Browsing by Subject "HPV"

Sort by: Order: Results:

Now showing items 1-20 of 29
  • Lundberg, Marie; Renkonen, Suvi; Haglund, Caj; Mattila, Petri S.; Leivo, Ilmo; Hagstrom, Jaana; Makitie, Antti A. (2016)
    Conclusions BMI-1 is an upstream repressor of tumor suppressor p16 and their inverse expression patterns have been linked with patient survival in OPSCC. In this material only p16 remained a relevant prognostic marker in OPSCC. Objectives HNSCC tumors carry variable phenotypes and clinical outcomes depending on their anatomical location. In OPSCC, expression of tumor suppressor p16 is used as a surrogate marker of HPV infection and has prognostic value. There are no good prognostic biomarkers for HNSCC tumors of other anatomical locations. Aim To study the expression patterns of p16 and BMI-1 in not only oropharyngeal but also oral, hypopharyngeal, and laryngeal squamous cell carcinomas and to clarify their putative connections with clinical parameters, survival, and each other. Method Hospital records on 130 patients (59 OPSCC, 18 OSCC, 20 HPSCC, and 33 LSCC) diagnosed between 1997-2008 at the Helsinki University Hospital, Finland, were reviewed. BMI-1 and p16 expressions were studied by immunohistochemistry. Results Sixty-eight per cent of OPSCC expressed p16 and expression correlated with lower age, lower T- and higher N-category, and with improved OS and DFS. BMI-1 expression was most prevalent in OPSCC and LSCC, but had no clinical correlations. No correlation between p16 and BMI-1 expression was found.
  • Louvanto, Karolina; Eriksson, Tiina; Gray, Penelope; Apter, Dan; Baussano, Iacopo; Bly, Anne; Harjula, Katja; Heikkila, Kaisa; Hokkanen, Mari; Huhtinen, Leila; Ikonen, Marja; Karttunen, Heidi; Nummela, Mervi; Soderlund-Strand, Anna; Veivo, Ulla; Dillner, Joakim; Elfstöm, Miriam; Nieminen, Pekka; Lehtinen, Matti (2020)
    Less frequent cervical cancer screening in human papillomavirus (HPV) vaccinated birth cohorts could produce considerable savings without increasing cervical cancer incidence and loss of life-years. We report here the baseline findings and interim results of safety and accuracy of infrequent screening among HPV16/18 vaccinated females. The entire 1992-1994 birth-cohorts (30,139 females) were invited to a community-randomized HPV16/18-vaccination trial. A total of 9,482 female trial participants received HPV16/18-vaccination in 2007-2009 at age of 13-15. At age 22, 4,273 (45%) of these females consented to attend a randomized trial on frequent (ages 22/25/28; Arm 1: 2,073 females) vs. infrequent screening (age 28; Arm 2: 2,200 females) in 2014-2017. Females (1,329), who had got HPV16/18 vaccination at age 18 comprised the safety Arm 3. Baseline prevalence and incidence of HPV16/18 and other high-risk HPV types were: 0.5% (53/1,000 follow-up years, 10(4)) and 25% (2,530/10(4)) in the frequently screened Arm 1; 0.2% (23/10(4)) and 24% (2,413/10(4)) in the infrequently screened Arm 2; and 3.1% (304/10(4)) and 23% (2,284/10(4)) in the safety Arm 3. Corresponding prevalence of HSIL/ASC-H and of any abnormal cytological findings were: 0.3 and 4.2% (Arm 1), 0.4 and 5.3% (Arm 2) and 0.3 and 4.7% (Arm 3). Equally rare HSIL/CIN3 findings in the infrequently screened safety Arm A3 (0.4%) and in the frequently screened Arm 1 (0.4%) indicate no safety concerns on infrequent screening despite the up to 10 times higher HPV16/18 baseline prevalence and incidence in the former.
