- Email: [email protected]
Intraepithelial neoplasia, wart virus and colposcopy
Current Obstetrics & Gynaecology (2001) 11, 164 ^171
c 2001 Harcourt Publishers Ltd doi:10.1054/cuog.2001.0157, available online at http://www.idealibrary.com on
Intraepithelial neoplasia, wart virus and colposcopy S. Nazeer* and M. I. Sha¢{ *Me¤decin Consultant, Charge¤e d’Enseignement, WHO Collaborating Centre for Research in Human Reproduction, Dept. of Gynaecology & Obstetrics, Geneva University Hospital, 30 Blvd. de la Cluse,1211 Geneva 14, Switzerland; {Consultant Gynaecological Surgeon & Oncologist, Birmingham Women’s Hospital, Edgbaston, Birmingham B15 2TG, UK
KEYWORDS cervical cancer, human papilloma virus, colposcopy
Summary Cervical cancer is both preventable and curable. The disease has a long natural history with a prolonged precancerous phase, which is easily detectable and treatable. The Pap smear remains the mainstay for screening of precancerous lesions, cervical intraepithelial neoplasia (CIN). Assessment of women presenting with abnormal cervical cytology and the selection of those requiring treatment relies mainly on colposcopic impression of the cervical transformation zone and histological appraisal of a directed punch biopsy. Colposcopy remains a subjective technique requiring extensive training and experience. There is high interobserver variability that a¡ects, amongst other factors, the adequacy of directed punch biopsies. Although the grade of CIN correlates with the size of the lesion,CIN III may occur as a small focus and CIN I may be extensive. Cure rates for CIN correlate principally with geographical extent. It has been shown that small lesions similarly have high cure rates regardless of histological grade. Management of cervical precancerous lesions has changed signi¢cantly over the last few years.The need to maximise the clinicalresources, quicker and more e¡ective management of patients, limit postoperative complications and preserve reproductive function has led to the popularity of local excisional methods. Although the cure rates for all local ablative and excisional methods is in excess of 90% after one treatment, the excisional methods provides a more reliable histopathological diagnosis and the patient may be treated atthe ¢rst visitöthe‘see and treat’approach. It is now established that 95% of cervical cancer cases are associated with oncogenic types of human papilloma virus.Important advances have recently been made to develop recombinant vaccines to prevent and treat this infection.Clinical trials on preventive and therapeutic vaccines are underway. The vital question however prevails as to what will come ¢rstöan e¡ective screening tool or a preventive vaccine?
c 2001Harcourt Publishers Ltd
INTRODUCTION On a global scale, cervical cancer may be the most preventable major form of cancer, given the fact that most of its risk factors are preventable. Moreover, the disease has a long natural history with a prolonged precancerous phase that is easily detectable and treatable (Table 1). Cervical cancer is the most common form of cancer in women in virtually all developing countries and the second most common form of cancer in women in the world. It comprises12% (approx.) of all cancers in women. Globally, there are an estimated 452 000 new cases and more than 234 000 deaths from cervical cancer each year Table 1.
Correspondence to: S.N., E-mail: [email protected]
There are marked regional and intraregional di¡erences in prevalence of cervical cancer indicating e¡ect of socio-economic and cultural in£uence. Highest incidences have been recorded from Recife, Brazil (84/ 100 000); Cali, Columbia (48/100 000) and Madras, India (48/100 000). The lowest incidences have been recorded from Kuwait (3/100 000) and Israel (4/100 000). In the United Kingdom, in 1997 there were 2740 new cases of invasive cervical cancer with 1222 women dying of this disease (NHS Cervical Screening Programme ¢gures).
CLASSIFICATIONOF CERVICAL INTRAEPITHELIAL NEOPLASIA The British Society for Clinical Cytology proposed the cytological terminology for smear reporting in 1987.
INTRAEPITHELIAL NEOPLASIA,WART VIRUS AND COLPOSCOPY
The appearances of the cells are classi¢ed into mild, moderate and severe dyskaryosis with borderline nuclear abnormalities used for changes which fall short of dyskaryosis. ‘Severe dyskaryosis? invasive disease’ may be used, as may ‘?glandular neoplasia’ in those cases where the dyskaryosis appears to be in glandular cells. The CIN classi¢cation introduced by Richart in1967 for histogenetic classi¢cation of cervical precancerous lesions has generally replaced the World Health Organization (WHO) classi¢cation.CIN I, II, and III corresponds to mild, moderate and severe dysplasia/carcinoma in-situ respectively. In1990, a revised classi¢cation was suggested by Ri-
Table 1 Annual estimates of new cases globally (WHO 1999)
Breast Cancer Cervical Cancer Ovarian Cancer Endometrial Cancer
Table 2
Incidence
Mortality
795 000 452 000 165 000 142 000
313 000 234 000 101000 42 000
165
chart with high-grade lesions (CIN II/III) likely to be true cancer precursors and low-grade lesions (CIN I/HPV) with unknown or low progressive potential.The CIN classi¢cation has been retained in the United Kingdom. The National Cancer Institute of the United States developed the Bethesda system in1988.This classi¢es abnormalities as atypical squamous or glandular cells of undetermined signi¢cance (ASCUS), low grade squamous intraepithelial lesions, LSIL (encompassing HPVand CIN I) and high grade squamous intraepithelial lesions, HSIL (encompassing CIN II and CIN III) (Table 2).
NATURAL HISTORYOF CERVICAL CANCER Contrary to the common belief, cervical cancer a¡ects women in their prime years, with peak incidence for invasive cancer being at age 45 and for CIN III at 35 years. Adenocarcinoma of cervix, which now comprises approximately 22% of all cervical cancers, often a¡ects women under 35 years of age. Cervical cancer has a long precancerous phase with cytologic changes progressing through di¡erent grades,
Summary of terms used for cervical intraepithelial neoplasia
Original Papanicolaou and WHO system Cytology Class I Class II Histology Normal In£ammatory/Reparative Responses HPV Related? United Kingdom System Cytology Negative
BNA (Borderline nuclear abnormalities) Histology Normal In£ammatory/ Reparative Responses HPV Related? Richart and The Bethesda System ASCUS Cytology Within Normal Limits Histology Normal In£ammatory/Reparative Responses HPV Related?
