Evidence Of Human Papillomavirus Infection Research Articles

Abstract 6196: Fanconi anemia pathway deficiency drives copy number variation in squamous cell carcinoma

Abstract Fanconi anemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink (ICL) repair resulting in chromosome breakage. The FA repair pathway comprises at least 22 FANC proteins including BRCA1 and BRCA2 and protects against carcinogenic endogenous and exogenous aldehydes. Individuals with FA are hundreds to thousands-fold more likely to develop head and neck (HNSCC), esophageal and anogenital squamous cell carcinomas (SCCs) with a median onset age of 31 years. The aggressive nature of these tumors and poor patient tolerance of platinum and radiation-based therapy have been associated with short survival in FA. Molecular studies of SCCs from individuals with FA (FA SCCs) have been limited, and it is unclear how they relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or human papillomavirus (HPV) infection. Here, by sequencing FA SCCs, we demonstrate that the primary genomic signature of FA-deficiency is the presence of a high number of structural variants (SVs). SVs are enriched for small deletions, unbalanced translocations, and fold-back inversions that arise in the context of TP53 loss. The SV breakpoints preferentially localize to early replicating regions, common fragile sites, tandem repeats, and SINE elements. SVs are often connected forming complex rearrangements. Resultant genomic instability underlies elevated copy number alteration (CNA) rates of key HNSCC-associated genes, including PIK3CA, MYC, CSMD1, PTPRD, YAP1, MXD4, and EGFR. In contrast to sporadic HNSCC, we find no evidence of HPV infection in FA HNSCC, although positive cases were identified in gynecologic tumors. A murine allograft model of FA pathway-deficient SCC was enriched in SVs, exhibited dramatic tumor growth advantage, more rapid epithelial-to-mesenchymal transition, and enhanced autonomous inflammatory signaling when compared to an FA pathway-proficient model. In light of the protective role of the FA pathway against SV formation uncovered here, and recent findings of FA pathway insufficiency in the setting of increased formaldehyde load resulting in hematopoietic stem cell failure and carcinogenesis, we propose that high copy-number instability in sporadic HNSCC may result from functional overload of the FA pathway by endogenous and exogenous DNA crosslinking agents. Our work lays the foundation for improved FA patient treatment and demonstrates that FA SCC is a powerful model to study tumorigenesis resulting from DNA crosslinking damage. Citation Format: Andrew L. Webster, Mathijs A. Sanders, Krupa Patel, Ralf Dietrich, Raymond J. Noonan, Francis P. Lach, Ryan R. White, Audrey M. Goldfarb, Kevin Hadi, Matthew M. Edwards, Frank X. Donovan, Moonjung Jung, Sunandini Sridhar, Olivier Fedrigo, Huasong Tian, Joel Rosiene, Thomas Heineman, Jennifer Kennedy, Lorenzo Bean, Rasim O. Rosti, Rebecca Tryon, Ashlyn-Maree Gonzalez, Allana Rosenberg, Ji-Dung Luo, Thomas Carrol, Eunike Velleuer, Jeff C. Rastatter, Susanne I. Wells, Jordi Surrallés, Grover Bagby, Margaret L. MacMillan, John E. Wagner, Maria Cancio, Farid Boulad, Theresa Scognamiglio, Roger Vaughan, Amnon Koren, Marcin Imielinski, Settara Chandrasekharappa, Arleen D. Auerbach, Bhuvanesh Singh, David Kutler, Peter J. Campbell, Agata Smogorzewska. Fanconi anemia pathway deficiency drives copy number variation in squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6196.

HPV Infection Downregulates the Expression of Autophagy-Related Genes in Condylomata Acuminata

