Pathophysiology
A study involving 107 female patients with cervical lesions found that SEC62 overexpression, indicative of 3q amplification, was associated with enhanced cell migration abilities in cervical cancer cells, likely through EMT induction (PMID: 27553742). This suggests SEC62 as a potential marker for understanding the transition from high-grade squamous intraepithelial neoplasia to invasive cervical cancer.
The study by Lloyd JM et al. (1984) demonstrated that the Ca 1 antibody stains normal cervical epithelium positively, implying a possible involvement in the early detection of cellular alterations that may precede high grade squamous intraepithelial neoplasia (PMID: 6368596).
Epidemiology
The study context emphasizes the significant risk of progression to cervical cancer within 10 years for untreated cervical HSIL cases, reinforcing the importance of timely intervention through methods like CKC and PDT [PMID: 41294652].
In Beijing, the prevalence of HSIL among women is notably high at approximately 70.4 per 100,000, emphasizing the need for robust screening and management strategies [PMID: 40489843].
The research highlights a demographic shift towards younger women experiencing cervical HSIL, impacting clinical management strategies to balance cancer risk reduction with reproductive health concerns (PMID: 39739926).
Although focused on diagnostic improvements, Kurita Y et al. (2024) implicitly highlight the role of advanced screening technologies like AI in potentially lowering cervical cancer incidence by enhancing early detection of precursors like HSIL. (PMID: 39174613)
In LMICs such as China, approximately 20–80% of women have lesions in transformation zone 3 (TZ3), which are more challenging to identify via colposcopy alone, contributing to a higher rate of false negatives in HSIL+ cases (PMID: 35399061).
Given the high prevalence of cervical cancer among underscreened women in LMICs, there is a critical need for screening methods that are both sensitive and feasible in resource-limited settings, highlighting the potential impact of FRD (PMID: 34011097).
Despite tailored surgical approaches, post-menopausal women treated with CKC still face substantial risks of HSIL progression to invasive cancer, highlighting the importance of regular follow-up and monitoring [PMID:33975589].
During a 12-year study involving 1,905 endocervical polypectomy cases, Park et al. identified 21 cases (1.1%) of HSILs and 2 cases (0.1%) of SCCs involving ECPs, aligning with previously reported prevalence rates. [PMID:32871791]
Clinical Presentation
The research indicates that during the late proliferative phase of the menstrual cycle, HSILs tend to present more frequently as scattered single cells rather than syncytial aggregates in liquid-based cytology samples, highlighting the importance of considering menstrual cycle phase in clinical interpretation (Okedo M et al., 2022; PMID: 35700714).
Diagnosis
The paper by Bellevicine et al. (PMID: 41428572) highlights the importance of detailed documentation in interventional cytopathology, including FNA procedures, which can improve diagnostic precision and quality in pathological assessments like high grade squamous intraepithelial neoplasia.
Patients diagnosed with HSIL were allocated to either Photodynamic Therapy (PDT) or Cold Knife Conization (CKC) based on informed preference after detailed counseling, highlighting the importance of patient choice alongside clinical comparability between treatments [PMID: 41294652].
The study demonstrates that implementing the Techcyte SureView™ System with artificial intelligence significantly improves diagnostic accuracy in cervical cytology, matching or exceeding human pathologist performance (PMID: 40387263).
Liu et al. (2025) emphasize the importance of comprehensive pathological examination post-conization to detect invasive carcinoma, which aids in differentiating between nonprogression (HSIL or less) and progression to invasive cancer (PMID: 39739926).
Kurita Y et al. (2024) developed an AI-based system using advanced algorithms to evaluate cytological slides, aiming to reduce diagnostic delays and human error while maintaining or improving diagnostic accuracy for conditions like HSIL, which are critical for early cervical cancer detection. This approach leverages more realistic clinical data to enhance screening processes beyond traditional manual methods. (PMID: 39174613)
Subjective factors like poor colposcopy image quality, presence of atypical blood vessels, biopsy sampling technique, and lesion visibility on the cervix are associated with a higher likelihood of pathological upgrading from CIN3 to cervical cancer (Li et al., 2024; PMID: 38561685). These factors should be carefully considered during diagnostic procedures.
