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REVIEW • Braz. J. Pharm. Sci. 61 • 2025 • https://doi.org/10.1590/s2175-97902025e24596 linkcopy

Open-access Current insights on human Papillomavirus-independent cervical cancers: a systematic review

AuthorshipSCIMAGO INSTITUTIONS RANKINGS

Abstract

A small subset of cervical cancers tests negative for human Papillomavirus (HPV) DNA, being associated with poorer prognosis and higher aggressiveness. This study systematically reviewed the current status of HPV DNA-independent cervical cancers from clinical, diagnostic and prognostic perspectives, in comparison to HPV-associated cervical cancers. Relevant terms were searchedin databases including PubMed, EMBASE, LILACS, Web of Science, Scopus, CINAHL and the Cochrane Controlled Trials Registered between January 2018 and December 2023. We focused on studies published in peer-reviewed English-language with available abstracts. Researchers independently screened the titles and abstracts and the selected articles were then read in full text. After reaching a consensus, 31 papers were selected for data extraction. Various techniques were employed for HPV testing, primarily based on polymerase chain reaction (PCR) and different types of clinical samples were analyzed. A total of 9.2% of the cases were found to be HPV-negative (mean age of 55.8 years). HPV-independent cervical cancers exhibit distinct characteristics; however, several challenges in interpreting the data were identified. Our findings demonstrate the difficulty in distinguishing truly HPV-independent cervical cancers from false-negative ones. Moreover, there is a critical need for new, more comprehensive and rigorously controlled studies to better elucidate the complexities surrounding HPV-independent cervical cancers.

Keywords:
Prognosis; Presentation; Cervical cancer; HPV DNA-independent.

INTRODUCTION

In 2020, more than 606,000 women were diagnosed positive for cervical cancer with around 341,831 deaths worldwide. This scenario demonstrates that cervical cancer is the fourth most common type of cancer in women (6.5%) (Ferlay et al., 2021; Sung et al., 2021; Singh et al., 2023). Thus, despite cervical cancer being a preventable disease due to the existence of effective screening methods (cytology and human Papillomavirus-HPV testing) as well as preventive vacines (Poljak, 2015), it remains one of the most common cancers and causes of female cancer-related deaths worldwide (Ferlay et al., 2021; Sung et al., 2021; Singh et al., 2023).

The leading cause of cervical cancer is recognized as the persistent infection by HPV, particularly oncogenic high-risk types (hrHPV) (Woodman, Collins, Young, 2007; De Sanjose et al., 2010; Serrano et al., 2015; IARC, 2022). Since the discovery of HPV’s association with cervical cancer in the early 1980s (Dürst et al., 1983), scientific research has predominantly focused on HPV DNA-related cervical cancer, aiming to develop diagnostic methods, HPV vaccines and targeted therapies (Lee et al., 2022). Approximately 90% of cervical cancers are attributed to hrHPV infections (Katki et al., 2011; Geraets et al., 2012). Despite significant improvements in hrHPV testing sensitivity in recent years, around 5.5-11% of cervical cancers are reported to be HPV DNA-independent (Li et al., 2011; Guan et al., 2012; Blatt et al., 2015; Petryet al., 2017). HPV DNA negativity rates vary, being the cervical squamous cell carcinoma rarely reported as HPV- negative and rates of HPV DNA negativity for cervical adenocarcinoma ranging from approximately 15-38% (Holl et al., 2015; Petry et al., 2017). HPV-negative cervical cancers, now classified by the World Health Organization (WHO) as independent of HPV (Höhn et al., 2021), often present at advanced stages with poor prognosis, expected to persist even in the post-HPV vaccination era (Yoshida, Shiraishi, Kato, 2021). Currently, specific therapies for HPV-independent cervical cancer are lacking, leading to reliance on treatment strategies developed for HPV- associated cervical cancer (Xing et al., 2020). Therefore, understanding recent clinical, diagnostic and prognostic insights into HPV-independent cervical cancers is crucial for developing appropriate management and treatment strategies for these patients.

