DIAGNOSIS AND MANAGEMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA

GYNECOLOGIC ONCOLOGY FOR THE GENERALIST

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DIAGNOSIS AND MANAGEMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA Lisa C. Flowers, MD, and Michael A. McCall, MD

HISTORY OF CERVICAL SCREENING

In 1941, Papanicolaou and Traut reported that vaginal smears could be used to identify malignancies in the female genital tract.4I These techniques for exfoliative cytology led to the Papanicolaou smear for cervical cancer screening. Similar techniques have been used since to screen for cancer in almost every hollow organ in the body. Wide use of the Papanicolaou smear as a screening tool for cervical cancer did not begin until the late 1950s and early 1960s. Boyes and colleagues demonstrated clear benefits of this cytologic screening in 1981, when they reported a decrease in the incidence of invasive cancer in their population from 28.4 cases per 100,000 women in 1955 to 7.7 cases per 100,000 women in 1977.4 Other studies worldwide have shown that cytologic screening programs for carcinoma of the cervix reduce the mortality from cervical cancer in direct relation to the proportion of the population screened. In the United States, death rates from cervical cancer have dropped from the number one cause among all cancers to number eight.59In the United States from 1973 to 1991, a 42% decline in the age-specific mortality rate and a 36% decline in the incidence of invasive cervical cancer were observed. Cervical cancer still remains the number one cause of death for women in third-world Current methods and management of cervical intraepithelial neoplasia (CIN) are reviewed and described in this article. ~

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From the Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, Emory University School of Medicine, Atlanta, Georgia

OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA

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VOLUME 28 NUMBER 4 * DECEMBER 2001

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DIAGNOSIS OF CERVICAL INTRAEPITHELIAL NEOPLASIA The Bethesda System In the early years of cervical cancer screening, it was noted that there was a wide spectrum of change associated with cervical cytology before the development of invasive cancer. The term carcinoma in situ (CIS) did not adequately cover this spectrum of histologic and cytologic changes. Papanicolaou classification terminology changed often and inconsistently over the years as data from widespread screening showed the development of cervical cancer to be far more complicated than once believed. Widespread confusion of pathologists and health care providers about inconsistent definitions and changing terminology resulted in a National Cancer Institute Workshop convened in Bethesda, Maryland, in 1988 with the hope of developing a standardized system of nomenclature. The outcome of this meeting was the "Bethesda System," which was revised in a second workshop in 1991.15,46,55 The Bethesda system listed below incorporates the evaluation of specimen adequacy and descriptive diagnoses, making close communication with pathologists and providers paramount. The Bethesda System for Reporting Cervical/ Vaginal Cytologic Diagnoses Epithelial cell abnormalities Adequacy of the Specimen Satisfactory for evaluation Squamous cell Atypical squamous Satisfactory for evaluation but cells of limited by (specify reason) undetermined Unsatisfactory for evaluation significance (specify reason) (qualify+) General Categorization (Optional) Low-grade Within normal limits squamous Benign cellular changes (see intraepithelial descriptive diagnoses) lesion Epithelial cell abnormality encompassing (see descriptive diagnoses) Human papilloma Descriptive Diagnoses viruses (HPV)t Benign cellular changes Mild dysplasia Infection Trichomonas cervical vaginalis intraepithelial Fungal organisms neoplasia (CIN 1) morphologically High-grade consistent with squamous Candida spp intraepithelial Predominance of lesion coccobacilli encompassing consistent with Moderate and severe shift in vaginal dysplasia flora CIS/CIN 2 and Bacteria cIN3

DIAGNOSIS AND MANAGEMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA

morphologically consistent with Actinomyces spp Cellular changes associated with herpes simplex virus Other Reactive Changes Reactive cellular changes associated with Inflammation (includes typical repair) Atrophy with inflammation (atrophic vaginitis) Radiation Intrauterine contraceptive device Other

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Squamous cell carcinoma Glandular cell Endometrial cells, cytologically benign, in a postmenopausal woman Atypical glandular cells of undetermined significance (qualify*) Endocervical adenocarcinoma Endometrial adenocarcinoma Extrauterine adenocarcinoma Adenocarcinoma, not otherwise specified Other malignant neoplasms (specify) Hormonal evaluation (applied to vaginal smears only) Hormonal pattern compatible with age and history Hormonal evaluation not possible owing to specify

*Atypicalsquamous or glandular cells of undetermined significance should be further qualified as to whether a reactive or a premalignant/maligt process is favored. tCellular changes of HPV-previously termed koilocytosis atypia or condylomatous atypia-are included in the category of low-grade squamous intraepithelial lesion.

Benign infectious changes include yeasts, bacteria, protozoans (Pichomanas vaginalis), and viral infections. Viral infections associated with herpes simplex virus I1 and HPV are the most common viral changes seen. Reactive and reparative changes are cellular responses to cellular injury (physical or chemical) and inflammation that are often associated with infection and may lead to false-positive findings. Changes associated with a lack of estrogen, such as atrophic vaginitis, are also listed under this category. Epithelial cell abnormalities are divided into atypia, low-grade lesions, high-grade lesions, and squamous carcinoma. Atypical lesions in this category often resemble exaggerated reactive changes but do not express changes associated with neoplasia. Low-grade lesions include koilocytotic atypia, condyloma, HPV effect, mild dysplasia, and cervical intraepithelial neoplasia (CIN) grade 1. High-grade lesions include moderate dysplasia, CIN grade 2, severe dysplasia, CIN grade 3, and carcinoma in situ (CIS).