A retrospective study at Putuo Hospital, Shanghai, involving women with TZ3 who underwent colposcopy due to positive screening tests or abnormal clinical symptoms between February 2020 and March 2023 found that nearly 20% of colposcopic assessments were inadequate due to TZ3, highlighting the need for adjunctive procedures like endocervical canal curettage (ECC) to improve diagnostic accuracy (PMID: 38528547).
A retrospective multicenter study in China (PMID: 35399061) found that integrating referral screening results like cytology and HPV testing with colposcopy can enhance the identification of HSIL+ lesions, especially in TZ3 where colposcopic detection rates are lower due to anatomical challenges and potential skill gaps among colposcopists.
The study by Cheng et al. (PMID: 34561435) demonstrates that CNN-based approaches enhance the detection of cervical lesion cells, potentially leading to more efficient and accurate diagnosis of HSIL through whole slide image (WSI) analysis, which could reduce false negatives typically associated with manual cytopathology.
The study by Wang et al. (PMID: 34376717) explores the application of artificial intelligence in rapidly identifying cervical HSIL and squamous cell carcinoma, suggesting a potential enhancement over conventional cytological examination techniques used in Pap smear screenings.
Following an initial LEEP conization revealing positive margins for HSIL, reassessment through cytology with endocervical sampling at 4–6 months is recommended to detect any residual disease (PMID: 34011112).
Differential Diagnosis
The comparative study highlights that although both PDT and CKC are effective for HSIL, PDT offers a less invasive approach with reduced risks of surgical complications like bleeding and infections, aiding in differential diagnosis and treatment planning [PMID: 41294652].
Previous studies indicate that patients with HPV16-positive lesions or who underwent LEEP have a higher likelihood of residual or recurrent HSIL, emphasizing the need for closer surveillance and timely colposcopic evaluation (PMID: 40156312).
For ASC-H lesions analyzed, pathohistological results showed chronic cervicitis in 48.6% of cases, HSIL in 13.5%, highlighting the necessity for histological verification to differentiate between these conditions (Jahic M, Hadzimehmedovic A, Medical Archives 2020).
Accurate diagnosis of HSIL with positive margins necessitates a thorough diagnostic approach combining cytology, colposcopy, and histology to differentiate from other cervical lesions (Chen JY et al., 2018). [PMID: 30313104]
The study demonstrated that E6/E7 mRNA positivity was notably higher in women with HSIL compared to those with benign cytological results, aiding in differential diagnosis (PMID: 27022787).
The study highlights that LSIL-H cases, characterized by ambiguous features between LSIL and ASC-H, can be better differentiated through immunocytochemical analysis of p16 INK4a/Ki-67 and HPV L1 capsid protein, providing clearer diagnostic distinctions (PMID: 24151431).
Among patients undergoing repeat conization, those with lesions larger than 5 mm or endocervical margin involvement were more likely to have residual high-grade CIN rather than micro-invasive carcinoma, aiding in differential diagnosis (PMID: 35894500).
Among 49 ASC-H cases, those with atypical immature squamous metaplastic cells without HCGs showed HSIL/CIN 3 without endocervical gland involvement (10 cases), distinguishing them from HCGs which often indicate glandular involvement (PMID: 34019341).
Management
According to Bellevicine et al. (PMID: 41428572), ensuring quality in interventional cytopathology involves practical aspects like the use of local anesthetics and careful management of antithrombotic medications, contributing to safer and more comfortable procedures that are beneficial in managing pathological conditions including high grade squamous intraepithelial neoplasia.
