharynx and larynx, in our population. Prospective studies on younger patients could provide more information.

BACKGROUND Whether higher grade cervical intraepithelial neoplasia (CIN grade 2 or greater [CIN ≥ 2]) that develops because of human papillomavirus (HPV) genotypes not included in vaccines may progress to cervical cancer is largely unknown. The objectives of this study were to document expression of the cyclin-dependent kinase inhibitor 2A (p16) tumor-suppressor protein p16INK4A as a biomarker of cervical carcinogenesis or of malignant potential and to evaluate whether its expression differs between lesions associated with vaccine and nonvaccine high-risk (HR) human papillomavirus (HPV) genotypes. METHODS The study population consisted of 371 women who had not received HPV vaccines. Women were categorized into vaccine and nonvaccine HR-HPV genotypes and lesions associated with those types. Logistic regression analyses were used to determine the association between positive expression p16INK4A and the risk of being diagnosed with CIN 2 or CIN 3. Differences in the proportion of CIN ≥2 lesions that were positive for p16INK4A expression by vaccine-related or nonvaccine-related HR-HPV genotype were determined using the Pearson chi-square test. RESULTS Specimens that were positive for p16INK4A expression were 5.3 and 16.6 times more likely to be diagnosed as CIN 2 and CIN 3 lesions, respectively, compared to CIN 1 lesions. CIN ≥ 2 lesions that were negative for the bivalent and 9-valent HR-HPV genotypes had similar rates of positive p16INK4A expression compared with lesions that were positive for those HR-HPV genotypes. CONCLUSIONS Lesions that may develop because of HR-HPV genotypes not included in HPV vaccines are likely to have similar malignant potential, suggesting that well developed screening programs combined with nonvaccine-based approaches may be needed to manage the residual risk of developing cervical cancer in the post-HPV vaccination era. Cancer 2016;122:3615-23. © 2016 American Cancer Society.

Vulvar squamous cell carcinoma (VSCC) develops through 2 distinct molecular pathways, one involving high-risk human papillomavirus (HPV) infection and the other through early p53 suppressor gene mutation. We sought to evaluate the influence of p53 mutation, HPV status, and p16 expression on local recurrence and disease-specific mortality in early stage VSCC.We performed a retrospective chart review of all patients with stage I VSCC at the Maine Medical Center from 1998 to 2007 (n = 92). Tumor size, depth of invasion, lymphatic/vascular space invasion, and growth pattern were recorded. Paraffin-embedded tissue blocks were stained by immunohistochemistry for p16 and p53; high-risk HPV was detected by polymerase chain reaction assay. Margin distance was determined by a gynecologic pathologist. Survival analyses were conducted to examine predictors of VSCC recurrence and disease-specific mortality.Age, depth of invasion, lymphatic/vascular space invasion, growth pattern, and margin status were not significant predictors of recurrence or disease-specific mortality. Tumor size of greater than 4.0 cm indicated a 4-fold increase in disease-specific mortality but did not significantly increase recurrence. p16-Positive patients were less likely to recur and had no VSCC-related deaths. Human papillomavirus-positive patients were less likely to recur and had no VSCC-related deaths. p53-positive patients were 3 times more likely to recur and nearly 7 times more likely to die from vulvar cancer.Our findings suggest that HPV and the surrogate biomarker p16 indicate a less aggressive type of vulvar cancer. p53 positivity was associated with poor prognosis and significantly increased both recurrence and disease-specific mortality.

In our previous study of the etiologic role of oncogenic human papillomavirus (HPV) types other than HPV16 and 18, we observed a significantly higher risk of cervical intraepithelial neoplasia Grades 2-3 (CIN2/3) associated with certain lineages of HPV types 31/33/45/56/58 [called high-risk (HR) variants] compared with non-HR variants. This study was to examine whether these intra-type variants differ in persistence of the infection and persistence-associated risk of CIN2/3. Study subjects were women who had any of HPV types 31/33/45/56/58 newly detected during a 2-year follow-up with 6-month intervals. For each type, the first positive sample was used for variant characterization. The association of reverting-to-negativity with group of the variants and CIN2/3 with length of positivity was assessed using discrete Cox regression and logistic regression, respectively. Of the 598 newly detected, type-specific HPV infections, 312 became undetectable during follow-up. Infections with HR, compared with non-HR, variants were marginally more likely to become negative [adjusted hazard ratio = 1.3; 95% confidence interval (CI), 0.9-1.8]. The adjusted odds ratio associating with the development of CIN2/3 was 3.0 (95% CI, 1.2-7.4) for persistent infections with HR variants for 6 months and 10.0 (95% CI, 3.8-38.0) for persistent infections with HR variants for 12-18 months as compared with the first positive detection of HR variants. Among women with non-HR variants, there were no appreciable differences in risk of CIN2/3 by length of positivity. Findings suggest that the lineage-associated risk of CIN2/3 was not mediated through a prolonged persistent infection, but oncogenic heterogeneity of the variants.