HPV-independent cervical cancers canbe categorized into truly negative and false-negative types (Yoshida, Shiraishi, Kato, 2021). Although a consensus definition of HPV-independent cervical cancer is lacking, some authors suggest restricting this term to cases of primary cervical cancer without a plausible explanation for a false-negative hrHPV test result (Xing et al., 2020; Yoshida, Shiraishi, Kato, 2021). Various hrHPV tests exhibit different sensitivities and specificities (Abreu et al., 2012; Cuzick et al., 2013), including nucleic acid amplification methods such as polymerase chain reaction (PCR) and transcription-mediated amplification, as well as non-nucleic acid amplification methods like hybridization capture and invader chemistry (Sitarz, Szostek, 2019). HPV in situ hybridization (ISH) has also been employed (Mills et al., 2017; Sitarz, Szostek, 2019; Zheng, Heller,2020). Before diagnosing truly HPV-independent cervical cancer, potential scenarios leading to false-negative HPV test results should be considered (Yoshida, Shiraishi, Kato, 2021), such as integration of HPV-DNA fragments into the host genome (Tjalma, Depuydt, 2013; Akagi et al., 2014; Banister et al., 2017; Tsakogiannis et al., 2017), very low viral loads in latent HPV infections (Katki et al., 2011), cervical cancers caused by non-high-risk HPV types undetectable by HPV testing (González-Bosquet et al., 2006; Guimerà et al., 2013a; Guimerà et al., 2013b; Petry et al., 2017), inadequate sampling and various pre-analytical factors (Pirog et al., 2014; Poljak et al., 2016; Tsakogiannis et al., 2017). Despite these possibilities of false-negative HPV test results, it has been hypothesized that truly HPV-independent cervical cancers may represent a biologically distinct subset of the disease with a poorer prognosis and more aggressive behavior compared to HPV-associated cancers (Nicolás et al., 2019; Stolnicu et al., 2019). Nonetheless, HPV-independent cervical cancers remain poorly understood (Lee et al., 2022).

This systematic review provides an overview of the current status of HPV-independent cervical cancers from clinical, diagnostic and prognostic perspectives to identify research gaps and aid in developing appropriate patient diagnosis, management and treatment strategies.

METHODS

Search strategy

This systematic review was conducted through the PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) checklist (Moher et al., 2009; Page et al., 2021) and was registered using the National Institutes for Health Research (NIHR) PROSPERO tool (International Prospective Register of Systematic Reviews) (CRD42022379090).

The review proposes to answer the following question: “What is the evidence of etiology, clinic, and prognosis in HPV-independent cervical cancer compared to HPV-associated cervical cancer?”. For this, PICO strategy (participants, intervention, comparisons, outcomes) was modified to PCO in our investigation: (P) Cervical cancer (patients or samples) without HPV involvement (HPV not detectable at the time of diagnosis); (I) Specific exposure or intervention will not be evaluated; (C) Cervical cancer (patients or samples) with HPV involvement (HPV detectable at the time of diagnosis); (O) Main types of tumor in HPV-independent cervical cancer and its characteristics and prognosis.

Eligibility criteria

The review includes studies published between 01/01/2018 and 31/12/2023, in English language and with abstracts available (both qualitative and quantitative studies were included). Duplicates, review articles, comments, editorials, letters, interviews, news, congress abstracts, guidelines, errata publications and articles not directly associated with the research questions were not included. Studies that did not performed HPV DNA by a molecular test and those that were only in vitro or in vivo preclinical studies were excluded.

The searches were conducted using PubMed, EMBASE, LILACS, Web of Science, Scopus, CINAHL and Cochrane Controlled Trials Register databases. The search was carried out in May, 22, 2024 and the descriptors were selected by the researchers ABCS, GP, LM, LRC, MVS, and MA, with support and validation of a specialist (JJVT). The descriptors were divided into two blocks and were combined with the Boolean operator AND (Table I).

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TABLE I
Databases used and search strategy

Search results were exported to EndNote and duplicates were removed before screening. To identify additional articles, the authors searched the references during the eligibility assessment phase of full-text articles and did free searches.

Study selection

Researchers (ABCS, GP, LM, LRC, MVS, and MA) were divided into pairs and independently screened the title and abstracts. The selected articles were readed in full-text version. Any disagreement was resolved by discussing with the senior author (MELC). To increase the sensitivity of the search, the references of the original articles were carefully reviewed for recovery articles that could be additionally utilized in this review. To ensure that all relevant data from each paper were included in the review, a final consensus was achieved following an additional examination of the full texts by two individual experts (VRSS, MELC). After consensus, the papers most closely associated with the theme descriptors were selected for data extraction.

