1Health Science University, Haseki Teaching and Research Hospital, Department of Gynecology, 34130, Istanbul, Turkey 2Health Science University, Zeynep Kamil Training and Research Hospital, Department of Gynecologic Oncology, 34668, Istanbul, Turkey 3Health Science University, Bakirkoy Sadi Konuk Training and Research Hospital,

29 Mayıs 2022

Behiye Pinar Goksedef1, Burak Giray2, Canan Kabaca2, Murat Ekmez1, Sinan Gulec1, Esra Keles2, Isa Aykut Ozdemir3, Suleyman Salman4, Derya Sivri Aydin1

Department of Gynecologic Oncology, 34147, Istanbul, Turkey

4Health Science University Taksim Gaziosmanpasa Training and Research Hospital, Department of Gynecology, 34255, Istanbul, Turkey

Summary

Objective: We aimed to analyze the colposcopy-guided biopsy results in women aged 21-24 years with clinical suspicion for cervical lesion and/or cytological abnormality. Methods: This was a retrospective cohort study conducted on 461 patients undergoing colpo scopic examination and biopsy between the ages of 21-24. The colposcopy-guided biopsy results of women with atypical squamous cells of undetermined significance (atypical squamous cells of undetermined significance) cytology were cervical intraepithelial neoplasia (cervical intraepithelial neoplasia) 2 in 9 patients and cervical intraepithelial neoplasia 3 in 5 patients. Results: The colposcopy-guided biopsy results of women with low-grade squamous intraepithelial lesion (low-grade squamous intraepithelial lesion) cytology were cer vical intraepithelial neoplasia 2 in 17 patients, cervical intraepithelial neoplasia 3 in 10 patients, and invasive cancer in 1 patient. One of the high-grade squamous intraepithelial lesion (high-grade squamous intraepithelial lesion) patients had invasive cervical cancer. The cytology results of women with cervical intraepithelial neoplasia 1 after 6 months from colposcopy-guided biopsy were atypical squamous cells of undetermined significance (n = 11), and low-grade squamous intraepithelial lesion (n = 6). The cytology results of women with cervical intraepithelial neoplasia 1 after 12 months were atypical squamous cells of undetermined significance in 2 women, and low-grade squamous intraepithelial lesion in 2 women. The cytology results after 12 months from colposcopy-guided biopsy were high-grade squamous intraepithelial lesion in 16 of 433 women who underwent follow-up (3.7%). There were no significant statistically differences between cervical intraepithelial neoplasia 2 patients with and without treatment in terms of cytology results at 6 months (p = 1.00). However, there were significant statistically differences between cervical intraepithelial neoplasia 2 patients with and without treatment in terms of cytology results at 12 months (p= 0.042). Conclusions: Colposcopic examination should perform in women aged 21-24 years with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion due to the possibility of high-grade squamous intraepithelial lesion and invasive cancer.

Key words: Cervical intraepithelial neoplasia; Colposcopy; Human papillomavirus.

Introduction

Cervical cancer is common among women worldwide. The presence of screening and human papillomavirus (HPV) vaccination programs decreased the incidence and mortality rates. While a fall in cervical cancer rates result ing from screening strategy, when and whom to screen, and frequency are still debated. The benefits and harms of cer vical cancer screening vary with age. The age-adjusted in cidence of cervical cancer in women under 20 years is very low. Adolescents are also more likely to spontaneously clear HPV infection and the most of low-grade lesions as well as many high-grade lesions in adolescent women, will resolve spontaneously [1, 2].

