Cervical intraepithelial neoplasia: Management

INTRODUCTION — Cervical intraepithelial neoplasia (CIN) is a premalignant squamous lesion of the uterine cervix diagnosed by cervical biopsy and histologic examination [1]. The goal of management is to prevent possible progression to cancer while avoiding overtreatment since lesions can spontaneously regress and treatment can have morbid effects.

The initial approach to management of patients with CIN is reviewed here. This approach is derived from 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, the Society of Gynecologic Oncology, the American Cancer Society, the Centers for Disease Control and Prevention, and the National Cancer Institute. These guidelines are intended for use in the United States and Canada and other high-resource settings.

The algorithms for the consensus guidelines can also be found online [2].

Related issues, including terminology (figure 1), epidemiology, pathogenesis, treatment (excision, ablation), and adverse effects of treatment, are discussed separately:

●(See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention".)

●(See "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment".)

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

●(See "Cervical intraepithelial neoplasia: Ablative therapies".)

●(See "Reproductive effects of cervical excisional and ablative procedures".)

OVERVIEW

Rationale — The initial approach to management of CIN is primarily based on the patient's risk for progression to cancer, but also considers treatment-related morbidity and the likelihood of compliance with a management plan. There are two general approaches:

●Close observation with human papillomavirus (HPV) testing, cervical cytology, and/or colposcopy.

●Treatment with excision or ablation of the cervical transformation zone, which is the anatomic area containing the transition from the squamous epithelium of the ectocervix to the glandular epithelium of the endocervix and specialized cells that are thought to be susceptible to HPV infection and transformation. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention".)

Hysterectomy is occasionally performed instead of excision or ablation but is unacceptable as a primary treatment for CIN in most instances. Medical therapies have also been described. (See 'Investigational therapies' below.)

A patient's risk for progression to cancer is related in large part to their age and CIN grade:

●Age – Patients younger than 25 years have a lower risk of developing cervical cancer than patients 25 years and older [3-6].

●CIN grade – CIN 1 is a low-grade lesion that has a low potential for progression to malignancy and a high potential for regression [7], while CIN 2,3 is a high grade lesion that has a higher potential for progression and a lower potential for regression [8-14].

Thus, observation is the preferred approach for most younger patients and those with CIN 1. Because some CIN 2 lesions will regress, observation is also an option for some patients with CIN 2, such as those who plan future childbearing and are concerned about the potential adverse obstetric outcomes (eg, preterm delivery) that have been associated with treatment of CIN. CIN 3, however, is a direct precursor to cervical cancer, and treatment is always recommended in these cases.

Although age and CIN grade are predictive of risk for progression to cancer, other factors also affect this risk. These factors include the patient's HPV and cytology results preceding the diagnosis of CIN. For this reason, the American Society for Colposcopy and Cervical Pathology's recommendations for management of CIN also take these factors into account in determining an patient's risk for progression and in formulating a plan for observation versus treatment [2,15,16]. These risk estimates were derived from a cohort study of over 1.5 million patients followed for more than a decade [16].

Unlike age and CIN grade, HPV vaccination status does not affect our approach and patients are managed similarly irrespective of HPV vaccination status [15,17].

Evidence

●Effect of age – The low risk of cervical cancer in young patients is supported by data from the United States (1999 to 2008) showing that the annual incidence of cervical cancer at ages 20 to 24 years and 25 to 39 years was 1.4 per 100,000 females and 5.9 to 14.2 per 100,000 females, respectively [3].

Although virtually all cases of CIN and cervical cancer are attributable to HPV infection and the rate of HPV infection is high in younger patient populations, the infection and associated cervical intraepithelial lesions often regress spontaneously in this population [4-6]. As an example, in a cohort study of 2065 patients 18 to 29 years of age, 61 percent of patients with a newly diagnosed, high-risk HPV infection cleared the infection at 12 months of follow-up [6].

●Natural history of CIN 1 – The natural history of CIN 1 was shown in the following retrospective study of 680 patients (mean age 29.2 years) with biopsy-proven CIN 1 [7]:

•At six months, 49 percent regressed to negative, 35 percent had persistent CIN 1, and 7 percent had high-grade lesions.

