Salivary cytokines as biomarkers of oral cancer: a systematic review and meta-analysis

Abstract

Background Oral cancer (OC) is usually diagnosed at advanced clinical stages due to its asymptomatic nature and absence of pathognomonic signs in its early development phase. Delayed diagnosis is one of the major causes of OC treatment failure and poor prognosis. Development of alternative diagnostic approaches are imperative for improving early detection and therapeutic success rates. Salivary cytokines (SC) have been studied as potential diagnostic biomarkers for OC and may represent a potential tool for improvement of its early detection. Methods In this systematic review and meta-analysis we identified SC studied as OC biomarkers by systematically reviewing the PubMed and Cochrane Library databases using the terms: “oral cancer”, “cytokine”, and “saliva”, and also combined with “interleukin” or “interferon”. Only case-control studies that measured SC by ELISA from treatment naïve patients were included in the qualitative review. For the meta-analysis were included all comparable studies that provided enough data (sample size, mean and standard deviation or standard error of the mean) for SC levels in OC patients, non-cancer controls and patients with oral potentially malignant disorders (OPMD), including leukoplakia. Comparisons with patients with oral lichen planus (OLP) and gingivitis were included in the qualitative analysis. Results A total of 28 articles (from 2004 to 2018) were included in the systematic review, describing 10 different SC, being IL-8 and IL-6 the most studied ones. SC levels were consistently higher among OC patients when compared to healthy controls and to patients with OPMD, OLP and gingivitis. Meta-analysis including 23 eligible studies showed that IL-8, IL-6, TNF-α, IL-1β and IL-10 salivary levels were significantly higher in OC patients compared to controls; and that IL-8, IL-6, TNF-α and IL-1β salivary levels were also higher in OC patients compared to individuals with OPMD. When compared to healthy controls, OPMD patients showed significantly higher IL-6 and TNF-α salivary levels. Conclusions Our analyses showed that the salivary levels of some cytokines are consistently different among OC, OPMD and healthy patients, indicating that these SC may represent potential diagnostic biomarkers for OC and OPMD. Despite of that, SC levels were highly variable among studies, suggesting that further technical improvement and standardization for SC measurement by ELISA is needed in order to successfully translate these biomarkers to the clinical practice.

Saliva and Serum Cytokine Profiles During Oral Ulceration in Behçet’s Disease

“…In Marques, et al's study, they found an increase in IFN-g, IL-10, IL-17, IL-1b, IL-6, and IL-4 in SLE patients without periodontal disease compared to HC (136). Also in a meta-analysis, IL-8, IL-1b, TNF-a, IL-6, and IL-1a were found to be increased in oral cancer compared to HC and leukoplakia and were suggested as cancer biomarkers (137) In our study, the significant differences between HC and BD-MQ is an important finding to be able to differentiate the levels of cytokines present in "normal" saliva content and orally asymptomatic BD patients saliva. Increased detection of IL-8, IL-1b, and TNF-a may not be specific to BD for diagnostics, but can still be useful to monitor the level of oral inflammation in order to deter further ulcerations, and potentially, accompanying systemic manifestations.…”

Characterization of Oral Squamous Cell Carcinoma Associated Inflammation: A Pilot Study

“…Several studies have evaluated blood and saliva cytokines in head and neck squamous cell carcinomas. Recent studies found different salivary levels of some cytokines among oral cancer, OPMD, and healthy patients, suggesting these cytokines as potential diagnostic biomarkers for oral cancer and OPMD [ 12 ]. Rhodus et al studied levels of proinflammatory, angiogenic, NF-kB dependant cytokines IL-1, IL-6, IL-8, and TNF-a in whole stimulated saliva and showed that these were significantly elevated in OSCC patients compared to subjects with oral premalignant disorders (OPMD) and controls [ 13 ].…”

Salivary Cytokines as Biomarkers for Oral Squamous Cell Carcinoma: A Systematic Review

“…In recent times, several reviews, which summarize and analyze the evidence of salivary cytokines as potential OSCC biomarkers, have been published [26,60,61]. The most distinguishing aspects that differentiate the present review from those works are: (1) the inclusion of longitudinal prospective studies, in which subjects are followed over time with repeated cytokine level monitoring; (2) the inclusion of studies investigating the cytokine level discriminatory power to distinguish early from advanced OSCC stages; and (3) the inclusion of several studies that use multiplex immunoassays to simultaneously quantify several salivary cytokines and chemokines.…”