Abstract
Background/Objectives: When the squamocolumnar junction is not fully visible (type 3 transformation zone), colposcopy-directed biopsy may under-sample endocervical disease. Endocervical curettage (ECC) is recommended in selected settings, but its incremental diagnostic yield in this setting, and whether this yield is concentrated in women with HPV16/18, remains clinically debated. Methods: We performed a retrospective cohort study of women referred to colposcopy because of HPV16/18 positivity regardless of cytology, persistent non-16/18 high-risk HPV positivity, and non-16/18 high-risk HPV positivity with abnormal cytology. Persistent non-16/18 high-risk HPV positivity was defined as repeated positivity on two tests performed at least 6 months apart. Eligible women had type 3 transformation zone documented and underwent paired ectocervical biopsy plus ECC at the same visit; biopsy was obtained in all women, including targeted sampling of the most abnormal ectocervical area when no discrete lesion was evident. Women were stratified by HPV genotype into HPV16/18 and non-16/18 high-risk HPV groups. The primary outcome was index high-grade cervical lesion, defined histologically as CIN2, CIN3, or carcinoma in situ; invasive cervical cancer was excluded. The added diagnostic yield of ECC was defined as ECC-only CIN2+, that is, CIN2+ detected on ECC when biopsy was <CIN2. Results: The cohort included 690 women (HPV16/18: 310; non-16/18 high-risk HPV: 380). Baseline cytology was negative for intraepithelial lesion or malignancy in 116 individuals (16.8%), ASC-US in 155 (22.5%), LSIL in 205 (29.7%), and ASC-H/HSIL in 214 (31.0%). On index composite histology, 122/690 (17.7%) had CIN2, 198/690 (28.7%) had CIN3, and 11/690 (1.6%) had carcinoma in situ. ECC identified CIN2+ not detected by biopsy in 19/690 (2.8%) cases, representing 19/331 (5.7%) of all CIN2+ diagnoses. ECC-only CIN2+ was more frequent in HPV16/18 than non-16/18 high-risk HPV (4.5% vs. 1.3%, p = 0.017). In multivariable analysis, HPV16/18 was associated with increased odds of ECC-only CIN2+ (aOR 3.22, 95% CI 1.10–9.44). No invasive cervical cancers were included in the analytic cohort. Conclusions: In type 3 transformation zone colposcopy, ECC adds a modest incremental yield for CIN2+ detection, with higher yield in HPV16/18-positive women. These findings support a risk-weighted approach to ECC rather than universal routine sampling.
Keywords: colposcopy, endocervical curettage, transformation zone 3, cervical intraepithelial neoplasia, additional yield, biopsy
1. Introduction
Cervical cancer remains a major and largely preventable cause of cancer morbidity and mortality worldwide. Contemporary global estimates based on GLOBOCAN 2022 data confirm a substantial annual burden, with marked geographic inequalities that closely track differences in HPV vaccination coverage, screening access, and timely treatment of precancerous lesions [1,2,3]. The WHO elimination strategy has further emphasized that high-performance screening and effective management of cervical precancer are central levers for reducing incidence and mortality at population level [1,4].
High-risk human papillomavirus (hrHPV) infection is the necessary causal factor for virtually all cervical cancers, and screening is increasingly centered on HPV-based testing with risk stratification to guide colposcopy and treatment [5,6,7]. Within hrHPV types, HPV16 and HPV18 consistently represent the highest-oncogenic-potential group, and genotype information is increasingly used to triage women toward colposcopy and closer surveillance [7,8]. Large longitudinal screening datasets and risk-stratification studies also show that HPV16/18 positivity is associated with the highest immediate and cumulative risk for CIN3+ compared with other genotypes, supporting genotype-informed management thresholds in modern guidance [6,9].
Colposcopy remains the key diagnostic step after abnormal screening, aiming to detect clinically relevant high-grade disease and obtain representative histology for management [10,11]. Even with contemporary standards, colposcopy is imperfect, and sensitivity improves when clinicians obtain more than one targeted biopsy in the presence of multiple acetowhite areas [10,12]. A persistent challenge arises when the squamocolumnar junction is not fully visible, classified as a type 3 transformation zone (TZ3), because clinically relevant lesions may extend into the endocervical canal beyond direct visualization [11,13,14]. This anatomical limitation is particularly relevant in older women and in those with risk factors for endocervical disease, where visual impression and ectocervical biopsy alone may under-sample the true extent of precancer [7,13].
Endocervical curettage (ECC) was developed to address this blind spot by sampling the endocervical canal during colposcopy [10,14]. Updated colposcopy standards and consensus recommendations specifically support ECC when the squamocolumnar junction is not fully visualized (TZ3) and in higher-risk referral profiles, including high-grade cytology and HPV16/18 infection; ECC is also preferred in older age groups in several guidance documents [14]. At the same time, ECC is not a benign “add-on.” It can increase procedure time and discomfort, and its overall incremental diagnostic yield is often modest, which explains the ongoing debate about when ECC meaningfully changes management. Recent clinical studies report incremental ECC yields for CIN2+ that are generally in the low single digits, while also suggesting added yield concentrates in selected subgroups such as high-grade cytology, HPV16/18 positivity, older or postmenopausal patients, and those with TZ3 anatomy [15,16,17].
Despite clear biologic plausibility, clinically useful evidence is still heterogeneous regarding the extent to which ECC adds actionable detection specifically in TZ3 colposcopy, and whether this incremental yield is disproportionately driven by HPV16/18 infections compared with non-16/18 hrHPV [14,15]. Clarifying this point matters because HPV16/18 status is already a central risk modifier in contemporary cervical screening pathways, and a more selective ECC strategy could potentially preserve detection while reducing unnecessary instrumentation in lower-yield scenarios [6,18,19]. Therefore, in a retrospective cohort of women with TZ3 colposcopy undergoing paired biopsy and ECC, we evaluated the added diagnostic yield of ECC for detecting histologic CIN2+ and examined whether ECC-only CIN2+ detection is concentrated among women with HPV16/18 compared with those with non-16/18 hrHPV [16,20,21].
2. Methods
2.1. Study Design and Setting
We conducted a retrospective observational cohort study in a tertiary university-affiliated center of Obstetrics and Gynaecology in western Romania. The study period extended from 1 January 2022 to 31 December 2025. The source population consisted of adult women referred to colposcopy within routine clinical care pathways. Data were retrieved from institutional electronic records and pathology archives, and were abstracted into a dedicated, de-identified research dataset. The study was designed and reported in line with STROBE principles for observational studies.