•Among patients with negative results at 6 months and followed to 12 months, 80 percent remained negative, 16 percent had low-grade lesions, and 4 percent had high-grade lesions.

•Among patients with persistent CIN 1 at 6 months and followed to 12 months, 50 percent regressed to negative, 46 percent had low-grade lesions, and 4 percent had high-grade lesions.

●Natural history of CIN 2,3 – Data on the natural history of untreated high-grade disease (CIN 2,3) are limited since most patients are treated.

•For CIN 3, the estimated spontaneous regression rate is 32 to 47 percent, with 12 to 40 percent progressing to invasive cancer if untreated [8-13]. The best data on the natural history of histologically confirmed CIN 3 are from an historic study that evaluated the incidence of invasive cancer over time in two groups of patients with CIN 3 (not all patients with CIN 3 received treatment): 143 patients received close follow-up but no treatment, and 593 patients received adequate or probably adequate treatment [13]. The cumulative incidence of invasive cancer of the cervix/vaginal vault was significantly higher in untreated patients at 10 years (20.0 versus 0.3 percent) and 30 years (31.0 versus 0.7 percent). Ninety-two of the 143 patients who were managed with close follow-up but no treatment had cytologic evidence of persistent disease 6 to 24 months after the initial diagnosis of CIN 3. In this subgroup, the cumulative incidence of invasive cancer of the cervix/vaginal vault at 10 and 30 years was 31 and 50 percent, respectively. Given the high rate of progression to invasive cancer, prolonged follow-up of persistent CIN is no longer recommended.

•For CIN 2, it appears that at least one-half of patients will have regression if left untreated [14,18,19]. In a meta-analysis of 36 studies (both randomized trials and observational studies) including 3160 patients with CIN 2, at 24 months, lesions regressed in 50 percent of patients, persisted in 32 percent, and progressed to CIN 3+ in 18 percent [14]. The rate of progression increased with time, from 5 percent at 3 months to 24 percent at 36 months; this result is expected as most patients regress and those remaining are likely at a higher risk of progression. Progression rates were lower in patients with negative HPV testing at baseline; however, this was based on few data since HPV status was not reported in most studies and most patients regressed at 24 months regardless of initial HPV status. There were 15 cases of adenocarcinoma in situ and 15 cases of invasive cervical cancer (2 of these were advanced-stage disease). In a subsequent retrospective study including over 27,500 patients with a new diagnosis of CIN 2 managed with either surveillance or excision, 104 patients developed cervical cancer during the 20-year follow-up period [20]. The cumulative risk of cancer at 20 years was higher in patients undergoing surveillance compared with excision (2.75 and 0.89 percent, respectively). Rates remained higher when the analysis was adjusted for subsequent excision for persistent or progressive disease in the surveillance group.

One explanation for the lower rate of progression of CIN 2 compared with CIN 3 is that CIN 2 is more likely to be caused by oncogenic HPV subtypes 31, 33, 35, 39, 45, 51, 52, and 58, which have a weaker association with development of cancer than the more highly oncogenic subtypes HPV 16 and 18, which are commonly found with CIN 3 [21].

MANAGEMENT OF PATIENTS ≥25 YEARS

CIN 1

Preceded by LSIL or less — Patients with CIN 1 preceded by low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells of undetermined significance (ASC-US), or cytology that is negative for intraepithelial lesion or malignancy (NILM) but positive for human papillomavirus (HPV) are at low risk for the development of cervical cancer, and observation is therefore recommended [15].

In a cohort study in which over 100,000 patients had colposcopic biopsies demonstrating CIN 1 and were followed for a decade, the risk of developing CIN 3+ when preceding cytology was LSIL or less was [16]:

●For LSIL, HPV-positive – One- and five-year risks were 0.7 and 2.3 percent, respectively.

●For ASC-US, HPV-positive – One- and five-year risks were 0.5 and 2.6 percent, respectively. The following algorithm provides an example as to how these patients are managed (algorithm 1).

●For NILM, HPV-positive – One- and five-year risks were 0.7 and 2.8 percent, respectively.

In all three of these examples, given the low risk of developing CIN 3+, one-year follow-up with HPV-based testing is recommended [15,16].