In this prospective cohort study, we compared the performance of human papillomavirus (HPV) mRNA and DNA testing of women with atypical squamous cells of undetermined significance (ASC-US) during cervical cancer screening. Using a nationwide Danish pathology register, we identified women aged 30-65 years with ASC-US during 2005-2011 who were tested for HPV16/18/31/33/45 mRNA using PreTect HPV-Proofer (n = 3,226) or for high-risk HPV (hrHPV) DNA using Hybrid Capture 2 (HC2) (n = 9,405) or Linear Array HPV-Genotyping test (LA) (n = 1,533). Women with ≥1 subsequent examination in the register (n = 13,729) were followed for up to 9.5 years for high-grade cervical intraepithelial neoplasia (CIN) or cancer. After 3 years' follow-up, mRNA testing had higher specificity for CIN3 or worse (CIN3+) than HC2 testing (88.1% [95% confidence interval (CI): 86.8-89.6%] versus 59.3% [95% CI: 58.1-60.4%]) and higher positive predictive value (PPV) (38.2% [95% CI: 33.8%-43.1%] versus 19.5% [95% CI: 17.8-20.9%]). However, the sensitivity of mRNA testing was lower than that of HC2 testing (66.7% [95% CI: 59.3-74.5%] versus 97.0% [95% CI: 95.5-98.4%]), and women testing mRNA negative had higher 3-year risk for CIN3+ than those testing HC2 negative (3.2% [95% CI: 2.2-4.2%] versus 0.5% [95% CI: 0.3-0.7%]). Patterns were similar after 18 months and 5 years'; follow-up; for CIN2+ and cancer as outcomes; across all age groups; and when comparing mRNA testing to hrHPV DNA testing using LA. In conclusion, the HPV16/18/31/33/45 mRNA test is not optimal for ASC-US triage due to its low sensitivity and the substantial risk for precancer following a negative test.

The sinonasal tract is one of the least frequent sites for squamous cell carcinoma in the head and neck. However, it is still a complex tumor type for pathologists because there are numerous histologic variants with unusual morphologic features, several non-squamous carcinomas in the differential diagnosis that can have similar morphology and even squamous differentiation, and because of the increasing recognition of human papillomavirus (HPV) in a subset of the tumors. In addition, the unique and complex anatomy of the sinonasal tract can make proper staging and management of patients’ tumors quite challenging. This article reviews sinonasal tract squamous cell carcinoma in depth and provides the latest data on Schneiderian papillomas and HPV in their pathogenesis.

Human papillomaviruses (HPVs) are small, non-enveloped, double-stranded DNA viruses that infect epithelial tissues. Specific genotypes of human papillomavirus are the single most common etiological agents of cervical intraepithelial lesions and cervical cancer. Cervical cancer usually arises at squamous metaplastic epithelium of transformation zone (TZ) of the cervix featuring infection with one or more oncogenic or high-risk HPV (HR- HPV) types. A hospital- based study in a rural set up was carried out to understand the association of HR-HPV with squamous intraepithelial lesions (SILs) and cervical cancer. In the present study, HR-HPV was detected in 65.7% of low-grade squamous intraepithelial lesions (LSILs), 84.6% of high-grade squamous intraepithelial lesions (HSILs) and 94% of cervical cancer as compared to 10.7% of controls. The association of HPV infection with SIL and cervical cancer was analyzed with Chi square test (p

Objective The aim of the study was to evaluate the association between the size of cervical lesions as detected by colposcopy and multiple human papillomavirus (HPV) infection in subjects with cervical intraepithelial neoplasia (CIN). Methods A case series of 898 subjects with CIN diagnosed by histopathology and infected by high-risk HPV. Human papillomavirus genotypes were identified using the INNO-LIPA genotyping system. Results The rates of CIN 1, CIN 2, and CIN 3+ lesions were 53.1% (477/898), 14.1% (127/898), and 32.7% (294/898), respectively. Among CIN lesions diagnosed by loop electrosurgical excision procedure or by cold-knife conization, the rates of multiple as compared with single HPV infections increased from 31.7% (59/186) in lesions covering 0% to 25% of the cervix to 39.2% (40/102), 41.9% (13/31), and 48.9% (45/92) in those covering 26% to 50%, 51% to 75%, and more than 75% of the cervix, respectively (χ for trend = 7.9; p = .005). In ordered logistic regression, after correction for confounders, odds ratios (ORs) of larger cervical lesions were higher in multiple as compared with single infections (OR = 1.82; 95% CI = 1.24-2.66; p = .002). This association was confirmed among subjects infected by HPV 16 (OR = 2.45; 95% CI = 1.14-5.26; p = .02) and in CIN 3+ lesions (OR = 2.43; 95% CI = 1.23-4.80; p = .01). Conclusions Multiple high-risk HPV infection is associated with larger cervical lesions as detected by colposcopy. This association was confirmed among subjects infected by HPV 16 and in CIN 3+ lesions.

