CLINICAL OBSTETRICS AND GYNECOLOGY Volume 57, Number 2, 302–315 r 2014, Lippincott Williams & Wilkins
Secondary Prevention of Cervical Cancer Part 3: Evidence-based Management of Women With Cervical Intraepithelial Neoplasia RICHARD GUIDO, MD,* NEAL M. LONKY, MD, MPH,w and JUSTIN DIEDRICH, MDz *Magee-Womens Hospital of the UPMC System, University of Pittsburgh, Pittsburgh, Pennsylvania; w Southern California Permanente Medical Group, Department of Obstetrics and Gynecology, Kaiser Permanente, Anaheim, and Department of Obstetrics and Gynecology, University of California School of Medicine, Irvine, California; and z Washington University, St. Louis, St Louis, Missouri Abstract: The management of cervical intraepithelial neoplasia has evolved over the last 20 years. Observation has replaced aggressive therapy in many cases. Evidence based guidelines now guide therapy. This chapter presents an overview of various treatment options, as well as the most recent guidelines of therapy. Key words: cervical intraepithelial neoplasia, treatment guidelines
the precursors to cervical cancer. It has been through effective screening and early intervention of cervical dysplasia that there was a dramatic fall in the number of cervical cancer cases in developed countries. In the United States, cervical cancer incidence fell from second to ninth among cancers in women.1 A good understanding of the natural history of HPV and its role in cervical cancer has not only resulted in a reduction of cervical cancer cases but, over the last 25 years, resulted in a move to less intervention in the management of lesion of the cervix that are representative of HPV infection and will ultimately not lead to cervical cancer. This shift is reflected in the management guidelines that were
Introduction Much has been learned over the past 50 years about human papillomavirus (HPV), its role in cervical cancer, and Correspondence: Richard Guido, MD, Magee-Womens Hospital of the UPMC System, University of Pittsburgh, Pittsburgh, PA. E-mail: rguido@mail. magee.edu Richard Guido is a board member for ASCCP. The other authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
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Management of Cervical Intraepithelial Neoplasia developed in the most recent ASCCP consensus guidelines.2 This chapter covers the various recommendations for the management of histologically confirmed cervical dysplasia of the cervix as recommended by the ASCCP.
Promoting Healthy Habits Managing any women with a health condition is best achieved by improving the women’s knowledge of the underlying condition and promoting good health habits related to that condition. HPV-related diseases of the lower genital tract are no different. It is well established that the immune response to HPV is critical for eliminating or reducing the burden of the disease. Women who smoke have been found to have a relative risk (RR) of 1.60 [95% confidence interval (CI), 1.48-1.73] of developing cervical cancer as compared with those who have never have smoked.3 The mechanism of action of smoking is not proven, but it is likely that a combination of the direct carcinogenic effects of cotinine, nicotine, and nitrosamines and local immunosuppression manifest by decreasing density and function of Langerhans cells are both contributory.4–6 Smokers have a higher rate of recurrence than nonsmokers following therapy for cervical intraepithelial neoplasia (CIN). Therefore, it is very important to use the opportunity of HPV-related diseases of the lower genital tract as an opportunity to promote smoking cessation. Women who present for management of HPV-related diseases of the lower genital tract have been shown to successfully discontinue smoking at rates of 12% to 32%.7,8 There are numerous other potential healthy lifestyle changes that may have an impact on the immune system; however, none are as well associated with cervical dysplasia and cancer as smoking.
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well as CIN 2+ for special populations of women. The driving force for change has been a better understanding of the natural history of HPV infections and biopsyproven CIN. The decision of treatment versus observation is one that balances the benefits of treatment versus the risk associated with the various procedures used to treat cervical cancer. The majority of which are either ablative or excisional in nature. The benefits of therapy for CIN include a high rate of success of both ablative and excisional treatments. The quoted success rates of both type of therapies range from 90% to 95%.9 The downside of therapy includes the cost of the various procedures as well as the impact the treatments have on subsequent pregnancies. Although there is still some debate of the negative impact of treatment on pregnancy, the majority of evidence demonstrate that these interventions increase the rate of preterm labor, low birth weight infants, and an increase in the cesarean section rate. A large meta-analysis of 27 studies demonstrate that cold knife conization (CKC) is associated with an increase in the RR of preterm labor 2.59 (CI, 1.80-3.72) and low birth weight delivery 2.53 (CI, 1.19-5.36) as defined by a weight 5 mm and should be covered entirely by the cryoprobe. www.clinicalobgyn.com
In low resource setting cryotherapy has been used based on a positive screening test. The ability to quickly triage and treat in these setting outweight the potential for treating a small cancer. This use of cryotherapy is always performed in the setting of some visual inspection of the cervix with acetic acid application (VIA) or in the setting of a positive HPV test. The most recent WHO guidelines for the use of cryotherapy in the treatment of histologically confirmed CIN does comment that treatment in low resource setting can be conducted given the potential benefit of treatment versus no treatment.11 The WHO guidelines provide additional recommendation regarding the techniques used for cryotherpy. The double-freeze method of freezing for 3 minutes followed by a 5-mintue thaw, and a second 3-minute freeze is recommended. Carbon dioxide (CO2) gas is prefered to nitrous oxide (N2O). Prophylactic antibiotics are not required for cryotherapy, and alternative therapies are recommended in the setting of the lesion covering over 75% of the surface of the cervix. Cryotherapy should not be performed in the setting of invasive cervical cancer, pregnancy, a history of in utero DES exposure because of an increased risk of cervical stenosis, acute cervicitis, and disease extending into the cervical canal beyond 5 mm as demonstrated by colposcopy, or a postive ECC.
Laser Therapy Laser therapy of the cervix was very popular in its use before the advent of the LEEP procedure. It is best used today in the setting of lesions on the cervix that are not amenable to either cryotherapy or LEEP. Typically, these situation arise when the lesion on the cervix is large or the disease extends beyond the boundries of the cervix and on to the vagina.