Background: Condylomata acuminata are benign anogenital warts caused by human papillomavirus (HPV) infection with a high recurrence rate. Autophagy plays an important role in maintaining internal environmental stability. However, the role of autophagy regulation in the anogenital warts caused by HPV infection remains unknown. Objective: A multigroup case-control study was designed to identify the autophagy gene fingerprint involved in anogenital warts arising from infections with different HPV genotypes. Methods: Human autophagy PCR arrays were performed on the initial 18 participants grouped by their different HPV genotypes for gene expression-profiling analysis. The negative control was skin samples collected during plastic surgery on the chest from a group of individuals who showed none of the clinical symptoms or evidence of HPV infection. Real-time polymerase chain reaction (qPCR) was performed to validate the microarray results in another 24 individuals. Results: Out of 84 genes involved in autophagy, different autophagic responses were found among the 29 genes that encode autophagy machinery components, and expression levels of 13 of these genes were downregulated. Finally, we verified that the expression levels of 2 key genes that participate in the formation of autophagosomes, ATG3 and ­BECLIN1, were downregulated in the HPV infection groups independently of genotype compared with the control group. Conclusions: These findings showed that HPV infection downregulated the expression of ATGs in CA. Additionally, there were no differences in the expression of ATGs between the different HPV genotype infection groups. This study provided new insights into the autophagic response to HPV infection.

The association between cervical inflammation and histologic evidence of HPV in PAP smears and adverse pregnancy outcome in low risk population

ObjectiveRecent studies suggest an association between Human Papilloma Virus (HPV) infection, cervical inflammation and obstetric complications (i.e. spontaneous preterm parturition and cervical insufficiency). It has been proposed that viral inflammation of the placenta causes changes in the mother's immune reaction to bacterial pathogens, which leads to enhanced inflammatory reaction and preterm delivery. Therefore, the aim of this population-based study was to determine the association between abnormal cervical cytology prior to pregnancy and obstetric outcomes. Study designA Retrospective population-based cohort study was designed, including all women who had a Pap smear up to two years prior to delivery or during first trimester of pregnancy (n = 15,357). Women were divided into the following groups, according to Pap smear results: group 1 – Normal PAP smear (n = 11,261); group 2 – Pap smear with evidence of an inflammatory process (n = 3895); and group 3 – Pap smear with evidence of HPV infection (n = 201). Obstetrical outcomes, gestational age at delivery, and pregnancy complications were compared among the groups. ResultsThe rate of HPV infection in our study population was 1.3%. The rate of preterm delivery (group 1 – 8.5%, group 2 – 8.5%, group 3 – 7%, p = 0.7), preterm PROM (group 1 – 1.7%, group 2–1.6%, group 3 – 2%, p = 0.66) and cervical insufficiency (group 1 – 0.5%, group 2 – 0.7%, group 3 – 1.5%, p = 0.11) did not differ significantly among the study groups. There was no statistical difference in the rate of premature rapture of membranes, newborn small-for-gestational-age, preeclampsia or placental abruption. Women with abnormal cervical cytology, either due to inflammation or HPV infection, had similar obstetric outcome in comparison to those with a normal cervical cytology. ConclusionThis population-based retrospective cohort study indicates no association between positive HPV testing with Pap smear and obstetric complications such as preterm delivery, cervical insufficiency, placental abruption, PROM, Preterm PROM, neonatal SGA and preeclampsia, in a population with low prevalence HPV infection.

Identification of human papillomavirus in pterygium.

The purpose of this study was to evaluate the involvement of human papillomavirus in the pathogenesis of primary and recurrent pterygium in northern Israel. A retrospective study examined 100 randomly chosen pterygium specimens with solar elastosis, from 100 patients who underwent pterygium surgery during 2012-2013 at the Emek Medical Center. All the specimens were analysed for evidence of human papillomavirus infection by immunohistochemistry. Human papillomavirus was not detected in any of the 100 pterygia samples by immunohistochemistry. These used samples were taken from 100 patients with mean age of 51.5 years and a primary: recurrent ratio of 8.09:1. We conclude from our study that human papillomavirus infection does not appear to be an important pathogenic factor of pterygium in Israel.

Impact of bivalent human papillomavirus (HPV) vaccination upon the risk of acquisition of other HPV types

