Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment

INTRODUCTION — Cervical intraepithelial neoplasia (CIN) is a premalignant lesion of the uterine cervix that is classified as low grade (CIN 1) or high grade (CIN 2,3) based on the risk of progression to malignancy. In managing patients with CIN, the goal is to prevent possible progression to invasive cancer while avoiding overtreatment of lesions that are likely to regress. Surveillance or observation is appropriate for some patients with low-risk lesions whereas treatment with an excisional or ablative procedure is recommended for patients with higher risk lesions.

Excisional treatments are referred to as cone biopsies or cervical conization and include cold knife conization, loop electrosurgical excision procedure (LEEP; also called large loop excision of the transformation zone [LLETZ]), and laser conization. Ablative treatments include cryotherapy, CO₂ laser ablation, and thermal ablation (eg, diathermy, cold coagulation). Hysterectomy is unacceptable as a primary treatment for CIN but is an option for patients who are incompletely treated with excision or ablation or who have recurrent CIN.

This topic will discuss choosing between excision and ablation in patients who are candidates for surgical treatment. It will also discuss the prognosis after this treatment and recommendations for follow-up. The overall approach to management of CIN (surveillance versus observation versus treatment) and details about the various excisional and ablative techniques are reviewed separately.

●(See "Cervical intraepithelial neoplasia: Management".)

●(See "Cervical intraepithelial neoplasia: Diagnostic excisional procedures" and "Cervical intraepithelial neoplasia: Ablative therapies".)

CHOOSING THE TREATMENT APPROACH

Factors to consider in choosing excision versus ablation — In the United States, excision, specifically with loop electrosurgical excision procedure (LEEP), has largely replaced the practice of ablation. In our practice, when treatment is performed, we prefer excision over ablation for all CIN grades because it provides a diagnostic specimen, which we like to review even when a diagnostic specimen is not essential. This is consistent with the World Health Organization, which recommends LEEP over cryotherapy in settings where LEEP is available [1]. By comparison, the American Society for Colposcopy and Cervical Pathology states that excision or ablation is acceptable treatment for CIN 1 (when treatment is indicated) but prefers excision over ablation for CIN 2,3. (See "Cervical intraepithelial neoplasia: Management".)

Clinicians and patients should consider the following factors when choosing a treatment approach.

Is a diagnostic specimen needed? — A diagnostic specimen is needed, and therefore an excisional procedure is required, when:

●A lesion extends into the cervical canal and cannot be fully visualized [1].

●A lesion covers >75 percent of the ectocervix or is beyond the reach of the cryoablation tip [1].

●The endocervical curettage demonstrates CIN 2+ (or CIN that cannot be graded) [2].

●The patient has had a previous excision for CIN 2+ [2].

●Glandular disease (including adenocarcinoma in situ [AIS]) is present [3]:

•Glandular disease may be located in the transformation zone or endocervical canal, and lesions are often not contiguous ("skip lesions"); therefore, an excisional biopsy is needed to confirm the diagnosis and assess the extent of disease. (See "Cervical cytology: Evaluation of atypical and malignant glandular cells" and "Cervical adenocarcinoma in situ", section on 'Confirmation of diagnosis and assessment of extent of disease'.)

The incidence of occult squamous carcinoma and glandular disease detected by an excisional procedure was illustrated in a study of 1189 patients who underwent LEEP; 6 patients (0.5 percent) had microinvasive squamous carcinoma and 15 (1.3 percent) had AIS [3]. Two (33 percent) of the squamous carcinomas and 10 (67 percent) of the AIS patients were not recognized by cytology and colposcopy. Another series of 3738 patients who underwent laser ablation for CIN reported nine cervical cancers (0.24 percent) during follow-up [4].

●There is diagnostic uncertainty [2]:

•Patients with an inadequate colposcopic examination (eg, the entire squamocolumnar junction or lesion cannot be visualized).

•Patients with inconsistent findings on cytology versus colposcopy (ie, high-grade squamous intraepithelial lesion [HSIL] on cervical cytology followed by a colposcopic finding of CIN 1 in patients 25 years and older). (See "Cervical intraepithelial neoplasia: Management", section on 'Preceded by ASC-H or HSIL'.)

●There is a high risk of invasive disease [2]:

•For patients in whom cervical cancer is suspected, it is crucial to obtain diagnostic information and evaluation of surgical margins.

•Use of p16 staining of the colposcopic biopsy specimen may improve classification and risk stratification of these lesions [5]. However, reporting of p16 status is not universally available.

