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Management options for cervical intraepithelial neoplasia
Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 641–651
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Management options for cervical intraepithelial neoplasia Karl U. Petry, MD, Professor, Head of Department of Obstetrics Gynaecology and Gynaecologic Oncology * Klinikum Wolfsburg, Sauerbruchstr. 7, 38440 Wolfsburg, Germany
Keywords: CIN colposcopy management cervical transformation zone HPV-testing LLETZ conisation
Management of cervical intraepithelial neoplasia (CIN) needs to protect women at risk from developing cervical cancer and to avoid over-treatment as well as obstetrical complications in women undergoing invasive treatment. Strong evidence shows that CIN3 is a true precursor and must be treated, whereas CIN1 lesions do not benefit from immediate surgery and should be followed conservatively. Although the clinical course of CIN2 differs from CIN3, it should be treated the same way for legal reasons. Colposcopy plays a central role in selection of patients and treatments. Treatment of CIN2 and 3 should be excisional. Large loop excision of the transformation zone, high-frequency-needle or laser conisation are equally good, whereas cold-knife conisation is associated with an excess risk for subsequent obstetrical complications. Human papillomavirus testing and cytology at 6 months seems to be the best post-treatment monitoring, although this needs to be confirmed by randomised-controlled trials. Future research needs to focus more on how the quality of colposcopy and the overall management concept determines the clinical outcome instead of exploring the role of single technical methods. Furthermore, it seems to be necessary to evaluate the best management of CIN2 in young and in vaccinated women. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction The major ethical and medical aim of all management options for cervical intraepithelial neoplasia (CIN) is the prevention of cervical cancer. The second most important aim is to achieve this with as little harm to the woman as possible. Finally, management of CIN should be cost-efficient without
* Klinikum der Stadt Wolfsburg, Department of Obstetrics, Gynaecology and Gynaecologic Oncology, Sauerbruchstr. 7, 38440 Wolfsburg, Germany. Tel.: þ49 5361 801270; Fax: þ49 5361 801613. E-mail address: [email protected]. 1521-6934/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpobgyn.2011.04.007
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compromising any of its two major aims. As only a minority of CIN will progress to cervical cancer, and because any kind of invasive treatment is associated with adverse events, good management of CIN is based on a good selection of women who are really in danger of developing cervical cancer and need to be treated, compared with those who are not at risk of cancer and should be protected from over-treatment. With the deep understanding of the human papillomavirus (HPV)-dependant genesis of cervical cancer, we are able to calculate risks of progression of CIN quite accurately, and have learned about minimum periods for each step of cervical carcinogenesis. One important principle, however, in the management of CIN is over-treatment. We know that, even with the best available selection, we will treat CIN lesions that would never progress to cancer, and this is acceptable as long as it is not excessive over-treatment. State-of-the-art treatment of CIN has moderate side-effects, whereas cervical cancer is a deadly malignant disease. Selection of women in need of protection from cervical cancer depends mainly on the grade of CIN, the type of the transformation zone, and age of the woman. It is well-established that persistent infection of certain HPV is an essential precondition in the genesis of cervical cancer. Virtually all primary cervical cancers contain HPV DNA. HPV-induced carcinogenesis, however, is a rather slow process, with at least four important steps: incident infection with a high-risk HPV-type; establishment of a persistent HPV infection; transformation of human keratinocytes in pre-invasive neoplastic cells; and malignant transformation of intraepithelial neoplasia into invasive cancer. The process is reversible at any pre-invasive stage. Most genital HPV infections are transient, and more than 90% will be cleared spontaneously within 18 months in young women.1 Persistent HPV infections and low-grade intraepithelial neoplasia will regress without any treatment within 2–5 years in 60–80% of all cases. Spontaneous resolution is observed in at least 40% of lesions with biopsy-proven moderate dysplasia (cervical intraepithelial neoplasia grade II). Only a 20% minority of CIN2 will progress to CIN3, and less than 5% to invasive cancer.25 It is quite obvious that the morphology-based grading of pre-invasive cervical neoplasia does not always reflect the risk of progression to invasive disease. We have learned from observational studies and from large randomised-controlled HPV vaccine trials that, in young, HPV-naive women at baseline, incident HPV infections may be associated with CIN1 and even CIN2 within a few months.6,7 Although these lesions cannot be distinguished by cyto- or histomorphology from persisting CIN1 or CIN2, the clinical course seems to be different, with a much higher likelihood of regression. Although the natural history of CIN2 resembles that of low-grade lesions in most cases, it is regarded as a high-grade lesion in most clinical management guidelines for legal reasons. There is sufficient evidence that CIN3 is a true precursor of cervical cancer. At the National Women’s Hospital, Auckland, New Zealand, treatment of CIN3 was withheld from a substantial number of women between 1965 and 1974 as part of an unethical clinical study. During long-term follow up, 31.3% of women managed with punch biopsies only developed invasive cancer. In the subset of 92 such women who had persistent disease within 24 months after biopsy-proven CIN3, invasive disease occurred even in 50.3% (37.3–64.9).8 Principles, outcomes and standards of observational management Excisional treatment of CIN is associated with a significantly increased risk of preterm delivery, late miscarriage, and perinatal mortality in subsequent pregnancies.9,10 Therefore, it should be used only in well-selected women with a clear indication for invasive treatment. As pointed out, CIN1 is common, especially in adolescents and young women. In many cases, these lesions are just cellular changes of self-limiting, permissive HPV infections with a high rate of spontaneous regression. Even in persisting CIN1, the risk of progression is low, and most of these lesions will finally undergo spontaneous regression.3 The European guidelines and the 2006 American Society for Colposcopy and Cervical Pathology (ASCCP) consensus guidelines recommend observational management in women with CIN1.1113 Compared with the 2001 ASCCP guidelines, cytological follow up became the only recommended management option in the 2006 recommendations, regardless of whether the colposcopic examination is satisfactory, for women with CIN1 who have a low-grade referral cervical cytology. Treatment of CIN1 is particularly discouraged in adolescents. For the management of CIN, it is important that cytologic low-grade squamous intraepithelial lesion (LSIL) is not equivalent to histologic CIN1 and cytologic high-grade squamous intraepithelial lesion
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(HSIL) is not equivalent to histologic CIN2 and 3. Because the prevalence of CIN2 or greater was 12–16% at initial colposcopy among women with LSIL in randomised-controlled trials (RCTs),14,15 the ASCCP guidelines recommend colposcopy for managing all women with LSIL, with the exception of adolescents who should be followed with annual Pap smears. This recommendation, however, is questioned by the results of a large RCT in the UK. The Trial of Management of Borderline and Other Low Grade Abnormal Smears (TOMBOLA) compared cytological surveillance with immediate referral to colposcopy in the management of women with low-grade cervical abnormality in 4439 eligible women. Immediate referral to colposcopy detected more CIN2 or greater lesions at baseline, but the trial found no significant difference in the cumulative incidence during 3 years’ follow up. Immediate colposcopy, however, resulted in a large number of referrals of women with no relevant cervical disease.16 Although HPV testing proved to be efficient in the triage of ASCUS/borderline cytology, HPV testing is of little use in LSIL cytology because about 80% will be associated with HPV.14,17 From the view of a colposcopy clinic, women transferred because of borderline or LSIL cytology should undergo colposcopic assessment with biopsies. The TOMBOLA trials could show, with a high level of evidence, that immediate large loop excision of the transformation zone (LLETZ) will not increase the rate of CIN2 or CIN3 compared with targeted punch biopsies by experienced colposcopist, but results in over-treatment and unnecessary morbidity in healthy women.18 Another RCT in Canada and Brazil compared immediate LLETZ and expectant management in women with biopsy-proven CIN1. No significant difference was found in the risk of progression to CIN2 or 3 between the two study arms. The authors concluded that expectant management of biopsy-proven CIN1 up to 18 months is a reasonable management strategy.19 Both RCTs support the broad consensus that, in women with biopsy-proven CIN1 and satisfactory colposcopy, invasive treatment is not indicated. These women should be followed with intensified screening. Because the risk of underlying high-grade disease is low, even in women with LSIL and unsatisfactory colposcopy, most guidelines also recommend observational management in these cases.20 Graphic 1 summarizes the management options of LSIL (Graphic 1 near). However, in women referred to colposcopy because of HSIL cytology, who receive a histologic diagnosis of CIN1 in corresponding targeted biopsies, most guidelines recommend a diagnostic excision of the transformation zone because the risk of underlying high-grade disease is high. In women younger than 25 years, the incidence of invasive cervical cancer is low, whereas the rates of HPV infections, CIN1 and CIN2 are high.6 As most of these lesions will regress spontaneously, many national screening programmes recommend screening only in women who are 25 years or older to protect younger women from over-treatment. In countries with an earlier start of screening, this should be kept in mind. The 2006 ASCCP guidelines encouraged expectant management of CIN2/3 in adolescents. In our own experience, expectant management of biopsy-confirmed CIN2 in women with satisfactory colposcopy is safe and avoids over-treatment in women younger than 30 years. HPVgenotyping seems to be useful in predicting the clinical course of CIN2. Although CIN2 lesions associated with HPV16 carry a high risk of progression, most CIN2 associated with other HPV types will regress spontaneously.3,5 Expectant management of CIN2 outside of trials, however, should be restricted to women younger than 25 years with a good compliance, and the follow-up should be controlled by an experienced colposcopy clinic. During pregnancy, invasive treatment of any grade of CIN should be postponed until 2 months after delivery. Invasive disease must be excluded by colposcopy. If biopsies need to be taken at the 18th week of gestation or later in pregnancy, loop biopsies are more appropriate than standard punch biopsies to obtain a histological specimen with sufficient stroma. When invasive cancer can be excluded with high reliability, the remaining risk for CIN3 lesions to progress to malignancy during pregnancy is small, whereas the fetal and maternal risks related to invasive treatment of the cervix are high, and complete excision of lesions cannot be achieved in almost half of the cases.21 Principles, standards and outcomes of surgical treatment modalities Surgical treatment of CIN3 is the accepted treatment standard worldwide. Conisation and LLETZ are the most common surgical methods. In many countries, invasive treatment is obligatory for CIN3 and CIN2, although the risk of progression to invasive disease is low in CIN2, and many CIN2 lesions will regress spontaneously in younger women.