Preceded by ASC-H or HSIL — CIN 1 preceded by atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H) or high-grade squamous intraepithelial lesion (HSIL) is associated with an increased risk for subsequent high-grade disease compared with CIN 1 preceded by low-grade lesions (eg, ASC-US, LSIL) [15]. In these patients, the concern is that an underlying high-grade lesion has been missed by colposcopy and biopsy. In the cohort study described above, in which over 100,000 patients had colposcopic biopsies demonstrating CIN 1 and were followed for a decade, the risk of developing CIN 3+ when preceding cytology was ASC-H or HSIL was [16]:

●For ASC-H – One- and five-year risks were 1.4 and 5.6 percent, respectively.

●For HSIL – One- and five-year risks were 3.9 and 6.5 percent, respectively.

Given these data, patients with a history of HSIL cytology are managed more aggressively than patients with a history of ASC-H [15]. Specific recommendations are as follows [2,15]:

●When preceded by HSIL cytology (algorithm 2):

•An immediate diagnostic excisional procedure or observation (HPV testing and colposcopy at one year) is acceptable provided the entire squamocolumnar junction (SCJ) and lesion are visible on colposcopy and the endocervical curettage (ECC) is less than CIN 2.

The choice of an excisional procedure or observation should take into account the patient's preferences, ability to comply with follow-up, and future childbearing plans (excisional procedures may impact future pregnancies). (See "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment" and "Reproductive effects of cervical excisional and ablative procedures".)

In our practice, we counsel patients about the options of an excisional procedure and observation and suggest observation for patients who desire future childbearing and who are willing and able to comply with long-term follow-up. For other patients, we suggest a diagnostic excisional procedure.

•When observation is chosen:

-Colposcopy and HPV-based testing are performed at one year; if negative, then repeat HPV testing is recommended in one year.

-If HPV testing continues to be negative, then repeat HPV testing is recommended in three years, at which time long-term surveillance can begin. (See "Screening for cervical cancer in resource-rich settings".)

-If any test is abnormal during observation, repeat colposcopy is recommended, and management is based on the biopsy result.

-If HSIL cytology is found at the one- or two-year visit, then a diagnostic excisional procedure is recommended.

●When preceded by ASC-H cytology (algorithm 3):

•Observation is recommended provided the entire SCJ and lesion are visible on colposcopy and an ECC, if collected, is negative. A diagnostic excisional procedure is not recommended.

-HPV-based testing is performed at one year; if negative, then repeat HPV testing is recommended in one year.

-If HPV testing continues to be negative, then repeat HPV testing is recommended in three years, at which time long-term surveillance can begin. (See "Screening for cervical cancer in resource-rich settings".)

-If any test is abnormal during observation, repeat colposcopy is recommended, and management is based on the biopsy result.

-If HSIL cytology is found at the one- or two-year visit, or if ASC-H is persistent at the two-year visit, then a diagnostic excisional procedure is recommended.

Persistent for two years — Persistent CIN 1 has a low risk of progression to CIN 3+. In the cohort study described above, after two consecutive colposcopic biopsies demonstrated CIN 1, 48 percent of patients continued to be HPV-positive, and of those, over 90 percent had follow-up cytology that was LSIL or less [16]. In addition, in a study of 126 patients undergoing loop electrosurgical excisional procedure (LEEP) for persistent CIN 1 (diagnosed on two consecutive colposcopic biopsies), 87 percent had CIN 1 or NILM on the excised specimen versus 13 percent with CIN 2+ [22]. These data support a conservative approach to management. Options include [2,15]:

●Observation is preferred. In our practice, we perform HPV-based testing in one year.

●Treatment with a diagnostic excisional procedure (LEEP, cold knife cone, and laser cone biopsy) or ablation (with cryotherapy, laser ablation, and thermoablation) is acceptable. Further details about how to choose between the two treatment options are discussed elsewhere. (See "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment".)

Preceded by AGC — CIN 1 preceded by atypical glandular cells (AGC) increases the risk of subsequent high-grade disease regardless of age; management of these patients is discussed separately. (See "Cervical cytology: Evaluation of atypical and malignant glandular cells", section on 'Follow-up of patients with negative or low-grade histologic findings on initial evaluation (colposcopy and biopsy)'.)