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Papanicolaou Screening

The American College of Obstetricians and Gynecologists (ACOG) recommends that all women who have been sexually active or are at least 18 years old undergo an annual Papanicolaou test and pelvic examination.lYThe ACOG and the US Preventative Service Task Force agree that if three annual Papanicolaou screens are normal, screening may be performed less frequently than yearly at the discretion of the physician based on the woman’s risk fact01-s.~~ High-risk groups for CIN are as follows: Genital HPV infection Positive HIV status Multiple sexual partners Early age of intercourse High parity Cigarette smoking Low socioeconomic status History of prior sexually transmitted disease other than HPV With regular screening, accurate diagnosis of disease, and timely and appropriate treatment, cervical cancer can be a preventable disease. Screening for cervical cancer focuses on outreach programs for Papanicolaou smears and treatment of disease and is limited by the accuracy of the screening test programs. The traditional Papanicolaou smear has a sensitivity of 50% to 60% and a specificity of approximately 90%. Performance of the smear improves with repeated interval screening.5yAttempts at improving cytologic evaluation have led to the development of several screening modifications. Autocyte (Cytyc Corporation, Boxborough, Massachusetts) and Thinprep (Tripath Imaging, Burlington, North Carolina) cytologic preparations are gaining popularity based on recent studies, which have shown equal if not improved detection of dysplastic Despite all of the new screening technology and the excellent treatment modalities that exist for CIN, significant issues remain unresolved. As Burke states in his report,48”If every woman would visit her physician or health provider on a regular basis; if that individual would examine the patient adequately and administer the appropriate testing; if these test specimens were handled and processed correctly; if the laboratory adequately examined and reported the result; and if both the medical provider and patient acted properly with these results, on a theoretical basis we should be able to eradicate invasive squamous cell carcinoma of the cervix.” indications for Colposcopy

The American Society for Colposcopy and Cervical Pathology (ASCCP) has established guidelines for referring patients for colposcopy

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based on the cytologic findings of atypical squamous cells of undetermined significance (ASCUS),low-grade squamous intraepithelial lesions (LGSIL), and atypical glandular cells of undetermined significance (AGUS).13,14,52 The goal of these examinations should be to obtain a "satisfactory colposcopy" whenever possible. The entire transformation zone, squamocolumnar junction, and entire extent of the lesion must be visualized colposcopically. Atypical Squamous Cells of Undetermined Significance Management of ASCUS can follow two different directions based on the clinical profile of the patient population, the rate of squamous intraepithelial lesions to ASCUS ratio, and the correlation of cytologic evaluation to biopsy-proved disease by the pathologist. One management option is repeating the Papanicolaou smear every 4 to 6 months over a 1- to 2-year period until there have been at least three consecutive satisfactory normal smears. If any smear during this period is abnormal, referral for colposcopy is recommended. Another option is to refer the patient for colposcopy after one ASCUS Papanicolaou smear, especially if the patient is at high risk for dysplasia or noncompliant. The pros and cons of each option are well discussed in the ASCCP guidelines and deal with cost, burden to the system, overdiagnosis, overtreatment of disease, and delay of treatment.13 In an attempt to resolve the controversy surrounding how to manage ASCUS and LGSIL found on Papanicolaou smears and to evaluate the usefulness of diagnostic tools (e.g., HPV typing) to assist with identifying subgroups of patients with actual dysplastic disease, the ASCUS/LGSIL Triage Study (ALTS) was performed. A large, randomized, multicenter trial, the ALTS compared the following three evaluation arms for detecting CIN 3: (1) immediate colposcopy (the gold standard), (2) triage to colposcopy based on HPV results from hybrid capture and thin-layer cytology results, and (3) triage based on cytology More than 3400 women with ASCUS findings on Papanicolaou smears were enrolled. The prevalence of biopsy-confirmed CIN 3 in this group was 5.1%. The sensitivity of detecting CIN 3 or higher by testing for oncogenic HPV DNA was 96.3% in the 5% of patients with CIN 3. Fiftysix percent of women with ASCUS findings were HPV positive and referred for colposcopy. In contrast, the sensitivity of using a single repeat cytology specimen with high-grade squamous intraepithelial lesions (HGSIL) or higher (e.g., CIS, squamous cell carcinoma [SCCA]) was 44.1%0,with 6.9% patients referred for colposcopy. Lowering the cytologic threshold to ASCUS or higher increased the sensitivity to 85.39'0, with 58.6%of patients referred. The ALTS concluded that the use of HPV testing increased the sensitivity of identifying CIN 3 or higher in the ASCUS category. Low-Grade Squamous Intraepithelial Lesions Management of LGSIL can follow two directions as well. The traditional route of management is referral for colposcopy after the initial

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LGSIL Papanicolaou smear. This action provides immediate information to the patient and health care provider about the lesion and the need for observation or treatment. If the colposcopy is satisfactory and no lesion is present, reassurance is provided the patient, and a longer interval can be planned before follow-up cytologic assessment. The second route of management is repeating the Papanicolaou smear every 4 to 6 months for a 1- to 2-year period. If all repeat smears are negative, the patient can return for annual Papanicolaou smears. If any repeat smear shows ASCUS or greater, the authors recommend that the patient be referred for colposcopy. The ASCCP guidelines give the provider the option to perform HPV typing in the presence of an ASCUS Papanicolaou smear without proceeding to c01poscopy;~~ however, the authors discourage delaying evaluation by colposcopy unless the ASCUS Papanicolaou smear reveals an associated vaginal infection. In choosing conservative management (e.g., HPV typing or repeating the smear) versus direct referral to colposcopy, the rate of SIL in the population being screened and patient compliance need to be considered. In the ALTS trial, HPV testing was not shown to be helpful in the LGSIL group in reducing referral to colposcopy. Approximately 83% of the LGSIL Papanicolaou smears tested positive for HPV, which would have required referral to colpo~copy.~~ High-Grade Squamous lntraepithelial Lesions Any patient with HGSIL or findings suspicious for cancer on a Papanicolaou smear should be immediately referred for colposcopy. Atypical Glandular Cells of Undetermined Significance Patients with a cytologic diagnosis of AGUS may have a greater risk of dysplastic disease than patients with ASCUS and LGSIL. As many as 30% to 50% of these patients are diagnosed with CIN, Adenocarcinoma in situ (AIS), or cancer'*; therefore, patients with AGUS should be referred for colposcopy for a thorough evaluation of the vagina, ectocervix, endocervical canal, and uterus. The evaluation should be tailored to patient complaints, menopausal status, and the most likely source of pathology. If the colposcopic evaluation is negative (no ectocervical lesions and negative Endocervical currettage [ECC]) and no endometrial pathology is present, the patient can be followed up with Papanicolaou smears every 4 to 6 months until four normal results occur sequentially, and then annually. A conization should be performed if the ECC is positive. Cone biopsy should be performed also if a follow-up Papanicolaou smear shows AGUS. If the cone specimen from the AGUS patient is negative, investigation must continue into extrauterine sites (ovary, fallopian tube, breast, and gastrointestinal).'*

