Analysis of clinicopathological outcomes of atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesions (ASC-H) in cervical cancer screening for women

The cytological diagnosis of atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesions (ASC-H) is subjective and entails great variation in the risk of HSIL+. Therefore, we retrospectively analyzed the clinicopathological outcomes of patients with ASC-H cytology from January 2018 to June 2021 to determine associated predictors for diagnosing HSIL+ and explore their appropriate clinical management. Overall, 279 patients with ASC-H cytology were enrolled, 64.9% (181/279) of whom were histopathologically confirmed as HSIL+. Further analysis showed that only human papillomavirus (HPV) positivity was an independent risk factor for HSIL+ in ASC-H patients. Additionally, no significant difference was observed in the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the three HPV testing methods (hybrid capture (HC) II, HPV E6E7 mRNA and HPV genotyping testing) for detecting HSIL+ (p > 0.05). The perfect agreement between colposcopy and final histology was 40.5%, with a κ value of 0.145. The sensitivity, specificity, PPV and NPV of colposcopy for detecting HSIL+ were 32.6%, 91.8%, 87.9% and 42.3%, respectively. After cervical conization, none of the patients diagnosed with normal/benign histopathology by cervical biopsy was reclassified to HSIL+, while 39.5% (17/43) of the low-grade squamous intraepithelial lesion (LSIL) patients were reclassified as HSIL. During follow-up, ASC-H patients diagnosed with LSIL had a high rate of normalization (70%) and a low rates of persistence (20%) and progression (10%). In four ASC-H patients younger than 30 years old with HSIL (cervical intraepithelial neoplasia (CIN) 2), two normalized and two persisted during follow-up. In conclusion, ASC-H patients should be directly referred for colposcopy and undergo biopsy irrespective of their age, menopausal status and HPV status. Relatively conservative management might be more suitable for ASC-H patients with LSIL− or ASC-H patients younger than 30 years with HSIL (CIN2).

ASC-H; HSIL+ HPV; Colposcopy-directed cervical biopsy; Cervical conization

[1] Aoki ES, Yin R, Li K, Bhatla N, Singhal S, Ocviyanti D, et al. National screening programs for cervical cancer in Asian countries. Journal of Gynecologic Oncology. 2020; 31: e55.

[2] Solomon D, Davey D, Kurman R, Moriarty A, O’Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002; 287: 2114–2119.

[3] Sørbye SW, Suhrke P, Revå BW, Berland J, Maurseth RJ, Al-Shibli K. Accuracy of cervical cytology: comparison of diagnoses of 100 Pap smears read by four pathologists at three hospitals in Norway. BMC Clinical Pathology. 2017; 17: 18.

[4] Alli PM, Ali SZ. Atypical squamous cells of undetermined significance—rule out high-grade squamous intraepithelial lesion: cytopathologic characteristics and clinical correlates. Diagnostic Cytopathology. 2003; 28: 308–312.

[5] Bornstein J, Bentley J, Bösze P, Girardi F, Haefner H, Menton M, et al. 2011 colposcopic terminology of the international federation for cervical pathology and colposcopy. Obstetrics & Gynecology. 2012; 120: 166–172.

[6] Ao M, Zheng D, Wang J, Gu X and Xi M. Risk factors analysis of persistence, progression and recurrence in vaginal intraepithelial neoplasia. Gynecologic Oncology. 2021; 162: 584–589.

[7] Li J, Wang W, Yang P, Chen J, Dai Q, Hua P, et al. Analysis of the agreement between colposcopic impression and histopathological diagnosis of cervical biopsy in a single tertiary center of Chengdu. Archives of Gynecology and Obstetrics. 2021; 304: 1033–1041.

[8] Ratree S, Kleebkaow P, Aue-Aungkul A, Temtanakitpaisan A, Chumworathayi B, Luanratanakorn S. Histopathology of women with “atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion” (ASC-H) smears. Asian Pacific Journal of Cancer Prevention. 2019; 20: 683–686.

[9] Ortashi O, Abdalla D. Colposcopic and histological outcome of atypical squamous cells of undetermined significance and atypical squamous cell of undetermined significance cannot exclude high-grade in women screened for cervical cancer. Asian Pacific Journal of Cancer Prevention. 2019; 20: 2579–2582.

[10] Sung CO, Oh YL, Song SY. Cervical cytology of atypical squamous cells, cannot exclude high-grade squamous intra-epithelial lesion: significance of age, human papillomavirus DNA detection and previous abnormal cytology on follow-up outcomes. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2011; 159: 155–159.

[11] Mokhtar GA, Roustan Delatour NLD, Assiri AH, Gilliatt A, Senterman M, Islam S. Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion: cytohistologic correlation study with diagnostic pitfalls. Acta Cytologica. 2008; 52: 169–177.

[12] Kietpeerakool C, Srisomboon J, Tantipalakorn C, Suprasert P, Khunamornpong S, Nimmanhaeminda K, et al. Underlying pathology of women with “atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion” smears, in a region with a high incidence of cervical cancer. The Journal of Obstetrics and Gynaecology Research. 2008; 34: 204–209.

[13] Louro AP, Roberson J, Eltoum I, Chhieng DC. Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion. A follow-up study of conventional and liquid-based preparations in a high-risk population. American Journal of Clinical Pathology. 2003; 120: 392–397.

[14] Ryu K, Lee S, Min K, Kim JW, Hong JH, Song JY, et al. Reflex human papillomavirus test results as an option for the management of korean women with atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion. The Oncologist. 2015; 20: 635–639.

[15] Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, et al. Five-year risks of CIN 3+ and cervical cancer among women who test Pap-negative but are HPV-positive. Journal of Lower Genital Tract Disease. 2013; 17: S56–S63.

[16] Xu L, Verdoodt F, Wentzensen N, Bergeron C and Arbyn M. Triage of ASC-H: a meta-analysis of the accuracy of high-risk HPV testing and other markers to detect cervical precancer. Cancer Cytopathology. 2016; 124: 261–272.

[17] Perkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. Journal of Lower Genital Tract Disease. 2020; 24: 102–131.

[18] Marujo AT, Correia L, Brito M, Paula T, Borrego J. ASC-H cytological result: clinical relevance and accuracy of colposcopy in predicting high-grade histological lesions—a 7-year experience of a single institution in Portugal. Journal of the American Society of Cytopathology. 2017; 6: 248–253.

[19] Kudela E, Laucekova Z, Nachajova M, Visnovsky J, Bielik T, Krivus S, et al. Colposcopic scoring indexes in the evaluation of cervical lesions with the cytological result of atypical squamous cells, cannot exclude high-grade lesion. The journal of Obstetrics and Gynaecology Research. 2020; 46: 314–319.

[20] Nogara PRB, Manfroni LAR, Consolaro MEL. Cervical cytology of atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H): histological results and recurrence after a loop electrosurgical excision procedure. Archives of Gynecology and Obstetrics. 2011; 284: 965–971.