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This narrative review synthesizes evidence on cervicovaginal cytology and molecular analysis of Pap test material, highlighting limited cytologic sensitivity but meaningful predictive cytologic patterns and emerging tumor-derived DNA and multi-omic biomarkers. 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Published by MDPI on behalf of the Lithuanian University of Health Sciences. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Department of Gynaecological and Breast Oncology, University Medical Centre Maribor, 2000 Maribor, Slovenia; [leylaalmahdawi@ukc-mb.si](leylaalmahdawi@ukc-mb.si) (L.A.M.); [maja.pakiz@ukc-mb.si](maja.pakiz@ukc-mb.si) (M.P.); [jure.knez@ukc-mb.si](jure.knez@ukc-mb.si) (J.K.); [andraz.dovnik@ukc-mb.si](andraz.dovnik@ukc-mb.si) (A.D.)  \n2 Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia  \n3 Department of Life Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; [mludovisi@gmail.com](mludovisi@gmail.com)  \n* Correspondence: [andrej.cokan@ukc-mb.si](andrej.cokan@ukc-mb.si)[ ](andrej.cokan@ukc-mb.si)† These authors contributed equally to this work.  \nAbstract  \nThe Papanicolaou (Pap) smear, a cornerstone of cervical cancer prevention, has emerged as a compelling, though unconventional, biospecimen for the detection of ovarian cancer (OC) . This structured narrative review synthesizes the evolving evidence on the utility of cervicovaginal cytology and molecular analysis of Pap test material for OC detection. While conventional cytology provides a proof of concept, its sensitivity is low, ranging from incidental detection of OC in 0.004% of routine screens to 19.3% in patients with known OC. Specific cytologic findings, however, carry significant predictive value: atypical glandular cells (AGC) confer a two-fold increased OC risk, and psammoma bodies (PB) are strongly associated with serous malignancies. Driven by the sensitivity limitations of morphology, the field has undergone a paradigm shift towards molecular detection. Foundational studies confirmed tumor-derived DNA, including hallmark TP53 mutations, is detectable in Pap samples years before diagnosis, though sensitivity is constrained by low DNA abundance and confounded by background clonal mutations. To overcome this, strategies have expanded to target broader genomic signatures, such as somatic copy number alterations (EVA test: 75% sensitivity, 96% specificity), and multi-gene mutation panels (PapSEEK: 33–45% sensitivity) . The most promising advances lie in multi-omic approaches, particularly DNA methylation biomarkers, which have demonstrated sensitivities up to 81% with high specificity. Collectively, this evidence argues against repurposing the Pap test as a standalone OC screen but supports its strategic integration into a risk-stratified clinical algorithm. We propose a “reflex-to-molecular” model where high-risk cytology (e.g., AGC, PB) automatically triggers advanced molecular testing on the same sample. This model efficiently leverages existing infrastructure to triage high-risk women for definitive diagnostics. Prospective validation of this integrated approach is the essential nextstep toward transforming this test into a sentinel for malignancies of the upper female reproductive tract.  \nKeywords: cervicovaginal cytology; DNA methylation; molecular biomarkers; liquid biopsy; early detection  \n1. Introduction  \nOvarian cancer (OC) remains one of the most lethal gynecologic malignancies, with an estimated 324,398 new cases and 206,839 deaths worldwide in 2022, reflecting a persistently high mortality-to-incidence ratio [1] . Notably, both incidence and mortality show marked geographic and socioeconomic disparities, with higher mortality rates o","cbCaic4Ya2whEtIi","https://ap.wps.com/l/cbCaic4Ya2whEtIi","pdf",893265,17,"English","# Introduction\n## Ovarian cancer burden and geographic disparities\n## Limits of population-wide screening and prevention\n## Rationale for the Papanicolaou (Pap) smear in OC detection","[{\"question\":\"Why is the Pap smear considered a potential tool for ovarian cancer detection?\",\"answer\":\"Exfoliated cells and biomolecules from the fallopian tubes, endometrium, and ovaries may be captured in Pap test material, enabling detection of cellular or molecular signatures relevant to OC.\"},{\"question\":\"What are the limitations of conventional cytology for ovarian cancer detection?\",\"answer\":\"Conventional cytology shows low sensitivity, ranging from incidental detection in routine screens to higher rates in patients with known OC.\"},{\"question\":\"How does molecular testing address cytology sensitivity constraints?\",\"answer\":\"Molecular approaches detect tumor-derived DNA and broader genomic signatures, and multi-omic biomarkers such as DNA methylation can achieve higher sensitivities with strong specificity. The review supports integrating these methods into a reflex-to-molecular model for high-risk cytology findings.\"}]","The Papanicolaou Smear Reimagined - A Narrative Review of Cervicovaginal Cytology and Molecular Biospecimens for Ovarian Cancer Detection | PDF",1790109612,43]