The index visit was defined as the colposcopy encounter at which the transformation zone was classified as type 3 (TZ3) and paired tissue sampling was performed.
2.2. Exposure Definition
The primary exposure was HPV genotype risk group, categorized as HPV16/18 versus non-16/18 high-risk HPV (hrHPV) based on available genotyping results recorded before or at the index colposcopy visit. For descriptive purposes, the HPV16/18 group included HPV16 and/or HPV18 positivity, while the non-16/18 group included hrHPV positivity without HPV16 or HPV18.
2.3. Inclusion and Exclusion Criteria
Eligible women met all of the following criteria: age ≥18 years; referral for colposcopy between 1 January 2022 and 31 December 2025 for HPV16/18 positivity regardless of cytology, persistent non-16/18 high-risk human papillomavirus positivity, or non-16/18 high-risk human papillomavirus positivity with abnormal cytology; type 3 transformation zone at the index colposcopy; available HPV genotyping allowing classification as HPV16/18 or non-16/18 high-risk human papillomavirus; paired ectocervical biopsy and endocervical curettage performed at the same visit; and interpretable index histology.
Exclusion criteria were: absence of paired ectocervical biopsy and endocervical curettage at the same visit; missing HPV genotyping; insufficient documentation to assign an index histologic outcome; invasive cervical carcinoma diagnosed before inclusion or on index histology; prior gynecologic oncologic disease; and prior surgical intervention involving the cervix, vagina, or uterus that could alter colposcopic or histologic assessment.
2.4. Referral Indications and Operational Definitions
Women were referred for colposcopy if at least one of the following applied: (1) HPV16 and/or HPV18 positivity regardless of cytology; (2) persistent non-16/18 high-risk human papillomavirus positivity, defined as repeated non-16/18 high-risk human papillomavirus positivity on two tests at least 6 months apart; or (3) non-16/18 high-risk human papillomavirus positivity with abnormal cytology. Abnormal cytology was defined as LSIL or worse.
2.5. Colposcopy and Sampling Procedures
Colposcopy was performed according to local regulations. The transformation zone was classified by the examining clinician as TZ3 when the squamocolumnar junction was not fully visible. Endocervical curettage was performed during the same encounter using routine technique to sample the endocervical canal. ECC specimens were processed and reported by the pathology department as diagnostic categories or, when appropriate, as insufficient for diagnosis when the specimen contained inadequate evaluable endocervical epithelium (for example, scant tissue, blood/mucus only, or artifact precluding interpretation). In this study, insufficient ECC was retained as a specimen adequacy descriptor and was not treated as a negative result.
2.6. Histopathology and Outcome Definitions
All histology results were extracted from pathology reports. The primary endpoint was index composite CIN2+, defined as cervical intraepithelial neoplasia grade 2 or worse, namely CIN2, CIN3, or carcinoma in situ (CIS). The index composite histologic outcome for each participant was defined as the highest-grade diagnosis identified on either directed biopsy or ECC at the index visit. For descriptive reporting, index composite outcomes were summarized as no dysplasia/CIN1, CIN2, CIN3, and CIS. Subsequent conization, when performed within 12 weeks on routine clinical grounds, was recorded descriptively to contextualize discordant or insufficient index histology.
Women with index histology below CIN2 were managed according to routine clinical judgment based on referral risk, cytology, colposcopic impression, transformation zone type, and specimen adequacy. Immediate conization was considered in selected cases with persistent high-grade discordance or insufficient endocervical sampling despite persistent high-risk referral features, whereas women not selected for immediate excision underwent conservative follow-up with repeat HPV testing, cytology, and/or repeat colposcopy according to local protocol. For this study, persistent high-grade discordance was defined as high-grade referral cytology (ASC-H/HSIL) in the setting of a type 3 transformation zone with index biopsy and ECC below CIN2. Persistent high-risk referral features were defined as HPV16/18 positivity persisting for at least 6 months, persistent non-16/18 high-risk human papillomavirus positivity persisting for at least 6 months, ASC-H or HSIL cytology, or high-grade colposcopic impression despite non-diagnostic or insufficient ECC. No invasive cervical cancers were included in the analytic cohort.
To assess the incremental diagnostic value of ECC beyond biopsy, high-grade lesion cases were classified into three mutually exclusive groups: (1) biopsy-only cases, defined as CIN2 or worse detected by biopsy with ECC below CIN2 or non-diagnostic; (2) concordant cases, defined as CIN2 or worse detected by both biopsy and ECC; and (3) ECC-only cases, defined as CIN2 or worse detected by ECC with biopsy below CIN2. Cases in the ECC-only group were considered to represent the additional diagnostic yield of ECC.
2.7. Statistical Analysis
Data entry and cleaning were performed using Microsoft Excel 2016 (Microsoft Corp., Redmond, WA, USA) [22]. Statistical analyses were conducted using IBM SPSS Statistics version 26 (IBM Corp., Armonk, NY, USA) [23] and R version 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria) [24].
Continuous variables were assessed for distributional assumptions and are presented as mean ± standard deviation when approximately symmetric. Categorical variables are presented as counts and percentages. Between-group comparisons (HPV16/18 vs. non-16/18 hrHPV) were performed using Welch’s t-test for continuous variables and chi-square testing for categorical variables. Fisher’s exact test was used when expected cell counts were small, particularly for ECC-only CIN2+.
The incremental yield of ECC was reported as the proportion of ECC-only CIN2+ cases in the full cohort and within HPV strata. Confidence intervals for incremental yield were estimated using Wilson methods for proportions. The number needed for ECC to detect one additional CIN2+ case was calculated as the reciprocal of the ECC-only CIN2+ proportion.
A multivariable logistic regression model was constructed with ECC-only CIN2+ as the dependent outcome to evaluate independent associations with HPV16/18 status while adjusting for prespecified clinical covariates (age ≥40 years, high-grade cytology, and high-grade colposcopic impression). Effect sizes are reported as adjusted odds ratios (aORs) with 95% confidence intervals. All tests were two-sided, and p-values < 0.05 were considered statistically significant.
2.8. Ethical Considerations
The study was conducted in accordance with the Declaration of Helsinki [25] and applicable data protection requirements. Given the retrospective, non-interventional design and the use of anonymized routinely collected clinical data, the requirement for individual informed consent was waived according to institutional policy. The protocol was approved by the local Ethics Committee (approval number 117/1 January 2022). Data handling complied with the General Data Protection Regulation (EU 2016/679) [26].