Class III Mild Dysplasia (koilocytosis, koilocytotic atypia, £at condyloma)
Class IV Moderate Dysplasia
Class V Severe Dysplasia
Mild Dyskaryosis
Moderate Dyskaryosis
Severe Dyskaryosis
?Invasive disease
CIN grade I
CIN grade II
CIN grade III
Invasive cancer
Low-grade SIL
High-grade SIL
Invasive cancer
Low-grade CIN
High-grade CIN
Invasive cancer
Carcinoma In situ
Invasive cancer
166
de¢nable cytologically (dyskaryosis) or histologically (dysplasia or cervical intraepithelial neoplasia). It is very rare to ¢nd dysplastic changes in cervical epithelium within 2 years of debut of sexual activity. It generally takes 3^5 years for the changes to progress from one grade to the next. It has been estimated that the mean time from detectable cytologic abnormality to development of invasive cancer may take as long as 15^20 years. Thus, progression of CIN to invasive cancer, although it can be swift, is usually a slow process. Many CIN lesions will regress over time. The regression rate depends, amongst other factors, mainly upon the grade of CIN and the age of the woman. Regression is much more common in women under 30 years than those above 30 years of age. Taken together, in the absence of intervention, roughly one third of early precursor lesions disappear spontaneously, one third persist and one third progress to CIN III or from CIN III to invasive cancer.
GLANDULAR DISEASE It is well documented that the incidence of glandular disease is increasing and epidemiology of invasive adenocarcinoma is changing with a higher incidence recorded in women younger than 35 years old. Between 20 ^30% of cervical tumours are now classi¢ed as adenocarcinomas or adenosquamous carcinomas. These lesions pursue a more aggressive course than their squamous counterparts. The natural history and biology of CIN are well described, the situation with glandular lesions is less clear. Attempts have been made to mirror the range of cellular changes in glandular mucosa (Cervical Glandular Intraepithelial NeoplasiaöCGIN I, II, III). Because of uncertainty of the signi¢cance of this classi¢cation, any degree of glandular cell abnormality identi¢ed on a cervical smear should be followed up by colposcopy and possible endocervical curettage. The recommended treatment of CGIN III is excisional biopsy of the cervix. Risk factors for cancer of the cervix include: . . . .
. . .
.
Human PapillomaVirus (HPV) infection Early onset of sexual activity Multiple sexual partners (self or of the partner) Tobacco smoking ö there is evidence that it increases risk of invasive cervical cancer and also interacts with HPV in carcinogenic e¡ect Oral contraceptives ö long-term use Multiparity Malnutrition ö diets poor in fruit, vegetables and some micronutrients (vitamin C, beta carotene, folate) Low socio-economic status
CURRENT OBSTETRICS & GYNAECOLOGY
HUMAN PAPILLOMAVIRUS Genital HPV, one of the most common sexually tranmitted diseases is reponsible for anogenital cancers both in women and men. It is now known that HPV is an important cause of cervical cancer. Human Papilloma Virus oncogenic types are found in 95% of squamous cell carcinomas and 60% of adenocarcinomas. Out of the 70 known HPV genotypes, 30 are known to infect the genital tract.Out of these 20 have been identi¢ed as carcinogenic with types 16 and 18 found most commonly in malignant lesions. The common types are classi¢ed according to their oncogenic potential as follows: Low risk: 6,11, 41, 44 Intermediate risk: 31, 33, 35 High risk: 16,18, 45, 56
NATURAL HISTORYOF HPV INFECTION Both high- and low-risk HPV infections in women occur mostly in adolescent age groups (16 ^24 years). Reported incidences from di¡erent countries have been 10 ^30%. The incidence drops to about 5% above age of 30 years. Most of of these HPV infections are transient, about 80% clear spontaneously within1^2 years.The rest may result in CIN lesions. However, most of the women with HPV positive smears who develop CIN lesions are still able to clear the virus in 2^3 years and will subsequently have regressive CIN. Above age 30 years the regression rate is much lower. Among women with persistent infection, CIN lesions can develop within 2^ 4 years. It is known that two characteristics of HPV that are important for causing dysplastic changes in epithelial cells are viral load and viral persistance. Both are measurable. However, little is known about the host factors which determine the dysplastic/oncogenic changes. So far it has been established that age of the host (430 years) and immune status determine oncogenic progression. In some studies, concommittent sexually transmitted diseases (STDs) especially, chlamydia and bacterial vaginosis have been suggested to play a catalytic role. The progression rate of CIN in women with high-risk, HPV-positive, cytologically normal or abnormal smear is about 5% per year. In women above age 30 with high-risk HPV positivity, and a cytologically normal smear the risk of developing CIN III is116 times higher than women with an HPV-negative cytologically normal smear.
HPV VACCINES Currently, vaccines against HPV are being evaluated. In theory, cervical cancer can be prevented and treated by HPV vaccine therapy. Important progress has been made
INTRAEPITHELIAL NEOPLASIA,WART VIRUS AND COLPOSCOPY
towards producing recombinant, type-speci¢c vaccines both preventive and therapeutic. Phase I & II clinical trials are underway at some centres. This research holds promise for having a profound impact on this disease, perhaps even helping to eliminate it. The likely time course for such a scenario to unfold will be prolonged.Once a‘perfect’ HPV prophylactic vaccine is synthesised, it will take many years to complete all phases of clinical study and then introduce the vaccine into clinical practice. In this context, hepatitis B vaccine has been administered to less than 1% of the world’s children, despite the decades that have elapsed since the successful development of that vaccine.
