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Original research
Incidence of pre-neoplastic and neoplastic lesions of the cervix before and after the COVID-19 pandemic
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  1. Miriam Dellino1,
  2. Marco Cerbone1,
  3. Francesca Fortunato2,
  4. Teresa Capursi1,
  5. Achiropita Lepera1,
  6. Tiziana Mancini1,
  7. Antonio Simone Laganà3,
  8. Antonio Malvasi1,
  9. Paolo Trerotoli4,
  10. Gennaro Cormio1,5,
  11. Ettore Cicinelli1,
  12. Gerardo Cazzato6,
  13. Carmine Carriero1,
  14. Vincenzo Pinto1,
  15. Eliano Cascardi6 and
  16. Amerigo Vitagliano1
  1. 1Department of Interdisciplinary Medicine (DIM), University of Bari Aldo Moro, Bari, Puglia, Italy
  2. 2Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
  3. 3Unit of Obstetrics and Gynecology, “Paolo Giaccone” Hospital, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
  4. 4Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Puglia, Italy
  5. 5Department of Gynecology, University of Bari, Bari, Puglia, Italy
  6. 6Section of Molecular Pathology, Department of Precision and Regenerative Medicine and IonianArea (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy, Bari, Puglia, Italy
  1. Correspondence to Dr Miriam Dellino, Department of Interdisciplinary Medicine (DIM), University of Bari Aldo Moro, Bari, Puglia, Italy; miriamdellino{at}hotmail.it

Abstract

Objective The COVID-19 pandemic had significant effects on healthcare systems worldwide, including the disruption of routine screening programs for cervical cancer. This study aimed to compare the incidence of cervical intra-epithelial neoplasia (CIN)2 and CIN3 lesions, adenocarcinoma, and squamous carcinoma of the cervix before and after the COVID-19 pandemic.

Methods A retrospective analysis was performed using archive data from the Policlinico di Bari, Unit of Gynecology and Obstetrics. The study included patients who tested positive for high-risk human papillomavirus (HPV) at the level I screening test (HPV test) and were subsequently referred to level II screening, which involves the Papanicolaou (Pap) test and colposcopic examination. We excluded individuals who did not comply with the recommended follow-up, patients with low-risk HPV infection, those with autoimmune diseases, oncologic diseases, or those undergoing immunosuppressive therapies. The time period spanned from January 2020 to December 2022. The incidence of CIN2/CIN3 lesions, adenocarcinoma, and squamous carcinoma of the cervix was compared between the pre-screening period (2017–2019) and the post-screening period (2020–2022).

Results The study comprised a cohort of 1558 consecutive European sexually active women with a median age of 34 years (range 25–65) who underwent colposcopic evaluation of the uterine cervix as a level II screening program. The comparison between the pre-screening and post-screening periods showed an increase in the incidence of CIN2/CIN3 lesions, rising from 23.9 to 63.3 per 100 000 (HR 2.62, 95% CI 1.64 to 4.20; p<0.001). Additionally, although there was an absolute increase in the incidence of cervical carcinoma and adenocarcinoma, the comparison did not reach statistical significance (squamous carcinoma: 2017–2019, 2.5 per 100 000; 2020–2022 3.4 per 100 000, p=0.72; adenocarcinoma: 2017–2019, 3.5 per 100 000; 2020–2022 7.6 per 100 000, p=0.24).

Conclusion This study showed a significant increase in the incidence rate of CIN2/CIN3 lesions after the COVID-19 pandemic. Our findings may be attributed to the temporary suspension of follow-up programs during the pandemic, although the study does not rule out direct effects of SARS-CoV-2 on the risk of pre-neoplastic and neoplastic conditions of the cervix.

  • Cervical Cancer
  • COVID-19

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/ijgc-2023-004743

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • The COVID-19 pandemic had significant effects on healthcare systems worldwide, including delays to routine screening programs for cervical cancer.

    WHAT THIS STUDY ADDS

    • This study showed an increase in cervical intra-epithelial neoplasia (CIN)2/CIN3 lesions but no increase in either squamous carcinoma or adenocarcinoma of the cervix during the COVID-19 pandemic.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Future studies should explore the potential direct or indirect effects of COVID-19 infection on the pathophysiology of human papillomavirus and, consequently, the development of cervical cancer. If our findings are corroborated by future research, the study could lead to changes in the target population for cervical cancer screening, recommending stricter follow-up for sub-populations at higher risk of cervical cancer based on their COVID-19 infection history.