Data extraction and analysis

Six reviewers (ABCS, GP, LM, LRC, MVS, and MA) independently used a standardized data abstraction form to capture variables of interest: sample size, sample type, HPV molecular tests performed and results of clinicopathological features and prognostics of HPV-negative cervical cancers in human studies. The extracted information was validated by the senior author (MELC). Data was analyzed and then processed using ExcelTM with the aim to display all relevant information in an organized manner.

Quality assessment

The risk of bias (ROB) and the quality of each study were individually assessed by six researcher specialists (ABCS, GP, LM, LRC, MVS, and MA) and the results were organized in a table. Observational studies were assessed by adherence to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations (Von Elm et al., 2007; Vandenbroucke et al., 2014). Based on the assessment of its quality, no study was excluded. ROB results were described using a plot that was performed by the Risk of Bias visualization tool (ROBVIS) (Mcguinness, Higgins, 2021) and detailed risk of bias assessments for the individual studies in table format is available on the supplementary file Figure S1).

RESULTS

Study selection

The study selection process is shown in Figure 1. In brief, a total of 12,703 articles were retrieved from the seven databases. After applying the filters and remove the duplicates, 2,104 publications were screened by the title and abstract and then 127 were readed in full text. Of these 127 articles, 26 studies were found matching the inclusion and exclusion criteria and another 5 were retrieved for the references. The final sample comprised 31 articles (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Stolnicu et al., 2018; Wang et al., 2018; Chong et al., 2019; Liu et al., 2019; Nicolás et al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Zhou et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Liu et al., 2021; Ren et al., 2021; Ruiz et al., 2021; Bulutay et al., 2022; Chen et al., 2022a; Chen et al., 2022b; Kugelman et al., 2022; Shi et al., 2022; Stolnicu et al., 2022; Du et al., 2023; Kinoshita et al., 2023; Lu et al., 2023; Stolnicu et al., 2023).

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FIGURE 1
Workflow for the selection of studies, according to PRISMA guidelines.

Each study was briefly described in Table II, sequentially discussed throughout the text and summarized in Table III.

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TABLE II
Overall clinicopathological features and prognostics of HPV-independent cervical cancers compared to HPV-associated cervical cancers (continues)
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TABLE III
Synthesis of the main data on HPV DNA-negative cervical cancers compared to HPV-positive cervical cancers

Characteristics of the included studies

The studies analyzed demonstrated that different types of cervical samples were used for HPV testing including tumor tissue obtained by resection, biopsy, hysterectomy, conization and trachelectomy, as those fixed in formalin and embedded in paraffin (FFPE) (Hallowell et al., 2018; Stolnicu et al., 2018; Chonget al., 2019; Nicolás et al., 2019; Stolnicu et al., 2019; Zhou et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Liu et al., 2021; Ren et al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Shi et al., 2022; Stolnicu et al., 2022; Du et al., 2023; Lu et al., 2023; Stolnicu et al., 2023). They also used cervical mucus, fluids and smears, obtained through swabs or scraping (Chong et al., 2018; Ibragimova et al., 2018; Chong et al., 2019; Chen et al., 2022a; Chen et al., 2022b; Kinoshita et al., 2023). Four studies used database cohorts alone or in conjunction with clinical patient samples (Zhang et al., 2019; Ruiz et al., 2021; Stolnicu et al., 2022; Lu et al., 2023). Finally, 2 studies did not list the types of samples used for HPV testing (Wang et al., 2018; Liu et al., 2019) (Table II).