Avoiding of unnecessary diagnostic procedures and treatment in this age group, cervical cancer screening be

initiated no earlier than age 21. International guidelines vary: United Kingdom screening policy and was based on evidence that screening at ages 20–24 provided no pop ulation benefit in terms of cancer prevention [3]. World Health Organization guidelines for screening and treatment of precancerous lesions for cervical cancer prevention rec ommendations apply to women 30 years of age and older because of their higher risk of cervical cancer and may extend to younger and older women depending on their baseline risk of cervical intraepithelial neoplasia (CIN) 2+. United States professional organizations suggest initiating screening at age 21, regardless of the age of initiation of sexual activity [4-7]. However, a recently updated guide line for management of abnormal cervical cancer screening test and cancer precursors advised that women aged 21-24

Eur. J. Gynaecol. Oncol. - ISSN: 0392-2936 XLI, n. 5, 2020

This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

doi: 10.31083/j.ejgo.2020.05.5405

686 Behiye Pinar Goksedef, Burak Giray, Canan Kabaca, Murat Ekmez...

years need less invasive management for minor cytological abnormalities and even cervical intraepithelial lesions CIN 2/3 can be managed conservatively [8]. Women over age 30 were invited for population-based screening via HPV DNA and conventional cytology in Turkey [9]. The opportunis tic cervical cancer screening be initiated as United States professional organizations. But the management of cervi cal cytological abnormalities in women aged 21-24 years depends on the institutional decision whether follow up or colposcopy intervention.

In this multicenter study we analyzed the colposcopy and biopsy results in women aged 21-24 years with clinical sus picion for cervical lesion and/or cytological abnormality for defining necessity of both intervention and follow up.

Materials and Methods

Study design and setting

This was a retrospective cohort study conducted on a sample of patients undergoing colposcopic examination and biopsy because of clinical suspicion for cervical lesion or/and abnormal cytology result which was performed at four tertiary gynecology and obstetrics education and re search hospital between January 2009 and March 2019.

Table 1. — Demographic and clinical characteristics of the patients.

n = 461

Age (year) 22.65 ± 1.30 Number of biopsies (median, range) 2 (0-7) Cytology results

Normal 54 (11.7%) ASCUS 195 (42.3%) LSIL 190 (41.2%)

HSIL 22 (4.8%) HPV status

Not screened 132 (28.6%) Positive 67 (14.5%) Negative 262 (56.8%)

ASCUS: atypical squamous cells of undetermined signifi cance; LSIL: low-grade squamous intraepithelial lesion; HSIL: high-grade squamous intraepithelial lesion; HPV: human papillomavirus.

Participants

Four-hundred sixty-one patients undergoing colposcopic examination and biopsy between the ages of 21-24 were in cluded in the study. Data were collected retrospectively from the electronic medical database system of four hos pitals that included ages, liquid-based smear results, HPV results, pathology reports, and follow-up (6 months, 1 year) records. Patients were informed prior to colposcopy and a signed written consent were taken for possible risks and allowing to use their data, in obedient to declaration of Helsinki. All colposcopic examinations and biopsies were

performed by high-level skilled advanced colposcopist. A data worksheet was recorded at the end of colposcopy. All pathological specimens were performed by specialized gyneco-pathologists. After colposcopic biopsy patients were followed by cytology every 6 months for 12 months. The trial was approved by the local ethical committee (ap proval number: 274/2018).

Statistical analysis

Data were analyzed by SPSS (Version 20.0. 2011, IBM SPSS Statistics for Windows; IBM Corp. Armonk, NY, United States of America). The histogram and normality plots and Shapiro-Wilk normality test were used for data distribution analysis. Descriptive statistics (mean, standard deviation, median, range, percentage) were used in the anal ysis of quantitative data. Kruskal–Wallis tests and Fisher’s exact tests were used to compare groups. A p-value 0.05 was considered as statistically significant.

