Abstract
Context:
Quality assurance in cervical cytology is based on the cyto-histological correlation that is performed in several countries even without standardized protocols.
Aims:
To evaluate the quality of the Pap smear with the Clinical and Laboratory Standards Institute (CLSI) EP12-A2 guideline in a Peruvian hospital.
Settings and Design:
This prospective study was carried out at tertiary care national hospital.
Methods and Material:
The 156 cyto-histological results were collected and coded according to the Bethesda 2014 and FIGO system. The evaluation with the CLSI EP12-A2 guide allowed estimating the performance and quality of the test.
Statistical Analysis Used:
We performed a descriptive analysis of the cytological and histological data and correlation with the weight Kappa test. From the calculation of the likelihood ratios, the post-test probability was estimated using Bayes’ theorem.
Results:
In cytology, 57 (36.5%) were undetermined abnormalities, 34 (21.8%) low-grade squamous intraepithelial lesion (SIL), and 42 (26.9%) high-grade SIL. Of the total biopsies, 56 (36.9%) were cervical intraepithelial neoplasia (CIN) grade 1, 23 (14.7%) were both CIN grade 2 and 3. We determined sensitivity, specificity, a positive and negative predictive value of 94%, 74.6%, 58%, and 97.1%, respectively. We determined a moderate cyto-histological agreement (κ = 0.57). Atypical squamous cells of undetermined significance (40%), and cannot exclude high-grade squamous intraepithelial lesions (42.1%) that showed higher overdiagnosis results.
Conclusions:
The quality and performance of the Papanicolaou test show high sensitivity and moderate specificity. The concordance found was moderate and the proportion of underdiagnosis was higher in abnormalities of undetermined significance.
Keywords: Cervical cancer, histology, intraepithelial lesion, Pap test, Peru, quality
INTRODUCTION
Exfoliative cytology (under the Papanicolaou stain) is one of the most powerful tools for preventing cervical cancer (CC). Since its inception, this test has allowed the screening of a large number of squamous intraepithelial lesions (SIL) and CC, helping to reduce morbidity and mortality rates in several countries (mainly in high-income countries with organized healthcare programs).[1,2,3]
However, the limitations that the rate of CC has not decreased dramatically in low-and middle-income countries are related to numerous factors such as government public policies, disorganized and opportunistic CC prevention systems, epidemiologic changes, and resources limited (both technologically and humanly).[2,3] One of the most important technological limitations of the Papanicolaou test (PAP) is its low sensitivity.[4,5] Although this limitation improves with the repetition of the test during gynaecological follow-up, the sensitivity fluctuates between 30 and 80%, affecting the detection of people with the disease (false negatives), which is necessary for geographic contexts where the population attends the control discontinuously annual.[2,6,7]
Cervical cancer detection strategies in Peru are based on cytology, and human papillomavirus (HPV) detection has not yet been implemented nationwide. Apparently, these strategies are not succeeding in reducing CC mortality rates, since this is the second leading cause of female mortality.[3] Ensuring the quality of the PAP (reducing uncertainty through continuous improvement actions) not only allows a correct CC diagnosis and compliance with the indicators and quality goals of health institutions but also addresses the prevention of maternal illness as an essential topic of the Fourth goal of the United Nations Sustainable Development Goals.[7]
In this sense, in this study, we evaluated the quality of PAP in a Peruvian hospital based on the EP12-A2 guidelines of the Clinical and Laboratory Standards Institute (CLSI). This analysis included the determination of quality through performance per test and the frequency of under and overdiagnosis in Atypical Squamous Cells (ASC).
SUBJECTS AND METHODS
Design and study center
A prospective cross-sectional study was carried out at the Hospital Nacional Docente Madre Niño San Bartolomé in 2016. This specialized tertiary care hospital located in Lima, Peru specializes in the care of mothers, children, adolescents, and neonates, and has agreements with the health networks of Northern and Central Lima that provide 80% of Pap tests annually.[8,9] The hospital has seven medical technologists and five pathologists that make up the cytology team.
