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.

Keywords: Biomarkers; Cytokines; Head and neck cancer; Oral cancer; Saliva.

Fig. 1

PRISMA flow diagram of study selection process (Moher, Liberati, Tetzlaff, Altman, & PRISMA Group, 2009)

Fig. 2

Sample size distribution among the investigated studies according to: A) Salivary cytokines assessed. IL-8, IL-6, TNFα and IL-1β were the cytokines investigated in the biggest number of patients; B) Patient clinical groups (OC = Oral Cancer; Control = healthy individuals; OPMD = Oral Potentially Malignant Disorders, OLP = Oral Lichen Planus). Healthy patients were the most numerous among control groups, followed by individuals with OPMD; C) Salivary cytokines assessed per each patient clinical group

Fig. 3

Random-effects meta-analysis of the salivary cytokine levels in oral cancer patients in comparison to healthy controls (SMD = 0)

Fig. 4

Random-effects meta-analysis of salivary cytokine levels in patients with oral potentially malignant disorders (OPMD) in comparison to healthy controls (a) and in patients with oral cancer in comparison to individuals with OPMD (b). In both cases, SMD = 0 for the second group referred