Prognostic Value and Stage/Nodal Correlates of Serum and Salivary CRP, CYFRA 21-1, and SCC-Ag Biomarkers in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis
5 affiliations
- 1Department of Dentistry, Komar University of Science and Technology, Sulaimani 46001, Iraq.
- 2Bio-Cultural Anthropology, Law, Ethics and Health Laboratory (ADES), Faculty of Medical and Paramedical Sciences, Aix-Marseille University, French National Center of Scientific Research (CNRS), French Blood Establishment (EFS), 13005 Marseille, France.
- 3College of Medicine, Sulaymaniyah University, Sulaymaniyah 46001, Iraq.
- 4Health Systemic Process (P2S) UR4129, Université Lyon 1, 69008 Lyon, France.
- 5Department of Oral Surgery, Timone Hospital, Assistance Publique-Hôpitaux de Marseille, 13385 Marseille, France.
Abstract
Background: Oral squamous cell carcinoma (OSCC) has a relatively poor survival, and TNM staging alone offers limited prognostic discrimination. C-reactive protein (CRP) is a non-specific inflammatory marker and is one of the most studied candidate prognostic biomarkers of OSCC, while CYFRA 21-1 and squamous cell carcinoma antigen (SCC-Ag) are tumor-derived keratin proteins reflecting malignant cell turnover, often examined alongside CRP. However, no prior review has synthesized the value of these three markers together in OSCC. Methods: Following the PRISMA 2020 guidelines, PubMed, Embase, and Web of Science were searched for studies reporting an extractable hazard ratio (HR), odds ratio, or comparable association of serum and/or salivary CYFRA 21-1, SCC-Ag, and/or CRP with disease-free survival (DFS), recurrence, or overall survival (OS) in OSCC. HRs were pooled using Knapp-Hartung random-effects models, wherever at least two independent cohorts contributed; salivary CYFRA 21-1 and recurrence were pooled as a standardized mean difference (SMD). Studies reporting only cross-sectional associations with tumor stage, grade, or metastasis and non-independent (same-registry) studies were synthesized descriptively following Synthesis without Meta-analysis (SWiM) guidance. Risk of bias was assessed with QUIPS and certainty of evidence with the GRADE framework. Results: Twenty-eight studies were included (21 quantitative, 7 narrative), representing ~3500 study participants across published cohorts, with some overlap between studies. For OS, two independently pooled single-marker estimates were both non-significant: serum SCC-Ag alone (n = 2, HR 1.43, 95% CI: 0.09-23.14, p = 0.35, I² = 66%) and serum CRP alone (n = 5, HR 1.33, 95% CI: 0.89-1.99, I² = 52%). A further seven non-independent, same-registry studies reporting combined SCC-Ag + CRP or single-marker models ranged from HR 1.82 to 11.11, directionally consistent with the pooled estimates. For DFS, pooled serum CYFRA 21-1 alone gave HR 1.61 (95% CI: 0.39-6.61; p = 0.15, I² = 0%), with six further non-independent or single-study estimates (HR 1.38-4.05) in the same direction. For recurrence, pooled salivary CYFRA 21-1 gave an SMD of Hedges' g = 0.79 (95% CI: 0.04-1.55; p = 0.048, I² = 0%). All outcomes were rated very low certainty by GRADE. Conclusions: Within the limitations of the study and the small number of contributing studies, salivary CYFRA 21-1 showed some prognostic value for recurrence, while pooled estimates for serum CRP alone, serum SCC-Ag alone, and serum CYFRA 21-1 alone for DFS all trended toward increased risk but did not reach statistical significance. Given the very low evidence certainty, these findings are hypothesis-generating and require further validation in independent, multicenter, prospective cohorts before clinical application.
