Carcinoma of the cervix
The role of Human Papilloma Virus and prospects for primary prevention
Dr. R.A. Kwame-Aryee
University of Ghana Medical School
Tutor: Dr. Pierre Vassilakos
University of Geneva
See also presentation
Cancer of the cervix is the most common female genital cancer in developing countries. Every year about 500,000 women acquire the disease and about 75% are from developing countries. About 300,000 women also die from the disease annually and of these 75% are from developing countries.
The objectives of this paper are to review the aetiology of carcinoma of the cervix and the possible preventive procedures that are available.
The literature was reviewed using databases from the PUBMED, MEDLINE, OB/GYN.NET / MEDCARE and the WHO and its collaborative institutions such as Path.
The aetiology of cervical carcinoma is basically from HPV infection which occurs usually as a sexually transmitted disease. The mode of infection and the host factors that enhance the acquisition and persistence of the virus in host cells have been described. The literature has revealed the mode of inhibition of the cervical cellular p53 and Rb anti-ongenes by the production of proteins from the viral genome E6 and E7 regions, the integration of viral DNA into the host cell and mutation of the host cell nucleus resulting in uninhibited proliferation of cervical cells with subsequent carcinoma formation. Other host factors favouring the persistence of HPV in the female genital tract have also been clearly outlined. Factors such as early coitarche, frequent change of sexual partners, cigarette smoking and prolonged use of combined oral contraceptives and immune suppression have been shown to be associated with carcinoma of the cervix.
The different cervical screening procedures with their attendant problems are discussed. Screening with the traditional Pap smear technique shows sensitivity and specificity of 51% and 98% respectively. Other screening procedures such as VIA have been shown to be effective in screening for the cervical cancer with a sensitivity and specificity of 76% and 64%, respectively (1). VIA may hold the key to effective screening in low resource areas of the world. DNA testing has also been developed and this is likely to enhance the detection of the HPV in the female genital tract.
It is also worth noting that different vaccines are in the process of development and this may well prove cost effective for the primary prevention of carcinoma of the cervix. Until the vaccine is fully certified for use for the prevention of cancer of the cervix it is advised that safe sex should be practised by all.
Cancer of the cervix uteri is the most common female cancer in developing countries. Worldwide about 500 000 women acquire the disease annually and about 75% are from developing countries (1). About 300 000 women die of the disease annually.
Until recently the aetiology of cancer of the cervix has not been clear. Many suggestions were made to link cancer of the cervix with certain viral infections. In the seventies and early eighties Cytomegalovirus and Herpes Simplex II were implicated as their proteins were found in a large number of invasive cervical cancer lesions (2). Until recently the Human Papilloma Virus (HPV) had not been linked with the pathogenesis of cervical cancer. The Human Papilloma Virus has been known since antiquity to be associated with warty growths of the hands, vulva and vagina and other parts of the skin (3) but the link with cancer of the cervix has now been elucidated.
HPV is now considered a sexually transmitted disease with particular types being highly oncogenic. The WHO’s International Agency for Research on Cancer (IARC) has classified the HPV into three groups: “carcinogenic (HPV types 16 and 18); probably carcinogenic (HPV types 31 and 33) and possibly carcinogenic (other HPV types except 6 and 11) (4). Today over 120 types of the HPV have been described. The diagnosis of genital HPV infection has been done by indirect means (cytology). Recently highly specific HPV DNA tests (e.g. Polymerase Chain Reaction tests and the Hybrid II Capture tests) have been developed for the detection of HPV in cervical / vaginal preparations. These tests are very sensitive and could contribute significantly to the early detection of the virus in the genital tract in the very near future.
Screening for precursor lesions of the cervix have been in use for a long time in the industrially advanced countries. The screening test has led to a marked reduction in cervical cancer death rate by about 70% (1). The main screening test, the Pap smear, developed by George Papanicolaou in 1943 has been the gold standard of for the detection of pre-malignant and indeed early malignant lesions of the cervix.
In developing countries or low resource countries, the development of the naked eye visual inspection of the cervix (VIA) is likely to help reduce the high morbidity and mortality associated with cancer of the cervix. The VIA has been shown to be sensitive and specific enough to take the role of a good screening method. It has also been shown to be easy to teach nurses and midwives to perform the test and to go one step ahead to treat premalignant changes in the cervix by cryotherapy.