    Introduction

    Cervical cancer is recognized as the fourth most common malignancy among women worldwide, accounting for 569 847 new cases every year.1 In Italy the age-standardized incidence rate of cervical cancer is reported as 6.9 per 100 000 women, with more than 2400 new cases in the year 2020.2 3 The pathophysiological link between human papillomavirus (HPV) and cancer progression has led to the recognition of cervical cancer as a preventable disease.4 Primary prevention through HPV vaccination and secondary prevention through cervical cancer screening programs are effective approaches to prevent cervical cancer.5 6 In 2016, 22 European Union (EU) member states actively organized population-based cervical cancer screening programs compared with 17 EU member states in the previous decade. These screening programs will impact over 77.0 million women aged 30–59 years who are at risk of cervical cancer.5

    In recent times, the global COVID-19 pandemic has emerged as a significant health crisis spreading rapidly across the world. The unprecedented scale and impact of the pandemic have placed immense strain on healthcare systems worldwide, posing challenges to the effective delivery of ambulatory procedures within hospital settings. The rapid spread of COVID-19 in 2019 resulted in the temporary suspension of outpatient services, including screenings, with a primary focus on delivering urgent care services. This phenomenon may have negatively impacted the management of various cancers.7 Regarding screening services, studies in the literature have already identified a surveillance gap in other cancer screenings (such as breast and colorectal), resulting in an increased detection of invasive cases during the pandemic.7 8 However, to date, the impact of the pandemic on the incidence of high-grade dysplasia in Italy as part of the cervical carcinoma screening program has not yet been investigated. Analysis of these data unquestionably strengthens the evidence supporting the significance of prevention and early diagnosis. Nonetheless, it is imperative to quantify the impacts of the COVID-19 pandemic on screening programs, particularly in the most vulnerable sub-populations, to identify possible targeted and evidence-based strategies for recovery.7 This study aimed to compare the incidence rate of cervical intra-epithelial neoplasia (CIN)2 and CIN3 lesions, adenocarcinoma, and squamous carcinoma of the cervix before and after the COVID-19 pandemic.

    Methods

    Study Design

    The study was designed as a retrospective single-center observational study. Histological examinations from medical records of patients enrolled in the level II screening program of cervical cancer at our University Hospital (Policlinico di Bari, Bari, Italy) were consulted. This study focuses on patients with high-risk HPV who, according to Italian national guidelines, are candidates for a second-level investigation (colposcopy and Pap test).9 Women who were candidates for surgery with suspected cervical pathology and specific histological findings (CIN 2+, squamous carcinoma, or cervical adenocarcinoma) were selected.

    Study Aim

    The study aim was to assess whether there was an increase in the severity of cervical HPV-related lesions before and after the COVID-19 pandemic by comparing the incidence of cases between the two periods 2017–2019 and 2020–2022.

    Study Population

    In this study the inclusion criteria focused on patients with high-risk HPV infection who were enrolled in the level II screening program for cervical cancer. This included two specific groups: (1) women aged 25–30 years who had an abnormal PAP smear and were found to have high-risk HPV infection; and (2) women aged 30–65 years who were undergoing periodic follow-up, in accordance with the Guidelines of the level II cervical cancer screening program (SICPPV-GISCI 2020) and were identified with high-risk HPV infection.9

    Patients who did not comply with the recommended follow-up procedures or discontinued their participation in the level II screening of cervical cancer were excluded from the study. Also excluded from the analysis were individuals with low-risk HPV infection, patients who tested positive for HPV but were not associated with the cervical cancer level II screening, and individuals with autoimmune diseases, oncologic diseases, or those undergoing immunosuppressive therapies. These exclusion criteria were implemented to ensure a homogeneous and relevant patient cohort for the investigation.

    Statistical Analysis

    The number of cases of CIN2+, squamous carcinoma, and adenocarcinoma during the pre-COVID-19 period (2017–2019) was compared with the number of cases observed in the post-COVID-19 period (2020–2022). To assess the impact of the pandemic, incidence hazard ratios (IRRs) along with their corresponding 95% CIs were calculated using Poisson regression models. The statistical analyses were conducted using Stata MP 15 software for Mac OS (College Station, Texas, USA). The incidence rates of each condition were calculated as new cases per 100 000 inhabitants. The effects of the pandemic on the risk of new diagnoses were determined using the IRR, defined as the hazard in the post-screening group divided by the hazard in the pre-screening group.

    Results

    Study Population

    A total of 1558 consecutive European sexually active patients with a median age of 34 years (range 25–65), of which 1006 underwent a level II screening program between January 2017 and December 2019 and 1014 underwent a level II screening program between January 2020 and December 2022, were considered eligible and enrolled in the study.