CIN 2,3 — CIN 2 and 3 are discussed together because histologic distinction between the two grades of CIN is poorly reproducible and both grades have an increased risk for progression to cancer. Given this increased risk, prompt treatment is recommended, with the exception of pregnant patients and patients younger than 25 years of age. Patient compliance is another factor to consider when deciding whether to treat or manage expectantly. (See 'Pregnant patients' below and 'CIN 2,3' below and 'Patients with compliance issues' below.)

Management of nonpregnant patients ≥25 years is as follows (algorithm 4 and algorithm 5) [2,15]:

●If histologic HSIL is unspecified (reported as histologic HSIL or HSIL [CIN 2,3] without distinction of CIN 2 or CIN 3):

•Treatment is preferred; in these patients, CIN 3 cannot be excluded, and, therefore, patients are managed as if CIN 3 were present.

•Observation (with colposcopy and HPV testing at 6 and 12 months) is acceptable.

●If CIN 2 is specified:

•Treatment is recommended.

•Observation (with colposcopy and HPV testing at 6 and 12 months for up to two years) is acceptable if all of the following are present:

-The patient's concerns about potential adverse pregnancy outcomes after an excisional procedure outweigh the concerns about cancer. (See "Reproductive effects of cervical excisional and ablative procedures".)

-The entire SCJ and lesion are visible on colposcopy, and ECC does not demonstrate CIN 2+ or ungraded CIN.

●If CIN 3 is specified, if the entire SCJ or lesion are not visible on colposcopy, or if the ECC is CIN 2+:

•Treatment is recommended.

When treatment is planned, a diagnostic excisional procedure (LEEP, cold knife cone, and laser cone biopsy) is preferred. An ablation (with cryotherapy, laser ablation, and thermoablation) is an acceptable alternative. Further details about each method and how to choose between the two treatment options are discussed elsewhere. (See "Cervical intraepithelial neoplasia: Diagnostic excisional procedures" and "Cervical intraepithelial neoplasia: Ablative therapies" and "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment".)

Hysterectomy is not acceptable for the primary treatment of HSIL (CIN 2 or 3). Nonsurgical therapies, including topical agents, therapeutic vaccines, and other biologics, are also unacceptable outside the setting of a clinical research trial.

MANAGEMENT OF PATIENTS <25 YEARS

CIN 1

Preceded by LSIL or less —  (algorithm 6) [2,15]:

●Cytology should be performed in one year.

•If cytology is low-grade squamous intraepithelial lesion (LSIL) or less (LSIL, atypical squamous cells of undetermined significance [ASC-US], negative for intraepithelial lesion or malignancy [NILM]), cytology should be repeated in one year.

-If NILM, routine screening (with cytology when <25 years, and with human papillomavirus-based testing when ≥25 years) can resume.

-If ASC-US or greater, colposcopy should be performed.

•If cytology is high-grade squamous intraepithelial lesion (HSIL) or greater, colposcopy should be performed. If biopsies demonstrate CIN 2+, management is described below. (See 'CIN 2,3' below.)

Preceded by ASC-H or HSIL —  (algorithm 2 and algorithm 3) [2,15]:

●Observation is recommended provided that the entire squamocolumnar junction (SCJ) and lesion are visible on colposcopy and endocervical curettage is less than CIN 2.

•If the preceding cytology was HSIL, then observation consists of colposcopy and cytology in one and two years.

•If the preceding cytology was atypical squamous cells cannot exclude HSIL (ASC-H), then observation consists of cytology alone in one and two years.

If during observation CIN 2+ is diagnosed, then management is based on the biopsy results. (See 'CIN 2,3' below.)

If during observation high-grade cytology (ASC-H or HSIL) persists for two years in the absence of a histologic HSIL, then a diagnostic excisional procedure is recommended.

●A diagnostic excisional procedure is recommended if the entire SCJ or lesion is not visible on colposcopy.