With the advances in technology vaccines are being developed against the HPV with the hope of achieving primary prevention of the disease. It is my fervent hope that it will not take too long for the vaccines to be approved for use. Until the vaccine becomes available for mass population use it will still be prudent to practise safe sex.
The objectives of this study are:
- To conduct a review of literatures on the available evidence on the aetiology of carcinoma of the cervix.
- To study the different types of screening methods available and their efficacy as well as to find which of them may be more useful in low resource settings.
- To identify possible preventive measures to reduce the risk of carcinoma of the cervix.
This literature review is undertaken through electronic search using the databases such as PUBMED, MEDLINE, Cochrane library, etc. to find most up to date studies on the subject. Recent publications from the WHO and collaborative institutions such as PATH were also reviewed.
For the electronic search the following key words were used:
- Cervical carcinoma / cancer.
- Human Papilloma Virus.
- Screening for cervical cancer.
- Cervical cytology.
Manual searches were also conducted at the WHO and the Geneva Medical School libraries. An extensive body of knowledge is available on this topic; therefore, the search was limited to recent literature published between 1995-2003. A few references were sought from earlier years.
References related to the following topics were reviewed:
- The Human Papilloma Virus as an aetiological factor for cancer of the cervix.
- The characteristics of the Human Papilloma Virus.
- Cervical screening procedures and the methods of reporting.
- New cervical screening procedures.
- Use of cervical DNA test in the detection of HPV in the female genital tract.
- The use of vaccines to prevent HPV infection in women.
The findings are discussed under the different headings below.
Aetiology of cervical carcinoma
A number of papers reviewed the aetiology of cervical carcinoma. In the 1960s and 1970s and early eighties the cause of cervical carcinoma was attributed to the Cytomegalovirus and later the Herpes Simplex Type II infections (2) as viral antibodies were found in cervical cancer patients. After many years of research it has now become evident, beyond all reasonable doubt, that the cancer is closely related to certain highly oncogenic strains of the HPV, notably types 16 and 18 (1,5). A press release in 1996 by the WHO (1), summarising the conclusions of an informed Technical Consultation involving, 55 experts from 17 countries, declared HPV as a major cause of the cancer of the cervix.
From the literature review it would appear that there are other strains of the HPV which are also oncogenic but by far the commonest type causing cervical cancer is the type 16 which can be retrieved in over 80% of cervical cancer specimens. Type 18 which may be seen in a few cancer specimens may be associated with a rapid onset of disease and it usually affects the endocervical glands. To date over 99.7% of cases of cervical cancer and severe CIN II/III are associated with previous oncogenic HPV infection (6,7). The other types involved in cervical changes include but are not limited to the following: types 31, 33, 51, 53, 35 etc.
Recently, anecdotal reports from a few investigators have indicated that not be all cases of cervical carcinoma can be traced to HPV infection. Morrison et al (8) provide evidence for 5 cases of unusual variants of large invasive squamous cell carcinoma of the cervix diagnosed during hysterectomy for benign uterine disease (prolapse – 2, fibroids 1 and VVF – 2). Four of the patients had normal Pap smears and the fifth had ASCUS. HPV PCR test could not detect HPV DNA in the specimens. (Could the lesions have been due to yet unidentified types of HPV)?
It must be emphasised that HPV is the most prevalent sexually transmitted infection in the world occurring in up to 75% of sexually active women (9,10). Men and women get infected soon after becoming sexually active but it may take up to 20 years for the cervical cancer changes to appear on the cervix. Only about 10% of infected women would go on to develop cervical dysplasia and of these and only a few would develop overt cancer of the cervix. From the mechanisms of malignant change (discussed below) it becomes fairly obvious that other risk factors may be involved in the carcinomatous change. It seems that even though the infection is sexually transmitted there seem to be a number of behavioural, social, cultural and economic factors playing roles as risk factors for the carcinomatous change.
The following risk factors which have been known for a long time to be associated with carcinoma of the cervix may play key roles in the cancer formation. Early onset of intercourse and the change of multiple partners increase exposure to HPV and other sexually transmitted diseases. The sexual behaviour of the woman’s male partner may also increase the risk of exposure (10) for it has been known that partners of men that develop penile carcinoma are at high risk of developing carcinoma of the cervix.
