Skip to main content

Advertisement

SpringerLink
Log in

Salivary and serum interleukin-6 levels in proliferative verrucous leukoplakia

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Background

Cytokines and chemokines have been analysed in patients with oral squamous cell carcinoma and potentially malignant disorders. We selected interleukin-6 (IL-6) because it is a multifunctional interleukin reported to be altered in potentially malignant oral disorders and in malignant lesions. To date, this has not been evaluated or tested in proliferative verrucous leukoplakia (PVL), however.

Objectives

This study aimed to analyse the differences in serum and saliva IL-6 levels among patients with PVL, oral squamous cell carcinoma (OSCC) and healthy controls and to examine the relationship between salivary IL-6 levels and the extent of the verrucous area.

Methods

Using an enzyme-linked immunosorbent assay, we determined the serum and saliva IL-6 levels in three groups: 20 patients with PVL, 20 with OSCC and 20 healthy controls.

Results

There were significant (p < 0.01) differences in the serum and saliva IL-6 levels among the three groups and among the three grades of extent of the verrucous areas (p = 0.01). In the OSCC group, there was a significant difference in the saliva IL-6 levels between patients with and without lymph node metastasis at diagnosis (p = 0.02).

Conclusions

We found that patients with OSCC had the highest salivary and serum IL-6 levels, while PVL had lower values than OSCC, but higher than the controls, and these altered levels were associated with the extent of the verrucous areas.

Clinical relevance

Salivary and plasma IL-6 are altered in patients with PVL, with more extensive verrucous areas being associated to the highest IL-6 levels. This could be a significant tool for monitoring patients with PVL, their progression to more advances stages and their recurrences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Hansen LS, Olson JA, Silverman S Jr (1985) Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol 60:285–298

    Article  PubMed  Google Scholar 

  2. Silverman S Jr, Gorsky M (1997) Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84(2):154–157

    Article  PubMed  Google Scholar 

  3. Gandolfo S, Castellani R, Pentenero M (2009) Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol 80:274–281

    Article  PubMed  Google Scholar 

  4. Bagán JV, Murillo J, Poveda R, Gavaldá C, Jiménez Y, Scully C (2004) Proliferative verrucous leukoplakia: unusual locations of oral squamous cell carcinomas, and field cancerization as shown by the appearance of multiple OSCCs. Oral Oncol 40:440–443

    Article  PubMed  Google Scholar 

  5. Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, Scully C (2003) Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med 32:379–382

    Article  PubMed  Google Scholar 

  6. Pentenero M, Meleti M, Vescovi P, Gandolfo S (2014) Oral proliferative verrucous leukoplakia: are there particular features for such an ambiguous entity? A systematic review. Br J Dermatol 170:1039–47

    Article  PubMed  Google Scholar 

  7. Zakrzewska JM, Lopes V, Speight P, Hopper C (1996) Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:396–401

    Article  PubMed  Google Scholar 

  8. Eversole LR (2000) Papillary lesions of the oral cavity: relationship to human papillomaviruses. J Calif Dent Assoc 28:922–927

    PubMed  Google Scholar 

  9. Palefsky JM, Silverman S Jr, Abdel-Salaam M, Daniels TE, Greenspan JS (1995) Association between proliferative verrucous leukoplakia and infection with human papillomavirus type 16. J Oral Pathol Med 24:193–197

    Article  PubMed  Google Scholar 

  10. Gopalakrishnan R, Weghorst CM, Lehman TA, Calvert RJ, Bijur G, Sabourin CL, Mallery SR, Schuller DE, Stoner GD (1997) Mutated and wild-type p53 expression and HPV integration in proliferative verrucous leukoplakia and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:471–477

    Article  PubMed  Google Scholar 

  11. Campisi G, Giovannelli L, Ammatuna P, Capra G, Colella G, Di Liberto C, Gandolfo S, Pentenero M, Carrozzo M, Serpico R, D’Angelo M (2004) Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol 40:835–840

    Article  PubMed  Google Scholar 

  12. Fettig A, Pogrel MA, Silverman S Jr, Bramanti TE, Da Costa M, Regezi JA (2000) Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90:723–730

