OBJECTIVES: The incidence of oral and oropharyngeal cancer is continually rising and affects increasingly younger patients. Consequently, many studies focus on early diagnosis using appropriate biomarkers. Neopterin and interleukin-6 (IL-6) are promising predictive and prognostic markers of immune response activation, both systemic and local, due to the anatomical proximity of malignancies to the salivary glands. MATERIAL AND METHODS: We collected oral fluid samples from 50 patients before and after the surgical resection of squamous cell carcinoma of the oral cavity and oropharynx. Additionally, blood samples were withdrawn from 20 of these patients and levels of neopterin and IL-6 were estimated using ELISA commercial kits. All gathered data were subsequently statistically analyzed for evaluation and compared to values from a control group of healthy individuals. RESULTS: In patients with oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC), there was a significant decrease in neopterin and IL-6 levels in saliva following the surgical removal of the malignancy. These postoperative levels approached those of the control group. There was no significant decrease in neopterin and IL-6 levels in plasma. CONCLUSION: Detection of neopterin and IL-6 in saliva is a reliable diagnostic method for early detection of OSCC and its recurrence, as well as for monitoring therapeutic success, compared to plasma. Neopterin and IL-6 appear to be promising prognostic and predictive markers of the disease.

Department of Biochemistry Faculty of Medicine Masaryk University Brno Czech Republic

Department of Medical Biophysics Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Department of Oncology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Czech Republic

Department of Oral and Maxillofacial surgery Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Czech Republic

See more in PubMed

Chen, Z. , Malhotra P. S., Thomas G. R., et al. 1999. “Expression of Proinflammatory and Proangiogenic Cytokines in Patients With Head and Neck Cancer1.” Clinical Cancer Research 5, no. 6: 1369–1379. PubMed

Elisa, N. Instructions for Use. Ibl‐international.com. Accessed October 3, 2024. https://ibl-international.com/media/mageworx/downloads/attachment/file/r/e/re59321_ifu_eu_en_neopterin_elisa_2018-10_sym6.pdf.

Gottumukkala, S. N. V. S. , C. A., Venkata R. K. S., Penmetsa G. S., Koneru S., and Pasupuleti S.. 2022. “Estimation of Salivary Neopterin Levels in Aggressive and Chronic Periodontitis After Nonsurgical Periodontal Therapy: A Cohort Study.” Journal of Advanced Oral Research 13, no. 2: 200–206.

Hamerlinck, F. F. V. 1999. “Neopterin: A Review.” Experimental Dermatology 8, no. 3: 167–176. 10.1111/j.1600-0625.1999.tb00367.x. PubMed DOI

Heneberk, O. , Vernerova A., Kujovska Krcmova L., Wurfelova E., and Radochova V.. 2022. “Neopterin Levels in Periodontitis and After Nonsurgical Periodontal Therapy: Evaluation of Gingival Crevicular Fluid, Oral Fluid, Serum and Urinary Samples—A Case‐Control Study.” Biomedicines 10, no. 12: 3200. PubMed PMC

Hoffmann, G. , Wirleitner B., and Fuchs D.. 2003. “Potential Role of Immune System Activation‐Associated Production of Neopterin Derivatives in Humans.” Inflammation Research 52, no. 8: 313–321. PubMed

Huang, J. , Chan S. C., Ko S., et al. 2023. “Disease Burden, Risk Factors, and Trends of Lip, Oral Cavity, Pharyngeal Cancers: A Global Analysis.” Cancer Medicine 12, no. 17: 18153–18164. 10.1002/cam4.6391. PubMed DOI PMC

Juretić, M. , Cerović R., Belušić‐Gobić M., et al. 2013. “Salivary Levels of TNF‐α and IL‐6 in Patients With Oral Premalignant and Malignant Lesions.” Folia Biologica 59, no. 2: 99–102. PubMed

IBL International GmbH . 2012. “Neopterin ELISA: Instructions for Use, RE59321.” IBL International GmbH.

IBL International GmbH . 2014. “Interleukin‐6 ELISA: Instructions for use, BE53061.” IBL International GmbH. https://www.ibl-international.com/media/mageworx/downloads/attachment/file/3/0/30147231_ifu_ww_en_il-6_elisa_2020-01_01_sym5.pdf.

