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2021, Volume 37, Number 1, Page(s) 032-038
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DOI: 10.5146/tjpath.2020.01505 |
Evaluation of the Performance of CinTec® PLUS in SurePathTM Liquid-Based Cervico-Vaginal Samples |
Pooja SHARMA1, Parikshaa GUPTA1, Nalini GUPTA1, Vanita SURI2, Arvind RAJWANSHI1 |
1Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India 2Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India |
Keywords: Cervical cytology, Pap smear, Liquid-based cytology, CINtec PLUS, p16, Ki-67 |
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Objective: Cervical cytology and Human papillomavirus (HPV) testing are effective screening techniques but both have limitations. A few
recent studies in the literature have highlighted the role of co-expression of p16INK4a and Ki-67 for cervical cancer screening. The present study
was undertaken to evaluate the diagnostic performance of the CINtec® PLUS kit (dual immunostaining for p16 and Ki-67) in SurePathTM
liquid-based (LBC) cervico-vaginal samples.
Materials and Methods: This was a prospective study performed on 52 cervico-vaginal SurePath™ LBC samples reported as having squamous
epithelial cell abnormality (ECA). All the samples were stained using CINtec® PLUS kits. Additionally, HPV-DNA testing was also done and the
results were compared.
Results: The age range was 34-74 years. ECA included 18 (34.6%) cases of ASC-US, 9 (17.3%) cases of low-grade squamous intraepithelial lesion
(LSIL), 11 (21.2%) cases of high-grade squamous intraepithelial lesion (HSIL), and 14 (26.9%) cases of squamous cell carcinoma (SCC). Cervical
biopsies were available in 19 (36.5%) cases. A total of 34/52 (65.4%) cases were positive for HPV-DNA (5/18-ASC-US; 6/9-LSIL; 10/11-HSIL;
13/14-SCC). The CINtec® PLUS test was positive in 41/52 (78.8%) cases (11/18-ASC-US; 6/9-LSIL; 11/11-HSIL; 13/14-SCC). On comparing
CINtec® PLUS positivity (78.8%) with HPV positivity (65.4%), dual positivity was seen in 3/18 cases of ASC-US, 6/9 cases of LSIL, 10/11 cases of
HSIL, and 12/14 cases of SCC. One case each of HSIL and SCC was negative on the HPV test and was positive on CINtec® PLUS.
Conclusions: CINtec® PLUS test helps to improve the detection of pre-cancerous cervical lesions as compared to cervical cytology or HPV testing
alone and hence can serve as a potentially useful diagnostic and triage tool, especially for indeterminate cases. |
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Cervical cancer screening using Papanicolaou-stained
cervical smears is the most successful cancer screening
program launched till date. The use of this screening
method has lead to a significant increase in the detection
rates of pre-cancerous lesions and a decrease in morbidity
and mortality. Human papillomavirus (HPV) is the most
common viral infection affecting the female genital tract
and also the most important causative agent of cervical
cancer. In the majority of the females, this viral infection is
transient and self-limiting. However, in less than 10% of the
cases, the virus persists and the epithelial cell abnormalities
may progress to high-grade lesion or invasive cancer, which
usually occurs over a period of several years 1. Several
studies have demonstrated that HPV testing improves the
sensitivity of detection of high-grade precursor lesions as
compared to cervical cytology alone 2.
Cell cycle alterations induced by HPV oncoproteins
during cervical neoplasia can serve as newer biomarkers
that can be used to identify women who are at increased
risk for developing cervical cancer precursors. Two such
useful biomarkers are- p16INK4a, also known as p16 (a
tumor suppressor protein), and Ki-67 (a cell proliferation
marker) 3. Increased expression of p16INK4a and Ki-67 has
been found to be associated significantly more commonly
with high-grade cervical lesions 4. Thus, testing for these
markers may provide enhanced specificity and diagnostic
accuracy in HPV-positive women within an organised
cervical screening programme.
The CINtec® PLUS test uses a dual immunostaining
technique for detection of simultaneous p16INK4a and Ki-
67 expression in the exfoliated cervical epithelial cells.