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The primary goal in the management of CIN2 and 3 is to prevent the development of invasive cancer by complete surgical destruction of all neoplastic tissue. To achieve this with as little loss of cervical function as possible is an important secondary goal. The healthy uterine cervix protects the uterine and abdominal cavities from ascending infections and plays an important role in the regulation of fertility and during pregnancy. As the mean age of women with CIN3 is about 31–34 years in most populations, destructive treatment of the cervix may affect fertility and increase significantly the number of late miscarriages, premature labour, preterm delivery, and perinatal mortality in subsequent pregnancies. This high risk of obstetrical complications after invasive treatment of the uterine cervix was confirmed by two meta-analyses.9,10 Colposcopy is the single method of identifying the exact topography of cervical lesions, and thus plays a crucial role in selecting the appropriate surgical treatment of individual CIN3. The target host cells of primary HPV infection are the basal cells that are exposed superficially at the squamocolumnar junction. Furthermore, it seems to be one peculiarity of the cervical transformation zone that its metaplasia cells are especially prone to oncogenic transformation induced by HPV because these cells need to provide different pathways of cell differentiation. This explains the well-known observation that almost all high-grade cervical lesions are located within the cervical transformation zone, whereas vaginal intraepithelial neoplasia is rare, although vagina and uterine cervix are exposed to HPV at a similar rate. To achieve high cure rates in the treatment of premalignant disease of the cervix, it is necessary to destroy the complete transformation zone and any neighbouring lesions. As the extension of individual CIN3 lesions and transformation zones differ significantly, colposcopically guided surgical treatment will remove neoplastic tissue with high accuracy and avoid unnecessary destruction of neighbouring healthy tissue. It seems to be a matter of course for Anglo-Saxon countries that colposcopy plays a central role in the management of atypical screening results and guidance of invasive treatment, but this is not reality in many other countries. A retrospective nationwide study in Germany found that more than 90% of women who were treated because of LSIL or HSIL smears never had colposcopy assessment and underwent directly diagnostic cold-knife biopsy or even hysterectomy. This management resulted in significant over-treatment and increased costs.22 This is in line with the TOMBOLA evaluation that colposcopic evaluation of LSIL smears are cost efficient.23 Any method of treating CIN 3 carries a small risk of subsequent development of invasive cancer. This event seems to occur less frequently after excisional treatment with cold-knife-, needle-, laser-cone biopsy or LLETZ than after destructive treatment using laser vaporisation, electrocoagulation diathermy, cryotherapy or cold coagulation. Therefore, and because of the better histological evaluation, excisional methods are the standard treatment for CIN.24,25 The use of destructive techniques should only be applied for extended and multifocal lesions. No single excisional method could ever prove superior cure rates in randomised, multicentre trials, and the multiple smaller observational or single-centre studies differ significantly in study design and do not allow for a general recommendation of one method of surgical treatment of CIN3. It is possible, however, to recommend the best surgical method for each individual CIN3 based on the colposcopical categorisation of the transformation zone and the evidence-based risk–benefit profile of available surgical methods. Surgical treatment of CIN requires the complete removal of the transformation zone. The International Federation for Colposcopy and Cervical Pathology defined three different types of TZ: Type 1 The complete TZ is located on the ectocervix Type 2 The TZ extends into the endocervical canal but the upper border/Squamous columnar junction is visible on colposcopy Type 3 The TZ extends into the endocervix and the upper border is not visible on colposcopy In all types of transformation zone, the ectocervical or vaginal border of the lesion, and in types 1 and 2, even the endocervical extension can be identified by colposcopy. To achieve a full thickness resection of a type 1 transformation zone with clear basal margins, the cutting depth for the external orifice must be 8 mm, whereas 5 mm may be sufficient for the periphery of the transformation zone. LLETZ26 is the best suited treatment for CIN located in transformation zone type 1 and 2. The loops are tailored for an optimal bowl-like resection of the transformation zone. The size of the transformation identified on colposcopy determines the size of the loop. The cutting effect is achieved by
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light arches that spark between the 0.2-mm thin wire and the tissue. Modern high-frequency (HF-) generators regulate electronically the needed optimal cutting currency. Properly performed LLETZ causes only minimal thermonecrosis that marks the definite surgical resection margin. The obtained samples allow a full histopathological review. The outpatient procedure is safe, easy, can be carried out under local anaesthesia, and causes little bleeding and complications. Haemostasis can be achieved easily by application of Monsell’s solution. Transformation zone types 1 and 2, with minimal extension to the endocervix, can be resected completely with a loop in one piece, and the treated cervix will heal without significant scarring or deformations in most cases (see Picture 1 near). Transformation zone type 2 that extends 7–10 mm into the endocervix may require a second resection of the adjacent canal with a smaller loop to achieve clear endocervical margins. For a complete excision of type 3 transformation zones,the relatively flat ectocervical transformation zone with a maximum depth of 7–8 mm and the involved endocervical canal must be resected. The shape of the correctly removed sample resembles a hat or an Indian pagoda more than a true cone. Although a complete resection can be achieved with all excisional methods, LLETZ with additional loop resection of the endocervical canal and laser or HF-needle conisation seem to be the best suited methods of treatment. Cold-knife conisation of type 3 transformation zone has the disadvantages that it should be done under general anaesthesia, is an inpatient procedure and causes significantly more bleeding and scarring (Picture 2 near) than laser or needle conisation.27,28 Loops are not designed for an optimal removal of type 3 transformation zone. Either large loops with 20–25 mm diameter need to be used, which will unnecessarily remove uninvolved tissue of the cervical stroma in some cases or the excision will be carried out in multiple pieces. A histological evaluation of such specimens may be difficult. Furthermore, deep endocervical resection may cause reasonable bleeding, and precise cutting with a loop will be not possible in some circumstances. Laser and needle conisation are outpatient treatments, and may be carried out under local anaesthesia and colposcopic guidance. The cones obtained show as little thermonecrosis as LLETZ and do not disturb histological assessment. As the equipment for HF-needle conisation is much cheaper than for laser conisation, it is likely that this method will replace laser conisation as treatment of CIN3 located in type 3 transformation zone. However, needle and laser need intensive training, especially when the laser is used with a micromanipulator under colposcopy guidance. LLETZ with separate endocervical resection is much easier to carry out, and therefore loop resection is already the standard treatment of CIN in many places. After resection of the transformation zone by any of the above mentioned excisional and destructive methods, residual endocervical disease needs to be excluded either by endocervical curettage or brush.