Background/Aim. In patients with premalignant cervical lesions, human papillomavirus infection, at any moment, may be spontaneously eliminated, or may persist or lead to the transformation of cervical epithelium to a lower of higher degree. Due to that, it is necessary to wisely select the patients who are at high risk of cancer development. Aim of the study is to establish the interdependence between suspicious Papanicolaou test and colposcopy with the infection caused by high-risk genotypes of human papillomavirus and the presence of premalignant cervical lesions. Methods. This prospective study used cytological, colposcopy, real-time polymerase chain reaction of high-risk genotypes of human papillomavirus and histopathological analysis of cervical biopsy specimen. Our research included 2,578 female patients in Clinical Centre of Montenegro, who were sent to cytological analyses during 2012, 2013 and 2014. The study included 80 women who had to submit their biopsy specimens due to a suspicious Pap test and atypical colposcopy results. Results. In the group of 80 (3.1% n=80/2578) of the selected female patients with suspicious Papanicolaou test and colposcopy, 2/3 or 56 of them (70%) had cervicitis, and 1/3 or 24 (30%) had cervical intraepithelial neoplasia. The most common type in cervical intraepithelial neoplasia was HPV16 in 8 female patients, i.e. 61.53% out of the number of infected or 33.33% out of the total number of premalignant lesions. Conclusion. Patients with suspicious Papanicolaou test, colposcopy results and infection which is caused by high-risk human papilloma virus infection (HPV 16 in particular) often have premalignant cervical lesions. In these cases, pathohistological confirmation of lesions is mandatory, since it serves as a definitive diagnostic procedure.

Background Human papillomavirus (HPV) are responsible for a broad spectrum of mucocutaneous infections and may cause squamous cell carcinoma following long-standing infection . Oncogenic HPV, most commonly HPV 16, are detectable in over 90% of cervical intraepithelial neoplasia and anal intraepithelial neoplasia (AIN). Human immunodeficiency virus (HIV) infection is strongly associated with a higher prevalence of chronic HPV infection, a higher incidence of AIN and an increased risk for anal cancer (AC). In September 2013, guidelines concerning prevention, screening and treatment of AIN for patients affected by HIV were issued by the German AIDS society. Objective In order to validate the suggested screening procedure, we analysed data from 123 male and female patients with HIV infection that regularly present in our outpatient clinic. Methods Anal cytology, HPV typing and high-resolution anoscopy (HRA) were performed. Results Our results show that screening by anal cytology only identifies a minority of patients with high grade AIN (AIN 3) histology. Patients with normal cytology (NILM, cytology graded negative for intraepithelial lesion or malignancy; n = 5, 29.4%), atypical squamous cells of undetermined significance (ASCUS; n = 5, 71.4%) and low grade squamous intraepithelial lesion (LSIL; n = 8, 44.5%) showed highly dysplastic lesions (AIN 2 and 3) in the histological workup more frequently than expected. Additionally, high-grade squamous intraepithelial lesion (HSIL) was strongly associated with detection of high-risk oncogenic HPV. Conclusion Anal cytology as the solitary screening tool for anal cancer fails to detect anal dysplasia in a considerable number of patients. Additionally, HPV typing and possibly further biomarkers might be applied to identify those patients with a higher risk of developing anal carcinoma, in order to monitor them more closely or directly transfer them to HRA.