Out of the 31 articles included, 12 exclusively analyzed adenocarcinomas (Stolnicu et al., 2018; Stolnicu et al., 2019; Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020; Zhang et al., 2020; Renet al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Shi et al., 2022; Stolnicu et al., 2022; Du et al., 2023), 5 solely focused on squamous cell carcinoma (Wang et al., 2018; Liu et al., 2019; Zhou et al., 2019; Lu et al., 2023; Stolnicu et al., 2023), 12 investigated both adenocarcinomas, squamous cell carcinoma and adenosquamous cell carcinoma (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Zhang et al., 2019; Hirose et al., 2020; Kaliff et al., 2020; Diop-Ndiayeet al., 2021; Ruiz et al., 2021; Kugelman et al., 2022; Kinoshita et al., 2023) and 2 did not specify the type of cervical cancer analyzed (Liu et al., 2021; Chen et al., 2022a). A total of 9,406 samples were analyzed in the selected studies and the age ranged from 22 to 91 years (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Stolnicu et al., 2018; Wang et al., 2018; Chong et al., 2019; Liu et al., 2019; Nicolás et al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Zhou et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Liu et al., 2021; Ren et al., 2021; Ruiz et al., 2021; Bulutay et al., 2022; Chen et al., 2022a; Chen et al., 2022b; Kugelman et al., 2022; Shi et al., 2022; Stolnicu et al., 2022; Du et al., 2023; Kinoshita et al., 2023; Lu et al., 2023; Stolnicu et al., 2023). Furthermore, 22 studies described the International Federation of Gynecology and Obstetrics (FIGO) stage of tumors (Chong et al., 2018; Stolnicu et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Jung et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Ren et al., 2021; Ruiz et al., 2021; Bulutay et al., 2022; Chen et al., 2022a; Kugelman et al., 2022; Shi et al., 2022; Du et al., 2023; Kinoshita et al., 2023; Lu et al., 2023; Stolnicu et al., 2023), with the majority being stage I, followed by stage II and stage III (Table II).

Considering that only studies that adopted at least one HPV DNA molecular detection test were included, a wide variety of different HPV tests were observed to have been performed in the different studies. However, the vast majority of studies (74.2%) detected HPV DNA using at least one PCR-based molecular test (Chonget al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Wang et al., 2018; Chong et al., 2019; Liu et al., 2019; Nicolás et al., 2019; Zhou et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Liu et al., 2021; Bulutay et al., 2022; Chen et al., 2022a; Kugelman et al., 2022; Stolnicu et al., 2022; Du et al., 2023; Kinoshita et al., 2023; Lu et al., 2023). ISH, which allowed concurrent HPV DNA detection and localization of infected cells while preserving the morphology (Poljak et al., 2020), was the second most method performed (32.3%) (Stolnicu et al., 2018; Stolnicu et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Ren et al., 2021; Bulutay et al., 2022; Shi et al., 2022; Stolnicu et al., 2022; Lu et al., 2023; Stolnicu et al., 2023). Finally,1 study performed TMA-based HPV testing (Chen et al., 2022b), another PathSeq RNAseq data (Ruiz et al., 2021) and 1 study did not specify the methodology. (Zhang et al., 2019) (Table II).

In this review, 14 studies conducted two or more tests to confirm HPV results (Chong et al., 2018; Hallowell et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Jenkins et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Bulutay et al., 2022; Kugelman et al., 2022; Stolnicu et al., 2022; Lu et al., 2023); however, few addressed the comparison between the results of the initial HPV test and subsequent tests.

Characteristics of the HPV-independent cases

A total of 866 (9.2%) samples/cases analyzed in the selected studies were HPV-independent, ranging 0.1% to 70.8% (Table II). The mean age of the HPV- independent group was 55.8 years and varied from 31 to 88 years old. Fourteen studies did not compare the mean ages between the HPV-independent and HPV- associated groups (Chong et al., 2018; Stolnicu et al., 2018; Wang et al., 2018; Liu et al., 2019; Zhou et al., 2019; Hirose et al., 2020; Jenkins et al., 2020; Liu et al., 2021; Chen et al., 2022a; Stolnicu et al., 2022; Du et al., 2023; Kinoshita et al., 2023; Lu et al., 2023; Stolnicu et al., 2023). Sixteen studies detailed that the HPV-independent group presented a higher mean age than the HPV-associated group (Hallowell et al., 2018; Ibragimova et al., 2018; Chong et al., 2019; Nicoláset al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Hodgson et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Ren et al., 2021; Ruiz et al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Kugelman et al., 2022; Shi et al., 2022) (Table III). Only one study described that the HPV-independent group was not older than the HPV-associated group (Jung et al., 2020) (Table II).