The first human papillomavirus (HPV) vaccine was approved by the FDA in 2006, protecting against 2 carcinogenic types, 16 and 18. There is limited information about whether that vaccination may affect the prevalence of other HPV types in a community over time. Our study aimed to examine this issue. We used published data from The Costa Rica Vaccine Trial. Women were vaccinated with either the Cervarix® HPV vaccine or the hepatitis A vaccine (the control group). Based upon laboratory data, each of these arms can be divided into a naive cohort with no evidence of HPV infection on trial entry and the rest considered a non-naive cohort with baseline infection with HPV.At the end of a 4-year follow-up, women in the combined non-naive cohort had higher rates of HPV (mean number of HPV types detected per woman = 1.22) compared to the combined naive cohort (mean number of HPV types detected per woman = 0.917), consistent with their presumptive higher risk profile upon study entry. However, there was considerable variation by HPV type. Comparing those vaccinated against HPV to the control group, those in the non-naive cohort had an increased prevalence of HPV type 35 (RR=1.37, 95%CI [0.88, 2.11]), and significantly increased prevalence of HPV types 51 and 59 (RR=1.34 [1.03, 1.74] and 1.86 [1.15, 3.00]) respectively). This could be the result of increased HPV infection with these types after HPV 16/18 vaccination or HPV infection before trial entry. Among the naive cohort, there was decreased prevalence in the HPV vaccine arm of HPV type 31 (RR=0.30, 95% CI [.12, .79]) and type 45 (RR=0.18, 95% CI [0.02, 1.46]), suggesting possible cross protection to these HPV types.The protective effects from the bivalent HPV vaccine in the non-naive cohort further support the current public health practice of administering the HPV vaccine to young women, without regard to baseline HPV status.On December 10, 2014, the FDA approved Gardasil 9®, which vaccinates for an additional 5 carcinogenic types of HPV (31, 33, 45, 52 and 58). The addition of these types to the HPV vaccine will be beneficial in decreasing infection with these HPV types, but our analysis looks at the possible implications of how this can affect acquisition types not featured in the vaccine. There was a high prevalence of HPV types 16, 51 and 52 among the total cohort. Types 51 and 52 are not in the prior HPV vaccines and type 51 is not in the new Gardasil 9® vaccine, so type 51 may continue at a high prevalence in some geographic areas and may pose especial risk in the coming years. The prevalences of the various HPV types differ, sometimes substantially, by region. Therefore, further studies examining the prevalence of HPV types over time by geography will be critical for providing guidance to vaccine manufacturers, as well as screening guidelines for clinicians.

Abstract 4175: TGFBR1 and other immune-related genes modify susceptibility to HPV-associated head and neck cancer

Abstract OBJECTIVES: Human papilloma virus (HPV)-related cancer of the oropharynx (OPC) makes up an increasing proportion of head and neck cancers (HNC). Since viral infection and progression to cancer are both strongly influenced by the immune system, the host immune response is one potential determinant of susceptibility to HPV-related cancers. The overall goal of this project is to identify immune-genetic variants associated with an increased risk of developing virally-mediated HNC. STUDY DESIGN: Data from a HNC Genome Wide Association Study (GWAS) performed by the International Agency for Research on Cancer (IARC) and the Centre National de Gestion (CNG) was evaluated for associations between genetic variants in immune genes and the risk of developing OPC. METHODS: An association analysis using multivariate logistic regression was performed on the HNC GWAS data limited to OPC. We analyzed all SNPs intersecting immune genes based on Gene Ontology using a multi tier computational approach which included single gene analysis, gene-gene interaction (GGI) analysis, pathway analysis and protein-protein interaction (PPI) analysis. Results were validated in 2 in-silico replications: the HNC GWAS limited to individuals with serologic evidence of HPV infection, and a cervical cancer GWAS. RESULTS: The OPC GWAS found 17 immune SNPs to be associated with OPC at a significance level of p<10-4 -10-7. GGI analysis demonstrated a high degree of significant functional connection amongst the top ranked immune genes, and PPI analysis identified three significant functional clusters of immune genes related to TGFBR1 signaling, innate immunity, or Th1/Th2 immune balance. Pathway analysis identified multiple immune pathways significantly enriched in the OPC GWAS including 4 cell death, 5 innate immunity, 4 NFKB, 2 T-cell activation, and 4 TGFB signaling pathways. While several immune genes were found to overlap multiple modes of analysis, TGFBR1 intersected all tiers of analysis and was thus selected for validation. Replication in the GWAS dataset limited to serologically HPV+ HNC cases validated 14 out of the 15 significant genes including TGFBR1. Replication in a cervical cancer GWAS demonstrated TGFBR1 to be significantly associated with cancer risk and an identical TGFBR1 containing pathway to be highly significant in both cervical cancer and OPC GWAS. CONCLUSIONS: The high degree of concordance among multiple independent tiers of analysis, strongly implicates variations in immune-related genes as modulators of susceptibility to HPV-mediated HNC and highlights TGFB signaling as a process potentially dysregulated across HPV-related cancers. Thus data highlights the role of host immunogenetics as a modulator of virally-related cancer risk and the utility of multi-component computational strategies in testing biologically based hypothesis about mechanisms of disease susceptibility. Citation Format: Chaya Levovitz, Dan Chen, Emma Ivansson, Ulf Gyllensten, James McKay, Paul Brennan, Paolo Boffetta, Andrew Sikora. TGFBR1 and other immune-related genes modify susceptibility to HPV-associated head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4175. doi:10.1158/1538-7445.AM2014-4175

