Journal of the National Cancer Institute Advance Access originally published online on May 12, 2009
JNCI Journal of the National Cancer Institute 2009 101(10):696-697; doi:10.1093/jnci/djp097
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© The Author 2009. Published by Oxford University Press.
EDITORIALS |
Women With Cervical Intraepithelial Neoplasia: Requirement for Active Long-Term Surveillance After Therapy
Affiliation of author: Department of Pathology, University of Florida College of Medicine, Gainesville, FL
Correspondence to: Edward J. Wilkinson, MD, Department of Pathology, University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL 32610-0275 (e-mail: wilkinso{at}pathology.ufl.edu).
In this issue of the Journal, Melnikow et al. (1) present a retrospective long-term follow-up analysis of 37 142 women who were treated for cervical intraepithelial neoplasia (CIN) 1, 2, and 3 from 1986 through 2000 and were under active surveillance after therapy through 2004. These women were compared with a cohort of women with no previous diagnosis of CIN who were under active surveillance.
This retrospective long-term follow-up study demonstrates that our screening methods are not as sensitive as we might hope and that high-grade CIN (ie, CIN 2 or 3 [CIN 2/3]) and/or cervical carcinoma can elude active surveillance methods. Results of this study also support evidence that active surveillance has value in identifying the majority of the high-grade CIN lesions and cervical carcinomas and that the majority of cervical carcinomas can be identified at an early stage. These data also support a recent study (2) and current American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines (3,4) that women with a previous diagnosis of CIN have an increased risk of subsequent high-grade CIN and cervical carcinoma and require continued surveillance and follow-up for 20 years or more.
There is some debate as to what methods of follow-up are sufficiently sensitive and also acceptable to the woman being followed up. Data for this study were collected at a time when cytology, physical examination, and colposcopy were the main methods of surveillance. With the additional use of validated tests for oncogenic human papillomavirus in surveillance after therapy, as recommended in the ASCCP guidelines, the sensitivity of the testing for CIN after therapy should improve with persistent or recurrent CIN 2/3 being detected earlier, with greater reliability, and before the onset of invasive squamous carcinoma (3,4).
Melnikow et al. report several findings of special importance in the long-term management of women with CIN. The most clinically significant finding is that the risk of invasive carcinoma of the cervix in women who had been treated for CIN was markedly higher than that observed in the cohort of women who had not been diagnosed with CIN (the non-CIN cohort). The rate of cervical cancer in the CIN group was 37 cervical cancers per 100 000 women as compared with six cervical cancers per 100 000 women in the non-CIN group. These results support data from three large studies (2,5,6) that have reported a rate from 23 to 56 cervical cancers per 100 000 women. An increased rate of vaginal intraepithelial neoplasia and vaginal carcinoma has also been reported after treatment of CIN 3 (2). These lesions were not addressed in the analysis by Melnikow et al. Of the 145 women with cervical carcinoma that was diagnosed during follow-up, 112 (77.2%) had stage I disease; however, 10.3% had stage II disease, 3.5% had stage III disease, and 2.1% had stage IV disease. These observations of subsequent invasive cervical carcinoma may be conservative because women with histopathologically confirmed invasive cervical carcinoma within 6 months of the diagnosis of CIN were excluded from the study because the original CIN biopsy was thought to have missed the invasive carcinoma. The issues of identifying invasive carcinoma in women under active surveillance are also evident in the non-CIN cohort group, in which 49 invasive carcinomas were identified, including 34 (68.6%) with stage I disease, nine (19.6%) with stage II disease, no stage III disease, and one with stage IV disease.
The risk of CIN or invasive carcinoma after therapy for CIN was found to be age related, with the greatest risk being found in women aged 40 years or older. The risk of subsequent high-grade CIN or cervical carcinoma was lowest in women with CIN 1, greater in women with CIN 2, and highest in women with CIN 3.