A retrospective study comparing PDT with CKC for cervical HSIL found PDT to be a viable non-invasive treatment option, reducing risks typically associated with surgical interventions like CKC, including major bleeding, infections, and complications related to cervical insufficiency, miscarriage, and preterm birth [PMID: 41294652].
Wang et al. (2025) developed a nomogram based on various risk factors to predict positive margins after CKC in HSIL patients, aiming to improve surgical outcomes by identifying high-risk individuals. This tool could help surgeons tailor their approach to minimize residual precancerous cells post-procedure [PMID: 40489843].
Adoption of digital pathology workflows with AI support, exemplified by the Techcyte SureView™ System, enhances diagnostic consistency and efficiency, crucial for managing cervical cytology cases effectively (PMID: 40387263).
Following successful CKC for CIN3 with negative margins, initial management involves HPV testing 6 months post-surgery, with the possibility of extending testing intervals to 3 years if three consecutive negative tests are confirmed at 12-month intervals (PMID: 40156312).
The study by Liu et al. (2025) suggests that evaluating the risk of progression to invasive carcinoma through their prediction model can guide whether to proceed with conization or consider delayed treatment options like ablative therapies for HSIL patients, particularly focusing on preserving fertility in younger women (PMID: 39739926).
The study by Kurita Y et al. (2024) proposes an AI workflow designed to expedite the diagnosis of cervical abnormalities, including HSIL, thereby potentially improving patient management through faster and more accurate screening results. This could reduce delays in initiating appropriate treatment protocols. (PMID: 39174613)
A retrospective study involving patients diagnosed with CIN3 between January 2012 and December 2022 found that about 10-11% experienced pathological upgrading to cervical cancer post-conical resection (Li et al., 2024; PMID: 38561685). This underscores the importance of thorough surgical removal and subsequent monitoring for high-risk patients.
Given the higher rate of diagnostic inaccuracies in TZ3 cases, performing ECC alongside colposcopy can enhance the identification of CIN2+ lesions, reducing unnecessary procedures such as unnecessary biopsies and conization surgeries (PMID: 38528547).
Enhancing colposcopic practices by incorporating cytology and HPV genotyping results could significantly improve the detection of HSIL+ lesions, potentially leading to more effective management and treatment strategies (PMID: 35399061).
According to Srijarusith N, Rodpenpear N (PMID: 35225479), a retrospective study indicated that LEEP with a cone depth within the range of 10-19.9 mm achieved negative margins in 73% of cases, highlighting the importance of appropriate excision depth to minimize positive margins which could indicate residual disease.
Cheng et al. (PMID: 34561435) propose a computer-aided diagnosis system based on deep learning that addresses challenges in WSI analysis, generalization across diverse staining techniques, and inference speed, suggesting potential improvements in clinical management through automated screening tools.
According to Wang et al. (PMID: 34376717), women identified with ASC-H, despite being less common, carry a significantly higher risk of having high-grade lesions and thus require immediate referral for colposcopy to ensure timely intervention.
A retrospective study from Qilu Hospital of Shandong University involving 267 patients with positive margins after LEEP conization found that reassessment with cytology and endocervical sampling at 4–6 months post-treatment is preferred according to ASCCP guidelines (PMID: 34011112). Repeat diagnostic excisional procedures or hysterectomy may be considered based on individual patient factors such as age and fertility requirements.
Complications
The study by Srijarusith N, Rodpenpear N (PMID: 35225479) suggests that although deeper excisions can increase pregnancy complications, finding the precise cone depth that ensures negative margins without exacerbating these risks is critical for patient management post-LEEP procedures.
Although LEEP is considered safe for treating CIN 2-3 lesions due to its practicality and efficacy, it can still lead to complications including bleeding, infection, incompetent cervix, and cervical stenosis, potentially impacting future pregnancy-related issues (Poomtavorn et al., 2019; PMID: 30912403).