    Incidence Trends of Pre-neoplastic and Neoplastic Lesions

    Between 2017 and 2019 a total of 241 patients with CIN2/CIN3, 25 patients with squamous cancer, and 35 patients with adenocarcinoma were observed, accounting for a total of 301 pre-cancerous and cancerous cases. In the period between 2020 and 2022, the numbers increased to 642 patients with CIN2/CIN3, 34 patients with squamous cancer, and 77 patients with adenocarcinoma, accounting for a total of 753 pre-cancerous and cancerous cases. Comparing the periods 2017–2019 and 2020–2022, there was a significant increase in the incidence of all pre-neoplastic and neoplastic lesions (IRR 2.46, 95% CI 1.61 to 3.76, p<0.001). Specifically, there was a significant and increasing trend in the incidence of CIN2/CIN3 lesions. Comparing the incidence of CIN2/CIN3 and cervical cancer between the periods 2017–2019 and 2020–2022, a statistically significant increase in the incidence of CIN2/CIN3 lesions was observed, rising from 23.9 to 63.3 per 100 000 (IRR 2.62, 95% CI 1.64 to 4.20, p<0.001). However, although there was an absolute increase in the incidence of cervical carcinoma and adenocarcinoma, the comparison did not reach statistical significance (squamous carcinoma: 2017–2019, 2.5 per 100 000; 2020–2022, 3.4 per 100 000; adenocarcinoma: 2017–2019, 3.5 per 100 000; 2020–2022 7.6 per 100 000). The details are shown in Table 1 and Figure 1 illustrates the trends.

    Figure 1
    Figure 1

    Comparison of incidence hazard ratios (IRRs) of cervical intra-epithelial neoplasia (CIN)2/CIN3, squamous cancer, and adenocarcinoma between the periods 2017–2019 and 2020–2022.

    View this table:
    Table 1

    Incidence of cervical intra-epithelial neoplasia (CIN)2+, squamous carcinoma, and cervical adenocarcinoma between the years 2017–2019 and 2020–2022

    Discussion

    Summary of Main Results

    An increasing trend in the incidence of CIN2+ was observed during the COVID-19 pandemic. Although the results regarding cancer incidence showed a rise, they were not statistically significant. These findings should be considered preliminary, and further investigations are warranted to explore the direct impact of COVID-19 on such lesions.

    Results in the Context of Published Literature

    Since the beginning of 2020, the measures implemented by governments worldwide to control the spread of COVID-19 have had a significant impact on various healthcare services. One area affected by these measures is access to screening programs,9 10 including those for breast, uterus, and cervical cancers, which were considered non-urgent and consequently suspended during the pandemic in several European countries.11 However, these screening tests are crucial for early detection and treatment, especially in the era of precision medicine.12

    The disruption of these services could lead to an increase in the diagnosis of cervical dysplasia, particularly high-grade lesions, in the coming years.13–17 Therefore, continuous monitoring of this phenomenon at both global and local levels is necessary.14 18 19 Recent evidence suggests that COVID-19 can directly cause transient gynecological dysfunction in some cases.20–22 Hence, it is worth investigating whether COVID-19 may have indirectly contributed to the increase in cervical dysplastic lesions, particularly in certain sub-populations.6 20 21 This consideration is further supported by the introduction of the HPV test since 2020, which may have led to an increased detection of uterine cervical lesions compared with the past. The HPV test is more sensitive than the previously used PAP test as the primary screening method.23–26 It is important to note that about 90% of women with CIN2, CIN3, and cervical cancer are HPV-positive, specifically for serotypes HPV16 and HPV18. Therefore, the COVID-19 pandemic has had a significant impact on primary and secondary prevention measures for cervical cancer.

    The impact of the pandemic on cervical cancer prevention has been observed globally. In the USA, HPV vaccination rates decreased by over 50–70% in 2020, resulting in a substantial deficit in vaccinations. Cervical cancer screenings also dropped by 94% during stay-at-home orders, causing thousands of missed screenings. Similar trends were reported in Europe, with screening services suspended in 19 countries, leading to increased diagnoses, mortality, and morbidity related to cervical cancer. In addition to the gap caused by the temporary interruption of screening, it is important to evaluate whether these results are a consequence of the impact of COVID-19 on each individual. The literature suggests that the generation of reactive oxygen species, reactive nitrogen, and sulfur composites contributes to the inflammatory response and pathophysiology of various systemic alterations in COVID-19 infection. CD4 and CD8 T lymphocytes play a major role in this process by triggering a hyperinflammatory state through the release of interleukins (IL-1β, IL-2R, IL-6) and chemokines (CCL-2, CCL-3, and CCL-10) in patients with COVID-19.26 Furthermore, it has been reported in the literature that the simultaneous increase in reactive oxygen species leads to mitochondrial dysfunction and subsequent multi-organ damage following COVID-19 infection.27 28 As a result, women with previous COVID-19 infection may experience post-COVID syndrome, characterized by underlying biological molecular mechanisms such as neuroinflammation, coagulation alterations, autoimmunity activation, and viral persistence.