3. Results
3.1. Study Population
Between January 2022 and December 2025, 690 women met the study eligibility criteria and were included in the analytic cohort. Of these, 310/690 (44.9%) were classified in the HPV16/18 group and 380/690 (55.1%) in the non-16/18 high-risk human papillomavirus group. An insufficient ECC specimen was recorded in 158/690 (22.9%). Baseline characteristics are summarized in Table 1.
Table 1.
Baseline characteristics of the TZ3 cohort by HPV group.
| Variable | Total (N = 690) | HPV16/18 (n = 310) | Non-16/18 hrHPV (n = 380) | p-Value |
|---|---|---|---|---|
| Age, years (mean ± SD) | 39.9 ± 9.4 | 38.9 ± 8.8 | 40.6 ± 9.8 | 0.019 |
| Age ≥ 40 years | 308 (44.6%) | 121 (39.0%) | 187 (49.2%) | 0.009 |
| High-grade cytology (ASC-H/HSIL) | 214 (31.0%) | 132 (42.6%) | 82 (21.6%) | <0.001 |
| High-grade colposcopic impression | 182 (26.4%) | 110 (35.5%) | 72 (18.9%) | <0.001 |
| ECC specimen insufficient | 158 (22.9%) | 66 (21.3%) | 92 (24.2%) | 0.414 |
Values are n (%) unless otherwise stated. p-values from Welch’s t-test (age) and chi-square tests (categorical variables). High-grade cytology includes ASC-H/HSIL. “Insufficient ECC” indicates inadequate material for histologic interpretation.
3.2. Baseline Characteristics
Patients in the HPV16/18 group were slightly younger than those with non-16/18 hrHPV (mean 38.9 ± 8.8 vs. 40.6 ± 9.8 years; p = 0.019). The proportion aged ≥40 years was lower in HPV16/18 (39.0%) than non-16/18 (49.2%; p = 0.009).
High-grade cytology (ASC-H/HSIL) was more frequent in HPV16/18 (42.6%) than in non-16/18 (21.6%; p < 0.001). A high-grade colposcopic impression was also more frequent in HPV16/18 (35.5%) than non-16/18 (18.9%; p < 0.001). The rate of insufficient ECC was similar between groups (p = 0.414). Details are shown in Table 1.
3.3. Histologic Outcomes and Detection Pathways
On index composite histology, defined as the highest-grade diagnosis on paired biopsy and/or ECC at the index visit, 331/690 (48.0%) women had CIN2+ and 209/690 (30.3%) had CIN3+. Index composite outcomes were no dysplasia/CIN1 in 359 (52.0%), CIN2 in 122 (17.7%), CIN3 in 198 (28.7%), and CIS in 11 (1.6%). No invasive cervical cancers were included in the analytic cohort.
CIN2+ was more common in HPV16/18 than non-16/18 hrHPV (60.6% vs. 37.6%, p < 0.001), and the same pattern was observed for CIN3+ (41.3% vs. 21.3%, p < 0.001).
3.4. Index Composite Histology and Added Diagnostic Yield of ECC
Across the full cohort, 19/690 (2.8%) cases of index composite CIN2+ were detected only by ECC, representing the incremental yield of ECC beyond ectocervical biopsy. In absolute terms, this corresponds to 19/331 (5.7%) of all CIN2+ diagnoses in the cohort with ECC-only.
The incremental yield differed by HPV group. ECC-only CIN2+ occurred in 14/310 (4.5%) in HPV16/18 versus 5/380 (1.3%) in non-16/18 hrHPV (p = 0.017). The corresponding number needed for ECC to detect one additional CIN2+ was 22.1 in HPV16/18 and 76.0 in non-16/18 hrHPV (overall: 36.3). These results are detailed in Table 2 and visualized in Figure 1.
Table 2.
Index composite histology and CIN2+ detection by biopsy and ECC (TZ3 cohort).
| Outcome | Total (N = 690) | HPV16/18 (n = 310) | Non-16/18 hrHPV (n = 380) | p-Value | |
|---|---|---|---|---|---|
| Final histology | No dysplasia/CIN1 | 359 (52.0%) | 122 (39.4%) | 237 (62.4%) | <0.001 |
| CIN2 | 122 (17.7%) | 60 (19.4%) | 62 (16.3%) | 0.298 | |
| CIN3 | 198 (28.7%) | 122 (39.4%) | 76 (20.0%) | <0.001 | |
| CIS | 11 (1.6%) | 6 (1.9%) | 5 (1.3%) | 0.555 | |
| CIN2+ (CIN2/CIN3/CIS) | 331 (48.0%) | 188 (60.6%) | 143 (37.6%) | <0.001 | |
| Detection pathway for CIN2+ | Both biopsy+ECC CIN2+ | 97 (14.1%) | 57 (18.4%) | 40 (10.5%) | 0.003 |
| Biopsy-only CIN2+ | 215 (31.2%) | 117 (37.7%) | 98 (25.8%) | 0.001 | |
| ECC-only CIN2+ (incremental yield) | 19 (2.8%) | 14 (4.5%) | 5 (1.3%) | 0.017 | |
| Number needed to ECC to detect 1 additional CIN2+ | 36.3 | 22.1 | 76.0 | — |
CIN2+ includes CIN2, CIN3, and CIS. CIN3+ includes CIN3 and CIS. “ECC-only CIN2+” indicates CIN2+ detected on ECC with biopsy < CIN2. p-values for categorical comparisons were derived from chi-square tests or Fisher’s exact test, as appropriate; the number needed for ECC is a descriptive measure.
Figure 1.
Incremental yield of ECC (ECC-only CIN2+) by HPV group. Overall: 2.8% (19/690), 95% CI 1.8–4.3%, HPV16/18: 4.5% (14/310), 95% CI 2.7–7.4%; Non-16/18 hrHPV: 1.3% (5/380), 95% CI 0.6–3.0%; Between-group comparison (HPV16/18 vs. non-16/18): p = 0.017; 95% CIs are Wilson intervals for proportions. p-value from Fisher’s exact test comparing ECC-only CIN2+ rates between HPV groups.