Is excision more effective than ablation? — In patients with high-grade disease (CIN 2,3), use of any therapy other than excision should be supported by high-quality evidence showing that forgoing the diagnostic information provided by excision does not worsen prognosis; however, there are few high-quality data comparing outcomes of excision versus ablation in this setting. Although the efficacy rate (eg, residual disease after treatment) for both ablation and excision has been reported to be approximately 90 to 95 percent [6-8], the meta-analyses below indicate that it remains unclear whether ablation is as effective as excision. Therefore, many practices and societal organizations prefer excision [1,2].

●A 2022 network meta-analysis including over 19,000 patients with CIN and stage IA1 cervical cancer from 71 randomized and observational studies evaluated the risk of treatment failure with various treatment methods. Compared with LLETZ (the most commonly used technique), patients treated with ablation methods had higher rates of treatment failure (laser ablation: odds ratio [OR] 1.8, 95% CI 1.3-2.3; cryotherapy OR 1.8, 95% CI 1.3-2.6) [9].

●A 2018 meta-analysis including four randomized trials demonstrated that patients with CIN (all grades) who were treated with LEEP compared with cryotherapy had lower rates of disease persistence on 6-month follow-up biopsy (20.0 versus 22.4 percent, relative risk [RR] 0.87, 95% CI 0.76-0.99) and lower rates of disease recurrence on 12-month follow-up biopsy (26.6 versus 31.0 percent, RR 0.91, 95% CI 0.84-0.99) [10]. Subgroup analysis also demonstrated a benefit of LEEP for the primary endpoint (persistence of disease on six-month follow-up biopsy) in patients with CIN 2+ (RR 0.89, 95% CI 0.77-0.98) and in trials including only HIV-positive female patients (RR 0.88, 95% CI 0.76-0.99). A limitation of this analysis is the relatively small magnitude of risk reduction coupled with a confidence interval that approaches one.

●A 2013 meta-analysis of five randomized trials, including two trials also included in the 2018 meta-analysis, compared patients with CIN (all grades) treated with an excisional method versus an ablative method, and found that there were insufficient data to conclude that one method was superior for the treatment of CIN [6].

Is future pregnancy planned? — Patients planning a future pregnancy may choose to avoid excision because it has been associated with an increased risk of adverse obstetric outcomes (eg, second-trimester pregnancy loss, preterm prelabor rupture of membranes, preterm delivery). Ablation, in theory, has a lower risk of adverse obstetric outcomes given that the cervix is better preserved than with excision. However, CIN itself may pose an increased risk of preterm birth, regardless of treatment method. Patients should be counseled about these issues, which are discussed in detail separately. (See "Reproductive effects of cervical excisional and ablative procedures".)

Does excision have greater morbidity than ablation? — Excisional methods are typically thought to be associated with greater morbidity than ablative therapy. In both of the meta-analyses discussed above [6,10], no significant difference in complications (eg, hemorrhage) or selected adverse effects (eg, pain) were found, but the analyses were not powered to detect small differences in these outcomes for specific techniques. Adverse effects that are typically reported include:

●Excision – Intraoperative bleeding, infection, and delayed hemorrhage (usually one to two weeks postoperatively).

●Ablation – Posttreatment bleeding and infection; a prolonged, heavy, watery vaginal discharge can occur after cryotherapy.

This is discussed in more detail elsewhere. (See "Cervical intraepithelial neoplasia: Diagnostic excisional procedures", section on 'Complications' and "Cervical intraepithelial neoplasia: Ablative therapies", section on 'Adverse effects and complications'.)

Other — Additional deciding factors that require shared decision making between the provider and patient include cost, availability, and convenience. For example, laser ablation equipment is costly, requires additional specialized training, and a laser procedure may require general or regional anesthesia in an inpatient setting. These issues are discussed in more detail elsewhere. (See "Cervical intraepithelial neoplasia: Ablative therapies", section on 'Choosing an ablation technique'.)

Potential candidates for hysterectomy — Hysterectomy is not a first-line treatment for CIN because the risk of significant morbidity is higher than with less invasive, yet effective, treatment modalities (eg, excision and ablation). Hysterectomy is reserved for patients with [2]:

●CIN 2,3 and positive excisional margins who have completed childbearing and in whom an additional excisional procedure cannot be performed. (See 'Positive margins' below.)

●Recurrent or persistent CIN 2,3 who have completed childbearing and in whom a repeat excisional procedure is not feasible or desired.

●Scarring or shortening of the cervix from prior treatments that prohibits a repeat excisional procedure. Scarring may increase the risk of complications of a repeat excisional procedure or limit the results of further testing (ie, scarring may obscure premalignant cells).