Infection with high-risk human papillomavirus (HR-HPV) is an essential cause of cervical cancer. Because of substantial geographical variation in the HPV genotype distribution, data regarding HPV type-specific prevalence for a particular country are mandatory for providing baseline information to estimate effectiveness of currently implemented HPV-based cervical cancer prevention. Accordingly, this review was conducted to evaluate the HR-HPV genotype distribution among Thai women with precancerous cervical lesions i.e. cervical intraepithelial neoplasia grade 2-3 (CIN 2-3), adenocarcinoma in situ (AIS), and invasive cervical cancer by reviewing the available literature. The prevalence of HR-HPV infection among Thai women with CIN 2-3 ranged from 64.8% to 90.1% and the three most common genotypes were HPV 16 (38.5%), HPV 58 (20.0%), and HPV 18 (5.5%). There were high squamous cell carcinoma/CIN 2-3 prevalence ratios in women with CIN 2-3 infected with HPV 33 and HPV 58 (1.40 and 1.38, respectively), emphasizing the importance of these subtypes in the risk of progression to invasive cancer among Thai women. Data regarding the prevalence and genotype distribution of HR-HPV in Thai women with AIS remain unavailable. Interesting findings about the distribution of HPV genotype in cervical cancer among Thai women include: (1) a relatively high prevalence of HPV 52 and HPV 58 in invasive squamous cell carcinoma; (2) the prevalence of HPV 18-related adenocarcinoma is almost double thepreviously reported prevalence, and (3) 75% of neuroendocrine carcinomas are HPV18-positive when taking into account both single and multiple infections.

Objectives: Morphologic evaluation of anal dysplasia remains problematic, especially in cases with limited biopsy samples or obscuring inflammation. Studies in cervical neoplasia have shown that human papillomavirus (HPV) L1 capsid production is highest in low-grade squamous intraepithelial lesions (LSILs) and progressively decreases in high-grade squamous intraepithelial lesions (HSILs). The combined utility of HPV L1 and p16 expression in assessing anal squamous intraepithelial lesions (SILs) has never been analyzed and forms the basis of this study. Methods: In total, 145 anal lesions were reviewed and immunohistochemically stained for HPV L1 and p16. p16 expression was recorded as negative, patchy/focal, or diffuse. For analytical purposes, condylomas were evaluated separately from rest of the LSILs. Results: There were 34 (23%) condylomas, 64 (44%) LSILs, and 47 (32%) HSILs. HPV L1 was significantly associated with condylomas (68%) and LSILs (52%) compared with HSILs (9%; P < .0001). Diffuse p16 staining was present only in HSILs ( P < .0001), whereas a patchy/focal p16 staining pattern was observed in both LSILs and condylomas. Conclusions: HPV L1 and diffuse p16 expression is mutually exclusive in most anal SILs and helps separate LSIL and HSIL cases. Application of both HPV L1 and p16 can not only facilitate accurate grading but also contribute to risk assessment in anal neoplasia.

Background. Current guidelines recommend initial colposcopy with biopsy regardless of human papillomavirus (HPV) test results in women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). The purpose of this study was to evaluate the value of HPV testing in women with ASC-H based on colposcopic pathology results. Materials and Methods. A multicenter cross-sectional study was carried out at three academic hospitals and involved 40,847 Korean women who underwent cervical cancer screening with cytology and HPV tests with or without subsequent colposcopic biopsies between January 2007 and December 2013. Results. ASC-H was diagnosed in 276 women (0.7%). Only 6 of 68 (8.8%) women with ASC-H who were HPV negative had cervical intraepithelial neoplasia grade ≥2 (CIN ≥2) lesions, whereas 47.4% of the women with ASC-H who were HPV positive had CIN ≥2 lesions. No cases of invasive cervical cancer were diagnosed among women with ASC-H who were HPV negative. Logistic regression analysis was performed using the group with normal Papanicolaou test results and HPV-negative status as the reference group. Women with ASC-H who were HPV positive had a significantly increased risk of CIN ≥2 lesions, whereas no significant increase was observed in patients with ASC-H and HPV-negative status. Conclusion. If the result of the HPV test was negative, the risk of CIN ≥2 lesions in Korean women with ASC-H cytology was low. Reflex HPV testing should be an option for the management of women with cytology showing ASC-H to decrease unnecessary colposcopic biopsies, which are expensive and invasive. Implications for Practice: Current American Society for Colposcopy and Cervical Pathology guidelines recommend universal colposcopy for the management of women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) on cytology, regardless of human papillomavirus (HPV) test results. The present study suggested that HPV cotesting in patients with ASC-H cytology can provide more detailed and useful information regarding the risk of high-grade cervical intraepithelial neoplasia (CIN) lesions and the need for further treatment. When the result of the HPV test was negative, the risk of CIN lesions of grade ≥2 in women with ASC-H cytology was low. Consequently, reflex HPV testing, rather than immediately performance of invasive and expensive colposcopy with biopsy, should be an option for the management of women with ASC-H.