Cervical lntraepithelial Neoplasia in Pregnancy

Three to five percent of pregnancies are complicated by abnormal cervical cytology. Most of these cases are CIN 1 or 2; however, 1%to 5%

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of these women have biopsy-proven CIN 3.48In pregnancy, referral for colposcopy is the same as in a nonpregnant patient; however, follow-up and management may differ owing to fetal and maternal concerns. If the Papanicolaou smear shows LGSIL, referral for colposcopy should be made. If the colposcopy is satisfactory but no lesion is seen, the colposcopy can be repeated postpartum without further cytologic evaluation during pregnancy. If a lesion is found, a biopsy should be performed. If the findings are negative or show CIN 1, repeat colposcopy can be postponed until postpartum. If the biopsy specimen shows CIN 2 or 3, colposcopy should be repeated every 8 weeks during pregnancy. In patients who have HGSIL, satisfactory colposcopy, and a visible lesion with the histologic diagnosis of CIN 1, 2, or 3, colposcopy should be repeated in 8 weeks. If no lesion is seen even after careful evaluation of the entire lower genital tract (vulva, vagina, and cervix), close supervision can be carried out, with repeat colposcopies every 8 weeks. Any histologic diagnosis of microinvasion on biopsy requires conization to rule out invasive disease. Conization should be performed if the colposcopic impression has features (e.g., atypical vessels) suggestive of microinvasion or invasive disease, even if the cervical biopsies are unable to confirm invasive disease. In such patients, if possible, the conization should be performed before 20 weeks’ gestation to allow options for early termination of pregnancy if invasive disease is discovered. Because progression rates of CIN to CIS in pregnant patients are slow, it is appropriate to delay management and treatment to the postpartum.4s Many of these CIN lesions regress spontaneously, and repeating colposcopy postpartum and avoiding biopsy of the milder lesions, such as CIN 1, to confirm disease seems reasonable. Cervical lntraepithelial Neoplasia in the HIV Patient

In 1993, cervical cancer was designated as an acquired immunodeficiency syndrome (AIDS)-defining condition by the Centers for Disease Control (CDC) and Prevention.8Although initial studies by Maiman and colleagues35demonstrated a significant rate of cervical cancer in their population of HIV-seropositive women, this relationship has not been seen in recent studies in Africa and in other populations with a high prevalence of HIV infection. In fact, the rate of cervical cancer in African women who are HIV seropositive is not significantly different from the ~ 53, 6o Patients with the HIV virus rate in the general p o p u l a t i ~ n33,. ~47,~so, harbor the HPV virus as well, and there is an interaction between the two viruses that may increase the development of dysplasia and accelerate di~ease.2~. 47, 5o Women who are severely immunosuppressed (CD4 cell counts less than 2OO/pL) have a high HPV viral load twice as often as women with higher CD4 Many of the studies examining HIV and cervical neoplasia are not well controlled, lacking consistent definitions for immunodeficiency and having minimal information on the effects of antiviral therapy on the development and recurrence of CIN. Mandelblatt and c o - ~ o r k e r idens~~

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tified five well-controlled studies in which the estimated relative risk of CIN in HIV-seropositive women was approximately five times that of HIV-seronegative women. When these studies were combined, the rate of HIV-seropositive women with CIN was 30.1% compared with 8.3% of HIV-seronegative controls. Vigorous evaluation of the study data and methods in this population is warranted. There are different opinions regarding the surveillance of HIVseropositive women for cervical disease. Some authorities recommend that these women should be followed up with colposcopy, whereas others believe that regular cytologic evaluation is appropriate.l8, Because HPV infection and immunosuppression have an important role in the development, persistence, and progression of cervical dysplasia in HIV-seropositive women, evaluation with colposcopy every 6 months in patients who are markedly immunosuppressed may be appropriate. Otherwise, CDC recommendations for the HIV-seropositive patient are appropriate (see Box 1).

Box 1. HPV-Associated Genital Epithelial Cancers in HIV-Infected Women* After a complete history of previous cervical disease has been obtained, HIV-infected women should have a pelvic examination and a Papanicolaou smear. The smear should be obtained twice in the first year after the diagnosis of HIV infection and, if the results are normal, annually thereafter. *1997 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. MMWR Morb Mortal Wkly Rep (RR12):146, 1997

Many studies have demonstrated that immunosuppressed HIV-seropositive women are at a higher risk for progression and failure after treatment for CIN. Cryotherapy has been shown to be a poor treatment for dysplasia in this With the exception of cryotherapy, other previously mentioned therapies, whether excisional or ablative, are appropriate for treatment, with the understanding that close followup will be necessary. Another consideration is treatment via hysterectomy; however, these patients continue to be at risk for vaginal intraepithelial neoplasia and cancer. TREATMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA Ablative Treatment Chemical Topical concentrated trichloroacetic acid (TCA 50% to 85%) or bichloracetic acids are desiccant acids that have been used to treat CIN.

