Salivary and Serum Interleukin-6 Levels in Oral Premalignant Disorders and Squamous Cell Carcinoma: Diagnostic Value and Clinicopathologic Correlations

  • Dineshkumar, Thayalan (SRM Dental College and Hospitals) ;
  • Ashwini, Balakuntla Krishnamurthy (Department of Oral and Maxillofacial Pathology, AECS Maaruti College of Dental Sciences and Research Centre) ;
  • Rameshkumar, Annasamy (Department of Oral and Maxillofacial Pathology, SRM Dental College, SRM University) ;
  • Rajashree, Padmanaban (National Centre for Nanoscience and Nanotechnology (NCNSNT), University of Madras, Guindy Campus) ;
  • Ramya, Ramadas (Department of Oral and Maxillofacial Pathology, SRM Dental College, SRM University) ;
  • Rajkumar, Krishnan (Department of Oral and Maxillofacial Pathology, SRM Dental College, SRM University)
  • Published : 2016.11.01


Aim: To assess the diagnostic utility of serum and salivary interleukin 6 (IL-6) levels in the differential diagnosis of potentially malignant lesions and conditions (PMLs/PMCs) and oral squamous cell carcinoma (OSCC) in a high oral cancer prevalence region. Methods: After appropriate ethical clearance and informed consent, salivary and blood samples were collected from 100 participants in each group (OSCC, PMLs, and healthy controls). Serum and salivary IL-6 levels were measured by enzyme-linked immunosorbent assay and data were subjected to appropriate statistical analysis. Results: Significant differences in IL-6 concentration were noted between OSCC and PML/C patients in both serum and saliva, with salivary levels being 2 to 3 fold higher than serum values in all the groups. Receiver operating characteristic curve analysis demonstrated 96% specificity and 99% sensitivity for salivary IL-6 in differentiating PML from OSCC. Conclusions: The results of the present study suggest that the pro-inflammatory cytokine, IL-6, is elevated in the saliva of patients with OSSC compared to PMD and controls, and thus may prove to have diagnostic and/or prognostic significance.