Results

Demographic characteristics including ages, median number of cervical biopsies, cytology results, and HPV status were presented in Table 1; and colposcopy-guided biopsy results of 461 patients were presented in Table 2. Two patients (0.43%) had invasive cervical cancer. Endo cervical curettage was performed in 294 (63.8%) patients. The results of endocervical curettage were normal in 273 (92.9%) women, CIN 1 in 13 (4.4%) women, CIN 2 in 4 (1.4%) women, CIN 3 in 3 (1%) women, and invasive can cer in 1 (0.3%) woman. Sixty-seven cases (14.5%) were positive for HPV (HPV 16 or/and 18, n = 45; other HPV types, n = 22). Twenty-eight (6.1%) of 461 patients un derwent surgical procedures including cervical excisional procedure (n = 26) (5.7%) and radical hysterectomy (n = 2) (0.4%). Loop electrosurgical excision procedure (LEEP) was performed in all patients with CIN 3 (n = 19), and 7 of 32 patients with CIN 2. All of the patients who under went LEEP had negative surgical margin both the endo cervical and ectocervical margins. Mean cone size docu mented from the pathology reports of the patients was 1.62 ± 1.43 cm3. None of the patients with CIN 1 (n = 144) underwent excisional procedure. The cytology results of women with CIN 1 after 6 months from colposcopy-guided biopsy were atypical squamous cells of undetermined sig nificance (ASCUS) (n = 11), and low-grade squamous in traepithelial lesion (LSIL) (n = 6). Additionally, the cy tology results of women with CIN 1 after 12 months were ASCUS in 2 women, and LSIL in 2 women. Twenty-eight patients who underwent cervical excisional procedure or radical hysterectomy had any high-grade lesion throughout the follow-up period. The cytology results after 12 months from colposcopy-guided biopsy were high-grade intraep ithelial lesion in 16 of 433 women who underwent follow up (3.7%). The cytology results of 32 patients with CIN 2 after 6 and 12 months were presented in Table 3. There were no significant statistically differences between CIN 2 patients with and without treatment in terms of cytology re-

Utility of colposcopy in the management of ASCUS and LSIL... 687

Table 2. — Colposcopy-guided biopsy results of the patients.

Cervical biopsy results (n = 461)

No lesion (n = 264) CIN 1 (n = 144) CIN 2 (n = 32) CIN 3 (n = 19) Invasive cancer (n = 2)

Normal (n = 54) 40 13 1 - - Cytology ASCUS (n = 195) 134 47 9 5 - results LSIL (n = 190) 83 79 17 10 1

HSIL (n = 22) 7 5 5 4 1 57.30% 31.20% 6.90% 4.10% 0.40%

ASCUS: atypical squamous cells of undetermined significance; LSIL: low-grade squamous intraepithelial lesion; HSIL: high-grade squamous intraepithelial lesion; CIN: cervical intraepithelial neoplasia.

Table 3. — The cytology results of CIN 2 patients after 6- and 12-months follow-up.

Patients underwent follow up (n=25)

Patients underwent LEEP (n=7)

Patients with abnormal cytology results at 6 months follow up 1 0 1 Patients with abnormal cytology results at 12 months follow up 0 2 0.042

LEEP: Loop electrosurgical excision procedure.

sults at 6 months (p = 1.00). However, there were signifi cant statistically differences between CIN 2 patients with and without treatment in terms of cytology results at 12 months (p = 0.042) (Table 3).

Discussion

Historically, a population based cervical screening pro gram in Turkey was started in 2004 using the Papanico laou (Pap) smear. However, organized population screen ing achieved annual coverage rates of only 1–2%. In 2013 a new HPV based screening strategy was developed for in creased compliance rates. Women aged between 30 and 65 years (∼ 16 million) are invited for HPV based screening by primary level health staff every five years. All screen ing processes are free of charge for the eligible individu als. Women under 30-year-old is still under opportunistic screening by Pap smear test and all of our cases referred colposcopic examination of our out patients colposcopy clinic. Thus, we could not demonstrate the abnormal cytol ogy rates in this age group but the most of the abnormal cy tology results under the age of 25 year were low-grade cyto logical abnormality. Abnormal Pap smear rate was reported 12% on 133,947 women aged 21–24 undergoing screening between 2003–2010 at Kaiser Permanente Northern Cali fornia (KPNC) and 1.4% of them had high grade squamous intraepithelial lesion (HSIL) [10]. Abnormal Pap and/or HPV test result rates were 12.3% and 13.3% among women aged 25-29 and 30-64, and high grade cytologic findings are detected higher compared the women younger 25-year-old. (7.5% and %13.7, respectively) [11]. HSIL cytologic ab normality was detected 4.8% of the women under the age of 25 year with abnormal cytology results in present study. This rate is slightly higher compared the previous study and probably it can be related to use of referred cytologic abnor mality for this analysis. Only one invasive cancer was diag