COLPOSCOPY Colposcopy has become recognised as an essential tool in assessing patients with abnormal cytological smears (Figure 1). The basic principles of colposcopy comprise low power magni¢cation and illumination of the uterine cervix. These principles ¢rst described by Hans Hinselmann almost 75 years ago still apply. Apart from re¢ning the optical and illumination systems there has been little technological advancement other than the introduction of the green ¢lter to enhance vascular appearances at the time of colposcopic assessment. The objectives of colposcopic assessment are: . To further assess abnormalities detected on cervical smear . To con¢rm diagnosis by directed biopsy . To rule out invasive disease . To aid in out-patient management of precancerous lesions . Follow-up after treatment Colposcopic assessment continues to be a subjective assessment and expertise in this technique is gained by a period of apprenticeship. This consequently leads to observer variability.The interobserver variability among experienced colposcopists reveals lower levels of agreement for diagnosing low-grade lesions than for highgrade lesions. The same levels of agreement have been found amongst pathologists for the histopathological diagnosis of cervical lesions. Predictive accuracy of the colposcopic assessment depends on the use of exact colposcopic criteria which comprises of the sharpness of the cervical lesion border, the degree of acetowhitening, angioarchitecture and iodine staining reaction. An attempt has been made to address the subjective nature of colposcopy by introducing colposcopic indices in order to standardise visual parameters. This attempt has proved di⁄cult to standardise, lacks robustness when applied to clinical situation and has not been validated in prospective studies. Computer imaging
167
technology is now becoming available that may allow characterisation of CIN at the time of colposcopic assessment based on a host of objective variables including lesion surface area. This technology however, requires further re¢nement and critical analysis. There is a need to characterise colposcopic abnormalities objectively and particularly to develop models di¡erentiating high and low grade lesions. The identi¢cation of patients with either high or low grade CIN is useful as it may allow identi¢cation of those patients that have true cancer precursors. It will also highlight those patients with low-grade disease who may be treated by local excision or managed in a more conservative manner. With increasing use of local excisional methods of treatment for CIN, often undertaken at the ¢rst visit, it is obvious that there is a need to be more selective in treatment protocols in order to avoid overtreatment. Loop biopsy (LLETZ) has been found to be more accurate in detecting CIN than colposcopically directed biopsies. The underdiagnosis of 20 percent of all cases was found when histopathological diagnosis of directed biopsies was compared with large loop biopsies. Therefore, some investigators advise LLETZ rather than directed biopsies when investigating high-grade cervical lesions.
TREATMENT METHODS AND OUTCOME The two main conservative methods of treatment are ablative or excisional techniques.The cure rates for both techniques are in excess of 90%. The need for conservative treatment is apparent considering the morbidity of the more radical procedures, their e¡ect on reproductive function and the high incidence of precancerous lesions among younger age groups. The decision for conservative management relies on accurate colposcopic assessment, visualisation of the lesion in its entirety and the exclusion of invasive disease by directed biopsy/biopsies.When considering the choice of actual technique, an important consideration is the depth of the tissue destruction required. Recently there has been a tendency towards using excisional methods. This allows better histopathological interpretation of the excised specimen and in certain circumstances allows a ‘see and treat’ strategy under local anaesthetic at the initial visit. This policy however, can lead to overtreatment of insigni¢cant lesions.Therefore, a ‘select and treat’ strategy is recommended as is practiced in most colposcopy units (Table 3). Cryocautery destroys tissue by freezing using probes of various shapes and sizes and is probably best reserved for small lesions.Whilst lesion size is important in determining success or failure of any of the treatment modalities used, it is especially important when using
168
CURRENT OBSTETRICS & GYNAECOLOGY
Figure 1 Flow diagram of the management of women with abnormal cervical cytology.
cryocautery. The duration of the freeze is 2 min from the appearance of the ice ball. With larger lesions, multiple applications may be necessary. The depth of destruction is approximately 4 mm and this may be inadequate for some of the CIN lesions. Depth of destruction cannot be accurately gauged and incomplete eradication of disease may lead to regenerating epithelium covering the residual disease. Despite these reservations the tech-
nique is worthy of consideration as cryoprobes are cheap and widely available and can be used in an outpatient setting without analgesia with minimal discomfort to the patient. Healing is rapid and, the endocervical canal is not compromised and therefore fertility is not impaired. Electrodiathermy destroys tissue more e¡ectively than cryocautery. It does require general, regional or local anaesthesia. Under colposcopic control it is possible
INTRAEPITHELIAL NEOPLASIA,WART VIRUS AND COLPOSCOPY
Table 3
169
Treatment methods
Ablative
Excisional
Cryocautery Electrodiathermy Cold coagulation Carbon dioxide laser
Loop excision of TZ (LLETZ/LEEP) Laser excision of TZ Laser cone biopsy Loop cone biopsy Cold knife cone biopsy Hysterectomy
to destroy up to1cm depth using a combination of needle and ball electrodes. The needle is reinserted repeatedly at 1^2 mm intervals until the whole transformation zone has been covered. The apparatus required is cheap and easy to maintain.There may be considerable thermal necrosis leading to discharge and slough following therapy. Fibrosis is more common than with other destructive therapy but does not appear to a¡ect fertility. In cold coagulation technique, heat is applied to tissue using a Te£on-coated thermosound, the ‘Semm cold coagulator’. The procedure does not usually require analgesia and the device is cheap and easy to maintain. Measurement of depth of destruction is di⁄cult. The whole of the transformation zone is destroyed by overlapping applications of thermosound for 20 s at1008C per area. Depth of destruction is approximately 2.5^ 4 mm or more after treatment at1008C for 30 s and always exceeds 4 mm after treatment at 1208C for 30 s. Laser is an acronym for Light Ampli¢cation by Stimulated Emission of Radiation. A micromanipulator attached to the colposcope is used to manipulate the laser and treatment is conducted under direct vision. As the technique is precise it gives good control over depth of destruction, good haemostasis and excellent healing, as there is minimal damage to the adjacent tissue. The technique is particularly useful for treating lesions with vaginal involvement. As there are no gland crypts in the vaginal epithelium, destruction to 2^3 mm of depth is adequate. Healing is rapid with new cells appearing within 10 ^12 days. Cure rates of 94% have been quoted in selected patients. Diathermy loop excision using low power voltage apparatus is now widely practiced (Figure 2).The technique is referred to as large loop excision of transformation zone (LLETZ) in Europe and as loop electrosurgical excision procedure (LEEP) in North America. In the UK, this is now the most common method of local treatment for CIN lesions. Laser excision is technically more demanding than laser vaporisation and requires a high power density beam with a small spot size that can function in a cutting mode. Both laser and diathermy loop can be used to fashion cone biopsies of the cervix.
Figure 2 Diagramatic representation of largeloop excision of the transformation zone.
