Optimizing biopsy procedures during colposcopy and detection of high-grade cervical lesions / 中华妇产科杂志

Objective:To investigate the value of biopsies on diagnosing cervical intraepithelial neoplasia of grade 2 or worse (CIN Ⅱ +), and optimize biopsy procedures of risk-based colposcopy practice. Methods:A prospective study was performed on 346 women referred to colposcopy following abnormal cervical cancer screening results at the First Affiliated Hospital of Nanjing Medical University, from April 2017 to December 2019. Up to 4 cervical biopsies were taken during colposcopy and each biopsy specimen was evaluated separately in histology. CIN Ⅱ + identified by any biopsy was the reference standard of disease used to evaluate the diagnostic value of targeted biopsy and random biopsy, and to quantify the improved detection of CIN Ⅱ + by taking multiple biopsies. Cervical cytology, HPV genotyping, and colposcopic impression were used to establish different risk strata to select various multiple biopsies procedures during colposcopy to improve accuracy and efficiency of CIN Ⅱ + detection. Results:In total 346 women, 190 (54.9%, 190/346) cases of them were diagnosed as CIN Ⅱ +. (1) In total 346 women, 96.8% (184/190) CIN Ⅱ + were detected by targeted biopsies, 27.9% (53/190) CIN Ⅱ + were detected in biopsies targeted grade 1 abnormal colposcopic findings (G1) on the cervix, and 68.9% (131/190) CIN Ⅱ + were detected in biopsies targetrd grade 2 abnormal colposcopic findings (G2) on the cervix. Colposcopy had a sensitivity of 68.9% when the biopsy threshold was G2, sensitivity increased to 96.8% when the biopsy threshold was defined to be G1. Among women with G1, adding 2 targeted biopsies to the first biopsy were sufficient to detect all CIN Ⅱ +, among women with G2, adding 1 targeted biopsy was sufficient. (2) Among 270 women, random biopsies targeted normal colposcopic findings on the cervix were performed in addition to targeted biopsies and in total 3.2% (6/190) additional CIN Ⅱ + were detected. As the number of cervical quadrants involved by abnormal colposcopic images increased, random biopsy detected fewer CIN Ⅱ + that would have otherwise been missed by targeted biopsies ( P=0.010). (3) Women with atypical squamous cells,cannot exclude high grade squamous intraepithelial lesion (ASC-H), high grade squamous intraepithelial lesion (HSIL) or atypical glandular cell (AGC) referral cytology, HPV 16-positive, G2 were more likely to have CIN Ⅱ +( P<0.01); for those meeting only one category, the yield of CIN Ⅱ + increased from 34.0% for one biopsy to 51.0% for two biopsies, the absolute increase in CIN Ⅱ + yield increased from the first to the second biopsy was 17.0%, two biopsies were sufficient to detect all CIN Ⅱ +; for those meeting at least two categories, the yield of CIN Ⅱ + increased from 90.7% for one biopsy to 92.6% for two biopsies, the absolute increase in CIN Ⅱ + yield increased from the first to the second biopsy was 1.9%, two biopsies were sufficient to detect all CIN Ⅱ +; for those not meeting any category, the yield of CIN Ⅱ + increased from 8.8% for one biopsy to 17.6% for two biopsies, to 23.5% for three biopsies, the absolute increase in CIN Ⅱ + yield increased from the first to the second biopsy, from the second to the third biopsy was 8.8%, 5.9%, three biopsies were sufficient to detect all CIN Ⅱ +. Conclusions:Performing multiple targeted biopsies could improve efficiency of CIN Ⅱ + detection. Adding random biopsies to multiple targeted biopsies showed very limited additional benefit for detection of CIN Ⅱ +. The biopsy procedures undertaken during the colposcopy visit could be modified based on various colposcopic impressions and reasons for referral.