Preceded by AGC — CIN 1 preceded by atypical glandular cells (AGC) increases the risk of subsequent high-grade disease; management of these patients is discussed separately. (See "Cervical cytology: Evaluation of atypical and malignant glandular cells", section on 'Follow-up of patients with negative or low-grade histologic findings on initial evaluation (colposcopy and biopsy)'.)

CIN 2,3 — High-grade CIN is also more likely to regress in younger patients than in older patients and is less likely to progress to cancer [14,23-25]. In a meta-analysis, patients younger than 30 years with CIN 2 had a regression rate of 60 percent at 24 months, which was slightly higher than the 50 percent regression rate in the overall study population [14]. In one study, patients ages 20 to 24 years with CIN 3 were estimated to have a 0.5 percent progression rate to cancer in one year [26], which is substantially lower than the 10 percent per year risk for patients ≥80 years old.

Management of CIN 2,3 in nonpregnant patients <25 years is as follows (algorithm 5) [2,15]:

●If histologic HSIL is unspecified (reported as histologic HSIL or HSIL [CIN 2,3]):

•Observation or treatment is acceptable.

●If CIN 2 is specified:

•Observation is preferred.

•Treatment is an acceptable option.

●If CIN 3 is specified or if the entire SCJ or lesion is not visible on colposcopy:

•Treatment is recommended.

When observation is performed:

●Observation should initially consist of cytology and colposcopy at 6 and 12 months.

●If cytology is less than ASC-H and histology is less than CIN 2, then subsequent testing should occur in one year.

●If CIN 2 or unspecified HSIL persists for more than two years, then treatment is recommended.

When treatment is planned, a diagnostic excisional procedure is performed; ablation is an acceptable alternative. This is discussed in detail elsewhere. (See "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment".)

SPECIAL POPULATIONS

Pregnant patients — The rate of progression to cervical cancer in pregnant patients is similar to that of nonpregnant patients [15]. However, the physiologic changes to the cervix during pregnancy (eg, hyperemia) make colposcopy and identifying cancerous lesions more difficult. In addition, the morbidity associated with cervical conization during pregnancy is substantial (see "Cervical cancer in pregnancy", section on 'Indications for and performance of conization'). Therefore, during pregnancy, colposcopy is deferred until postpartum for minor abnormalities (CIN 1), colposcopy is performed during pregnancy for high-grade lesions (CIN 2,3), and treatment is performed only if invasive disease is suspected.

●CIN 1 – Pregnant patients with CIN 1 should not undergo cervical excision or ablation, regardless of the duration of the abnormality and irrespective of whether the preceding tests were high grade (high-grade squamous intraepithelial lesion [HSIL] or atypical squamous cells cannot exclude HSIL [ASC-H]). The patient should be reevaluated four weeks postpartum and managed based on those results.

●CIN 2,3 – Pregnant patients with CIN 2 or 3 in whom invasive disease is not suspected are managed accordingly [15]:

•Observation with colposcopy and cytology (with human papillomavirus [HPV] if age appropriate) every 12 to 24 weeks during the pregnancy is preferred. A biopsy may be repeated only if the appearance of the lesion worsens or if cytology suggests invasive disease. Endocervical sampling with a curette and endometrial sampling should not be performed as there is a risk of disturbing the pregnancy.

•Deferring colposcopy until after four weeks postpartum is an acceptable alternative.

•Treatment of CIN 2 or 3 is not recommended.

●Invasive disease suspected – A diagnostic excisional procedure is performed only if invasive disease is suspected. (See "Cervical cancer in pregnancy", section on 'Indications for and performance of conization'.)

Adolescents inadvertently screened — Cervical cancer screening should be started at age 21 years, according to guidelines from the American College of Obstetricians and Gynecologists, the United States Preventive Services Task Force, the American Society for Colposcopy and Cervical Pathology, the American Cancer Society, and the American Society for Clinical Pathology. If adolescents are inadvertently screened, the management of abnormal results should follow the recommendations for patients younger than 25 years. (See 'Management of patients <25 years' above.)

This approach is conservative since the incidence of cervical cancer in adolescents (0.15 per 100,000 females annually in one United States study) is even lower than in patients younger than 25 years (1.4 per 100,000) [3]. As with patients younger than 25 years, the rate of HPV infection is high, and infection and cervical intraepithelial lesions often regress spontaneously [4,5].