This dual immunostaining kit reportedly helps to improve
the detection of pre-cancerous cervical lesions. Only a
few studies have assessed the utility of the CINtec® PLUS test on cervical samples, the majority of them being from
developed countries of the world 5-7. There is paucity of
data from the Indian subcontinent with only a few studies
available 8. Therefore, the present study was undertaken
to evaluate the diagnostic performance of CINtec® PLUS
in SurePathTM liquid-based cervico-vaginal samples
as compared to cervical cytology using the SurePath™
liquid-based cytology (LBC) technique and HPV testing
performed with the Qiagen Hybrid Capture (HC2) assay
and subsequent histopathology, wherever available. |
Top
Abstract
Introduction
Methods
Results
Disscussion
References
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Target Population: Women aged 25 to 70 years, presenting
to the gynaecology out-patient department with available
Pap smears showing squamous epithelial cell abnormalities.
Ethical approval: The study was approved by the institute’s
ethics committee and a waiver of consent was granted
(Reference No: NK/4102/Res, Date: 23.03.2018).
Study type: This was a prospective study, wherein a total
of 52 cervico-vaginal samples, obtained during the study
period (June 2017 to July 2018) and reported on cervical
SurePath™ cytology as having squamous epithelial cell
abnormality (as per The Bethesda System, 2014), were
included. These samples were routinely screened by
SurePath™ liquid-based cervical cytology in the Department
of Cytology and Gynaecological Pathology, at a tertiary care
centre. The samples collected in the SurePath™ preservative
fluid collection vials were transferred to the concentration
tubes, as is being done routinely for all SurePath™ cytology
samples in the laboratory. All these cases were stained for
dual immunostaining for p16 and Ki-67 using CINtec® PLUS
kits on the samples from either the SurePath™ collection
vials or the concentration tubes. HPV DNA testing was
performed on these samples by using the Qiagen Hybrid
Capture (HC2) assay.
Sample processing from sample collection vials: After the
routine LBC smear preparation, the residual sample in
the collection vial was equally divided into two parts: one
was utilized for HPV testing and the second was used for
performing the CINtec® PLUS test. The sample in the vial
for CINtec® PLUS was vortexed, followed by centrifugation
at 1500 rpm for 10 minutes. The supernatant was then
discarded and the sediment resuspended in a tube, and this
tube was then kept in the SurePathTM stainer for preparation
of the LBC smears.
Sample processing from concentration tubes: After the
routine LBC smear preparation, the residual material from
the concentration tube was collected in a tube that was then used for LBC smear preparation using the SurePathTM
stainer.
CINtec® PLUS staining: Prior to the staining procedure,
the smears were rehydrated and treated with the Epitope
retrieval solution followed by the staining procedure and
aqueous mounting. CINtec® PLUS testing was performed
manually as per the manufacturer’s protocol in all 52 cases.
The test involves a two-step immunocytochemical staining
procedure for the cytological specimens. For detection of
the antigens, primary monoclonal antibodies are used and
the chromogen reactions are based on the horseradish
peroxidase-mediated conversion of 3, 3-diaminobenzidine
(DAB) chromogen and alkaline phosphatase-mediated
conversion of fast red chromogen to visible reaction
products. The smears were prepared as per the routine
SurePathTM protocol. Double immuno-reactive cells in
smears indicate positive staining for both proteins. p16
shows nucleo-cytoplasmic positivity in the transformed
cells. Ki-67, being a proliferative marker, stains the nucleus.
Since DAB is used for p16 detection, p16 staining is seen
as a brown color and similarly, as fast red is used for Ki-67
detection, Ki-67 staining is seen as red nuclear staining.
The performance of CINtec® PLUS was evaluated by
comparing the results of dual immunostaining obtained
from samples in the SurePathTM collection vials with the
samples obtained from the concentration tubes. All the
cases were analyzed blindly, without the information of
patient’s identification, previous cytology results, HPV test
results, follow-up biopsy, or any other relevant data, which
could influence the results. Additionally, we also evaluated
the diagnostic efficacy of the CINtec® PLUS test in detecting
epithelial cell abnormalities in cervico-vaginal samples as
compared to cervical cytology and HPV testing. |
Top
Abstract
Introduction
Methods
Results
Disscussion
References
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A total of 52 cases were included in the study. The age range
was 34-74 years.
Cervical smear cytology: Squamous epithelial cell
abnormalities in these cases included 18 (34.6%) cases
of ASC-US (atypical squamous cell- undetermined
significance), 9 (17.3%) cases of LSIL, 11 (21.2%) cases of
HSIL and 14 (26.9%) cases of squamous cell carcinoma
(SCC). Subsequent cervical biopsies were available in 19
(36.5%) cases. The histopathological diagnoses obtained on
follow-up biopsies have been listed in Table I.