    Article  PubMed  Google Scholar 

  13. Kresty LA, Mallery SR, Knobloch TJ, Li J, Lloyd M, Casto BC, Weghorst CM (2008) Frequent alterations of p16INK4a and p14ARF in oral proliferative verrucous leukoplakia. Cancer Epidemiol Biomarkers Prev 17:3179–3187

    Article  PubMed  Google Scholar 

  14. Klanrit P, Sperandio M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, Odell EW (2007) DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol 43:310–316

    Article  PubMed  Google Scholar 

  15. Cabay RJ, Morton TH Jr, Epstein JB (2007) Proliferative verrucous leukoplakia and its progression to oral carcinoma: a review of the literature. J Oral Pathol Med 36:255–261

    Article  PubMed  Google Scholar 

  16. Bagan J, Scully C, Jimenez Y, Martorell M (2010) Proliferative verrucous leukoplakia: a concise update. Oral Dis 16:328–332

    Article  PubMed  Google Scholar 

  17. Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, Bagan L (2011) Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol 47:732–735

    Article  PubMed  Google Scholar 

  18. Carrard VC, Brouns ER, van der Waal I (2013) Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal 18:e411–e413

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jureti M, Cerovi R, Belui-Gobi M, Brekalo Pro I, Kqiku L, Palj S, Pezelj-Ribari S (2013) Salivary levels of TNF- and IL-6 in patients with oral premalignant and malignant lesions. Folia Biol 59:99–102

    Google Scholar 

  20. Lisa Cheng YS, Jordan L, Gorugantula LM, Schneiderman E, Chen HS, Rees T (2014) Salivary interleukins 6 and 8 in oral cancer patients and in patients with chronic oral inflammatory diseases. J Periodontol 85:956–65

    Article  PubMed  Google Scholar 

  21. Brailo V, Vucicevic-Boras V, Lukac J, Biocina-Lukenda D, Zilic-Alajbeg I, Milenovic A, Balija M (2012) Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer. Med Oral Patol Oral Cir Bucal 17:e10–e15

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chang KP, Kao HK, Wu CC, Fang KH, Chang YL, Huang YC, Liu SC, Cheng MH (2013) Pretreatment interleukin-6 serum levels are associated with patient survival for oral cavity squamous cell carcinoma. Otolaryngol Head Neck Surg 148:786–791

    Article  PubMed  Google Scholar 

  23. Sato J, Goto J, Murata T, Kitamori S, Yamazaki Y, Satoh A, Kitagawa Y (2010) Changes in saliva interleukin-6 levels in patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110:330–336

    Article  PubMed  Google Scholar 

  24. Korostoff A, Reder L, Masood R, Sinha UK (2011) The role of salivary cytokine biomarkers in tongue cancer invasion and mortality. Oral Oncol 47:282–287

    Article  PubMed  Google Scholar 

  25. Vairaktaris E, Yapijakis C, Serefoglou Z, Avgoustidis D, Critselis E, Spyridonidou S, Vylliotis A, Derka S, Vassiliou S, Nkenke E, Patsouris E (2008) Gene expression polymorphisms of interleukins-1 beta, -4, -6, -8, -10, and tumor necrosis factors-alpha, -beta: regression analysis of their effect upon oral squamous cell carcinoma. J Cancer Res Clin Oncol 134:821–832

    Article  PubMed  Google Scholar 

  26. St John MA, Li Y, Zhou X, Denny P, Ho CM, Montemagno C, Shi W, Qi F, Wu B, Sinha U, Jordan R, Wolinsky L, Park NH, Liu H, Abemayor E, Wong DT (2004) Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 130:929–935

    Article  PubMed  Google Scholar 

  27. Chang KP, Chang YT, Liao CT, Yen TC, Chen IH, Chang YL, Liu YL, Chang YS, Yu JS, Wu CC (2011) Prognostic cytokine markers in peripheral blood for oral cavity squamous cell carcinoma identified by multiplexed immunobead-based profiling. Clin Chim Acta 412:-12

    Google Scholar 

  28. Punyani SR, Sathawane RS (2013) Salivary level of interleukin-8 in oral precancer and oral squamous cell carcinoma. Clin Oral Investig 17:517–524