Human papillomavirus (HPV) is found in most women with high-grade cervical intraepithelial neoplasia (CIN) 2/3 in cervical cytology and biopsies. Multiple high-risk HPV (hrHPV) genotypes are present in 15% to 50% of cytology samples. We have shown by laser-capture microscopy (LCM)-polymerase chain reaction (PCR) that each lesion is associated with a single hrHPV type. Attribution of hrHPV types to CIN2/3 is important to understand the oncogenic role of different types and the limitations of cytologic typing. We studied hrHPV genotypes in 257 women with histologic CIN2/3 referred on the basis of abnormal cytology. HPV typing was done on cytology and CIN2/3 biopsies. If the whole-tissue section of the biopsy was positive for multiple hrHPV types, LCM-PCR was performed. We found 181 (70%) single and 71 (28%) multiple hrHPV infections in cytology, with 5 (2%) cases HPV-positive only on whole-tissue section PCR. Of cases with multiple cytologic hrHPV infections, 47/71 (66%) showed a single type in CIN2/3 lesions. In total, in 232 of 257 (90%) women with CIN2/3, a single hrHPV type caused CIN2/3. One was nonattributable on the LCM level. The remaining 24 women had 2 or more contiguous or separated lesions, each associated with a single hrHPV infection. The probability of HPV16 being present in CIN2/3, if detected in cytology, was 0.96 (95% confidence interval=0.90-0.98). LCM-PCR confirms that only 9% of histologic CIN2/3 is associated with multiple hrHPV types, much less than cytology would indicate, and each lesion was associated with a single hrHPV infection.

Our aims were to evaluate the clinical performance of human telomerase RNA gene component (hTERC gene) amplification assay with high-risk human papillomavirus (HR-HPV) DNA test of Hybrid Capture 2 DNA test (HC2), for the detection of high grade cervical precancerous lesions and cancer (CIN 2+). In addition, the association shown between hTERC gene amplification and HPV DNA test positive in women with and without cervical neoplasia was assessed. There were 92 women who underwent cytology, HR-HPV DNA test, hTERC gene amplification test, colposcopy and biopsy. We compared the clinical performance of hTERC gene test along with HR-HPV DNA test of women with colposcopy and routine screening. The samples were histology- confirmed high-grade cervical intraepithelial neoplasia (CIN 2) or worse (CIN2+) as the positive criterion. The test of hTERC gene showed the hTERC gene amplification positivity increased with the severity of histological abnormality and cytological abnormality. The test of hTERC gene showed higher specificity than HR-HPV DNA test for high-grade lesions (84.4% versus 50%) and also higher positive predictive value (90.4% versus 76.5%). Our results predicted that hTERC gene amplification demonstrated more specific performance for predicting the risk of progression and offer a strong potential as a tool for triage in cervical cancer screening, with the limited sensitive as HR-HPV DNA test.

Increased awareness of human papillomavirus (HPV) as an etiological cause of head and neck squamous cell carcinoma has increased the interest in analysis of distinct oral sub-sites. It is currently under debate, whether HPV plays a role in the development of squamous cell carcinoma of the oral cavity (OSCC). The weakness in most published studies is the lack of performing different HPV detection tests combined with analysis for biological activity of the virus. In addition, different sub-sites of the oral cavity had been combined to a single entity, which retrospectively leads to a highly heterogeneous basis of data. In this review we mainly discuss the unclear role of HPV in OSCC development.

The bovine papillomavirus (BPV) causes papillomas that regress spontaneously, but can also progress to malignancy. This study evaluated the role of BPV in oncogenesis. Twenty-four samples from uninfected calves and the papillomas of BPV infected cattle were subjected to molecular diagnosis, as well as histopathological and immunohistochemical analyses. The comet assay (CA) was used to evaluate the clastogenic potential of BPV. The results confirmed the presence of BPV-2, 3, 5, and 9 in infected samples. Histopathological analysis revealed acanthosis, koilocytosis, hypergranulosis, hyperkeratosis, and transformed fibroblasts.E7 and L1 BPV proteins were detected in the epithelium, as well as in the connective tissues, indicating productive infection at different sites. CA results showed that BPV-2, 5, and 9 exhibit the same level of clastogenicity. These findings support the oncogenic action of BPV in establishing a favorable microenvironment for oncogenesis.

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) comprises approximately 25% of all head and neck cancers (head and neck squamous cell carcinoma, HNSCC). Epidemiologic studies have shown a dramatic increase of HPV-OPSCC in the past 2 decades, whereas tobacco-related HNSCC rates are decreasing worldwide. The distinctions between HPV-OPSCC and oral cavity cancers are now reflected in the most recent editions of the World Health Organization Classification of Tumors of the Head and Neck and the American Joint Committee on Cancer Staging Manual, respectively. This review describes current understanding of the link between HPV infection and OPSCC.