3.5. Subsequent Conization and Clinically Discordant Cases
Subsequent conization within 12 weeks was performed in 268/690 (38.8%) women, more often in the HPV16/18 group than in the non-16/18 high-risk human papillomavirus group (172/310 [55.5%] vs. 96/380 [25.3%], p < 0.001). Among these, 214/268 (79.9%) underwent conization because CIN2 or worse had already been identified on index biopsy and/or ECC. The remaining 54/268 (20.1%) underwent conization despite index biopsy and ECC below CIN2. In this subgroup, indications for excision were persistent high-grade discordance in a type 3 transformation zone (37/54, 68.5%) and insufficient ECC with persistent high-risk referral features, as described above (17/54, 31.5%).
Among the 54 women with index biopsy and ECC below CIN2 who underwent conization, 17/54 (31.5%) were upgraded on excisional histology, including 6/54 (11.1%) with CIN2, 10/54 (18.5%) with CIN3, and 1/54 (1.9%) with carcinoma in situ, whereas 37/54 (68.5%) remained below CIN2. Of these 54 women, 33 were HPV16/18-positive and 21 were non-16/18 high-risk human papillomavirus-positive.
Among the 359 women with index histology below CIN2, 305/359 (85.0%) did not undergo conization and were managed conservatively with cytological, genotype and colposcopy reevaluation at 6–12 months. Management in this non-excisional subgroup was similar between HPV genotype groups.
These findings are summarized in Table 3.
Table 3.
Management and excisional outcomes among women with index histology below CIN2. (A) Indication for conization among women with index histology below CIN2 (n = 54); (B) Final excisional histology among women with index histology below CIN2 who underwent conization (n = 54).
| Variable | n/N | % of Respective N |
| Women with index histology below CIN2 | 359/690 | 52.0 |
| Underwent subsequent conization within 12 weeks | 54/359 | 15.0 |
| Did not undergo conization | 305/359 | 85.0 |
| (A) | ||
| Variable | n/N | % of respective N |
| High-grade discordance in TZ3 despite index histology below CIN2 | 37/54 | 68.5 |
| Insufficient ECC with persistent high-risk referral features | 17/54 | 31.5 |
| (B) | ||
| Variable | n/N | % of respective N |
| No dysplasia/CIN1 | 37/54 | 68.5 |
| CIN2 | 6/54 | 11.1 |
| CIN3 | 10/54 | 18.5 |
| CIS | 1/54 | 1.9 |
| Upgraded to CIN2+ on conization | 17/54 | 31.5 |
CIN2+ includes CIN2, CIN3, and carcinoma in situ (CIS). Percentages in the first three rows are calculated using the subgroup with index histology below CIN2 as denominator (n = 359). Percentages in the indication and excisional histology sections are calculated using the subgroup that underwent conization despite index histology below CIN2 as denominator (n = 54). TZ3, type 3 transformation zone; ECC, endocervical curettage.
4. Discussion
4.1. Interpretation of the Results
In this TZ3 cohort, ECC provided a modest but clinically relevant diagnostic gain beyond directed biopsy. The overall ECC-only CIN2+ rate was 2.8%, which is consistent with the low single-digit added yield reported for ECC as an adjunctive test rather than a substitute for biopsy [14,16]. This benefit was not evenly distributed. ECC-only CIN2+ was more frequent in HPV16/18-positive women than in those with non-16/18 hrHPV (4.5% vs 1.3%), and HPV16/18 remained independently associated with ECC-only CIN2+ in multivariable analysis. This is clinically plausible, as HPV16/18 is linked to higher short-term risk of high-grade disease, and current guidance gives greater weight to ECC when HPV16/18 is present and the squamocolumnar junction is not fully visible, as in TZ3 [17].
The number needed for ECC reinforces the same point. In our cohort, one additional CIN2+ case was identified for about every 22 ECCs in HPV16/18-positive women, compared with about 76 ECCs in the non-16/18 group. Taken together, these data support a selective, risk-based approach to ECC in TZ3 rather than routine universal use. Most CIN2+ lesions were still detected by biopsy, meaning that ECC was more often complementary than decisive, which is expected when directed sampling is carefully performed.
An additional practical finding was the 22.9% rate of non-diagnostic ECC. The value of ECC depends not only on incremental yield, but also on how often the specimen is interpretable in routine care. This is why we retained “insufficient ECC” as a feasibility marker rather than classifying it as negative histology. Current standards also acknowledge that ECC adequacy depends on sampling technique, handling, and patient tolerance [5,14,27]. Baseline differences in our cohort, including more high-grade cytology and high-grade colposcopic impression in HPV16/18-positive women, further support the interpretation that this group was risk-enriched. More broadly, age and TZ type are known to influence colposcopic performance, which helps explain why TZ3 anatomy and older age are repeatedly emphasized in ECC guidance [28,29].
4.2. Comparison with Current Literature
Our overall ECC-only CIN2+ rate of 2.8% is close to the range reported in recent prospective and large retrospective studies. Jareemit et al. reported an added yield of 2.9% for CIN2+ missed by colposcopy-directed biopsy, while a nationwide screening-based analysis also found a low overall additional yield that increased in selected clinical settings [16,17]. In a very large cohort of 47,134 women, the overall added yield of ECC was 1.4%, with greater benefit in those with more severe final disease [30]. Differences across studies likely reflect variation in referral patterns, biopsy strategy, and outcome definitions. In a multicenter TZ3 cohort, ECC identified 0.8% of HSIL+ lesions missed by biopsy alone, which is lower than in our study but still supports the same overall principle: ECC is usually low-yield in unselected populations, but becomes more useful in anatomically or clinically higher-risk groups, including TZ3 [14,31,32,33].
Our finding that the added yield was concentrated in HPV16/18-positive women also agrees with recent evidence. HPV16, or HPV16/18 more broadly, has been identified as a predictor of ECC benefit in both prospective and retrospective series [17,30,31]. Likewise, the association we observed between higher-risk referral features and ECC performance is consistent with the broader literature showing that high-grade cytology and high-grade colposcopic impression increase the likelihood of detecting CIN2+ on ECC [8,9,21,32]. This fits with ASCCP standards, which emphasize ECC particularly when colposcopy is limited by incomplete visualization and when other high-risk factors are present [7]. Overall, the literature supports a simple hierarchy: ECC contributes most when pretest risk is high and the transformation zone is not fully visible.
