Saturday, October 5, 2013
‘t Pand, Ghent, Belgium
During the Belgian Week of Pathology
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The subject is timely since recent research work profoundly changed cervical carcinogenesis concepts with major emphasis on human papilloma virus infection and the role of stromal factors. International cervical cancer statistics publications show dynamics between the North and South, East and West in a speed that has never been seen before. A phenomenon that causes considerable concern among health workers and governmental bodies. Economic factors probably play an important part but other issues important as well. Also, vaccination policies have changed significantly our attitude towards primary prevention and ethical apprehensions complete the pallet of current discussions. The impact of these new insights and concerns affects screening programs, primary prevention strategies and even contemporary treatments and treatment algorithms. The extension to clinical topics and the entering of molecular biology into all virtually all aspects of this disease will enable us to provide a comprehensive state-of the art overview of cervical cancer anno 2013.
|Prof. Theodorus Agorastos||Gynecology – Papageorgiou Gen Hospital – Thessaloniki, Greece|
|Prof. Aristotle Bamias||Clinical Therapeutics – Alexandra Hospital – Athens – Greece|
|Prof. Johannes Bogers||Pathology – University Antwerp – Antwerp – Belgium|
|Dr. Jack Cuzick||Epidemiology – Wolfson Inst Preventive Medicine – London – UK|
|Prof. Eric de Jonge||Gynecology- Hospital Oost-Limburg, Genk, Belgium|
|Dr. Patricia Duvivier||Gynecology – Jessa Ziekenhuis – Hasselt – Belgium|
|Dr. Mikel Gorostidi||Gynecology – Hospital Univ. Donostia – San Sebastian, Spain|
|Dr. Sylvia Franceschi||Epidemiology – Infections & Cancer Epidemiology – IARC – Lyon – France|
|Prof. Paul Ide||Gynecological Oncology, Hasselt, Belgium|
|Prof. Robert Jach||Jagiellonian Univ. Medical Collega – Dept. Gynecology Krakov, Poland|
|Prof. Jaak Ph. Janssens||ECP – Hasselt – Belgium|
|Dr. Belinda J. Johnson||Lady Sobell GI unit – Berkshire Bowel Cancer Screening – Berkshire – UK|
|Dr. Jos Kemps||Gynecology – Diest – Belgium|
|Prof. Carlo La Vecchia||Epidemiology – Ist di Ricerche Farmacologiche “Mario Negri”, Milan, Italy|
|Dr. Mustapha Mouallif||Experimental Pathology, CHU Sart-Tilman, Univ Liège, Morocco – Belgium|
|Dr. Eddie Murta||Gynecology – Univ Triangulo Mineiro – Abadia – Brasil|
|Dr. Vian Namanya||Gynecology, Univ of Gulu- Uganda|
|Prof. Yuzuru Niibe||Radiology & Radiation Oncology, Ktasato Univ School of Medicine, Japan|
|Dr. Daniela Paepke||Integrative Medicine and gynecology, Tech Univ München, Germany|
|Prof. Gad Rennert||Epidemiology – CHS National Israeli Cancer Control Center – Haifa – Israel|
|Dr. Isabelle Ray-Coquard||Medical Oncology – Centre Léon Bérard – Lyon – France|
|Dr. Joachim Rom||Gynecology – Universitâts Frauenklinik – Heidelberg – Germany|
|Dr. Peter Sieprath||Gynecology- Hospital Oost-Limburg, Genk, Belgium|
|Dr. Elke Sleurs||Gynecology – University Hospital Gent – Gent – Belgium|
|Prof. Dr. Dietmar Schmidt||Pathology – Univ of Kiel – Kiel – Germany|
|Dr. Henk ter Brugge||Gynecology – Isala hospitals – Zwolle – The Netherlands|
|Dr. Marcel Verjans||Gynecology – Regional Hospital – Tienen – Belgium|
Part 1 -Chairman: Prof. Eric de Jonge, Genk, Belgium & Dr. Eddie Murta, Abadia, Brazil
The impact of new insights and concerns about vaccines affects screening programs, primary prevention strategies and even contemporary treatments. The extension of today’s program to clinical topics and the entering of molecular biology into all virtually all aspects of this disease will enable us to provide a comprehensive state-of the art overview of cervical cancer anno 2013.
Prof. Jaak Ph. Janssens, Hasselt, Belgium
09.10 Oral contraceptive use, HPV and cervical cancer
Long-term use of oral contraceptives could be a cofactor that increases risk of cervical carcinoma by up to four-fold in women who are positive for cervical HPV DNA. In the absence of worldwide information about HPV status, extra effort should be made to include long-term users of oral contraceptives in cervical screening programs.