Sample processing
The samples follow the Standardized Operational Processes for the preanalytical, analytical, and post-analytical stages.[10,11] The samples were fixed in each health center and referred to the hospital for their diagnostic reading. The analytical stage was carried out in an automated way with the Leica ST5010 autostainer XL stainer (Leica Biosystems, Wetzlar, Germany) that stains and mounts 200 slides per hour.
The PAP was performed according to Peruvian guidelines[12] and following the 2014 Bethesda guide cytology interpretation.[13] Slide reading was performed by medical technologists for screening and selection of smears with findings suggestive of malignancy or indeterminate results such as atypical cells of undetermined significance (ASCUS), atypical high-grade suggestive cells (ASC-H), and atypical cells glandular (AGUS). Findings suggestive of malignancy included low-grade (LSIL), and high-grade (HSIL) of SIL, squamous carcinomas, and adenocarcinomas. All of these screening results were confirmed by pathologists.
The hospital’s average annual PAP is ~70 thousand, however, as these are derived from periurban and urban primarycare clinic, not all patients continue their histopathological evaluations in the hospital and therefore a small number are performed biopsies for the confirmatory diagnosis of CC.
The FIGO 2015 nomenclature was used to record the pathological findings of the cervix, which corresponds to grade 1 (CIN 1), grade 2 (CIN 2), and grade 3 (CIN 3) cervical intraepithelial neoplasia, and carcinomas and other tissue.[14]
Quality analysis
For the quality analysis, the CLSI EP12-A2 guideline was used with guidelines for quality evaluation for qualitative tests.[15] Thus, cytological data were obtained from the SIGHOS (Sistema de Gestión Hospitalaria) computer system and the histology data reporting system of the hospital. We performed the paired coding of the 2016 cytological and histological results supervised by two computer technicians and two pathologists (indeterminate results were excluded because they did not have a corresponding category in cervical histopathology). The indeterminate results (ASCUS, ASC-H, and AGUS) were evaluated based on their histopathological findings, with which they determined the proportion of underdiagnosis and overdiagnosis.
Statistical analysis
We performed a descriptive analysis of the cytological and histological data. The previous evaluation of 100 cases was considered negative cyto-histological tests (data no-show). Then, the determination of the diagnostic tests was carried out with the contingency tables, and the determination of the degree of correlation with Cohen’s bivariate weight Kappa test, considering a value of P < 0.05 and a confidence interval (CI) of 95% as significant. The quality and performance evaluations of cervical cytology followed the evaluation steps of the CLSI EP12-A2 guideline.[15] From the calculation of the likelihood ratios, the post-test probability was estimated using Bayes’ theorem. The evaluations of global quality and diagnostic inter-category were carried out. The data analysis was performed in IBM SPSS v22.0 (Armonk, USA) for Chrome.
Ethical aspects
This research has the approval of the Hospital’s Ethics and Research Committee (OID-HONADOMANI-SB-N° 17013-16, 15 Oct, 2016).
RESULTS
Distribution of cyto-histological findings
One hundred and seventy-seven cyto-histology results were included during 2016, but 21 (11.9%) were excluded due to not presenting available results. In the 156 available results between cervical cytology and histology, the mean age of the patients was 41.1 ± 12.6 years (95%CI, 39.1–43.1), the maximum age being 80 years. The cyto-histopathological findings are detailed in Figure 1.
Figure 1.
Distribution of cyto-histopathological findings of the cervix of the Hospital Nacional Docente Madre Niño San Bartolomé, 2016. While the cytological results (a) indicate a high proportion of indeterminate results and HSIL, the histological findings (b) indicate a high proportion of CIN 1 (mild dysplasia)
In cervical exfoliative cytology, 36.5% (57 cases) with indeterminate changes were determined, where ASCUS, ASC-H, and AGUS represented 22.4% (35 cases), 12.2% (19 cases), and 1.9% (3 cases), respectively. We also determined 34 (21.8%) cases with LSIL, of which 10 (6.4%) presented pathognomonic changes of infection by HPV and LSIL. Forty-two (26.9%) cases of HSIL were found where 7 (4.5%) presented pathognomonic changes of infection by HPV and HSIL. Finally, seven (4.5%) cases of carcinoma were found, six (3.8%) of them corresponding to carcinoma in situ.