PurposeWe examined overall survival in a large cohort of patients with human papillomavirus (HPV)-positive and HPV-negative non-oropharyngeal squamous cell carcinoma of the head and neck (non-OPSCC).MethodsPatients diagnosed with non-OPSCC and known HPV status were identified in the National Cancer Database (NCDB). Multivariate logistic regression was applied to examine factors associated with HPV status. Multivariate analysis was utilized to determine factors correlated with overall survival. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in survival analyses. Multiple imputation method was used for sensitivity analysis.ResultsWe identified 19,993 non-OPSCC patients with 5070 being positive for HPV in the NCDB. Median follow-up was 23.5months. HPV-positive patients were more commonly male, white, with a lower comorbidity index score, presenting with T-stage

Objective To delineate the association between characteristics of adult-onset laryngeal squamous cell papilloma and human papillomavirus (HPV) infection. Methods Clinical records and paraffin-embedded specimens of 77 papilloma patients who had been treated between 1998 and 2014 were collected. Of the 77 cases, 34 were identified in the larynx, 28 in the oral cavity and 15 in the oropharynx. Specimens were investigated by polymerase chain reaction (PCR) to detect HPV 6, 11, 16, 18, 31, 33, 35, 52b and 58, and immunohistochemical (IHC) staining for anti-p16INK4a antibody. Results In 21 cases (61.8%) with laryngeal squamous cell papilloma, various types of HPV were detected: 14 cases (41.2%) were positive of high-risk HPV, 18 (52.9%) were positive of low-risk HPV and 11 (32.4%) were positive of both high-risk HPV and low-risk HPV. Younger patients (

Objective This study was designed to investigate the co-prevalence of cervical and oropharyngeal human papillomavirus (HPV) infection in patients with HPV-related high-grade disease of the uterine cervix (high-grade squamous intraepithelial lesion [HSIL]). Materials and methods In a prospective cohort study, women with abnormal cervical cytology admitted to our colposcopy units received HPV testing of the uterine cervix and the oropharynx via smear. From a subset of patients, oral lavage was collected to compare detection rates of HPV DNA between lavage and swab. Patients with confirmed high-risk HPV (HR-HPV)-positive HSIL of the cervix were further investigated. Sexual behavior and lifestyle factors were documented with a standardized questionnaire. Results Two hundred thirty-five women were included in the study. Of the 235 women, 135 (57.5%) were cervically HR-HPV positive with histologically confirmed high-grade cervical intraepithelial lesion (median [range] age = 30 [21-45] years). Of these, only 6 (4.4%) also had a positive oral specimen. In 3 (50%) of the 6 cases, the same HPV type was detected in oral and cervical samples (HPV 16, 35, and 45). Oral HPV detection was not higher when combining swab and lavage compared with swab alone. A relation between sexual behavior and oral HPV detection could not be demonstrated. Conclusions Oral HPV prevalence in women with cervical HPV infection and HSIL is low. Simultaneous testing of oropharyngeal and cervical HPV infection does not seem promising as future screening strategy.

Two groundbreaking reports were published in Acta Cytologica at the transition of 1976 to 1977. One appeared in the last issue of 1976 [Meisels and Fortin: Acta Cytol 1976;20:505-509] and the other in the first issue of 1977 [Purola and Savia: Acta Cytol 1977;21:26-31]. Today, 40 years later, it is not an overstatement to conclude that these are the two most influential studies ever published in this journal. Two reports with a similar content being published so close together (in the same journal) raised the question “Which of the two reports was truly submitted first?” In this commentary, this enigma is clarified beyond reasonable doubt, based on the well-considered testimonial of Prof. Leopold G. Koss, the reviewer of one of the two papers. To fully appreciate the significance of the novel discovery made in these two reports, it is essential to align them in the right context, both retrospectively and prospectively. This commentary will assist the reader by summarizing the existing knowledge on human papillomavirus (HPV) before these two milestone papers appeared, and describe the incredibly rapid progress that they evoked during the subsequent decades, which made HPV the single most important human tumor virus. As the final proof of virus-cancer causality, prophylactic HPV vaccines have been effective in preventing (a) virus transmission and HPV infection, (b) benign HPV-induced tumors (genital warts), and (c) cervical intraepithelial neoplasia (CIN). Formal evidence of the prevention of cervical cancer by these HPV vaccines still awaits confirmation, and the same applies to the eventual prevention of human cancers at other anatomic sites, part of the global burden of oncogenic HPVs.