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BibTeX
@article{qadir2026prognostic,
title = {{Prognostic Value and Stage/Nodal Correlates of Serum and Salivary CRP, CYFRA 21-1, and SCC-Ag Biomarkers in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis}},
author = {Balen Hamid Qadir and Mohammed Khalid Mahmood and Hazha Abdulla Mohammed Ameen and Yad Mariwan Mohammed Amin and Ariwan Othman Saeed and Florence Carrouel and Romain Lan},
journal = {Medical Sciences},
year = {2026},
month = sep,
doi = {10.3390/medsci14060610},
url = {https://hal.science/hal-05766304v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Prognostic Value and Stage/Nodal Correlates of Serum and Salivary CRP, CYFRA 21-1, and SCC-Ag Biomarkers in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis
AU - Balen Hamid Qadir
AU - Mohammed Khalid Mahmood
AU - Hazha Abdulla Mohammed Ameen
AU - Yad Mariwan Mohammed Amin
AU - Ariwan Othman Saeed
AU - Florence Carrouel
AU - Romain Lan
PY - 2026
DA - 2026/09/27
JO - Medical Sciences
DO - 10.3390/medsci14060610
UR - https://hal.science/hal-05766304v1
AB - Background: Oral squamous cell carcinoma (OSCC) has a relatively poor survival, and TNM staging alone offers limited prognostic discrimination. C-reactive protein (CRP) is a non-specific inflammatory marker and is one of the most studied candidate prognostic biomarkers of OSCC, while CYFRA 21-1 and squamous cell carcinoma antigen (SCC-Ag) are tumor-derived keratin proteins reflecting malignant cell turnover, often examined alongside CRP. However, no prior review has synthesized the value of these three markers together in OSCC. Methods: Following the PRISMA 2020 guidelines, PubMed, Embase, and Web of Science were searched for studies reporting an extractable hazard ratio (HR), odds ratio, or comparable association of serum and/or salivary CYFRA 21-1, SCC-Ag, and/or CRP with disease-free survival (DFS), recurrence, or overall survival (OS) in OSCC. HRs were pooled using Knapp-Hartung random-effects models, wherever at least two independent cohorts contributed; salivary CYFRA 21-1 and recurrence were pooled as a standardized mean difference (SMD). Studies reporting only cross-sectional associations with tumor stage, grade, or metastasis and non-independent (same-registry) studies were synthesized descriptively following Synthesis without Meta-analysis (SWiM) guidance. Risk of bias was assessed with QUIPS and certainty of evidence with the GRADE framework. Results: Twenty-eight studies were included (21 quantitative, 7 narrative), representing ~3500 study participants across published cohorts, with some overlap between studies. For OS, two independently pooled single-marker estimates were both non-significant: serum SCC-Ag alone (n = 2, HR 1.43, 95% CI: 0.09-23.14, p = 0.35, I² = 66%) and serum CRP alone (n = 5, HR 1.33, 95% CI: 0.89-1.99, I² = 52%). A further seven non-independent, same-registry studies reporting combined SCC-Ag + CRP or single-marker models ranged from HR 1.82 to 11.11, directionally consistent with the pooled estimates. For DFS, pooled serum CYFRA 21-1 alone gave HR 1.61 (95% CI: 0.39-6.61; p = 0.15, I² = 0%), with six further non-independent or single-study estimates (HR 1.38-4.05) in the same direction. For recurrence, pooled salivary CYFRA 21-1 gave an SMD of Hedges' g = 0.79 (95% CI: 0.04-1.55; p = 0.048, I² = 0%). All outcomes were rated very low certainty by GRADE. Conclusions: Within the limitations of the study and the small number of contributing studies, salivary CYFRA 21-1 showed some prognostic value for recurrence, while pooled estimates for serum CRP alone, serum SCC-Ag alone, and serum CYFRA 21-1 alone for DFS all trended toward increased risk but did not reach statistical significance. Given the very low evidence certainty, these findings are hypothesis-generating and require further validation in independent, multicenter, prospective cohorts before clinical application.
SN - 2076-3271
ER -