Management of Cervical Intraepithelial Neoplasia The most common used laser for treatment of cervical dysplasia is the CO2 laser. This laser has unique properties that make it ideal for treating disease of the lower genital tract. The laser is easily adapted to a colposcope. This along with the ability to make the spot size of the laser vary from 1 to 10 mm, which allows for precise control of the areas of treatment. The laser is also a superficial laser and therfore has minimal impact on surrouding tissue. It can be used in the office and in the operating room. The laser is, however, expensive to acquire, require specially trained personal to safely operate, and often times represents a more costly method of treating cervical disease. The CO2 laser can be used as an excisional tool as well as an ablative tool. Treatment of cervical dysplasia by any method must treat to an adequate depth to eradicate the disease. CIN can extend into the underlying cervical crypts. Higher grade lesions [severe dysplasia and carcinoma in situ (CIS)] extend into cervical crypts up to 5.2 mm but, in most cases, crypt depth varies between 1.24 mm and 1.6 mm.12–14 In CIN 3 lesions (severe dysplasia/CIS) 85% to 95% will have some crypt extension.15 However, 96% of these cases have depth of disease extension of 100 mL or heavy bleeding requiring suturing, packing, or other procedures varied between 9.3% and 15% of all CKCs.25–30
Management of the Women With CIN Using Established Therapies The ASCCP Consensus Guidelines were updated in 2013. The guidelines
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incorporated risk assessment in determining the appropriate therapy for a given histologic diagnosis and incorporated the approach that when equal risk of CIN 3 exist, equal treatment will occur. The risk assessments were developed primarily from data generated by Kaiser Permanente of Northern California and summarized by a series of articles by Katki et al.31,32
CIN 1 Preceded by a ‘‘Lesser Abnormality’’ CIN 1 is a manifestation of HPV infection. The majority of CIN 1 lesions resolve spontaneously. The management of CIN 1 is driven by the preceding cytology. CIN 1 when preceded by a pap that is LSIL or ASC-US, HPV+ has a 5-year risk of CIN 3+ of 3.8%, whereas those with CIN 1 after HSIL had a 5-year risk of CIN 3+ of 15%.33 Because of this variation in risk, the management of women diagnosed following what is termed a ‘‘lesser abnormality’’ is to undergo a pap and HPV (cotesting) at 12 months. Those individuals who are HPVnegative and cytology negative can then return to screening at 3 years. Although routine screening for women over 30 years with a negative pap and HPV test can be 5 years, at the time of the consensus conference there was not enough data to allow women with biopsy-proven CIN 1 to be followed up 5 years later. Any abnormality in follow-up, either a pap that is Z ASC-US or a + HPV test will require a colposcopy. There are a few points of clarification with this recommendation. Because of the high rate of HPV present in women aged 25 to 29 years, the follow-up examination at 12 months will only include cytology. Recommendations differ for women ASC-H or HSIL
Manage per ASCCP Guideline for Women Ages 21-24 with ASC-H or HSIL using postcolposcopy path for No CIN2,3
Repeat Cytology @ 12 mos Negative
> ASC
Colposcopy
Routine Screening © Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved.
FIGURE 2. Management algorithm for women aged 21 to 24 years with CIN 1. CIN indicates cervical intraepithelial neoplasia. rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
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used in this setting as it will not impact the management and adds cost to the care of the patient. Figure 2 summarizes the management algorithm for this clinical situation.
CIN 2 + CIN 3 is considered a true cancer precursor. In the ALTS trial35,36 it was clearly demonstrated that CIN 3 generally does not resolve without treatment and when left untreated can result in cervical cancer. CIN 2 is a more difficult diagnosis from both the standpoint of agreement between pathologist and its rate of resolution. It is, however, considered the benchmark for treatment of most women in the United States except for special circumstances, such as women aged below 25 years and pregnancy. Management of women with CIN 2, CIN 3, or CIN 2+ is determined by the age of the patient and the status of the assessment of the endocervical canal. Women who have an unsatisfactory colposcopy or a positive ECC for CIN 2, CIN 3, and CIN 2+ if the specimen cannot be graded require an excisional procedure. Those women who have an adequate colposcopic examination and no evidence or CIN 2+ in the canal can undergo an ablative or excisional procedure. The type of treatment that is chosen in this setting is determined by the extent of the lesion and the treatment methods available. Follow-up of women after treatment is determined by the inherent risk of recurrence. As women who have been treated for CIN 2+ are at highest risk for recurrence, they require 2 negative co-test to be declared satisfactory for screening in 3 years. Any abnormality that is identified, either a positive HPV test or an abnormal pap test of any type, will require colposcopic evaluation. The consensus guidelines conference has now eliminated the frequent pap test following treatment and replaced this with an annual co-test at 12 and 24 months. This approach eliminates the potential for falsepositive cytology in the setting of the early www.clinicalobgyn.com
healing phase following treatment. This is also more in-line with the annual gynecologic care recommendedfor women. Figure 3 summarizes the treatment of women with CIN 2+ . The management of young women aged 21 to 24 years with biopsy-confirmed CIN 2, CIN 3, or CIN 2+ is unique as there are a number of studies that have demonstrated that in adolescent and young women the rate of resolution without treatment is high, specifically for CIN 2 and CIN 2+ . In the case of CIN 2, Moscicki et al37 have specifically demonstrated that 63% of adolescents and young women resolve CIN 2 without therapy in 2 years. As it is not costeffective to test for HPV testing in this population, the recommendations is to monitor those with CIN 2 with a colposcopy examination every 6 months. If the patient has a negative pap and colposcopy at 2 subsequent visits, then cotesting is recommended in one year. If the co-test is negative then the patient can return to screening at 3-year intervals. If, however, during follow-up the colposcopy worsens, or the HSIL pap persists for 1 year, then a repeat biopsy is recommended. The same treatment plan is acceptable for CIN 2+ in young women. When CIN 3 is specifically identified or if the colposcopy exam is not adequate, it is preferred to treat the patient with an excisional procedure. Figure 4 summarizes the care of young women with biopsy-confirmed CIN 2, CIN 2+ , and CIN 3.
Adenocarcinoma In Situ
AIS tends to occur in a younger cohort,38 involves the endocervical canal, and thus makes colposcopic evaluation challenging. Excisional treatment appears to be problematic as margins do not appear as reliable and indicator of cure in biopsy-proven cases of AIS.2 Screening for glandular neoplasia also appears daunting and lower than squamous lesions regarding detection of precursors.39 If excision is performed,
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FIGURE 3. Treatment of women with CIN 2+ . CIN indicates cervical intraepithelial neoplasia. rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
CKC is preferred because of superior interpretation of cut margins for clearance, and HPV testing seems predictive (positive preoperative testing converts to negative therapy in postexcision cases) of clearance or cure. Last, if a woman has completed childbearing, because of the lower power of existing screening to detect residual or recurrent disease, and the challenge of assuring that excision was effective, total hysterectomy is the treatment of choice for AIS.2
Pregnancy The primary objective for care of women with abnormal cytology and histology is to evaluate the patient for the potential for invasive disease. Short of clear-cut
invasive disease, the majority of treatments for dysplasia can be postponed until 6 weeks after delivery. When CIN 1 is identified during pregnancy treatment is not warranted and is unacceptable. Patients who have CIN 1 should not require any additional evaluation during the pregnancy and should have a followup examination 6 weeks postpartum using the appropriate algorithm for their initial cytology and age. Women who are diagnosed with CIN 2, CIN 3, or CIN 2+ without evidence of invasion do not require therapy. They can be monitored with colposcopy at a frequency of no more frequent than 12 weeks. It is acceptable, when invasion has been ruled out, to defer follow-up examinations to 6 weeks postpartum. Cone biopsies during pregnancy www.clinicalobgyn.com
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FIGURE 4. Care of young women with biopsy-confirmed CIN 2, CIN 2+ , and CIN 3. CIN indicates cervical intraepithelial neoplasia. rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
are rarely required, require special expertise, and have a high rate of preterm labor.