4.3. Type 3 Transformation Zone and the Diagnostic Excision Question
TZ3 should be understood as a limitation of colposcopic visualization rather than a reassuring finding, because clinically relevant disease may extend into the endocervical canal beyond direct view. This is the central reason why ECC is recommended in TZ3 examinations [14,16]. However, ECC does not completely eliminate this blind spot. When screening risk remains high but biopsy and ECC are negative, low-grade, or non-diagnostic, diagnostic excision may still be justified [34,35,36,37]. The 2023 Canadian Colposcopy Guideline supports excision in cases of persistent discordance, particularly when high-grade cytology coexists with TZ3, and European expert guidance similarly recognizes type 3 excision as an appropriate strategy in selected complex cases [38,39]. This is supported by evidence showing that biopsy can underestimate CIN2+ in older women with TZ3 when compared with excisional histology [40]. At the same time, excision is not benign, especially in women with future reproductive plans, since cervical excision is associated with a higher risk of preterm birth [41]. For that reason, escalation should remain selective and risk-based.
This interpretation is also supported by our clinically selected conization subgroup, in which 17 women with biopsy and ECC both <CIN2 at the index visit were subsequently upgraded to CIN2+ on excision, underscoring that negative or low-grade index histology does not fully exclude clinically relevant endocervical disease in TZ3.
An important finding of the clinically selected conization subgroup was that 17/54 women (31.5%) with biopsy and ECC both below CIN2 at the index visit were subsequently upgraded on excisional histology. This proportion should not be interpreted as the false-negative rate of biopsy and ECC in the whole cohort, because these women were selected for excision precisely because persistent high-grade discordance or insufficient endocervical sampling maintained a high level of concern. In type 3 transformation zone examinations, persistent discordance between referral risk and index histology justifies a lower threshold for excision, particularly when high-grade cytology is present [38].
4.4. Future Perspectives
Future refinement of TZ3 management will likely depend on better risk stratification. Extended HPV genotyping is already being incorporated into guideline frameworks because not all high-risk genotypes carry the same CIN3+ risk, and this may help identify which TZ3 patients are most likely to benefit from endocervical assessment [42,43]. Biomarker triage is also becoming more relevant. p16/Ki-67 dual stain is now accepted in formal guidance as a triage tool for HPV-positive women, and WHO has also endorsed its use in this setting [44,45]. Methylation-based triage is another promising direction, particularly for non-16/18 infections where management is often less straightforward [46,47,48].
AI-assisted colposcopy is another evolving area. Recent studies suggest that AI-based assessment of cervical images can achieve clinically relevant accuracy for CIN2+/CIN3+ and may reduce observer variability [49,50,51]. Some multicenter studies have already shown that AI can be incorporated into digital image workflows, although heterogeneity in endpoints, devices, and validation remains substantial [52,53,54].
Another useful next step would be a prospective TZ3-focused study with standardized biopsy number, ECC technique, and pathology reporting, along with prespecified criteria for when discordance should prompt excision. Such a design would better define when ECC truly changes management and when newer risk-stratification tools might safely reduce unnecessary procedures.
4.5. Limitations
This study has the typical limitations of retrospective colposcopy research. Referral and sampling decisions were made in routine care, so selection bias is possible. ECC adequacy and colposcopic assessment are operator-dependent, and the relatively high rate of insufficient ECC reflects real-world variability in technique and specimen quality [7,37]. In addition, ECC-only CIN2+ was an uncommon endpoint, which limits model stability and increases uncertainty around adjusted estimates. Finally, because TZ3 implies incomplete visualization, verification bias cannot be fully excluded without systematic excisional reference histology. Existing data suggest that biopsy may underestimate CIN2+ in TZ3, especially in older women, so some residual uncertainty remains even after biopsy with or without ECC [40].
Because the cohort was restricted to women who underwent paired ectocervical biopsy and ECC at the same visit, the study may have excluded selected cases in which ECC was performed without biopsy, such as women with a normal-appearing ectocervix but persistent endocervical risk; this may have led to underestimation of the diagnostic contribution of ECC.
Because only a selected subset of women with index histology below CIN2 underwent conization, upgrade rates in this subgroup reflect clinician-selected high-risk cases and should not be generalized to all women with negative or low-grade index histology.
5. Conclusions
In women with TZ3, ECC provided a small but clinically meaningful added yield for detecting CIN2+ beyond directed biopsy. This benefit was concentrated in HPV16/18-positive women, supporting a selective rather than universal approach to ECC in this setting. TZ3 should be viewed as a limitation of visualization, not a low-risk finding, and ECC appears most useful when combined with other markers of higher pretest risk.
Clinically, ECC is best interpreted as a triage tool rather than a stand-alone rule-out test. A positive ECC increases confidence in occult endocervical disease, whereas a negative or non-diagnostic ECC should be interpreted cautiously when high-risk features persist. In such cases, especially with ongoing discordance between screening risk and histology, a lower threshold for diagnostic excision may be appropriate.
Acknowledgments
We would like to acknowledge “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania, for their support in covering the costs of publication for this research paper.
Abbreviations
| CIS | carcinoma in situ |
| aOR | adjusted odds ratio |
| ASC-H | atypical squamous cells-cannot exclude HSIL |
| ASC-US | atypical squamous cells of undetermined significance |
| ASCCP | American Society for Colposcopy and Cervical Pathology |
| CI | confidence interval |
| CIN | cervical intraepithelial neoplasia |
| CIN2+ | cervical intraepithelial neoplasia grade 2 or worse (CIN2, CIN3, or carcinoma in situ) |
| CIN3+ | cervical intraepithelial neoplasia grade 3 or worse (CIN3 or carcinoma in situ) |
| ECC | endocervical curettage |
| EU | European Union |
| GDPR | General Data Protection Regulation |
| GLOBOCAN | Global Cancer Observatory cancer incidence and mortality database |
| HPV | human papillomavirus |
| hrHPV | high-risk human papillomavirus |
| HSIL | high-grade squamous intraepithelial lesion |
| LSIL | low-grade squamous intraepithelial lesion |
| NILM | negative for intraepithelial lesion or malignancy |
| R | R statistical computing environment |
| SCJ | squamocolumnar junction |
| SD | standard deviation |
| SPSS | Statistical Package for the Social Sciences |
| STROBE | Strengthening the Reporting of Observational Studies in Epidemiology |
| TZ | transformation zone |
| TZ3 | type 3 transformation zone |
| WHO | World Health Organization |
Author Contributions
Conceptualization: E.L.R. and V.B.B.; data curation: J.C. and L.B.; validating the results: J.C. and L.B.; statistical analysis: D.M.S. and J.C.; writing the initial draft: E.L.R. and V.B.B.; writing—review and editing: E.L.R., V.D.C. and V.B.B.; formal analysis: D.M.S. and J.C.; supervision: V.D.C.; project administration: E.L.R., V.B.B. and V.D.C. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
The study was approved by the Ethics Committee of the Municipal Emergency Hospital Timișoara in collaboration with the Ethics Committee of the Victor Babeș University of Medicine and Pharmacy (approval number: 117; approval date: 1 January 2022).