Prof. Carlo La Vecchia, Milan, Italy
09.40 Replacement of cytology by an HPV-based screening method: which is the best option?
Novel strategies for cervical cancer screening could improve early detection
Prof. Theodorus Agorastos, Thessaloniki, Greece
10.00 Diagnostics and surgical treatment of premalignant lesions
The Dutch approach compared to the different screening polices in Europe and the diagnostic and treatment decisions after abnormal Pap-smears. The work-up in policlinic see and treat setting by colposcopy including LLETZ for CIN lesions is combined with information and a lifestyle program.
Dr. Henk ter Brugge, Zwolle, The Netherlands
11.00 The importance of stromal factors
The interface between stromal and epithelial factors has generated substantial interest in the near past and has consequences in our understanding of carcinogenesis. Also in diagnosis and treatment of early disease these factors become increasingly decisive.
Prof. Johannes Bogers, Antwerp, Belgium
Optimal age for vaccination, value in older women, newer HPV vaccines, integrating vaccination and screening.
Dr. Jack Cuzick, London, UK
11.40 Awareness of cervical cancer and human papillomavirus (HPV) and acceptability of the HPV vaccine in Morocco.
The study consisted of a questionnaire-based survey in a sample of 852 parents with at least one unmarried daughter ≤26 years in Morocco. We found very low HPV and HPV vaccine awareness. None of the participants had vaccinated their daughters against HPV. Only 32% of mothers and 45% of fathers were willing to consider doing so in the future. Higher education and income, previous awareness of the HPV vaccine and endorsement of the belief that a recommendation from the ministry of health to have the vaccine would be encouraging, were associated with mothers’ HPV vaccine acceptance. Non-acceptance among parents was associated with many factors but fears that HPV vaccination would increase sexual promiscuity was not a barrier.
Dr. Mustapha Mouallif, Liège, Belgium- Morocco
12.00 Knowledge, attitudes and acceptability of HPV vaccination among primary school girls in Uganda
Sound knowledge and positive attitudes highly influence acceptability and uptake as the vaccine becomes available. Acceptability studies are thus mandatory to highlight potential barriers and guide immunization policies. There is generally limited knowledge about cervical cancer and HPV vaccine that requires massive community sensitization to improve on vaccine uptake amongst the targeted population.
Drs. Vian Namanya, Gulu, Uganda
Part 2: Chairman: Prof. Dr. Dietmar Schmidt, Kiel, Germany & Dr. Peter Sieprath, Genk, Belgium
14.00 European screening strategies
Budgetary constraints but also new disease insights govern the implementation of screening strategies. What are the implications for the European Countries on an international and national level?
Dr. Elke Sleurs, Gent, Belgium
14.20 Clinical-molecular scoring system to predict CIN outcome
Clinical, virological, epidemiological and molecular biology data are the source of cervical cancer understanding. This may modify diagnostic and therapeutic approach, especially in pre-invasive and early invasive cervical cancer cases. Selecting the progression factors which lead CIN to an invasive cancer is of clinical importance, because most CIN cases are diagnosed in women aged 30–40, so in their reproductive period of life. The multivariate logistic regression analysis discriminated eight risk factors of CIN progression (p <0,001). For this risk factors an original punctuation scale or CIN progression risk was designed.
Prof. Robert Jach, Krakow, Poland
14.40 Colposcopic findings in ‘in situ” adenocarcinoma
‘in situ’ adenocarcinoma of the cervix is an infrequent finding. Characteristics of this condition can be differentiated during colposcopic examination. Advances and limitations of the technology will be evaluated.
Prof. Paul Ide, Hasselt-Leuven, Belgium
15.00 Trachelectomy: a conservative approach
The place of vaginal/abdominal removal of the cervix is evaluated as an option for surgery in younger women in fertility age.
Prof. Alexandros Rodolakis, Athens, Greece
16.00 Surgery for invasive lesions
Robotic or traditional surgery; laparoscopic or vaginal approach… for cervical cancer and in what stages? The new paradigms are discussed.
Dr. Joachim Rom, Heidelberg, Germany
16.20 Staging of advanced cervical cancer: Laparoscopy or robotics? Advantages and disadvantages
Surgical staging of paraaortic area is the best way to establish the field of radiation in cervical cancer. Affected nodes are found in 26.1% of negative PET patients. The laparoscopic retroperitoneal access for paraaortic lymphadenectomy in advanced cervical cancer is widely known. Complex oncological procedures are increasingly performed robotically in hospitals where this resource is available. The advantages of robotics are the use of wristed instrumentation, high definition 3D optics, downscaling of movements, better equipment precision, improved ergonomics and improved excision of interaortic nodes. The disadvantages of robotics are the cost, the loss of haptic perception, with risk of iatrogenic injuries, the need of greater size and number of ports, more time, the unavailability of advanced sealing devices for our model that makes more difficult the excision of left infrarenal nodes (as electricity is the only energy available in robotics, it is vital to correctly dissect and cauterize tissues prior to section) and the constrained operating field in retroperitoneal access. We find little advantages with robotics for retroperitoneal lymphadenectomy in cervical cancer.