New Horizons 5-fluorouracil (5-FU) is a treatment being evaluated in small studies for cervical dysplasia. Rahangdale et al40 randomized women with CIN 2 to observation or intravaginal treatment with 5-FU every 2 weeks for 8 treatments. After 6 months, regression was noted in 93% of women in the treatment arm versus 56% of those in the observational arm (P = 0.01), giving an RR of regression of 1.62 (95% CI, 1.12.6). Another treatment modality involves photodynamic therapy, which involves administering laser light to the cervix and endocervical canal after giving a www.clinicalobgyn.com
photosensitizing agent. This has been shown to be associated with regression of dysplasia in some small observational trials.36–39 A potential approach may be the use of therapeutic vaccination against targeted HPV subtypes. At present, this research is ongoing and may have promise.41
Experimental Treatments There are many trials underway evaluating nondestructive methods of treating cervical dysplasia. A comprehensive outline of existing and experimental therapies is provided in Table 1. A compound of vaginal progesterone is being studied (NCT00247169), as are several intravaginal gels such as compound 851B (NCT00312286), aloe vera with concomitant b-interferon (PMID 17177657), or gel
Management of Cervical Intraepithelial Neoplasia TABLE 1.
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Current and Investigational Therapeutic Modalities for Cervical Neoplasia
Conventional therapies Cold knife conization Laser conization Loop electro-excisional procedure Cryotherapy Biopsy as therapy Imiquimod Investigational therapies 851B (NCT00312286)
Indications
Method
Invasiveness
CIN 2/3 CIN 2/3 CIN 2/3
Excision of transformation zone Excision of transformation zone Excision of transformation zone
Invasive Invasive Invasive
CIN 1, CIN 2, HPV+ CIN 2/3
Topical application of cryoprobe
Invasive
Local excision of affected area
CIN 1, CIN 2
Moderately invasive Topical application of imiquimod Minimally invasive
LGSIL
Intravaginal gel 851B
Minimally invasive, phase II A007 (NCT00285207) HSIL Topical gel A007 applied to HSIL Minimally invasive, lesions phase II Aloe vera interferon (PMID High-risk Aloe vera beta-interferon vaginal Minimally invasive 17177657) HPV + suppository Amolimogene, ZYC101a CIN 2/3 Intramuscular injection of Minimally invasive, (NCT00264732) ZYC101a phase II Anti-cytokine: Celecoxib CIN 2/3 Oral COX-2 inhibitor Minimally invasive, (NCT00081263) phase I Beta carotene CIN 1, CIN 2 Carotenoid rich diet vs. standard Minimally invasive, (NCT00003094) diet phase II C1/Colvir (NCT01303328) CIN 2/3 Topical antiviral gel applied to Minimally invasive, cervix phase II Di-indolylmethane CIN 2/3 Oral di-indolylmethane Minimally invasive, (NCT00212381) supplement phase II Eflornithine (NCT00006079) CIN 2/3 Systemic chemotherapeutic Minimally invasive, phase I Em-1421 (NCT00154089) CIN 2/3 Topical application of Minimally invasive, chemotherapeutic antiviral phase I Folic Acid (NCT00703196) rCIN 1 Oral folic acid supplement Minimally invasive, phase II Green Tea extracts CIN 1 Polyphone E oral supplement Minimally invasive, (NCT00303823) phase II HspE7 (NCT00060099) CIN 2/3 Systemic chemotherapeutic Minimally invasive, phase II Nelfinavir (NT01925378) HSIL, CIN 2/3 Oral Nelfinavir Minimally invasive, phase II Polygamma glutamic acid CIN 1 Oral administration Minimally invasive, (NCT01826045) phase II RO5217790 (NCT01022346) CIN 2/3 Subcuticular injection of Minimally invasive, RO5217790 phase II Vaccines (NCT00501189) CIN 1, CIN 2 Gardasil vaccine as therapy for Minimally invasive low-grade CIN Vaginal Progesterone CIN 1, CIN 2 Vaginal progesterone Minimally invasive, (NCT00247169) phase II Zolendronic acid CIN 2/3 Systemic chemotherapeutic Minimally invasive, (NCT00278434) phase II
CIN indicates cervical intraepithelial neoplasia.
applied topically on high-grade lesions such as A007 (NCT00285207). Antivirals such as topical C1/Colvir (NCT01303328)
and a chemotherapeutic medication called Em-1421 (NCT00154089) is being tested in phase 1 and 2 trials for its use in treatment www.clinicalobgyn.com
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of various tumors. The oral antiviral nelfinavir is studied in NCT01925378. Oral supplements are being studied, such as folic acid administration (NCT00703196), green tea extracts (NCT003023823), and di-indolymethane (NCT00212381). In another study, high b-carotene diets are being evaluated versus standard diets (NCT00003094). Chemotherapeutic agents such as zoledronic acid (NCT00278434), HSPe7 (NCT00075569), and eflornithine hydrochloride (NCT0000 6079) have early trials. Celecoxib is being compared with placebo in a phase 2 trial for high-grade CIN (NCT00081263). Subcutaneous injection of RO5217790 (NCT01022346) is being evaluated, as well as intramuscular ZYC101a (NCT00 264732). Oral polygamma glutamic acid is studied in NCT01826045. The Gardasil vaccine as therapy for low-grade CIN is being evaluated as well (NCT00501189). If nondestructive agents can induce regression in lesions less than CIN 3+ , our approach to cervical cancer prevention might focus more on the infectious disease nature of HPV rather than the outcome, the end-stage of cellular immortalization, and the near-malignant stage, wherein treatment is universally applied.