History of cervical carcinoma in close relatives may also be an important (12) factor. Cigarette smoking has also been implicated as a co-factor. The nicotine and other by-products of smoke are concentrated in the cervical mucous with a resultant reduction in the immunity of the Langerhan's (dendritic) cells. Ylitalo et al 1999 (13), in a case control study in a population based cohort consisting of women participating in a cytological screening test in a Swedish county between 1965 and 1999 confirm the association between smoking and cervical cancer.
Conditions that reduce the immunity are also associated with cancer formation (14,15) as they enhance viral persistence in host cervical cells. The Human Immune Deficiency Syndrome is therefore a contributor to carcinomatous change. The chronic use of corticosteroids such as for unrelenting asthmatic attacks may also play a role in cervical cancer formation.
Recently the role of the combined oral contraceptive pill as a risk factor for cervical carcinoma has also been clarified (16).
The Human Papilloma Virus
Much research has been done to characterise the Human Papilloma Virus. In 1995 the WHO (2) published in its monograph the Summary of Data Reported and Evaluation of the the Human Papilloma Virus. In this monograph much of the information on HPV has been summarised. The HPV, a Papovavirus, is a small double-stranded DNA virus with a diameter of 55 nm. It is encased in a protein capsid with the viral genome existing in a circular or epitomal configuration. The viral genome can be divided into 3 regions: the Upstream Regulatory Region (URR), the Early Region (E) and the Late Region (L). The URR is involved in viral replication and the control of transcription in some sequences in the Early region. The Early Region encodes for proteins that are responsible for viral replication which occurs early in the viral life cycle. The late region encodes for viral structural proteins necessary for capsid production late in the viral life cycle. The Early Region is responsible for maintaining high numbers of HPV and the oncogenic types also encode for proteins that promote the transformation of the host cell to cancer (immortalisation). There are some areas in the Early Region that can encode for proteins and are designated as E1, E2, E3, E4, E5, E6 and E7. The E6 and E7 regions are responsible for the oncogenic properties of the HPV.
Thomas Cox et al (3) indicate that nearly 120 types of HPV have been described with about 20-30% unclassified. The types are numbered according to their discovery and a new type is identified if it has at least 10% of the gene sequence at E6, E7 and L1 different from any previously known type. Types 16, 18, 31, 35, 45, 51, 52 and 56 are considered high risk types because of the association lower genital tract cancers and pre-cancers.
It is well established that HPV is transmitted sexually and may persist in the genital tract for a very long time with resultant cervical changes. Genital-to-genital transmission is easy as micro-trauma at the fourchette, labia minora or vagina may enhance the entry of the viruses into the host cells. The viruses may take up to 3 months after exposure to show any clinical lesion (1,3) and may take up to 20 years to show carcinomatous change. Some of the infections may be sub-clinical without any visible expression.
As the virus invades the genital cell the HPV loses its protein capsule but to be infective the capsule is required. The HPV DNA therefore exists in the host cell without its shell. Infective HPV may be found only in the upper layers of the epithelium where infective genomes of HPV are released as dying koilocytes. The 2 late regions of the HPV are responsible for proteins involved in the construction of the capsid of the infective HPV genome. The infection is usually found at the basal cell layer and it does not go through the basement membrane of the epithelium. The infection of the female genital tract may take 2 main courses – transient infection and persistent infection. Up to 65% of infected individuals may show disease expression but most of the infections quickly resolve due to a complex interplay of host, viral and environmental factors with resultant increased dominance over the viral intruder (2,3). When the virus escapes the host's immune reaction the infection becomes persistent. Persistence of the viral genome in the host's cells may ultimately result in the cervical changes leading to carcinoma (2,3).
The host cell genes p53 and Rb (the retinoblastoma gene) are responsible for repairing damages (mistakes, or mutations) during cell replication. If the damage is irreparable the cell is destroyed by a process called apoptosis. In persistent HPV infection the anti-oncogenic activity of p53 and Rb is blocked by the production of proteins by E6 and E7 from the HPV resulting in un-inhibited host cellular growth and lack of repair of damaged cells. Abnormal cell proliferation then results with the integration of the viral DNA into the host cellular DNA with resultant immortalisation of the host cell which then becomes capable of invasion (17). Some of the wildly growing cells may develop irreparable, permanent changes in the genetic structure (mutation). This eventually results in the production of cancerous cells.