  • Carpen, Timo; Syrjänen, Stina; Jouhi, Lauri; Randen-Brady, Reija; Haglund, Caj; Mäkitie, Antti; Mattila, Petri S.; Hagström, Jaana (2020)
    Background The etiological role of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is confirmed. However, the role of other oncoviruses in OPSCC is unknown. Materials and methods A total of 158 consecutive OPSCC patients treated with curative intent were included. DNA extracted from tumor sections was used to detect Epstein-Barr virus (EBV), HPV, and the following polyomaviruses: John Cunningham virus (JCV), Simian virus 40 (SV40), and BK virus (BKV) with PCR. In addition, p16 expression was studied by immunohistochemistry, and EBV-encoded small RNA (EBER) transcripts were localized by in situ hybridization. The effect of viral status on overall survival (OS) and disease-free survival (DFS) was analyzed. Results A total of 94/158 samples (59.5%) were HPV-positive, 29.1% contained BKV DNA, 20.3% EBV DNA, 13.9% JCV DNA, and 0.6% SV40 DNA. EBER was expressed only in stromal lymphocytes adjacent to the tumor and correlated with HPV positivity (p = 0.026). p16 expression associated only with HPV. None of the three polyomaviruses had an impact on survival. Patients with EBER-positive but HPV-negative OPSCC had significantly poorer OS and DFS than those with HPV-positive OPSCC and slightly worse prognosis compared with the patients with EBER-negative and HPV-negative OPSCC. Conclusion Polyomaviruses are detectable in OPSCC but seem to have no impact on survival, whereas HPV was the strongest viral prognostic factor. EBER expression, as a sign of latent EBV infection, may have prognostic impact among patients with HPV-negative OPSCC. EBER analysis may identify a new subgroup of OPSCCs unrelated to HPV.
  • Ruuskanen, Miia; Irjala, Heikki; Minn, Heikki; Vahlberg, Tero; Randen-Brady, Reija; Hagström, Jaana; Syrjänen, Stina; Leivo, Ilmo (2019)
    Background Nasopharyngeal carcinoma (NPC) is related to Epstein-Barr virus (EBV) in endemic areas; however, the role of viruses in nonendemic countries is unclear. Our nationwide study investigated the prevalence and prognostic significance of EBV and human papillomaviruses (HPVs) in Finnish NPC tumors. Methods We analyzed samples from 150 patients diagnosed between 1990 and 2009. Viral status was determined using EBV and HPV RNA in situ hybridizations, and p16 immunohistochemistry. Patient and treatment characteristics were obtained from patient records. Results In our white patient cohort, 93 of 150 (62%) patients were EBV-positive and 21/150 (14%) patients were HPV-positive with no coinfections. Thirty-six (24%) tumors were negative for both viruses. The 5-year disease-specific survival for patients with EBV-positive, HPV-positive, and EBV/HPV-negative tumors was 69%, 63%, and 39%, respectively. In multivariable-adjusted analysis, overall survival was better among patients with EBV-positive (P = .005) and HPV-positive (P = .03) tumors compared to patients with EBV/HPV-negative tumors. Conclusions In our low-incidence population, EBV and HPV are important prognostic factors for NPC.
  • Gray, Penelope; Palmroth, Johanna; Luostarinen, Tapio; Apter, Dan; Dubin, Gary; Garnett, Geoff; Eriksson, Tiina; Natunen, Kari; Merikukka, Marko; Pimenoff, Ville; Soderlund-Strand, Anna; Vanska, Simopekka; Paavonen, Jorma; Pukkala, Eero; Dillner, Joakim; Lehtinen, Matti (2018)
    Efficacy of human papillomavirus (HPV) vaccines promises to control HPV infections. However, HPV vaccination programs may lay bare an ecological niche for non-vaccine HPV types. We evaluated type-replacement by HPV type and vaccination strategy in a community-randomized trial executed in HPV vaccination naive population. Thirty-three communities were randomized to gender-neutral vaccination with AS04-adjuvanted HPV16/18 vaccine (Arm A), HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (Arm B) and gender-neutral HBV vaccination (Arm C). Resident 1992-95 born boys (40,852) and girls (39,420) were invited. 11,662 boys and 20,513 girls were vaccinated with 20-30% and 45-48% coverage, respectively. HPV typing of 11,396 cervicovaginal samples was performed by high throughput PCR. Prevalence ratios (PR) between arms and ranked order of HPV types and odds ratio (OR) for having multiple HPV types in HPV16 or 18/45 positive individuals were calculated. The ranked order of HPV types did not significantly differ between arms or birth cohorts. For the non-HPV vaccinated 1992-1993 birth cohorts increased PR, between the gender-neutral intervention versus control arms for HPV39 (PRA 1.84, 95% CI 1.12-3.02) and HPV51 (PRA 1.56, 95% CI 1.11-2.19) were observed. In the gender-neutral arm, increased clustering between HPV39 and the vaccine-covered HPV types 16 or 18/45 (ORA16 = 5.1, ORA18/45 = 11.4) was observed in the non-HPV vaccinated 1994-1995 birth cohorts. Comparable clustering was seen between HPV51 and HPV16 or HPV18/45 (ORB16 = 4.7, ORB18/45 = 4.3), in the girls-only arm. In conclusion, definitively consistent postvaccination patterns of HPV type-replacement were not observed. Future occurrence of HPV39 and HPV51 warrant investigation.