Among the 12 studies that exclusively analyzed adenocarcinomas (Stolnicu et al., 2018; Stolnicu et al., 2019; Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020; Zhang et al., 2020; Ren et al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Shi et al., 2022; Stolnicu et al., 2022; Du et al., 2023), the prevalence of HPV- independent cases ranged from 14.4% to 70.8%. Among the studies with histological types of adenocarcinomas described, those with a higher prevalence of HPV- independent cases were endocervical, followed by gastric type and clear cell carcinomas (Table II).

Among the 5 studies that solely focused on squamous cell carcinoma (Wang et al., 2018; Liu et al., 2019; Zhou et al., 2019; Lu et al., 2023; Stolnicu et al., 2023), the prevalence of HPV-independent cases ranged from 0.1% to 30.5%. Finally, among the 12 studies that evaluated both adenocarcinomas and squamous cell carcinoma and/or adenosquamous carcinomas (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Zhang et al., 2019; Hirose et al., 2020; Kaliff et al., 2020; Diop-Ndiaye et al., 2021; Ruiz et al., 2021; Kugelman et al., 2022; Kinoshita et al., 2023), the prevalence of HPV-independent cases ranged from 7% to 60.0%. Adenocarcinomas and/or adenosquamous carcinomas presented more HPV-independent results than squamous cell carcinoma (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Zhang et al., 2019; Kaliff et al., 2020; Diop-Ndiaye et al., 2021; Ruiz et al., 2021; Kugelman et al., 2022; Kinoshita et al., 2023) (Tables II and III).

Twenty studies presented the FIGO stages (Stolnicu et al., 2018; Chong et al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Zhang et al., 2020; Kaliff et al., 2020; Diop-Ndiaye et al., 2021; Ren et al., 2021; Ruiz et al., 2021; Kugelman et al., 2022; Shi et al., 2022; Stolnicu et al., 2022; Stolnicu et al., 2023), with the majority of HPV-independent cases being in stages I/II (Table II). However, when compared to the HPV-associated group, the HPV-independent group presented more cases with higher FIGO stage (Chong et al., 2018; Stolnicu et al., 2018; Nicolás et al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Hodgson et al., 2020; Jung et al., 2020; Ren et al., 2021; Ruiz et al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Kugelman et al., 2022; Shi et al., 2022) (Table III).

Regarding the prognosis, most of the studies showed that compared to HPV-associated group, the HPV-independent group presented higher rates of recurrence (Chong et al., 2018; Stolnicu et al., 2018; Hodgson et al., 2020; Kaliff et al., 2020; Bulutay et al., 2022; Shi et al., 2022; Stolnicu et al., 2023), metastasis (Nicolás et al., 2019; Jung et al., 2020) and poor survival including worse rates in diseasefree survival, overall survival, relapse-free survival, disease-specific survival or progression-free survival (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Stolnicu et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Stolnicu et al., 2019; Jung et al., 2020; Kaliff et al., 2020; Ren et al., 2021; Ruizet al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Kugelman et al., 2022; Shi et al., 2022; Stolnicu et al., 2022; Lu et al., 2023). On the other hand, 4 studies presented contrary results, with the majority of HPV- independent cases not presenting higher metastasis or recurrence (Stolnicu et al., 2022; Kinoshita et al., 2023), neither worse overall survival rates (Zhang et al., 2019; Ren et al., 2021) (Table II).

Risk of bias of the included studies

Adherence to STROBE recommendations for observational studies is displayed in Figure 2.

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FIGURE 2
Adherence to STROBE recommendations.

Tree studies meet all the criteria and the majority presented a high risk of bias. Detailed risk of bias assessments for the individual studies in table format is available in the supplementary file (Figure S1), also the PRISMA checklist is provided in the Appendix (Table S1).

DISCUSSION

Main findings of the included studies

HPV-independent cervical cancers can be classified into truly negative and false-negative categories. Truly negative cervical cancers exhibit an HPV-independent pathogenesis with specific pathological types, where HPV vaccination and testing are likely to have minimal effect on prevention (Yoshida, Shiraishi, Kato, et al., 2021). For false-negative cervical cancers, retesting using alternative HPV testing methods should be considered based on their specific characteristics after analyzing the reasons for the initial false-negative HPV results. However, in many cases, distinguishing truly negative cervical cancer cases from false-negative ones is challenging due to various factors influencing HPV DNA testing that may go undetected. This hypothesis is supported by the observation that among the studies reviewed in this study, there was significant variation in several parameters including sampling methods, types of HPV DNA tests performed and types and staging of cervical cancer included, as discussed below.