nosed in women HSIL cytology and was clear cell pathol ogy. CIN2+ lesion rates were 41% of the HSIL cytology in our cohort. CIN2+ lesions were detected in 10% of the pa tients with all kind of abnormal cytology or high-risk HPV DNA (+) women in present study.

In recent report, 41% of the patients had CIN2+ lesion on biopsy results and cumulative 5-year risk of CIN3+ and cancer for women aged 21-24 was calculated as 28% and was comparable to in those of older women. Another study published at 2010, which also included KPNC data, showed that untreated CIN 2 lesions less progression to CIN 3 was not common in the 1–2 years following the CIN-2 diagnosis [12]. In a database review, Fuchs et al. reported that 39% of adolescents with untreated CIN 2 showed regression to normal with 92% showing CIN 1 or less after 3 years. Only 8% had CIN 2 persistence or progression. Certainly, rates of cervical cancer are low in adolescents and young women supporting that progression of CIN 2 to cancer in this age group is extremely rare [13]. Surgical intervention was per formed in 7 women with CIN 2 biopsy results. In addition to high regression rate of the observation group, significantly higher abnormal cytology results were detected in treatment group compared with observation group at 12th month cy tologic evaluation. Nevertheless, it cannot be speculated that surgical excision could negatively affect the 12 months cytology. Seven patients who underwent LEEP had more than 1 involved quadrant according to initial pathology re ports. So, it might affect the decision on the management and surgery might be preferred rather than follow up. In ad dition, more than 1 involved quadrant in patients who un derwent LEEP could negatively affect the 12 months cytol ogy.

Patients with clinical suspicion for cervical lesion but without abnormal cytology result had no CIN 3 or inva sive cancer on the colposcopy directed biopsy specimen. On the other hand, 4.6% and 2.6% of the patients with AS-

688 Behiye Pinar Goksedef, Burak Giray, Canan Kabaca, Murat Ekmez...

CUS cytology had CIN 2 and CIN 3 lesions, respectively. Additionally, one of the patients with LSIL cytology had invasive cancer, 17 of the patients with LSIL cytology had CIN 2, and 10 of the patients with LSIL cytology had CIN 3.

Not all younger patients with ASCUS or LSIL were received a colposcopic examination. Reflex HPV testing could be performed for women aged 21-24 years with minor cytological abnormalities. But HPV testing is performed only at a few tertiary centers in women younger than 30 years of age in Turkey. Therefore, a colposcopic examina tion could be preferred. As the colposcope becomes more widespread in clinical practice, using a colposcope would be more attainable. Therefore, we recommend colposcopic examination when considering women aged 21-24 years with abnormal cytology including ASCUS, LSIL, and HSIL as a credible and feasible strategy.

The present study has some limitations which have to be pointed out. First, retrospective design and small number of cohorts can be viewed as limitations of the study. Addi tionally, not all of the patients included in this study tested for HPV and information about HPV subtype could not be presented for patients.

Conclusions

The management of cervical cytological abnormalities in women aged 21-24 years depends on the institutional de cision whether follow up or colposcopy intervention. Re flex HPV testing could be a choice for women aged 21- 24 years with minor cytological abnormalities. However, our current data demonstrated that colposcopy in addition to cytology is associated with increased detection of prema lignant lesions of the cervix uteri even if not high-grade cy tology. With the increased accessibility of colposcopy, col poscopic examination could be performed in women aged 21-24 years with ASCUS or LSIL due to possibility of high grade squamous intraepithelial lesion and cervical invasive cancer.