  • Mäkitie, Antti A.; Almangush, Alhadi; Youssef, Omar; Metsälä, Markus; Silen, Suvi; Nixon, Iain J.; Haigentz, Missak; Rodrigo, Juan P.; Saba, Nabil F.; Vander Poorten, Vincent; Ferlito, Alfio (2020)
    Head and neck cancer (HNC) comprises a heterogeneous group of upper aerodigestive tract malignant neoplasms, the most frequent of which is squamous cell carcinoma. HNC forms the eighth most common cancer type and the incidence is increasing. However, survival has improved only moderately during the past decades. Currently, early diagnosis remains the mainstay for improving treatment outcomes in this patient population. Unfortunately, screening methods to allow early detection of HNC are not yet established. Therefore, many cases are still diagnosed at advanced stage, compromising outcomes. Exhaled breath analysis (EBA) is a diagnostic tool that has been recently introduced for many cancers. Breath analysis is non-invasive, cost-effective, time-saving, and can potentially be applied for cancer screening. Here, we provide a summary of the accumulated evidence on the feasibility of EBA in the diagnosis of HNC.
  • Mohamed, Hesham; Haglund, Caj; Jouhi, Lauri; Atula, Timo; Hagström, Jaana; Mäkitie, Antti (2020)
    Oropharyngeal squamous cell carcinoma (OPSCC) is subclassified by the World Health Organization into two different entities: human papillomavirus (HPV)-positive and HPV-negative tumors. HPV infection promotes the epithelial-to-mesenchymal transition (EMT) and transformation of keratinocyte stem cells into cancer stem cells. EMT is a crucial process in the carcinogenesis of epithelial-derived malignancies, and we aimed to study the role of its markers in OPSCC. This study consists of 202 consecutive OPSCC patients diagnosed and treated with curative intent. We examined E-cadherin, beta-catenin, and vimentin expression using immunohistochemistry and compared these with tumor and patient characteristics and treatment outcome. We found that the cell-membranous expression of beta-catenin was stronger in HPV-positive than in HPV-negative tumors, and it was stronger in the presence of regional metastasis. The stromal vimentin expression was stronger among HPV-positive tumors. A high E-cadherin expression was associated with tumor grade. No relationship between these markers and survival emerged. In conclusion, beta-catenin and vimentin seem to play different roles in OPSCC: the former in the tumor tissue itself, and the latter in the tumor stroma. HPV infection may exploit the beta-catenin and vimentin pathways in carcinogenic process. More, beta-catenin may serve as a marker for the occurrence of regional metastasis:
  • Mohamed, Hesham; Aro, Katri; Jouhi, Lauri; Makitie, Antti; Remes, Satu; Haglund, Caj; Atula, Timo; Hagstrom, Jaana (2018)
    Hormone receptors play an important role in many types of cancers. Alongside factors associated with human papillomavirus (HPV) infection, hormonal receptors may impact the tumorigenesis of oropharyngeal cancer. This study consists of 199 consecutive oropharyngeal squamous cell carcinoma (OPSCC) patients diagnosed and treated with a curative intent. We examined androgen (AR), estrogen (ER; both alpha and beta), and progesterone receptor (PR) expressions using immunohistochemistry comparing tumor and patient characteristics. AR was expressed in 16%, PR in 27% and ER-beta in 63% of the tumors. HPV- and p16-positive tumors expressed more AR and less PR than their negative counterparts. High PR expression was associated with poor disease-specific and locoregional recurrence-free survival. AR, PR, and ER-beta are expressed in OPSCC, and AR and PR expressions are associated with HPV and p16 status. Furthermore, PR appears to have prognostic significance. This may allow us to investigate the role of anti-hormone receptors in the treatment of OPSCC.