Immunocompromised patients — CIN in patients with immunosuppressive conditions, including HIV infection, is discussed in detail elsewhere [27]. (See "Preinvasive and invasive cervical neoplasia in patients with HIV infection".)

Patients with compliance issues — Immediate or "expedited" treatment can be used for nonpregnant patients with high-grade cytology who are unlikely to comply with a management plan or who do not follow up promptly after abnormal cervical cytology results.

In a retrospective study of over 8000 patients with abnormal cervical cytology, 19 percent were lost to follow-up, including 8 percent of those with HSIL [28]. During a period of time when a patient is lost to follow-up, lesions may regress or worsen, and reevaluation is often necessary.

In our practice, when a patient is diagnosed with CIN 2,3 and treatment is delayed, we proceed with the planned treatment without reevaluation if the interval from the time of diagnosis is up to 6 to 12 months. Once the treatment delay has been more than 12 months, we reassess the patient with cervical cytology, colposcopy, biopsy, and endocervical curettage. In such cases, the goals of reevaluation are to:

●Exclude the development of a lesion suspicious for microinvasive or invasive carcinoma. In the case of a suspected microinvasive carcinoma, a conization would be indicated. In the case of a gross lesion suspicious for cancer, all that may be needed is a cervical biopsy to confirm the diagnosis, and conization of a gross lesion would and should be avoided.

●Assess the patient for potential resolution of the high-grade lesion. As discussed above, regression is particularly likely in patients younger than 25 years and particularly important for any patient who is desirous of future fertility for whom the treatment-associated risk of preterm delivery has to be considered in the context of higher spontaneous regression rates of CIN 2,3. (See "Reproductive effects of cervical excisional and ablative procedures".)

Expedited treatment is discussed in more detail elsewhere. (See "Cervical cancer screening: Risk assessment, evaluation, and management after screening", section on 'Expedited treatment: Immediate risk >60 percent'.)

CANDIDATES FOR HPV VACCINATION

HPV vaccination in patients with CIN — For patients who are candidates for human papillomavirus (HPV) vaccination (all patients ages 11 to 26 and selected patients ages 27 and older), a history of cervical dysplasia or genital warts is not a contraindication to vaccination. While vaccination does not have a therapeutic effect on preexisting HPV infection or cervical neoplasia, data suggest that HPV vaccination is associated with a lower rate of CIN recurrence [29]. This may be particularly important in the shared decision-making discussion with patients ≥27 years old in whom administration of the HPV vaccine is not routine. In our practice, for patients who have not previously received the HPV vaccination series, we offer vaccination as part of the management of CIN to lower the rate of CIN recurrence. This is consistent with expert guidelines [30,31].

In a meta-analysis including six studies of HPV-unvaccinated patients with CIN 2+, the risk of recurrence of CIN 2+ was lower among patients who underwent excision with adjuvant HPV vaccination than excision alone (1.9 versus 5.9 percent, relative risk 0.36, 95% CI 0.23-0.55); the risk was also reduced for CIN of any type (CIN 1+) and for CIN 2+ lesions caused by HPV 16 and 18 [29]. This is discussed in detail separately. (See "Human papillomavirus vaccination", section on 'Pre-existing HPV-associated disease'.)

HPV vaccination in health care workers — Smoke generated from excisional and ablative procedures for CIN can expose health care workers to HPV and increase the risk of developing HPV infection and HPV-associated upper aerodigestive (nasal and oropharyngeal) disease, such as papillomatosis and cancer [32]. In addition to personal protective equipment (eg, N-95 masks) and smoke evacuation systems, we agree with guidance from the American Society for Colposcopy and Cervical Pathology and others that all health care workers with this exposure (eg, physicians, nurses, operating room staff) receive the HPV vaccine, if not already vaccinated [33].

This is discussed in more detail elsewhere. (See "Cervical intraepithelial neoplasia: Diagnostic excisional procedures", section on 'Health care workers at risk for occupational exposure' and "Human papillomavirus vaccination", section on 'Health care workers at risk for occupational exposure'.)