 Click Here to Zoom |
Table I: Correlation of cervical cytology with cervical biopsies (n=19). |
HPV testing by HC2 assay: HPV testing was performed
by Qiagen Hybrid Capture HC 2 assay in all 52 cases. The
values were represented in relative light units (RLUs).
A total of 34/52 (65.4%) cases were positive for human
Papilloma virus (HPV) by HC2 assay. There were 5 (27.8%)
ASC-US, 6 (66.7%) LSIL, 10 (90.9%) HSIL, and 13 (92.8%)
cases of SCC positive for HPV.
CINtec® PLUS testing: The CINtec® PLUS test was performed
on all 52 cases. LBC concentration tubes were used in 25
(48.1%) cases and collection vials with preservative fluid
were used in 27 (51.9%) cases. The CINtec® PLUS test was
positive in 41/52 (78.8%) cases. The results from LBC
concentration tubes and collection vials were comparable
with 80% CINtec® PLUS positivity in the samples from LBC
concentration tubes and 81.5% CINtec® PLUS positivity
from the samples in LBC collection vials. This highlights
that both sample types can be used for CINtec® PLUS testing
with equal diagnostic efficacy. The CINtec® PLUS test was
positive in 41/52 (78.8%) cases with positivity in 11 (61.1%)
ASC-US, 6 (66.7%) LSIL, 11 (100%) HSIL, and 13 (92.8%)
SCC cases.
Correlation of CINtec® PLUS test results with cervical
cytology and tissue biopsies: Out of 19 cases with followup
biopsies available, 4 cases (21.1%) (3 reported as ASCUS
and 1 reported as LSIL on cytology) did not show any epithelial cell abnormality on follow-up biopsies. Out of 14
SCC cases, 8 were confirmed on follow-up histopathology.
Among the cases reported as LSIL on cytology, 1 case
was upgraded to CIN3/HSIL and 1 case was reported as
squamous metaplasia on subsequent cervical biopsy. One
of the cases reported as HSIL on cervical cytology was
upgraded as SCC on subsequent histopathology. All the
cases reported as ASC-US, with follow-up cervical biopsies
(n=3), showed features of chronic cervicitis and squamous
metaplasia. No dysplasia or malignancy was noted in these
cervical biopsies. On comparing CINtec® PLUS positivity
with cervical cytology, CINtec® PLUS positivity was seen in
10 cases of ASC-US, 6 cases of LSIL, 10 cases of HSIL, and
13 cases of SCC (Figures 1A-C, 2A-C, 3A-C).
 Click Here to Zoom |
Figure 1: A) SurePathTM liquid-based preparation showing squamous epithelial cells reported as atypical squamous cells of undetermined
significance (Papanicolaou; x 20). B) SurePathTM liquid-based preparation showing negative staining for p16 and Ki-67 by CINtec® PLUS,
indicated by the absence of brown cytoplasmic staining and red nuclear staining (CINtec® PLUS; x20). C) Section from the same case
showing squamous metaplasia without any evidence of dysplasia or malignancy (H&E; x20). |
 Click Here to Zoom |
Figure 2: A) SurePathTM liquid-based preparation showing scattered koilocytes in a smear reported as low-grade squamous intraepithelial
lesion (Papanicolaou; x20). B) SurePathTM liquid-based preparation showing positive staining for p16 (brown nucleocytoplasmic staining)
and Ki-67 (red nuclear staining) by CINtec® PLUS (CINtec® PLUS ; x20). C) Section from the same case showing low-grade squamous
intraepithelial lesion with many koilocytes (H&E; x20). |
 Click Here to Zoom |
Figure 3: A) SurePathTM liquid-based preparation from a case reported as high-grade squamous intraepithelial lesion (Papanicolaou;
x20). B) SurePathTM liquid-based preparation showing positive staining for p16 (brown nucleocytoplasmic staining) and Ki-67 (red
nuclear staining) by CINtec® PLUS (CINtec® PLUS; x20). C) Section from the same case showing high-grade squamous intraepithelial
lesion with full-thickness dysplasia (H&E; x20). |
Correlation of CINtec® PLUS test results with HPV testing:
On comparing CINtec® PLUS positivity (34/52; 78.8%) with
HPV positivity (41/52; 65.4%), dual positivity was seen in
three cases of ASC-US, 6 cases of LSIL, 10 cases of HSIL,
and 13 cases of SCC (Figures 1A-C, 2A-C, 3A-C). One case
each of HSIL and SCC was negative on the HPV test and
positive on CINtec® PLUS. Additionally, there was one case
of SCC that was positive on HPV test but where CINtec® PLUS immunostaining was negative. Similarly, there
were an additional six cases of ASCUS that were positive
for the CINtec® PLUS test but negative for the HPV test.