Analysis of related factors for cervical intraepithelial neoplasia Ⅱ + detection in grade 1 abnormal colposcopic finding of cervix / 中华妇产科杂志

Objective:To screen out high risk factors of cervical intraepithelial neoplasia (CIN) of grade Ⅱ or worse (CIN Ⅱ +) by analyzing related factors for CIN Ⅱ + detection in grade 1 abnormal colposcopic finding (G1) of cervix and provide reference for individual management of colposcopic performance. Methods:A retrospective study was performed on patients who were reffered to colposcopy for abnormal results of cervical cancer screening and only had G1 colposcopic findings of cervix at the First Affiliated Hospital of Nanjing Medical University, from April 2017 to January 2021. The factors influencing the detection of CIN Ⅱ + were analyzed by univariate and multivariate analysis. Results:(1) A total of 403 patients were included in this study whose median age was 38 years old (range: 22-67 years old), and utimately 108 had high-grade squamous intraepithelial lesion, 1 had adenocarcinoma in situ and 1 had adenocarcinoma. The overall detection rate of CIN Ⅱ + was 27.3% (110/403). (2) Univariate analysis showed that the detection rate of CIN Ⅱ +, in patients ≥50 years old was higher than that in patients <50 years old (38.3% vs 25.4%; χ2=4.328, P=0.037), and in HPV 16 positive cases was higher than that in non-HPV 16 positive cases (41.8% vs 21.8%; χ2=16.080, P<0.01); as the cytological severity ( χ2=6.775, P=0.009) and the number of involving quadrants ( χ2=31.117, P<0.01) increased, the risk of CIN Ⅱ + detection increased; but the types of colpolscopic signs were not related to detection of CIN Ⅱ +( χ2=0.323, P=0.851). Multivariable analysis showed that the age of ≥50 years old ( OR=2.504, 95% CI: 1.299-4.830, P=0.006), HPV 16 positive type ( OR=3.353, 95% CI: 2.004-5.608, P<0.01) and the increase of involving quadrants ( OR=1.899, 95% CI: 1.518-2.376, P<0.01) were independent risk factors. (3) The detection rate of CIN Ⅱ + was highest in the women with HPV 16 positive type and four quadrants of G1 (73.7%), while lowest in the women with non-HPV 16 positive type and one quadrant of G1 (10.4%). Conclusions:The age of ≥50 years old, HPV 16 positive type and the increase of involving quadrants are independent risk factors of detecting CIN Ⅱ + in G1 colposcopic findings. So the key point of the individual management of G1 groups with different risk stratification is to adequately biopsy in high-risk group to avoid miss diagnosis of CIN Ⅱ +.

Discussion on the diagnosis and treatment of high-grade squamous intraepithelial lesions in post-menopausal women / 中华妇产科杂志

Objective To analyze the performance of colposcopy and investigate the diagnosis and treatment characteristics of high-grade squamous intraepithelial lesion (HSIL) diagnosed by cervical tissue sampling in post-menopausal women. Methods A retrospective study was performed on 1 449 patients with HSIL diagnosed by cervical tissue sampling under colposcopy and treated by loop electrosurgical excision procedure (LEEP) or extrafascial hysterectomy as the primary therapy at the First Affiliated Hospital of Nanjing Medical University, from November 2015 to October 2017. In order to investigate the diagnosis and treatment of HSIL in post-menopausal women, a case-control study was conducted to compare the difference in performance of colposcopy and treatment modality between 213 post-menopausal patients (14.7%, 213/1 449) and 1 236 pre-menopausal patients (85.3%, 1 236/1 449). Results (1)The proportion of cases pathologically upgraded to cervical cancer was significantly greater in post-menopausal patients (9.4%, 20/213) compared with pre-menopausal patients (3.8%, 47/1 236; P<0.05). (2) The proportion of ≥HSIL diagnosed by colposcopy showed no significant difference between post-menopausal patients (76.1%, 162/213) and pre-menopausal patients (78.2%, 967/1 236; P=0.479). The proportion of typeⅢtransformation zone (TZ) was significantly greater in post-menopausal patients (91.1%, 194/213) compared with pre-menopausal patients (59.1%, 731/1 236; P<0.05). The rate of missed diagnosis of cervical cancer was significantly higher in typeⅢTZ (6.4%, 59/925) compared with typeⅠand(or)ⅡTZ (1.5%, 8/524; P<0.05). The proportion of HSIL detected by endocervical curettage alone was greater in post-menopausal patients (9.9%, 21/213) compared with pre-menopausal patients (2.6%, 32/1 236; P<0.05). (3)Initial treatment with LEEP: the positive rate of endocervical margin was significantly greater in post-menopausal patients (20.5%, 36/176) compared with pre-menopausal patients (10.5%, 130/1 236;P<0.05); in patients who were diagnosed as HSIL after LEEP, the positive rate of endocervical margin and the residual rate were both greater in post-menopausal patients compared with pre-menopausal patients [15.4% (25/162) versus 8.8% (105/1 189), P=0.008; 52.0% (13/25) versus 26.7% (28/105), P=0.014]. (4)Thirty-seven post-menopausal patients were treated by extrafascial hysterectomy as the primary therapy, 5 cases (13.5%, 5/37) were diagnosed as cervical cancer (stage Ⅰa1) after the surgery. Conclusions (1) The lesions of HSIL in post-menopausal patients still have definite features under colposcopy as same as pre-menopausal patients. Endocervical curettage could help detect more HSIL in post-menopausal patients. Compared with pre-menopausal patients, post-menopausal HSIL patients have an increased risk of cervical cancer and are more likely missed by cervical tissue sampling. (2) LEEP has the dual effects of diagnosis and treatment, and is still the recommended treatment for post-menopausal HSIL patients. However, the increase in positive rate of endocervical margin and residual rate requires further active intervention. (3) Considering those post-menopausal HSIL patients who cannot accept conization as the initial treatment, the selection of hysterectomy type requires more thorough study.