  • Forsell, Sabrina; Kalliala, Ilkka; Halttunen, Mervi; Redman, Charles W. E.; Leeson, Simon; Tropé, Ameli; Moss, Esther; Kyrgiou, Maria; Pyörälä, Eeva; Nieminen, Pekka (2020)
    Simple Summary Cervical cancer prevention is presently undergoing a thorough reformation due to introduction of human papillomavirus (HPV)-testing and vaccines in primary prevention. The screening program, however, is more than a single test or preventive intervention-the possible lesion has to be found, located and treated. Colposcopy plays a major role in this management. Literature dealing with training and learning, especially with colposcopy, is extremely scarce. The aim of the European Federation of Colposcopy, EFC, is to improve the education and training in colposcopy, e.g., by organizing colposcopy courses. The aim of our prospective interventional study was to pilot this intensive participant activating EFC Basic Colposcopy Course on the short- and long-term learning of colposcopy-related knowledge, image recognition and the diagnostic confidence. High-quality colposcopy is essential in cervical cancer prevention. We performed a multicentre prospective interventional pilot-study, evaluating the effect of a six-hour case-based colposcopy course on short- and long-term learning of colposcopy-related knowledge, diagnostic accuracy levels and confidence. We recruited 213 colposcopists participating in three European Federation of Colposcopy (EFC) basic colposcopy courses (Finland, Norway, UK). The study consisted of three tests with identical content performed before, after and 2 months after the course, including ten colposcopic images, ten patient cases and scales for marking confidence in the answers. Outcome measures where mean scores in correct case-management, diagnosis (including high-grade lesion recognition), transformation-zone recognition and confidence in answers. Results were compared between the three tests and stratified according to experience. Mean test scores improved after the course for all participants. The increase was highest for beginners. Confidence in answers improved and the number of colposcopists showing high confidence with low scores decreased. A structured case-based course improves skills and confidence especially for inexperienced colposcopists; however, trainers should be aware of the risk of overconfidence. To complement theoretical training, further hands-on training including high-quality feedback is recommended. Conclusions drawn from long-term learning are limited due to the low participation in the follow-up test.
  • Carpen, Timo; Sorsa, Timo; Jouhi, Lauri; Tervahartiala, Taina; Haglund, Caj; Syrjänen, Stina; Tarkkanen, Jussi; Mohamed, Hesham; Mäkitie, Antti; Hagström, Jaana; Mattila, Petri S. (2019)
    Background An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC. Materials and methods A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS). Results High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels. Conclusion Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.
  • Jaakola, Anna; Roger, Michel; Faucher, Marie-Claude; Syrjanen, Kari; Grenman, Seija; Syrjänen, Stina; Louvanto, Karolina (2021)
    BackroundHuman leukocyte antigen (HLA)-G may have an important role in the natural history of human papillomavirus (HPV) infection. Our aim was to evaluate the role of HLA-G in the outcome of genital and oral HPV infections in women.MethodsAnalyses included 306 women from the Finnish Family HPV-study and were followed-up for six years. Genital and oral samples were tested for 24 different HPV types with multiplex HPV genotyping. HLA-G alleles were determined through direct DNA-sequencing. Unconditional logistic regression was used to determine the associations between HLA-G genotypes and HPV infection outcomes.ResultsTen HLA-G alleles were identified. Most common HLA-G genotypes were the wild type G*01:01:01/01:01:01 (31.3%) followed by G*01:01:01/01:01:02 (26.8%). G*01:01:01/01:01:01 genotype was associated with increased risk of oral HPV infections by any HPV type or single-type with OR=1.86 (95% CI 1.14-3.04, P=0.01) and 2.22 (95% CI 1.14-3.71, P=0.02), respectively. G*04:01+ allele and the G*01:01:01/01:04:01 genotype both protected from any and single oral HPV infections; OR=0.46 (95% CI 0.23-0.89, P=0.02) and 0.53 (95% CI 0.23-0.97, P=0.03), respectively. G*01:01:02/01:04:01 genotype increased significantly the risk of infertility and its treatments, with respective OR=5.06 (95% CI 1.22-21.02, P=0.03) and OR=9.07 (95% CI 1.22-39.50, P=0.03). Both HLA-G alleles and genotypes showed several significant associations with the outcomes of oral HPV infections, but none of them had any impact on the outcomes of genital HPV infections in these women.ConclusionsThe host HLA-G genotypes appear to impact the outcomes of oral HPV infections in women but have little if any effect on genital HPV status or infection outcomes.