Picture 1. Visible squamous columnar junction 6 months after large loop excision of the transformation zone.
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Picture 2. Scarring and deformation of the uterine cervix 6 months after cold knife conisation.
Haemostasis can be achieved by application of Monsell’s solution onto the wound surface. Graphic 2 shows our proposed management of CIN3 (Graphic 2 near) Monitoring success of treating cervical intraepithelial neoplasia A large population-based cohort study with more than 300,000 observation years in women treated for CIN 1, 2 and 3 in British Columbia showed that the risk of recurrent CIN 2/3 was significantly increased in the first 6 years after invasive treatment, with a peak in the first 2 years.29 This is best explained with residual disease that was detected in the first 2 years and an elevated risk for the development of new CIN2/3 lesions because of persistent HPV infections. All guidelines pay attention to the high risk of residual or recurrent disease after invasive treatment of CIN. Three different followup methods can confirm cure of CIN: colposcopy, cytology and HPV testing.12,13 Because colposcopy follow up is the most expensive, it is usually only indicated in women with a high risk of recurrence, especially in women with involvement of the endocervical resection margin, positive endocervical curettage, or both, as well as in women with atypical findings during follow up. Cytology-based follow
LSIL
Observation with cytologyfor 3 years
Colposcopy
CIN 1
Observation for 18 months
Graphic 1. Evidence-based management of low-grade squamous intraepithelial lesion smears and cervical intraepithelial neoplasia 1. CIN, cervical intraepithelial neoplasia; LSIL, low-grade squamous intraepithelial lesion.
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Graphic 2. Proposed management of high-grade squamous intraepithelial lesionand cervical intraepithelial neoplasia 3. CIN, cervical intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesion; LLETZ, large loop excision of the transformation zone.
up was the standard in all other women after treatment of CIN. During the past decade, a number of studies have evaluated a possible role of HPV testing in this setting. An early trial from the Netherlands found that HPV testing was more predictive for recurrent CIN2/3 than cytology, with similar specificity for both methods. The negative predictive value in negative HPV and Pap smears in women 6 months after invasive treatment was 99% and improved current guidelines.30 Although recommendations for a possible role of primary HPV screening for cervical cancer in women who are 30 years or older are based on eight large RCTs with a high level of evidence,31 and the efficacy of HPV in well-defined triage settings was also confirmed by RCTs,17 HPV testing in the monitoring of women after treatment of CIN was so far only evaluated in cohort studies. Another problem with studies in this setting is the use of different HPV tests, especially the use of non-validated, sometimes home-brewed polymerase chain reaction tests. Therefore trials evaluating HPV testing need to use either Hybrid Capture 2 or validated polymerase chain reaction tests, such asGP5þ/GP6þ.32 One meta-analysis evaluated post-treatment HPV testing for recurrent CIN. Hybrid Capture 2 testing identified 91% of women with residual or recurrent disease but was associated with a 30% referral rate to colposcopy.33 In a UK-based multicentre trial, 917 women who underwent invasive treatment of CIN1, 2 or 3 were followed with cytology and HPV testing at 6 and 12 months. A total of 14.6% had positive HPV results and 10.7% non-negative cytology. Nine out of 10 cases of recurrent CIN3 and ACIS occurred in women with positive HPV, and the investigators concluded that women who are HPV-negative and cytology-negative 6 months after treatment can safely be returned to routine screening.34 These findings are in line with the early Dutch trial and our own experience, but a confirmation by RCTs is still needed for recommendations based on a high level of evidence. Comparative efficacy and safety of different surgical treatment methods for cervical intraepithelial neoplasia As previously highlighted, evidence is lacking to recommend the superiority of any one excisional treatment modality over another in achieving better cure rates. A number of studies have attempted to answer this question, but these trials cannot be compared because of different definitions of ‘cure’ and differences in carrying out invasive treatment methods. In some studies, the procedures were carried out without any colposcopy assessment, whereas other trials carried out the invasive treatment under colposcopic guidance. The British Columbia study found the best cure rates in women treated with cone biopsies, followed by LLETZ, laser and finally cryotherapy. This analysis, however, is based on patient data from 1984–2000, most CIN2 and CIN3 were treated with destructive methods, and LLETZ forms the smallest group, because it was introduced into clinical practice in the second half of the observation period and may reflect the learning curve.29 From these data it can be concluded that destructive methods, especially cryotherapy, carry a significantly greater risk of residual and recurrent CIN2 and 3. Furthermore, women treated with cryotherapy showed a three-fold increased risk for
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subsequent invasive cervical cancers compared with all other treatment methods. Another important finding of the study was the four-fold increased risk of cervical cancer in women treated for CIN3 compared with women who underwent treatment of CIN1 and 2 and an increased risk for recurrent CIN2 and 3.29 Once again, this study showed that CIN3 and CIN2 are lesions with different biology, and the artificial category CIN2/3 may be useful in clinical practice but is a handicap for sound scientific evaluation. Therefore, clinical trials that evaluate the outcomes of different treatment methods cannot be compared unless they distinguish between CIN2 and CIN3 If treatment failure is defined as detection of CIN2 or greater within 12 months after invasive therapy, cure rates of 95% or more can be achieved with all excisional and destructive treatment modalities carried out under colposcopc surveillance. Strong evidence, however, suggests that cold-knife conisation is inferior to all other treatment modalities in treatment-related morbidity and cost efficiency. Apart from the already mentioned disadvantages, cold-knife conisation was associated with the highest rates of complications in subsequent pregnancies. Two different meta-analyses found significantly elevated risks for preterm delivery before 28 weeks of gestation (RR 5.33), preterm delivery before 37 weeks of gestation (RR 2.59) and perinatal mortality (RR 2.87) in women with a history of cold-knife conisation.9,10,35,36 Laser conisation and LLETZ were also associated with increased risks for preterm delivery but not as strong as cold-knife conisation. Laser vaporisation and cryotherapy did not result in any increase in obstetrical complications. Although sufficient evidence supports a ban of cold-knife conisation as an inferior treatment method for use in the treatment of CIN, questions remain about the overall performance of laser- and HF-needle conisation, LLETZ and destructive methods. It would be premature to conclude that laser vaporisation is superior to LLETZ and laser conisation in associated morbidity. Although this hypothesis needs to be confirmed, it seems likely that the amount of removed cervical tissue, especially stroma tissue, may show a correlation with subsequent obstetrical complications. As laser vaporisation was almost exclusively used for the treatment of atypical transformation zones of type 1 and 2, it destroys only a small amount of stroma tissue, whereas laser conisation as a preferred treatment method for type 3 transformation zones must result in more significant destruction. This would mean that the estimated extension of lesions and transformation zone could have a greater effect on associated morbidity than the treatment modality itself. Current data and studies in progress on these issues Several hot topics in this field that need further research. Do we really need to treat all cervical intraepithelial neoplasia 2 with surgery? The natural course of most CIN2 lesions resembles the course of low-grade lesions and not CIN3.2 Furthermore CIN2 lesions show poor reproducibility.37 An important risk factor of progression of CIN2 to CIN3 is HPV type 16.3 Therefore, it is likely that CIN2 lesions diagnosed in vaccinated women will have a low risk of progression. Further research is needed to discriminate CIN2 in need of treatment from those CIN2 that will undergo spontaneous regression. Imiquimod, an immune-response modulator (IRM) has proved to be an effective topical treatment in VIN2 and 3.38 Some promising IRM candidates and therapeutic HPV vaccines are in the pipeline for the treatment of CIN. When should we treat cervical intraepithelial neoplasia 1? CIN1 should not undergo invasive treatment – but for how long? Of course, the few progressing lesions need to be treated and a large number will regress spontaneously, but what should be done with persisting CIN1? Is it cost-efficient to follow these women with intensified screening for many years? What subgroups benefit from invasive treatment and can we apply destructive methods in these women to avoid unnecessary morbidity?