Informed Consent Statement
Due to the retrospective nature of this study, the need for individual informed consent was waived.
Data Availability Statement
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
Funding Statement
This research received no external funding.
Footnotes
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References
- 1.Singh D., Vignat J., Lorenzoni V., Eslahi M., Ginsburg O., Lauby-Secretan B., Arbyn M., Basu P., Bray F., Vaccarella S. Global estimates of incidence and mortality of cervical cancer in 2020: A baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. Lancet Glob. Health. 2023;11:e197–e206. doi: 10.1016/S2214-109X(22)00501-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J. Clin. 2024;74:229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]
- 3.Li Z., Liu P., Yin A., Zhang B., Xu J., Chen Z., Zhang Z., Zhang Y., Wang S., Tang L., et al. Global landscape of cervical cancer incidence and mortality in 2022 and predictions to 2030: The urgent need to address inequalities in cervical cancer. Int. J. Cancer. 2025;157:288–297. doi: 10.1002/ijc.35369. [DOI] [PubMed] [Google Scholar]
- 4.Das M. WHO launches strategy to accelerate elimination of cervical cancer. Lancet Oncol. 2021;22:20–21. doi: 10.1016/S1470-2045(20)30729-4. [DOI] [PubMed] [Google Scholar]
- 5.Behrens A.S., Dietl A.K., Adler W., Geppert C., Hartmann A., Knöll A., Beckmann M.W., Mehlhorn G., Koch M.C., Schulmeyer C., et al. Evaluation of endocervical curettage (ECC) in colposcopy for detecting cervical intraepithelial lesions. Arch. Gynecol. Obstet. 2024;310:3037–3045. doi: 10.1007/s00404-024-07721-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Schiffman M., Mirabello L., Egemen D., Befano B., Xiao Y., Wentzensen N., Raine-Bennett T., Nayar R., Cheung L.C., Rositch A., et al. The combined finding of HPV 16, 18, or 45 and cytologic Atypical Glandular Cells (AGC) indicates a greatly elevated risk of in situ and invasive cervical adenocarcinoma. Gynecol. Oncol. 2023;174:253–261. doi: 10.1016/j.ygyno.2023.05.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Perkins R.B., Guido R.S., Castle P.E., Chelmow D., Einstein M.H., Garcia F., Huh W.K., Kim J.J., Moscicki A.-B., Nayar R., et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J. Low. Genit. Tract Dis. 2020;24:102–131. doi: 10.1097/LGT.0000000000000525. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Gori S., Venturelli F., Carozzi F., Giorgi Rossi P., Del Mistro A. Italian guidelines for cervical cancer screening. Multisocietal Recomm. Use Biomark. HPV Screen. Risk-Based Approach GRADE methodology. Br. J. Cancer. 2025;133:1076–1084. doi: 10.1038/s41416-025-03161-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Rad A., Sørbye S.W., Tiwari S., Løchen M.-L., Skjeldestad F.E. Risk of Intraepithelial Neoplasia Grade 3 or Worse (CIN3+) among Women Examined by a 5-Type HPV mRNA Test during 2003 and 2004, Followed through 2015. Cancers. 2023;15:3106. doi: 10.3390/cancers15123106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Khan M.J., Werner C.L., Darragh T.M., Guido R.S., Mathews C., Moscicki A.-B., Mitchell M.M., Schiffman M., Wentzensen N., Massad L.S., et al. ASCCP Colposcopy Standards: Role of Colposcopy, Benefits, Potential Harms, and Terminology for Colposcopic Practice. J. Low. Genit. Tract Dis. 2017;21:223–229. doi: 10.1097/LGT.0000000000000338. [DOI] [PubMed] [Google Scholar]
- 11.Waxman A.G., Conageski C., Silver M.I.P., Tedeschi C.R., Stier E.A., Apgar B., Huh W.K., Wentzensen N., Massad L.S., Khan M.J., et al. ASCCP Colposcopy Standards: How do we perform colposcopy? Implications for establishing standards. J. Low. Genit. Tract Dis. 2017;21:235–241. doi: 10.1097/LGT.0000000000000336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Wentzensen N., Walker J.L., Gold M.A., Smith K.M., Zuna R.E., Mathews C., Dunn S.T., Zhang R., Moxley K., Bishop E., et al. Multiple biopsies and detection of cervical cancer precursors at colposcopy. J. Clin. Oncol. 2015;33:83–89. doi: 10.1200/JCO.2014.55.9948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Effah K., Tekpor E., Wormenor C.M., Essel N.O.M. Transformation zone types: A call for review of the IFCPC terminology to embrace practice in low-resource settings. Ecancermedicalscience. 2023;17:1612. doi: 10.3332/ecancer.2023.1612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Massad L.S., Perkins R.B., Naresh A., Nelson E.L., Spiryda L., Gecsi K.S., Mulhem E., Kostas-Polston E., Zou T., Giles T.L., et al. Colposcopy Standards: Guidelines for Endocervical Curettage at Colposcopy. J. Low. Genit. Tract Dis. 2023;27:97–101. doi: 10.1097/LGT.0000000000000710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Bruno M.T., Cavallaro A.G., Sudano M.C., Fratto M.C., Pagana A., Fiore M., Valenti G. Role of endocervical curettage in detecting CIN2 + in postmenopausal women with persistent high-risk HPV and type 3 transformation zone. BMC Cancer. 2025;25:1486. doi: 10.1186/s12885-025-14868-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Akgor U., Ozgul N., Gunes A.C., Turkyılmaz M., Gultekin M. Evaluation of Endocervical Curettage in Colposcopy in the Turkish Cervical Cancer Screening Program. J. Clin. Med. 2024;13:4417. doi: 10.3390/jcm13154417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Jareemit N., Theerarojanapong L., Laokulrath N., Achariyapota V., Khemworapong K., Kuljarasnont S., Ittiamornlert P., Poonyakanok V., Inthasorn P. Yield of endocervical curettage in detecting cervical intraepithelial neoplasia grade 2 or higher during colposcopy: A prospective, cross-sectional study. Int. J. Gynaecol. Obstet. 2025;169:105–111. doi: 10.1002/ijgo.16074. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Derchain S.F.M., Rabelo-Santos S.H., Sarian L.O., Zeferino L.C., Zambeli E.R.d.O., Westin M.C.D.A., Andrade L.A.L.d.Â., Syrjänen K.J. Human papillomavirus DNA detection and histological findings in women referred for atypical glandular cells or adenocarcinoma in situ in their Pap smears. Gynecol. Oncol. 2004;95:618–623. doi: 10.1016/j.ygyno.2004.08.033. [DOI] [PubMed] [Google Scholar]