  • Tuominen, Heidi; Rautava, Jaana; Kero, Katja; Syrjänen, Stina; Collado, Maria C; Rautava, Samuli (BioMed Central, 2021)
    Abstract Background Aberrant microbiota composition has been linked to disease development at numerous anatomical sites. Microbiota changes in reaction to viral infections, such as human papillomavirus (HPV), have been investigated almost exclusively in the female reproductive tract. However, HPV infection may also affect male health by reducing semen quality and fertility. The aim of this study was to investigate whether present HPV DNA is associated with detectable changes in semen bacterial microbiota composition and diversity. Methods This study relied on stored semen samples from 31 fertile healthy men who participated in the Finnish family HPV Study during the years 1998–2001. DNA was extracted from semen with PCR template preparation kit. HPV was genotyped using Luminex-based Multimetrix® assay. Microbiota was analyzed from the V3-V4 region of 16S rDNA gene following sequencing on an Illumina MiSeq platform. All statistical analyses were performed with Calypso software version 8.84. Results HPV DNA was detected in 19.4% (6/31) of the semen samples. HPV status in the semen did not impact the α-diversity estimations, as measured by Chao1 and Shannon indices, nor ß-diversity. Nevertheless, HPV-positive semen samples exhibited differences in the taxonomic composition of the bacterial microbiota including higher abundances of Moraxellaceae (p = 0.028), Streptococcus (p = 0.0058) and Peptostreptococcus (p = 0.012) compared to HPV-negative semen samples. Conclusion HPV infection is associated with altered bacterial microbiota composition in semen, and this might have in impact to male health in general. As of present, it is unclear whether these changes result from HPV infection or whether altered bacterial microbiota increases susceptibility to HPV infection. More research is needed on viral-bacterial interactions in the male reproductive system.
  • Tuominen, Heidi; Al-Samadi, Ahmed; Salo, Tuula; Rautava, Jaana (2020)
    Background This study was designed to investigate the invasion of human papillomavirus (HPV) positive human cervical carcinoma cell lines in human leiomyoma-based extracellular matrices in vitro,and to test the suitability of the model for studying the irradiation effects on the cancer cell invasion. Methods HPV positive cervical carcinoma cell lines SiHa and CaSki, and HPV negative squamous cell carcinoma cell line HSC-3 were used. CaSki cells contain around 600 copies of HPV 16 virus in the genome, whereas SiHa have only 1-2 copies per cell. Cells were analyzed using two different human tumor derived extracellular matrix methods (3D myoma disc model, and Myogel Transwell invasion assay). Cultures were irradiated with 4 Gy. Myoma invasion area and the depth of invasion were measured with ImageJ 1.51j8 software. Statistical analyses were performed with SPSS Statistics (IBM SPSS (R) Statistics 25). Results All cells invaded through Myogel coated Transwell membranes and within myoma discs. In myoma discs, a difference in the invasion depth (p = 0.0001) but not in invasion area (p = 0.310) between the HPV positive cell lines was seen, since SiHa (less HPV) invaded slightly better than CaSki (more HPV). HSC-3 cells (HPV negative) invaded deepest (p = 0.048) than either of the HPV positive cell line cells. No difference was detected in the invasion area (p = 0.892) between HPV positive and HPV negative cells. The ionized radiation significantly reduced the invasion depth of HSC-3 (p = 0.008), SiHa (p = 0.0001) and CaSki (p = 0.005). No significant effect on the invasion area was detected in any of the cell lines. However, a significant difference was observed between SiHa and CaSki in the reduction of the invasion depth after radiation (p = 0.013) as the reduction was greater with SiHa than CaSki. Conclusions Both solid and gelatinous human leiomyoma-based extracellular matrix models were suitable platforms to study the invasion of HPV positive cervical carcinoma cells in vitro. SiHa cells with less HPV copy number cells invaded slightly better and were slightly more sensitive to irradiation than CaSki cells with high HPV copy number. However, there was no drastic differences between the invasion properties of these carcinoma cells.
