Effect of Pap Smear Cytology, HPV Genotyping on the Concordance of Colposcopy and Conization Results
By Hanife Saglam1, Funda Atalay2Affiliations
doi: 10.29271/jcpsp.2023.09.972ABSTRACT
Objective: To evaluate the conization results performed due to human papillomavirus (HPV), smear, colposcopy results or clinician's decision and determine the factors that predict ≥CIN2.
Study Design: Retrospective comparative study.
Place and Duration of the Study: Department of Gynaecology and Obstetrics, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey, between January 2011 and December 2021.
Methodology: Women with known HPV results who underwent conization in the Gynaecology clinic were retrospectively included. Age, HPV genotypes, conization, and colposcopy results of the patients were recorded. Patients were divided into two groups as those with and without ≥CIN2 and compared in terms of clinicopathological features.
Results: Four hundred and twenty eight (82.8%) of the 517 patients were premenopausal and perimenopausal, and 89 (17.2%) of the patients with a median age of 42 years (range: 30-65 years) were postmenopausal. While 374 were HPV 16/18 positive, 143 were non-16/18 HPV positive. Conization result was normal in 202 (39.1%) patients, CIN1 in 129 (25.0%) patients, and CIN 2-3 in 186 (36.0%) patients. In the HPV 16/18 positive group, conization result was normal in 38.2% of patients, CIN1 in 20.9%, and CIN 2-3 in 40.9%; these rates were 41.3%, 35.7%, and 23.1% in the HPV-other group, respectively (p <0.001). In the logistic regression model, age, HPV type (16/18), and smear cytology results (≥ASC-US) were tested as independent factors predicting ≥CIN2.
Conclusion: HPV 16/18 positivity and smear cytology result (≥ASC-US) were the factors predicting ≥CIN2. Smear and HPV genotyping can make an important contribution to detecting false <NIC2 results as a result of colposcopy.
Key Words: CIN, Colposcopy, Conization, Cervix, Cervical cancer, Neoplasia, HPV.
INTRODUCTION
Cervical cancer is the most common gynaecological cancer. Almost all of cervical cancer is associated with human papillomavirus (HPV).1 With the availability of an effective HPV vaccine, the incidence of cervical cancer has decreased in the recent years.2 However, HPV has not yet entered the routine vaccination programme due to its cost in under-developed countries.3 Therefore, an early diagnosis of pre-invasive lesions (cervical intraepithelial neoplasia, CIN) that may pose a risk for cervical cancer is still crucial. Historically, cytological evaluation was performed with Pap-smear for screening and treatment decisions of premalignant lesions.4 After revealing the relationship between HPV and cervical cancer, HPV became a critical test for screening pre-invasive lesions.5 Today, there are numerous screening triages in which HPV and smear tests are evaluated together in cervical cancer screening.5
Among the strains of HPV, 16 and 18 pose a high risk for cervical cancer. On the other hand, there are strains other than HPV 16 and 18 that are oncogenic for cervical cancer (HPV 31, 33, 35, 39, etc.).6 HPV strains can show heterogeneity between countries. In Turkey, women between 30 to 65 years are included in the cervical cancer screening program.5 Pap-smear and HPV samples taken simultaneously from women by primary care clinicians are evaluated in two central laboratories.7 Patients with HPV type 16/18 positivity or other HPV positivity with abnormal Pap-smear results are referred to colposcopy for further evaluation in Turkey (Turkish triage).7 Further examination is planned according to the colposcopy results of the patients. Since colposcopy is a procedure that requires experience, a colposcopy cannot be performed sufficiently in some centres in Turkey. Diagnostic or therapeutic conization can be applied according to cytology and HPV results, especially in patients with insufficient colposcopies. Colposcopy can be performed with different indications, apart from the patients who are found to be at a risk in the cervical cancer screening.8 Abnormal cervical findings and post-coital bleeding noticed during the examination are other colposcopy indications.8
Since the conversion rates of CIN1 detected to CIN3 and cervical cancer are low, a conservative approach is recommended for this group of patients.9 On the other hand, CIN3 has a high risk of conversion to cervical cancer, so its treatment is recommended.9 It has been reported in the literature that approximately 50-61% of CIN2s regress spontaneously, and 10-18% of them progress to CIN3 or cervical cancer.9 Although it is not clear which factors predict the progression of CIN2s, it has been suggested that HPV 16 and HSIL cytology may be predictors.10 Due to these uncertainties, there is no clear consensus on the management of CIN2.
This study aimed to evaluate the conization results performed due to HPV, smear, colposcopy results or clinician's decision and determine the factors that predict ≥CIN2. In addition, it aimed to determine the factors that may predict patients who were reported as false <CIN2 according to colposcopy.
METHODOLOGY
Patients who underwent conization between January 2011 and December 2021, in the Department of Gynaecology and Obstetrics, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey, were retrospectively scanned. Five hundred and seventeen women with known HPV results were included in the study. Being 18 years or older and conization for any reason were the inclusion criteria. Those without smear and HPV test results were excluded from the study.