Dr. Mikel Gorostidi, San Sebastian, Spain
16.40 Systemic therapy in advanced-inoperable disease
Chemotherapy remains the mainstay of systemic therapy in advanced disease. What is the standard? How is the prognosis determined? Molecular biology of cancer tissues may offer therapeutic targets. Patient selection to ensure the best treatment option for the individualized patient represents the goal of current research. The personalized diagnostics and treatment for patients with cervical cancer are summarized.
Prof. Aristotle Bamias, Athens, Greece
17.00 Integrative Oncology: an example from the gynecological department of the Technical University of München
Integrative oncology, concentration to the personality of the patient, can be applied to the entire medicine and in particular to gynecology. The Technical University of München is the only one to offer this complementary medicine to their patients. The experience of the center will be highlighted as well as the therapeutic potentials of Viscum Album in cervical cancer.
Dr. Daniela Paepke, München, Germany
(the integral version of the summary will be published in an upcoming issue of the European Journal of Cancer Prevention.)
Cervical cancer can be extremely lethal when the disease strikes in its most aggressive way. Communication, competence and comfort are then prerequisites for maximal quality and duration of remaining life[i]. Cure is rare in advanced diseases despite the availability of new innovative therapeutic means such as improved surgery, targeted therapy, cytotoxic chemotherapies, better supportive care, or combinations of these[ii]. It is sad to learn that the 5-year overall survival of patients with systemic disease hardly changed over the last 30 years. In addition, despite reasonable hope that all kinds of therapies will always improve, there is no clear indication that substantial progress on the 5 and 10 years survival will be made in the coming years. As a consequence, all efforts should be put in place to increase maximal protection through primary and secondary prevention.
The impression that the only treatment of early disease is radical surgery and/or radiotherapy seems no longer supported by recent clinical research. Of course, both treatment modalities are particularly effective and remain standard practice but are now gradually turned into less invasive and more efficacious innovations for very early lesions or premalignancy[iii],[iv]. It is anticipated that this shift to patient friendly minimal surgery will result in a substantial increase in awareness and willingness to detect the disease in its earliest stages[v]. Again, supporting the adagio that “the smaller the lesion, the less aggressive treatment”. Although still debatable, a “see and treat” option is now open to selected cases in some high level clinical centers[vi].
The enigmatic presentations of cervical cancer continue to impress clinicians. Classical teaching dogmas, such as the “cervix en tonneau” for adenocarcinomas, are no longer valid as the disease can present in totally different ways and without typical cytological correlates[vii]. In addition, better understanding of the first symptoms and characteristics, improved visualization of the cervix by high quality colposcopy, and early histology through improved tissue sampling can prevent wrong or late diagnosis. Risk assessment, whether based on pathology, molecular or other factors, is possible during premalignancy in a stage that is remote from the deadly invasive cancer[viii]. Proper selection of women that need treatment for non-invasive lesions can both reduce morbidity and mortality, and at the same time preserve fertility and avoid pelvis discomfort.
Basic research points to the importance of carcinogenic viruses and stromal factors in the origin of cervical cancer. Stromal factors, that initiate and promote the first invasive steps of a transformed malignant epithelium, have recently been better identified and characterized. In particular the local immune response to viral attack seems to be one of most critical factors to develop cancer. And because the stroma becomes easily accessible during routine clinical work-up, attention to the stroma becomes essential for determining prognosis and immediate risk in premalignant and early stages of invasive malignancies[ix].
Of paramount importance in the carcinogenic process is human papillomavirus. This causal role has been known since the pioneering work of Prof. Harald zur Hausen. It is contemporary belief that without infection, there will be no malignancy and no premalignant lesions. Hence the hypothesis that suppression of the virus infection will eradicate this cancer. A most hopeful perspective for a potential lethal disease.
The association (co-infection) of HIV (human immunodeficiency virus) with HPV, especially in developing countries, is well known. There is HIV-HPV synergy, each virus infection giving higher risk to the other. HIV/AIDS leads to the progression of HPV infection into dysplastic changes and invasive forms of malignancy. According to the World Health Organization, invasive cervical carcinogenesis is an HIV stage IV condition, making it also an AIDS related pathology.
Low and high risk precancerous lesions can be detected by traditional Pap smear but sensitivity and specificity are not in the range clinicians had hoped for. An improvement could be to identify women at high risk by their infection status since this infection is prerequisite for later malignancy. Quite a number of HPV tests are now available and even self-testing kits look acceptable as a tool in screening programs for none responders. Time has come to consider replacement of cytology by HPV-based screening methods also because the costs of screening are an central issue in most countries[x].