Koontongkaew, S. 2013. “The Tumor Microenvironment Contribution to Development, Growth, Invasion and Metastasis of Head and Neck Squamous Cell Carcinomas.” Journal of Cancer 4, no. 1: 66–83. PubMed PMC

Kreiner, F. F. , Kraaijenhof J. M., von Herrath M., Hovingh G. K. K., and von Scholten B. J.. 2022. “Interleukin 6 in Diabetes, Chronic Kidney Disease, and Cardiovascular Disease: Mechanisms and Therapeutic Perspectives.” Expert Review of Clinical Immunology 18, no. 4: 377–389. PubMed

Lacina, L. , Brábek J., Král V., Kodet O., and Smetana K.. 2018. “Interleukin‐6: A Molecule With Complex Biological Impact in Cancer.” Histology & Histopathology 34, no. 2: 125–136. 10.14670/HH-18-033. PubMed DOI

Melichar, B. 2013. “Laboratory Medicine and Medical Oncology: The Tale of Two Cinderellas.” Clinical Chemistry and Laboratory Medicine (CCLM) 51, no. 1: 99–112. PubMed

Melichar, B. , Spisarová M., Bartoušková M., Krčmová L. K., Javorská L., and Študentová H.. 2017. “Neopterin as a Biomarker of Immune Response in Cancer Patients.” Annals of Translational Medicine 5, no. 13: 280. PubMed PMC

Navazesh, M. , and Kumar S. K. S.. 2008. “Measuring Salivary Flow.” Journal of the American Dental Association 139: 35S–40S. PubMed

Oshin, M. , Kulkarni P. G., Shyam Prasad Reddy D., Deepthi G., Keerthi Sai S., and Jishnu K S.. 2024. “Salivary and Serum interleukin‐6: A Credible Marker for Predicting Oral Leukoplakia and Oral Squamous Cell Carcinoma by Enzyme‐Linked Immunosorbent Assay (ELISA).” Cureus 16, no. 4: e59113. PubMed PMC

Pazdera, J. 2022. Základy ústní, čelistní a obličejové chirurgie, 263–276. Univerzita Palackého v Olomouci.

Pink, R. , Melichar B., Tomandl J., Blažková L., Tvrdý P., and Zapletalová J.. 2016. “Salivary Neopterin Concentrations in Patients With Cancer of the Oral Cavity.” Pteridines 27, no. 3–4: 53–58.

Pink, R. , Simek J., Vondrakova J., et al. 2009. “Saliva as a Diagnostic Medium.” Biomedical Papers 153, no. 2: 103–110. PubMed

Pittet, M. J. , Michielin O., and Migliorini D.. 2022. “Clinical Relevance of Tumour‐Associated Macrophages.” Nature Reviews Clinical Oncology 19, no. 6: 402–421. PubMed

Rahman, Q. B. , Iocca O., Kufta K., and Shanti R. M.. 2020. “Global Burden of Head and Neck Cancer.” Oral and Maxillofacial Surgery Clinics of North America 32, no. 3: 367–375. 10.1016/j.coms.2020.04.002. PubMed DOI

Raudenska, M. , Balvan J., Hanelova K., Bugajova M., and Masarik M.. 2023. “Cancer‐Associated Fibroblasts: Mediators of Head and Neck Tumor Microenvironment Remodeling.” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 1878, no. 5: 188940. PubMed

Rašková, M. , Lacina L., Kejík Z., et al. 2022. “The Role of IL‐6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities.” Cells 11, no. 22: 3698. PubMed PMC

Sato, J. , Ohuchi M., Wada M., et al. 2015. “Differences in Sequential Posttreatment Salivary IL‐6 Levels Between Patients With and Patients Without Locoregional Recurrences of Oral Squamous Cell Carcinoma: Part Iii of a Cohort Study.” Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 120, no. 6: 751–760.e2. PubMed

St. John, M. A. R. , Li Y., Zhou X., et al. 2004. “Interleukin 6 and Interleukin 8 as Potential Biomarkers for Oral Cavity and Oropharyngeal Squamous Cell Carcinoma.” Archives of Otolaryngology–Head & Neck Surgery 130, no. 8: 929. 10.1001/archotol.130.8.929. PubMed DOI

Sung, H. , Ferlay J., Siegel R. L., et al. 2021. “Global Cancer Statistics 2020: Globocan Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.” CA: A Cancer Journal for Clinicians 71, no. 3: 209–249. PubMed

Vrecko, K. , Staedtler P., Mischak I., Maresch L., and Reibnegger G.. 1997. “Periodontitis and Concentrations of the Cellular Immune Activation Marker Neopterin in Saliva and Urine.” Clinica Chimica Acta 268, no. 1–2: 31–40. PubMed