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Volume 7, Issue 3 (May & June 2022)                   J Obstet Gynecol Cancer Res 2022, 7(3): 151-157 | Back to browse issues page


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Mousavi A, Akhavan S, Sabzi shahrbabaki F, Izadi-mood N, Yarandi F, Ghazimoghadam M, et al . Assessment of the Diagnostic Value of High-Risk HPV Molecular-based Methods for Triage of Iranian Women with Abnormal Cytological Findings of ASC-US and LSIL. J Obstet Gynecol Cancer Res. 2022; 7 (3) :151-157
URL: http://jogcr.com/article-1-437-en.html
1- Department of Gynecology-Oncology, Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran , Azamsadat_mousavi@yahoo.com
2- Department of Gynecology-Oncology, Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
3- Department of Gynecology and Obstetrics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
4- Department of Pathology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
5- Department of Gynecology-Oncology, Yas Hospital, Tehran University of Medical Sciences, Tehran, Iran
6- Department of Pathology, Armin Pathobiology and Genetics Laboratory, Tehran, Iran
7- Department of Molecular Diagnosis, Armin Pathobiology and Genetics Laboratory, Tehran, Iran
8- Department of Gynecology and Obstetrics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
9- Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Introduction


Cervical cancer (CC) is the fourth most common type of cancer among women. In 2018, near 569,000 women were diagnosed with this cancer, and 311,000 deaths from CC were recorded (1). Infection with human papillomavirus (HPV), especially the high-risk (HR) genotypes, is the predominant cause of CC (2). Based on the studies and according to the clinical pathogenicity of HPV genotypes, types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 could be considered as the HR genotypes, and persistent infection with these genotypes is highly associated with CC progression (3-5).  There are various screening approaches available for early detection and prevention of CC. Cervical cytology test considerably decreased CC and mortality rates by 79% and 70%, respectively. Due to the higher rate of false-negative results of this test, screening tests with higher clinical sensitivity have been suggested. To confirm the abnormal findings during the screening process, colposcopy, and if needed, histopathological examination of the cervix should be performed (6-9). Recent advances in molecular testing of HPV have increased the accuracy of cervical screening programs (10, 11); therefore, doing HR-HPV tests as well as cytological testing of the cervix at the same time (co-test) have been commonly used as acceptable approaches for CC screening and evaluating patients who face abnormal cytological results (12).
Although the combination of DNA-based methods for detecting HR-HPV genotypes with the cytological testing of the cervix has increased the sensitivity of CC screening (13-15), higher clinical sensitivity may reduce the clinical specificity of DNA-based methods for the determination of cervical intraepithelial neoplasia (CIN). On the other hand, almost all of the HPV infections could be resolved spontaneously; hence the positive result for the HR-HPV DNA test cannot be considered as CIN (16, 17). Since the development of CC depends on the activity of E6/E7 oncoproteins, the mRNA assessment of these proteins could exhibit improved specificity compared to the HR-HPV DNA test for predicting moderate to severe cervical dysplasia (18-21).
Considering that a few data are available in surveys about the evaluation of diagnostic value of HPV molecular-based tests in our region and that patients with transient HR-HPV infections are at risk of overtreatment, we evaluated the HR-HPV DNA- and E6/E7 mRNA-based assays as well as doing histopathological evaluation of cervix in women who had abnormal cytological findings as atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) to estimate the diagnostic value of these methods for triage of Iranian women in our region.


 

Materials and Methods

Study Participants and Design

First, 7907 Iranian women (≥ 21 years) who had referred to Vali-e-Asr Hospital from Apr 2017 to March 2021 enrolled in this cross-sectional study. Out of the enrolled women, 360 non-pregnant women who had abnormal cytological results (ASC-US and LSIL) were selected based on the inclusion criteria, and an informed consent was obtained from them. They accepted to refer for further diagnostic tests. While patients with a history of HPV vaccination, pre-cancerous change of the cervix, cervical cancer, abnormal Pap test in the last 12 months, hysterectomy, immunological abnormalities, or disorders were excluded. The Ethics Committee of Imam Khomeini Hospital Complex approved this research protocol (IR.TUMS.IKHC.REC.1399.140).
Sample Collection, Preparation, and Routine Cervical Screening at the Baseline
Cervical specimen was collected and subjected to cytological testing using the ThinPrep® (TP) PreserCyt solution (Hologic, Inc. USA). The TP 2000 system (Hologic, Inc. USA) was used to prepare the Pap test slides. Slide preparation and staining procedure were performed according to the TP staining protocols. Two different cytopathologists evaluated the slides based on the Bethesda 2014 system.
 