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These acids may be used safely in the vagina, cervix, and in pregnancy. Coloposcopic application is essential for best results. Failure rates with single application of cervical TCA have been significant. Boothby and co-workers3performed a randomized, double-blind study of 34 patients with histologic HPV without dysplasia who were treated with 50% TCA in a single application. They concluded that 50% TCA in a single application was ineffective in reducing HPV infection. Cold Coagulation

Cold coagulation is also a highly effective ablative treatment for CIS. The name is counterintuitive: that is, this method involves heat destruction of tissue, although the amount of heat is less than that used with other coagulation methods. A 100°CTeflon probe is applied directly to the cervical tissue. Therapy is performed using two to five applications of less than a minute's duration in a single sitting. This technique allows destruction of the transformation zone and lower endocervix. Lesion destruction via thermal transfer has been noted to be approximately 4 mm. This technique is widely used in Europe and the United Kingdom. Duncan and Gordonz1reported failure rates for treating CIS of about 7% using this method. Advantages and disadvantages are similar to those in cryotherapy. Treatment is relatively inexpensive, technically straightforward, and requires local or no anesthesia, and operative time is brief, taking 3 to 5 minutes. As is true for cautery and cryotherapy, posttreatment necrosis results in a heavy vaginal discharge, and there is destruction of tissue adjacent to the area treated. Cryotherapy

Cryotherapy is a relatively safe, easy, and inexpensive ablative treatment for CIN. As is true in any method of treatment for cervical dysplasia, the goal is destruction of the lesion, including the abnormal transformation zone. Because no pathologic specimen will be available for evaluation, strict criteria for choosing ablative treatment need to be met. Women with biopsy-confirmed CIN may be treated with cryotherapy. The severity and size of the lesion may limit the use of cryotherapy in each patient. Cryotherapy is not suitable for the following findings: lesions larger than two cervical quadrants, lesions greater than 3 cm in diameter, lesions that extend greater than 5 mm into the endocervical canal, and in patients with an unsatisfactory colposcopic examination.= Cryotherapy is also contraindicated in cases of cervical cancer, acute cervicitis, active menses, cryoglobulinemia,or in women with diethylstilbestrol in uter~.~O The cryotherapy should be performed during the early proliferative phase of the menstrual cycle to avoid possible menstrual

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flow obstruction owing to postoperative edema of the endocervical ~anal.2~ Pregnancy must be ruled out. The choices of refrigerants are carbon dioxide, liquid nitrogen, and the one most commonly used-nitrous oxide. The equipment necessary for nitrous oxide therapy entails a 20-pound gas cylinder, pressure gauge, cryogun, and cryoprobe tips. The efficacy of cryotherapy depends on maintaining adequate gas pressures within the cylinder. Low levels of pressure indicated by the pressure gauge can be secondary to true low levels of liquid nitrous oxide insufficient to generate nitrous oxide gas, or may result because the gas phase is depleted. Time will allow regeneration of the gas phase to normal levels adequate for treatment. The cryoprobes are available in various shapes and sizes; however, they should conform to the shape of the tissue. The flat and nippleshaped probes with diameters of 25 or 19 mm are typically used. The nipple-shaped probe should have an intracervical tip less than or equal to 5 mm in length. The lesion should be completely covered by the cryoprobe or the iceball created by the probe on the first freeze. A small amount of watersoluble gel is applied to the tip of the cryoprobe to assist in an even transfer of heat from the tissue to the probe. In cryotherapy, heat is removed from the cervix to the cryoprobe at a faster rate than heat can be delivered to the cervix by blood flow from the cervical vessels. As the gas exits the cylinder and enters the probe, it expands and results in the reduction of temperature at the probe tip. The final temperature produced and the duration of freeze determine the amount of tissue injury. For tissue necrosis to occur, the temperature of the tissue should be below -2O0C.=Above this temperature, the tissue could be viable. The "double-freeze" method entails a 3-minute freeze followed by a 5minute thaw followed by a repeat 3-minute freeze. This double-freeze method has been shown to be more effective than the single 5-minute freeze16,51 and seems to be better tolerated by the patient. Freeze duration seems to be less important than the extent of lateral iceball spread from the intracervical probe. This measurement equates to the depth of the freeze and tissue destruction in almost a one-to-one relati0nship.5~ The lethal zone is the area of cells that undergo necrosis; the temperature within that region is below - 20°C. In the region of recovery, the temperature ranges from - 20°C to O"C, and the cells, although initially frozen, are able to recover and remain viable. This region is usually 2 mm from the leading edge of the iceball.= Extensive glandular involvement by dysplastic cells, which can occur with larger and more severe lesions such as in CIN 3, may not be treated successfully if the depth of freeze is not at least 6 mm (e.g., the depth of glandular extension).To eradicate disease, an iceball of 7 mm lateral depth is necessary (e.g., a lethal zone of 5 mm plus 2 mm of depth involving tissue that will recover.= The double-freeze technique has reduced the failure rate from 49% to 19%.16 The patient should be instructed to expect a foul, profuse, watery discharge for the next 4 weeks and asked not to insert any physical structure into the vagina during this time. Nonsteroidal anti-inflamma-