Success rates following local excisional techniques are similar to those for laser ablation and cold coagulation. There appears to be no adverse e¡ect on fertility and the outcome of subsequent pregnancies. Cold knife cone biopsy and hysterectomy still retain a place in the management of CIN. The size and shape of the cone biopsy is governed by the colposcopic ¢ndings. The internal os and as much of the endocervical canal is left intact as is possible within the con¢nes of disease eradication. This limits haemorrhage and fertility will be little compromised. Cone biopsy performed for therapeutic and diagnostic purposes may give cure rates of 93%. Advent of colposcopy has led to smaller cone biopsies with fewer complications but equal therapeutic results. In the absence of colposcopy, Schiller’s iodine can be used to determine the limit of the incision on the ectocervix. The two major problems with cone biopsy are haemorrhage and postoperative cervical stenosis, depending on the length of the cone performed. The latter can lead to menstrual dysfunction and dysmenorrhoea. It also makes colposcopic and cytological follow-up more problematic. Hysterectomy may need to be performed in a woman with CIN who has other gynaecological conditions such as ¢broids, menorrhagia or prolapse. Prior to operation colposcopy will identify the extent of the lesion to avoid incomplete excision which may result in vaginal intraepithelial neoplasia (VaIN). If the lesion is seen to extend to the vagina, this may be excised as part of the hysterectomy procedure. An alternative is to ablate the vaginal extension of CIN, using laser or diathermy, and then proceed to excision or hysterectomy as indicated. Although data suggest that cone biopsy and hysterectomy are e¡ective forms of management, even so there is a 0.3^ 0.4% incidence of invasive cancer following these procedures.
170
CURRENT OBSTETRICS & GYNAECOLOGY
FOLLOW-UP AFTER TREATMENT Women who have undergone treatment of CIN remain at high risk for invasive cervical disease.This necessitates close surveillance, cytologically and colposcopically following treatment.Those women that have abnormal cervical cytology following treatment are at much increased risk compared to those with normal smear after treatment. Cytological abnormality following treatment, no matter how minor, should be considered as an indication for colposcopic assessment. Colposcopic assessment is technically more di⁄cult in women who have undergone treatment. Foci of CIN and or invasive disease may be buried under an apparently normal epithelium. Moreover, the transformation zone may be di⁄cult to visualize in its entirety because of scarring. In cases of failed initial treatments it is recommended to use an excisional method in preference to an ablative technique. Histological incomplete excision at the time of cone biopsy represents a management dilemma. Although involvement of endocervical margins in cone biopsy specimens with CIN lesions would imply incomplete excision, the true residual rate, as evidenced by a positive smear at 6 months, is less than 5%. Follow-up cervical cytology may in fact be a more useful prognostic guide to residual disease than excision cone margins. A repeat smear should be performed at 6 months. If the smear is abnormal, a repeat cone or excisional procedure should be undertaken. A negative second smear would indicate routine follow-up for the woman. If the margins of the cone are clear, the woman should have colposcopy and cervical smear performed at 6 months. If the smear is negative, a repeat negative smear at 6 months would indicate subsequent routine follow-up of the woman.
PRACTICE POINTS . For purposes of standardisation, the British system is used for classi¢cation of Pap smears in the UK. Alternative classi¢cation schemes may be used, such as the Bethesda system, as appropriate to local experience and usage. . Women with Pap smears reported as moderate dyskaryosis, or worse, including atypical glandular cells should be referred for further evaluation as soon as possible. . In up to 30 ^ 40% of women presenting with mild dyskaryosis, CIN II^III exists within the cervix. Even in women with persistent borderline nuclear abnormalities 8 ^14% will harbour such a highgrade lesion. . The size of the lesion can be a good predictor of histological grade of the precancerous lesion, e.g.
. .
.
.
if the lesion size is large and involves three or more quadrants of the cervix in the presence of low-grade cytology, there may be a high-grade epithelial lesion present in this area. Punch biopsy/biopsies, even directed, lead to a high rate of undercall especially for high-grade lesions. For the local treatment of cervical pre-cancerous lesions an important aspect is the depth of destruction of the treatment modality used. A destructive depth of 5^ 8 mm is recommended based on the studies to assess the depth of crypt involvement. If the depth of destruction is inadequate, this deepseated component may be a source of residual or recurrent disease. Colposcopy is a subjective technique requiring formal training and a suitable volume of patients must be seen yearly in order to maintain skills.
RESEARCH DIRECTIONS . More objective diagnostic methods are needed for the triage of cytologic mild dyskaryotic lesions. . Further research in characterising cervical images using di¡erent models. . Re¢ning a standardised diagnostic method which is sensitive and speci¢c for detection of HPV. . Introduction of standardised training, assessment and accreditition system for colposcopy training. . De¢ning precisely the incidence of HPV in general population. . Identifying co-factors that in£uence HPV transmission and that may promote carcinomatous changes in cervical lesions. . Finding e¡ective treatments for HPV infections especially immunologic therapies e.g. HPV vaccine. . Determine the e⁄cacy and cost-e¡ectiveness of HPV screening in prospective randomised controlled trials.
FURTHER READING Nazeer S. Memorandum from a WHO Meeting.Cervical cancer control in developing countries. Bull Wrld Hlth Org1996; 74: 345^351. Miller AB. Cervical cancer screening programmes: Managerial guidelines.World Health Organization monograph; 1992. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in1990. Int J Cancer 1999; 80: 827^ 841. National Cancer Institute Workshop.The1998 Bethesda System for reporting cervical/vaginal cytological diagnoses. JAMA 1989; 262: 931^934. SyrjÌnen K, Kataja V, Yliskoski M et al. Natural history of cervical HPV lesions does not substantiate the biologic relevance of the Bethesda system. Obstet Gynecol 1992; 79: 675^ 682. Hristova L, Hakama M. E¡ect of screening for cancer in the Nordic countries on deaths, cost and quality of life up to the year 2017. Acta Oncol 1997; 36 Suppl 9:1^ 60.
INTRAEPITHELIAL NEOPLASIA,WART VIRUS AND COLPOSCOPY
Sha¢ MI, Jordan JA. The treatment of CIN. Current Obstetrics & Gynaecology 1991; 1: 137^142. Miller AB, Nazeer S et al.Report on Consensus Conference on cervical, cancer screening and management. Int J Cancer 2000; 86: 440 ^ 447.
