A Commentary on

Piyarathne N S, Rasnayake R M S G K, Angammana R et al.

Diagnostic salivary biomarkers in oral cancer and oral potentially malignant disorders and their relationships to risk factors - A systematic review. Expert Rev Mol Diagn 2021; 21: 789-807.

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Commentary

Despite numerous efforts to improve its diagnosis and management, oral cancer remains a substantial public health concern, with lip and oral cavity cancer ranking the sixteenth most common type of cancer in the global cancer statistics in 2020.1 Oral cancers typically have a poor prognosis following diagnosis with reported five-year survival rates of less than 50%.2 Prognosis is dependent on the stage at diagnosis, and early detection has been associated with reduced mortality and a better quality of life. This systematic review attempts to identify a suitable biomarker panel for screening and early detection of oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs), and to study the relationship between salivary biomarkers and risk factors for these diseases.

In this review, the authors followed the PRISMA guidelines and clearly identified the data parameters assessed. The literature search was found to be adequate as four electronic databases (Medline [OVID], Web of Science, Embase and Scopus) were explored. However, grey literature was not included and the search was limited to the English language, meaning relevant studies in other languages may have been missed.

In total, 346 articles were divided between four pairs of trained blinded reviewers for screening of the full text. Disagreements within each pair were resolved by discussion or through involvement of a third reviewer. There was no statistical measurement of inter-reviewer agreement. Overall, 295 articles fulfilled the selection criteria and were included in the final study. There was a variation in the sample sizes of individual studies, ranging from 18-300. The studies assessing interleukins as potential biomarkers for OSCC and OPMDs (28 studies) were published between 2004 and 2020. The years of publication were not clearly stated for studies assessing the relationship of salivary biomarkers and risk factors for OSCC and OPMDs (33 studies). The risk factors assessed included smoking, alcohol, betel quid chewing, viral infections, periodontitis, body mass index, education level, mitochondrial DNA, SLPI protein, mouthwash use and oral health status.

Statistical significance was measured using P values and area under curve (AUC). The results were presented in a narrative format and results of individual studies were provided in tables. Quality assessment was carried out and risk of bias was evaluated using the Newcastle-Ottawa Scale.

Of the studies assessing for potential biomarkers, 52% reported protein biomarkers and thus these were chosen for further analysis. Among proteins, interleukins were chosen by the reviewers as appropriate biomarkers to study. Twenty-eight applicable articles out of 295 were found, and these were all case-control studies. The majority of these were considered to be of fair quality. Interestingly, two of these studies did not include OSCC. From the data reported, IL1β, IL6 and IL8 were identified as being statistically significant and most suitable for early identification of OSCC and OPMDs.

Thirty-three out of 295 articles were found to assess the relationships between biomarkers (including proteins, DNA, RNA, metabolites and microbials) in saliva and risk factors in OSCC and OPMDs. The majority of these were case-control studies and were of fair quality. In smokers, there were statistically significant differences in epidermal growth factor (EGF), loss of heterozygosity (LOH), secretory leucocyte protease inhibitor (SLPI), IL-10, hypermethylation of the promoter region of MGMT gene, and macrophage migration inhibitor factor (MIF) in comparison to former smokers and non-smokers. All biomarkers assessed for the potential association with alcohol (13 studies) and other risk factors showed statistically non-significant relationships.

As the authors have stated, one important limitation of this study is the absence of a meta-analysis. Significant differences were reported in IL1β, IL6 and IL8 levels in OSCC and OPMDs compared to controls. The authors have suggested that these biomarkers used in combination have a high predictive power for OSCC and OPMDs.

It can be summarised that these group of interleukins are strongly associated with OSCC and OPMDs; however, interleukins have a diverse role in inflammation and there are questions regarding their specificity. Therefore, further research is required to assess the specificity of these biomarkers and the usefulness of their application in a clinical setting. Additionally, more research is required to understand the association between biomarkers and risk factors, and the role of biomarkers in the progression of these diseases.