Chinese expert consensus on the management of cervical intraepithelial neoplasia grade 2 (CIN 2) (2026 edition)

Incidence of CIN 2

Currently, there is a lack of globally unified registration and statistical data on the incidence of CIN 2. A cervical cancer screening study of unvaccinated women in the UK showed that approximately 2–3% of women are diagnosed with CIN 2/CIN 3 each year, with the highest incidence rate of up to 10% in women aged 25–29 years.5 In China, the age-standardised prevalence of pathologically confirmed CIN 2 and CIN 3 or higher lesions was 1.3% and 1.2%, respectively.6

Spontaneous outcome rates of CIN 2

Multiple international studies have reported that 50–60% of women with CIN 2 experience spontaneous regression within 2 years of follow-up, 23–32% have persistent disease, and 18–23% progress to CIN3 or higher, with regression rates reaching 60% in women aged <30 years.2 3 Chinese studies have indicated that among reproductive-aged women with CIN 2 followed up for 3–66 months, the regression rate is 63–78.6%, the persistence rate is 9.2–22%, and 12.2–15% progress to CIN 3, with no cases of progression to invasive cervical cancer reported.7 8

Colposcopic features of CIN 2

Achieving substantial concordance between colposcopic and histological diagnoses of CIN 2 remains challenging.9

1. Location: most CIN 2 lesions are located in the cervical transformation zone(TZ), adjacent to the squamocolumnar junction (SCJ) and may present as isolated lesions (figure 1A) or be mixed within extensive lesions (figure 1B).

2. Colour: after acetic acid application, the acetowhite change of CIN 2 is more opaque than that of CIN 1 but less dense than that of CIN 3, with a longer duration than CIN 1 but shorter than CIN 3.10

3. Contour: CIN 2 lesions often appear as patchy and mildly thickened areas, and their contour cannot be accurately distinguished from that of CIN 1 or CIN 3.

4. Border: the border morphology of CIN 2 often lacks the irregular or map-like changes seen in CIN 1.

5. Vascular signs: when vascular signs are present in CIN 2, they are usually of small to medium calibre and less prominent than those in CIN 3. The vascular spacing is generally similar to or slightly larger than that in CIN 1 or close to that in CIN 3 in a few cases (figure 1C). The presence of atypical blood vessels warrants vigilance for the coexistence of invasive cervical cancer and high-grade lesions.

6. Iodine staining: CIN 2 lesions may show iodine non-staining (figure 1D), and in a few cases, partial yellowish-brown iodine staining may also occur.11

Studies have shown that the inability of expert colposcopists to visualise some HSIL is associated with thinner epithelium.12 Therefore, attention should be paid to thin HSIL, defined as histological epithelial thickness of less than 10 cell layers.13 A Study from China has shown that thin HSIL often presents as small focal lesions on colposcopy, which are easily misdiagnosed as low-grade lesions (91.6%), and 83.3% of such lesions are pathologically diagnosed as CIN 2.14 Therefore, during colposcopically directed biopsy, multiple biopsies should be performed in the acetowhite epithelial areas regardless of the colposcopic impression (whether metaplasia or higher-grade abnormalities).15

Studies on endocervical curettage (ECC) have shown that in women with type-3 TZ and low colposcopic impression, no CIN 2 or higher lesions (CIN 2+) are detected by ECC in those with low-grade cytological abnormalities (atypical squamous cell of undetermined significance (ASC-US)/LSIL).16 High-grade cytological abnormalities (ASC cannot exclude HSIL (ASC-H) and above) are the only independent factor for detecting CIN 2+, and the additional diagnostic yield of ECC for missed CIN 2+ by colposcopically directed biopsy is 2.9%. Multivariate analysis has revealed an independent correlation between HPV 16 positivity and the additional diagnostic benefit of ECC.17 At present, there is insufficient evidence to support the routine recommendation of ECC in women with CIN 2.1 However, ECC and accurate assessment should be emphasised in populations with type 3 transformation zone, lesions extending into the endocervical canal, high-grade cytological abnormalities and persistent HPV 16/18 infection.