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Dillner J.Can cervical cancer screening programs be improved by incorporating screening for human paillomavirus infection? The Cancer Journal 1998; Vol 11; 6:272^275. IARC Monographs on the evaluation of carcinogenic risks to humans: Human Papilloma viruses.1995; Vol 64.
c 2001 Harcourt Publishers Ltd doi:10.1054/cuog.2001.0157, available online at http://www.idealibrary.com on
Intraepithelial neoplasia, wart virus and colposcopy S. Nazeer* and M. I. Sha¢{ *Me¤decin Consultant, Charge¤e d’Enseignement, WHO Collaborating Centre for Research in Human Reproduction, Dept. of Gynaecology & Obstetrics, Geneva University Hospital, 30 Blvd. de la Cluse,1211 Geneva 14, Switzerland; {Consultant Gynaecological Surgeon & Oncologist, Birmingham Women’s Hospital, Edgbaston, Birmingham B15 2TG, UK
KEYWORDS cervical cancer, human papilloma virus, colposcopy
Summary Cervical cancer is both preventable and curable. The disease has a long natural history with a prolonged precancerous phase, which is easily detectable and treatable. The Pap smear remains the mainstay for screening of precancerous lesions, cervical intraepithelial neoplasia (CIN). Assessment of women presenting with abnormal cervical cytology and the selection of those requiring treatment relies mainly on colposcopic impression of the cervical transformation zone and histological appraisal of a directed punch biopsy. Colposcopy remains a subjective technique requiring extensive training and experience. There is high interobserver variability that a¡ects, amongst other factors, the adequacy of directed punch biopsies. Although the grade of CIN correlates with the size of the lesion,CIN III may occur as a small focus and CIN I may be extensive. Cure rates for CIN correlate principally with geographical extent. It has been shown that small lesions similarly have high cure rates regardless of histological grade. Management of cervical precancerous lesions has changed signi¢cantly over the last few years.The need to maximise the clinicalresources, quicker and more e¡ective management of patients, limit postoperative complications and preserve reproductive function has led to the popularity of local excisional methods. Although the cure rates for all local ablative and excisional methods is in excess of 90% after one treatment, the excisional methods provides a more reliable histopathological diagnosis and the patient may be treated atthe ¢rst visitöthe‘see and treat’approach. It is now established that 95% of cervical cancer cases are associated with oncogenic types of human papilloma virus.Important advances have recently been made to develop recombinant vaccines to prevent and treat this infection.Clinical trials on preventive and therapeutic vaccines are underway. The vital question however prevails as to what will come ¢rstöan e¡ective screening tool or a preventive vaccine?
c 2001Harcourt Publishers Ltd
INTRODUCTION On a global scale, cervical cancer may be the most preventable major form of cancer, given the fact that most of its risk factors are preventable. Moreover, the disease has a long natural history with a prolonged precancerous phase that is easily detectable and treatable (Table 1). Cervical cancer is the most common form of cancer in women in virtually all developing countries and the second most common form of cancer in women in the world. It comprises12% (approx.) of all cancers in women. Globally, there are an estimated 452 000 new cases and more than 234 000 deaths from cervical cancer each year Table 1.
Correspondence to: S.N., E-mail: [email protected]
There are marked regional and intraregional di¡erences in prevalence of cervical cancer indicating e¡ect of socio-economic and cultural in£uence. Highest incidences have been recorded from Recife, Brazil (84/ 100 000); Cali, Columbia (48/100 000) and Madras, India (48/100 000). The lowest incidences have been recorded from Kuwait (3/100 000) and Israel (4/100 000). In the United Kingdom, in 1997 there were 2740 new cases of invasive cervical cancer with 1222 women dying of this disease (NHS Cervical Screening Programme ¢gures).
CLASSIFICATIONOF CERVICAL INTRAEPITHELIAL NEOPLASIA The British Society for Clinical Cytology proposed the cytological terminology for smear reporting in 1987.
INTRAEPITHELIAL NEOPLASIA,WART VIRUS AND COLPOSCOPY
The appearances of the cells are classi¢ed into mild, moderate and severe dyskaryosis with borderline nuclear abnormalities used for changes which fall short of dyskaryosis. ‘Severe dyskaryosis? invasive disease’ may be used, as may ‘?glandular neoplasia’ in those cases where the dyskaryosis appears to be in glandular cells. The CIN classi¢cation introduced by Richart in1967 for histogenetic classi¢cation of cervical precancerous lesions has generally replaced the World Health Organization (WHO) classi¢cation.CIN I, II, and III corresponds to mild, moderate and severe dysplasia/carcinoma in-situ respectively. In1990, a revised classi¢cation was suggested by Ri-
Table 1 Annual estimates of new cases globally (WHO 1999)
Breast Cancer Cervical Cancer Ovarian Cancer Endometrial Cancer
Table 2
Incidence
Mortality
795 000 452 000 165 000 142 000
313 000 234 000 101000 42 000
165
chart with high-grade lesions (CIN II/III) likely to be true cancer precursors and low-grade lesions (CIN I/HPV) with unknown or low progressive potential.The CIN classi¢cation has been retained in the United Kingdom. The National Cancer Institute of the United States developed the Bethesda system in1988.This classi¢es abnormalities as atypical squamous or glandular cells of undetermined signi¢cance (ASCUS), low grade squamous intraepithelial lesions, LSIL (encompassing HPVand CIN I) and high grade squamous intraepithelial lesions, HSIL (encompassing CIN II and CIN III) (Table 2).
NATURAL HISTORYOF CERVICAL CANCER Contrary to the common belief, cervical cancer a¡ects women in their prime years, with peak incidence for invasive cancer being at age 45 and for CIN III at 35 years. Adenocarcinoma of cervix, which now comprises approximately 22% of all cervical cancers, often a¡ects women under 35 years of age. Cervical cancer has a long precancerous phase with cytologic changes progressing through di¡erent grades,
Summary of terms used for cervical intraepithelial neoplasia
Original Papanicolaou and WHO system Cytology Class I Class II Histology Normal In£ammatory/Reparative Responses HPV Related? United Kingdom System Cytology Negative
BNA (Borderline nuclear abnormalities) Histology Normal In£ammatory/ Reparative Responses HPV Related? Richart and The Bethesda System ASCUS Cytology Within Normal Limits Histology Normal In£ammatory/Reparative Responses HPV Related?
