گزارش دکتر ملیحه حسن زاده، دانشیار دانشگاه علوم پزشکی مشهد از کنگره EUROGIN, June 2016

In the name of GOD

The Eurogin is one of the most important conferences on human papillomavirus infection and related cancers. The program also encompasses state-of-the art science on anogenital and head & neck cancer, inspires collaboration, and provides forums to share expertise and learn from the leading experts in these fields.

The EUROGIN 2016 Congress aims at developing a full review of current scientific developments in the field of cancer and human papillomavirus related diseases, raising the public health profile and increasing the need for responsible health services in this area. The event endeavors to translate scientific and evidence-based research into clinical practice while highlighting the following aspects:

– Recent advances and updated scientific insights in HPV screening, testing and management
– The impact of HPV and associated cancers on public health
– Strategies to prevent and treat HPV related diseases
– Exchanging information on early detection, new diagnostic and therapeutic procedures and prevention strategies including screening and HPV vaccination

Speakers include international leaders from academic, government and private organizations, representatives of medical and scientific societies, as well as women’s health associations who discuss and exchange ideas on issues relevant to both individuals and public health

Key Scientific events of the conference were:

  1. The German Austrian Workshop
  2. International experts of the HPV and Head & Neck Forum
  3. The satellite course on Quality Assurance in Cervical Cancer
  4. Prospects for Immunotherapy in HPV associated Cancer
  5. Other Training Courses
  6.  Vulvar Disease Course
    Colposcopy Training Course with cases studies

The EUROGIN 2016 congress offered excellent opportunities for learning and networking with professionals from many different disciplines.

  1. Human papillomavirus is one of the most common viral agents infecting skin and mucoses in humans. It is now well established that persistent HPV infection with some specific HPV types, the so called high risk types, leads to a deregulation of viral gene expression and altered cell functions including cell proliferation, poor DNA repair, and accumulation of genetic changes. All these changes are linked to anogenital cancers including cervix, vagina, vulva, anal canal, penis, and head and neck cancers, particularly oropharyngeal. In every world region, the burden of HPV related cancer is driven by cervical cancer incidence. Differences in the burden of HPV related cancer between the two sexes in any world region thus depends mainly on: 1) the effectiveness of cervical screening programs; and, to a lesser extent, 2) the fraction of oropharyngeal cancer attributable to HPV.
  2. Vaccines against HPV have been introduced in most developed countries over the last decade. In a number of settings, vaccine induced reductions in infections with vaccine included HPV types and cervical cancer precancerous abnormalities have already been documented in young women.
  3. Approaches for triage of HPV positive women may be divided into those which seek additional information from cytologic slide preparations and those which utilize molecular testing independent of intact cells. Slide based options include improvements in computerized interpretation of standard cytologic preparations, and immune histochemistry staining of cytology preparations for recognition of p16 and Ki67. Investigation of possible improvements in computer imaging is being actively considered. Preliminary data on p16/Ki67 triage from Kaiser Permanente Northern California indicate that p16/Ki67 dual staining is as sensitive and has better specificity, NPV and PPV than cytology for CIN2+ in 1669 HPV positive women, which could permit a significant reduction in colposcopy.1 Molecular approaches include risk stratification by more complicated sorting of HPV types or subtypes,2 which are associated with significantly different risk. Among the DNA types identified as “high risk” there is a wide variation in risk, informing variations in clinical management. Among the subtypes of HPV 16 identified to date, unpublished data suggests significant variation in risk and variation in association with squamous versus glandular cancers. DNA methylation at specific sites has been shown to be predictive of CIN3+, and recognition of methylation at CADM1 and MAL sites is associated with dysplasia but not normal cervical tissue on biopsy and can be assessed on cervical scrape specimens.
  4. HPV based cervical cancer screening requires triage markers to decide who should be referred to colposcopy. One candidate triage marker is detection of p16 or p16/Ki67 stained cells (dual stain) in cytology. p16 and the dual stain have been evaluated for triage of ASCUS and LSIL cytology, for primary screening, and more recently for triage of HPV positive and HPVpositive/cytology negative women. A study at Kaiser Permanente Northern California (KPNC) showed that the dual stain assay can be implemented after limited training with high reproducibility. Furthermore, automated evaluation approaches are currently being developed. A prospective evaluation of p16 in an Italian cervical cancer screening trial showed that p16 is a viable option for triage of HPV positive women, possibly allowing extending follow up intervals of p16 negative women. Similarly, in an evaluation of the dual stain among women undergoing HPV cytology cotesting at KPNC, dual stain positive women had a risk of precancer higher than the colposcopy referral threshold while the risk among dual stain negatives was below the threshold for a 1 year repeat test. Similar results were observed for HPV positive/cytology negative women in the same population. These findings suggest that the dual stain could be an effective triage strategy for HPV positive and HPV positive/cytology negative women.
  5. DNA methylation plays a crucial role in activating and silencing genes during normal development. Tumor virus genomes are subject to selective differential methylation with important regulatory consequences

HPV16 has ~113 dispersed CpG sites, many of which are differentially methylated. Increased methylation of the LI, L2 and E2 genes is consistently associated with cervical carcinogenesis.

Methylation values of some CpG sites in the L1-L2 regions in normal tissues typically range from 0 to 10%, with persistent infections showing higher methylation than transient infections. Methylation values in CIN2/3 are significantly elevated compared to normal, while in cancers methylation levels often reach 50 to 100%. Methylation levels are strongly associated with HPV integration. In contrast to the L1-L2 regions the CpGs in the URR are usually unmethylated in normal and CIN specimens.

However, E2 protein binding sites can show increased methylation in cancers, which facilitates continued production of HPV16 E6-E7 oncogenes. Methylation patterns in other hrHPVs resemble HPV16, being significantly higher in CIN2+ compared to <CIN2. Interestingly methylation of L1-L2 in single infections of HPV18, HPV31 or HPV45 in CIN2+ were higher than when present as combinations with HPV16, suggesting that HPV16 is usually the driver virus and is more often targeted by the cellular methylation machinery.

HPV methylation patterns are complex and strongly associated with neoplasia. Similar methylation patterns have been shown in HPV16, HPV18, HPV31, HPV33, HPV45, HPV52 and HPV58 and may be characteristic of most or all hrHP Vs. There is a typical progression of methylation level with persistence and carcinogenic change. Development and validation of robust routine methylation assays may allow better disease risk profiling of hrHPV+ women.

Dr. Malihe Hasanzadeh