Histopathological findings showed that 15 (9.6%) cases corresponded with cytopathic changes corresponding to HPV (mainly koilocytes), 56 (36.9%) corresponded to CIN 1 (where 45 cases had pathognomy of HPV infection). For CIN 2 and CIN 3, there were 23 (14.7%) cases each, presenting 10 (6.4%) and 6 (3.8%) cases with pathognomy of HPV infection and cervical neoplasia, respectively.
Regarding carcinomas, 6 (3.8%) cases were carcinoma in situ, 7 (4.5%) were squamous carcinomas, and 1 (0.6%) was cervical adenocarcinoma.
Overall performance
The quality assessment showed that the overall performance was moderate [Table 1]. We determined a sensitivity of 94% (95% CI, 83.8–97.9), a specificity of 74.6% (95% CI, 66.6–81.2), a Positive Predictive Value (PPV) of 58% (95% CI, 47.2–68.2), and, a Negative Predictive Value (NPV) of 97.1% (95% CI, 91.8–99). The Bayesian analysis allowed estimating the likelihood ratios of positive and negative results. The positive likelihood ratios show small increases (3.7%, 95% CI 2.75–4.99) to find a positive result in patients with CC, and the negative likelihood ratios had insignificant decreases (0.08%, 95% CI 0.03–0.24) to find a negative result in patients with CC. In addition, the positive post-test probability (PPPP) and post-test negative probability (PPPN) indicated the probability that the patients have (58.1%, 95%CI, 47.2–68.2) or do not have (2.9%, 95%CI, 1–8.2) CC if the test is positive or negative, respectively.
Table 1.
Cervical cytology performance epitome according to the CLSI EP12-A2 guideline for the diagnosis of CC
| Performance measure | N% | CI (95%) |
|---|---|---|
| Sensitivity | 94 | 83.8–97.9 |
| Specificity | 74.6 | 66.6–81.2 |
| Positive predictive value | 58 | 47.2–68.2 |
| Negative predictive value | 97.1 | 91.8–99 |
| Proportion of false positives | 25.4 | 18.8–33.4 |
| False negative proportion | 6 | 2.1–16.2 |
| Accuracy | 79.9 | 73.5–85 |
| Diagnostic odds ratio | 46.08 | 13.46–157.7 |
| Youden J index | 0.7 | - |
| Weight Kappa Index | 0.57 | 0.45–0.70 |
| Likelihood + | 3.7 | 2.75–4.99 |
| Likelihood - | 0.08 | 0.03–0.24 |
| Pretest probability | 27.2 | - |
| Positive Post-Test Probability (PPPP) | 58.1 | 47.2–68.2 |
| 1 - PPPP | 41.9 | 31.8–52.8 |
| Negative Post-Test Probability (PPPN) | 2.9 | 1–8.2 |
| 1 - PPPN | 97.1 | 91.8–99 |
Of the total, 47 (29.9%) cases were concordant, and the estimated Kappa index was 0.57 (95% CI, 0.44–0.69) indicating a moderate agreement, with a total proportion observed of 0.79 and a random proportion expected of 0.53.
Intergroup performance
The inter-group evaluation allowed to differentiate the performance according to cytological findings [Table 2], where changes in the qualitative quality of the method were evidenced. Sensitivity was high in LSIL and HSIL with 85% (95% CI, 64–94.98) and 89.7% (95% CI, 73.6–96.4), respectively. For HSIL, high performance in PPV was also evidenced with 61.9% (95% CI, 46.8–75), J-Youden index of 0.8, post-test probability of 20%, and diagnostic agreement (κ = 0.65, 95% CI, 0.5–0.8). For carcinomas, the accuracy was high, being 94.5% for carcinoma in situ (95% CI, 88.5–97.5) and 97.1% (95% CI, 91.9–99) for squamous carcinoma.
Table 2.