Class III Mild Dysplasia (koilocytosis, koilocytotic atypia, £at condyloma)
Class IV Moderate Dysplasia
Class V Severe Dysplasia
Mild Dyskaryosis
Moderate Dyskaryosis
Severe Dyskaryosis
?Invasive disease
CIN grade I
CIN grade II
CIN grade III
Invasive cancer
Low-grade SIL
High-grade SIL
Invasive cancer
Low-grade CIN
High-grade CIN
Invasive cancer
Carcinoma In situ
Invasive cancer
166
de¢nable cytologically (dyskaryosis) or histologically (dysplasia or cervical intraepithelial neoplasia). It is very rare to ¢nd dysplastic changes in cervical epithelium within 2 years of debut of sexual activity. It generally takes 3^5 years for the changes to progress from one grade to the next. It has been estimated that the mean time from detectable cytologic abnormality to development of invasive cancer may take as long as 15^20 years. Thus, progression of CIN to invasive cancer, although it can be swift, is usually a slow process. Many CIN lesions will regress over time. The regression rate depends, amongst other factors, mainly upon the grade of CIN and the age of the woman. Regression is much more common in women under 30 years than those above 30 years of age. Taken together, in the absence of intervention, roughly one third of early precursor lesions disappear spontaneously, one third persist and one third progress to CIN III or from CIN III to invasive cancer.
GLANDULAR DISEASE It is well documented that the incidence of glandular disease is increasing and epidemiology of invasive adenocarcinoma is changing with a higher incidence recorded in women younger than 35 years old. Between 20 ^30% of cervical tumours are now classi¢ed as adenocarcinomas or adenosquamous carcinomas. These lesions pursue a more aggressive course than their squamous counterparts. The natural history and biology of CIN are well described, the situation with glandular lesions is less clear. Attempts have been made to mirror the range of cellular changes in glandular mucosa (Cervical Glandular Intraepithelial NeoplasiaöCGIN I, II, III). Because of uncertainty of the signi¢cance of this classi¢cation, any degree of glandular cell abnormality identi¢ed on a cervical smear should be followed up by colposcopy and possible endocervical curettage. The recommended treatment of CGIN III is excisional biopsy of the cervix. Risk factors for cancer of the cervix include: . . . .
. . .
.
Human PapillomaVirus (HPV) infection Early onset of sexual activity Multiple sexual partners (self or of the partner) Tobacco smoking ö there is evidence that it increases risk of invasive cervical cancer and also interacts with HPV in carcinogenic e¡ect Oral contraceptives ö long-term use Multiparity Malnutrition ö diets poor in fruit, vegetables and some micronutrients (vitamin C, beta carotene, folate) Low socio-economic status
CURRENT OBSTETRICS & GYNAECOLOGY
HUMAN PAPILLOMAVIRUS Genital HPV, one of the most common sexually tranmitted diseases is reponsible for anogenital cancers both in women and men. It is now known that HPV is an important cause of cervical cancer. Human Papilloma Virus oncogenic types are found in 95% of squamous cell carcinomas and 60% of adenocarcinomas. Out of the 70 known HPV genotypes, 30 are known to infect the genital tract.Out of these 20 have been identi¢ed as carcinogenic with types 16 and 18 found most commonly in malignant lesions. The common types are classi¢ed according to their oncogenic potential as follows: Low risk: 6,11, 41, 44 Intermediate risk: 31, 33, 35 High risk: 16,18, 45, 56
NATURAL HISTORYOF HPV INFECTION Both high- and low-risk HPV infections in women occur mostly in adolescent age groups (16 ^24 years). Reported incidences from di¡erent countries have been 10 ^30%. The incidence drops to about 5% above age of 30 years. Most of of these HPV infections are transient, about 80% clear spontaneously within1^2 years.The rest may result in CIN lesions. However, most of the women with HPV positive smears who develop CIN lesions are still able to clear the virus in 2^3 years and will subsequently have regressive CIN. Above age 30 years the regression rate is much lower. Among women with persistent infection, CIN lesions can develop within 2^ 4 years. It is known that two characteristics of HPV that are important for causing dysplastic changes in epithelial cells are viral load and viral persistance. Both are measurable. However, little is known about the host factors which determine the dysplastic/oncogenic changes. So far it has been established that age of the host (430 years) and immune status determine oncogenic progression. In some studies, concommittent sexually transmitted diseases (STDs) especially, chlamydia and bacterial vaginosis have been suggested to play a catalytic role. The progression rate of CIN in women with high-risk, HPV-positive, cytologically normal or abnormal smear is about 5% per year. In women above age 30 with high-risk HPV positivity, and a cytologically normal smear the risk of developing CIN III is116 times higher than women with an HPV-negative cytologically normal smear.
HPV VACCINES Currently, vaccines against HPV are being evaluated. In theory, cervical cancer can be prevented and treated by HPV vaccine therapy. Important progress has been made
INTRAEPITHELIAL NEOPLASIA,WART VIRUS AND COLPOSCOPY
towards producing recombinant, type-speci¢c vaccines both preventive and therapeutic. Phase I & II clinical trials are underway at some centres. This research holds promise for having a profound impact on this disease, perhaps even helping to eliminate it. The likely time course for such a scenario to unfold will be prolonged.Once a‘perfect’ HPV prophylactic vaccine is synthesised, it will take many years to complete all phases of clinical study and then introduce the vaccine into clinical practice. In this context, hepatitis B vaccine has been administered to less than 1% of the world’s children, despite the decades that have elapsed since the successful development of that vaccine.