Analysis of the missed diagnosis of invasive carcinoma under the microscope in HSIL diagnosed by colposcopy-guided biopsy and related influencing factors / 中华妇产科杂志

Objective To observe the missed diagnosis of invasive carcinoma under the microscope (ICUM) in high grade squamous intraepithelial neoplasia (HSIL), and analyze associated factors influencing missed ICUM. Methods A retrospective study was performed on patients diagnosed with HSIL by colposcopy-guided biopsy and treated with loop electrosurgical excision procedure(LEEP)at the First Affiliated Hospital of Nanjing Medical University, from December 2014 to December 2016. They were non-pregnant, ≤50 years old and the cervical volume without obvious enlargement and exogenous surface without and ulcerative lesions. A total of 283 cases with early cervical cytology results, never received cervical traumatic treatment or cervical biopsy in another hospital before, and their colposcopic images were clear enough to reevaluate. The ultimate pathological diagnosis was based on the higher-level pathological diagnosis between the results of cervical biopsy and LEEP to evaluate ICUM missed in HSIL and the risk factors. Results (1) Among the 283 cases with HSIL diagnosed by colposcopy-directed biopsy,44 cases (15.5％,44/283) were missed diagnosis of ICUM, which consisted of 29 cases Ⅰa1, 4 cases Ⅰa2 and 11 cases Ⅰb1 in the ultimate pathology.(2)Analysis of associated factors for missed ICUM:univariate analysis showed that,as the age increased, the risk of missed ICUM also increased(the rates of missed diagnosis for<30, 30-39, 40-50 years were 7.7％, 11.5％, 22.0％, respectively;χ2=6.254, P=0.012 by trend test). The more the number of high-grade features, the higher risks(the rates of missed diagnosis for 1, 2, 3, 4 high-grade features were 10.2％, 17.6％, 23.8％, 30.8％, respectively;χ2=7.686,P=0.006 by trend test). The locations of HSIL were only endocervical, only ectocervical and mixed, the risk increased by this sequence(2.8％, 5.1％, 28.7％; χ2=26.193,P<0.01 by trend test). The rate of missed diagnosis for not completely visible squamocolumnar junction(SCJ)was higher than that of the completely visible one(22.3％ vs 2.1％;χ2=19.680, P<0.01). The rate of missed diagnosis was higher for existing atypical vessels than those without(60.7％ vs 10.6％;χ2=48.279, P<0.01). The rate of missed diagnosis for visible lesion size≥40 mm2 was higher than that of<40 mm2(27.3％vs 4.2％;χ2=28.921, P<0.01). The rate of missed diagnosis for the proportion of visible lesion size in ectocervical size ≥0.75 was higher than that of <0.75 (83.3％ vs 14.1％;P<0.01). The rate of missed diagnosis for the maximum linear length of visible lesion≥10 mm was higher than that of<10 mm(46.9％vs 9.0％;χ2=44.473, P<0.01). But the different severity of cervical cytology before colposcopy was not associated with missed ICUM(P>0.05). Multivariable analysis found that visibility of SCJ, atypical vessels, visible lesion size and maximum linear length of visible lesion were associated with missed diagnosis of ICUM(all P<0.05). Conclusions The diagnostic value of HSIL by colposcopy is limited. Meanwhile, for the patients who are ≤50 years old with HSIL diagnosed by cervical biopsy, invisibility of SCJ, atypical vessels, visible lesion size and maximum linear length of visible lesion evaluated by colposcopy are the independent risk factors of missed ICUM. Thereby, it is necessary to take active intervention for HSIL with these risk factors.