References 1. Krone KR, Kiviat NB, Koutsky LA. The epidemiology of cervical neoplasms. In: Luesley D, Jordan J, Richart RM eds. Intraepithelial Neoplasia of the Lower Genital Tract. Churchill Livingston: Edinburgh;1995:49–60. 2. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17: S1–S27. 3. Acladious NN, Sutton C, Mandal D, et al. Persistent human papillomavirus infection and smoking increase risk of failure of treatment of cervical intraepithelial neoplasia (CIN). Int J Cancer. 2002;98:435–439. 4. Schiffman MH, Haley NJ, Felton JS, et al. Biochemical epidemiology of cervical neoplasia: measuring cigarette smoke constituents in the cervix. Cancer Res. 1987;47:3886–3888.
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5. Hellberg D, Nilsson S, Haley NJ, et al. Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. Am J Obstet Gynecol. 1988;158:910–913. 6. Szarewski A, Maddox P, Royston P, et al. The effect of stopping smoking on cervical Langerhans’ cells and lymphocytes. BJOG. 2001;108:295–303. 7. Santoso JT, Crigger M, English E, et al. Smoking cessation counseling in women with genital intraepithelial neoplasia. Gynecol Oncol. 2012; 125:716–719. 8. Chellini E, Gorini G, Gasparrini A, et al. Cervical cancer screening visit as an occasion for counseling female smokers to quit. Tumori. 2012;98: 27–32. 9. Kyrgiou M, Tsoumpou I, Vrekoussis T, et al. The up-to-date evidence on colposcopy practice and treatment of cervical intraepithelial neoplasia: the Cochrane colposcopy & cervical cytopathology collaborative group (C5 group) approach. Cancer Treat Rev. 2006;32:516–523. 10. ASCCPMayeaux E, Cox J. Modern Colposcopy Textbook and Atlas. 3rd ed. Philadelphia PA: Lippincott Williams & Wilkins. 11. WHO. Use of cryotherapy for cervical intraepithelial neoplasia. 12. Abdul-Karim FH, Fu YS, Reagan JW, et al. Morphometric study of intraepithelial neoplasia of the uterine cervix. Obstet Gynecol. 1982;60:210–214. 13. Anderson MC, Hartley RB. Cervical crypt involvement by intraepithelial neoplasia. Am J Obstet Gynecol. 1980;55:546–549. 14. Boonstra H, Aalders JG, Koudstaal J, et al. Minimum extension and appropriate topographic position of tissue destruction for treatment of cervical intraepithelial neoplasia. Obstet Gynecol. 1990;75:227–231. 15. Fisher JC. Qualitative and quantitative tissue effects of light from important surgical lasers: optimal surgical principles. In: Wright VC, Fisher JC eds. Laser Surgery in Gynecology. Philadelphia: WB Saunders Company;1993:73–78. 16. Spitzer M, Chernys AE, Seltzer VL. The use of large loop excision of the transformation zone in an inner city population. Obstet Gynecol. 1993;82: 731–735. 17. Prendiville W, Cullimore J, Norman S. Large loop excision of the transformation zone (LLETZ: a new method of management for women with intraepithelial neoplasia. Br J Obstet Gynecol. 1989;96:1054–1060. 18. Wright TC, Gagnon S, Richart RM, et al. Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol. 1992;79:173–178. 19. Luesley DM, Cullimore J, Lawton FG, et al. Loop diathermy excision of the cervical
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transformation zone in patients with abnormal cervical smears. Br J Med. 1990;330:1690–1693. Bigrigg MA, Codling BW, Pearson P, et al. Colposcopic diagnosis and treatment for cervical dysplasia at a single clinic visit. Lancet. 1990;336: 229–231. 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;52:175–179. Ostegard DR. Prediction of clearance of cervical intraepithelial neoplasia by conization. Obstet Gynecol. 1980;56:77–80. Killackey MA, Jones WB, Lewis J Jr. Diagnostic conization of the cervix: review of 460 consecutive cases. Obstet Gynecol. 1986;67:766–770. Benedet JL, Anderson GH, Boyes DA. Colposcopic accuracy in the diagnosis of microinvasive and occult invasive carcinoma of the cervix. Obstet Gynecol. 1985;65:551–561. Bjerre B, Eliasson G, Linell F. Conization as only treatment of carcinoma in situ of the uterine cervix. Am J Obstet Gynecol. 1976;125:143–152. Berkus M, Daly JW. Cone biopsy: an outpatient procedure. Am J Obstet Gynecol. 1980;137: 953–958. Hester LL, Read RA. An evaluation of cervical conization. Am J Obstet Gynecol. 1960;80:715–721. Bostofte E, Berget A, Larsen JF, et al. Conization by carbon dioxide laser or cold knife in the treatment of cervical intraepithelial neoplasia. Acta Obstet Gynecol Scand. 1986;65:199–202. Villasanta U, Durkan JP. Indications and complications of cold conization of the cervix. Observation on 200 consecutive cases. Obstet Gynecol. 1965;27:717–723. Larsen G. Conization for cervical dysplasia and carcinoma in situ: long term follow-up of 1013 women. Annales Chirugiae et Gynaecologiae. 1981;70:79–85. Katki HA, Schiffman M, Castle PE, et al. Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines. J Low Genit Tract Dis. 2013;17:S28–S35.
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32. Katki HA, Schiffman M, Castle PE, et al. Fiveyear risk of CIN 3+ to guide the management of women aged 21 to 24 years. J Low Genit Tract Dis. 2013;17:S64–S68. 33. 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. 34. Fukuchi E, Fetterman B, Poitras N, et al. Risk of cervical precancer and cancer in women with cervical intraepithelial neoplasia grade 1 on endocervical curettage. J Low Genit Tract Dis. 2013;17: 255–260. 35. ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of LSIL cytologic interpretations. Am J Obstet Gynecol. 2003;188:1393–1400. 36. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytologic interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188:1383–1392. 37. Moscicki A-B, Ma Y, Wibbelsman C, et al. Rate of and risks for regression of cervical intraepithelial neoplasia 2 in adolescents and young women. Obstet Gynecol. 2010;116:1373–1380. 38. Schwartz S M, Weiss N. Increased incidence of adenocarcinoma of the cervix in young women in the United States. Am J Epidemiol. 1986;124: 1045–1047. 39. Mitchell H, Medley G, Gordon I, et al. Cervical cytology reported as negative and risk of adenocarcinoma of the cervix: no strong evidence of benefit. Br J Cancer. 1995;71:894–897. 40. Rahangdale L, Lippmann QK, Garcia K, et al. Topical 5-fluorouracil for treatment of cervical intraepithelial neoplasia 2: a randomized controlled trial. Am J Obstet Gynecol. 2013. [Epub ahead of print]. 41. Rieck GC, Fiander AN. Human papillomavirus, cervical carcinogenesis and chemoprevention with indole derivates—a review of pathomechanisms. Mol Nutr Food Res. 2008;52:105–113.