The study highlights that positive surgical margins post-conization are predictive of residual or recurrent disease and notes increased risks of obstetrical complications like preterm delivery, rupture of membranes, and low birth weight when conization depth exceeds 10 mm (PMID: 27401478).
The meta-analysis revealed significantly lower rates of adverse events such as vaginal bleeding (OR: 0.10 [0.03, 0.33]; P = 0.0002), cervical canal adhesion (OR: 0.16 [0.03, 0.90]; P = 0.04), and cervical scar formation (OR: 0.04 [0.01, 0.30]; P = 0.002) with PDT compared to conization (LEEP/CKC). [PMID:40058445]
Given the significant association between conization outcomes and factors like age and histological results, obligatory follow-up post-conization underscores the risk of disease recurrence and potential complications (PMID: 23607318).
The study noted minimal tissue coagulative changes in both RF cone biopsy (104 patients) and LLETZ (82 patients) methods, indicating similar complication profiles regarding tissue handling and diagnostic clarity (PMID: 21446324).
An audit of the 'see and treat' approach for HSIL at Chiang Mai University Hospital (PMID: 19603324) reported primary haemorrhage in 13 (5.3%) women and inpatient admissions due to LEEP complications in 4 (1.6%) patients, indicating manageable complication rates.
LEC2 demonstrated fewer complications including reduced specimen fragmentation (0% vs. 5.9%) and lower rates of positive margins (12.7% vs. 33.3%) compared to LEC1, suggesting a safer procedural method for treating CINs. [PMID: 19293589]
Among the women studied, positive cone margins were identified in 16.8% of cases and were significantly linked to a higher risk of recurrent or residual disease (PMID: 17712659).
Prognosis & Follow-up
The study indicates that PDT, utilizing 5-aminolevulinic acid (5-ALA), demonstrates comparable efficacy to CKC for managing HSIL, potentially providing a safer option for patients concerned about fertility preservation due to reduced risks of obstetric complications [PMID: 41294652].
Studies indicate that women undergoing CKC with positive margins have an increased risk of recurrent cervical intraepithelial neoplasia (CIN) and cervical cancer over time, underscoring the importance of thorough follow-up and potential additional interventions [PMID: 40489843].
Improved diagnostic accuracy achieved with AI in digital pathology systems could facilitate more tailored follow-up plans for patients with HSIL, potentially improving long-term prognosis (PMID: 40387263).
A retrospective cohort study of 2257 patients who underwent CKC for CIN3 with negative margins found that extending HPV testing intervals to 3 years post-surgery is appropriate after three consecutive negative tests at 12-month intervals, supporting a minimum follow-up period of 25 years (PMID: 40156312).
The study indicates a decline in HPV persistence rates from 14.3%–50.0% at 6 months to 2.2%–22.4% at 12 months post-CKC, justifying extended follow-up intervals for patients with negative margins (PMID: 40156312).
Liu et al. (2025) developed a clinical prediction model using retrospective data from 3337 patients treated with cervical conization for HSIL at Hunan Provincial Maternal and Child Health Care Hospital (PMID: 39739926). The model evaluates risk factors associated with pathological progression to invasive cervical cancer, enabling clinicians to decide on delayed or ablative treatment based on individual patient risk.
Special Populations
Given the decline in estrogen levels and cervical atrophy common in post-menopausal women, this study highlights the necessity for customized cervical conization techniques, particularly deeper resections (Type III), to effectively manage HSIL [PMID:33975589].
In a Thai population sample, women older than 35-40 years had approximately twice the risk of severe histopathology, underscoring the need for age-specific screening strategies (PMID: 26514516).
Among postmenopausal women diagnosed with ASC-H, prior HPV-DNA testing showed potential utility in identifying higher risks for high-grade lesions, contrasting with higher incidences of negative/CIN1 outcomes observed in this demographic (PMID: 23749686).