As the HPV cells occupy the host cells various cellular changes occur in the epithelial squamous cells detectable by cytology. The first to occur is the koilocytic atypia in which the host cellular nucleus is displaced to the side with a 'hollow' appearance of the cytoplasm (perinuclear cavitation) (18). The squamous cells, as the disease advances, then begin to show signs of change in size and shape with sometimes nuclear changes. The cellular atypia resulting is termed Atypical Squamous Cells of Undetermined Significance (ASCUS). The equivalent in the cervical glandular cells is Atypical Glandular Cells of Undetermined Significance (AGUS). About 60% of such cases may regress spontaneously; 20-35% would persist unchanged and the remaining 10% are likely to develop High Grade Intra-epithelial Lesion (HGIL) with increased cellular changes, reduced nuclear/cytoplasmic ratio and mitotic elements. As the whole epithelium is replaced with mutant cells cervical intra-epithelial neoplasia (CIN) III or carcinoma in situ develops. Tongues of growing squamous cells first break through the basement membrane (micro-invasion) and as more tongues grow and coalesce frank invasion may occur. Detection of CIN III peaks between 25 – 29 years about 4 to 7 after the peak incidence of CIN I. In Caucasian women it takes approximately 15 years after the peak incidence of CIN III to develop invasive cancer which may therefore be seen between the ages of 40 and 45 years (2).
Screening for premalignant lesions of the cervix
Screening for pre-malignant lesions of the cervix using exfoliated cells (cervical cytology) has been going on for well over 50 years. In the 1940's George Papanicolaou (19) first described five classes of cellular changes in exfoliated cells of the cervix. His classification was as follows:
- Class 1: Absence Of Atypical Or Abnormal Cells
- Class 2: Atypical Cytology But No Evidence Of Malignancy.
- Class 3: Cytology Suggestive But Not Conclusive.
- Class 4: Cytology Strongly Suggestive Of Malignancy
- Class 5: Cytology Conclusive For Malignancy.
This original classification was adopted worldwide and it has been the cornerstone of the screening programs in the Nordic countries since the 1960's (20,21). These Nordic authors have indicated the usefulness of the Papanicolaou classification in acquiring a highly successful screening programme in Finland. They do not see the need for change of the classification.
In order to correlate the histological findings with the appropriate cytological abnormality the British Society for Clinical Cytology (BSCC) introduced a new system of classification of the cytological specimens in the 1980's. This system employed the term dyskariosis which was further subdivided into mild, moderate and severe. These subdivisions are supposed to correlate very well with the histological grades of CIN I, II, and III (22).
In 1988 the National Cancer Institute of the USA came out with a new system, the Bethesda System (TBS) for reporting cervical and vaginal cytological diagnosis (23) . Still not satisfied with the new classification the National Cancer Institute reconvened another workshop in 1991. After the workshop the report was published in the Journal of the American Medical Association in 1992 (24) and in a monograph (25) in 1994. This new system simplified the three system of mild, moderate and severe dyskariosis, to Low Grade Squamous Intra-epithelial Lesion (LSIL) High Grade Squamous Intra-epithelial Lesion (HSIL). Cytological reports are then given as follows:
within normal limits
atypical squamous cells of undetermined significance
Cellular changes suggestive of :
With the better understanding of the disease process and the development of more sophisticated techniques of detecting HPV and cervical pre-cancer it was found necessary to review the 1991 Bethesda System of cytology reporting. In 2001 the third Bethesda System was published in the JAMA by Solomon et al (26). In the same edition of JAMA Wright et al (27) published the 2001 Consensus Guidelines For The Management Of Women With Cervical Cytological Abnormalities. The 2001 system sees a lot of improvement in the previous system. It is however too complex to repeat here.
It is not intended to go into the details of the classification systems but whichever system is used the literature reveals adequate guidelines for the management of the patients.
Traditionally the cervical specimens have been taken by wooden or plastic spatulae or brushes. The specimen is then smeared on a glass slide and fixed immediately with alcohol.
Even though the cytological screening methods have been used for years and has been definitely associated with 70% reduction in cervical cancer deaths (1,28) in areas with well developed screening it is still associated with many false negative reports which may need re-examination with repeat pap smears / cytology and / or colposcopy.