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What will be the best management of cervical intraepithelial neoplasia in vaccinated women? Within a few years, vaccinated women will enter screening programs. HPV 16/18 infections are associated with the highest risk for development of CIN3 and cancer compared with all other so called ‘high-risk’ HPV-types.39,40 In large, RCTs, HPV vaccination offered almost complete protection from HPV 16/18 infections and associated lesion in the per protocol populations.6,7 In these women, the most important driving force of progression of CIN will be missing, and it is likely that expectant management or non-invasive treatment with new drugs will become the new standard in CIN1/2 and may be even women with CIN3. Colposcopic findings might change too. The typical intense acetowhite reaction of high-grade CIN seems to be most common in lesions associated with HPV 16. Therefore, colposcopy assessment of cervical lesions may need a revision in vaccinated women. What is the best treatment modality for cervical intraepithelial neoplasia? So far, research on this question has paid too much attention to the technical methods instead of the overall management concepts. It is interesting that, with a high level of evidence, two methods were identified to be worse than others. Cryotherapy shows the highest risk of subsequent development of invasive cancer, and cold-knife biopsies are associated with the highest rate of obstetrical complications. Both methods are widely used by medical personel without specific expertise in the management of CIN and, in many cases, without colposcopy. It is likely that the quality of colposcopy is the most important factor in determining the quality of indications for treatment and for quality of treatment success. Any research into this matter is flawed by the fact that colposcopy still is a medical art and its quality depends on individual skills. Research is needed to explain why colposcopically guided punch biopsies show a poor correlation with underlying disease in some studies,41 whereas colposcopy was as good and cost-efficient in detecting CIN3 as immediate LLETZ in the TOMBOLA studies.16,18 Standards in training and independent quality control of those who practice colposcopy are strongly needed. Similarly, it needs to be evaluated if the observed obstetrical complications associated with invasive treatment of CIN are attributable to the technical methods or depend on the excised tissue volume irrespective of the used method.42 One prospective trial using magnetic resonance tomography to calculate the loss of tissue is already under way, but results are still pending.43 What is the best post-treatment monitoring? HPV and cytology testing after 6 months seems to be the most promising post-treatment monitoring but still lacks confirmation by RCTs. Conclusion On the basis of current evidence, observational management seems to be appropriate in women with cytologic LSIL, and is the recommended standard of care for women with cytologic LSIL and biopsy proven CIN1 on colposcopy, irrespective if colposcopy is considered satisfactory or not. CIN3 as a true precursor lesion with a high risk of malignant progression must be treated. Although the corresponding risk of malignant progression is lower in CIN2, and the reproducibility of these lesions is poor, it is recommended that CIN2 is treated the same way as CIN3 for legal reasons. Excision of the transformation zone under colposcopic guidance is state-of-the-art treatment, whereas destructive treatment of CIN, especially cryotherapy, is associated with an increased risk of subsequent invasive cervical cancer. On the basis of sufficient evidence, the use of cold-knife conisation should be discouraged because this method is associated with an increased rate of severe bleeding and severe obstetrical complications and cannot be used under colposcopic guidance. Furthermore, as an inpatient procedure, it is not cost efficient compared with other methods. LLETZ and HF-needle or laser conisation are recommended methods of similar efficacy. For technical reasons, we favour the use of LLETZ when CIN2 and 3 is located in type 1 or 2 transformation zones and prefer laser or HF-needle conisation for the resection of type 3 transformation zones.
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Post-treatment monitoring of success with cytology and HPV-testing after 6 months seems to be efficient in women with low to moderate risk of residual or recurrent disease, whereas women who are at high risk benefit from colposcopic follow up. Future research will evaluate a possible role of adjunct tests to identify CIN2 that may benefit from expectant management and CIN1 that should be treated. Prospective trials will clarify if obstetrical complications are linked to specific treatment techniques or explained by loss of cervical tissue volume. Other issues will be the influence of HPV vaccination on the management of CIN, drugs for immune therapy of CIN, and confirmation of the most efficient concept to prove post-treatment success.
Practice points LLETZ and laser conisation show the best balance of efficacy and safety in the treatment of CIN2þ. Cold-knife conisation increases the risk for obstetrical complications significantly and should no longer be used. LSIL results and biopsy proven CIN1 in women with LSIL should be managed expectantly. With the exception of HSIL findings, atypical cytology results should not undergo immediate surgical treatment. A combination of cytology and HPV testing at least 6 months after treatment of CIN2þ is the most efficient proof of cure.
Research agenda Effectiveness of treatment of CIN with new drugs. Effectiveness of HPV genotyping and molecular markers in developing better individualised treatment strategies for women with CIN 1 and CIN2. Best management strategies in vaccinated women with CIN. Effectiveness of colposcopy guidance to minimise obstetrical complications. Effectiveness of HPV post-treatment monitoring in RCTs.
References 1. Ho GYF, Bierman R, Beardsley L et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; 338: 423–428. *2. Castle PE, Schiffman M, Wheeler CM et al. Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol 2009; 113: 18–25. 3. Brummer O, Hollwitz B, Böhmer G et al. Human papillomavirus-type persistence patterns predict the clinical outcome of cervical intraepithelial neoplasia. Gynecol Oncol 2006; 102: 517–522. 4. Östör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 1993; 12: 186–192. 5. Petry KU, Böhmer G, Iftner T et al. Factors associated with an increased risk of prevalent and incident grade III cervical intraepithelial neoplasia and invasive cervical cancer among women with Papanicolaou tests classified as grades I or II cervical intraepithelial neoplasia. Am J Obstet Gynecol 2002; 186: 28–34. 6. Kjaer SK, Sigurdsson K, Iversen OE et al. A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. Cancer Prev Res (Phila) 2009; 2: 868–878. 7. Paavonen J, Naud P, Salmeron J et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009; 374: 301–314. *8. McCredie MR, Sharples KJ, Paul C et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol 2008; 9: 425–434. *9. Arbyn M, Kyrgiou M, Simoens C et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008; 337. a1284.
