Non-invasive biomarkers of oral and oropharyngeal squamous cell carcinoma: a quantitative synthesis of data on diagnostic and prognostic value

Relevance . The high incidence of and mortality from oral and oropharyngeal squamous cell carcinoma, together with the limitations of conventional diagnostic and surveillance methods, highlight the need for objective, non-invasive, and accessible biomarkers for early detection and prognostic assessment. Objective . To systematically review and quantitatively assess the diagnostic and prognostic value of non-invasive biomarkers for oral squamous cell carcinoma (OSCC) and human papillomavirus (HPV)-associated oropharyngeal cancer, and to evaluate the quality of the available studies. Materials and methods . The review was conducted in accordance with the PRISMA 2020 reporting guidelines, published in 2021. PubMed/MEDLINE, eLibrary, CyberLeninka, and Google Scholar were searched for publications dated January 1, 2021, through April 5, 2026, using combinations of Russian and English keywords, including Medical Subject Headings (MeSH). Eligible human studies included patients with histologically confirmed OSCC or HPV-associated oropharyngeal cancer, patients with precancerous lesions (leukoplakia or erythroplakia), or healthy controls; assessed biomarkers in saliva, oral fluid, plasma, or serum; and reported quantitative measures of diagnostic accuracy (sensitivity, specificity, or area under the receiver operating characteristic curve [AUC]) or prognostic performance (hazard ratio [HR], positive predictive value [PPV], or negative predictive value [NPV]). Study quality was assessed using QUADAS-2 and the Newcastle–Ottawa Scale. Two reviewers independently performed study selection and data extraction. Results . Seven studies of high or moderate quality, with sample sizes ranging from 48 to 1,076 participants, were included. Salivary podoplanin differentiated OSCC from leukoplakia and healthy controls with an AUC of 0.987, a sensitivity of 93.3%, and a specificity of 95%. p16 immunohistochemistry identified transcriptionally active HPV with a sensitivity of 95.9% and a specificity of 90.5%, using HPV messenger RNA as the reference standard. Salivary CD44 and total protein were predictors of recurrence (adjusted HRs of 1.13 and 3.51, respectively). In one study, plasma tumor tissue-modified viral HPV DNA (TTMV-HPV DNA) testing yielded a PPV and NPV of 95% each. In another study, sensitivity was 73%, specificity was 98%, and the HR was 75. Rising anti-E7 antibody titers predicted death or recurrence with a specificity of 100% and a sensitivity of 36%. PCR-based detection of HPV-16 DNA in plasma and saliva yielded a sensitivity of 65%, a specificity of 87%, and an HR of 13.15. Conclusion . The biomarkers assessed, including podoplanin, CD44, TTMV-HPV DNA, anti-E7 antibodies, and p16, have high diagnostic and prognostic value. Particularly promising results were reported for TTMV-HPV DNA testing in recurrence surveillance, with PPV reaching 95% and NPV reaching 97%, and for podoplanin in early diagnosis, with an AUC exceeding 0.97. However, large prospective studies are needed to standardize cutoffs, validate these tests in routine clinical practice, and assess their impact on survival before they can be incorporated into clinical guidelines.