Few studies have described the epidemiology of human papillomavirus (HPV) in vulvar intraepithelial neoplasia (VIN). The aim of this study was to genotype HPV on formalin fixed paraffin-embedded tissues in VIN lesions. A 5-year retrospective study was conducted by including all patients attending the teaching hospital of Nice with a diagnosis of VIN between 1st January 2010 and 31st December 2014. For all patients, HPV genotyping was performed with the PapilloCheck® microarray kit, routinely used on cervical cytology samples, and optimized for formaldehyde fixed paraffin-embedded tissues in VIN. Forty patients were included in the study: 39 patients had usual VIN and one presented with differentiated VIN. Among the 39 patients with usual VIN, the prevalence of HPV was 90% (35/39). Thirty-two patients had high grade VIN (82%) and seven low grade VIN (18%). In high grade VIN, the most represented HPV types were: HPV 16 (21/32 66%), HPV 56 (3/32 9%) and HPV 33 (2/32 6%). In low grade VIN, the most represented HPV types were: HPV 16 (4/7 57%) and HPV 6 (3/7 43%). Interestingly, 5/39 (13%) of patients diagnosed with usual VIN also had co-existing lichen sclerosus. We have optimized a HPV genotyping technique, routinely used on cervical cytology samples, and on paraffin fixed embedded tissue showing VIN. Moreover, we have identified five patients with lichen sclerosus co-existing with usual VIN. This association has rarely been reported and proves that these two entities can coexist.

Summary Most cervical low-grade squamous intraepithelial lesions (LSILs) do not progress to high-grade squamous intraepithelial lesions (HSILs); however, reliable biomarkers that predict LSIL progression are lacking. We investigated the association of cytokeratin 7 (CK7), human papillomavirus-L1 capsid protein (HPV-L1), and koilocytosis with clinical outcomes of patients with LSIL. CK7, HPV-L1, Ki67, and p16-INK4A expression was determined in 72 cervical LSIL and 28 HSIL biopsy samples; koilocytosis was evaluated by reviewing biopsy slides. Fifty patients with LSIL received follow-up. CK7, HPV-L1, and koilocytosis were detected in 48.6%, 44.4%, and 52.0% of LSIL tissues and in 78.6%, 10.7%, and 64.3% of HSIL tissues, respectively. Lesion grade was correlated directly with CK7 expression ( P =.007) and inversely with HPV-L1 expression ( P =.004). CK7 expression in LSILs was correlated inversely with HPV-L1 expression and directly with p16-INK4A and Ki67 status. Furthermore, koilocytosis was significantly associated with HPV-L1 and p16-INK4A expression. Progression to cervical intraepithelial lesions of grades ≥2 occurred in 34% of cases. CK7 negativity and HPV-L1 positivity were significantly associated with lower HSIL progression rates. HPV-L1–positive and CK7-negative LSILs showed significantly lower progression rates compared with HPV-L1–negative and CK7-positive LSILs (6.3% v–positive cases showed a significantly lower progression rate (17.6%) compared with nonkoilocytic and HPV-L1–negative cases (50%). CK7-negative, HPV-L1–positive, and koilocytic LSILs showed a progression rate of 7.7%. Koilocytosis and p16-INK4A were not significantly associated with clinical outcomes. Hence, evaluating HPV-L1, CK7, and koilocytosis profiles combined may be more reliable for LSIL prognostication.

The Papillomaviridae family comprises a large number of viruses that can infect a broad range of hosts giving rise to benign lesions of the skin or mucosal membranes. Until today, seven viruses termed EcPV1-7 were identified in equine papillomas. Two trotter stallion siblings at the age of two were referred to the Equine Clinic of Free University of Berlin, because of erythema, alopecia and crusting. After a diagnosis of immune-mediated skin disease, the horses underwent long-term treatment with glucocorticoids and azathioprine. Two months later, both horses developed hundreds of small wart-like proliferations on the head, neck, chest and trunk. Six healthy horses, housed in the same stable, were used to assess the occurrence of the virus in healthy skin. Biopsies were obtained for histopathology and for amplification and cloning of the papillomavirus genome as well as for sequence analysis. Histopathology revealed well demarcated cup-shaped epidermal proliferations. Foci were covered by parakeratotic, or abnormally formed, keratin. In deeper layers, numerous enlarged cells with cytoplasmic eosinophilic inclusion-like structures and occasional intranuclear basophilic inclusion bodies were striking, existing beside cells with a peripheral cytoplasmic clearing (koilocytes). Histopathological findings were consistent with endophytic papilloma similar to the Le Net-type described in immunosuppressed dogs caused by a distinct canine papillomavirus. Furthermore, papillomavirus DNA was detected in tissue samples using a broad range PCR analysis. Preliminary phylogenetic analysis of a partial sequence from the L1 gene indicated a putative new papillomavirus that has not been described in horses so far. Biopsies of the control horses showed no abnormalities in histopathology and were tested negative for the putative novel papilloma virus DNA.