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Secondary Prevention of Cervical Cancer Part 3: Evidence-based Management of Women With Cervical Intraepithelial Neoplasia RICHARD GUIDO, MD,* NEAL M. LONKY, MD, MPH,w and JUSTIN DIEDRICH, MDz *Magee-Womens Hospital of the UPMC System, University of Pittsburgh, Pittsburgh, Pennsylvania; w Southern California Permanente Medical Group, Department of Obstetrics and Gynecology, Kaiser Permanente, Anaheim, and Department of Obstetrics and Gynecology, University of California School of Medicine, Irvine, California; and z Washington University, St. Louis, St Louis, Missouri Abstract: The management of cervical intraepithelial neoplasia has evolved over the last 20 years. Observation has replaced aggressive therapy in many cases. Evidence based guidelines now guide therapy. This chapter presents an overview of various treatment options, as well as the most recent guidelines of therapy. Key words: cervical intraepithelial neoplasia, treatment guidelines
the precursors to cervical cancer. It has been through effective screening and early intervention of cervical dysplasia that there was a dramatic fall in the number of cervical cancer cases in developed countries. In the United States, cervical cancer incidence fell from second to ninth among cancers in women.1 A good understanding of the natural history of HPV and its role in cervical cancer has not only resulted in a reduction of cervical cancer cases but, over the last 25 years, resulted in a move to less intervention in the management of lesion of the cervix that are representative of HPV infection and will ultimately not lead to cervical cancer. This shift is reflected in the management guidelines that were
Introduction Much has been learned over the past 50 years about human papillomavirus (HPV), its role in cervical cancer, and Correspondence: Richard Guido, MD, Magee-Womens Hospital of the UPMC System, University of Pittsburgh, Pittsburgh, PA. E-mail: rguido@mail. magee.edu Richard Guido is a board member for ASCCP. The other authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
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Management of Cervical Intraepithelial Neoplasia developed in the most recent ASCCP consensus guidelines.2 This chapter covers the various recommendations for the management of histologically confirmed cervical dysplasia of the cervix as recommended by the ASCCP.
Promoting Healthy Habits Managing any women with a health condition is best achieved by improving the women’s knowledge of the underlying condition and promoting good health habits related to that condition. HPV-related diseases of the lower genital tract are no different. It is well established that the immune response to HPV is critical for eliminating or reducing the burden of the disease. Women who smoke have been found to have a relative risk (RR) of 1.60 [95% confidence interval (CI), 1.48-1.73] of developing cervical cancer as compared with those who have never have smoked.3 The mechanism of action of smoking is not proven, but it is likely that a combination of the direct carcinogenic effects of cotinine, nicotine, and nitrosamines and local immunosuppression manifest by decreasing density and function of Langerhans cells are both contributory.4–6 Smokers have a higher rate of recurrence than nonsmokers following therapy for cervical intraepithelial neoplasia (CIN). Therefore, it is very important to use the opportunity of HPV-related diseases of the lower genital tract as an opportunity to promote smoking cessation. Women who present for management of HPV-related diseases of the lower genital tract have been shown to successfully discontinue smoking at rates of 12% to 32%.7,8 There are numerous other potential healthy lifestyle changes that may have an impact on the immune system; however, none are as well associated with cervical dysplasia and cancer as smoking.
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well as CIN 2+ for special populations of women. The driving force for change has been a better understanding of the natural history of HPV infections and biopsyproven CIN. The decision of treatment versus observation is one that balances the benefits of treatment versus the risk associated with the various procedures used to treat cervical cancer. The majority of which are either ablative or excisional in nature. The benefits of therapy for CIN include a high rate of success of both ablative and excisional treatments. The quoted success rates of both type of therapies range from 90% to 95%.9 The downside of therapy includes the cost of the various procedures as well as the impact the treatments have on subsequent pregnancies. Although there is still some debate of the negative impact of treatment on pregnancy, the majority of evidence demonstrate that these interventions increase the rate of preterm labor, low birth weight infants, and an increase in the cesarean section rate. A large meta-analysis of 27 studies demonstrate that cold knife conization (CKC) is associated with an increase in the RR of preterm labor 2.59 (CI, 1.80-3.72) and low birth weight delivery 2.53 (CI, 1.19-5.36) as defined by a weight 5 mm and should be covered entirely by the cryoprobe. www.clinicalobgyn.com
In low resource setting cryotherapy has been used based on a positive screening test. The ability to quickly triage and treat in these setting outweight the potential for treating a small cancer. This use of cryotherapy is always performed in the setting of some visual inspection of the cervix with acetic acid application (VIA) or in the setting of a positive HPV test. The most recent WHO guidelines for the use of cryotherapy in the treatment of histologically confirmed CIN does comment that treatment in low resource setting can be conducted given the potential benefit of treatment versus no treatment.11 The WHO guidelines provide additional recommendation regarding the techniques used for cryotherpy. The double-freeze method of freezing for 3 minutes followed by a 5-mintue thaw, and a second 3-minute freeze is recommended. Carbon dioxide (CO2) gas is prefered to nitrous oxide (N2O). Prophylactic antibiotics are not required for cryotherapy, and alternative therapies are recommended in the setting of the lesion covering over 75% of the surface of the cervix. Cryotherapy should not be performed in the setting of invasive cervical cancer, pregnancy, a history of in utero DES exposure because of an increased risk of cervical stenosis, acute cervicitis, and disease extending into the cervical canal beyond 5 mm as demonstrated by colposcopy, or a postive ECC.
Laser Therapy Laser therapy of the cervix was very popular in its use before the advent of the LEEP procedure. It is best used today in the setting of lesions on the cervix that are not amenable to either cryotherapy or LEEP. Typically, these situation arise when the lesion on the cervix is large or the disease extends beyond the boundries of the cervix and on to the vagina.