A diverse array of HPV DNA tests were employed by the different studies, with the majority (74.2%) performing at least one PCR-based molecular test (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Wang et al., 2018; Chong et al., 2019; Liu et al., 2019; Nicolás et al., 2019; Zhou et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Liu et al., 2021; Bulutay et al., 2022; Chen et al., 2022a; Kugelman et al., 2022; Stolnicu et al., 2022; Du et al., 2023; Kinoshita et al., 2023; Lu et al., 2023). PCR is known for its flexibility, high sensitivity and ability to conduct multiplex analyses. However, it is crucial to acknowledge that false negative results can occur due to misclassification, specimen inadequacy, sensitivity issues, HPV DNA integration events (resulting in disruption and partial loss of sequences), sequence variability and undetected HPV types (Mühr et al., 2020). Additionally, factors such as DNA fragmentation, DNA-protein crosslinking from formaldehyde exposure and the presence of paraffin can adversely impact the performance of PCR and other HPV DNA tests (Castro et al., 2015). In this context, 13 (41.9%) studies reported using FFPE samples, in which the quality of HPV DNA may be compromised, contributing to the occurrence of falsenegative outcomes (Xing et al., 2020).

It is also important to note that in 32.3% of the studies, ISH was the second most commonly method performed (Stolnicu et al., 2018; Stolnicu et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Ren et al., 2021; Bulutay et al., 2022; Shi et al., 2022; Stolnicu et al., 2022; Lu et al., 2023; Stolnicu et al., 2023).

Finally, to minimize the risk of false-negative results, some authors performed a second molecular HPV DNA test in cases where the first test yielded HPV- negative results, or initially employed two different HPV DNA tests (Rodríguez-Carunchio et al. 2015; Mühr et al. 2020). Among the studies analyzed, 51.9% performed two or more tests to confirm HPV positivity; however, few studies addressed the comparison between the results of the initial test and subsequent sequential tests (Chong et al., 2018; Hallowell et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Hirose et al., 2020; Hodgson et al., 2020; Jenkins et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Bulutay et al., 2022; Kugelman et al., 2022; Stolnicu et al., 2022; Lu et al., 2023). Nevertheless, we recommend that to confirm a case of cervical cancer as truly HPV-independent, it would be advisable to validate HPV DNA-negative results using at least two different tests, preferably PCR-based.

Taken together, the evidence demonstrates that the possibility of false negative results for HPV DNA cannot be excluded in the studies analyzed, due to limitations such as preanalytical procedures, different HPV DNA detection methods and their technical limitations, sampling methods (quality of genetic material), lossof L1 gene, infection by HPV types not covered bythe HPV probes, higher rates of adenocarcinoma and adenosquamous carcinoma, advanced stage and tumors of other origins (Chong et al., 2018; Hallowell et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Diop- Ndiaye et al., 2021; Kugelman et al., 2022). Therefore, we emphasize the importance of recommendations made by other authors (Vassilakos et al., 2017; Xing et al., 2020) regarding the improvement of HPV DNA detection strategies through the development of standardized and high-quality HPV DNA tests, which are crucial for reducing false negativity. Additionally, laboratories performing HPV DNA testing should be accredited by institutions and adhere to international standards.

Main findings of the HPV DNA-negative/ independet cervical cancers

The HPV DNA-negative samples/cases performed 9.2%, ranging 0.1% to 70.8%. However, other studies reported lower rates of HPV DNA-independent cervical cancers, ranging from 5.5% to 11% (Li et al., 2011; Petry et al., 2017; Tjalma, 2018; Xing et al., 2020). Additionally, a significant number of classical and recent publications supported the notion that HPV- independent cervical tumors are very rare (Walboomers et al., 1999; Martel et al., 2020; IARC, 2022). These conflicting rates of HPV DNA-independent cervical cancers can be explained, at least in part, by differences in the HPV DNA test used, sample type and preservation, type of cervical cancer analyzed, geographic location of the studied population, among other factors.