Verrucous carcinoma of the nail bed in two patients with evidence of Human Papillomavirus infection

Digital squamous cell carcinoma is relatively rare and may present a diagnostic challenge by mimicking benign conditions, such as verruca vulgaris. We describe two patients with longstanding verrucous lesions of the nail bed, which proved to be squamous cell carcinoma at the histopathology examination, with molecular and cytological evidence of HPV infection. Complete excision was performed. The cases highlight the necessity of a high index of suspicion in longstanding verrucous lesions of the digits, resistant to conventional anti-verruca vulgaris treatments.

Systematic Review and Meta-Analysis of L1-VLP-Based Human Papillomavirus Vaccine Efficacy against Anogenital Pre-Cancer in Women with Evidence of Prior HPV Exposure

BackgroundIt is unclear whether L1-VLP-based human papillomavirus (HPV) vaccines are efficacious in reducing the likelihood of anogenital pre-cancer in women with evidence of prior vaccine-type HPV exposure. This study aims to determine whether the combined results of the vaccine trials published to date provide evidence of efficacy compared with control (hepatitis A vaccine/placebo).MethodsA systematic review and meta-analysis was conducted. Randomized-controlled trials (RCTs) were identified from MEDLINE, Embase, Web of Science, PubMed, Cochrane Central Register of Controlled Trials and references of identified studies. The bivalent vaccine containing HPV-16 and 18 VLPs from GlaxoSmithKline Biologicals (Rixenstart, Belgium), the quadrivalent vaccine containing HPV-6, 11, 16, and 18 VLPs from Merck & Co., Inc., (Whitehouse Station, NJ USA), and the HPV-16 monovalent vaccine from Merck Research Laboratories (West Point, PA USA) were evaluated.FindingsThree RCT reports and two post-trial cohort studies were eligible, comprising data from 13,482 women who were included in the vaccine studies but had evidence of HPV infection at study entry. Data on efficacy was synthesized using the Mantel-Haenszel weighted fixed-effect approach, or where there was heterogeneity between studies, the DerSimonian and Laird weighted random-effect approach. The mean odds ratio (OR) and 95% confidence interval (CI) for the association between Cervarix, Gardasil and HPV-16 monovalent vaccine and HPV-associated cervical intraepithelial neoplasia grade 3 or worse was 0·90 (95% CI: 0·56, 1·44). For the association between Gardasil and HPV-associated vulval/vaginal intraepithelial neoplasia grades 2–3, the overall OR and 95% CI was 2.25 (95% CI: 0·78, 6.50). Sample size and follow-up were limited.ConclusionsThere was no evidence that HPV vaccines are effective in preventing vaccine-type HPV associated pre-cancer in women with evidence of prior HPV exposure. Small effects of vaccination however cannot be excluded and a longer-term benefit in preventing re-infection remains possible.

Patients with HPV-related tonsil squamous cell carcinoma rarely harbour oncogenic HPV infection at other pharyngeal sites

Patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) have a reduced risk of developing second primary upper aerodigestive tract (UADT) tumours compared to patients with HPV-negative primary tumours at the same site. To determine whether this finding might be explained by a lack of viral-induced field cancerisation or multifocal infection, we investigated whether there was epithelial dysplasia and/or evidence of HPV infection at other pharyngeal mucosal sites in patients presenting with the disease. Sixty-three patients with primary tonsil SCC and 108 pharyngeal endoscopic biopsies, representing at least one pharyngeal subsite from each patient, were included in this study. Tissue samples were tested using HPV PCR (GP5+/6+), p16 immunohistochemistry (IHC) and high risk HPV DNA in situ hybridisation (ISH). There were 46 patients with HPV-related SCC and 17 patients with HPV-negative disease. PCR detected HPV DNA in a fifth of pharyngeal endoscopic biopsies and was equally likely to be from a patient with HPV-related SCC as from a patient with HPV negative disease. All PCR positive cases were tested using p16 IHC and high risk HPV ISH and only three biopsies were positive. Significantly, these three biopsies all showed evidence of epithelial dysplasia and were from patients with an HPV positive index tumour. Our data suggest that virus-induced field cancerisation and/or multifocal oncogenic HPV infection of the pharynx is uncommon in OPSCC and supports the concept that these patients have a lower risk of developing second primary tumours of the UADT.