Histopathological features of CIN 2

The pathological manifestations of CIN 2 are intermediate between CIN 1 and CIN 3, with morphological characteristics of both CIN 1 and CIN 3, and the interobserver diagnostic consistency for CIN 2 is low.18 CIN 2 presents with squamous epithelial dysplasia, an increased nuclear-cytoplasmic ratio, and mitotic figures (including atypical ones), typically involving the lower half or less of the epithelium. Unlike CIN 3, CIN 2 retains partial epithelial differentiation, particularly in the middle and superficial layers where cells show characteristics of intermediate and superficial squamous cells. Similar to CIN 1, HPV-induced koilocytes are commonly seen in these upper layers. Nevertheless, CIN 2 demonstrates greater overall proliferative activity and atypia than CIN 1, evidenced by an increased nuclear-cytoplasmic ratio in the basal and parabasal layers, increased frequency of mitoses, and the presence of mitotic figures reaching the middle third of the epithelium. (figure 2A and B). In addition, CIN 2 needs to be differentiated from some non-HPV-infected epithelial proliferative and metaplastic lesions, such as immature squamous metaplasia, transitional metaplasia and inflammatory reactive hyperplasia. It is worth noting that HSIL almost invariably exhibits block-type p16 staining, as does a significant proportion of LSIL. Consequently, an HSIL diagnosis is extremely unlikely without this staining pattern, though p16 may be negative in rare HPV-independent HSIL cases. It is helpful to use p16 immunohistochemistry in morphologically ambiguous cases where HSIL is suspected, especially in young women (aged <30 years), because this should be downgraded in the absence of block-type p16 staining.13

The Ki-67 proliferation index in CIN 2 is usually characterised by the extension of positive cells to the middle and upper epithelial layers, with a significantly higher positive ratio than that in CIN 1, but a unified diagnostic threshold is still lacking (figure 2C and D).19 Studies have shown that the above immune markers have no clear predictive value for the regression or progression of CIN 2,20 and subsequent management should be comprehensively considered in combination with clinical manifestations, patient age and other factors.

The pathological diagnostic reporting of CIN 2 should be standardized in description: the type of specimen (biopsy or conization) must be specified, and the diagnosis should state: HSIL/CIN 2 ; p16 and Ki-67 immunohistochemical staining should be performed when necessary, with descriptions including the p16 staining pattern, the percentage of Ki-67 staining and the localization of the positive staining.

Key determinants of active surveillance for CIN 2

1. Age: Age is one of the most critical factors predicting the progression or regression of CIN 2. For young women, particularly those aged <25 years who are sexually active, the prevalence of HPV infection is higher. However, owing to a more robust immune system and a stronger immune response, these HPV infections are predominantly transient. Studies show that in women <25 years old with CIN 2, 88% of lesions can regress, with a mean time to regression of 21 months. 21 Domestic data also indicate that the HSIL regression rate in patients aged <25 years is significantly higher than in those aged ≥25 years, and the median time to lesion regression is significantly shorter (12 months vs.15 months, p < 0.05).7 Conversely, women aged ≥30 years with CIN2 face a higher risk of invasive carcinoma during long-term follow-up;4 thus, more rigorous monitoring and evaluation are required when opting for active surveillance.

2. HR-HPV genotype: Studies demonstrate that the risk of CIN 2 progression in HR-HPV-positive individuals (25%) is significantly higher than in those who are negative (3%). Among them, HPV 16 positivity carries the highest progression risk (71%), followed by HPV 18 (48%). 22 After 24 months of active surveillance, 47% of HPV 16-positive CIN 2 patients progressed to CIN 3+. Multivariate analysis reveals that HPV 16 increases the risk of progression by 1.97 to 4.8 times.23

3. Cytological abnormalities: In patients with high-grade cytological abnormalities (ASC-H and above), the risk of CIN 2 progression is as high as 25% to 60%.24 For CIN 2 with cytology indicating HSIL, the risk of missing CIN 3+ during colposcopy, or of lesion persistence or progression, increases by 3.8 to 5.0 times.25 26 The regression time for CIN 2 with cytology HSIL or HPV 16 positivity is 2 to 3 times longer than that of cases with low-grade cytological abnormalities (ASC-US/LSIL) or non-HPV 16 positivity; however, no cervical cancer was detected at a median follow-up of 25 months.27

4. Colposcopic visibility of the SCJ: The visibility of the SCJ under colposcopy is a crucial factor influencing decision-making in active surveillance. Studies indicate that the risks of missing cervical cancer when the SCJ is not fully visible versus fully visible under colposcopy are 0.6% and 0.3%, respectively (P = 0.011).28 A study from China also demonstrated that when the SCJ is not fully visible, the risk of a missed diagnosis in women with CIN 2 increases by 9.6 times.29