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tory agents can be used 30 to 60 minutes before the procedure to decrease discomfort from the cramping and for postoperative pain. Debridement of the bullous lesion 48 hours after surgery will decrease the foul odor but will have no effect on the discharge.23Complications such as bleeding and infection are uncommon. Cervical stenosis occurs in 5% or less of women, and cervical incompetence is rare. Infertility has not been shown to be a problem after cryotherapy? Difficulty visualizing the squamocolumnar junction may be an issue, and sampling of the endocervical canal with a brush is helpful. Close follow-up should be reinforced because 5% to 15% of women treated will have residual di~ease.2~ Papanicolaou smears every 4 months for 1 year and at least one colposcopy should be done in the follow-up period. Treatment success depends largely on the size of the lesion, not necessarily on the severity of the lesion? The best results can be expected from lesions that are less than 3 cm in diameter, occupying two or fewer quadrants of the cervix, and extending no more than 5 mm into the endocervical canal. Also important is the involvement of endocervical glands with dysplastic cells that typically occurs in lesions of CIN 3 and CIS. The insulating effect of the iceball and the heat delivered by the cervical vessels can negate the freezing effect of the cryogen and limit ablation of dysplastic cells in the endocervical glands. In fact, higher treatment failures have been noted for lesions located at the 3 and 9 o’clock positions, where the cervical branches of the uterine artery are present.= CIS and CIN 3 should be treated with an excisional procedure because of the higher likelihood of glandular disease and failure with cryotherapy. Overall success rates of 89% to 91% have been reported (Table 1). Creasman and co-workers17 reported a 10% persistence rate for CIN in 770 patients that was reduced to 4% after a second freeze. Long-term 5-year follow-up has demonstrated reasonable and prospective studies have shown no significant differences among cryotherapy, laser conization, or a loop electrosurgical excision procedure (LEEP); however, patient selection is important to ensure successful results. Electrocoagulation

Cervical lesions have been treated with monopolar electrocoagulation for years with good success reported. With this method, there is a Table 1. CURE RATES FOR CRYOTHERAPY IN SQUAMOUS INTRAEPITHELIAL LESIONS Study

CIN 1 (%)

CIN 2 (“7)

Overall (%)

CIN 3 (%) ~~

Ostergard, 1980 Benedet et al, 1981 Stuart et al, 1982 Ferris et al, 1993

93.7 95.0 94.4 94.0

CIN = cervical intraepithelia neoplasia.

92.5 90.0 92.5 93.0

80.4 86.5 82.8 84.0

91.6 88.0 89.8 -

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continuous flow of electrons from the generator to the handpiece tip back to the generator via the grounding pad and the patient. The electron flow is highly "channeled" through the small surface area of the handpiece tip and spread over a large-area grounding pad as the electrons make the circuit. The result is a concentrated thermal effect at the handpiece tip and no thermal effect at the grounding pad. At 45"C, irreversible tissue damage occurs that is not usually visible to the naked eye. At 100°C, desiccation occurs. At greater than 1OO"C, vaporization and carbonization occur. The most efficient way to obtain deep thermal damage at the tissue level is a low continuous current (e.g., cutting current) with a large-surface-area handpiece tip (e.g., a ball electrode). The ball should be used in contact mode (placed directly on the tissue) and held in place long enough to obtain deep penetration into the cervical glands. Firm pressure on the tip against the surface is essential to achieve the broad surface contact. The initial effect of the electrons spreading to seek a ground will be instant superficial disiccation. This damage looks effective, but, in fact, no significant underlying thermal damage has occurred. As the tip is left in the same place a longer time, the electrons pass through gaps in the partially charred superficial layer via a discontinuous, spotty fashion to the deeper layers. Heat is created in the deeper layers. This same method has been shown to be effective in endometrial ablation using hysteroscopic rollerball techniques. Electrocautery has been shown to be effective in the treatment of ~ CIN, with failure rates ranging from approximately 3% to 1 3 Y 0 . ~The incidence of serious complications, such as an incompetent cervix, bleeding, infection, and sexual dysfunction, has been extremely low. In most reports, regional or general anesthesia has been required to perform electrocautery. Local cervical anesthesia is not generally effective to obtain true thermal destruction to deeper cell layers. Another disadvantage of electrocautery is that no biopsy specimen remains to rule out invasive disease. Given that there will be no specimen to evaluate, the provider must be sure the sampling before treatment is adequate to rule out preinvasive or invasive disease. Laser Vaporization

Carbon dioxide laser vaporization continues to be used widely, with excellent success rates for treating CIN. The CO, laser is unique in that the energy is almost entirely absorbed by very thin layers of water. This effect of makes deep tissue penetration difficult if the cell structure contains water. Distribution of the CO, laser beam is not uniform; it is greatest in the beam center and decreases as it reaches the periphery. The result is tissue destruction primarily at the vaporization site. This limitation adds a margin of safety that some surgeons prefer. The CO, laser may be mounted on a colposcope and controlled using a micromanipulator (e.g., toggle switch) to move the beam. The spot size and power and mode settings may be adjusted to the surgeon's

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preference. The entire transformation zone must be visualized using acetic acid, Schiller's, or Lugol's solution. Only when the most atypical areas of pathology are noted should the surgeon proceed with laser treatment. Most authorities agree that, for adequate success rates in treating CIN, the following factors are important: (1) destruction over the lesion to a visual depth of 5 to 7 mm (sometimes, a measurement of 8 to 10 mm from the most distal plane of the ectocervix) so that glandular involvement is treated; (2) a 5-mm visible width of destruction beyond the visible lesion; (3) a continuous tissue exposure mode setting; and (4) high-power settings of 20 to 25 W. Effective surgical anesthesia can be obtained using a paracervical block with a local anesthetic. Bleeding can be managed using a defocused beam. Vasopressive agents can be added to the anesthetic (dilute vasopressin or epinephrine) if desired to aid with hemostasis. The success of CO, laser vaporization for treating CIN has been shown to be excellent, with failure rates of approximately 5% to 6%.5 Although similar failure rates have been reported with cryotherapy, laser vaporization offers several advantages. First, treatment can be localized to the area of pathology using colposcopic guidance. Tissue healing with the laser is faster and more efficient than with cryotherapy. Complete healing is seen in about 3 weeks. The new squamocolumnar junction is located at the level of the external os, allowing easy, close follow-up. There is minimal tissue necrosis and less vaginal discharge in comparison with the effects of cryotherapy. Disadvantages of laser ablation are the high equipment cost, advanced training required, and a small risk of hemorrhage.