P3.372 Systematic Review and Meta-Analysis of L1-VLP-based Human Papillomavirus Vaccine Efficacy Against Anogenital Pre-Cancer in Women with Evidence of Prior HPV Exposure

BackgroundIt is unclear whether L1-VLP-based human papillomavirus (HPV) vaccines are efficacious in preventing anogenital pre-cancer in women with prior vaccine-type HPV exposure. Participants in the phase III efficacy trials were...

No evidence of HPV DNA in esophageal squamous cell carcinoma in a population of Southern Brazil

To investigate the association between human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) in southern Brazil. We studied 189 esophageal samples from 125 patients from three different groups: (1) 102 biopsies from 51 patients with ESCC, with one sample from the tumor and another from normal esophageal mucosa distant from the tumor; (2) 50 esophageal biopsies from 37 patients with a previous diagnosis of head and neck squamous cell carcinoma (HNSCC); and (3) 37 biopsies from esophageal mucosa with normal appearance from 37 dyspeptic patients, not exposed to smoking or alcohol consumption. Nested-polymerase chain reaction (PCR) with the MY09/11 and GP5/6 L1 primers was used to detect HPV L1 in samples fixed in formalin and stored in paraffin blocks. All PCR reactions were performed with a positive control (cervicovaginal samples), with a negative control (Human Genomic DNA) and with a blank reaction containing all reagents except DNA. We took extreme care to prevent DNA contamination in sample collection, processing, and testing. The histological biopsies confirmed the diagnosis of ESCC in 52 samples (51 from ESCC group and 1 from the HNSCC group) and classified as well differentiated (12/52, 23.1%), moderately differentiated (27/52, 51.9%) or poorly differentiated (7/52, 13.5%). One hundred twenty-eight esophageal biopsies were considered normal (51 from the ESCC group, 42 from the HNSCC group and 35 from dyspeptic patients). Nine had esophagitis (7 from the HNSCC and 2 from dyspeptic patients). Of a total of 189 samples, only 6 samples had insufficient material for PCR analysis: 1 from mucosa distant from the tumor in a patient with ESCC, 3 from patients with HNSCC and 2 from patients without cancer. In 183 samples (96.8%) GAPDH, G3PDH and/or β-globin were amplified, thus indicating the adequacy of the DNA in those samples. HPV DNA was negative in all the 183 samples tested: 52 with ESCC, 9 with esophagitis and 122 with normal esophageal mucosa. There was no evidence of HPV infection in different ESCC from southern Brazil.

Decreased blood levels of B lymphocytes and NK cells in patients with systemic lupus erythematosus (SLE) infected with papillomavirus (HPV)

Patients with systemic lupus erythematosus (SLE) show an enhanced risk to develop human papillomavirus (HPV) infection, and aggressive forms of this condition are seen in these patients. The aim of this study was to assess the possible relationship among HPV infection, immunosuppressive therapy and levels of leukocyte subsets in patients with SLE. The following individuals were included in the study: (1) SLE patients under immunosuppressive therapy and with lesions caused by HPV (n=16); (2) SLE patients under immunosuppressive therapy and no evidence of HPV infection (n=20); (3) untreated SLE patients with no evidence of HPV infection (n=7), and; (4) healthy female subjects without evidence of HPV infection (n=10). Peripheral blood was obtained and the percentages of different lymphocyte subsets were determined by flow cytometry, with the use of the following monoclonal antibodies: CD3, CD4, CD8, CD16, CD19, CD20, CD22, CD56, and CD335 (NKp46). We found that SLE patients under immunosuppressive therapy and with lesions caused by HPV showed significantly lower levels of B lymphocytes and NK cells compared to other groups. In contrast, SLE patients receiving immunosuppressive drugs and with no evidence of HPV infection showed similar levels of B and NK cells than healthy controls. Those patients receiving mycophenolate mofetil (MMF) had a diminished number of B cells, and a positive correlation was detected between the dose of MMF and the number of HPV skin lesions. Our data suggest that therapy of SLE patients with MMF is associated with diminished levels of B and NK cells and an enhanced risk for HPV infection.