5. CIN 2 lesion characteristics: A domestic study showed that the regression rate in cases with multi-quadrant CIN 2 involvement (42%) is lower than in cases with single-quadrant involvement (80%), while the progression rate is higher in the former (27% vs. 6%).8 An international study demonstrated that within a 3-month follow-up of women with CIN 2, the extent of lesion involvement was significantly associated with regression; patients with lesions confined to a single quadrant had a significantly higher regression rate than those with involvement of two or more quadrant.30 Additionally, when high-grade lesions extensively involve the endocervical crypts, presenting as expansile CIN, the risk of disease progression may increase. This requires careful consideration during clinical decision-making.1

Process of active surveillance for CIN 2

Prior to initiating active surveillance for women with CIN 2, a comprehensive evaluation encompassing medical history, cytology, colposcopic findings, and histopathology is essential to definitively exclude glandular epithelial lesions and suspected invasive carcinoma. Patients must receive comprehensive counseling regarding the objectives of this conservative approach. This discussion should explicitly address the inherent limitations of colposcopy (e.g., the potential for underdiagnosis), the risk of lesion persistence or progression, and the potential clinical implications of deferring definitive treatment. Strict adherence to scheduled follow-ups is mandatory, and formal written informed consent must be obtained.The process of active surveillance is shown in figure 3.

1. Routine monitoring during active surveillance: Monitoring involves age-based testing: For patients < 25 years, cytology is performed; for those ≥ 25 years, HPV-based testing (primary HPV testing or HPV/cytology co-testing) is utilized, alongside colposcopic evaluation. Targeted biopsy ± ECC should be performed on all discrete acetowhite areas, regardless of whether the colposcopic impression indicates metaplasia or a higher-grade abnormality. Although cervical biopsy may exert a therapeutic effect that promotes lesion regression,31 the inherent risk of CIN 2 progression warrants meticulous serial monitoring.

2. Novel monitoring markers for conservative observation: (1) methylation testing: studies have shown that positive methylation testing combined with high-grade cytological abnormalities can predict CIN 2 progression,32 and the clinical regression rate is significantly higher in patients with negative FAM19A4/miR124-2 methylation (74.7%) than in those with positive methylation (51.4%).33 (2) HR-HPV gene integration: studies have shown that the risk of progression to HSIL in the HR-HPV integration-positive group is 5.6 times that in the integration-negative group34; an ongoing study on the natural outcome of HR-HPV integration in women with CIN 2/3 has shown that the persistent/progressive rate of CIN 2 is 58.82% in the integration-positive group compared with 15.29% in the integration-negative group. At present, these markers are still in the clinical research stage, and more large-sample data are needed for verification.

3. Indications for terminating active surveillance: surveillance should be discontinued and cervical excisional treatment initiated under the following conditions:(1) detection of CIN 3 or worse (CIN 3+), or persistence of CIN 2 for 2 years; (2) enlargement of the lesion, extension of the lesion into the endocervical canal, inability to visualize the upper limit of the lesion via colposcopy, or a completely invisible SCJ.

4. Follow-up protocol after CIN 2 regression: after two consecutive results (at 6-month intervals) of cytology < ASC-H, or a negative HPV test coupled with colposcopy-directed biopsy histopathology < CIN 2, patients should undergo annual age-based testing. If these subsequent tests remain negative, annual follow-up should continue for another 2 years, followed by routine screening every 3 years for at least 25 years.

Ablative therapy

Ablative therapy has the advantages of simple operation, no anaesthesia or only local anaesthesia required and rapid post-treatment recovery. However, it cannot obtain histological specimens for pathological evaluation. It has been shown that there is no significant difference in clinical efficacy or pregnancy outcomes between CO₂ laser ablation and LEEP.35 In addition, cervical cryotherapy and thermal ablation are also effective for the treatment of CIN 2.36 37 A systematic review has shown that the risk of persistent/recurrent lesions after ablative therapy (cryotherapy, thermal ablation, laser) for HSIL is significantly higher than that after excisional treatment (relative risk (RR): 1.65, 95% CI 1.25 to 2.19; at 12 months of follow-up, RR: 1.78, 95% CI 1.27 to 2.51), with comparable safety.38 Therefore, ablative therapy should be carefully selected after a comprehensive exclusion of the risks of invasive cancer and glandular lesions.