MANAGEMENT OF SEXUAL PARTNERS

Male partners — HPV testing in males is not commercially available. Studies of patients with CIN have found the following prevalence of associated conditions in their male sexual partners: high-risk HPV infection (58 percent [34]) and penile intraepithelial neoplasia (9 to 33 percent [35,36]). Randomized trial data show that condom use promotes regression of HPV-associated lesions in patients with CIN and their male sexual partners [37,38]. As an example, in a randomized trial, patients with CIN and their male sexual partners who did use condoms versus those who did not had higher rates of regression of CIN lesions (53 versus 35 percent) and clearance of high-risk HPV infection (23 versus 4 percent) [37].

A detailed discussion of penile premalignant lesions and penile cancer can be found separately. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Differential diagnosis'.)

Female partners — HPV infection occurs in females who have female partners, including those who have not had sexual contact with male partners [39,40]. Strategies to prevent persistence and reinfection of HPV have not been identified for patients with CIN who have same-sex partners. (See "Sexual and gender minority women (lesbian, gay, bisexual, transgender, plus): Medical and reproductive care".)

INVESTIGATIONAL THERAPIES — Medical therapies, such as imiquimod and 5-fluorouracil (5-FU), have been evaluated as an alternative, or in addition, to excision or ablation procedures for the treatment of high-grade dysplasia [41-46]. These medications appear to be more effective than placebo or no treatment [47]; however, trials have been small and with limitations. Thus, these treatments are considered investigational.

In one randomized trial including 86 patients (age 25 to 50 years) with histologically proven CIN 2 or CIN 3 treated with loop electrosurgical excision procedure (LEEP), those pretreated with topical 5% imiquimod weekly for 12 weeks (46 patients) had higher rates of histologic regression (to CIN 1 or less) compared with patients not receiving imiquimod (61 versus 23 percent, response difference 38 percent, 95% CI 18-58) [46]. While adverse events in the imiquimod group were frequent, the majority were mild (eg, abdominal pain); more severe symptoms occurred in three patients and included vaginal ulcer, vaginal pruritus, and moderate pelvic pain. In a subsequent meta-analysis of randomized trials and one prospective study including patients with CIN 2 or CIN 3, those treated with imiquimod compared with placebo or no treatment had higher rates of histologic regression (pooled odds ratio [OR] 4.27, 95% CI 2.11-8.66; three studies) and low rates of treatment discontinuation due to bothersome side effects [47].

Other potential agents, such as retinoids, interferons, antivirals, and hormonal therapy, have also been evaluated, but data are even more limited [43,44].

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

•Cervical intraepithelial neoplasia (CIN) is a premalignant squamous lesion of the uterine cervix diagnosed by cervical biopsy and histologic examination. (See 'Introduction' above.)

•The two main management approaches to CIN are observation (with human papillomavirus [HPV] testing, cervical cytology, and/or colposcopy) or treatment with excision or ablation of the cervical transformation zone; the choice between treatment options is discussed in detail elsewhere. Hysterectomy is unacceptable as a primary treatment for CIN in most instances. (See 'Overview' above and "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment".)

●Rationale – A patient's risk for progression to cancer is related in large part to their age and CIN grade. CIN often regresses spontaneously in younger patients (<25 years compared with ≥25 years), and the risk for progression to cervical cancer is lower in this younger patient population. In addition, low-grade CIN (CIN 1) has a low potential for progression to malignancy, while high-grade CIN (CIN 2,3) has a high potential for progression. (See 'Rationale' above.)

●Management – Our approach to management of patients with CIN is generally consistent with consensus guidelines of the American Society for Colposcopy and Cervical Pathology in collaboration with multiple professional societies and government organizations in the United States and Canada and is described based on patient age group, CIN grade, and previous cytology and HPV results, if appropriate. This approach assumes that the entire squamocolumnar junction and lesion are visible on colposcopy and the endocervical curettage is consistent with, or less than, the preceding lesion. (See 'Introduction' above.)