Human Papillomavirus in Infants: Transmission, Prevalence, and Persistence

Human Papillomavirus (HPV) is very common in reproductive age women. It has been demonstrated that this infection can be transmitted from mother to infant. Evidence of HPV infection can be seen in infant and toddlers. A review of the literate was undertaken to examine the manner in which HPV can be transmitted, the rate at which transmission occurs, and if HPV can persist. The manifestations of HPV were also reviewed. It is not clear what effect the quadravalent HPV vaccine, given to mothers will have on HPV infections in infants.

Investigation of human papillomavirus in bladder cancer in a series of Tunisian patients

The association between human papillomavirus (HPV) infection and development of bladder cancer is variable. Furthermore, the prevalence of HPV DNA in bladder carcinoma subtypes varies from study to study. To clarify the impact of HPV infection on the development of bladder carcinoma, we performed a retrospective study on Tunisian patients to determine the status of HPV infection in urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma. A total of 125 formalin-fixed, paraffin-embedded archival tissue specimens of bladder carcinoma were reviewed and classified according to the World Health Organization (WHO) classification of tumors (119 urothelial carcinomas, five squamous carcinomas, and one adenocarcinoma). Anogenital HPV DNA detection was performed using three different polymerase chain reaction (PCR) techniques: the first one used primers pU-2R/pU-1M specific to high-risk oncogenic HPV; the second one used primers PU-2R/PU-31B specific to low-risk oncogenic HPV; and the third one employed consensus primers (E1-547R/E1-350L). No evidence of HPV infection was detected by morphological examination and PCR in any case of bladder carcinoma. Our study shows that the anogenital HPVs investigated are not associated with the pathogenesis of bladder cancer in Tunisia; however, the question of whether other subtypes of HPV contribute to bladder carcinogenesis remains to be clarified.

Clinical, Pathologic, and Molecular Features of Early-onset Colorectal Carcinoma

The incidence of colorectal carcinoma has increased among patients <40 years of age for unclear reasons. In this study, we describe the clinical, pathologic, and molecular features of colorectal carcinomas that developed in young patients. We compiled a study group of 24 patients <40 years of age with colorectal carcinoma, and 45 patients > or =40 years of age served as controls. Cases were evaluated for clinical risk factors of malignancy and pathologic features predictive of outcome. The tumors were immunohistochemically stained for O6-methylguanine methyltransferase, MLH-1, MSH-2, MSH-6, beta-catenin, chemokine (C-X-C motif) receptor 4, epidermal growth factor receptor, TP53, p16, survivin, and alpha-methylacyl-CoA racemase; assessed for microsatellite instability and mutations in beta-catenin, APC, EGFR, PIK3CA, KRAS, and BRAF; evaluated for micro-RNA expression (miR-21, miR-20a, miR-183, miR-192, miR-145, miR-106a, miR-181b, and miR-203); and examined for evidence of human papillomavirus infection. One study patient each had ulcerative colitis and hereditary nonpolyposis colorectal cancer. Ninety-two percent of tumors from young patients occurred in the distal colon (P=0.006), particularly the rectum (58%, P=0.02), and 75% were stage III or IV. Tumors from young patients showed more frequent lymphovascular (81%, P=0.03) and/or venous (48%, P=0.003) invasion, an infiltrative growth pattern (81%, P=0.03), and alpha-methylacyl-CoA racemase expression (83%, P=0.02) compared with controls. Carcinomas in this group showed significantly increased expression of miR-21, miR-20a, miR-145, miR-181b, and miR-203 (P< or =0.005 for all comparisons with controls). These results indicate that early-onset carcinomas commonly show pathologic features associated with aggressive behavior. Posttranslational regulation of mRNA and subsequent protein expression may be particularly important to the development of colorectal carcinomas in young patients.