  1. Bharadwaj U, Li M, Zhang R, Chen C, Yao Q (2007). Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation. Cancer Res, 67, 5479-88.
  2. Brailo V, Vucicevic-Boras V, Cekic-Arambasin A, et al (2006). The significance of salivary interleukin 6 and tumor necrosis factor alpha in patients with oral leukoplakia. Oral Oncol 42, 370-3.
  3. Chang KP, Kao HK, Wu CC, et al (2013). Pretreatment interleukin-6 serum levels are associated with patient survival for oral cavity squamous cell carcinoma. Otolaryngol Head Neck Surg, 148, 786-91.
  4. Chen CJ, Sung WW, Lin YM, et al (2012). Gender difference in the prognostic role of interleukin 6 in oral squamous cell carcinoma. PLoS One, 7, 50104.
  5. Chiu YH, Spiegelman D, Dockery DW, et al (2011). Secondhand smoke exposure and inflammatory markers in nonsmokers in the trucking industry. Environ Health Perspect, 119, 1294-300.
  6. Dikshit R, Gupta PC, Ramasundarahettige C, et al (2012). Cancer mortality in India: a nationally representative survey. Lancet 379, 1807-16.
  7. Duffy SA, Taylor JM, Terrell JE, et al (2008). Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer, 113, 750-7.
  8. Eskinazi DP, Perna JJ, Mihail R (1987). Mononuclear cell subsets in patients with oral cancer. Cancer, 60, 376-81.<376::AID-CNCR2820600315>3.0.CO;2-B
  9. Ewa J, Leszek P, Zyta G (1997). Serum levels of IL-$1{\beta}$, IL-6, TNF-$\alpha$, sTNFR1 and CRP in patients with oral cavity cancer. Pathol Oncol Res, 3, 126-9.
  10. Ferlay J, Soerjomataram I, Ervik M, et al (2012).GLOBOCAN v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from:, accessed on 05/08/2015.
  11. Hockertz S, Emmendorffer A, Scherer G, et al (1994). Acute effects of smoking and high experimental exposure to environmental tobacco smoke (ETS) on the immune system. Cell Biol Toxicol, 10, 177-90.
  12. Kim HK, Song KS, Park YS, et al (2003). Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor. Eur J Cancer, 39, 184-91.
  13. Kross KW, Heimdal JH, Olsnes C, Olofsson J, Aarstad HJ (2005). Head and neck squamous cell carcinoma spheroid- and monocyte spheroid-stimulated IL-6 and monocyte chemotactic protein-1 secretion are related to TNM stage, inflammatory state and tumor macrophage density. Acta Otolaryngol, 125, 1097-104.
  14. Kross KW, Heimdal JH, Olsnes C, Olofsson J, Aarstad HJ (2007). Tumour-associated macrophages secrete IL-6 and MCP-1 in head and neck squamous cell carcinoma tissue. Acta Otolaryngol, 127, 532-9.
  15. Lam-ubol A, Hopkin D, Letuchy EM, et al (2010). Squamous carcinoma cells influence monocyte phenotype and suppress lipopolysaccharide-induced TNF-alpha in monocytes. Inflammation, 33, 207-23.
  16. Lederle W, Depner S, Schnur S, et al (2011). IL-6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines. Int J Cancer, 128, 2803-14.
  17. Lippitz BE (2013). Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol, 14, 218-28.
  18. Lisa Cheng YS, Jordan L, Gorugantula LM, et al (2014). Salivary interleukin-6 and -8 in patients with oral cancer and patients with chronic oral inflammatory diseases. J Periodontol, 85, 956-65.
  19. Maccio A, Madeddu C (2013). The role of interleukin-6 in the evolution of ovarian cancer: clinical and prognostic implications - a review. J Mol Med (Berl), 91, 1355-68.
  20. Menetrier-Caux C, Montmain G, Dieu MC, et al (1998). Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood, 92, 4778-91.
  21. Ohishi W, Cologne JB, Fujiwara S, et al (2014). Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study. Int J Cancer, 134, 154-63.
  22. Panneer Selvam N, Sadaksharam J (2015). Salivary interleukin-6 in the detection of oral cancer and precancer. Asia Pac J Clin Oncol, 11, 236-41.
  23. Rajkumar K, Dineshkumar T, Rajashree P, et al (2014). Association of serum and salivary tumor necrosis factor-$\alpha$ with histological grading in oral cancer and its role in differentiating premalignant and malignant oral disease. Asian Pac J Cancer Prev, 15, 7141-48
  24. Rhodus NL, Ho V, Miller CS, Myers S, Ondrey F (2005). NF-kappaB dependent cytokine levels in saliva of patients with oral preneoplastic lesions and oral squamous cell carcinoma. Cancer Detect Prev, 29, 42-5.
  25. Rose-John S, Scheller J, Elson G, Jones SA (2006). Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80, 227-36.
  26. Singh PK, Chandra G, Bogra J, et al (2015). Association of interleukin-6 genetic polymorphisms with risk of OSCC in Indian population. Meta Gene, 15, 142-51.
  27. St John MA, Li Y, Zhou X, Denny P, Ho CM, Montemagno C et al (2004), Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg, 130, 929-35.
  28. Sugiyama H, Inoue K, Ogawa H, et al (1996). The expression of IL-6 and its related genes in acute leukemia. Leuk Lymphoma, 21, 49-52.
  29. Tripsianis G, Papadopoulou E, Anagnostopoulos K, et al (1996). Coexpression of IL-6 and TNF-alpha: prognostic significance on breast cancer outcome. Neoplasma, 61, 205-12.
  30. Tsantoulis PK, Kastrinakis NG, Tourvas AD, Laskaris G, Gorgoulis VG (2007). Advances in the biology of oral cancer. Oral Oncol, 43, 523-34.
  31. Van Tubergen E, Vander Broek R, Lee J, et al (2011). Tristetraprolin regulates interleukin-6, which is correlated with tumor progression in patients with head and neck squamous cell carcinoma. Cancer, 117, 2677-89.
  32. Vucicevic Boras V, Cikes N, Lukac J, Virag M, Cekic-Arambasin A (2005). Salivary and serum interleukin 6 and basic fibroblast growth factor levels in patients with oral squamous cell carcinoma. Minerva Stomatol, 54, 569-73.
  33. Warnakulasuriya S (2009). Global epidemiology of oral and oropharyngeal cancer. Oral Oncol, 45, 309-16.