Abbreviations: M1, Triage model 1; M1A, Triage model 1A; M2, Triage
model 2; DS, p16/Ki67 dual staining test; HSIL/CIN2+, histologic
high-grade squamous intraepithelial lesion with a quantification of
cervical intraepithelial neoplasia in grade 2 or worse; PPV, positive
predictive value; NPV, negative predictive value; CI, confidence
interval.
Discussion
The landscape of cervical cancer prevention has evolved significantly
with the approach of primary HPV-based screening and limited genotyping.
Our critical examination of the necessity of obligatory colposcopy
referral for all major screening abnormalities detected through this
approach highlights several key points. Overreliance on colposcopy for
all major screening abnormalities detected through primary HPV-based
screening with limited genotyping may lead to overtreatment. In our
population-based non-interventional analysis the PPV for detection of
HSIL/CIN2+ in both triage models with reflex DS (M1A and M2) was
significantly higher than for model with reflex cytology alone (M1),
44.2% vs. 28.3% (p < 0.0001) and 45.7% vs. 28.3% (p
< 0.0001), respectively. Also, both M1A and M2 triage models
were associated with an approximately 40% reduction in number of
colposcopies required compared to M1 (95/92 vs. 152). The difference in
PPV between triage models with DS incorporation, M1A and M2, was
insignificant and almost imperceptible (44.2% vs. 45.7%), as well as
difference in number of colposcopies needed to detect one HSIL/CIN2+
case (2,26 vs. 2,19) and number of missed HSIL/CIN2+ cases (1 case per
each triage model). The highest PPV was achieved in HPV 16/18+
DS-positive cases in M2 (45.7%). NPVs of both models with DS triage
were very high (98.3%, no statistically significant difference),
highlighting patients’ good protection. All analyzed models had a PPV
levels above 10%, meeting the criterion for the acceptable triage
strategy in cervical cancer screening [38].
The results we obtained for selected combinations of screening tests
results were similar to many other studies, including data presented by
Wright et al [39]. The PPV in HPV 16/18+ cases with DS triage
published in that paper was slightly lower (35.1% vs. 45.7% in our
study) with nearly identical NPV for the same group (96.5% vs. 98.3%,
respectively). Also, data presented by FDA was in similar range,
although analyzed separately for HPV 16+ and HPV 18+, both with DS
triage (PPV: 44.0%/23.9% and NPV: 93.8/95.3%, HPV 16+/HPV 18+
respectively) [18]. Our study showed lower PPV and higher NPV in the
HPV 16/18+ DS-positive cases compared to Øvestad et al. (PPV: 45.7% vs.
70.3%, NPV: 98.3% vs. 84.4%) [40]. The PPV in HPV 16/18+ cases
presented by Naucler et al. was nearly identical to the result in our
analysis (25.1% vs. 28.3%) and the value obtained by El-Zein et al.
was around 15% higher than in our study (43.8% vs. 28.3%)
[41,42].
In
turn, PPV for group analyzed in M1A model (NILM/ASC-US/LSIL DS-positive
and ASC-H+ cases), with a triage strategy using cytology combined with
DS, we have not found a reliable comparator to our research. This is the
first study analyzing the following approach. Due to no full-fledged
studies on the subject available, a complete in detail comparison of all
PPV levels obtained in HPV 16/18-positive patients with major screening
abnormalities with other studies was not possible.
In our analysis the highest PPV was obtained in model with DS-alone
triage (M2) with statistically insignificant difference between this
triage model and model with cytology combined with DS (M1A). Also, both
triage models allowed just an effective reduction in number of
colposcopies required in each model comparing to M1 and missed the same
number of HSIL/CIN2+ cases – only 1 case per model, ensuring high
safety. That confirms the use of DS as a triage test in primary
HPV-based cervical cancer screening strategy for women with selected
major screening abnormalities, allowing accuracy improvement and
reduction in number of invasive procedures (e.g., colposcopy). The
important difference between these two triaging models is the
possibility to refer patients directly to expedited treatment, not only
colposcopy. In M1A due to reflex cytology, for selected screening tests
results colposcopy/expedited treatment or expedited treatment is
recommended.
In
M2 triage, it does not bring such potential, DS-positive cases need to
be referred to colposcopy and DS-negative cases should go to 1 year
follow-up.
In our study AGC results were excluded from the evaluated models and
were managed based on separate ASCCP 2019 recommendations algorithm
[14,15]. European Consensus Statement on Expert Colposcopy 2023 also
recommends distinct management for all AGC cases, compared to squamous
epithelial lesions [43].
There are several strengths of the study. The non-interventional
analysis of the largest number of LBS results in Poland and Central
Eastern Europe, the insight into the results of screening tests in
private-based opportunistic cervical cancer screening and the wide age
range of participants are some of most important. Joint analysis of all
locally approved cervical cancer screening tests (liquid-based cytology,
HRHPV and DS), which allowed us to compare their accuracy and assess
potential of these tests to be used in a triage strategy for women with
major screening abnormalities in primary HPV-based screening has also
been a strength. Moreover, the study introduces one of the largest
investigations on cytologic-virologic-immunocytochemical-histologic
correlations in cervical cancer screening. A qualified gynecologic
cytopathologist evaluated all LBC and DS. However, the study has
limitations, such as being a retrospective analysis and not all patients
with abnormal screening results had a colposcopy with biopsy at the
Center. The results of colposcopic biopsies carried out outside the
facility were not included in the study due to different colposcopic
protocols and/or histologic terminology and/or lack of p16 stain in
cervical histologic specimens. Our study was conducted in a single
private funds-based Center and the results may not be generalized to
other populations. The sample size was another limitation and could
affect the accuracy of the PPV estimates. To confirm our results further
studies with the multicenter design and greater sample sizes are
required.
Conclusions
In conclusion, the evolution of cervical cancer secondary prevention
strategies calls for a comprehensive assessment of clinical practices.
As we move toward more accurate and personalized approaches, such as
primary HPV-based screening with limited genotyping, the necessity of
obligatory colposcopy referral for all major screening abnormalities
warrants careful consideration. The use of DS as a triage test allows
reduction in number of colposcopy referrals while ensuring safety for
the HPV 16/18-positive patients.
The
strategy incorporating cytology as the first triage testing might also
improve referrals to expedited treatment in selected HPV-positive cases.
Author Contributions: Conceptualization, Karolina Mazurec,
Maciej Mazurec and Martyna Trzeszcz; Data curation: Maciej Mazurec and
Karolina Mazurec; Analysis of data: Karolina Mazurec; Interpretation of
data: Karolina Mazurec and Maciej Mazurec; Investigation: Maciej
Mazurec, Martyna Trzeszcz and Karolina Mazurec; Methodology: Karolina
Mazurec, Maciej Mazurec and Martyna Trzeszcz; Writing draft: Karolina
Mazurec, Maciej Mazurec and Martyna Trzeszcz; Draft editing: Karolina
Mazurec, Maciej Mazurec and Martyna Trzeszcz; Supervision and review:
Robert Jach; Review: Agnieszka Halon and Joanna Streb. All authors have
read and agreed to the published version of the manuscript.
Data Availability Statement : The data presented that support
the findings are available from the corresponding author upon reasonable
request.