Abstract
Background: Atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) are the two most common results of positive Pap smears. Aim: The aim of this study was to compare the management of patients with ASCUS and LSIL. Patients and Methods: All procedures were performed between 2003 and 2014 in an outpatient clinic affiliated to a tertiary referral center, and included Pap smears, colposcopy, histology and invasive treatment. Results: There were 131 patients in the ASCUS group and 84 in the LSIL group. Further negative cytological results were obtained more frequently among the ASCUS group than the LSIL group [relative risk (RR)=1.18, 95% confidence interval (CI)=1.33-2.40; p<0.001]. Histological results revealed higher occurrence of cervical intraepithelial neoplasia grade III or invasive squamous cancer in the LSIL group than the ASCUS group [RR=6.8 (95% CI=0.95-144.63), p=0.033]. Patients from the LSIL group more frequently required invasive treatment [RR=2.53, 95% CI=1.40-4.67, p=0.001]. Conclusion: Diagnosis of ASCUS is associated with more frequent cases of total remission in follow-up Pap smears and requires for less-invasive management.
According to data presented by GLOBOCAN 2012, cervical cancer is the fourth most common cancer in women worldwide and 87% of the cases occur in less developed countries with poorer access to prophylaxis (1).
Management of patients with early-stage precancerous cervical lesions is possible due to widespread screening programs. Regular evaluation of cervical area is a valuable part of gynecological care, as dysplasia diagnosed early is a fully treatable condition. The Pap smear was introduced over 50 years ago; since then, there has been a gradual 75% decrease in cervical cancer incidence and mortality (2,3). Although data show great improvement in detecting cervical cancer, the sensitivity of the conventional Pap smear is only estimated to be approximately 50% (between 30% and 87%, depending on the study) (4, 5). To increase the test's sensitivity, the specimen should be obtained with precision from both the external orifice and the endocervical canal. Additionally, guidelines emphasize the role of testing for human papillomavirus (HPV) in planning further diagnostic strategies, as HPV infection is responsible for the majority of malignant changes in the cervix (6).
The Bethesda system is a classification used to adequately assess the quality of a collected specimen and the appearance of cervical epithelial cells (7). The majority of abnormal Pap smears reveal lesions with minor changes, most probable for low-grade pathologies.
Atypical squamous cells of undetermined significance (ASCUS) may be detected in various cases of cervical infection and inflammation. Most cases do not progress to cervical cancer, but each case requires further monitoring. The risk of malignancy in patients with ASCUS with unknown HPV status ranges from 2.6% to 3.9% (8,9).
Low-grade squamous intraepithelial lesion (LSIL) is the second most frequent cytological abnormality of the cervical epithelium. The risk of developing cancerous lesions in LSIL cases reaches 6.1% (10).
The aim of this study was to compare results of follow-up of patients with first abnormal Pap smear results representing minor change pathologies: ASCUS and LSIL. The need for further diagnostic procedures and invasive treatment was analyzed.
Patients and Methods
This was a retrospective cohort study performed using data collected from medical records. Patients were assigned to two groups according to their first positive cytological result, forming an ASCUS group and a LSIL group. The exclusion criterion was pregnancy during specimen collection.
Further diagnostic and therapeutic interventions were analyzed. Diagnostics included repeated Pap smears, colposcopy and histology. Pap smear outcomes were assessed according to the Bethesda system (7) and were evaluated as follows: negative results suggesting spontaneous remission, ASCUS, atypical squamous cells – cannot exclude high-grade squamous intraepithelial lesion (ASC-H), LSIL, high-grade squamous intraepithelial lesion (HSIL), atypical glandular cells of undetermined significance (AGUS) or cancer cells. Visual inspection was performed using acetic acid. Visible changes after applying the acid were assessed as one of the following: negative colposcopic examination, acetowhite changes without any other alterations, punctuations, mosaicism or other. If more than one specific type of change was visible, the most advanced colposcopic lesions were considered. Other changes included polyps and cervical ectopy.
Histological results comprised of negative examinations, cervical intraepithelial neoplasia grade I (CIN1), grade II (CIN2), grade III (CIN3), invasive squamous cancer, invasive glandular cancer, non-specific inflammation and other.
Applied invasive therapeutic methods included conization – either loop electrosurgical excision procedure (LEEP) or cold knife cone biopsy, as well as amputation of the cervix and hysterectomy.
All procedures were performed between 2003 and 2014 in an outpatient clinic affiliated to the Second Department of Obstetrics and Gynecology, Medical University of Warsaw, which is a tertiary referral hospital. Data were analyzed using the Fisher's exact test for categorical data comparison with p-values less than 0.05 considered significant.
Results
There were 131 patients in the ASCUS group and 84 in the LSIL group. Further negative cytological results without invasive treatment were more frequent in the ASCUS group than the LSIL group [relative risk (RR)=1.18 95% confidence interval (CI)=1.33-2.40; p<0.001] (Figure 1).