COLPOSCOPY Colposcopy has become recognised as an essential tool in assessing patients with abnormal cytological smears (Figure 1). The basic principles of colposcopy comprise low power magni¢cation and illumination of the uterine cervix. These principles ¢rst described by Hans Hinselmann almost 75 years ago still apply. Apart from re¢ning the optical and illumination systems there has been little technological advancement other than the introduction of the green ¢lter to enhance vascular appearances at the time of colposcopic assessment. The objectives of colposcopic assessment are: . To further assess abnormalities detected on cervical smear . To con¢rm diagnosis by directed biopsy . To rule out invasive disease . To aid in out-patient management of precancerous lesions . Follow-up after treatment Colposcopic assessment continues to be a subjective assessment and expertise in this technique is gained by a period of apprenticeship. This consequently leads to observer variability.The interobserver variability among experienced colposcopists reveals lower levels of agreement for diagnosing low-grade lesions than for highgrade lesions. The same levels of agreement have been found amongst pathologists for the histopathological diagnosis of cervical lesions. Predictive accuracy of the colposcopic assessment depends on the use of exact colposcopic criteria which comprises of the sharpness of the cervical lesion border, the degree of acetowhitening, angioarchitecture and iodine staining reaction. An attempt has been made to address the subjective nature of colposcopy by introducing colposcopic indices in order to standardise visual parameters. This attempt has proved di⁄cult to standardise, lacks robustness when applied to clinical situation and has not been validated in prospective studies. Computer imaging
167
technology is now becoming available that may allow characterisation of CIN at the time of colposcopic assessment based on a host of objective variables including lesion surface area. This technology however, requires further re¢nement and critical analysis. There is a need to characterise colposcopic abnormalities objectively and particularly to develop models di¡erentiating high and low grade lesions. The identi¢cation of patients with either high or low grade CIN is useful as it may allow identi¢cation of those patients that have true cancer precursors. It will also highlight those patients with low-grade disease who may be treated by local excision or managed in a more conservative manner. With increasing use of local excisional methods of treatment for CIN, often undertaken at the ¢rst visit, it is obvious that there is a need to be more selective in treatment protocols in order to avoid overtreatment. Loop biopsy (LLETZ) has been found to be more accurate in detecting CIN than colposcopically directed biopsies. The underdiagnosis of 20 percent of all cases was found when histopathological diagnosis of directed biopsies was compared with large loop biopsies. Therefore, some investigators advise LLETZ rather than directed biopsies when investigating high-grade cervical lesions.
TREATMENT METHODS AND OUTCOME The two main conservative methods of treatment are ablative or excisional techniques.The cure rates for both techniques are in excess of 90%. The need for conservative treatment is apparent considering the morbidity of the more radical procedures, their e¡ect on reproductive function and the high incidence of precancerous lesions among younger age groups. The decision for conservative management relies on accurate colposcopic assessment, visualisation of the lesion in its entirety and the exclusion of invasive disease by directed biopsy/biopsies.When considering the choice of actual technique, an important consideration is the depth of the tissue destruction required. Recently there has been a tendency towards using excisional methods. This allows better histopathological interpretation of the excised specimen and in certain circumstances allows a ‘see and treat’ strategy under local anaesthetic at the initial visit. This policy however, can lead to overtreatment of insigni¢cant lesions.Therefore, a ‘select and treat’ strategy is recommended as is practiced in most colposcopy units (Table 3). Cryocautery destroys tissue by freezing using probes of various shapes and sizes and is probably best reserved for small lesions.Whilst lesion size is important in determining success or failure of any of the treatment modalities used, it is especially important when using
168
CURRENT OBSTETRICS & GYNAECOLOGY
Figure 1 Flow diagram of the management of women with abnormal cervical cytology.
cryocautery. The duration of the freeze is 2 min from the appearance of the ice ball. With larger lesions, multiple applications may be necessary. The depth of destruction is approximately 4 mm and this may be inadequate for some of the CIN lesions. Depth of destruction cannot be accurately gauged and incomplete eradication of disease may lead to regenerating epithelium covering the residual disease. Despite these reservations the tech-
nique is worthy of consideration as cryoprobes are cheap and widely available and can be used in an outpatient setting without analgesia with minimal discomfort to the patient. Healing is rapid and, the endocervical canal is not compromised and therefore fertility is not impaired. Electrodiathermy destroys tissue more e¡ectively than cryocautery. It does require general, regional or local anaesthesia. Under colposcopic control it is possible
INTRAEPITHELIAL NEOPLASIA,WART VIRUS AND COLPOSCOPY
Table 3
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Treatment methods
Ablative
Excisional
Cryocautery Electrodiathermy Cold coagulation Carbon dioxide laser
Loop excision of TZ (LLETZ/LEEP) Laser excision of TZ Laser cone biopsy Loop cone biopsy Cold knife cone biopsy Hysterectomy
to destroy up to1cm depth using a combination of needle and ball electrodes. The needle is reinserted repeatedly at 1^2 mm intervals until the whole transformation zone has been covered. The apparatus required is cheap and easy to maintain.There may be considerable thermal necrosis leading to discharge and slough following therapy. Fibrosis is more common than with other destructive therapy but does not appear to a¡ect fertility. In cold coagulation technique, heat is applied to tissue using a Te£on-coated thermosound, the ‘Semm cold coagulator’. The procedure does not usually require analgesia and the device is cheap and easy to maintain. Measurement of depth of destruction is di⁄cult. The whole of the transformation zone is destroyed by overlapping applications of thermosound for 20 s at1008C per area. Depth of destruction is approximately 2.5^ 4 mm or more after treatment at1008C for 30 s and always exceeds 4 mm after treatment at 1208C for 30 s. Laser is an acronym for Light Ampli¢cation by Stimulated Emission of Radiation. A micromanipulator attached to the colposcope is used to manipulate the laser and treatment is conducted under direct vision. As the technique is precise it gives good control over depth of destruction, good haemostasis and excellent healing, as there is minimal damage to the adjacent tissue. The technique is particularly useful for treating lesions with vaginal involvement. As there are no gland crypts in the vaginal epithelium, destruction to 2^3 mm of depth is adequate. Healing is rapid with new cells appearing within 10 ^12 days. Cure rates of 94% have been quoted in selected patients. Diathermy loop excision using low power voltage apparatus is now widely practiced (Figure 2).The technique is referred to as large loop excision of transformation zone (LLETZ) in Europe and as loop electrosurgical excision procedure (LEEP) in North America. In the UK, this is now the most common method of local treatment for CIN lesions. Laser excision is technically more demanding than laser vaporisation and requires a high power density beam with a small spot size that can function in a cutting mode. Both laser and diathermy loop can be used to fashion cone biopsies of the cervix.
Figure 2 Diagramatic representation of largeloop excision of the transformation zone.