    It is well known that immune dysregulation can contribute to the reactivation of other viral types including herpes viruses such as Epstein–Barr virus and human herpesvirus 6.29 30 It can be hypothesized that this mechanism may also favor the virulence of HPV and the progression of HPV-related lesions, although there is currently a lack of studies in the literature investigating this association. Similarly, COVID-19 is known to cause various temporary gynecological dysfunctions through the activation of different pathways. Moreover, there is increasing evidence of a correlation between COVID-19 infection and gut microbiota dysbiosis.31–36 The cytokine storm associated with COVID-19 can alter the intestinal flora and, conversely, the intestinal flora can influence the cytokine storm.37–39 Consequently, it is worth investigating the possibility that the COVID-19 cytokine storm could also alter the cervicovaginal microbiota. This could be a new aspect of study, considering that the cervicovaginal microbiota may play a role in the risk of progression of HPV-related cervicovaginal dysplastic lesions under certain conditions.40 However, these hypotheses remain speculative and require further studies and solid evidence.

    Strengths and Weaknesses

    Our study is the first to report an increase in cervical pre-cancerous lesions in Italy during the COVID-19 pandemic. These results further underline the importance of cervical screening as an effective tool for the prevention and early diagnosis of cervical oncological diseases. We have reported the data from the literature to hypothesize also the possibility of an interaction between COVID-related inflammatory processes and the dysplastic evolution of HPV-related lesions through alteration of the vaginal microbiota. These findings should be considered preliminary, and further investigations are warranted to explore the direct impact of COVID-19 on such lesions.

    The study has a number of of limitations. First, there is a lack of information on the age-standardized ratio. Second, there is no information on the specific HPV genotypes present or whether there is a correlation between lesion severity and high-risk HPV types or the presence of multiple strains. This is due to the fact that the current guidelines only recommend HPV testing without genotyping in patients undergoing level II screening. Additionally, it would have been important to acquire and analyze information on changes in sexual behavior and HPV vaccination status in these cohorts.

    Implications for Practice and Future Research

    Future translational science studies should explore the potential direct or indirect effects of COVID-19 infection on the pathophysiology of HPV and, consequently, the development of cervical cancer. If our findings are corroborated by future research, our study could lead to changes in the target population for cervical cancer screening, recommending stricter follow-up for sub-populations at higher risk of cervical cancer based on their history of COVID-19 infection.

    Conclusions

    This study showed an increase in the incidence of CIN2/CIN3 lesions and no increase in either squamous or adenocarcinoma of the cervix. The suspension of follow-ups and screening protocols due to stay-at-home orders likely influenced cervical cancer screening practices. While the possibility of a direct COVID-19 infection of female genital tract cells remains under investigation, the molecular mechanisms associated with neuroinflammation and immune disruption may contribute to increased virulence of papillomavirus, the primary cause of cervical cancer and, consequently, the progression of pre-neoplastic lesions to invasive cancer.

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study obtained approval from the ethics committee of Policlinico di Bari with the approval number 7675. The study protocol complied with ethical guidelines, ensuring patient privacy and rights. The researchers accessed and analyzed anonymized data collected during routine clinical activities, without performing any interventional procedures. Patients were not incentivized or remunerated for their participation in the study.

    Acknowledgments

    The authors thank the midwives Virginia Candidi, Olimpia Borghese and Mina Galliani, their indispensable daily helpers.

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    Footnotes

    • EC and AV are joint senior authors.

    • EC and AV contributed equally.

    • Contributors Conceptualization: MD, ECa, AV. Methodology: MD. Software: PT. Validation: FM, GCa. Formal analysis: PT, AM. Investigation, MC, FM. Data curation: AL, TM. Writing—original draft preparation: MD, ECa, MC. Writing—review and editing: ASL, GCo, GCa, CC. Supervision: ECi, ASL, VP, AV. All authors have read and agreed to the published version of the manuscript. MD is responsible for the overall content as guarantor.

    • Funding None

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.