Photodynamic therapy

Photodynamic therapy (PDT) is a targeted therapeutic technology combining drugs and medical devices, which is based on the synergistic effect of photosensitisers, specific wavelength light sources and oxygen molecules in tissues. Its main advantage is the minimal impact on cervical structure and adverse pregnancy outcomes such as miscarriage or premature delivery,40 41 making it suitable for young women with fertility requirements. At present, there are three types of PDT based on different administration routes and photosensitisers: (1) 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT): a domestic Chinese prospective cohort study has shown that the lesion regression rate is 92% in women with CIN 2 treated with ALA-PDT at 6 months after treatment.42 (2) Haematoporphyrin derivative photodynamic therapy (HpD-PDT): a small-sample domestic Chinese study has shown that the lesion regression rates of CIN 2 and CIN 3 are 100% and 84.2%, respectively, at 12 months of follow-up after HpD-PDT treatment,43 and strict photoprotection (light avoidance) is required. (3) Haexaminolevulinate photodynamic therapy (HAL-PDT): an integrated automatic device of photosensitiser and vaginal cold light source. A global multicentre, randomised, double-blind, placebo-controlled study has shown that the lesion regression rate is 95% in women with CIN 2 after 1–2 sessions of HAL-PDT treatment.44

Excisional treatment

Excisional cervical treatment options include LEEP and CKC, both of which demonstrate comparable efficacy and similar risks of postoperative residual or recurrent disease.39 However, to minimize adverse impacts on future pregnancies, it is recommended that women with CIN 2 who desire fertility preservation opt for LEEP whenever feasible45 46; Conversely, if screening results, colposcopic impressions, or histopathological findings cannot rule out invasive cervical cancer, CKC should be performed when deemed necessary.

Multiple studies have demonstrated that excisional cervical treatments may increase the risk of adverse pregnancy outcomes, such as preterm birth, premature rupture of membranes (PROM), and low birth weight.45 47 The risk of these adverse pregnancy outcomes is positively correlated with the depth of cervical tissue excision. Research indicates that the risk of preterm birth increases commensurately with excision depth,45 specifically, for every 1 mm increase in excision depth, the risk of preterm birth increases by approximately 6%.48 A Swedish study similarly found that the risk of preterm birth remains comparable for excision depths between 3 and 10 mm, but thereafter, each additional 1 mm in depth increases the risk by 15%.49 Studies show that 85.7% of women under 30 years of age present with a Type 1 or Type 2 transformation zone 50. Therefore, for women with CIN 2 in this age cohort, an excision depth of approximately 10 mm is generally adequate to ensure therapeutic efficacy while mitigating adverse effects on future pregnancies 51. Nevertheless, the actual excision depth should still be tailored to the patient’s individual anatomical characteristics.

Management Strategies for CIN 2 in Pregnancy

During pregnancy, the maternal immune system and physiological functions undergo significant adaptations. Currently, there is no evidence to suggest that pregnancy itself accelerates the progression of cervical precancerous lesions, nor is there evidence that intraepithelial lesions during pregnancy adversely affect obstetric outcomes.59 The clinical management for histologically confirmed CIN 2 during pregnancy is active surveillance.39 59 The mode of delivery is determined according to obstetric indications, and CIN 2 is not an indication for elective caesarean delivery.

Referral for colposcopy is warranted during pregnancy in the presence of any of the following: non-obstetric vaginal bleeding or postcoital bleeding; grossly abnormal cervical appearance or significant anomalies on pelvic examination; or abnormal cervical cancer screening results. The primary objective of colposcopy during pregnancy is to detect and exclude invasive cervical cancer. While there is no strict temporal requirement for the examination, it is optimally performed during the first or second trimester, as adequate cervical exposure becomes technically challenging in the third trimester. ECC is strictly contraindicated during pregnancy59.

It is highly recommended that colposcopy during pregnancy be performed by an experienced colposcopist. The procedural steps are identical to those for non-pregnant patients. Thorough preoperative counseling and informed consent must be obtained, and adequate preparations for potential biopsy and hemostasis must be in place. If typical features of a high-grade lesion are already evident following the application of 3%–5% acetic acid, Lugol’s iodine staining is not a mandatory procedural step. A directed biopsy is recommended if there is a suspicion of a high-grade lesion or worse. The use of micro-biopsy forceps is recommended to sample the most severe area of the lesion. Patients should be instructed to seek immediate medical attention if they experience heavy bleeding, abdominal pain, or other significant symptoms following the procedure59.