Colposcopy, Histopathological and Molecular HPV Assessment During the Second Visit
For evaluating the molecular-based HPV tests, gynecological specimens were collected in TP vials containing PreserCyt solution (Hologic, Inc. USA). To do the HR-HPV DNA-based test, an appropriate amount of the specimens were stored at -24℃. According to the Aptima HPV assay kit protocol (Hologic, Inc. USA), 1 mL of the specimens was transferred into the Aptima specimen transfer tube and stored at 2-8℃. The gynecologic oncologists of Vali-e-Asr Hospital did the colposcopy and cervical biopsy. Briefly, during this process, the cervical tissues of the patients without any signs of abnormities were randomly biopsied in four-quadrant positions of the transformation zone. In contrast, multiple biopsies were taken from abnormal areas of patients with any signs of abnormal colposcopy features. After formalin fixation, biopsies were paraffin embedded, slides were prepared, and hematoxylin and eosin staining was done. Then two different gynecologic pathologists evaluated the specimens according to the related classification system (22). The CIN-2 or higher pathological grades were considered positive, and other results were considered negative for histopathological findings. The HR-HPV molecular-based methods, including the HR-HPV DNA- and E6/E7 mRNA-based tests, were done as described by Mousavi et al. (23).
 
Statistical Analysis
The mean age±standard deviation (SD) was calculated for the participants. The positivity rate of the molecular-based methods, and cytological and histopathological results were calculated by frequency. The agreement between the molecular-based methods was calculated using the Kappa coefficient. Regarding Altman's classification method, k represents the agreement. Very good agreement is observed when the k is 0.8 or higher (24). Regarding the pathological cut-off, the diagnostic value of each molecular-based method was calculated. For this purpose, negative predictive value (NPV), positive predictive value (PPV), clinical specificity (true negative rate), clinical sensitivity (true positive rate), and 95% confidence interval (95% CI) were calculated for each molecular-based assay. Statistical analyses were performed using the STATA statistical package for Windows (Ver. 13, Released 2013, StataCorp L.P., College Station, Texas, USA) and SPSS 21 (IBM Corp, Armonk, New York, USA).


 

Results

The mean age of participants was 34.76±7.00 years. The cytological assessment showed that 260 individuals (72.2%) had ASC-US, and 100 (28.8%) had LSIL. The total positivity rate of the DNA-based test using the INNO-LiPA® HPV Genotyping Extra-II kit was 74.4% (268/360). This method showed 183 cases of HR-HPV-infected individuals (70.4%) had ASC-US; however, this infection rate was observed for 85 individuals (85.0%) with LSIL. The overall positivity rate of the mRNA-based method using the Aptima HPV assay was 64.2% (231/360). Among the individuals with ASC-US, 154 cases (59.2%) showed positive mRNA-based results; however, among the patients with LSIL, 77 cases (77.0%) showed a positive result for mRNA-based assay. Table 1 shows the concordance between the molecular-based tests regarding the kappa statistic.
The histopathological assessment showed 198 participants (55.0%) had normal results, 103 (28.6%) had CIN-1, and 59 (16.4%) had CIN-2 or high grade CIN-2+. Among the individuals with ASC-US, 156 (60.0%), 59 (22.7%), and 45 (17.3%) individuals revealed normal results, CIN-1, and CIN-2+, respectively. However, histopathological findings for the LSIL group showed that 42 (42.0%), 44 (44.0%), and 14 (14.0%) individuals had normal results, CIN-1, and CIN-2+, respectively. The diagnostic value of each method was assessed regarding CIN-2+ histopathological cut-off. The ratio of positivity for each molecular-based method regarding the histopathological cut-off sorted by cytological grades is shown in Table 2.
Table 3 demonstrates the clinical sensitivity, specificity, and positive and negative predictive values of each HPV molecular-based assay regarding the histopathological cut-off.