  • Tuominen, Heidi; Al-Samadi, Ahmed; Salo, Tuula; Rautava, Jaana (BioMed Central, 2020)
    Abstract Background This study was designed to investigate the invasion of human papillomavirus (HPV) positive human cervical carcinoma cell lines in human leiomyoma-based extracellular matrices in vitro, and to test the suitability of the model for studying the irradiation effects on the cancer cell invasion. Methods HPV positive cervical carcinoma cell lines SiHa and CaSki, and HPV negative squamous cell carcinoma cell line HSC-3 were used. CaSki cells contain around 600 copies of HPV 16 virus in the genome, whereas SiHa have only 1–2 copies per cell. Cells were analyzed using two different human tumor derived extracellular matrix methods (3D myoma disc model, and Myogel Transwell invasion assay). Cultures were irradiated with 4 Gy. Myoma invasion area and the depth of invasion were measured with ImageJ 1.51j8 software. Statistical analyses were performed with SPSS Statistics (IBM SPSS® Statistics 25). Results All cells invaded through Myogel coated Transwell membranes and within myoma discs. In myoma discs, a difference in the invasion depth (p = 0.0001) but not in invasion area (p = 0.310) between the HPV positive cell lines was seen, since SiHa (less HPV) invaded slightly better than CaSki (more HPV). HSC-3 cells (HPV negative) invaded deepest (p = 0.048) than either of the HPV positive cell line cells. No difference was detected in the invasion area (p = 0.892) between HPV positive and HPV negative cells. The ionized radiation significantly reduced the invasion depth of HSC-3 (p = 0.008), SiHa (p = 0.0001) and CaSki (p = 0.005). No significant effect on the invasion area was detected in any of the cell lines. However, a significant difference was observed between SiHa and CaSki in the reduction of the invasion depth after radiation (p = 0.013) as the reduction was greater with SiHa than CaSki. Conclusions Both solid and gelatinous human leiomyoma-based extracellular matrix models were suitable platforms to study the invasion of HPV positive cervical carcinoma cells in vitro. SiHa cells with less HPV copy number cells invaded slightly better and were slightly more sensitive to irradiation than CaSki cells with high HPV copy number. However, there was no drastic differences between the invasion properties of these carcinoma cells.
  • Joura, Elmar A.; Kyrgiou, Maria; Bosch, Francisco X.; Kesic, Vesna; Nieminen, Pekka; Redman, Charles W. E.; Gultekin, Murat (2019)
    Vaccines against human papillomavirus (HPV) are available in Europe since 2006. They have been highly effective in preventing infection and disease caused by the vaccine types. Clinical efficacy data are available for cervical, vulvovaginal and anal precancer and invasive cervical cancer. Disease reduction is best with early vaccination and a coverage of more than 70%. Gender-neutral vaccination provides direct protection for all men and improves the coverage. A good coverage is followed by herd protection of the unvaccinated men and women. School-based programs appear to be most effective; under the age of 15 years, two doses with an interval of 6-12 months are sufficient. From the age of 15 years, the standard regimen with three doses is recommended. A broad catch-up program for young adult women and men improves the effectiveness. The vaccines are also effective in sexually active women and men with previous but cleared infections. Vaccination in addition to local treatment of HPV-related disease appears to reduce recurrent or subsequent HPV-related disease. Combination of HPV vaccination and screening with HPV testing is the most effective approach to prevention of cervical cancer. The screening intervals may increase in the vaccinated cohorts. The upper age limit for vaccination remains to be evaluated, is country specific and depends on cost-effectiveness. The European Society of Gynaecologic Oncology and the European Federation for Colposcopy strongly support gender-neutral vaccination programs for children and young adolescents, with a catch-up program for young adults. (C) 2019 The Authors. Published by Elsevier Ltd.