In order to improve on the specimen collection with the hope of improving the sensitivity of the cytology the liquid based preparations of sample collection were developed. The spatula or brush is broken and the part used for collecting the specimen is inserted into a tube with preservative solution and sent to the laboratory with the necessary precautions. The advantage offered here is that all the cells harvested are sent to the laboratory. The specimen is centrifuged with removal of blood and mucus. The cellular pellet is removed and suspended in diluent and a nice smear is then made on the slide. The smear when dry is ready to be read by the cyto-technician or pathologist. This method improves on the sensitivity of the test with a higher SIL detection rate. Vassilakos (29) et al, working in 3 different laboratories in Europe demonstrated an increased detection of LSIL by 59% and HSIL by 78.9%. The rate of detection of ASCUS was also reduced by 43.38%. In a meta-analysis of 12 published papers using the liquid based thin prep 2000, Martha Hutchinson (30) indicates that the thin prep improves screening quality and increases the SIL detection rate. On average these studies demonstrate a 66% increase in the detection of LSIL and a 57% increase in the detection of HGIL with an attendant reduction in the diagnosis of ASCUS.
This system has been improved further with automation. In the automated computerised system the computer screens all the normal slides and refers those complicated slides to be read by the cyto- technician or the pathologist. This system can handle many cases daily and it has the good prospect for telemedicine use. Dr. P. Vassilakos (31) has been involved in the telemedicine practice for some time now. This may also pave the way for difficult slides taken in less endowed areas of the world to get assistance with the interpretation.
These systems that have been described so far are very expensive and are not within easy reach of most developing countries. There is therefore the need to develop screening systems with fairly high sensitivity and specificity but at the same time easily available, affordable and easily accessible and user friendly. These attributes can be given to the visual inspection (naked eye) of the cervix with acetic acid (VIA).
Visual Inspection of the cervix with Acetic Acid (VIA)
In low resource settings naked eye visualisation of the cervix was tried with the hope of diagnosing some of the pre-malignant lesions of the cervix. This technique was found to be woefully inadequate with very low sensitivity.
With the addition of acetic acid to the examination the results have markedly improved. In this approach the cervix is swabbed with 4-5% acetic acid or vinegar prior to visualisation. Abnormal cells temporarily turn white (aceto-white) as seen during colposcopy. This technique is simple, easy to perform and quite cheap. Nurses and midwives can be taught to do it. The other advantage is that diagnosis is made immediately and treatment may be given by cryotherapy or patient can be referred to hospital according to the stage of cervical disease.
Many comparative studies have been done which suggest that the efficacy of VIA is comparable to that of cytology. In 1999 the University of Zimbabwe and the JHPIEGO (32) published the results of their project involving 10 934 patients and found that VIA was more sensitive but less specific than cytology. The sensitivity for VIA was 76.7% (95% CI. 70.3-82.3) and that for cytology was 44.3% (95% CI, 37.3-51.4). The specificity for VIA was however less than that for cytology (64.1% versus 90.6%). Denny L (33) et al in South Africa also reported favourable findings after the examination of 2944 people aged between 35 and 65 years. The same authors (34) published in 2002 after studying 2754 patients their confirmation of the VIA test as a primary screening test for low resource areas. In the last test they indicated the sensitivity for VIA (without magnification) for HSIL as 70% with a specificity of 79%. (Magnification did not significantly improve the sensitivity). In rural China, after examining 1997 patients, Belinson et al in 2001 (35) showed a sensitivity of 71% for HSIL with a specificity of 74%. They concluded that the sensitivity of VIA equalled or exceeded reported rates for conventional cytology.
In his article ‘Costs and Benefits of Different Strategies To Screen For Cervical Cancer In Less-Developed Countries’ Mandelblatt explains the cost-effectiveness of VIA (36). From the foregoing VIA has everything to recommend it for routine use for low resource settings even though patients with false positive results still have to bear extra costs of hospital treatment or stand the risk of cryotherapy of their otherwise normal cervices.
Visual Inspection with Magnification (VIAM)
Studies are ongoing to find out if the addition of a hand-held magnifying glass would improve the sensitivity and specificity of the VIA. The Avi Scope, a low-power (x4), hand-held visual inspection device with an in-built light system is expected to improve the results of VIA. Even though the manufacturers have indicated a better sensitivity for the instrument (37) the South African study (34) did not show any improvement. Further randomised control trials of its use are awaited before its use can be disproved or encouraged. Its cost effectiveness is also yet to ascertain.
This involves the use of a camera. The cervix is photographed after the application of acetic acid. The photograph (cervigram) obtained are examined by a colposcopist as projected slides. Its sensitivity is said to approach those of cytology (38). The equipment is however expensive.