The method of treatment of the CIN was also related to the risk of subsequent CIN or squamous cell carcinoma. Within the initial 6-year period of follow-up among women aged 30–39 years, the rate of CIN 2/3 after treatment for CIN 2 as compared with CIN 3 and expressed as the rate per 1000 women was 35.0 vs 62.9 for cone biopsy, 42.2 vs 95.8 for the loop electrosurgical excision procedure, 73 vs 130.1 for laser excision or ablation, and 134.1 vs 265.1 for cryotherapy. The higher rates of recurrence for the group treated with laser or cryotherapy vs the group treated with the loop electrosurgical excision procedure or cone biopsy could be related to a number of factors. With ablative techniques such as ablative laser therapy and cryotherapy, no histopathologic evaluation of the specimen or the specimen margins is possible after the procedure. In contrast with the loop electrosurgical excision procedure or cone biopsy, the excised specimen undergoes histopathologic evaluation, an evaluation that includes a determination of the grade of the CIN as well as assessment of specimen margins. In the study by Melnikow et al., the lower rate of recurrence observed with these two excisional procedures could be underestimated because women with involved margins, which reflect incomplete excisional procedures, were excluded from the analysis. Furthermore, it could not be determined with confidence whether the lesion and the transformation zone could be completely visualized before treatment in all women undergoing cryotherapy or laser ablation. In addition, the method of cryotherapy was not specifically studied, including the freeze technique used, the duration of the freeze, whether the freeze was single or double procedure, or the size of the "ice ball" peripheral to the probe that was considered to be adequate (7). It is possible that lesions treated by cryotherapy or laser ablation may have been undertreated or a more severe lesion or a lesion deeper in the stroma or higher in the endocervical canal may not have been identified. The reported findings related to methods of therapy confirm other recent studies (8,9), demonstrating higher rates of both CIN and cervical carcinoma in women after cryotherapy or laser ablation than in women after a loop electrosurgical excision procedure. A meta-analysis of randomized control trials in the treatment of CIN reported an up to 15% of recurrence rate of CIN but found no difference by treatment type. In that study, the mean follow-up was rather short, at only 12 months (10).
The majority of women who later were diagnosed with CIN, regardless of grade of the CIN at the time of therapy, had CIN 2/3 observed within 2 years of the index treatment. This relatively short interval suggests that in most women, the subsequent CIN lesion was probably persistent CIN 2/3 rather than a new lesion. For patients with cytology results of low-grade squamous intraepithelial lesion within the ALTS (ie, ASCUS-LSIL [atypical squamous cells of undetermined significance–low-grade squamous intraepithelial lesion triage study] trial, the rate of CIN 2/3 observed was 8%–13%, with a preceding biopsy of CIN 1 or negative. In many of these women, the CIN 2/3 was most probably present at the time of the initial evaluation but was too small to be detected (11). In this analysis by Melnikow et al., 5% of the women with CIN 1 were subsequently found to have CIN 2/3 within the initial 6 years of surveillance, with the majority being identified in the first 2 years of treatment. For example, among women aged 30–39 years, the estimated rate of CIN 2/3 per 1000 women with initial CIN 1 was greater in the laser excision or ablation and cryotherapy groups than in other treatment groups, with rates for cone biopsy being 33.1, for loop electrosurgical excision procedure being 27.4, for laser excision or ablation being 53.5, and for cryotherapy being 64.1 CIN 2/3 diagnosed per 1000 women. In the CIN 3 group, the possibility of a persistent lesion, rather than a true recurrence of a new lesion, is supported by the finding that the majority of women with lesions that were found during surveillance after therapy were found within the first 2 years after therapy. In this group, estimated rates of CIN 2/3 were considerably higher in the groups treated with laser excision or ablation or cryotherapy than in groups treated with the loop electrosurgical excision procedure or cone biopsy. For example, among women aged 30–39 years, the rate of CIN 2/3 per 1000 women with initial diagnosis of CIN 3 by cone biopsy was 62.9, by loop electrosurgical excision procedure was 95.8, by laser excision or ablation was 130.1, and by cryotherapy was 265.1.
These findings, however, must also be weighed against the cost advantages and relative ease of use of cryotherapy and the potential complications of excisional methods of therapy for CIN. These complications include an increased risk of hemorrhage after the excisional procedure and the recognized increased risks of preterm delivery and associated neonatal complications of prematurity and perinatal mortality (12,13).
In summary, this work provides evidence that women with CIN who have undergone treatment need long-term surveillance after their therapy and remain at some risk for CIN as well as for cervical carcinoma for 20 years or more. Factors that influence risk include the grade of the CIN, the treatment type, and the age of the patient at the time of treatment.
NOTES
E. J. Wilkinson is a consultant for Merck, Inc. in regard to their human papillomavirus vaccine and is a pathology consultant for Guided Theraputics (SpectRx).
REFERENCES
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2. Strander B, Andersson-Ellstrom A, Misom I, et al. Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study. BMJ (2007) 335(7629):1077.
3. Wright TC, Massad LC, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. J Lower Genital Tract Dis (2007) 11(4):223–239.[CrossRef]
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9. Dey P, Gibbs A, Arnold DF, Saleh N, Hirsch PJ, Woodman CBJ. Loop diathermy excision compared with cervical laser vaporization for the treatment of intraepithelial neoplasia: a randomized controlled trial. BJOG (2002) 109(4):381–385.[CrossRef][Web of Science][Medline]
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11. Cox JT, Schiffman M, Solomon D. Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grad 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol (2003) 188(6):1406–1412.[CrossRef][Web of Science][Medline]
12. Albrechtsen S, Rasmussen S, Thoresen S, Irgens LM, Iversen OE. Pregnancy outcome in women before and after cervical conisation: population based cohort study. BMJ (2008) 337. doi:10.1136/bmj-01343.
13. 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, doi:10.1136/bmj.A1284.
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