●Unwillingness or inability to comply with long-term follow-up.

If invasive disease is suspected, a diagnostic excisional procedure may be performed and sent for frozen section prior to hysterectomy to confirm that cervical cancer is not present and that a radical hysterectomy is not indicated [11].

In a retrospective study including almost 500 patients with cervical dysplasia (>80 percent with confirmed CIN 3) who underwent two or more LEEP procedures, hysterectomy was eventually performed in 19 percent of patients; age >40 years was a risk factor for increased rates of hysterectomy [12].

PROGNOSIS AFTER EXCISION OR ABLATION

Poor prognostic factors — Higher rates of persistent disease are associated with:

●Positive margin status [13,14].

●Human papillomavirus (HPV) DNA positivity, especially with HPV 16, six months or more posttreatment [15-20].

●Large lesion size (eg, greater than two-thirds of the surface of the cervix) [21].

●Endocervical gland involvement [22].

Prognosis by margin status — Margin status, when available, is a predictor of both disease persistence and recurrence.

Negative margins — CIN appears to have a high rate of cure when the entire lesion has been excised, but few long-term studies are available. In one study of over 4400 patients with negative margins after an excisional procedure for CIN 3, a new high-grade cytologic or histologic lesion developed in only 0.35 percent of patients after a median of 8.9 years (range 3.3 to 16.8 years) [23].

Positive margins — Studies have consistently shown that patients with positive margins after an excisional procedure, compared with negative margins, are at significantly higher risk for residual or recurrent disease [13,24-26]. Recurrence can occur years after treatment; the mean time to recurrence was almost four years in one study [14].

●In a meta-analysis of 66 studies involving over 35,000 patients who underwent an excisional procedure for any grade of CIN, patients with positive margins, compared with those with negative or uncertain margins, were at an over fivefold increased risk of any grade posttreatment CIN (relative risk [RR] 5.47, 95% CI 4.37-6.83). This effect was also seen if posttreatment CIN 2,3 was used as the endpoint (18 versus 3 percent, RR 6.09, 95% CI 3.87-9.60) [13].

●A study of 390 patients with positive margins after cold-knife conization for CIN 3 reported that the combined risk of persistent, recurrent, or progressive disease when ectocervical, endocervical, or both margins were positive was 17, 21, and 52 percent, respectively, after 6 to 30 years of follow-up [26]. Five patients developed microinvasive disease, and one patient developed stage 1B carcinoma.

Prognosis when the entire excisional specimen is negative — A completely negative excisional specimen raises concern that the lesion was missed, and, therefore, these patients should be followed similarly to those with positive margins.

In a study including over 670 loop electrosurgical excision procedure (LEEP) specimens performed for biopsy-proven, high-grade CIN, the 14 percent of patients with no evidence of CIN in the LEEP specimen had a high recurrence rate (24 percent), which was similar to that in patients with positive margins (27 percent) [27].

Prognosis when HPV is positive on follow-up testing — HPV status following treatment also appears to predict risk of recurrence, and HPV-based testing is now the primary follow-up testing technique after treatment for CIN. (See 'Type and duration of testing' below.)

In a meta-analysis of 128 studies, HPV status was more effective than positive margins in predicting recurrence; the sensitivity and specificity to predict subsequent CIN 2+ were: margin status (56 and 84 percent), high-risk HPV status (91 and 84 percent), and combination of both margin and HPV status (99 and 58 percent) [28]. Absolute CIN 2+ risks associated with each measure were: negative margins (0.8 percent), positive margins (17 percent), HPV-negative (0.8 percent), and HPV-positive (28 percent).

FOLLOW-UP AFTER TREATMENT

Type and duration of testing — The evaluation approach presented here is provided by the 2019 consensus guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP) in collaboration with multiple professional societies and government organizations in the United States and Canada, including the American College of Obstetricians and Gynecologists (ACOG), the Society of Gynecologic Oncology, the American Cancer Society (ACS), the Centers for Disease Control and Prevention, and the National Cancer Institute. The algorithms for the consensus guidelines can be found online.

Studies have consistently reported that posttreatment human papillomavirus (HPV)-based testing is more sensitive than cytology alone in detecting persistent/recurrent CIN [7,16-19,29-37] (see 'Prognosis when HPV is positive on follow-up testing' above). Therefore, HPV-based testing, rather than cytology alone, should be used for surveillance in patients 25 years and older [2]. When cytology is used, either in patients younger than 25 years or in settings where HPV-based testing is not available, cytology should occur at more frequent intervals (eg, six-month intervals when one-year HPV-based testing is recommended, and one-year intervals when three-year HPV-based testing is recommended).