Table 1. Agreement percentage between the molecular-based methods

Groups Positive cases
(%)
DNA-,
mRNA-
DNA+,
mRNA-
DNA-,
mRNA+
DNA+,
mRNA+
% Agreement Kappa P-value
DNA+ mRNA+
ASC-US
n=260
183
(70.4)
154
(59.2)
76 30 1 153 88.09 0.74 <0.001
LSIL
n=100
85
(85.0)
77
(77.0)
13 10 2 75 88.00 0.61 <0.001
All
n=360
268
(74.4)
231
(64.2)
89 40 3 228 88.06 0.72 <0.001

DNA-, Negative result for DNA-based method: mRNA-, Negative result for mRNA-based method; DNA+, Positive result for DNA-based method; mRNA+, Positive result for mRNA-based method.
 
Table 2. Positivity rates of the molecular-based methods of HR-HPV regarding the histopathological cut-off

    Positive cases (%)
Group Histopathological Result DNA+ mRNA+
ASC-US
(n=260)
Negative
n=215
138
(64.2)
113
(52.6)
Positive
n=45
45
(100.0)
41
(91.1)
All
n=260
183
(70.4)
154
(59.2)
LSIL
(100)
Negative
n=86
71
(82.6)
63
(73.3)
Positive
n=14
14
(100.0)
14
(100.0)
All
n=100
85
(85.0)
77
(77.0)
Total
(360)
Negative
n=301
209
(69.4)
176
(58.5)
Positive
n=59
59
(100.0)
55
(93.2)
All
n=360
268
(74.4)
231
(64.2)

Negative histopathological result, <CIN-2; Positive histopathological result, CIN-2+; DNA+, Positivity rate of DNA-based method; mRNA+,  Positivity rate of mRNA-based method.

Table 3. The diagnostic value of each HPV molecular-based assay based on the CIN-2+ cut-off

Diagnostic value ASC-US
(n=260)
LSIL
(100)
Total
(360)
DNA mRNA DNA mRNA DNA mRNA
Clinical Sensitivity
(95% CI)
100.0 91.1
(82.8-99.4)
100.0 100.0 100.0 93.2
(86.8-99.6)
Clinical specificity
(95% CI)
35.8
(29.4-42.2)
47.4
(40.8-54.1)
17.4
(9.4-25.5)
26.7
(17.4-36.1)
30.6
(25.4-35.8)
41.5
(36.0-47.1)
Positive predictive value
(95% CI)
24.6
(18.4-30.8)
26.6
(19.6-33.6)
16.5
(8.6-24.4)
18.2
(9.6-26.8)
22.0
(17.1-27.0)
23.8
(18.3-29.3)
Negative predictive value
(95% CI)
100.0 96.2
(92.6-99.9)
100.0 100.0 100.0 96.9
(94.0-99.9)

DNA, DNA-based method; mRNA, mRNA based method


 