  • Jouhi, Lauri; Atula, Timo; Mäkitie, Antti; Keski-Santti, Harri (2019)
    PurposeOnly a minority of patients with oropharyngeal squamous cell carcinoma (OPSCC) are diagnosed without regional metastasis (cN0). Studies focusing on the management of cN0 neck in OPSCC are scarce.MethodsWe reviewed all OPSCC patients treated at our institution with cN0 neck between 2000 and 2009. The treatment of neck and pattern of regional control was analyzed. Median follow-up was 5years (range 3.5-9.0) or until death.ResultsOf the total 313 OPSCC patients treated within the period, 56 (18%) presented with cN0 neck. Of them, 51 (91%) received completed treatment with curative intent: 46 (90%) underwent elective neck treatment with either neck dissection (chemo)radiotherapy (C)RT (n=23) or (C)RT (n=23). A regional recurrence occurred in three patients (6%) and they all had a p16-negative soft palate midline primary tumor. Two of these patients had received RT on the neck.Conclusions While the overall prognosis of OPSCC is generally favorable and regional recurrences are infrequent, soft palate tumors, that are usually p16 negative, may form an subgroup warranting more aggressive treatment despite the clinical appearance of early stage.
  • Vento, Seija I.; Jouhi, Lauri; Mohamed, Hesham; Haglund, Caj; Mäkitie, Antti A.; Atula, Timo; Hagström, Jaana; Mäkinen, Laura K. (2018)
    The objective of this study was to determine if matrix metalloproteinase-7 (MMP-7) expression is related to human papilloma virus (HPV) status, clinical parameters, and outcome in oropharyngeal squamous cell carcinoma (OPSCC). Tumor tissue specimens from 201 OPSCC patients treated with curative intent were available for immunohistochemistry, and the samples were stained with monoclonal MMP-7 antibody. All the patients were followed up at least 3 years or until death. MMP-7 expression did not differ between HPV-positive and HPV-negative patients. MMP-7 was not prognostic among patients with HPV-negative OPSCC. In the HPV-positive subgroup, patients with moderate, high, or very high MMP-7 expression had significantly worse 5-year disease-specific survival (DSS) (56.6%) than patients with absent, or low MMP-7 expression (77.2%), and MMP-7 expression appeared as a prognostic factor in the multivariate analysis. In addition, among HPV-positive OPSCC with moderate, high, or very high MMP-7 expression, the 5-year distant recurrence-free survival was significantly lower (69.6%) than in those who had low or absent MMP-7 expression (97.5%). Our results suggest that among HPV-positive OPSCC patients, high MMP-7 expression is related to worse 5-year DSS and increased rate of distant recurrences.
  • Hämetoja, Hanna; Hagström, Jaana; Haglund, Caj; Bäck, Leif; Mäkitie, Antti; Syrjänen, Stina (2019)
    Our objective was to assess the presence of three polyomaviruses, namely SV40, JCPyV, and BKPyV, and human papillomaviruses (HPV) in adenoid cystic carcinomas (ACC) of the minor salivary glands (MiSG) in the head and neck region. The study comprised 68 MiSG ACC patients operated during 1974–2012 at the Helsinki University Hospital (Helsinki, Finland). Medical records and 68 histological samples were reviewed. Polyomaviruses were detected with quantitative PCR and the DNA-positive samples were further analyzed for the presence of viral tumor T antigen (T-ag) with immunohistochemistry. HPV genotyping was performed with a Multiplex HPV Genotyping Kit. Only JCPyV DNA was found in ACC samples, being present in 7 (10.3%) out of the 68 samples. The viral load of JCPyV was low varying between 1 to 226 copies/μg DNA. The JCPyV-positive samples originated from trachea (two samples), paranasal sinuses (one), and oral cavity (two). Additionally, JCPyV positivity was found in one lung metastasis of a tracheal tumor and one local disease failure of an oral cavity tumor. Three JCPyV DNA-positive samples showed weak nuclear staining for large T-ag. In conclusion, only JCPyV but not SV40, BKPyV, or HPV was found in ACC from the upper and lower airways. JCPyV copy numbers were low which might support its role as a “hit and run agent” in ACC carcinogenesis.