No Evidence for a Pathogenic Role of Human Papillomavirus Infection in Ocular Surface Squamous Neoplasia in Germany

Purpose: The etiology of ocular surface squamous neoplasia is unknown. Possible etiologic factors are physical and/or viral damage by human papillomavirus (HPV), especially in Sub-saharian populations. This study focused on the presence of human papillomavirus in ocular surface squamous neoplasia in comparison to pterygia and normal conjunctiva. Methods: Thirty-one consecutive samples of ocular surface squamous neoplasia from a single institution (24 conjunctival intraepithelial neoplasias of various grades and 7 invasive conjunctival squamous cell carcinomas) were analyzed for evidence of HPV infection by immunohistochemistry and multiplex polymerase chain reaction (PCR). The results were compared to 11 samples of pterygia and 5 of normal conjunctiva. Results: Twenty-one (68%) of 31 ocular surface squamous neoplasia showed solar elastosis, while all cases analyzed were negative for HPV. Six (19%) of 31 ocular surface squamous neoplasia specimens demonstrated overexpression of p53 with a lack of p21 upregulation indicating a functional tumor suppressor gene p53 (TP53) mutation. Carcinomas presented a dysbalance between proliferation and apoptosis possibly contributing to tissue transformation and tumor growth. Conclusions: In our study, exposition to ultraviolet (UV) appears to be an important risk factor for the development of ocular surface squamous neoplasia, while HPV infection was not detected. TP53 mutations were also rare but may play a role in the progression from conjunctival intraepithelial neoplasia to invasive carcinoma in a subset of cases.

Cáncer cervical uterino en el área sanitaria III de Asturias: eficacia del cribado oportunista

ObjectiveTo investigate the number of invasive cervical carcinomas detected in our hospital over a 10-year period (1996-2005), to study the mean age at diagnosis of squamous cell carcinomas, adenocarcinomas, and the relation of cervical screening in its diagnosis. Establish the mean number of negative smears in women without cervical human papilloma virus (HPV) infection. Material and methodsData on all diagnoses of cervical cancer, the presence of smear tests prior to biopsy, and the interval between the two procedures were gathered. The Mann-Whitney test was applied. The mean number of negative cytologies without evidence of HPV infection during the period studied was established. ResultsBetween 1996 and 2005, 67 cervical carcinomas (49 squamous cell carcinomas and 18 adenocarcinomas) were diagnosed. In 40% cytology had never been performed. The mean age at diagnosis was 59 years for squamous cell carcinoma and was 49 years for adenocarcinoma. The mean number of negative cytologies per healthy woman was 3.59. ConclusionsOpportunistic screening for cervical cancer, the most common form of screening in Spain, is not accessible to many women with cervical carcinoma and wastes substantial healthcare resources on performing unneccessary cytologies in healthy women.

Prophylactic Efficacy of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Women with Virological Evidence of HPV Infection

Prophylactic Efficacy of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Women with Virological Evidence of HPV Infection

Evidence of human papillomavirus infection, enhanced phosphorylation of retinoblastoma protein, and decreased apoptosis in sarcomatoid squamous cell carcinoma of uterine cervix

Sarcomatoid squamous cell carcinoma (SSCC) of the uterine cervix, characterized by biphasic components of sarcomatoid and squamous neoplastic cells, is a rare entity with uncertain pathogenesis. To date, less than 20 cases have been mentioned. Although the rarity of this diagnosis makes it difficult to draw firm conclusions from limited data, it does seem that SSCC is an aggressive tumor. In this study, we present a 31-year-old patient with abnormal vaginal bleeding. The diagnosis of SSCC was confirmed through pathologic examinations from hysterectomy specimen. Its epithelial origin was demonstrated by immunohistochemical studies. The expression of p53, HER2/neu, and c-kit was not enhanced in this tumor. Importantly, it was human papillomavirus type 16, positive by polymerase chain reaction and in situ hybridization studies. Enhanced immunostaining for phospho-retinoblastoma protein and decreased apoptosis compared with the squamous cell carcinoma counterpart were observed. This report characterizes the first description of molecular features in SSCC that may account for its aggressive behavior.

Evidence of human papillomavirus infection, enhanced phosphorylation of retinoblastoma protein, and decreased apoptosis in sarcomatoid squamous cell carcinoma of uterine cervix

Evidence of human papillomavirus infection, enhanced phosphorylation of retinoblastoma protein, and decreased apoptosis in sarcomatoid squamous cell carcinoma of uterine cervix