Performance analysis of cervical cytology for the diagnosis of CC according to diagnostic categories
| Performance measure | Cytopathological findings of the cervix | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| LSIL (n=34) | LSIL + HPV (n=10) | HSIL (n=42) | HSIL + HPV (n=7) | Carcinoma in situ (n=6) | Carcinoma (n=1) | |
| Sensitivity | 85 (64-94.8) | 62.5 (30.6-86.3) | 89.7 (73.6-96.4) | 57.1 (25-84.2) | 50 (18.8-81.2) | 25 (4.6-69.9) |
| Specificity | 85.5 (78-90.7) | 95.2 (89.3-97.9) | 86.2 (78.8-91.3) | 95.2 (89.3-97.9) | 97.1 (91.8-99) | 100 (96.3-100) |
| Positive predictive value | 50 (34.1-65.9) | 50 (23.7-76.3) | 61.9 (46.8-75) | 44.4 (18.9-73.3) | 50 (18.8-81.2) | 100 (20.7-100) |
| Negative predictive value | 97.1 (91.8-99) | 97.1 (91.8-99) | 97.1 (91.8-99) | 97.1 (91.8-99) | 97.1 (91.8-99) | 97.1 (91.8-99) |
| Proportion of false positives | 14.5 (9.3-22) | 4.8 (2.1-10.7) | 13.8 (8.7-21.2) | 4.8 (2.1-10.7) | 2.9 (1-8.2) | 0.0 (0.0-3.7) |
| False negative proportion | 15 (2.5-36) | 37.5 (13.7-69.4) | 10.3 (3.6-26.4) | 42.9 (15.8-75) | 50 (18.8-81.2) | 75 (30.1-95.4) |
| Accuracy | 85.4 (78.5-90.3) | 92.9 (86.6-96.4) | 86.9 (80.4-91.4) | 92.9 (86.6-96.4) | 94.5 (88.5-97.5) | 97.1 (91.9-99) |
| Diagnostic odds ratio | 33.3 (8.81-126.13) | 33.3 (6.15-180.6) | 54.2 (14.67-200.04) | 26.7 (4.65-152.8) | 33.3 (4.65-238.9) | - |
| Youden J index | 0.7 | 0.6 | 0.8 | 0.5 | 0.5 | 0.3 |
| Heavy Kappa Index | 0.53 (0.35-0.72) | 0.52 (0.20-0.84) | 0.65 (0.50-0.80) | 0.54 (0.19-0.90) | 0.47 (0.06-0.88) | 0.39 (0.01-1.07) |
| Likelihood + | 5.85 (3.63-9.42) | 13.3 (4.78-36.1) | 6.5 (4.06-10.4) | 12 (4.12-34.96) | 17.17 (4.35-67.7) | - |
| Likelihood - | 0.18 (0.06-0.51) | 0.39 (0.16-0.97) | 0.12 (0.04-0.35) | 0.45 (0.19-1.07) | 0.52 (0.23-1.16) | 0.75 (0.43-1.32) |
| Pretest probability | 14.6 | 7.1 | twenty | 6.3 | 5.5 | 3.8 |
| Positive Post-Test Probability (PPPP) | 50 (34.1-65.9) | 50.1 (23.7-76.4) | 61.9 (46.8-75) | 44.7 (19-73.5) | 50 (18.7-81.2) | - |
| 1 - PPPP | 50 (34.1-65.9) | 49.9 (23.6-76.3) | 38.1 (25-53.2) | 55.3 (26.5-81) | 50 (18.8-81.3) | - |
| Negative Post-Test Probability (PPPN) | 97.1 (91.8-99) | 97.1 (91.8-99) | 97.1 (91.8-99) | 97.1 (91.8-99) | 97.1 (91.8-99) | 97.1 (91.8-99) |
| 1 – PPPN | 2.9 (1-8.2) | 2.9 (1-8.2) | 2.9 (1-8.2) | 2.9 (1-8.2) | 2.9 (1-8.2) | 2.9 (1-8.2) |
The analysis of overdiagnosis and underdiagnosis of cytopathological findings is shown in Table 3. Atypical cells of undetermined significance demonstrated a higher proportion of overdiagnosis (40%), which was made up of 2 (5.7%) normal results, 1 (2.8%) unsatisfactory sample, 7 (20%) cytopathic changes compatible with HPV infection, and 5 (14.3%) benign changes such as cervicitis. The underdiagnosed results included 4 (11.4%) CIN 2 and 2 (5.7%) CIN 3 results.