Excisional Techniques Excisional techniques have been an effective treatment for CIN for many years. There has been a range of aggressiveness, ranging from Wertheim's hysterectomy in the 1940s to LEEP excision of specific lesions ~ * " determining the type of excisional technique to in the 1 9 9 0 ~ . ~Factors offer the patient are the pathology present, the prior CIN history, the colposcopic findings, the size of lesion, the desire for future fertility, HIV status, and patient compliance or access to follow-up.

Total Hysterectomy Historically, hysterectomy was a mainstay of excisional therapy for CIS. With the advent of more sensitive outpatient diagnostic modalities and less invasive treatment modalities, hysterectomy is now rarely indicated for CIN. Hysterectomy might be considered for (1) patients who have high-grade lesions who have failed conservative treatments, (2) patients who have high-grade lesions who desire sterilization, (3) patients who have high-grade lesions who cannot be treated adequately

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with local therapies, and (4) patients who have high-grade lesions who have no access for follow-up diagnostic procedures after a conservative therapy. Disadvantages of hysterectomy are the requirement for hospitalization, the requirement for regional or general anesthesia, the increased surgical risk, and the risk for complications. It is sometimes more difficult diagnostically to follow-up vaginal neoplasia that occurs posthysterectomy.

Cold-Knife Conization Excisional conization is the treatment of choice for patients with CIN and an unsatisfactory colposcopic examination. The cold-knife procedure involves surgical excision with a scalpel and requires an operating room and regional or general anesthesia. One advantage over Loop Electrical Excision Procedure (LEEP) conization is that the surgeon can excise any size or shape cone as needed to ensure removal of the entire lesion. Cold-knife conization also provides a specimen with no thermal artifact at the surgical margins. LEEP electrodes may be of insufficient size when the cervix is large, such as in pregnancy. Disadvantages of cold-knife as compared with LEEP conization are the risk of hemorrhage, infection, cervical stenosis, and increased pregnancy wastage.34Some surgical techniques for hemostasis with cold-knife conization may significantly alter the location of the transformation zone, making diagnostic follow-up more difficult. Furthermore, Faught and co-workers noted that LEEP was as safe and effective as cone biopsy in patients with unsatisfactory colposcopyl,22 Cold-knife conization is largely being replaced with LEEP conization. LEEP/LLETZ

Loop electrical excision procedure and large loop excision of the transformation zone (LLETZ) are relatively simple outpatient treatments for CIN. Indications for LLETZ are as follows: Unsatisfactory colposcopic examination Treatment of biopsy-proven CIN 2, CIN 3, and CIS Suspicion of squamous microinvasive disease or adenocarcinoma in situ Persistent CIN 1 for 1 year or noncompliant patient Two-grade discrepancy between the cytologic, colposcopic, or histologic diagnosis Symptomatic cervical ectropion Treatment success with LEEP has been shown to be comparable with the success of laser conization and cold-knife conization.28Cartier7 was the first to describe the use of loop diathermy for the diagnosis and treatment of CIN, and Prendville and Cullimore4 made some modifica-

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tions that improved the cautery effect and bleeding. A variety of electrosurgical units have been evaluated for safety, cautery effect, and design. LEEP/LLETZ can be performed for the treatment of CIN 1 to 3 for the same indications for which laser conization and cold-knife conization are used. The patient should have a colposcopic evaluation before LLETZ to delineate the extent of the lesion on the ectocervix and involvement of the endocervical canal. If dysplasia is noted on endocervical curettage, a “top-hat” shaped LLETZ conization for the endocervical transformation zone should be done. After the lesion is assessed colposcopically with 3% acetic acid and delineated with Lugol’s solution, local anesthesia can be administered. Intracervical infiltration versus paracervical infiltration with 10 mL of 1%lidocaine seems to be effective, although this technique is operator dependent. In patients without ischemic heart disease, intracervical infiltration of a local anesthetic mixed with a vasoconstrictive agent such as epinephrine or vasopressin may be used to minimize and often eliminate operative hemorrhage. The authors prefer a mixture of 1% lidocaine and vasopressin (5 U of vasopressin in 30 mL of 1% lidocaine). This mixture results in excellent hemostasis and avoids the anxiety and tachycardia associated with epinephrine preparations. Operative hemorrhage may be noted on occasion despite this technique; in these cases, cauterization with a ball electrode is effective in achieving hemostasis. Other options for postexcision bleeding are ferric subsulfate (Monsel’s solution), silver nitrate, and, of course, suturing the cervix, if necessary. Side effects are hemorrhage in 1%to 2% cases, infection, and cervical stenosis in rare cases.32,44 Ideally, the best specimen for pathologic evaluation is one with minimal cautery effect and is obtained using a pure cut current with the lowest effective wattage. Wattage will need to be increased or decreased proportionally to the surface area of the wire loop in contact with cervical tissue. In patients in whom hemostasis is an issue, such as in patients who are pregnant, a blend of cutting and coagulation current may be required. The choice of loop for removal of tissue should be based on the distribution of the lesion on the cervix and known glandular involvement. The goal of the LLETZ procedure is to remove the transformation zone with the lesion completely and obtain an adequate margin of normal tissue. A 5-mm margin surrounding the transformation zone is preferred. Identifying the 12 o’clock position with a suture is helpful for pathology staff for orientation and localization of disease. A smaller loop excision of the endocervix following the LLETZ should be done in patients with a positive endocervical curettage. Excellent treatment success rates and low complication rates have led to widespread use of LEETZ.I9 LLETZ has a greater than 90% success rate in treating CIS, with a low recurrence rate of between 4% and 57’0.3~

HPV Vaccine HPV-16 virus is known to be present in approximately 50% of all cervical cancers. HPV-18,31, and 45 account for the bulk of all the types