●Patients with CIN (all grades) treated with ablation or excision (and with negative margins) should be followed with [2,38] (see 'Negative margins' above):

•For patients ≥25 years (algorithm 1) – HPV-based testing at six months; cervical cytology is acceptable only if HPV-based testing is not available.

-If HPV is positive, then colposcopy and biopsies should be performed and managed based on these results.

-If HPV is negative, then HPV-based testing should occur annually for three years.

-If HPV remains negative, then HPV-based testing can occur every three years for at least 25 years.

•For patients <25 years – Cervical cytology at six months.

-If cervical cytology is high-grade squamous intraepithelial lesion (HSIL) or atypical squamous cells cannot exclude HSIL (ASC-H), then colposcopy with biopsies should be performed and managed based on these results.

-If cervical cytology is low-grade squamous intraepithelial lesion (LSIL) or less (LSIL, HPV-positive atypical squamous cells of undetermined significance [ASC-US]) and persists, then colposcopy with biopsies should be performed and managed based on these results.

-If cytology is negative, then cytology should occur at six-month intervals for three years.

-If cytology remains negative, then cytology can occur annually. When the patient reaches the age of 25, testing can transition to the HPV-based model and occur every three years, as above.

●Patients with CIN 2,3 treated with excision (and with margins and/or endocervical curettage [ECC] that is positive for CIN 2+) should be followed with [2,38] (see 'Positive margins' above):

•For patients <25 years or those ≥25 years in whom there is concern about the potential effect of treatment on future pregnancy outcomes, observation (with HPV-based testing in six months [preferred] or colposcopy plus ECC at six months) is recommended.

-If HPV is negative, then HPV-based testing should occur annually for three years. If testing remains negative, then HPV-based testing can occur every three years for at least 25 years.

-If HPV is positive, then colposcopy and targeted biopsies should be performed and managed based on these results.

-If CIN 2+ continues, repeat excision should be performed.

-If repeat excision is not feasible or desired, hysterectomy is recommended.

•For patients ≥25 years and in whom future pregnancy and potential obstetric outcomes are not a primary concern, repeat excision or observation (with HPV-based testing [preferred] or colposcopy plus ECC at six months) are acceptable.

●If hysterectomy is performed, management is as follows [2,38]:

•Patients with CIN 2,3 on hysterectomy specimen or patients who underwent a hysterectomy for a history of CIN 2,3 have an increased risk of disease recurrence [39-44] and should be followed with:

-HPV-based testing annually for three years.

-If HPV is positive, cytology should be performed. Interpretation and management of vaginal cytology results are discussed separately. (See "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Vaginal cytology'.)

-If HPV is negative for three consecutive years, long-term follow-up with HPV-based testing at three-year intervals is performed for 25 years.

•Patients with CIN 1 or less on the hysterectomy specimen and no history of CIN 2+ can discontinue follow-up testing.

A meta-analysis including 19 studies of hysterectomy patients reported the following rates of abnormal vaginal cytology in patients with a history of CIN: for patients with CIN 1,2 (3.1 percent abnormal cytology, 1.3 percent abnormal biopsy, no cancers) and for patients with CIN 3 (14.1 percent abnormal cytology, 1.7 percent abnormal biopsy, one vaginal cancer) [45]. In a retrospective study of patients with CIN 2,3 diagnosed before or at hysterectomy, 7 of 94 (7 percent) had vaginal neoplasia on follow-up (five cases of vaginal intraepithelial neoplasia and two vaginal cancers) [46].

●Patients in whom a complete history is not available – In our practice, we ask all patients about their cervical cancer screening history and obtain medical records whenever possible. The medical record is important because many patients do not recall their abnormal Papanicolaou (Pap) history, may not have been told a specific diagnosis, or may incorrectly report a normal screening history. If the medical records cannot be obtained, we rely on the patient's reported results:

•If a patient is certain that an excisional procedure or ablation has been performed, we regard this as a positive history of CIN 2,3 and follow the patient as described in the bullet above for patients with CIN (all grades) treated with ablation or excision (and with negative margins).

•If a patient reports a history of "an abnormal Pap smear," we regard the history as uncertain and begin age-based cervical cancer screening. (See "Screening for cervical cancer in resource-rich settings".)