Table 3.
Overdiagnosis and underdiagnosis of cervical cytology for the diagnosis of CC
| Cytopathological findings | Overdiagnosis | Underdiagnosis |
|---|---|---|
| Indeterminate atypical cells | ||
| ASCUS (n=35) | 14 (40) | 6 (17.1) |
| ASC-H (n=19) | 8 (42.1) | 5 (26.3) |
| AGUS (n=3) | 3 (100) | 0 (0) |
| Intraepithelial lesions | ||
| LSIL (n=17) | 6 (35.3) | 11 (64.7) |
| LSIL + HPV (n=5) | 2 (40) | 3 (60) |
| HSIL (n=16) | 13 (81.2) | 3 (18.8) |
| HSIL + HPV (n=3) | 0 (0) | 3 (100) |
| Carcinomas | ||
| Carcinoma in situ (n=3) | 0 | 3 (100) |
| Squamous carcinoma | - | - |
ASCUS: atypical cells of undetermined significance, ASC-H: suggestive high-grade atypical cells, AGUS: atypical glandular cells, LSIL: low-grade squamous intraepithelial lesions, HSIL: high-grade squamous intraepithelial lesions
For ASC-H (19 cases), we determined 8 (42.1%) cases of overdiagnosis, where 2 (10.5%) results were normal. For the 5 (26.3%) underdiagnosis cases, all were compatible with CIN 1. Fifteen (42.9%) and 6 (31.6%) results were reported for ASCUS and ASC-H within their recommended diagnostic category (CIN 1, and CIN2/NIC3/Carcinoma, respectively). All cases of AGUS were classified as overdiagnosis, where 2 (66.7%) were negative and 1 (33.3%) corresponded to CIN 1 with changes due to HPV.
For LSIL, 11 (64.7%) cases were underdiagnosed, where 5 (29.4%), 4 (23.5%), and 2 (11.7%) corresponded with CIN 2, CIN 3, and carcinoma in situ, respectively. Of the 13 cases of overdiagnosis in HSIL, 9 (56.2%) were CIN 1, 3 (18.7%) were cervicitis and cytopathic changes due to HPV infection, and 1 (6.25%) were unsatisfactory. The underdiagnosis cases for HSIL included 2 (12.5%) squamous carcinomas and 1 (6.3%) adenocarcinoma. For carcinomas in situ, the three (100%) cases of underdiagnosis were invasive squamous cell carcinomas [Figure 2].
Figure 2.
Diagnostic categories that had concordance with their histopathological pair. (a). Squamous carcinoma (patient 14). (b). LSIL and koilocytes (patient 4)
DISCUSSION
This quality assessment study conducted in 156 cyto-histopathological results demonstrated the applicability of the CLSI EP12-A2 guide, estimating sensitivity and specificity of 94% and 74.6%, respectively. Likewise, the agreement found was moderate and the proportion of underdiagnosis was higher in abnormalities of undetermined significance.