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*10. Kyrgiou M, Koliopoulos G & Martin-Hirsch P. Obstetrics outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006; 367: 489–498. *11. Jordan J, Arbyn M, Martin-Hirsch P et al. European guidelines for quality assurance in cervical cancer screening: recommendations for clinical management of abnormal cervical cytology, part 1. Cytopathology 2008; 19: 342–354. 12. Jordan J, Martin-Hirsch P, Arbyn M et al. European guidelines for clinical management of abnormal cervical cytology, part 2. Cytopathology 2009; 20: 5–16. 13. Wright Jr. TC, Massad LS, Dunton CJ et al. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. J Low Genit Tract Dis 2007; 11: 223–239. 14. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol 2003 Jun; 188: 1393–1400. 15. Alvarez RD & Wright TC. Effective cervical neoplasia detection with a novel optical detection system: a randomized trial. Gynecol Oncol 2007; 104: 281–289. *16. Cytological surveillance compared with immediate referral for colposcopy in management of women with low grade cervical abnormalities: multicentre randomised controlled trial. BMJ 2009; 339. b2546. 17. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003; 188: 1383–1392. *18. TOMBOLA group et al. Biopsy and selective recall compared with immediate large loop excision in management of women with low grade abnormal cervical cytology referred for colposcopy: multicentre randomised controlled trial. BMJ 2009; 339. b2548. 19. Elit L, Levine MN, Julian JA et al. Expectant management versus immediate treatment for low-grade cervical intraepithelial neoplasia: a randomized trial in Canada and Brazil. Cancer 2010; 117: 1438–1445. *20. Wright Jr. TC, Massad LS, Dunton CJ et al. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007; 197: 346–355. 21. Silverman MH, Hedley ML, Petry KU et al. Clinical trials in cervical intraepithelial neoplasia: balancing the need for efficacy data with patient safety. J Low Genit Tract Dis 2002; 6: 206–211. 22. Petry KU, Breugelmans JG, Benard S et al. Cost of screening and treatment of cervical dyskaryosis in Germany. Eur J Gynaecol Oncol 2008; 29: 345–349. 23. TOMBOLA group et al. Options for managing low grade cervical abnormalities detected at screening: cost effectiveness study. BMJ 2009; 339. b2549. 24. Bigrigg A, Haffenden DK, Sheehan AL et al. Efficacy and safety of the large-loop excision of the transformation zone. Lancet 1994; 343: 32–34. 25. Kennedy AW, Belinson JL, Wirth S et al. The role of the loop electrosurgical excision procedure in the diagnosis and management of early invasive cervical cancer. Int J Gynecol Cancer 1995; 5: 117–120. 26. Prendiville W, Cullimore J & Norman S. Large loop excision of the transformation zone (LLETZ). A new method of management for women with cervical neoplasia. Br J Obstet Gynaecol 1989; 96: 1054. 27. Mathevet P, Dargent D, Roy M et al. A randomized prospective study comparing three techniques of conization: cold knife, laser, and LEEP. Gynecol Oncol 1994; 54: 175–179. 28. Oyesanya OA, Amerasinghe CN & Manning EAD. Outpatient excisional management of cervical intraepithelial neoplasia. Am J Obstet Gynecol 1993; 168: 485–488. *29. Melnikow J, McGahan C, Sawaya GF et al. Cervical intraepithelial neoplasia outcomes after treatment: long-term follow-up from the British Columbia Cohort Study. J Natl Cancer Inst 2009; 101: 721–728. 30. Nobbenhuis MA, Meijer CJ, van den Brule AJ et al. Addition of high-risk HPV testing improves the current guidelines on follow-up after treatment for cervical intraepithelial neoplasia. Br J Cancer 2001; 84: 796–801. 31. Arbyn M, Ronco G, Meijer CJ et al. Trials comparing cytology with human papillomavirus screening. Lancet Oncol 2009; 10: 935–936. 32. Meijer CJ, Berkhof J, Castle PE et al. Guidelines for human papillomavirus DNA test requirements for primary cervical cancer screening in women 30 years and older. Int J Cancer 2009; 124: 516–520. 33. Chan BK, Melnikow J, Slee CA et al. Posttreatment human papillomavirus testing for recurrent cervical intraepithelial neoplasia: a systematic review. Am J Obstet Gynecol 2009; 200: 422–429. 34. Kitchener HC, Walker PG, Nelson L et al. HPV testing as an adjunct to cytology in the follow up of women treated for cervical intraepithelial neoplasia. BJOG 2008; 115: 1001–1007. 35. Alvarez RD, Helm CW, Edwards RP et al. Prospective randomized trial of LLETZ versus laser ablation in patients with cervical intraepithelial neoplasia. Gynecol Oncol 1994; 52: 175–179. 36. Petry KU, Glaubitz M, Maschek H et al. Electrosurgical loop excision of the transformation zone in treatment of cervix neoplasia [In German]. Geburtshilfe Frauenheilkd 1996; 56: 513–516. 37. Carreon JD, Sherman ME, Guillen D et al. CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples. Int J Gynecol Pathol 2007; 26: 441–446. 38. van Seters M, van Beurden M, ten Kate FJ et al. Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med 2008; 358: 1465–1473. 39. Khan MJ, Castle PE, Lorincz A et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-Specific HPV testing in clinical practice. J Natl Cancer Inst 2005; 97: 1072–1079. *40. Kjaer SK, Hogdall E, Frederiksen K et al. The absolute risk of cervical abnormalities in high-risk human papillomaviruspositive, cytologically normal women over a 10-year period. Cancer Res 2006; 66: 10630–10636. 41. Massad LS, Jeronimo J, Katki HA et al. The accuracy of colposcopic grading for detection of high-grade cervical intraepithelial neoplasia. J Low Genit Tract Dis 2009; 13: 137–144. 42. Fanning J & Padratzik J. Cold knife conization vs. LEEP. Are they the same procedure? J Reprod Med 2002; 47: 33–35. 43. Founta C, Arbyn M, Valasoulis G et al. Proportion of excision and cervical healing after large loop excision of the transformation zone for cervical intraepithelial neoplasia. BJOG 2010; 117: 1468–1474.
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Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
8
Management options for cervical intraepithelial neoplasia Karl U. Petry, MD, Professor, Head of Department of Obstetrics Gynaecology and Gynaecologic Oncology * Klinikum Wolfsburg, Sauerbruchstr. 7, 38440 Wolfsburg, Germany
Keywords: CIN colposcopy management cervical transformation zone HPV-testing LLETZ conisation
Management of cervical intraepithelial neoplasia (CIN) needs to protect women at risk from developing cervical cancer and to avoid over-treatment as well as obstetrical complications in women undergoing invasive treatment. Strong evidence shows that CIN3 is a true precursor and must be treated, whereas CIN1 lesions do not benefit from immediate surgery and should be followed conservatively. Although the clinical course of CIN2 differs from CIN3, it should be treated the same way for legal reasons. Colposcopy plays a central role in selection of patients and treatments. Treatment of CIN2 and 3 should be excisional. Large loop excision of the transformation zone, high-frequency-needle or laser conisation are equally good, whereas cold-knife conisation is associated with an excess risk for subsequent obstetrical complications. Human papillomavirus testing and cytology at 6 months seems to be the best post-treatment monitoring, although this needs to be confirmed by randomised-controlled trials. Future research needs to focus more on how the quality of colposcopy and the overall management concept determines the clinical outcome instead of exploring the role of single technical methods. Furthermore, it seems to be necessary to evaluate the best management of CIN2 in young and in vaccinated women. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction The major ethical and medical aim of all management options for cervical intraepithelial neoplasia (CIN) is the prevention of cervical cancer. The second most important aim is to achieve this with as little harm to the woman as possible. Finally, management of CIN should be cost-efficient without
* Klinikum der Stadt Wolfsburg, Department of Obstetrics, Gynaecology and Gynaecologic Oncology, Sauerbruchstr. 7, 38440 Wolfsburg, Germany. Tel.: þ49 5361 801270; Fax: þ49 5361 801613. E-mail address: [email protected]. 1521-6934/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpobgyn.2011.04.007
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compromising any of its two major aims. As only a minority of CIN will progress to cervical cancer, and because any kind of invasive treatment is associated with adverse events, good management of CIN is based on a good selection of women who are really in danger of developing cervical cancer and need to be treated, compared with those who are not at risk of cancer and should be protected from over-treatment. With the deep understanding of the human papillomavirus (HPV)-dependant genesis of cervical cancer, we are able to calculate risks of progression of CIN quite accurately, and have learned about minimum periods for each step of cervical carcinogenesis. One important principle, however, in the management of CIN is over-treatment. We know that, even with the best available selection, we will treat CIN lesions that would never progress to cancer, and this is acceptable as long as it is not excessive over-treatment. State-of-the-art treatment of CIN has moderate side-effects, whereas cervical cancer is a deadly malignant disease. Selection of women in need of protection from cervical cancer depends mainly on the grade of CIN, the type of the transformation zone, and age of the woman. It is well-established that persistent infection of certain HPV is an essential precondition in the genesis of cervical cancer. Virtually all primary cervical cancers contain HPV DNA. HPV-induced carcinogenesis, however, is a rather slow process, with at least four important steps: incident infection with a high-risk HPV-type; establishment of a persistent HPV infection; transformation of human keratinocytes in pre-invasive neoplastic cells; and malignant transformation of intraepithelial neoplasia into invasive cancer. The process is reversible at any pre-invasive stage. Most genital HPV infections are transient, and more than 90% will be cleared spontaneously within 18 months in young women.1 Persistent HPV infections and low-grade intraepithelial neoplasia will regress without any treatment within 2–5 years in 60–80% of all cases. Spontaneous resolution is observed in at least 40% of lesions with biopsy-proven moderate dysplasia (cervical intraepithelial neoplasia grade II). Only a 20% minority of