HPV DNA Testing
Two tests have been developed to identify the HPV DNA – the PCR test and the Hybrid Capture II test (HC II). The HC II test has been approved for use by the FDA of USA. It is being incorporated into some screening programmes because of its high sensitivity (80-90%) and a specificity of 57-89% (39). Large studies in Costa Rica and Zimbabwe reveal high sensitivity and specificity for HSIL (39,40). Other studies by Liaw et al show similar results (41).
Feitcher et al (18) have suggested that in industrialised countries application of HPV testing, as part of cervical cancer screening, is expected to reduce the cost of cervical cancer screening because of the increased precision of screening that would further justify longer screening intervals. They have also suggested that HPV testing is usually carried out to improve the quality of conventional cytological screening; improve the diagnosis of questionable cases such as ASCUS and identify asymptomatic patients at high risk of developing cervical cancer.
The detailed review of the various treatment modalities of the various types of cervical changes from ASCUS / AGUS, through LSIL, HSIL, and overt cancer is beyond the scope of this paper. It may suffice to indicate that for overt carcinoma of the cervix the following modalities of treatment have been effective according to the stage of the disease and the patient’s condition: radical surgery, radiotherapy (or a combination of the 2). The use of Cis-Platin based chemotherapy is being investigated.
The problem with management really lies with the precancerous lesions of ASCUS/AGUS, LSILand HSIL. LSIL can be managed with local cervical ablative surgery such as cryotherapy, laser photo-vaporisation, or electro-cautery of the cervix. Repeat cytology may be indicated. With HSIL colposcopic evaluation with directed biopsies are advised. Treatment may then involve conisation of the cervix using the cold knife or LLETZ.
Primary prevention of cervical carcinoma through vaccination
With the strong association found between the high-risk types of HPV and cervical carcinoma (compare hepatitis B infection with hepatocellular carcinoma) the stage is now set to develop an effective vaccine for primary prevention (prophylactic) and if possible for treatment (therapeutic) of the cancer.
Much work is being done in this field. As indicated by Steller MA (42) and Murakami M (43), prophylactic vaccine under investigation focuses on the induction of effective humoral and cellular- immune responses that are potentially protective against subsequent HPV infection. HPV-like particles have been synthesised to induce neutralising antibody responses and impressive prophylactic effects have been demonstrated. For therapeutic vaccine techniques to improve cellular immunity by enhancing viral antigen recognition are being studied. It is hoped that with successful prophylactic and therapeutic vaccines available the need for extensive cytological screening would be obviated (44) and probably the treatment for the disease would also be modified.
In this review the strong association between the high risk HPV infection and carcinoma of the cervix has been demonstrated. Notably high risk types such as types 16, 18, 31, 33 etc have been elucidated by DNA testing to be the main causes of cervical cancer.
VIA has also been found, from several randomised trials, to be effective as a screening tool for developing countries. The addition of immediate treatment by cryotherapy and the easy application that can be learnt by nurses and midwives make it a very remarkable test and I hope that Governments of poor nations would help institute the screening programs in their countries with the hope of eliminating or reducing the impact of the disease on the population.
Effective DNA tests have also been provided (PCR and Hybrid Capture II) for the detection of the cervical HPV infection. With the elucidation of the immortalisation process of the cervical cells by the HPV DNA effective prophylactic and therapeutic vaccines are currently being tried with the hope of conquering the disease once and for all. From the literature it would seem both feasible and cost effective and cost effective approach to the eradication of the virus and the prevention of cancer of the cervix.
If an effective vaccine comes into use it would still be advisable to practice safe behaviour in the form of ‘safe sex’ with the hope of reducing the incidence of sexually transmitted infections in general and HIV infection as well.
I am very grateful for the course organsiers of the Geneva Foundation for Medical Education and Research, Professor Aldo Campana and his team. Mrs Eva Marthur and Dr. Regina Kulier and Miss Silvie Ngo Ntama deserve my gratitude.
I am also grateful to all the teachers who has given me new dimensions in life.
My sincere gratitude go to my sponsors of IAMANEH through whose efforts I was able to join this wonderful programme. Finally I wish to thank Dr. A. H. K. Collison of the University of Ghana Medical School and Chairman of IAMANEH (Africa) for proposing me to join the course.
I also wish to thank Dr. Vassilakos, my tutor, for giving me a lot of reading material and supervising this work very closely.
Finally my special gratitude goes to Margaret Usher Patel and Archana Shah for helping me with the final corrections.