Management of Cervical Intraepithelial Neoplasia The most common used laser for treatment of cervical dysplasia is the CO2 laser. This laser has unique properties that make it ideal for treating disease of the lower genital tract. The laser is easily adapted to a colposcope. This along with the ability to make the spot size of the laser vary from 1 to 10 mm, which allows for precise control of the areas of treatment. The laser is also a superficial laser and therfore has minimal impact on surrouding tissue. It can be used in the office and in the operating room. The laser is, however, expensive to acquire, require specially trained personal to safely operate, and often times represents a more costly method of treating cervical disease. The CO2 laser can be used as an excisional tool as well as an ablative tool. Treatment of cervical dysplasia by any method must treat to an adequate depth to eradicate the disease. CIN can extend into the underlying cervical crypts. Higher grade lesions [severe dysplasia and carcinoma in situ (CIS)] extend into cervical crypts up to 5.2 mm but, in most cases, crypt depth varies between 1.24 mm and 1.6 mm.12–14 In CIN 3 lesions (severe dysplasia/CIS) 85% to 95% will have some crypt extension.15 However, 96% of these cases have depth of disease extension of 100 mL or heavy bleeding requiring suturing, packing, or other procedures varied between 9.3% and 15% of all CKCs.25–30
Management of the Women With CIN Using Established Therapies The ASCCP Consensus Guidelines were updated in 2013. The guidelines
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incorporated risk assessment in determining the appropriate therapy for a given histologic diagnosis and incorporated the approach that when equal risk of CIN 3 exist, equal treatment will occur. The risk assessments were developed primarily from data generated by Kaiser Permanente of Northern California and summarized by a series of articles by Katki et al.31,32
CIN 1 Preceded by a ‘‘Lesser Abnormality’’ CIN 1 is a manifestation of HPV infection. The majority of CIN 1 lesions resolve spontaneously. The management of CIN 1 is driven by the preceding cytology. CIN 1 when preceded by a pap that is LSIL or ASC-US, HPV+ has a 5-year risk of CIN 3+ of 3.8%, whereas those with CIN 1 after HSIL had a 5-year risk of CIN 3+ of 15%.33 Because of this variation in risk, the management of women diagnosed following what is termed a ‘‘lesser abnormality’’ is to undergo a pap and HPV (cotesting) at 12 months. Those individuals who are HPVnegative and cytology negative can then return to screening at 3 years. Although routine screening for women over 30 years with a negative pap and HPV test can be 5 years, at the time of the consensus conference there was not enough data to allow women with biopsy-proven CIN 1 to be followed up 5 years later. Any abnormality in follow-up, either a pap that is Z ASC-US or a + HPV test will require a colposcopy. There are a few points of clarification with this recommendation. Because of the high rate of HPV present in women aged 25 to 29 years, the follow-up examination at 12 months will only include cytology. Recommendations differ for women ASC-H or HSIL
Manage per ASCCP Guideline for Women Ages 21-24 with ASC-H or HSIL using postcolposcopy path for No CIN2,3
Repeat Cytology @ 12 mos Negative
> ASC
Colposcopy
Routine Screening © Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved.
FIGURE 2. Management algorithm for women aged 21 to 24 years with CIN 1. CIN indicates cervical intraepithelial neoplasia. rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
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used in this setting as it will not impact the management and adds cost to the care of the patient. Figure 2 summarizes the management algorithm for this clinical situation.
CIN 2 + CIN 3 is considered a true cancer precursor. In the ALTS trial35,36 it was clearly demonstrated that CIN 3 generally does not resolve without treatment and when left untreated can result in cervical cancer. CIN 2 is a more difficult diagnosis from both the standpoint of agreement between pathologist and its rate of resolution. It is, however, considered the benchmark for treatment of most women in the United States except for special circumstances, such as women aged below 25 years and pregnancy. Management of women with CIN 2, CIN 3, or CIN 2+ is determined by the age of the patient and the status of the assessment of the endocervical canal. Women who have an unsatisfactory colposcopy or a positive ECC for CIN 2, CIN 3, and CIN 2+ if the specimen cannot be graded require an excisional procedure. Those women who have an adequate colposcopic examination and no evidence or CIN 2+ in the canal can undergo an ablative or excisional procedure. The type of treatment that is chosen in this setting is determined by the extent of the lesion and the treatment methods available. Follow-up of women after treatment is determined by the inherent risk of recurrence. As women who have been treated for CIN 2+ are at highest risk for recurrence, they require 2 negative co-test to be declared satisfactory for screening in 3 years. Any abnormality that is identified, either a positive HPV test or an abnormal pap test of any type, will require colposcopic evaluation. The consensus guidelines conference has now eliminated the frequent pap test following treatment and replaced this with an annual co-test at 12 and 24 months. This approach eliminates the potential for falsepositive cytology in the setting of the early www.clinicalobgyn.com
healing phase following treatment. This is also more in-line with the annual gynecologic care recommendedfor women. Figure 3 summarizes the treatment of women with CIN 2+ . The management of young women aged 21 to 24 years with biopsy-confirmed CIN 2, CIN 3, or CIN 2+ is unique as there are a number of studies that have demonstrated that in adolescent and young women the rate of resolution without treatment is high, specifically for CIN 2 and CIN 2+ . In the case of CIN 2, Moscicki et al37 have specifically demonstrated that 63% of adolescents and young women resolve CIN 2 without therapy in 2 years. As it is not costeffective to test for HPV testing in this population, the recommendations is to monitor those with CIN 2 with a colposcopy examination every 6 months. If the patient has a negative pap and colposcopy at 2 subsequent visits, then cotesting is recommended in one year. If the co-test is negative then the patient can return to screening at 3-year intervals. If, however, during follow-up the colposcopy worsens, or the HSIL pap persists for 1 year, then a repeat biopsy is recommended. The same treatment plan is acceptable for CIN 2+ in young women. When CIN 3 is specifically identified or if the colposcopy exam is not adequate, it is preferred to treat the patient with an excisional procedure. Figure 4 summarizes the care of young women with biopsy-confirmed CIN 2, CIN 2+ , and CIN 3.