The natural history of cervical intraepithelial neoplasia Ⅰ and the clinical significance of p16INK4a protein as a marker of progression in cervical intraepithelial neoplasiaⅠ / 中华妇产科杂志

Objective To describe the natural history of cervical intraepithelial neoplasia(CIN)Ⅰand the biologic factors associated with the progression of CINⅠ and to analyze the predictive values of p16INK4a protein for the progression of CINⅠ. Methods From August 2010 to July 2013, 104 patients referred for abnormal cytology [≤ low-grade squamous intraepithelial lesion (LSIL); including negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASCUS), LSIL] and high-risk (HR) HPV positive,and were diagnosed CINⅠ by colposcopy-assisted biopsy and followed at 1-year intervals in the First Affiliated Hospital of Nanjing Medical University. In order to analyze the relationship between the progression of CINⅠ with clinical biologic factors, including patient age, cervical cytology before colposcopy, loads of HR HPV, HPV L1 capsid protein, p16INK4a protein,χ2 tests was used to compare the different frequencies of factors in groups of progressed and persisted/regressed CINⅠ, then five factors with progressed CINⅠwere processed into binary logistic regression analysis. Results (1) In the first year of follow-up, among 104 patients(including 15 cases NILM,78 cases ASCUS,11 cases LSIL), 52 cases of them were NILM and HR HPV negative, 30 cases were negative for intraepithelial lesion, 10 cases were CINⅠ, 5 cases were CINⅡand 7 cases were CINⅢ. In total, 82 cases (78.8%,82/104) cases had regressed, 10 cases (9.6%,10/104) persisted, 12 cases (11.5%,12/104) progressed [including 5 cases (4.8%,5/104) progressed to CIN Ⅱ, 7 cases (6.7%,7/104) progressed to CIN Ⅲ, none progressed to invasive cancer]. (2) All patients, 88 cases of them accepted immunohistochemical detection the expression of p16INK4a protein. The result shown that 30 cases (34%,30/88) were positive and 58 cases (66%,58/88) were negative. And 94 cases accepted immunocytochemical detection the expression of HPV L1 capsid protein, 49 cases (52%,49/94) were positive and 45 cases (48%,45/94) were negative. (3) Univariate analysis showed that age of the patient, loads of HR HPV, cervical cytology before colposcopy and the expression of HPV L1 capsid protein were not risk factors of the progression of CINⅠ(all P>0.05) except for the expression of p16INK4a protein (P<0.05). Multivariable analysis found that p16INK4a protein positive was associated with progression of CINⅠ(OR=5.1,95%CI:1.162-22.387,P=0.031). (4) Thirty-one cases were p16INK4a protein positive, 8 cases (27%,8/30) of them progressed,while 4 cases (7%,4/58) of 58 cases with p16INK4a protein negative progressed,in which there were significant difference (P<0.05). The sensitivity was 75%, the specificity was 71%, the positive predictive value was 27%and the negative predictive value was 93%for progression to CINⅡ-Ⅲof p16INK4a protein staining. Conclusions The progression rate of CINⅠwith abnormal cytology (≤LSIL) and HR HPV positive was lower, and there was no progression to invasion at 1-year intervals. Immunostaining of p16INK4a protein as the risk factors of CINⅠprogression could have a role in prediction of CINⅠand the management of high-risk CINⅠ.