    Article  PubMed  Google Scholar 

  29. Katakura A, Kamiyama I, Takano N, Shibahara T, Muramatsu T, Ishihara K, Takagi R, Shouno T (2007) Comparison of salivary cytokine levels in oral cancer patients and healthy subjects. Bull Tokyo Dent Coll 48:199–203

    Article  PubMed  Google Scholar 

  30. Rhodus NL, Cheng B, Myers S, Miller L, Ho V, Ondrey F (2005) The feasibility of monitoring NF-kappaB associated cytokines: TNF-alpha, IL-1alpha, IL-6, and IL-8 in whole saliva for the malignant transformation of oral lichen planus. Mol Carcinog 44:77–82

    Article  PubMed  Google Scholar 

  31. Sun A, Wang JT, Chia JS, Chiang CP (2005) Serum interleukin-8 level is a more sensitive marker than serum interleukin-6 level in monitoring the disease activity of oral lichen planus. Br J Dermatol 152:1187–1192

    Article  PubMed  Google Scholar 

  32. Gu GM, Martin MD, Darveau RP, Truelove E, Epstein J (2004) Oral and serum IL-6 levels in oral lichen planus patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 98:673–678

    Article  PubMed  Google Scholar 

  33. Brailo V, Vucievi-Boras V, Ceki-Arambasin A, Alajbeg IZ, Milenovi A, Lukac J (2006) The significance of salivary interleukin 6 and tumor necrosis factor alpha in patients with oral leukoplakia. Oral Oncol 42:370–373

    Article  PubMed  Google Scholar 

  34. Matsuki Y, Yamamoto T, Hara K (1992) Detection of inflammatory cytokine messenger RNA (mRNA)-expressing cells in human inflamed gingiva by combined in situ hybridization and immunohistochemistry. Immunology 76:42–47

    PubMed  PubMed Central  Google Scholar 

  35. Jones KG, Brull DJ, Brown LC, Sian M, Greenhalgh RM, Humphries SE, Powell JT (2001) Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms. Circulation 103:2260–2265

    Article  PubMed  Google Scholar 

  36. Nishimoto N (2010) Interleukin-6 as a therapeutic target in candidate inflammatory diseases. Clin Pharmacol Ther 87:483–487

    Article  PubMed  Google Scholar 

  37. Nibali L, Fedele S, D’Aiuto F, Donos N (2012) Interleukin-6 in oral diseases: a review. Oral Dis 18:236–243

    Article  PubMed  Google Scholar 

  38. Prasad G, McCullough M (2013) Chemokines and cytokines as salivary biomarkers for the early diagnosis of oral cancer. Int J Dent. 2013: Article 813756, 7 pages

  39. Navazesh M (1993) Methods for collecting saliva. Ann N Y Acad Sci 694:72–77

    Article  PubMed  Google Scholar 

  40. Sharma M, Bairy I, Pai K, Satyamoorthy K, Prasad S, Berkovitz B, Radhakrishnan R (2011) Salivary IL-6 levels in oral leukoplakia with dysplasia and its clinical relevance to tobacco habits and periodontitis. Clin Oral Investig 15:705–714

    Article  PubMed  Google Scholar 

  41. Shkeir O, Athanassiou-Papaefthymiou M, Lapadatescu M, Papagerakis P, Czerwinski MJ, Bradford CR, Carey TE, Prince ME, Wolf GT, Papagerakis S (2013) In vitro cytokine release profile: predictive value for metastatic potential in head and neck squamous cell carcinomas. Head Neck 35(11):1542–1550

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hwang YS, Lee SK, Park KK, Chung WY (2012) Secretion of IL-6 and IL-8 from lysophosphatidic acid-stimulated oral squamous cell carcinoma promotes osteoclastogenesis and bone resorption. Oral Oncol 48:40–48

    Article  PubMed  Google Scholar 

  43. Nibali D’AF, Donos N, Griffiths GS, Parkar M, Tonetti MS, HumphriesSE BPM (2009) Association between periodontitis and common variants in the promoter of the interleukin-6 gene. Cytokine 45:50–54