Adenocarcinoma In Situ
AIS tends to occur in a younger cohort,38 involves the endocervical canal, and thus makes colposcopic evaluation challenging. Excisional treatment appears to be problematic as margins do not appear as reliable and indicator of cure in biopsy-proven cases of AIS.2 Screening for glandular neoplasia also appears daunting and lower than squamous lesions regarding detection of precursors.39 If excision is performed,
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FIGURE 3. Treatment of women with CIN 2+ . CIN indicates cervical intraepithelial neoplasia. rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
CKC is preferred because of superior interpretation of cut margins for clearance, and HPV testing seems predictive (positive preoperative testing converts to negative therapy in postexcision cases) of clearance or cure. Last, if a woman has completed childbearing, because of the lower power of existing screening to detect residual or recurrent disease, and the challenge of assuring that excision was effective, total hysterectomy is the treatment of choice for AIS.2
Pregnancy The primary objective for care of women with abnormal cytology and histology is to evaluate the patient for the potential for invasive disease. Short of clear-cut
invasive disease, the majority of treatments for dysplasia can be postponed until 6 weeks after delivery. When CIN 1 is identified during pregnancy treatment is not warranted and is unacceptable. Patients who have CIN 1 should not require any additional evaluation during the pregnancy and should have a followup examination 6 weeks postpartum using the appropriate algorithm for their initial cytology and age. Women who are diagnosed with CIN 2, CIN 3, or CIN 2+ without evidence of invasion do not require therapy. They can be monitored with colposcopy at a frequency of no more frequent than 12 weeks. It is acceptable, when invasion has been ruled out, to defer follow-up examinations to 6 weeks postpartum. Cone biopsies during pregnancy www.clinicalobgyn.com
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FIGURE 4. Care of young women with biopsy-confirmed CIN 2, CIN 2+ , and CIN 3. CIN indicates cervical intraepithelial neoplasia. rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
are rarely required, require special expertise, and have a high rate of preterm labor.
New Horizons 5-fluorouracil (5-FU) is a treatment being evaluated in small studies for cervical dysplasia. Rahangdale et al40 randomized women with CIN 2 to observation or intravaginal treatment with 5-FU every 2 weeks for 8 treatments. After 6 months, regression was noted in 93% of women in the treatment arm versus 56% of those in the observational arm (P = 0.01), giving an RR of regression of 1.62 (95% CI, 1.12.6). Another treatment modality involves photodynamic therapy, which involves administering laser light to the cervix and endocervical canal after giving a www.clinicalobgyn.com
photosensitizing agent. This has been shown to be associated with regression of dysplasia in some small observational trials.36–39 A potential approach may be the use of therapeutic vaccination against targeted HPV subtypes. At present, this research is ongoing and may have promise.41
Experimental Treatments There are many trials underway evaluating nondestructive methods of treating cervical dysplasia. A comprehensive outline of existing and experimental therapies is provided in Table 1. A compound of vaginal progesterone is being studied (NCT00247169), as are several intravaginal gels such as compound 851B (NCT00312286), aloe vera with concomitant b-interferon (PMID 17177657), or gel
Management of Cervical Intraepithelial Neoplasia TABLE 1.
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Current and Investigational Therapeutic Modalities for Cervical Neoplasia
Conventional therapies Cold knife conization Laser conization Loop electro-excisional procedure Cryotherapy Biopsy as therapy Imiquimod Investigational therapies 851B (NCT00312286)
Indications
Method
Invasiveness
CIN 2/3 CIN 2/3 CIN 2/3
Excision of transformation zone Excision of transformation zone Excision of transformation zone
Invasive Invasive Invasive
CIN 1, CIN 2, HPV+ CIN 2/3
Topical application of cryoprobe
Invasive
Local excision of affected area
CIN 1, CIN 2
Moderately invasive Topical application of imiquimod Minimally invasive
LGSIL
Intravaginal gel 851B
Minimally invasive, phase II A007 (NCT00285207) HSIL Topical gel A007 applied to HSIL Minimally invasive, lesions phase II Aloe vera interferon (PMID High-risk Aloe vera beta-interferon vaginal Minimally invasive 17177657) HPV + suppository Amolimogene, ZYC101a CIN 2/3 Intramuscular injection of Minimally invasive, (NCT00264732) ZYC101a phase II Anti-cytokine: Celecoxib CIN 2/3 Oral COX-2 inhibitor Minimally invasive, (NCT00081263) phase I Beta carotene CIN 1, CIN 2 Carotenoid rich diet vs. standard Minimally invasive, (NCT00003094) diet phase II C1/Colvir (NCT01303328) CIN 2/3 Topical antiviral gel applied to Minimally invasive, cervix phase II Di-indolylmethane CIN 2/3 Oral di-indolylmethane Minimally invasive, (NCT00212381) supplement phase II Eflornithine (NCT00006079) CIN 2/3 Systemic chemotherapeutic Minimally invasive, phase I Em-1421 (NCT00154089) CIN 2/3 Topical application of Minimally invasive, chemotherapeutic antiviral phase I Folic Acid (NCT00703196) rCIN 1 Oral folic acid supplement Minimally invasive, phase II Green Tea extracts CIN 1 Polyphone E oral supplement Minimally invasive, (NCT00303823) phase II HspE7 (NCT00060099) CIN 2/3 Systemic chemotherapeutic Minimally invasive, phase II Nelfinavir (NT01925378) HSIL, CIN 2/3 Oral Nelfinavir Minimally invasive, phase II Polygamma glutamic acid CIN 1 Oral administration Minimally invasive, (NCT01826045) phase II RO5217790 (NCT01022346) CIN 2/3 Subcuticular injection of Minimally invasive, RO5217790 phase II Vaccines (NCT00501189) CIN 1, CIN 2 Gardasil vaccine as therapy for Minimally invasive low-grade CIN Vaginal Progesterone CIN 1, CIN 2 Vaginal progesterone Minimally invasive, (NCT00247169) phase II Zolendronic acid CIN 2/3 Systemic chemotherapeutic Minimally invasive, (NCT00278434) phase II
CIN indicates cervical intraepithelial neoplasia.
applied topically on high-grade lesions such as A007 (NCT00285207). Antivirals such as topical C1/Colvir (NCT01303328)
and a chemotherapeutic medication called Em-1421 (NCT00154089) is being tested in phase 1 and 2 trials for its use in treatment www.clinicalobgyn.com
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of various tumors. The oral antiviral nelfinavir is studied in NCT01925378. Oral supplements are being studied, such as folic acid administration (NCT00703196), green tea extracts (NCT003023823), and di-indolymethane (NCT00212381). In another study, high b-carotene diets are being evaluated versus standard diets (NCT00003094). Chemotherapeutic agents such as zoledronic acid (NCT00278434), HSPe7 (NCT00075569), and eflornithine hydrochloride (NCT0000 6079) have early trials. Celecoxib is being compared with placebo in a phase 2 trial for high-grade CIN (NCT00081263). Subcutaneous injection of RO5217790 (NCT01022346) is being evaluated, as well as intramuscular ZYC101a (NCT00 264732). Oral polygamma glutamic acid is studied in NCT01826045. The Gardasil vaccine as therapy for low-grade CIN is being evaluated as well (NCT00501189). If nondestructive agents can induce regression in lesions less than CIN 3+ , our approach to cervical cancer prevention might focus more on the infectious disease nature of HPV rather than the outcome, the end-stage of cellular immortalization, and the near-malignant stage, wherein treatment is universally applied.