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found in cervical cancers. Recently, efforts have been made to develop an HPV-16 vaccine. A phase I, double-blinded, placebo-controlled trial of the HPV-16 L1 VLP vaccine has been done. The study of 58 women and 14 men demonstrated a marked immune response to HPV-16 vaccine that was 40 times higher than the typical immune response seen with natural HPV infection. All of the vaccine preparations were well tolerated, and all of the study participants seroconverted. The most adverse side effect was a mild irritation in the area of vaccine injection.28a The potential of developing vaccines against even more aggressive HPV16 variants, which pose greater risk for cervical cancer, is encouraging. References 1. American College of Obstetricians and Gynecologists: Cervical Cytology: Evaluation and Management of Abnormalities. Technical Bulletin Number 183, August, 1993 2. Benedet JL, Miller DM, Nickerson KG, et a1 Results of cryosurgical treatment of cervical intraepithelial neoplasia at one, five and ten years. Am J Obstet Gynecol 157268,1987 3. Boothby RA, Carlson JA, Rubin M, et a1 Single application treatment of human papillomavirus infection of the cervix and vagina with trichloroacetic acid A randomized trial. Obstet Gynecol 76:278, 1990 4. Boyes DA, Worth AJ, Anderson GH: Experience with cervical screening in British Columbia. Gynecol Oncol 12143, 1981 5. Burke L: The use of carbon dioxide laser in cervical intraepithelial neoplasia. Am J Obstet Gynecol 144.337, 1982 6. Burke L Clinical opinion: Evolution of therapeutic approaches to cervical intraepithelial neoplasia. Journal of Lower Genital Tract Disease 1:267,1997 7. Cartier R Practical Colposcopy, ed 2. Paris, Laboratorie Cartier, 1984, pp 139-156 8. Centers for Disease Control and Prevention: 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. M W R Morb Mortal Wkly Rep 41:1, 1992 9. Chanen W, Rome RM: Electrocoagulation diathermy for cervical dysplasia and carcinoma insitu: A 15-year survey. Obstet Gynecol61:673, 1983 10. Chokunonga E, Levy LM, Bassett MT, et al: Cancer incidence in the African population of Harare, Zimbabwe: Second results from the cancer registry, 1993-1995. Int J Cancer 8554,2000 11. Clavton DH. Yuk-Yinp:SP: Safetv and immunoeenicitv trial in adult volunteers of 16L1 vi&hike partical v;ccine.'J Natl Cancer Inst 93,2001 h&an papiloma vi&: 12. Cox JT ASCCP practice guidelines: Management of glandular abnormalities in the cervical smear. Journal of Lower Genital Tract Disease 1:41,1997 13. Cox JT, Wilkinson E, Lonky N, et a1 ASCCP practice guidelines: Management guidelines for the follow-up of atypical squamous cells of undetermined significance.Journal of Lower Genital Tract Disease 499,2000 14. Cox JT: ASCCP practice guidelines: Management guidelines for the follow-up of cytology read as low grade squamous intraepithelial lesion. Journal of Lower Genital Tract Disease 483-92,2000 15. Cramer DW, Cutler SJ: Incidence and histopathology of malignancies of the female genital organs in the United States. Am J Obstet Gynecol 118:443, 1974 16. Creasman WT: Efficacy of cryosurgical treatment of severe cervical intraepithelial neoplasia. Obstet Gynecol4501, 1973 17. Creasman WT: Results of outpatient therapy of cervical intraepithelial neoplasia Gynecol Oncol 12306, 1984 18. Del Priore G: The value of cervical cytology in HIV-infected women. Gynecol Oncol 56395,1995 -

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19. DiSaia PJ, Creasman WT (eds): Preinvasive disease of the cervix, vagina and vulva. In Clinical Gynecologic Oncology, ed 5. St. Louis, CV Mosby, 1997, pp 1-50 20. Dorysey J H Recurrent cervical intraepithelial neoplasia (CIN) and the endocervical button. Colpo Gynecol Laser Surg 1:221,1984 21. Duncan ID, Gordon H: Effective destruction of Cervical Intraepithelial Neoplasia (CIN) 3 at 100°C using the Semm cold coagulator: Fourteen years experience. British Journal of Obstetrics and Gynaecology 9814-20,1991 22. Faught W, Prevost MR, Fung MFK, et al: Efficacy of loop electrosurgical excision procedure as compared to cold-knife cone biopsy in patients with unsatisfactory colposcopy. Journal of Lower Genital Tract Disease 3:116-120, 1999 23. Ferris DG: Cyrotherapy of the cervix. Journal of Lower Genital Tract Disease 2:2, 1998 24. Ferris DG, Crawley GR, Baxley EG, et ak Cryotherapy precision: Clinician’s estimate of cryosurgical iceball lateral spread of freeze. Arch Fam Med 2269, 1993 25. Ferris DG, Saxena S, Hainer BL, et a1 Gynecologic and dermatologic electrosurgical units: A comparative review. J Fam Pract 39:160, 1994 26. Galvin GA, TeLinde R W The present-day status of non-invasive cervical carcinoma. Am J Obstet Gynecol5715, 1949 27. Goedert JJ: The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oncol27390,2000 28. Gonzalez-Bosquet, et al: Treatment of cervical intraepithelial neoplasia in a prospective study comparing large-loop excision of the transformation zone, laser vaporization and knife cone biopsy. Journal of Lower Genital Tract Disease 1:4228, 1997 28a. Harro CD, Pang YS, Roden RB, et al: Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. Journal of the National Cancer Institute 93:4, 2001, pp 284-292 29. Heard I, Tassie JM, Schmitz, et a1 Increased risk of cervical disease among human immunodeficiency virus-infected women with severe immunosuppression and high human papillomavirus load. Obstet Gynecol96403,2000 30. Kalstone C: Cervical stenosis in pregnancy: A complication of cryotherapy in diethylstilbestrol-exposed women. Am J Obstet Gynecol 166502,1992 31. Klein RS,Ho GY, Vermund SH, et al: Risk factors for squamous intraepithelial lesions on pap smear in women at risk for human immunodeficiency virus infection. J Infect Dis 1701404,1994 32. Krumholz B A The treatment of premalignant lesions of the uterine cervix. Journal Lower Genital Tract Disease 1232, 1997 33. LaRuche G, et al: Human papillomavirus and human immunodeficiency virus infections: Relation with cervical dysplasia-neoplasia in African women. Int J Cancer 76:480, 1998 34. Leinman G, Harrison NA, Reuben A: Pregnancy following conization of the cervix: Complications related to cone size. Am J Obstet Gynecol 13614, 1980 35. Maiman M, Fmchter RG, Serure, et al: Human immunodeficiency virus infection and cervical neoplasia. Gynecol Oncol 38:377, 1990 36. Maiman M, Fruchter RG, Serure, et al: Recurrent cervical intraepithelial neoplasia in human immunodeficiency virus seropositive women. Obstet Gynecol 82:170, 1993 37. Mandelblatt JS, Fahs M, Garibaldi K, et a 1 Association between HIV infection and cervical neoplasia: Implications for clinical care of women at risk for both conditions. AIDS 6:173, 1992 38. Montero JA, Larkin JA, Houston SH, et al: Examining the complex relationship of human papillomavirus to cervical dysplasia and carcinoma. Medscape Womens Health 2:1, 1997 39. Ortiz R, Newton M, Tsai A Electrocautery treatment of cervical intraepithelial neoplasia. Obstet Gynecol 78:80, 1991 40. Ostergard D R Cryosurgical treatment of cervical intraepithelial neoplasia. Obstet Gynecol56231, 1980 41. Papanicolaou GN, Traut H F The diagnostic value of vaginal smears in carcinoma of the uterus. Am J Obstet Gynecol42193,1941 42. Parashevadis E, Jandial L, Mann EMF, et al: Patterns of treatment failure following