The correlation of CINtec® PLUS test results with cervical
cytology and HPV testing has been highlighted in Table II.
 Click Here to Zoom |
Table II: Correlation of CINtec® PLUS test results with cervical cytology and HPV testing |
CINtec® PLUS testing using LBC concentration tubes and
collection vials: The CINTec® PLUS test was positive in 20/25
(80%) cases done from the samples in LBC concentration
tubes and 22/27 (81.5%) cases done from the samples in LBC collection vials. There was no statistically significant
difference in the results obtained from both types of samples
(p>0.05). No technical difficulties were encountered during
testing from both sample types. The staining intensity,
percentage of positive cells and background staining results
were comparable with both sample types. This highlights
that either the LBC concentration tube or the LBC collection
vial can be used for performing CINTec® PLUS testing. |
Top
Abstract
Introduction
Methods
Results
Disscussion
References
|
|
Cervical cancer screening using Pap-stained cervical
smears is the most successful cancer screening program
launched till date. Use of this screening method has lead to
a significant increase in the detection rates of pre-cancerous
lesions and a decrease in morbidity and mortality; however,
the test has its own set of limitations. Similarly, human
papillomavirus (HPV) testing that is being used as an
equivalent effective screening strategy also has diagnostic
constraints.
Newer biomarkers are hence being proposed to overcome
these limitations. Two such biomarkers are p16INK4a and
Ki-67. The concurrent expression of a proliferation marker
(Ki-67) and a tumor suppressor protein (p16) may increase
the specificity of detection of epithelial cell abnormalities
in cases wherein the neoplastic process has been initiated
9. Co-expression of p16INK4a and Ki-67 has been found to
be of more diagnostic value than either of these markers
alone 10.
Nevertheless, cervical cytology still retains a pivotal role
in cervical cancer screening, especially in developing
countries and resource-limited settings. This is owing to
the fact that well-trained cytopathologists can accurately
diagnose cervical precancerous lesions on cytology, more
so with the routine use of liquid-based preparations like
ThinPrep and SurePathTM. Additionally, HPV testing, when
used as a stand-alone cervical cancer screening test, has
the disadvantage of not being able to evaluate the degree
of cytological abnormality for grading of the epithelial
lesions. This shortcoming, however, does not hold true for
CINtec® PLUS testing, wherein simultaneous evaluation
of cytological atypia, for the grading of the epithelial cell
abnormality, is possible along with the evaluation of the
dual immunostaining.
In a prospective cervical cancer screening study conducted
in Wolfsburg, Germany, 427 out of a total of 7,976 women
tested positive for HPV when the cervical Pap smear
was negative for any abnormalities. These women were
managed with repeat testing and colposcopic examinations
and cervical biopsies as clinically indicated. The same cases
were also tested with CINtec® PLUS. The CINtec® PLUS
kit detected 91.9% of the CIN2 cases and 96% of the CIN3
cases. It was shown to have high sensitivity with a very high
degree of specificity. In addition, a negative result for the
dual staining had a very high negative predictive value of
99.1% 11.
An international collaborative study was conducted in five
European countries to assess the sensitivity and specificity of p16/Ki-67 dual-stained cervical cytology for the detection
of high-grade CIN (HGCIN) in primary screening and
in ASC-US or LSIL triage settings. This study included
27,349 women attending routine cervical screening. The
sensitivity of dual-stained cervical cytology for high-grade
cervical lesions was significantly higher (90.1%) than Pap
smear cytology (66.4%) in screening. Specificity, however,
was similar for both tests (95.3% vs. 95.4%, respectively).
The sensitivity of HPV testing was 96.4%, but it had a lower
specificity of 90.2%, over all ages, as compared to cytologybased
tests. In women aged less than 30 years, specificity
of dual-stained cytology was 92.3% as compared to 81.4%
for HPV testing. In ASC-US and LSIL triage, dual-stained
cytology had high sensitivity, while reducing the number of
false-positive results by 43% compared to HPV testing 12.