    Article  PubMed  Google Scholar 

  44. Prso IB, Kocjan W, Simi H, Brumini G, Pezelj-Ribari S, Borci J, Ferreri S, Karlovi IM (2007) Tumor necrosis factor-alpha and interleukin 6 in human periapical lesions. Mediators Inflamm. 2007:38210

  45. Zhang Y, Lin M, Zhang S, Wang Z, Jiang L, Shen J, Bai J, Gao F, Zhou M, Chen Q (2008) NF-kappaB-dependent cytokines in saliva and serum from patients with oral lichen planus: a study in an ethnic Chinese population. Cytokine 41:144–149

    Article  PubMed  Google Scholar 

  46. Guimarães AL, Correia-Silva Jde F, Sá AR, Victória JM, Diniz MG, Costa Fde O, Gomez RS (2007) Investigation of functional gene polymorphisms IL-1beta, IL-6, IL-10 and TNF-alpha in individuals with recurrent aphthous stomatitis. Arch Oral Biol 52:268–272

    Article  PubMed  Google Scholar 

  47. Roescher N, Tak PP, Illei GG (2009) Cytokines in Sjögren’s syndrome. Oral Dis 15:519–526

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sato J, Ohuchi M, Abe K, Satoh T, Abe T, Yamazaki Y, Satoh A, Notani K, Kitagawa Y (2013) Correlation between salivary interleukin-6 levels and early locoregional recurrence in patients with oral squamous cell carcinoma: preliminary study. Head Neck 35:889–894

    Article  PubMed  Google Scholar 

  49. Sundelin K, Roberg K, Grénman R, Håkansson L (2005) Effects of cytokines on matrix metalloproteinase expression in oral squamous cell carcinoma in vitro. Acta Otolaryngol 125(7):765–773

    Article  PubMed  Google Scholar 

  50. Hodge DR, Peng B, Cherry JC, Hurt EM, Fox SD, Kelley JA, Munroe DJ, Farrar WL (2005) Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res 65(11):4673–4682

    Article  PubMed  Google Scholar 

  51. Tamura S, Ouchi KF, Mori K, Endo M, Matsumoto T, Eda H, Tanaka Y, Ishitsuka H, Tokita H, Yamaguchi K (1995) Involvement of human interleukin 6 in experimental cachexia induced by a human uterine cervical carcinoma xenograft. Clin Cancer Res 1(11):1353–1358

    PubMed  Google Scholar 

  52. Hu S, Arellano M, Boontheung P, Wang J, Zhou H, Jiang J, Elashoff D, Wei R, Loo JA, Wong DT (2008) Salivary proteomics for oral cancer biomarker discovery. Clin Cancer Res 14:6246–6252

    Article  PubMed  PubMed Central  Google Scholar 

  53. Duffy SA, Taylor JM, Terrell JE, Islam M, Li Y, Fowler KE, Wolf GT, Teknos TN (2008) Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 113(4):750–757

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Oral Medicine Department, Valencia University, Valencia, Spain

    Leticia Bagan & Jose V. Bagan

  2. Department of Biochemistry, School of Medicine, University of Valencia, Valencia, Spain

    Guillermo T. Sáez & M. Carmen Tormos

  3. Department of Stomatology, Valencia University, Valencia, Spain

    Carlos Labaig-Rueda

  4. Service of Stomatology and Maxillofacial Surgery, University General Hospital, Avda Tres Cruces s/n, 46014, Valencia, Spain

    Judith Murillo-Cortes & Jose V. Bagan

Authors
  1. Leticia Bagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guillermo T. Sáez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Carmen Tormos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos Labaig-Rueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Judith Murillo-Cortes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jose V. Bagan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose V. Bagan.

Additional information

The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see http://www.textcheck.com/certificate/xEqyq9.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bagan, L., Sáez, G.T., Tormos, M.C. et al. Salivary and serum interleukin-6 levels in proliferative verrucous leukoplakia. Clin Oral Invest 20, 737–743 (2016). https://doi.org/10.1007/s00784-015-1551-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-015-1551-z

Keywords

Search

Navigation