CIN2 will progress to CIN3, and less than 5% to invasive cancer.25 It is quite obvious that the morphology-based grading of pre-invasive cervical neoplasia does not always reflect the risk of progression to invasive disease. We have learned from observational studies and from large randomised-controlled HPV vaccine trials that, in young, HPV-naive women at baseline, incident HPV infections may be associated with CIN1 and even CIN2 within a few months.6,7 Although these lesions cannot be distinguished by cyto- or histomorphology from persisting CIN1 or CIN2, the clinical course seems to be different, with a much higher likelihood of regression. Although the natural history of CIN2 resembles that of low-grade lesions in most cases, it is regarded as a high-grade lesion in most clinical management guidelines for legal reasons. There is sufficient evidence that CIN3 is a true precursor of cervical cancer. At the National Women’s Hospital, Auckland, New Zealand, treatment of CIN3 was withheld from a substantial number of women between 1965 and 1974 as part of an unethical clinical study. During long-term follow up, 31.3% of women managed with punch biopsies only developed invasive cancer. In the subset of 92 such women who had persistent disease within 24 months after biopsy-proven CIN3, invasive disease occurred even in 50.3% (37.3–64.9).8 Principles, outcomes and standards of observational management Excisional treatment of CIN is associated with a significantly increased risk of preterm delivery, late miscarriage, and perinatal mortality in subsequent pregnancies.9,10 Therefore, it should be used only in well-selected women with a clear indication for invasive treatment. As pointed out, CIN1 is common, especially in adolescents and young women. In many cases, these lesions are just cellular changes of self-limiting, permissive HPV infections with a high rate of spontaneous regression. Even in persisting CIN1, the risk of progression is low, and most of these lesions will finally undergo spontaneous regression.3 The European guidelines and the 2006 American Society for Colposcopy and Cervical Pathology (ASCCP) consensus guidelines recommend observational management in women with CIN1.1113 Compared with the 2001 ASCCP guidelines, cytological follow up became the only recommended management option in the 2006 recommendations, regardless of whether the colposcopic examination is satisfactory, for women with CIN1 who have a low-grade referral cervical cytology. Treatment of CIN1 is particularly discouraged in adolescents. For the management of CIN, it is important that cytologic low-grade squamous intraepithelial lesion (LSIL) is not equivalent to histologic CIN1 and cytologic high-grade squamous intraepithelial lesion
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(HSIL) is not equivalent to histologic CIN2 and 3. Because the prevalence of CIN2 or greater was 12–16% at initial colposcopy among women with LSIL in randomised-controlled trials (RCTs),14,15 the ASCCP guidelines recommend colposcopy for managing all women with LSIL, with the exception of adolescents who should be followed with annual Pap smears. This recommendation, however, is questioned by the results of a large RCT in the UK. The Trial of Management of Borderline and Other Low Grade Abnormal Smears (TOMBOLA) compared cytological surveillance with immediate referral to colposcopy in the management of women with low-grade cervical abnormality in 4439 eligible women. Immediate referral to colposcopy detected more CIN2 or greater lesions at baseline, but the trial found no significant difference in the cumulative incidence during 3 years’ follow up. Immediate colposcopy, however, resulted in a large number of referrals of women with no relevant cervical disease.16 Although HPV testing proved to be efficient in the triage of ASCUS/borderline cytology, HPV testing is of little use in LSIL cytology because about 80% will be associated with HPV.14,17 From the view of a colposcopy clinic, women transferred because of borderline or LSIL cytology should undergo colposcopic assessment with biopsies. The TOMBOLA trials could show, with a high level of evidence, that immediate large loop excision of the transformation zone (LLETZ) will not increase the rate of CIN2 or CIN3 compared with targeted punch biopsies by experienced colposcopist, but results in over-treatment and unnecessary morbidity in healthy women.18 Another RCT in Canada and Brazil compared immediate LLETZ and expectant management in women with biopsy-proven CIN1. No significant difference was found in the risk of progression to CIN2 or 3 between the two study arms. The authors concluded that expectant management of biopsy-proven CIN1 up to 18 months is a reasonable management strategy.19 Both RCTs support the broad consensus that, in women with biopsy-proven CIN1 and satisfactory colposcopy, invasive treatment is not indicated. These women should be followed with intensified screening. Because the risk of underlying high-grade disease is low, even in women with LSIL and unsatisfactory colposcopy, most guidelines also recommend observational management in these cases.20 Graphic 1 summarizes the management options of LSIL (Graphic 1 near). However, in women referred to colposcopy because of HSIL cytology, who receive a histologic diagnosis of CIN1 in corresponding targeted biopsies, most guidelines recommend a diagnostic excision of the transformation zone because the risk of underlying high-grade disease is high. In women younger than 25 years, the incidence of invasive cervical cancer is low, whereas the rates of HPV infections, CIN1 and CIN2 are high.6 As most of these lesions will regress spontaneously, many national screening programmes recommend screening only in women who are 25 years or older to protect younger women from over-treatment. In countries with an earlier start of screening, this should be kept in mind. The 2006 ASCCP guidelines encouraged expectant management of CIN2/3 in adolescents. In our own experience, expectant management of biopsy-confirmed CIN2 in women with satisfactory colposcopy is safe and avoids over-treatment in women younger than 30 years. HPVgenotyping seems to be useful in predicting the clinical course of CIN2. Although CIN2 lesions associated with HPV16 carry a high risk of progression, most CIN2 associated with other HPV types will regress spontaneously.3,5 Expectant management of CIN2 outside of trials, however, should be restricted to women younger than 25 years with a good compliance, and the follow-up should be controlled by an experienced colposcopy clinic. During pregnancy, invasive treatment of any grade of CIN should be postponed until 2 months after delivery. Invasive disease must be excluded by colposcopy. If biopsies need to be taken at the 18th week of gestation or later in pregnancy, loop biopsies are more appropriate than standard punch biopsies to obtain a histological specimen with sufficient stroma. When invasive cancer can be excluded with high reliability, the remaining risk for CIN3 lesions to progress to malignancy during pregnancy is small, whereas the fetal and maternal risks related to invasive treatment of the cervix are high, and complete excision of lesions cannot be achieved in almost half of the cases.21 Principles, standards and outcomes of surgical treatment modalities Surgical treatment of CIN3 is the accepted treatment standard worldwide. Conisation and LLETZ are the most common surgical methods. In many countries, invasive treatment is obligatory for CIN3 and CIN2, although the risk of progression to invasive disease is low in CIN2, and many CIN2 lesions will regress spontaneously in younger women.
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The primary goal in the management of CIN2 and 3 is to prevent the development of invasive cancer by complete surgical destruction of all neoplastic tissue. To achieve this with as little loss of cervical function as possible is an important secondary goal. The healthy uterine cervix protects the uterine and abdominal cavities from ascending infections and plays an important role in the regulation of fertility and during pregnancy. As the mean age of women with CIN3 is about 31–34 years in most populations, destructive treatment of the cervix may affect fertility and increase significantly the number of late miscarriages, premature labour, preterm delivery, and perinatal mortality in subsequent pregnancies. This high risk of obstetrical complications after invasive treatment of the uterine cervix was confirmed by two meta-analyses.9,10 Colposcopy is the single method of identifying the exact topography of cervical lesions, and thus plays a crucial role in selecting the appropriate surgical treatment of individual CIN3. The target host cells of primary HPV infection are the basal cells that are exposed superficially at the squamocolumnar junction. Furthermore, it seems to be one peculiarity of the cervical transformation zone that its metaplasia cells are especially prone to oncogenic transformation induced by HPV because these cells need to provide different pathways of cell differentiation. This explains the well-known observation that almost all high-grade cervical lesions are located within the cervical transformation zone, whereas vaginal intraepithelial neoplasia is rare, although vagina and uterine cervix are exposed to HPV at a similar rate. To achieve high cure rates in the treatment of premalignant disease of the cervix, it is necessary to destroy the complete transformation zone and any neighbouring lesions. As the extension of individual CIN3 lesions and transformation zones differ significantly, colposcopically guided surgical treatment will remove neoplastic tissue with high accuracy and avoid unnecessary destruction of neighbouring healthy tissue. It seems to be a matter of course for Anglo-Saxon countries that colposcopy plays a central role in the management of atypical screening results and guidance of invasive treatment, but this is not reality in many other countries. A retrospective nationwide study in Germany found that more than 90% of women who were treated because of LSIL or HSIL smears never had colposcopy assessment and underwent directly diagnostic cold-knife biopsy or even hysterectomy. This management resulted in significant over-treatment and increased costs.22 This is in line with the TOMBOLA evaluation that colposcopic evaluation of LSIL smears are cost efficient.23 Any method of treating CIN 3 carries a small risk