Interestingly, among the 31 manuscripts included, 15 reported over than 20% of HPV- independent tumors (Ibragimova et al., 2018; Chong et al., 2019; Liu et al., 2019; Zhou et al., 2019; Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020; Zhang et al., 2020; Liu et al., 2021; Bulutay et al., 2022; Chen et al., 2022a; Chen et al., 2022b; Shi et al., 2022; Stolnicu et al., 2022; Kinoshita et al., 2023). Furthermore, among these 15 studies, 10 were conducted in Asian countries (Chong et al., 2019; Liu et al., 2019, Zhou et al., 2019, Jung et al., 2020, Zhang et al., 2020; Liu et al., 2021; Chen et al., 2022a; Chen et al., 2022b; Shi et al., 2022; Kinoshita et al., 2023). Several challenges were faced in interpreting the data regarding the potential higher prevalence of HPV DNA-independent cases in this region, including the wide range of sample types and HPV DNA tests performed in the studies, as well as differences in the objectives and types of cervical carcinoma analyzed. Additionally, a relative paucity of available data on clinical and diagnostic information hinders the understanding of HPV- independent cervical cancers. Taken together, this evidence demonstrates the difficulty in suggesting a higher prevalence of HPV-negative cases in Asian countries despite the high rates of HPV DNA negativity observed in this region.

Overall,mostHPVDNA-independent cases presented higher mean age at diagnosis than the HPV- associated ones, in agreement with several previously published data (Hallowell et al., 2018; Ibragimova et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Hodgson et al., 2020; Kaliff et al., 2020; Zhang et al., 2020; Diop-Ndiaye et al., 2021; Ren et al., 2021; Ruiz et al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Kugelman et al., 2022; Shi et al., 2022). Possible answers to this could be as follows: a) Viral vitality is gradually lost during tumor progression, especially in older patients with more time to develop cancer (Xing et al., 2020). b) Elderly patients develop cancer via an HPV-independent mechanism (Jenkins et al., 2021), as seen in vulvar carcinoma (Xing et al., 2020).

Adenocarcinomas and/or adenosquamous carcinomas presented more HPV DNA-independent results than squamous cell carcinoma (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Zhang et al., 2019; Kaliff et al., 2020; Diop-Ndiaye et al., 2021; Ruiz et al., 2021; Kugelman et al., 2022; Kinoshita et al., 2023), in agreement with other studies (Banister et al., 2017; Xing et al., 2020; IARC, 2022; Liu et al., 2022). Finally, the majority of HPV DNA -negative cases were in stages I/II (Stolnicu et al., 2018; Chong et al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Zhang et al., 2020; Kaliff et al., 2020; Diop-Ndiaye et al., 2021; Ren et al., 2021; Ruiz et al., 2021; Kugelman et al., 2022; Shi et al., 2022; Stolnicu et al., 2022; Stolnicu et al., 2023). However, when compared to the HPV- associated group, the HPV DNA-independent group presented more cases with higher FIGO stage (Chong et al., 2018; Stolnicu et al., 2018; Nicolás et al., 2019; Stolnicu et al., 2019; Zhang et al., 2019; Hodgson et al., 2020; Jung et al., 2020; Ren et al., 2021; Ruiz et al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Kugelman et al., 2022; Shi et al., 2022; Lu et al., 2023; Stolnicu et al., 2023). These data support the hypothesis that HPV DNA-independent cases of cervical cancer are predominantly adenocarcinomas and diagnosed at more advanced stages of the disease (Karamurzin et al., 2015; Xing et al., 2020; Yoshida, Shiraishi, Kato, 2021; Lee et al., 2022; Liu et al., 2022).

Regarding the prognosis, most studies showed that the HPV DNA-independent group presented higher rates of recurrence (Chong et al., 2018; Stolnicu et al., 2018; Hodgson et al., 2020; Kaliff et al., 2020; Bulutay et al., 2022; Shi et al., 2022), metastasis (Nicolás et al., 2019; Jung et al., 2020) and poor survival including worse rates in disease-free survival, overall survival, relapse-free survival, disease-specific survival and/ or progression-free survival (Chong et al., 2018; Hallowell et al., 2018; Ibragimova et al., 2018; Stolnicu et al., 2018; Chong et al., 2019; Nicolás et al., 2019; Stolnicu et al., 2019; Jung et al., 2020; Kaliff et al., 2020; Ren et al., 2021; Ruiz et al., 2021; Bulutay et al., 2022; Chen et al., 2022b; Kugelman et al., 2022; Shi et al., 2022; Stolnicu et al., 2022; Lu et al., 2023) than the HPV-associated cancers . This data reinforces previous studies that presented higher recurrence and metastasis taxes (Okuma et al., 2016; Nishio et al., 2019; Park, 2020; Liu et al., 2022), worse prognosis and shorter survival in HPV DNA-independent cervical cancer cases (Karamurzin et al., 2015; Xing et al., 2020; Yoshida, Shiraishi, Kato, 2021; Lee et al., 2022; Liu et al., 2022).