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laser for cervical intraepithelial neoplasia: Implications for follow-up protocol. Obstet Gynecol 78:80, 1991 43. Pearse W H Consensus report on frequency of Pap smear testing. American College of Obstetricians and Gynecologists Newsletter 323, 1988 44. Prendville W, Cullimore S Large-loop excision of the transformation zone (LLETZ): A new method of management for women with cervical intraepithelial neoplasia. Br J Obstet Gynaecol 96:1054, 1989 45. Richart RM, Townsend DE, Crisp W, et a 1 An analysis of ”long term” follow-up results in patients with cervical intraepithelial neoplasia treated by cryotherapy. Am J Obstet Gynecol 137823, 1980 46. Ries LAG, Miller BA, Hankey BF, et al: SEER Cancer Statistics Review, 1973-1991: Tables and graphs. NIH Publication No. 94-2789. Bethesda, MD, National Cancer Institute, 1994 47. Robinson W Invasive and preinvasive cervical neoplasia in human immunodeficiency virus-infected women. Semin Oncol27463, 2000 48. Rubin SC, et al: Cervical cancer preinvasive neoplasia. In Management of the Abnormal Pap Smear During Pregnancy. Philadelphia, Lippincott-Raven, 1996 49. Ruben SC, Hoskins WJ: Cervical cancer and preinvasive neoplasia. In Epidemiology of Cervical Neoplasia. Philadelphia, Lippincott-Raven, 1996, pp 1-12 50. Schafer A, Friedman W, Mielke M, et a1 Increased frequency of cervical dysplasia/ neoplasia in HIV-infected women is related to the extent of immunosuppression. Am J Obstet Gynecol 164:593, 1991 51. Schantz A, Thorman L: Cryosurgery for dysplasia of the uterine ectocervix: A randomized study of the efficacy of the single and double freeze techniques. Acta Obstet Gynecol Scand 63:417, 1984 52. Solomon D Comparison of three management strategies for patients with atypical squamous cells of undetermined sigruficance: Baseline results from a randomized trial. J Natl Cancer Inst 4293-299, 2001 53. Spitzer M Lower genital tract intraepithelial neoplasia in HIV-infected women: Guidelines for evaluation and management. Obstet Gynecol Sur 54:131,1999 54. Stuart GC, Anderson RJ, Corlett BM, et a 1 Assessment of failures of cryosurgical treatment in cervical intraepithelial neoplasia. Am J Obstet Gynecoll42658,1982 55. The National Cancer Institute Workshop: The 1988 Bethesda system for reporting cervical/vaginal cytological diagnoses. JAMA 262931, 1989 56. The National Cancer Institute Workshop: The Bethesda system for reporting cervical/ vaginal cytological diagnoses. Acta Cytol 37115, 1993 57. Torre D Understanding the relationship between lateral spread of freeze and depth of freeze. J Dermatol Surg Oncol551, 1979 58. Townsend DE: Cryosurgery for CIN. Obstet Gynecol Surv 345328, 1979 59. US Preventive Services Task Force: Screening for cervical cancer. In Guide to Clinical Preventative Services: An Assessment of the Effectiveness of 169 Interventions. Baltimore, Williams and Wilkins, 1989, pp 57-62 60. Vermund SH, Kelley KF, Klein RS, et al: High risk of human papillomavirus infection and squamous intraepithelial lesions among women with symptomatic human immunodeficiency virus infection. Am J Obstet Gynecol 165:392, 1992 61. Weed JC Jr, Curry SL, Duncan ID, et al: Fertility after cryotherapy of the cervix. Obstet Gynecol52:245-246, 1978 62. Wright TC Jr, Ellerbrock TV, Chiasson MA, et a1 Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: Prevalence, risk factors, and validity of Papanicolaou smears. Obstet Gynecol4591-597, 1994

Address reprint requests fo: Lisa C. Flowers, MD Department of Gynecology and Obstetrics Division of Gynecologic Oncology 1639 Pierce Drive, Room 4305 Atlanta, GA 30322 e-mail: [email protected]