  • Kalliala, Ilkka; Eriksson, Tiina; Aro, Karoliina; Hokkanen, Mari; Lehtinen, Matti; Gissler, Mika; Nieminen, Pekka (2021)
    A registry-based follow-up of pregnancy data until the end of 2014 was conducted based on a community randomized trial to assess human papillomavirus (HPV) vaccination strategies and a reference cohort from the same community with no intervention. Our objective was to determine whether prophylactic HPV vaccination (three doses of Cervarix? (AS04-HPV-16/18)-vaccine) affects preterm birth (PTB) rates. All identified 80,272 residents in 1992?95 birth cohorts in Finland were eligible for the trial and 20,513 of 39,420 (51.9%) females consented to participate. The final study population consisted of age-aligned 6226 HPV16/18 vaccinated females and 1770 HBV vaccinated (Engerix? B, hepatitis B-virus vaccine) females that did not receive HPV vaccine at the age of 18 from the 1992?93 birth cohorts, and 19,849 females from the 1990?91 non-vaccinated reference birth cohorts. We compared the rates of preterm (22 + 0?36 + 6 pregnancy weeks) and early preterm (22 + 0?31 + 6) per term (at least 37 + 0) singleton births among the HPVand non-HPV-vaccinated women, using nationwide Medical Birth Registry data. We observed 409 singleton first pregnancies lasting at least 22 + 0 weeks among 6226 HPV-vaccinated and 1923 among 21,619 non-HPV-vaccinated women. In the first pregnancy the PTB rate was 13/409 (3.2%) among the HPV-vaccinated and 98/1923 (5.1%) among the non-HPV-vaccinated (OR 0.61, 95% CI 0.34?1.09). Early preterm birth rate was 0/409 (0%) in the HPV-vaccinated women and 20/1923 (1.0%) in the non-HPV-vaccinated women (p = 0.04). PTB rate, especially early PTB rate, was lower among the HPVvaccinated women. Reduction of PTB incidence after prophylactic HPV vaccination would lead to public health benefits globally. Trial Registration:NCT00534638
  • Ilmarinen, Taru; Munne, Pauliina; Hagstrom, Jaana; Haglund, Caj; Auvinen, Eeva; Virtanen, Elina I.; Haesevoets, Annick; Speel, Ernst J. M.; Aaltonen, Leena-Maija (2017)
    Objectives: To analyze the prevalence of high-risk HPV (human papillomavirus) and genetic alterations in nonmalignant tonsils. Methods: We collected benign fresh tonsillar tissue specimens from 477 patients undergoing tonsillectomy because of chronic tonsillitis or tonsillar hypertrophy in 2012 (Group A, n = 237) and in 2015 (Group B, n = 240). Luminex xMAP technique served to detect E6/E7 DNA from 16 different high-risk HPV types. Tonsillar DNA and peripheral blood leukocyte DNA from the infected individuals were analyzed using Nimblegen SeqCap EZ Comprehensive Cancer Design panel. The panel targets 578 different genes that are relevant in carcinogenesis. HPV negative tonsillar specimens from age-and gender matched individuals were used as controls. All specimens harboring high-risk HPV were analyzed using fluorescence in situ hybridization (FISH). Results: Five of 477 (1.0%) patients tested positive for the following HPV types: HPV16 (two cases), HPV52 (one case), HPV66 (one case), HPV52 and HPV68 (coinfection, one case). FISH analyses showed that the appearance of HPV in specimens infected with HPV 16 was episomal. Benign tonsils infected with high-risk HPV harbored mutations in EP300, NF1, PIK3CA, and RB1 which are considered relevant in the development of HPV-associated head and neck squamous cell carcinoma (SCC). Conclusions: The prevalence of high-risk HPV in nonmalignant tonsils is low. High-risk HPV positive tonsils harbored mutations in genes that are commonly altered in HPV-associated head and neck SCC. The role of these mutations in tonsillar carcinogenesis is an interesting target for future research.