Patients from the LSIL group required colposcopy more frequently than did patients from the ASCUS group (RR=1.221, 1.005-1.441; p=0.035). No statistically significant difference between the groups was observed with respect to the distribution of colposcopic results among patients who underwent colposcopy (Table I).
Cervical biopsy was required more frequently in patients from the LSIL group (RR=1.84, 95% CI=1.24-2.69; p=0.001]. Results revealed a higher occurrence of CIN3 or invasive squamous cancer in the LSIL group than in the ASCUS group (RR=6.80, 95% CI=0.95-144.63; p=0.033) (Table II).
Patients from the LSIL group more frequently required invasive treatment such as conization or amputation of the cervix (RR=2.53, 95% CI=1.40-4.67; p=0.001) (Figure 2). Applied treatment techniques consisted of cold knife cone biopsy, LEEP and surgical amputation of the uterine cervix (Table III).
Discussion
Approximately 4% of all Pap smears performed during screening for cervical cancer lead to positive results. Up to 70% of patients with positive Pap smears are diagnosed with ASCUS, and approximately 25% are diagnosed with LSIL (11). This means that management of most patients should focus on deciding whether their abnormalities are associated with a high risk of malignancy, that would require prompt treatment, or indicate a low risk of invasive cancer, that could be safely monitored. Studies show that histology is less likely to reveal cancerous lesions in patients with ASCUS than in those with LSIL (8, 9). An ASCUS result is also associated with a higher rate of overdiagnosis due to the similar appearance of perimenopausal squamous cells and atrophy (12). Positive results of Pap smears may also be caused by hormonal contraception usage (13, 14).
Incidence of spontaneous remission in repeated Pap smears. ASCUS: Atypical squamous cells of undetermined significance; LSIL: low-grade squamous intraepithelial lesion.
Need for invasive treatment by cytology. ASCUS: Atypical squamous cells of undetermined significance; LSIL: low-grade squamous intraepithelial lesion.
The vast majority of patients enrolled in this study whose first positive result was ASCUS received negative results in subsequent examinations. Additionally, patients with ASCUS were less likely to undergo colposcopy, histology or invasive treatment in the future. In order to earlier predict which cases of ASCUS require deeper investigation, HPV testing may be useful (15, 16).
Distribution of colposcopy results.
Distribution of histological results.
Type of invasive treatment.
There were more cases of carcinoma in situ (CIN3) among patients with LSIL, and one-third of women from the LSIL group required some type of invasive treatment. However, none of them needed a procedure as invasive as hysterectomy. Therefore, patients in this group should be subject to further diagnostic tests at shorter intervals, i.e. more frequent monitoring (6).
Management of women with a first abnormal Pap smear should be selected on the basis of cytological results, HPV testing (if available) and patient age. Special adjustments are recommended in cases of pregnancy, immunosuppression or immunodeficiency. According to the guidelines of the American Society for Colposcopy and Cervical Pathology, different approaches are advised for patients with ASCUS and LSIL (6).
In cases of ASCUS and unknown HPV status, repeated cytology within a year is an acceptable first diagnostic step. The strategy may further develop into a return to routine screening or colposcopy, depending on the outcome of subsequent Pap smears. If the repeated result is ASCUS or worse, colposcopy is recommended. Endocervical sampling should be performed in patients with no lesions or inadequate colposcopic view. For women aged 21-24 years with repeated ASCUS results, immediate colposcopy is not recommended. A cytological follow-up at 12-month intervals is preferred for these patients. In pregnant women with ASCUS, colposcopy can be delayed until 6 weeks postpartum.
For patients receiving LSIL as a first abnormal cytological result, a different approach is recommended. For women that have not been tested for HPV, colposcopy is advised as the next management option. The necessity for sampling depends on the colposcopic view and it is preferred in cases with inadequate colposcopic examinations or those with no visible lesions; further sampling is also acceptable if the outcome is adequate with detected lesions. For women with LSIL aged 21-24 years, repeated cytology within 12 months is recommended instead of colposcopy. For pregnant women with LSIL, colposcopy and postpartum follow-up are preferred.
Co-testing of both Pap smear and HPV status is preferable in most cases. Different strategies can be implemented for either positive or negative HPV tests together with a positive cytological result.
Conclusion
Patients diagnosed with ASCUS more frequently achieve total remission in subsequent follow-up Pap smears and therefore require less-invasive management. Patients with LSIL usually require and undergo more diagnostic and therapeutic procedures than those with ASCUS.
Footnotes
↵* This paper was presented at the 5th International Charité-Mayo Conference, 15-18 April 2015, Berlin, Germany.
- Received December 6, 2015.
- Revision received January 18, 2016.
- Accepted January 19, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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