In another cross-sectional study involving the assessment
of the p16 and Ki-67 immunocytochemical expression in
negative and equivocal (ASC-US) liquid-based cytology
samples testing positive for high-risk HPV types with the
HC2 assay or polymerase-chain reaction (PCR), it was
concluded that a combination of these two markers can
be a useful means for management of these women with
equivocal cytology 13.
There have been a few previous studies on dualimmunostaining
of p16 and Ki-67 by CINtec® PLUS kit
in liquid-based cervical cytology samples 5,6,11-19. The
majority of these have been conducted on Thin Prep samples
and experience with dual-immunostaining by CINtec® PLUS
in SurePathTM liquid-based cervicovaginal samples is quite
limited. Therefore, a total of 52 SurePathTM LBC samples
reported as ‘squamous epithelial cell abnormality’ were
included in the present study to evaluate the performance
of the CINtec® PLUS test in LBC samples. Epithelial cell
abnormalities in these cases included 18 (34.6%) cases of
ASC-US, 9 (17.3%) cases of LSIL, 11 (21.2%) cases of HSIL,
and 14 (26.9%) cases of SCC. Subsequent cervical biopsies
were available in 19 (36.5%) cases. A total of 34/52 (65.4%)
cases were positive for HPV by the Hybrid Capture HC2
assay. There were 5/18 cases of ASC-US, 6/9 cases of LSIL,
10/11 cases of HSIL, and 13/14 cases of SCC that tested
positive for HPV. The CINtec® PLUS test was performed on
all 52 cases.
Both LBC concentration tubes and collection vials were used
for the CINtec® PLUS test and the results were comparable
with 80% CINtec® PLUS positivity in the samples from LBC
concentration tubes and 81.5% CINtec® PLUS positivity
from the samples in LBC collection vials. This highlights
that both sample types can be used for CINtec® PLUS testing
with equal diagnostic efficacy. The CINtec® PLUS test was positive in 41/52 (78.8%) cases with positivity in 61.1% of
ASC-US, 66.7% of LSIL, 100% of HSIL and 92.8% of SCC
cases. On comparing CINtec® PLUS positivity (78.8%) with
HPV positivity (65.4%), dual positivity was seen in three
cases of ASC-US, 6 cases of LSIL, 10 cases of HSIL, and 13
cases of SCC. One case of HSIL that was negative on the
HPV test was positive on the CINtec® PLUS test, thereby
highlighting an added advantage of the CINtec® PLUS
test over HPV testing to detect high-grade lesions. The
CINtec® PLUS test helps in detecting squamous epithelial
cell abnormality in the cervical smear itself, helping in
direct correlation with cytomorphology. The CINtec® PLUS
test has the capability of detecting even an occasional
transformed cell in cases such as ASC-US.
The present study was limited by a small population size
and lack of histopathological follow-up in all the cases.
Technical difficulties encountered in CINtec® PLUS testing
included glycerine mounting of the smears which was not
as stable as DPX mounting. The staining faded after a few
days; therefore, they had to be interpreted in the fresh state.
Another limitation of this test is the cost as compared to
routine cervical cytology or HPV testing.
Nevertheless, we believe that this test has the potential of
being a highly useful triage tool for indeterminate results on
cervical screening (whether by HPV testing or by cervical
cytology). The biggest advantage is that the cytopathologist
is able to do simultaneous/real-time assessment of cervical
cytological abnormalities along with the interpretation of
the immmunostaining, unlike in the case of HPV testing.
To conclude, the CINtec® PLUS test helps in detecting
precancerous cervical lesions in diagnostically challenging
cases or those having indeterminate results with cervical
cytology or HPV testing alone, and hence can be widely
applied as a triage tool for confirmation of the neoplastic
transformation of cervical epithelial cells, after the initial
screening protocol.
CONFLICTS of INTEREST
The authors declare no conflict of interest.
FUNDING
The study was supported by Intramural Research Funding
by the Post Graduate Institute of Medical Education and
Research (reference number 71/2-Edu-16/10)
AUTHORSHIP CONTRIBUTIONS
Concept: PG, NG, AR, Design: PG, NG, AR, Data
collection or processing: PS, PG, NG, VS, Analysis or
Interpretation: PS, PG, NG, VS, Literature search: PS, PG, NG, AR, Writing: PS, PG, NG, Approval: PS, PG, NG, VS,
AR. |
Top
Abstract
Introduction
Methods
Results
Discussion
References
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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