Quality assurance must be imperative for pathology laboratories worldwide since their processes guarantee results avoiding medically important errors. Exfoliative cytology, being a test with qualitative results, depends on multiple intrinsically related processes that vary from sample collection to delivery of results and storage of samples.[2,8,10,16] Although the national recommendations[12,17–20] for cervical cytology promote the development of practices that include the control of processes in each of the stages of cervical cytology, the recommendations for the evaluation of cytological performance have been based on isolated suggestions, in studies by expert groups or have been derived from their recommendations, such as efforts to improve pathological quality.[21,22,23] Given this, the CLSI has suggested the application of the CLSI EP12 guide to assessing the quality and performance of qualitative tests, which include exfoliative cytology, seeking to standardize the reporting of cyto-histological correlation processes.[15,24]
This study, which applies these regulations and develops for the first time an evaluation of quality and performance in exfoliative cytology in Peru, has made it possible to develop the global and intergroup evaluation of cytopathological findings against the gold standard test. Thus, our results demonstrated high sensitivity (94%) and moderate specificity (74.6%), in agreement with previous reports.[25–28] The diagnostic agreement showed a moderate degree (κ = 0.57). Previous studies in Peru have shown poor cyto-histological concordance in the Hospital Nacional Arzobispo Loayza,[28] moderate agreement in the National Maternal Perinatal Institute,[29] and Hospital PNP Luis N. Sáenz,[25] and good concordance in the Hospital Nacional Hipólito Unanue of Tacna,[30] and the Lambayeque Regional National Hospital.[26]
Our findings on the rate of concordant outcomes (47/157, 29.9%) differ from previous studies conducted in Nepal[31] (30/54, 55.5%), Noida[32] (249/341, 73%), and Karnataka[33] (64/98, 65.3%) in India, where better cyto-histological agreement has been evidenced, even 95% in a specialized tertiary hospital.[34] However, our findings are close to the results of the Q-Tracks program that evaluated 287,570 cyto-histology results in the United States laboratories in 2013 with a moderate correlation (34.2%) of 98,424 cases.[22] These differences in concordance between health clinics and countries can be mainly attributable to errors in the preanalytical phase, where a set of factors can affect the quality of the results and the screening of the CC.[8,16,21]
Another important aspect of the analysis is the estimation of the Youden Index, which assesses the quality of the result. This performance indicator has not been used in cervical exfoliative cytology. Our findings establish a high cytological quality when testing patients seen at the Hospital Nacional Docente Madre Niño San Bartolomé. Also, was important the analysis of the Bayesian estimate of probabilities of positive and negative results, with small increments to find a positive result in patients with CC and insignificant decreases to find a negative result in patients with CC, respectively. In future research, these two analyses should be used as regular parts of quality assessment.
On the other hand, the intergroup analysis allowed us to recognize that the distribution of intraepithelial lesions had high performance [Table 3]. Our results showed that LSIL found ~65% of discordant results with underdiagnosis, however, the disease progression will allow repetitions of the PAP, reducing this rate and improving diagnostic agreement.[35] The discordant results of HSIL could also be interpreted under the recommendations of the 2017 guideline of the American Society of Cytopathology (ASC).[36] Thus, according to the ASC, the 16 discordant cases could be considered as major cyto-histological discordance, the main reasons for histological discordance being CIN 1 and endocervicitis and cytopathic changes due to HPV infection. In this sense, the evaluation with the CLSI guide allows estimating results that coincide with the categories of the ASC 2017.
The results of the evaluation of the ASC showed 36.5% (57 cases) in the frequency of cases, being within the limit of results according to the Bethesda 2014 system.[37] Although in this regard it has been recommended to estimate the overall rate of ASCUS/SIL results in 2:1 or 3:1, in this study where cyto-histological samples have been selected a 1:2 rate has been evidenced. In other words, there is a lower proportion of ASCUS that are referred for pathological study compared to SIL. We also reported 42.9% of ASCUS results that coincided in their histological paired. The results for ASC-H were 31.6% differed from previous estimates.[13] Although the estimates of overdiagnosis and underdiagnosis in the ASCs were different between the subcategories (ASCUS, AS-CH, and AGUS), it is necessary to carry out continuous evaluations that allow estimating the error and the performance, since long-term monitoring improves the quality of the cyto-histological performance.[22]
The results of this study must be interpreted under the following limitations. First, due to the high proportion of samples from health networks, not all patients performed histopathological studies in the hospital, which may affect the sample size. Second, molecular tests were not performed for HPV or immunohistochemical (i.e., p24, E6) in cases with intraepithelial lesions.
In conclusion, we performed a quality evaluation of cervical exfoliative cytology with the CLSI EP12-A2 guide in a specialized tertiary hospital in Lima, Peru, estimating a high sensitivity, a moderate diagnostic agreement, and a high proportion of underdiagnosis in ASC. These evaluations must be carried out periodically applying this standardized regulation in health centers and cytology laboratories to estimate the performance of CC cytological screening tests in the user population in order to ensure the quality of their results.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
We are thankful to our patients for their cooperation and the staff of the Pathology Department of the Hospital Nacional Docente Madre Niño San Bartolome.
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