not present

Human papillomavirus (HPV) is the most clinically common sexually transmitted infection due to its carcinogenic power and the high number of lesions that it causes at different sites of the human body. Genital tract organs are the most common sites where the virus can be found, but by increasing the sensitivity of diagnostic technique, it is possible to identify viral presence in different regions of the body such as the stomach, the lung, and the urinary tract. These findings break with the traditional HPV skin/genital tropic profile and demonstrate that the virus is capable of infecting a wide variety of cells, tissues, and organs or can, at least, survive in these areas. The widespread presence of the HPV in the human body, often in latent form, led us to consider the hypothesis that HPV latency may be associated with no disease. This observation raises further questions about the possibility of the virus not causing disease in specific sites of the human body, but rather, behaving like a commensal/opportunistic microorganism.

Objective: Human papillomavirus vaccines are being introduced worldwide and are expected to reduce the incidence of cervical cancer. Here we report a cross-sectional study using a validated human papillomavirus genotyping method to reveal the human papillomavirus prevalence and genotype distribution in Japanese women with cervical intraepithelial neoplasia Grade 2/3 and invasive cervical cancer. Methods: Cervical exfoliated cells were collected from 647 patients with abnormal cervical histology (cervical intraepithelial neoplasia Grade 2, n ¼ 164; cervical intraepithelial neoplasia Grade 3, n ¼ 334; and invasive cervical cancer, n ¼ 149), and subjected to the PGMYPCR-based genotyping assay. The association between human papillomavirus infection and lesion severity was calculated using a prevalence ratio. Results: Overall, the prevalence of human papillomavirus deoxyribonucleic acid was 96.3% in cervical intraepithelial neoplasia Grade 2, 98.8% in cervical intraepithelial neoplasia Grade 3 and 88.0% in invasive cervical cancer (97.8% in squamous cell carcinoma and 71.4% in adenocarcinoma). The three most prevalent types were as follows: human papillomavirus 16 (29.3%), human papillomavirus 52 (27.4%) and human papillomavirus 58 (22.0%) in cervical intraepithelial neoplasia Grade 2; human papillomavirus 16 (44.9%), human papillomavirus 52 (26.0%) and human papillomavirus 58 (17.4%) in cervical intraepithelial neoplasia Grade 3; and human papillomavirus 16 (47.7%), human papillomavirus 18 (23.5%) and human papillomavirus 52 (8.7%) in invasive cervical cancer. The prevalence ratio of human papillomavirus 16 was significantly higher in cervical intraepithelial neoplasia Grade 3 compared with cervical intraepithelial neoplasia Grade 2 (prevalence ratio, 1.62; 95% confidence interval, 1.26‐2.13) and in squamous cell carcinoma compared with cervical intraepithelial neoplasia Grade 3 (prevalence ratio, 1.55; 95% confidence interval, 1.25‐1.87). Multiple infections decreased from cervical intraepithelial neoplasia Grade 2/3 (38.4/29.6%) to invasive cervical cancer (14.1%), whereas co-infections with human papillomavirus 16/52/58 were found in cervical intraepithelial neoplasia Grade 2/3. Conclusions: The results of this study provide pre-vaccination era baseline data on human papillomavirus type distribution in Japanese women and serve as a reliable basis for monitoring the future impact of human papillomavirus vaccination in Japan.

p16(INK4a) expression in dysplastic cervical lesions is related to high-risk human papillomavirus (HR-HPV) infection. The immunohistochemical expression of this protein in these lesions allows an increase in diagnostic reproducibility in biopsies and the introduction of prognostic factors in low-grade lesions. Here, we studied the immunohistochemical expression of p16 in 86 dysplastic cervical lesions, 54 cervical intraepithelial neoplasms-grade 1 (CIN-I), 23 CIN-II, and 9 CIN-III. In addition, we performed HPV detection and genotyping. We detected HR-HPV in 19/54 CIN-I, 21/23 CIN-II and 9/9 CIN-III cases. p16(INK4a) immunoreactivity was observed in 7/19 CIN-I HR-HPV-positive, 17/21 CIN-II HR-HPV-positive and all CIN-III cases. Immunoreactivity for p16(INK4a) was found in 7/54 CIN-I and in 17/23 CIN-II cases. In the follow-up, we detected 3 p16-positive high-grade squamous epithelial lesions (CIN-II and CIN-III) in the CIN-I/p16-negative group and 5 p16-positive high-grade squamous epithelial lesions cases in the CIN-II/p16-negative group. We conclude that p16 negativity in CIN-I and CIN-II biopsies does not always imply regression of the lesion and that the diagnosis of CIN-II should not be based solely on p16 results.