Evidence — Patients who have a history of CIN 2,3 or adenocarcinoma in situ and who have been appropriately treated or who had spontaneous regression of cervical neoplasia should have follow-up testing for at least 25 years following diagnosis, even if this extends screening past age 65 years, based on guidelines from ACOG, ASCCP, ACS, and the American Society for Clinical Pathology [2,38,47]. Testing may be discontinued earlier in patients in poor health and with a limited life expectancy.

Longitudinal studies have shown that patients with a history of CIN 2,3 have a 5- to 10-fold higher risk of cervical cancer compared with the general population. While most disease recurrence presented within two years, the risk persisted as long as 20 to 25 years [7,39-44,48]. One retrospective study of over 37,000 patients followed for 18 years after treatment found the rate of cervical cancer was higher in patients treated for CIN (81 percent with CIN 2,3; the remainder had CIN 1) compared with patients without CIN (37 versus 6 per 100,000 woman-years) [43]. In addition, a systematic review of retrospective studies of patients treated for CIN reported a rate of cervical cancer of 56 per 100,000 woman-years until 20 years after treatment (versus 5.6 per 100,000 woman-years in the general population); only three studies followed patients for 16 to 20 years [40].

While the professional societies' recommendation for prolonged screening applies only to patients with CIN 2,3, a major limitation of the data cited above is that they include patients treated for CIN 1. Other data show that the risk of cervical cancer following CIN 1 is significantly lower than for CIN 2,3. (See "Cervical intraepithelial neoplasia: Management".)

Timing of future pregnancy — There are few studies regarding how long patients should wait to conceive after treatment. We suggest an interval of three months or longer from an excisional procedure to conception. (See "Reproductive effects of cervical excisional and ablative procedures", section on 'Timing of conception after treatment of CIN'.)

Role of HPV vaccination — For patients who are candidates, HPV vaccination should be offered; a history of CIN is not a contraindication to vaccination. This is discussed in detail separately. (See "Cervical intraepithelial neoplasia: Management", section on 'HPV vaccination in patients with CIN'.)  

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical cancer screening, prevention, and management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Management of a cervical biopsy with precancerous cells (Beyond the Basics)" and "Patient education: Follow-up of low-grade abnormal Pap tests (Beyond the Basics)" and "Patient education: Follow-up of high-grade or glandular cell abnormal Pap tests (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – The mainstay of treatment of cervical intraepithelial neoplasia (CIN) is excision or ablation of the transformation zone (ie, the area of the cervix at which the ectocervical squamous epithelium transitions to the endocervical glandular epithelium). (See 'Introduction' above.)

●How to choose – For most patients with CIN who require treatment, we suggest excision rather than ablation (Grade 2C). The available evidence suggests that excision may have slightly greater efficacy compared with ablation. Excision also provides a diagnostic specimen, which may be required in some cases. However, ablation may be a reasonable alternative among select patients planning future pregnancy as excision may be associated with worse obstetric outcomes (eg, second-trimester pregnancy loss, preterm prelabor rupture of membranes, preterm delivery). (See 'Choosing the treatment approach' above.)

●Role of hysterectomy – Hysterectomy is not a first-line treatment for CIN. Hysterectomy is a reasonable option for patients with any of the following (see 'Potential candidates for hysterectomy' above):

•CIN 2,3 and positive excisional margins who have completed childbearing and in whom an additional excisional procedure cannot be performed.

•Recurrent or persistent CIN 2,3 who have completed childbearing and in whom a repeat excisional procedure is not feasible or desired.

•Scarring or shortening of the cervix from prior treatments that prohibits a repeat excisional procedure.

•Unwillingness or inability to comply with long-term follow-up.

●Risk factors for persistent disease – Risk factors for persistent disease after excision or ablation include positive margin status, human papillomavirus (HPV) DNA positivity posttreatment, large lesion size, and endocervical gland involvement. (See 'Prognosis after excision or ablation' above.)

●Follow-up

•After treatment, follow-up testing is determined by several factors (eg, patient age, CIN grade, margin status [if available], type of procedure [ie, excision or ablation versus hysterectomy]). Management of histologic HSIL is presented in the algorithm (algorithm 1). (See 'Type and duration of testing' above.)

•Although CIN appears to have a high rate of cure when the entire lesion has been excised, a completely negative excisional specimen raises concern that the lesion was missed; thus, these patients are followed similarly to those with positive margins. (See 'Prognosis when the entire excisional specimen is negative' above.)

•For patients who are candidates, HPV vaccination should be offered; a history of CIN is not a contraindication to vaccination. (See 'Role of HPV vaccination' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Christine Holschneider, MD, who contributed to earlier versions of this topic review.