- 19.Schiffman M., Hyun N., Raine-Bennett T.R., Katki H., Fetterman B., Gage J.C., Cheung L.C., Befano B., Poitras N., Lorey T., et al. A cohort study of cervical screening using partial HPV typing and cytology triage. Int. J. Cancer. 2016;139:2606–2615. doi: 10.1002/ijc.30375. [DOI] [PubMed] [Google Scholar]
- 20.Jung L., Klamminger G.G., Nigdelis M.P., Eltze E. Impact of HPV Testing Based on the 2020 Update of the German Cervical Cancer Screening Program-Data from a Retrospective Monocentric Study. Cancers. 2025;17:2024. doi: 10.3390/cancers17122024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Yalcin N., Alci A., Gokkaya M., Goksu M., Toptas T., Ureyen I. Evaluation of the Outcomes of Patients Undergoing Colposcopy for High-Risk Human Papillomavirus Positivity and/or Abnormal Cervical Cytology. Diagnostics. 2026;16:465. doi: 10.3390/diagnostics16030465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Microsoft–AI, Cloud, Productivitate, Calcul, Jocuri și Aplicații [Internet] [(accessed on 26 October 2025)]. Available online: https://www.microsoft.com/ro-ro.
- 23.IBM Corp . IBM SPSS Statistics for Windows. IBM Corp; Armonk, NY, USA: 2019. [(accessed on 12 September 2025)]. Version 26.0. Available online: https://www.scirp.org/reference/referencespapers?referenceid=3316867. [Google Scholar]
- 24.R: The R Project for Statistical Computing [Internet] [(accessed on 24 December 2025)]. Available online: https://www.r-project.org/
- 25.World Medical Association World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–2194. doi: 10.1001/jama.2013.281053. [DOI] [PubMed] [Google Scholar]
- 26.Mondschein C.F., Monda C. The EU’s General Data Protection Regulation (GDPR) in a Research Context. In: Kubben P., Dumontier M., Dekker A., editors. Fundamentals of Clinical Data Science. Springer; Cham, Switzerland: 2019. [(accessed on 26 October 2025)]. Available online: http://www.ncbi.nlm.nih.gov/books/NBK543521/ [PubMed] [Google Scholar]
- 27.Akel M., Ratra D., Wright M., Barroca C., Abdou A.A., Kaldas P., Bhatt S., Shah S., Borges S.H., Perez A.M. Anesthesia Usage and Pain Management in Colposcopy: A Scoping Review of Efficacy and Approaches. Cureus. 2024;16:e70384. doi: 10.7759/cureus.70384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Kong L., Xiao X., Wan R., Zhao S., Wang W. Immediate risk and 5-year cumulative risk of high-grade cervical lesions in high-risk HPV-positive patients with minor cytological abnormalities: A retrospective single-center study in China. BMC Cancer. 2025;25:1541. doi: 10.1186/s12885-025-14972-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Dai W., Wang T., Chen L., Qiu Z., Chen P., Chen D. Immediate risk of cervical intraepithelial neoplasia and diagnostic value of colposcopy among cytology-negative women with oncogenic HPV: A retrospective study. BMC Womens Health. 2024;24:419. doi: 10.1186/s12905-024-03258-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Chen R., Ye C., Li Y., Lin Z., Wang L., Fu Y., Cheng X. The distribution of colposcopy directed ectocervical biopsy and endocervical curettage results: A retrospective study of 47,134 cases. Ann. Med. 2025;57:2573149. doi: 10.1080/07853890.2025.2573149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Wei B., Li Q., Seery S., Qiao Y., Jiang Y. Endocervical curettage for diagnosing high-grade squamous intraepithelial lesions or worse in women with type 3 transformation zone lesions: A retrospective, observational study. BMC Women’s Health. 2023;23:245. doi: 10.1186/s12905-023-02297-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Cong Q., Xiao J., Tao X., Sui L. Risk of High-Grade Histopathology Diagnosed by Cervical Conization in Endocervical Curettage Cervical Intraepithelial Neoplasia 1: A Case-Control Study. J. Low. Genit. Tract. Dis. 2020;24:247–251. doi: 10.1097/LGT.0000000000000541. [DOI] [PubMed] [Google Scholar]
- 33.Poomtavorn Y., Suwannarurk K., Thaweekul Y., Maireang K. Diagnostic value of endocervical curettage for detecting dysplastic lesions in women with atypical squamous cells of undetermined significance (ASC-US) and low grade squamous intraepithelial lesion (LSIL) Papanicolaou smears. Asian Pac. J. Cancer Prev. 2014;15:3461–3464. doi: 10.7314/APJCP.2014.15.8.3461. [DOI] [PubMed] [Google Scholar]
- 34.Li X., Zhao Y., Xiang F., Zhang X., Chen Z., Zhang M., Kang X., Wu R. Evaluation of the diagnostic performance of colposcopy in the detection of cervical high-grade squamous intraepithelial lesions among women with transformation zone type 3. BMC Cancer. 2024;24:381. doi: 10.1186/s12885-024-12156-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Zhang X., Dou Y., Wang M., Li Y., Wang F., Xie X., Wang X. A retrospective analysis on 1901 women with high grade cervical intraepithelial neoplasia by colposcopic biopsy. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017;217:53–58. doi: 10.1016/j.ejogrb.2017.07.005. [DOI] [PubMed] [Google Scholar]
- 36.Hu S.-Y., Zhang W.-H., Li S.-M., Li N., Huang M.-N., Pan Q.-J., Zhang X., Han Y., Zhao F.-H., Chen W., et al. Pooled analysis on the necessity of random 4-quadrant cervical biopsies and endocervical curettage in women with positive screening but negative colposcopy. Medicine. 2017;96:e6689. doi: 10.1097/MD.0000000000006689. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Colposcopy Standards and Guidelines. American Society for Colposcopy and Cervical Pathology (ASCCP) [Internet] [(accessed on 2 March 2026)]. Available online: https://www.asccp.org/guidelines/management-guidelines-enduring-guidelines-process/colposcopy-standards-and-guidelines/