For women over 40 undergoing cervical conization, scalpel excision methods are recommended due to lower risks associated with positive margins, especially evident in women over 45 with CIN3 and glandular lesions (Perisic et al., 2011; PMID: 22053669).
The research highlights the need for tailored screening protocols in high-risk groups characterized by immunosuppression (OR = 3.45, 95% CI = 1.61-7.43), multiple vaginal deliveries (OR = 3.46, 95% CI = 1.90-6.27), abortion history (OR = 2.15, 95% CI = 1.07-4.35), and smoking (OR = 1.92, 95% CI = 1.13-3.27) to effectively manage CIN. (Russo E, Kupek E, Zanine RM. Journal of lower genital tract disease (2011); PMID: 21436727)
Postmenopausal women (35.4% had positive margins) exhibited a significantly higher risk of positive margins compared to premenopausal women (11.6%) during conization procedures for CIN 3. [PMID: 19628208]
Key Recommendations
Given the benefits highlighted in the study, it is recommended that laboratories adopt AI-assisted digital pathology tools like the Techcyte SureView™ System to enhance diagnostic precision and operational efficiency in cervical cytology (PMID: 40387263). (Evidence: Strong)
Based on the findings from Liu et al. (2025), it is recommended that clinicians integrate predictive models into their practice to personalize treatment plans for HSIL patients, particularly focusing on minimizing unnecessary surgical interventions that could affect future fertility (PMID: 39739926). (Evidence: Strong)
Given the advancements highlighted by Kurita Y et al. (2024), integrating AI technologies into routine cervical cytology screening processes is advised to improve diagnostic reliability and streamline patient care pathways, especially for identifying HSIL early. (PMID: 39174613) (Evidence: Strong)
Given the higher incidence of diagnostic inaccuracies in TZ3 cases, healthcare providers are recommended to consider performing ECC during colposcopy for women with TZ3 to improve detection rates of high-grade lesions (PMID: 38528547). (Evidence: Strong)
The study by Wang et al. (PMID: 34376717) recommends exploring AI technologies for cervical cancer screening to enhance diagnostic accuracy and streamline the management pathway for high-grade lesions like HSIL and squamous cell carcinoma in situ. (Evidence: Moderate)
Given the fertility concerns and recurrence risks associated with positive margins in women of reproductive age, it is recommended that they undergo follow-up surgery within three months to address residual disease effectively (Wang et al., 2021; PMID: 33962590). (Evidence: Strong)
Given the diagnostic variability and potential for significant underlying pathology in women with ASC-H smears, immediate referral for colposcopic examination and histological confirmation is advised to ensure precise diagnosis and tailored treatment plans (PMID: 30909664). (Evidence: Strong)
Although promising, the variability in microRNA level changes across studies necessitates additional validation to establish microRNA profiling as a reliable clinical tool for cervical neoplasia diagnosis (Abstract). (Evidence: Expert opinion)
Given the observed regression rates and metabolic benefits, recommending vitamin D supplementation (50,000 IU every 2 weeks for 6 months) could be considered for women diagnosed with CIN1 as part of a comprehensive management strategy (PMID: 28050798). (Evidence: Moderate)
References
1 Li X, Liu M, Ji Y, Qu P. The effectiveness of cold-knife conization (CKC) for post-menopausal women with cervical high-grade squamous intraepithelial lesion: a retrospective study. BMC surgery 2021. link 2 Park CK, Kim YW, Koh HH, Yoon N, Bae GE, Kim HS. Clinicopathological Characteristics of Squamous Cell Carcinoma and High-grade Squamous Intraepithelial Lesions Involving Endocervical Polyps. In vivo (Athens, Greece) 2020. link 3 Liu Y, Li R, Li C, Wu R. Comparative analysis of photodynamic therapy and conization for cervical high-grade squamous intraepithelial lesion: A systematic review and meta-analysis. Photodiagnosis and photodynamic therapy 2025. link
3 papers cited of 255 indexed.