For the surveillance of CIN 2 during pregnancy, it is recommended to repeat cervical cytology and colposcopy at intervals of approximately 12 weeks. A repeat biopsy is recommended if cytology or colposcopy raises suspicion of invasive carcinoma. This management should continue until a comprehensive re-evaluation using cytology and colposcopy is performed at 6 weeks postpartum59.

Management strategy for CIN 2 in postmenopausal women

In postmenopausal women, estrogen deficiency inevitably leads to lower genital tract atrophy. Consequently, lesions are predominantly located within the endocervical canal, and the sensitivity of ECC is compromised60. These anatomical and physiological changes collectively elevate the risk of missing CIN 2+ during colposcopy-directed biopsy. Studies indicate that in women aged ≥45 years, up to 54.5% of CIN 2+ lesions are missed initially, with the detection rate of CIN 2+ increasing by 17.7% following a LEEP procedure.61 A study from China demonstrated that in patients aged ≥50 years with histologically confirmed LSIL persisting for ≥2 years, the rate of upgrading to a pathological diagnosis of HSIL following cervical conization was 34.56% (specifically, 11.76% for CIN 2 and 22.79% for CIN 3),62 suggesting a high risk of missed diagnosis of high-grade lesions by colposcopy in postmenopausal women.63 Furthermore, high vigilance must be maintained regarding the missed diagnosis of invasive cervical cancer in postmenopausal women. A study from China revealed that among patients aged ≥50 years initially diagnosed with cervical HSIL via colposcopic biopsy, 11.5% were subsequently found to have invasive cervical cancer following excisional treatment.64

Given the compromised diagnostic accuracy of colposcopy and the significantly elevated risk of missing high-grade lesions and invasive carcinoma in this population, excisional treatment is the preferred modality for postmenopausal women with CIN 2.

In the absence of contraindications, a 1-to-2-week course of topical estrogen pretreatment may be administered prior to the procedure.

Total hysterectomy is not recommended as a primary treatment for CIN 2. It should only be considered in specific clinical scenarios, including: the presence of residual HSIL; severe lower genital tract atrophy making repeat excisional procedures technically unfeasible; HSIL concurrent with other gynecological conditions warranting a hysterectomy; or in patients with poor compliance or lacking access to postoperative follow-up.39

Management strategy for CIN 2 in immunocompromised populations

Patients with immunosuppression caused by human immunodeficiency virus (HIV) infection, or those with autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis) receiving long-term immunosuppressive therapy, face an elevated risk of persistent HPV infection, lesion progression, and treatment failure.1 65 66 Although antiretroviral therapy for HIV may increase the likelihood of CIN regression,67 evidence specific to these populations remains limited. Clinical decision-making must carefully weigh the disease risk against the impact of the patient’s immune status on both treatment efficacy and prognosis.

Follow-up management post-CIN 2 treatment

For patients with long-term follow-up conditions, HPV-based testing is recommended at 6 months after treatment. If the test result is positive, colposcopy is required. If the test result is negative, HPV-based testing is recommended at an interval of 12 months. After three consecutive negative results, follow-up is performed once every 3 years for at least 25 years.68 For patients over 65 years of age who have completed 25 years of follow-up, follow-up once every 3 years can be continued if health conditions permit. Colposcopy is required for patients with positive HPV testing.39

Health education and counseling

Patients should be informed that the 5-year recurrence risk following CIN 2 treatment ranges from 5% to 10%, emphasizing the paramount importance of standardized follow-up69. Consistent condom use throughout sexual intercourse can significantly improve both the regression rate of CIN 2 (53% vs. 35%) and the HPV clearance rate (23% vs. 9%) 70. Prophylactic HPV vaccination is recommended for women under 45 years of age. A prospective study from Italy demonstrated that the 4-year postoperative clinical recurrence rates for unvaccinated and vaccinated cohorts were 6.4% and 1.2%, respectively, indicating an 81.2% significant reduction in the risk of developing CIN 2+ in the vaccinated group.71 Furthermore, smoking cessation and regular physical exercise are strongly advocated.72 Additionally, clinical studies reveal that approximately 40% of patients experience anxiety symptoms; therefore, professional psychological counseling services should be provided.73