Discussion

The study aimed to determine the diagnostic value of DNA- and E6/E7 mRNA-based methods in detection of HR-HPV for triage of women who had faced abnormal cytological results (ASC-US and LSIL). Among the study participants, the overall positivity rate of DNA- and mRNA-based methods was 74.4% and 64.2%, respectively. As expected, and illustrated in Tables 1 and 2, the positivity rate of both methods increased in more severe cytological (LSIL compared to ASC-US) and histopathological (positive compared to the negative histopathological cut-off) grades. The majority of previous studies have found a similar positivity pattern. For example, a recent study in our region that used the Cobas HPV DNA test showed positivity rates of 54.2% and 66.6% for HR-HPV DNA-based test for ASC-US and LSIL groups, respectively (25). In a study that assessed the diagnostic value and performance of HR-HPV DNA- and E6/E7 mRNA-based methods for managing the women referred for colposcopy, the positivity rate of DNA- and mRNA-based tests using the Cobas HPV DNA and Aptima HPV assays were 41.7% and 25% for the patients with normal histopathological results, while these positivity rates were 82.9% and 84.3% for the patients with CIN-2; and 100.0% and 98.1% for the patients with CIN-3+ (26).
Due to the different positivity rates obtained for the two methods, not a very good agreement was observed (0.6≤k<0.8). Other similar results were recently reported between the two mentioned methods among Iranian women with NILM cytological results (23). These findings were observed as a result of the different invention basis of the two mentioned methods. Briefly, in this study, the DNA-based test was done using the INNO-LiPA® HPV Genotyping Extra-II kit, which uses the PCR technique for amplifying 65 bps of the L1 region of HPV, and the higher power for detection of the viral particle is expected, while the Aptima HPV assay was used to detect the E6/E7 mRNA of HPV, which uses the signal to the cut-off (S/CO) calculation to detect the CINs, and higher clinical specificity and lower sensitivity are expected. The higher positivity rate of the DNA-based method compared to the mRNA-based assay was also observed among the Iranian women with NILM cytological results (23). These findings confirmed this idea that the HR-HPV-mRNA detection might be less sensitive and more specific for detection of the CINs compared to the highly sensitive DNA-based PCR assays.
As shown in Table 3, the overall clinical sensitivity and NPV of the DNA-based method were higher than those of the mRNA-based assay, while the mRNA-based assay showed better PPV and clinical specificity for the detection of CIN-2+. So far, many studies have assessed the diagnostic value and clinical performance of several kinds of HR-HPV DNA- and mRNA-based assays for the detection of CIN-2+. Szarewski et al. found that the DNA-based method (Cobas HPV test) compared to the mRNA-based method (Aptima HPV assay) showed a higher sensitivity (94.9% versus 92.3%) and a lower specificity (25.1% versus 29.1%) in detection of CIN-2+ (27). This pattern was also observed for our data, as we found 100% clinical sensitivity for the DNA-based test and 93.2% for the mRNA-based assay. Although both studies showed a higher clinical sensitivity for the DNA-based test compared to the mRNA-based assay, we found a higher clinical sensitivity for the DNA-based method in contrast to the Cobas HPV test (27). This difference is explained by different goals defined for each HR-HPV DNA-based method. As mentioned above, we used one of the highly sensitive commercially approved PCR-based methods to detect HR-HPV genotypes, while the Cobas HPV test employs the clinical cut-off value for the detection of CIN-2+ (28).
In this study, among the patients with ASC-US, a higher clinical sensitivity was observed for the DNA-based test compared to the mRNA-based method (100.0% vs. 91.1%). Moreover, the mRNA-based method showed higher clinical specificity than the DNA-based method (47.4 % vs. 35.8%). Although the low number of CIN-2+ cases among the patients with LSIL made it difficult to determine the actual clinical performance of each method, the mRNA-based method showed the same clinical sensitivity and higher clinical specificity in comparison with the DNA-based method (Table 3). Castle et al. found equal clinical sensitivity for DNA- and mRNA-based methods in determination of CIN-2+ among women referred for colposcopy procedure following the ASC-US cytological results (89.4% vs. 91.4%) (29). However, the mentioned studies showed higher specificity for the mRNA-based method (42.0% vs. 63.1%) compared to the DNA-based method (31.2% vs. 59.3%) (29). This clinical performance pattern was also observed among several other studies, which compared the diagnostic value of different types of molecular methods for the detection of CIN-2+ (26, 27, 30, 31) and highly suggested the E6/E7 mRNA-based method for triage of women with abnormal cytological findings.
Although our results revealed valuable data for triage of Iranian women who had faced abnormal cytological results, follow-up of the study participants should be conducted to evaluate the long-term clinical performance of each method. At the moment, our data showed good clinical sensitivity and higher clinical specificity for the mRNA-based assay rather than the DNA-based test in detecting CIN-2+. Furthermore, low number of participants, especially in the LSIL group, may affect our assessment of the diagnostic value of each method; hence further studies with higher number of participants and enrollment of other cytological groups from Iranian women are highly recommended. Moreover, according to the availability of commercial molecular HPV kits in our region, evaluation of other DNA-based methods, especially those that use the clinical cut-off value and are validated for detecting the CINs, is highly suggested.

 

Conclusion

The HR-HPV DNA-based detection method using the INNO-LiPA® HPV Genotyping Extra-II kit and the HR-HPV E6/E7 mRNA-based detection method using the Aptima HPV assay kit revealed appropriate clinical sensitivity for detection of CIN-2+ among the Iranian women with ASC-US and LSIL cytological results. The HR-HPV mRNA-based assay displayed a higher clinical specificity for detecting CIN-2+ compared to the HR-HPV DNA-based method. Therefore, using molecular-based methods for triage of Iranian women with abnormal cytological results is highly recommended.

 

Acknowledgments

We would like to thank all the gynecologists, gynecologist-oncologists, cytopathologists, gyneco-logical-pathologists, and laboratory technicians for helping us with this project.

 

Conflicts of Interest

The authors declared no conflicts of interest.

 

Systematic Review: Original Research | Subject: Gynecology Oncology
Received: 2021/06/29 | Accepted: 2021/08/13 | Published: 2022/01/12

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