•Patients ≥25 years – For most patients ≥25 years with:

-New-onset CIN 1 and preceding atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), or atypical squamous cells cannot exclude high-grade squamous intraepithelial (ASC-H), we recommend observation rather than treatment (Grade 1B). Approximately 90 percent of these lesions will either regress to negative or remain CIN 1, saving these patients from a potentially morbid procedure. Follow-up for these patients is with HPV testing in one year (algorithm 3). However, treatment rather than observation may be reasonable in some patients (eg, patients in whom long-term follow-up may be difficult, patients who have completed childbearing and are not concerned about future obstetric complications). (See 'Preceded by LSIL or less' above and 'Preceded by ASC-H or HSIL' above and 'Evidence' above.)

Persistent CIN 1 (ie, lesions present for ≥2 years), we continue to prefer observation, but treatment is also acceptable. (See 'Persistent for two years' above.)

-CIN 1 and a preceding lesion of high-grade squamous intraepithelial lesion (HSIL) or CIN 2, treatment or observation is acceptable (algorithm 2). For most patients, we suggest treatment rather than observation (Grade 2C). However, for patients who desire future childbearing and are more concerned about the potential adverse obstetric outcomes (eg, preterm delivery) after an excisional procedure than risk of progression to cervical cancer, observation is a reasonable option (algorithm 5). (See 'Preceded by ASC-H or HSIL' above and 'CIN 2,3' above.)

-CIN 3, we recommend treatment with excision or ablation rather than observation (Grade 1B) (algorithm 4). CIN 3 is a direct precursor to cervical cancer; without treatment, up to 40 percent of patients will progress to cervical cancer. With treatment, this risk is essentially eliminated. The choice between excision or ablation is discussed in detail separately. (See 'CIN 2,3' above and "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment", section on 'Factors to consider in choosing excision versus ablation'.)

•Patients <25 years – For most patients <25 years with:

-CIN 1 and preceding lesions that are ASC-US, LSIL, ASC-H, or HSIL, we recommend observation rather than treatment (Grade 1B). In young patients, transient HPV infection is common, and the risk of progression to cancer is low for these lesions; treatment, however, is associated with potential adverse obstetric outcomes (eg, preterm delivery). Follow-up for these patients depends on the preceding cytology. For ASC-US and LSIL, repeat cytology is performed in one year (algorithm 6); for ASC-H, repeat cytology is performed in one and two years (algorithm 3); and for HSIL, colposcopy and cytology are performed in one and two years (algorithm 2). (See 'Preceded by LSIL or less' above and 'Preceded by ASC-H or HSIL' above and 'Evidence' above.)

-CIN 2, treatment or observation is acceptable. For most patients, we suggest observation rather than treatment (Grade 2C) (algorithm 5). In young patients, approximately 60 percent of these lesions will regress by 24 months, and the risk of progression to cervical cancer is lower than the risk of potential future adverse obstetric outcomes (eg, preterm delivery). Follow-up initially consists of cytology and colposcopy at 6 and 12 months. (See 'CIN 2,3' above.)

-CIN 3, we recommend treatment with excision or ablation rather than observation (Grade 1B) (algorithm 4). CIN 3 is a direct precursor to cervical cancer, and with treatment, the risk of progression to cervical cancer is essentially eliminated. The choice between excision or ablation is discussed in detail separately. (See 'CIN 2,3' above and "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment", section on 'Choosing the treatment approach'.)

●Pregnant patients – Pregnant patients with CIN 1 are reevaluated with colposcopy postpartum. Pregnant patients with CIN 2 and 3 in whom invasive cervical cancer is not suspected can be observed with colposcopy and cytology every 12 to 24 weeks during pregnancy, or evaluation can be deferred until postpartum. A biopsy is repeated if the appearance of the lesion worsens or if cytology suggests invasive disease. Endocervical sampling with a curette and endometrial sampling are not performed. Treatment is performed only if invasive disease is suspected. (See 'Pregnant patients' above.)

●HPV vaccination – For patients who are candidates for HPV vaccination, a history of cervical dysplasia or genital warts is not a contraindication to vaccination. While vaccination does not have a therapeutic effect on preexisting HPV infection or cervical neoplasia, HPV vaccination is associated with a lower rate of CIN recurrence. In our practice, for patients who have not previously received the HPV vaccination series, we offer vaccination as part of their management course. (See 'HPV vaccination in patients with CIN' above.)