- 38.Willows K., Selk A., Auclair M.-H., Jim B., Jumah N., Nation J., Proctor L., Iazzi M., Bentley J. 2023 Canadian Colposcopy Guideline: A Risk-Based Approach to Management and Surveillance of Cervical Dysplasia. Curr. Oncol. 2023;30:5738–5768. doi: 10.3390/curroncol30060431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.McGee A.E., Alibegashvili T., Elfgren K., Frey B., Grigore M., Heinonen A., Jach R., Jariene K., Kesic V., Küppers V., et al. European consensus statement on expert colposcopy. Eur. J. Obstet. Gynecol. Reprod. Biol. 2023;290:27–37. doi: 10.1016/j.ejogrb.2023.08.369. [DOI] [PubMed] [Google Scholar]
- 40.Gustafson L.W., Hammer A., Bennetsen M.H., Kristensen C.B., Majeed H., Petersen L.K., Andersen B., Bor P. Cervical intraepithelial neoplasia in women with transformation zone type 3: Cervical biopsy versus large loop excision. BJOG Int. J. Obstet. Gynaecol. 2022;129:2132–2140. doi: 10.1111/1471-0528.17200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Athanasiou A., Veroniki A.A., Efthimiou O., Kalliala I., Naci H., Bowden S., Paraskevaidi M., Arbyn M., Lyons D., Martin-Hirsch P., et al. Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: A systematic review and network meta-analysis. Lancet Oncol. 2022;23:1097–1108. doi: 10.1016/S1470-2045(22)00334-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Wentzensen N., Garcia F., Clarke M.A., Massad L.S., Cheung L.C., Egemen D., Guido R., Huh W., Saslow D., Smith R.A., et al. Enduring Consensus Guidelines for Cervical Cancer Screening and Management: Introduction to the Scope and Process. J. Low. Genit. Tract Dis. 2024;28:117. doi: 10.1097/LGT.0000000000000804. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Perkins R.B., Wolf A.M.D., Church T.R., Elkin E.B., Skates S.J., Etzioni R.D., Guerra C.E., Herzig A., Hoffman R.M., Oeffinger K.C., et al. Self-collected vaginal specimens for human papillomavirus testing and guidance on screening exit: An update to the American Cancer Society cervical cancer screening guideline. CA Cancer J. Clin. 2026;76:e70041. doi: 10.3322/caac.70041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Harper D.M., Paczos T., Ridder R., Huh W.K. p16/ki-67 dual stain triage of individuals positive for HPV to detect cervical precancerous lesions. Int. J. Cancer. 2025;156:2257–2264. doi: 10.1002/ijc.35353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.WHO Guideline for Screening and Treatment of Cervical Pre-Cancer Lesions for Cervical Cancer Prevention: Use of Dual-Stain Cytology to Triage Women After a Positive Test for Human Papillomavirus (HPV) [Internet] [(accessed on 2 March 2026)]. Available online: https://www.who.int/publications/i/item/9789240091658. [PubMed]
- 46.Su H., Jin X., Kong L., You Y., Wu H., Liou Y., Li L. The triage role of cytological DNA methylation in women with non-16/18, specifically genotyping high-risk HPV infection. Br. J. Cancer. 2025;132:1064–1071. doi: 10.1038/s41416-025-03005-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.SOX1/PAX1 Methylation for Triage of HPV-Positive Women in Cervical Cancer Screening: A Cohort Study-Xie-BJOG: An International Journal of Obstetrics & Gynaecology-Wiley Online Library [Internet] [(accessed on 2 March 2026)]. Available online: https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.70162? [DOI] [PMC free article] [PubMed]
- 48.Zhai X., Kong T., Yang X., Yu J., Dao Y., Yang H., Zhang H., Duan R. Clinical performance of triage strategies for HPV-positive women in cervical cancer screening in rural Yunnan China. BMC Cancer. 2025;26:57. doi: 10.1186/s12885-025-15375-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Wu T., Lucas E., Zhao F., Basu P., Qiao Y. Artificial intelligence strengthens cervical cancer screening–present and future. Cancer Biol. Med. 2024;21:864–879. doi: 10.20892/j.issn.2095-3941.2024.0198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Takahashi T., Kobayashi Y., Sakurai R., Matsuoka K., Akatsuka J., Kisu I., Iwata T., Takayama J., Matsuzaki M., Yamagami W., et al. A Systematic Review of the Application of Artificial Intelligence in Colposcopy: Diagnostic Accuracy for Cervical Intraepithelial Neoplasia and Cervical Cancer. Clin. Med. Insights Oncol. 2025;19:11795549251374908. doi: 10.1177/11795549251374908. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Liu L., Liu J., Su Q., Chu Y., Xia H., Xu R. Performance of artificial intelligence for diagnosing cervical intraepithelial neoplasia and cervical cancer: A systematic review and meta-analysis. eClinicalMedicine. 2025;80:102992. doi: 10.1016/j.eclinm.2024.102992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Wang X., Wang Q., Ding G., Wang J., Tang Y., Feng Y. Artificial intelligence for colposcopic and cytological image analysis in early cervical cancer detection. iScience. 2026;29:114627. doi: 10.1016/j.isci.2026.114627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Ouh Y.-T., Kim T.J., Ju W., Kim S.W., Jeon S., Kim S.-N., Kim K.G., Lee J.-K. Development and validation of artificial intelligence-based analysis software to support screening system of cervical intraepithelial neoplasia. Sci. Rep. 2024;14:1957. doi: 10.1038/s41598-024-51880-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Phiri H., Uwinkindi F., Diop M., Mwanahamuntu M., Gondongwe L., Guzha B.T., Barrett C., Joseph J.T., Horning M.P., Anne M., et al. Performance of an artificial intelligence-based tool for cervical precancer screening in five countries in Africa: A prospective, observational, diagnostic accuracy study. Lancet Glob. Health. 2026;14:e49–e60. doi: 10.1016/S2214-109X(25)00352-3. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.