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5. Hellberg D, Nilsson S, Haley NJ, et al. Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. Am J Obstet Gynecol. 1988;158:910–913. 6. Szarewski A, Maddox P, Royston P, et al. The effect of stopping smoking on cervical Langerhans’ cells and lymphocytes. BJOG. 2001;108:295–303. 7. Santoso JT, Crigger M, English E, et al. Smoking cessation counseling in women with genital intraepithelial neoplasia. Gynecol Oncol. 2012; 125:716–719. 8. Chellini E, Gorini G, Gasparrini A, et al. Cervical cancer screening visit as an occasion for counseling female smokers to quit. Tumori. 2012;98: 27–32. 9. Kyrgiou M, Tsoumpou I, Vrekoussis T, et al. The up-to-date evidence on colposcopy practice and treatment of cervical intraepithelial neoplasia: the Cochrane colposcopy & cervical cytopathology collaborative group (C5 group) approach. Cancer Treat Rev. 2006;32:516–523. 10. ASCCPMayeaux E, Cox J. Modern Colposcopy Textbook and Atlas. 3rd ed. Philadelphia PA: Lippincott Williams & Wilkins. 11. WHO. Use of cryotherapy for cervical intraepithelial neoplasia. 12. Abdul-Karim FH, Fu YS, Reagan JW, et al. Morphometric study of intraepithelial neoplasia of the uterine cervix. Obstet Gynecol. 1982;60:210–214. 13. Anderson MC, Hartley RB. Cervical crypt involvement by intraepithelial neoplasia. Am J Obstet Gynecol. 1980;55:546–549. 14. Boonstra H, Aalders JG, Koudstaal J, et al. Minimum extension and appropriate topographic position of tissue destruction for treatment of cervical intraepithelial neoplasia. Obstet Gynecol. 1990;75:227–231. 15. Fisher JC. Qualitative and quantitative tissue effects of light from important surgical lasers: optimal surgical principles. In: Wright VC, Fisher JC eds. Laser Surgery in Gynecology. Philadelphia: WB Saunders Company;1993:73–78. 16. Spitzer M, Chernys AE, Seltzer VL. The use of large loop excision of the transformation zone in an inner city population. Obstet Gynecol. 1993;82: 731–735. 17. Prendiville W, Cullimore J, Norman S. Large loop excision of the transformation zone (LLETZ: a new method of management for women with intraepithelial neoplasia. Br J Obstet Gynecol. 1989;96:1054–1060. 18. Wright TC, Gagnon S, Richart RM, et al. Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol. 1992;79:173–178. 19. Luesley DM, Cullimore J, Lawton FG, et al. Loop diathermy excision of the cervical
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transformation zone in patients with abnormal cervical smears. Br J Med. 1990;330:1690–1693. Bigrigg MA, Codling BW, Pearson P, et al. Colposcopic diagnosis and treatment for cervical dysplasia at a single clinic visit. Lancet. 1990;336: 229–231. 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;52:175–179. Ostegard DR. Prediction of clearance of cervical intraepithelial neoplasia by conization. Obstet Gynecol. 1980;56:77–80. Killackey MA, Jones WB, Lewis J Jr. Diagnostic conization of the cervix: review of 460 consecutive cases. Obstet Gynecol. 1986;67:766–770. Benedet JL, Anderson GH, Boyes DA. Colposcopic accuracy in the diagnosis of microinvasive and occult invasive carcinoma of the cervix. Obstet Gynecol. 1985;65:551–561. Bjerre B, Eliasson G, Linell F. Conization as only treatment of carcinoma in situ of the uterine cervix. Am J Obstet Gynecol. 1976;125:143–152. Berkus M, Daly JW. Cone biopsy: an outpatient procedure. Am J Obstet Gynecol. 1980;137: 953–958. Hester LL, Read RA. An evaluation of cervical conization. Am J Obstet Gynecol. 1960;80:715–721. Bostofte E, Berget A, Larsen JF, et al. Conization by carbon dioxide laser or cold knife in the treatment of cervical intraepithelial neoplasia. Acta Obstet Gynecol Scand. 1986;65:199–202. Villasanta U, Durkan JP. Indications and complications of cold conization of the cervix. Observation on 200 consecutive cases. Obstet Gynecol. 1965;27:717–723. Larsen G. Conization for cervical dysplasia and carcinoma in situ: long term follow-up of 1013 women. Annales Chirugiae et Gynaecologiae. 1981;70:79–85. Katki HA, Schiffman M, Castle PE, et al. Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines. J Low Genit Tract Dis. 2013;17:S28–S35.
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32. Katki HA, Schiffman M, Castle PE, et al. Fiveyear risk of CIN 3+ to guide the management of women aged 21 to 24 years. J Low Genit Tract Dis. 2013;17:S64–S68. 33. 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. 34. Fukuchi E, Fetterman B, Poitras N, et al. Risk of cervical precancer and cancer in women with cervical intraepithelial neoplasia grade 1 on endocervical curettage. J Low Genit Tract Dis. 2013;17: 255–260. 35. ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of LSIL cytologic interpretations. Am J Obstet Gynecol. 2003;188:1393–1400. 36. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytologic interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188:1383–1392. 37. Moscicki A-B, Ma Y, Wibbelsman C, et al. Rate of and risks for regression of cervical intraepithelial neoplasia 2 in adolescents and young women. Obstet Gynecol. 2010;116:1373–1380. 38. Schwartz S M, Weiss N. Increased incidence of adenocarcinoma of the cervix in young women in the United States. Am J Epidemiol. 1986;124: 1045–1047. 39. Mitchell H, Medley G, Gordon I, et al. Cervical cytology reported as negative and risk of adenocarcinoma of the cervix: no strong evidence of benefit. Br J Cancer. 1995;71:894–897. 40. Rahangdale L, Lippmann QK, Garcia K, et al. Topical 5-fluorouracil for treatment of cervical intraepithelial neoplasia 2: a randomized controlled trial. Am J Obstet Gynecol. 2013. [Epub ahead of print]. 41. Rieck GC, Fiander AN. Human papillomavirus, cervical carcinogenesis and chemoprevention with indole derivates—a review of pathomechanisms. Mol Nutr Food Res. 2008;52:105–113.
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