European health promoting strategies aim at giving women the same chance to combat the disease over the entire European Community. Differences in culture, social attitude, health care and insurance system are not helpful in giving women similar opportunities[xi]. Also the implementation of HPV tests instead of Pap smear cytology has to be addressed by policy makers in the near future.
The successful development of vaccines against HPV concluded years of intense and promising scientific research. The vaccines prove only effective if vaccination takes place before possible gynecological infection which is before any sexual intercourse at early puberty. But newer nanovalent vaccines might be useful up to the age of 50. For now, the ideal vaccination time remains during early puberty. Because HPV also causes genital warts, anal cancers, and pharyngeal cancers, both sexes should be vaccinated. Vaccination of boys could address the, for a number of countries, unacceptable cultural issue of vaccinating only girls, and could increase coverage in the population as well.
One or two doses seem as efficient as more doses for protection, an observation that could further reduce the costs[xii]. The success in cervical cancer protection might well be followed by successes in the other cancers the HPV causes. In addition, hope is there for other cancers that are caused by additional viral and/or bacterial agents.
Although the scientific merit of these vaccines is substantial, the vaccination coverage of the population is still problematic. In developed countries, cervical cancer is less prevalent and treatment options plentiful resulting in disappointing interest, and even disbelieve regarding efficacy and safety. In developing countries, where both prevalence and mortality of cervical cancer is high and with much lesser treatment possibilities, shortage of financial means and cultural barriers prevail[xiii]. Fortunately, some governments try hard to reach the target population by organized vaccination campaigns and in case cultural considerations are against vaccination, measures for personal hygiene may be the way to go[xiv].
Oral contraceptives, either estrogens and/or progestagens, may contribute to cancer risk as well. Although the main risk seems to be confined to women currently taking the pill or have taken it for a longer time, the relation is only seen in individuals with HPV infection . The causal link is even more apparent in developing countries but might be not that useful since contraceptives are real need in birth control. It is a relief to not that when HPV infection is eradicated, this causal factor becomes unimportant.
The dramatic decline in cervical cancer mortality in developed countries during the 20th century was closely related with the upcoming of personal hygiene. Personal hygiene for women and partner still proves to be standard approach when vaccines are not available yet to everyone. Altogether, it is fair to say that vaccination, personal hygiene and condom use, already considered in the prevention of human immune-deficiency virus (HIV), should be able to eradicate cervical cancer efficiently.
With poor cure rates in advanced cervical cancer, much more attention is given to early detection and prevention. This is certainly needed in developing countries. Earlier detection means nowadays also lesser mutilation from reduced surgery and more comfort after treatment. Early diagnosis of malignancy is traditionally based on clinical examination by an experienced physician and Pap-smear. But newer developments in molecular biology and the knowledge that cervical cancer is caused by HPV infection has led to the implementation of HPV detection kits. It is expected that HPV tests will gradually replace cytology in cervical cancer smears.
But the even better protection aims at avoiding the disease. Primary prevention through improved personal hygiene and vaccination of both males and females may not only eradicate cervical cancer but also a number of additional conditions with HPV origin. Vaccination is most probably going to be one of the greatest success stories of medicine in primary cancer prevention.
[i] Paepke D. Integrative Oncology: an example from the gynecological department of the Technical University of München. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[ii] Bamias A. Systemic therapy in advanced – inoperable cervical cancer. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[iii] Gorostidi M. Staging of advanced cervical cancer, Laparoscopy or Robotics? Advantages and disadvantages. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[iv] Rom J. Surgery for invasive lesions. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[v] Rodolakis A. Management of cervical carcinoma by trachelectomy: a conservative approach. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[vi] ter Brugge H. Diagnostics and surgical treatment of premalignant lesions. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[vii] Ide P. Colposcopic findings in ‘in situ’ adenocarcinoma. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[viii] Jach R. Clinical-molecular scoring system to predict CIN outcome. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[ix] Bogers J. Role of the stroma in cervical cancer. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[x] Agorastos T. Replacement of cytology by an HPV-based screening method: which is the best option? Annual ECP meeting on Cervical Cancer Prevention, 2013.
[xi] Sleurs E. European screening strategies. Annual ECP meeting on Cervical Cancer Prevention, 2013.
[xii] Cuzick J. Who needs HPV vaccination? Annual ECP meeting on Cervical Cancer Prevention, 2013.
[xiii] Mouallif M. Awareness of cervical cancer and Human Papilloma Virus (HPV) and parental acceptability of HPV vaccination in Morocco.
[xiv] Namanya V. Knowledge, attitudes and acceptability of HPV vaccination among primary school girls in Uganda. Annual ECP meeting on Cervical Cancer Prevention, 2013.