Taken together, the data of the studies reinforce the possibility that HPV-independent cervical cancers represent a distinct clinical entity, with diagnoses at more advanced stages and exhibiting poor clinical outcomes and prognosis. This hypothesis is supported by few recent studies that observed the HPV-independent cervical cancer group exhibiting distinct gene mutations and expressions compared to HPV-associated cancers, including a higher frequency of mutations in the TP53, PIK3CA, KRAS, STK11, PTEN, CDKN2A, ARID1A and GNAS genes (Hodgson et al., 2020; Jenkins et al., 2020; Jung et al., 2020) and lower gene/ protein expression mainly in lncRNA Sra1, miR-200a- 3p, Prame, Hmga2, Mex3a, Tm7sf2, and SLC19A1 (Liu et al., 2019; Liu et al., 2021; Chen et al., 2022a). These findings underscore the critical importance of delineating the genetic signature of HPV-negative cancers in the quest to identify prognostic biomarkers and develop precision-targeted therapies.

Strength and limitations

To our knowledge, this is the most recent systematic review to identify and synthesize the current evidence on the clinical, diagnostic and prognostic of HPV-independent cervical cancers to assist in the formulation of appropriate diagnostic, patient management and treatment strategies. Findings from this review should be viewed in light of its limitations. We did not include conference abstracts, books, reviews and articles published in other languages than English, so our findings may not fully represent the full body of the literature on HPV-independent cervical cancers. Furthermore, the retrospective nature of the included studies may have introduced bias in the results.

Several important gaps in the existing literature were identified in performing this systematic review. One of the core challenges in interpreting the data was the wide range of sample types and HPV DNA tests performed in the studies, as well as differences in the objectives and types of cervical carcinoma analyzed. This is particularly important as it makes difficult to distinguish truly negative cervical cancer cases from false-negative ones. Furthermore, a relative shortage of available data on clinical and diagnostic information to improve the understanding of HPV-independent cervical cancers was observed. Taken together, this evidence demonstrates the importance of developing new, more comprehensive and controlled studies to clarify the HPV-independent cervical cancers field.

CONCLUSION

This systematic review aimed to provide an overview of the current status of HPV-independent cervical cancers from clinical, diagnostic and prognostic perspectives to identify research gaps and aid in developing appropriate patient diagnosis, managementandtreatmentstrategies. Themainfindings reinforce that the cases of HPV DNA-independent cervical cancer have different characteristics from HPV DNA-positive, such as higher association with adenocarcinomas, diagnosis at more advanced stages, poor clinical and prognosis outcomes. In this way, understanding the HPV status at the time of diagnosis can assist in the prognosis and enhance management plans for HPV DNA-independent patients. However, several challenges in interpreting the data were observed including the wide range of types of samples and HPV DNA tests performed in the studies, as well as the differences in the objectives and types of cervical carcinoma analyzed. Furthermore, a relative paucity of available data on clinical and diagnostic information to improve the understanding of HPV- independent cervical cancers was observed. Taken together, this evidence demonstrates the difficulty to distinguish truly negative cervical cancer cases from false-negative ones. Also, the importance of developing new, more comprehensive and controlled studies to clarify the HPV-independent cervical cancers field.

DATA AVAILABILITY STATEMENT

Not Informed.

ACKNOWLEDGEMENT

This study was granted by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes), Brazilian Government, Grant/Award: fellowships.

Supplementary Materials

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FIGURE S1 - Adherence to STROBE recommendations table format.

TABLE S1

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PRISMA 2020 Checklist

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Edited by

  • Associated Editor:
    Silvya Stuchi Maria-Engler

Publication Dates

  • Publication in this collection
    12 Jan 2026
  • Date of issue
    2025

History

  • Received
    05 Aug 2024
  • Accepted
    03 Oct 2024
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