of subsequent development of invasive cancer. This event seems to occur less frequently after excisional treatment with cold-knife-, needle-, laser-cone biopsy or LLETZ than after destructive treatment using laser vaporisation, electrocoagulation diathermy, cryotherapy or cold coagulation. Therefore, and because of the better histological evaluation, excisional methods are the standard treatment for CIN.24,25 The use of destructive techniques should only be applied for extended and multifocal lesions. No single excisional method could ever prove superior cure rates in randomised, multicentre trials, and the multiple smaller observational or single-centre studies differ significantly in study design and do not allow for a general recommendation of one method of surgical treatment of CIN3. It is possible, however, to recommend the best surgical method for each individual CIN3 based on the colposcopical categorisation of the transformation zone and the evidence-based risk–benefit profile of available surgical methods. Surgical treatment of CIN requires the complete removal of the transformation zone. The International Federation for Colposcopy and Cervical Pathology defined three different types of TZ: Type 1 The complete TZ is located on the ectocervix Type 2 The TZ extends into the endocervical canal but the upper border/Squamous columnar junction is visible on colposcopy Type 3 The TZ extends into the endocervix and the upper border is not visible on colposcopy In all types of transformation zone, the ectocervical or vaginal border of the lesion, and in types 1 and 2, even the endocervical extension can be identified by colposcopy. To achieve a full thickness resection of a type 1 transformation zone with clear basal margins, the cutting depth for the external orifice must be 8 mm, whereas 5 mm may be sufficient for the periphery of the transformation zone. LLETZ26 is the best suited treatment for CIN located in transformation zone type 1 and 2. The loops are tailored for an optimal bowl-like resection of the transformation zone. The size of the transformation identified on colposcopy determines the size of the loop. The cutting effect is achieved by
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light arches that spark between the 0.2-mm thin wire and the tissue. Modern high-frequency (HF-) generators regulate electronically the needed optimal cutting currency. Properly performed LLETZ causes only minimal thermonecrosis that marks the definite surgical resection margin. The obtained samples allow a full histopathological review. The outpatient procedure is safe, easy, can be carried out under local anaesthesia, and causes little bleeding and complications. Haemostasis can be achieved easily by application of Monsell’s solution. Transformation zone types 1 and 2, with minimal extension to the endocervix, can be resected completely with a loop in one piece, and the treated cervix will heal without significant scarring or deformations in most cases (see Picture 1 near). Transformation zone type 2 that extends 7–10 mm into the endocervix may require a second resection of the adjacent canal with a smaller loop to achieve clear endocervical margins. For a complete excision of type 3 transformation zones,the relatively flat ectocervical transformation zone with a maximum depth of 7–8 mm and the involved endocervical canal must be resected. The shape of the correctly removed sample resembles a hat or an Indian pagoda more than a true cone. Although a complete resection can be achieved with all excisional methods, LLETZ with additional loop resection of the endocervical canal and laser or HF-needle conisation seem to be the best suited methods of treatment. Cold-knife conisation of type 3 transformation zone has the disadvantages that it should be done under general anaesthesia, is an inpatient procedure and causes significantly more bleeding and scarring (Picture 2 near) than laser or needle conisation.27,28 Loops are not designed for an optimal removal of type 3 transformation zone. Either large loops with 20–25 mm diameter need to be used, which will unnecessarily remove uninvolved tissue of the cervical stroma in some cases or the excision will be carried out in multiple pieces. A histological evaluation of such specimens may be difficult. Furthermore, deep endocervical resection may cause reasonable bleeding, and precise cutting with a loop will be not possible in some circumstances. Laser and needle conisation are outpatient treatments, and may be carried out under local anaesthesia and colposcopic guidance. The cones obtained show as little thermonecrosis as LLETZ and do not disturb histological assessment. As the equipment for HF-needle conisation is much cheaper than for laser conisation, it is likely that this method will replace laser conisation as treatment of CIN3 located in type 3 transformation zone. However, needle and laser need intensive training, especially when the laser is used with a micromanipulator under colposcopy guidance. LLETZ with separate endocervical resection is much easier to carry out, and therefore loop resection is already the standard treatment of CIN in many places. After resection of the transformation zone by any of the above mentioned excisional and destructive methods, residual endocervical disease needs to be excluded either by endocervical curettage or brush.
Picture 1. Visible squamous columnar junction 6 months after large loop excision of the transformation zone.
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Picture 2. Scarring and deformation of the uterine cervix 6 months after cold knife conisation.
Haemostasis can be achieved by application of Monsell’s solution onto the wound surface. Graphic 2 shows our proposed management of CIN3 (Graphic 2 near) Monitoring success of treating cervical intraepithelial neoplasia A large population-based cohort study with more than 300,000 observation years in women treated for CIN 1, 2 and 3 in British Columbia showed that the risk of recurrent CIN 2/3 was significantly increased in the first 6 years after invasive treatment, with a peak in the first 2 years.29 This is best explained with residual disease that was detected in the first 2 years and an elevated risk for the development of new CIN2/3 lesions because of persistent HPV infections. All guidelines pay attention to the high risk of residual or recurrent disease after invasive treatment of CIN. Three different followup methods can confirm cure of CIN: colposcopy, cytology and HPV testing.12,13 Because colposcopy follow up is the most expensive, it is usually only indicated in women with a high risk of recurrence, especially in women with involvement of the endocervical resection margin, positive endocervical curettage, or both, as well as in women with atypical findings during follow up. Cytology-based follow
LSIL
Observation with cytologyfor 3 years
Colposcopy
CIN 1
Observation for 18 months
Graphic 1. Evidence-based management of low-grade squamous intraepithelial lesion smears and cervical intraepithelial neoplasia 1. CIN, cervical intraepithelial neoplasia; LSIL, low-grade squamous intraepithelial lesion.
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Graphic 2. Proposed management of high-grade squamous intraepithelial lesionand cervical intraepithelial neoplasia 3. CIN, cervical intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesion; LLETZ, large loop excision of the transformation zone.
up was the standard in all other women after treatment of CIN. During the past decade, a number of studies have evaluated a possible role of HPV testing in this setting. An early trial from the Netherlands found that HPV testing was more predictive for recurrent CIN2/3 than cytology, with similar specificity for both methods. The negative predictive value in negative HPV and Pap smears in women 6 months after invasive treatment was 99% and improved current guidelines.30 Although recommendations for a possible role of primary HPV screening for cervical cancer in women who are 30 years or older are based on eight large RCTs with a high level of evidence,31 and the efficacy of HPV in well-defined triage settings was also confirmed by RCTs,17 HPV testing in the monitoring of women after treatment of CIN was so far only evaluated in cohort studies. Another problem with studies in this setting is the use of different HPV tests, especially the use of non-validated, sometimes home-brewed polymerase chain reaction tests. Therefore trials evaluating HPV testing need to use either Hybrid Capture 2 or validated polymerase chain reaction tests, such asGP5þ/GP6þ.32 One meta-analysis evaluated post-treatment HPV testing for recurrent CIN. Hybrid Capture 2 testing identified 91% of women with residual or recurrent disease but was associated with a 30% referral rate to colposcopy.33 In a UK-based multicentre trial, 917 women who underwent invasive treatment of CIN1, 2 or 3 were followed with cytology and HPV testing at 6 and 12 months. A total of 14.6% had positive HPV results and 10.7% non-negative cytology. Nine out of 10 cases of recurrent CIN3 and ACIS occurred in women with positive HPV, and the investigators concluded that women who are HPV-negative and cytology-negative 6 months after treatment can safely be returned to routine screening.34 These findings are in line with the early Dutch trial and our own experience, but a confirmation by RCTs is still needed for recommendations based on a high level of evidence. Comparative efficacy and safety of different surgical treatment methods for cervical intraepithelial neoplasia As previously highlighted, evidence is lacking to recommend the superiority of any one excisional treatment modality over another in achieving better cure rates. A number of studies have attempted to answer this question, but these trials cannot be compared because of different definitions of ‘cure’ and differences in carrying out invasive treatment methods. In some studies, the procedures were carried out without any colposcopy assessment, whereas other trials carried out the invasive treatment under colposcopic guidance. The British Columbia study found the best cure rates in women treated with cone biopsies, followed by LLETZ, laser and finally cryotherapy. This analysis, however, is based on patient data from 1984–2000, most CIN2 and CIN3 were treated with destructive methods, and LLETZ forms the smallest group, because it was introduced into clinical practice in the second half of the observation period and may reflect the learning curve.29 From these data it can be concluded that destructive methods, especially cryotherapy, carry a significantly greater risk of residual and recurrent CIN2 and 3. Furthermore, women treated with cryotherapy showed a three-fold increased risk for