- WHO/ 47. Press Realease. Cervical Cancer: Experts Confirmed Virus A Major Cause, New Detection Technologies Available. 3 July, 1996. [Free Full Text]
- WHO. Human Papilloma Virus (HPV). Summary of Data Reported and Evaluation. 1995.
- Cox T, Buck HW, Kinney W, Rubin MM. Human Papilloma Virus and Cervical Cancer. Clinical Proceedings. March 2001. [Free Full Text]
- International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans; Human Papillomaviruses. Lyon, World Health Organization. 1995.
- Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003 Jan 13;88(1):63-73. [PubMed]
- Judson FN. Interactions between Human Papilloma Virus and Human Immunodeficiency Virus Infections. Scientific Publications. 1992 119:199-207.
- Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999 Sep;189(1):12-9. [PubMed]
- Morrison C, Catania F, Wakely P Jr, Nuovo GJ. Highly differentiated keratinizing squamous cell cancer of the cervix: a rare, locally aggressive tumor not associated with human papillomavirus or squamous intraepithelial lesions. Am J Surg Pathol. 2001 Oct;25(10):1310-5. [PubMed]
- Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995 Jun 7;87(11):796-802. [PubMed]
- Groopman J. Contagion. The New Yorker. 1999 13 September:44–49.
- Schiffman MH, Brinton LA. The epidemiology of cervical carcinogenesis. Cancer. 1995 Nov 15;76(10 Suppl):1888-901. [PubMed]
- Magnusson PK, Sparen P, Gyllensten UB. Genetic link to cervical tumours. Nature. 1999 Jul 1;400(6739):29-30. [PubMed]
- Ylitalo N, Sorensen P, Josefsson A, Frisch M, Sparen P, Ponten J, Gyllensten U, Melbye M, Adami HO. Smoking and oral contraceptives as risk factors for cervical carcinoma in situ. Int J Cancer. 1999 May 5;81(3):357-65. [PubMed]
- Stentella P, Frega A, Ciccarone M, Cipriano L, Tinari A, Tzantzoglou S, Pachi A. HPV and intraepithelial neoplasia recurrent lesions of the lower genital tract: assessment of the immune system. Eur J Gynaecol Oncol. 1998;19(5):466-9. [PubMed]
- McDonald CJ. Cancer statistics, 1999: challenges in minority populations. CA Cancer J Clin. 1999 Jan-Feb;49(1):6-7. [Free Full Text]
- Schiffman MH, Brinton LA, Devessa SS, Fraumeni JF Jr. Cervical cancer. In: Schottenfeld D, Fraumeni JF Jr, editors. Cancer epidemiology and prevention. New York: Oxford University Press. 1996:1090-1116.
- Massimi P, Banks L. Repression of p53 transcriptional activity by the HPV E7 proteins. Virology. 1997 Jan 6;227(1):255-9. [PubMed]
- Feichter G, Meisels A. Task force consensus report on HPV-related changes of the lower female genital tract. Acta Cytol. 2002 Jul-Aug;46(4):630-2. [PubMed]
- Papanicolaou GN. Atlas of Exfoliative Cytology. Harvard University Press. 1963.
- Hakama M. Screening for cervical cancer: experience from the Nordic countries. In: Franco E, Monsonego J, eds. New Developments in Cervical Cancer Screening and Prevention. Oxford, England: Blackwell Science; 1997:190-199.
- Syrjänen KJ. Quality assurance in the cytopathology laboratories of the Finnish Cancer Society. In: Compendium on Quality Assurance, Proficiency Testing and Workload Limitations in Clinical Cytology. (eds.) George L. Wied, Catherine M. Keebler, Dorothy L. Rosenthal, Ulrich Schenck, Theresa M. Somrak, G. Peeter Vooijs. Tutorials of Cytology, Chicago, Illinois, USA. 1995:134-142.
- Evans DM, Hudson EA, Brown CL, Boddington MM, Hughes HE, Mackenzie EF, Marshall T. Terminology in gynaecological cytopathology: report of the Working Party of the British Society for Clinical Cytology. J Clin Pathol. 1986 Sep;39(9):933-44. [PubMed]
- The 1988 Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses. Developed and approved at a National Cancer Institute Workshop, Bethesda, Maryland, U.S.A., December 12-13, 1988. J Reprod Med. 1989 Oct;34(10):779-85. [PubMed]
- The Bethesda System for reporting cervical/vaginal cytologic diagnoses. Report of the 1991 Bethesda Workshop. Am J Surg Pathol. 1992 Sep;16(9):914-6. [PubMed]
- Kurman RJ, Solomon D. The Bethesda System for Reporting Cervical and Vaginal Cytologic Diagnosis. Definitions, Criteria and Explanatory Notes for Terminology and Specimen Collection. New York. Springer Verlag. 1994.
- Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright T Jr, Young N. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002 Apr 24;287(16):2114-9. [PubMed]
- Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002 Apr 24;287(16):2120-9. [PubMed]
- Monsonego J. Chapter Editors Introduction: Global challenge of cervical cancer screening and prevention. CME Journal of Gynecologic Oncology. 2000 5(1):5-7.
- Vassilakos P, Saurel J, Rondez R. Direct-to-vial use of the AutoCyte PREP liquid-based preparation for cervical-vaginal specimens in three European laboratories. Acta Cytol. 1999 Jan-Feb;43(1):65-8. [PubMed]
- Hutchinson ML. Liquid based ThinPrep 2000 cytology improves screening accuracy and specimen adequacy. CME Journal of Gynecologic Oncology. March 2000 5(1): 21-25.
- Vassilakos P. 2003. Personal Communication.
- Visual inspection with acetic acid for cervical-cancer screening: test qualities in a primary-care setting. University of Zimbabwe/JHPIEGO Cervical Cancer Project. Lancet. 1999 Mar 13;353(9156):869-73. [PubMed]
- Denny L, Kuhn L, Pollack A, Wright TC Jr. Direct visual inspection for cervical cancer screening: an analysis of factors influencing test performance. Cancer. 2002 Mar 15;94(6):1699-707. [PubMed]
- Denny L, Kuhn L, Pollack A, Wainwright H, Wright TC Jr. Evaluation of alternative methods of cervical cancer screening for resource-poor settings. Cancer. 2000 Aug 15;89(4):826-33. [PubMed]
- Belinson JL, Pretorius RG, Zhang WH, Wu LY, Qiao YL, Elson P. Cervical cancer screening by simple visual inspection after acetic acid. Obstet Gynecol. 2001 Sep;98(3):441-4. [PubMed]
- Mandelblatt JS, Lawrence WF, Gaffikin L, Limpahayom KK, Lumbiganon P, Warakamin S, King J, Yi B, Ringers P, Blumenthal PD. Costs and benefits of different strategies to screen for cervical cancer in less-developed countries. J Natl Cancer Inst. 2002 Oct 2;94(19):1469-83. [PubMed]
- Planning Appropriate Cervical Cancer Prevention Programs. Program for Appropriate Technology in Health (PATH). March 1997. [Free Full Text]
- Cuzick J. Human papillomavirus testing for primary cervical cancer screening. JAMA. 2000 Jan 5;283(1):108-9. [PubMed]
- Schiffman M, Herrero R, Hildesheim A, Sherman ME, Bratti M, Wacholder S, Alfaro M, Hutchinson M, Morales J, Greenberg MD, Lorincz AT. HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica. JAMA. 2000 Jan 5;283(1):87-93. [PubMed]
- Womack SD, Chirenje ZM, Gaffikin L, Blumenthal PD, McGrath JA, Chipato T, Ngwalle S, Munjoma M, Shah KV. HPV-based cervical cancer screening in a population at high risk for HIV infection. Int J Cancer. 2000 Jan 15;85(2):206-10. [PubMed]
- Kai-Li Liaw, Schiffman MH, Cope JU, Glass AG, Manos M, Sherman ME, Burk RD, Hildesheim A, Lörincz AT. Update on recent clinical studies using HPV testing for screening and diagnosis of cervical neoplasia. CME Journal of Gynecologic Oncology . March 2000 5(1):41-44.
- Steller MA. Cervical cancer vaccines: progress and prospects. J Soc Gynecol Investig. 2002 Sep-Oct;9(5):254-64. [PubMed]
- Murakami M, Gurski KJ, Steller MA. Human papillomavirus vaccines for cervical cancer. J Immunother. 1999 May;22(3):212-8. [PubMed]
- Davidson EJ, Kitchener HC, Stern PL. The use of vaccines in the prevention and treatment of cervical cancer. Clin Oncol (R Coll Radiol). 2002 Jun;14(3):193-200. [PubMed]