HPV and smear evaluations of the patients were made in the central laboratories determined by the Turkish Ministry of Health. Smear results were classified as inadequate sampling/ASC-US/ASC-H/LSIL/HSIL/AGC/Others according to Bethesda classification.11A ≥ASC-US was evaluated as an abnormal cytology result. In the Turkish triage, those with HPV 16/18 or HPV non-16/18 and abnormal smear cytology are referred to colposcopy.7
Colposcopic examinations were performed with the Olympus colposcopy device with a green filter, capable of 40 magnification. After washing the cervix with saline during colposcopy, it was scanned at low magnification and investigated vascular pathologies with a green filter, then 3-5% acetic acid was applied and after waiting for 30-60 seconds, the cervix was scanned at small and large magnifications. Aceto-white areas and vascular pathologies were detected with the green filter. Punch biopsy was taken from the areas of acetowhite, mosaic, punctuation, erosion, leukoplakia, and atypical vascularisation. In patients whose pathological appearance could not be detected, control biopsy was taken from 4 quadrants (12, 3, 6, and 9 o'clock).
According to the conization results, the patients were divided into two groups (≥CIN2, n:186 and <CIN2, n:331). The groups were compared according to patients' age, menopausal status, smear cytology, colposcopy results, and HPV genotyping. In addition, factors that could predict ≥CIN2 were determined. Positive predictive values for ≥CIN2 of triage scenarios were investigated. The factors affecting the ≥CIN2 ratio differences between colposcopy and conization results were evaluated.
In presenting the descriptive statistics of the study, continuous variables were given as median (interquartile range), and categorical variables were given as frequency (%). Kolmogorov-Smirnov test was used to evaluate the normality of the data. Mann-Whitney U test was used to compare nonparametric data, and the Chi-square test was used to compare categorical data. A binary logistic regression model was created to detect independent factors predicting ≥CIN2. All statistical tests were performed in two ways, and a p-value of <0.05 was considered statistically significant. Statistical analyses of the study were evaluated by SPSS version 25.0.
RESULTS
A total of 517 patients were included in the study. Majority (n=428, 82.8%) were pre-or perimenopausal and 17.2% (n=89) of the patients with a median age of 42 years (range: 30-65 years) were postmenopausal. Three hundred and seventy four (72.3%) were HPV 16 and/or 18 positive, and 143 (27.7%) were non-16/18 HPV positive.
There were 242 patients in the HPV 16/18 group with known smear cytology results. The results of the patients were reported as unsatisfactory in 3.3%, normal in 45.9%, ASC-US in 15.7%, ASCH in 5.0%, LSIL in 16.9%, HSIL in 12.4%, and AGC in 0.8%. In the HPV-other group, 102 patients had smear cytology: unsatisfactory in 1.0%, normal in 52.9%, ASC-US in 15.7%, ASCH in 3.9%, LSIL in 17.6%, HSIL in 6.9%, and AGC in 2.0%. The rates of ≥ASC-US in the HPV 16/18 group and the HPV-other group were similar (50.8% vs. 46.1%, p=0.421) as shown in Figure 1.
LEEP/conization was performed in 53 (14.2%) HPV 16/18 positive patients without colposcopy. Of the 321 patients who underwent colposcopy, 25 (7.8%) had normal results, 139 (43.3%) had CIN1, 111 (34.6%) had CIN2-3, 46 (14.3%) were inadequate. LEEP/conization was performed without colposcopy in 19 patients in the HPV–other group. Of 124 patients who underwent colposcopy, 16 (12.9%) results were normal, 60 (48.5%) had CIN1, 24 (19.3%) had CIN2-3, 24 (19.3%) were inadequate. The proportion of patients with a colposcopy result ≥CIN2 was 34.6% in the HPV 16/18 group and 19.4% in the HPV–other group (p=0.002, Figure 1).
Figure 1: Smear, colposcopy, LEEP/conization results of the patients.
Table I: Cone biopsy results of patients according to different triage scenarios and positive predictive values (PPV, %).
|
|
n |
Normal |
CIN1 |
≥CIN2 |
PPV % ≥CIN2 |
|
Any HPV (%) |
517 (100) |
202 (39.1) |
129 (25.0) |
186 (35.9) |
35.9 |
|
HPV 16/18 (%) |
374 (100) |
143 (38.3) |
78 (20.8) |
153 (40.9) |
40.9 |
|
HPV non 16/18 (%) |
143 (100) |
59 (41.2) |
51 (35.7) |
33 (23.1) |
23.1 |
|
Any HPV + Smear triage |
|||||
|
≥ ASC-US (%) |
170 (100) |
63 (37.1) |
33 (19.4) |
74 (43.5) |
43.5 |
|
≥ LSIL (%) |
100 (100) |
35 (35.0) |
21 (21.0) |
44 (44.0) |
44.0 |
|
≥ HSIL (%) |
41 (100) |
11 (26.9) |
4 (9.7) |
26 (63.4) |
63.4 |
|
HPV 16/18 and/or other HPV + abnormal smear ≥ ASC-US (Turkish triage) (%) |
421 (100) |
163 (38.7) |
93 (22.1) |
165 (39.2) |
39.2 |
|
HPV 16/18 + abnormal smear ≥ ASC-US (%) |
123 (100) |
43 (35.0) |
18 (14.6) |
62 (50.4) |
50.4 |
|
CIN: Cervical intraepithelial neoplasia, PPV: Positive predictive value, HPV: Human papillomavirus, ASC-US: Atypical squamous cells of undetermined significance, LSIL: Low-grade squamous intraepithelial lesion, HSIL: High grade squamous intraepithelial lesion. |
|||||
Table II: Comparison of patients with and without CIN2 lesions according to cone biopsy.
|
|
| |