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subsequent invasive cervical cancers compared with all other treatment methods. Another important finding of the study was the four-fold increased risk of cervical cancer in women treated for CIN3 compared with women who underwent treatment of CIN1 and 2 and an increased risk for recurrent CIN2 and 3.29 Once again, this study showed that CIN3 and CIN2 are lesions with different biology, and the artificial category CIN2/3 may be useful in clinical practice but is a handicap for sound scientific evaluation. Therefore, clinical trials that evaluate the outcomes of different treatment methods cannot be compared unless they distinguish between CIN2 and CIN3 If treatment failure is defined as detection of CIN2 or greater within 12 months after invasive therapy, cure rates of 95% or more can be achieved with all excisional and destructive treatment modalities carried out under colposcopc surveillance. Strong evidence, however, suggests that cold-knife conisation is inferior to all other treatment modalities in treatment-related morbidity and cost efficiency. Apart from the already mentioned disadvantages, cold-knife conisation was associated with the highest rates of complications in subsequent pregnancies. Two different meta-analyses found significantly elevated risks for preterm delivery before 28 weeks of gestation (RR 5.33), preterm delivery before 37 weeks of gestation (RR 2.59) and perinatal mortality (RR 2.87) in women with a history of cold-knife conisation.9,10,35,36 Laser conisation and LLETZ were also associated with increased risks for preterm delivery but not as strong as cold-knife conisation. Laser vaporisation and cryotherapy did not result in any increase in obstetrical complications. Although sufficient evidence supports a ban of cold-knife conisation as an inferior treatment method for use in the treatment of CIN, questions remain about the overall performance of laser- and HF-needle conisation, LLETZ and destructive methods. It would be premature to conclude that laser vaporisation is superior to LLETZ and laser conisation in associated morbidity. Although this hypothesis needs to be confirmed, it seems likely that the amount of removed cervical tissue, especially stroma tissue, may show a correlation with subsequent obstetrical complications. As laser vaporisation was almost exclusively used for the treatment of atypical transformation zones of type 1 and 2, it destroys only a small amount of stroma tissue, whereas laser conisation as a preferred treatment method for type 3 transformation zones must result in more significant destruction. This would mean that the estimated extension of lesions and transformation zone could have a greater effect on associated morbidity than the treatment modality itself. Current data and studies in progress on these issues Several hot topics in this field that need further research. Do we really need to treat all cervical intraepithelial neoplasia 2 with surgery? The natural course of most CIN2 lesions resembles the course of low-grade lesions and not CIN3.2 Furthermore CIN2 lesions show poor reproducibility.37 An important risk factor of progression of CIN2 to CIN3 is HPV type 16.3 Therefore, it is likely that CIN2 lesions diagnosed in vaccinated women will have a low risk of progression. Further research is needed to discriminate CIN2 in need of treatment from those CIN2 that will undergo spontaneous regression. Imiquimod, an immune-response modulator (IRM) has proved to be an effective topical treatment in VIN2 and 3.38 Some promising IRM candidates and therapeutic HPV vaccines are in the pipeline for the treatment of CIN. When should we treat cervical intraepithelial neoplasia 1? CIN1 should not undergo invasive treatment – but for how long? Of course, the few progressing lesions need to be treated and a large number will regress spontaneously, but what should be done with persisting CIN1? Is it cost-efficient to follow these women with intensified screening for many years? What subgroups benefit from invasive treatment and can we apply destructive methods in these women to avoid unnecessary morbidity?
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What will be the best management of cervical intraepithelial neoplasia in vaccinated women? Within a few years, vaccinated women will enter screening programs. HPV 16/18 infections are associated with the highest risk for development of CIN3 and cancer compared with all other so called ‘high-risk’ HPV-types.39,40 In large, RCTs, HPV vaccination offered almost complete protection from HPV 16/18 infections and associated lesion in the per protocol populations.6,7 In these women, the most important driving force of progression of CIN will be missing, and it is likely that expectant management or non-invasive treatment with new drugs will become the new standard in CIN1/2 and may be even women with CIN3. Colposcopic findings might change too. The typical intense acetowhite reaction of high-grade CIN seems to be most common in lesions associated with HPV 16. Therefore, colposcopy assessment of cervical lesions may need a revision in vaccinated women. What is the best treatment modality for cervical intraepithelial neoplasia? So far, research on this question has paid too much attention to the technical methods instead of the overall management concepts. It is interesting that, with a high level of evidence, two methods were identified to be worse than others. Cryotherapy shows the highest risk of subsequent development of invasive cancer, and cold-knife biopsies are associated with the highest rate of obstetrical complications. Both methods are widely used by medical personel without specific expertise in the management of CIN and, in many cases, without colposcopy. It is likely that the quality of colposcopy is the most important factor in determining the quality of indications for treatment and for quality of treatment success. Any research into this matter is flawed by the fact that colposcopy still is a medical art and its quality depends on individual skills. Research is needed to explain why colposcopically guided punch biopsies show a poor correlation with underlying disease in some studies,41 whereas colposcopy was as good and cost-efficient in detecting CIN3 as immediate LLETZ in the TOMBOLA studies.16,18 Standards in training and independent quality control of those who practice colposcopy are strongly needed. Similarly, it needs to be evaluated if the observed obstetrical complications associated with invasive treatment of CIN are attributable to the technical methods or depend on the excised tissue volume irrespective of the used method.42 One prospective trial using magnetic resonance tomography to calculate the loss of tissue is already under way, but results are still pending.43 What is the best post-treatment monitoring? HPV and cytology testing after 6 months seems to be the most promising post-treatment monitoring but still lacks confirmation by RCTs. Conclusion On the basis of current evidence, observational management seems to be appropriate in women with cytologic LSIL, and is the recommended standard of care for women with cytologic LSIL and biopsy proven CIN1 on colposcopy, irrespective if colposcopy is considered satisfactory or not. CIN3 as a true precursor lesion with a high risk of malignant progression must be treated. Although the corresponding risk of malignant progression is lower in CIN2, and the reproducibility of these lesions is poor, it is recommended that CIN2 is treated the same way as CIN3 for legal reasons. Excision of the transformation zone under colposcopic guidance is state-of-the-art treatment, whereas destructive treatment of CIN, especially cryotherapy, is associated with an increased risk of subsequent invasive cervical cancer. On the basis of sufficient evidence, the use of cold-knife conisation should be discouraged because this method is associated with an increased rate of severe bleeding and severe obstetrical complications and cannot be used under colposcopic guidance. Furthermore, as an inpatient procedure, it is not cost efficient compared with other methods. LLETZ and HF-needle or laser conisation are recommended methods of similar efficacy. For technical reasons, we favour the use of LLETZ when CIN2 and 3 is located in type 1 or 2 transformation zones and prefer laser or HF-needle conisation for the resection of type 3 transformation zones.
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Post-treatment monitoring of success with cytology and HPV-testing after 6 months seems to be efficient in women with low to moderate risk of residual or recurrent disease, whereas women who are at high risk benefit from colposcopic follow up. Future research will evaluate a possible role of adjunct tests to identify CIN2 that may benefit from expectant management and CIN1 that should be treated. Prospective trials will clarify if obstetrical complications are linked to specific treatment techniques or explained by loss of cervical tissue volume. Other issues will be the influence of HPV vaccination on the management of CIN, drugs for immune therapy of CIN, and confirmation of the most efficient concept to prove post-treatment success.
Practice points LLETZ and laser conisation show the best balance of efficacy and safety in the treatment of CIN2þ. Cold-knife conisation increases the risk for obstetrical complications significantly and should no longer be used. LSIL results and biopsy proven CIN1 in women with LSIL should be managed expectantly. With the exception of HSIL findings, atypical cytology results should not undergo immediate surgical treatment. A combination of cytology and HPV testing at least 6 months after treatment of CIN2þ is the most efficient proof of cure.
Research agenda Effectiveness of treatment of CIN with new drugs. Effectiveness of HPV genotyping and molecular markers in developing better individualised treatment strategies for women with CIN 1 and CIN2. Best management strategies in vaccinated women with CIN. Effectiveness of colposcopy guidance to minimise obstetrical complications. Effectiveness of HPV post-treatment monitoring in RCTs.
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