Success rates following local excisional techniques are similar to those for laser ablation and cold coagulation. There appears to be no adverse e¡ect on fertility and the outcome of subsequent pregnancies. Cold knife cone biopsy and hysterectomy still retain a place in the management of CIN. The size and shape of the cone biopsy is governed by the colposcopic ¢ndings. The internal os and as much of the endocervical canal is left intact as is possible within the con¢nes of disease eradication. This limits haemorrhage and fertility will be little compromised. Cone biopsy performed for therapeutic and diagnostic purposes may give cure rates of 93%. Advent of colposcopy has led to smaller cone biopsies with fewer complications but equal therapeutic results. In the absence of colposcopy, Schiller’s iodine can be used to determine the limit of the incision on the ectocervix. The two major problems with cone biopsy are haemorrhage and postoperative cervical stenosis, depending on the length of the cone performed. The latter can lead to menstrual dysfunction and dysmenorrhoea. It also makes colposcopic and cytological follow-up more problematic. Hysterectomy may need to be performed in a woman with CIN who has other gynaecological conditions such as ¢broids, menorrhagia or prolapse. Prior to operation colposcopy will identify the extent of the lesion to avoid incomplete excision which may result in vaginal intraepithelial neoplasia (VaIN). If the lesion is seen to extend to the vagina, this may be excised as part of the hysterectomy procedure. An alternative is to ablate the vaginal extension of CIN, using laser or diathermy, and then proceed to excision or hysterectomy as indicated. Although data suggest that cone biopsy and hysterectomy are e¡ective forms of management, even so there is a 0.3^ 0.4% incidence of invasive cancer following these procedures.
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CURRENT OBSTETRICS & GYNAECOLOGY
FOLLOW-UP AFTER TREATMENT Women who have undergone treatment of CIN remain at high risk for invasive cervical disease.This necessitates close surveillance, cytologically and colposcopically following treatment.Those women that have abnormal cervical cytology following treatment are at much increased risk compared to those with normal smear after treatment. Cytological abnormality following treatment, no matter how minor, should be considered as an indication for colposcopic assessment. Colposcopic assessment is technically more di⁄cult in women who have undergone treatment. Foci of CIN and or invasive disease may be buried under an apparently normal epithelium. Moreover, the transformation zone may be di⁄cult to visualize in its entirety because of scarring. In cases of failed initial treatments it is recommended to use an excisional method in preference to an ablative technique. Histological incomplete excision at the time of cone biopsy represents a management dilemma. Although involvement of endocervical margins in cone biopsy specimens with CIN lesions would imply incomplete excision, the true residual rate, as evidenced by a positive smear at 6 months, is less than 5%. Follow-up cervical cytology may in fact be a more useful prognostic guide to residual disease than excision cone margins. A repeat smear should be performed at 6 months. If the smear is abnormal, a repeat cone or excisional procedure should be undertaken. A negative second smear would indicate routine follow-up for the woman. If the margins of the cone are clear, the woman should have colposcopy and cervical smear performed at 6 months. If the smear is negative, a repeat negative smear at 6 months would indicate subsequent routine follow-up of the woman.
PRACTICE POINTS . For purposes of standardisation, the British system is used for classi¢cation of Pap smears in the UK. Alternative classi¢cation schemes may be used, such as the Bethesda system, as appropriate to local experience and usage. . Women with Pap smears reported as moderate dyskaryosis, or worse, including atypical glandular cells should be referred for further evaluation as soon as possible. . In up to 30 ^ 40% of women presenting with mild dyskaryosis, CIN II^III exists within the cervix. Even in women with persistent borderline nuclear abnormalities 8 ^14% will harbour such a highgrade lesion. . The size of the lesion can be a good predictor of histological grade of the precancerous lesion, e.g.
. .
.
.
if the lesion size is large and involves three or more quadrants of the cervix in the presence of low-grade cytology, there may be a high-grade epithelial lesion present in this area. Punch biopsy/biopsies, even directed, lead to a high rate of undercall especially for high-grade lesions. For the local treatment of cervical pre-cancerous lesions an important aspect is the depth of destruction of the treatment modality used. A destructive depth of 5^ 8 mm is recommended based on the studies to assess the depth of crypt involvement. If the depth of destruction is inadequate, this deepseated component may be a source of residual or recurrent disease. Colposcopy is a subjective technique requiring formal training and a suitable volume of patients must be seen yearly in order to maintain skills.
RESEARCH DIRECTIONS . More objective diagnostic methods are needed for the triage of cytologic mild dyskaryotic lesions. . Further research in characterising cervical images using di¡erent models. . Re¢ning a standardised diagnostic method which is sensitive and speci¢c for detection of HPV. . Introduction of standardised training, assessment and accreditition system for colposcopy training. . De¢ning precisely the incidence of HPV in general population. . Identifying co-factors that in£uence HPV transmission and that may promote carcinomatous changes in cervical lesions. . Finding e¡ective treatments for HPV infections especially immunologic therapies e.g. HPV vaccine. . Determine the e⁄cacy and cost-e¡ectiveness of HPV screening in prospective randomised controlled trials.
FURTHER READING Nazeer S. Memorandum from a WHO Meeting.Cervical cancer control in developing countries. Bull Wrld Hlth Org1996; 74: 345^351. Miller AB. Cervical cancer screening programmes: Managerial guidelines.World Health Organization monograph; 1992. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in1990. Int J Cancer 1999; 80: 827^ 841. National Cancer Institute Workshop.The1998 Bethesda System for reporting cervical/vaginal cytological diagnoses. JAMA 1989; 262: 931^934. SyrjÌnen K, Kataja V, Yliskoski M et al. Natural history of cervical HPV lesions does not substantiate the biologic relevance of the Bethesda system. Obstet Gynecol 1992; 79: 675^ 682. Hristova L, Hakama M. E¡ect of screening for cancer in the Nordic countries on deaths, cost and quality of life up to the year 2017. Acta Oncol 1997; 36 Suppl 9:1^ 60.
INTRAEPITHELIAL NEOPLASIA,WART VIRUS AND COLPOSCOPY
Sha¢ MI, Jordan JA. The treatment of CIN. Current Obstetrics & Gynaecology 1991; 1: 137^142. Miller AB, Nazeer S et al.Report on Consensus Conference on cervical, cancer screening and management. Int J Cancer 2000; 86: 440 ^ 447.
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Dillner J.Can cervical cancer screening programs be improved by incorporating screening for human paillomavirus infection? The Cancer Journal 1998; Vol 11; 6:272^275. IARC Monographs on the evaluation of carcinogenic risks to humans: Human Papilloma viruses.1995; Vol 64.