Monitoring carcinogenesis in a case of oral squamous cell carcinoma using a panel of new metabolic blood biomarkers as liquid biopsies

Abstract

Introduction

One of the common malignant tumors of the head and neck worldwide with generally unfavorable prognosis is squamous cell carcinoma (OSCC) of the oral cavity. Early detection of primary, secondary, or recurrent OSCC by liquid biopsy tools is much needed.

Case presentation

Twelve blood biomarkers were used for monitoring a case of OSCC suffering from precancerous oral lichen ruber planus mucosae (OLP). After curative R0 tumor resection of primary OSCC (buccal mucosa), elevated epitope detection in monocytes (EDIM)-Apo10, EDIM-transketolase-like-1 (TKTL1), squamous cell carcinoma antigen (SCC-Ag), total serum lactate dehydrogenase (LDH), and its anaerobic isoforms (LDH-4, LDH-5) decreased to normal levels. Three and six months after surgery, transformation of suspicious mucosal lesions has been accompanied with an increase of EDIM scores, total serum LDH values, and a metabolic shift from aerobic (decrease of LDH-1, LDH-2) to anaerobic (increase of LDH-4, LDH-5) conditions. Two months later, secondary OSCC was histopathologically analyzed after tissue biopsy. Cytokeratin fraction 21-1 (CYFRA 21-1), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were not affected during the clinical course of carcinogenesis.

Conclusions

A combination strategy using a standardized panel of established (metabolic) blood biomarkers (TKTL1, LDH, LDH isoenzymes) is worth and can be recommended among others (apoptosis resistance-related Apo10, SCC-Ag) for early detection and diagnosis of primary, secondary, and recurrent OSCC. A tandem strategy utilizing (metabolic pronounced) routine liquid biopsies with imaging techniques may enhance diagnosis of OSCC in the future. Although we demonstrated the diagnostic utility of separated liquid biopsies in our previous study cohorts, further investigations in a larger patient cohort are necessary to recommend this combination strategy (EDIM blood test, LDH value, metabolic shift of LDH isoenzymes, and others, e.g., SCC-Ag or immunophenotyping) as a diagnostic tool for the addition to the OSCC staging system and as a routine procedure in the aftercare.

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Abbreviations

OSCC:

oral squamous cell carcinoma

EDIM:

epitope detection in monocytes

TKTL1:

Transketolase-like-1

SCC-Ag:

squamous cell carcinoma antigen

CYFRA 21-1:

cyotokeratin fraction 21–-1

H&E:

Hematoxylin and Eosin

References

  1. 1.

    Rethman MP, Carpenter W, Cohen EE, Epstein J, Evans CA, Flaitz CM, Graham FJ, Hujoel PP, Kalmar JR, Koch WM, Lambert PM, Lingen MW, Oettmeier BW, Jr., Patton LL, Perkins D, Reid BC, Sciubba JJ, Tomar SL, Wyatt AD, Jr., Aravamudhan K, Frantsve-Hawley J, Cleveland JL, Meyer DM, American Dental Association Council on Scientific Affairs Expert Panel on Screening for Oral Souamous Cell C (2012) Evidence-based clinical recommendations regarding screening for oral squamous cell carcinomas. Tex Dent J 129 (5):491–507

    PubMed  Google Scholar 

  2. 2.

    Czerninski R, Basile JR, Kartin-Gabay T, Laviv A, Barak V (2014) Cytokines and tumor markers in potentially malignant disorders and oral squamous cell carcinoma: a pilot study. Oral Dis 20(5):477–481. doi:10.1111/odi.12160

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Lin WH, Chen IH, Wei FC, Huang JJ, Kang CJ, Hsieh LL, Wang HM, Huang SF (2011) Clinical significance of preoperative squamous cell carcinoma antigen in oral-cavity squamous cell carcinoma. Laryngoscope 121(5):971–977. doi:10.1002/lary.21721

    Article  PubMed  Google Scholar 

  4. 4.

    Rajkumar K, Ramya R, Nandhini G, Rajashree P, Ramesh Kumar A, Nirmala Anandan S (2015) Salivary and serum level of CYFRA 21-1 in oral precancer and oral squamous cell carcinoma. Oral Dis 21(1):90–96. doi:10.1111/odi.12216

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    da Silva SD, Ferlito A, Takes RP, Brakenhoff RH, Valentin MD, Woolgar JA, Bradford CR, Rodrigo JP, Rinaldo A, Hier MP, Kowalski LP (2011) Advances and applications of oral cancer basic research. Oral Oncology 47(9):783–791. doi:10.1016/j.oraloncology.2011.07.004

    Article  PubMed  Google Scholar 

  6. 6.

    Krimmel M, Hoffmann J, Krimmel C, Cornelius CP, Schwenzer N (1998) Relevance of SCC-Ag, CEA, CA 19.9 and CA 125 for diagnosis and follow-up in oral cancer. J Craniomaxillofac Surg Off Publ European Assoc Craniomaxillofac Surg 26(4):243–248

    CAS  Google Scholar 

  7. 7.

    Sawant SS, Zingde SM, Vaidya MM (2008) Cytokeratin fragments in the serum: their utility for the management of oral cancer. Oral Oncol 44(8):722–732. doi:10.1016/j.oraloncology.2007.10.008

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Grimm M, Cetindis M, Lehmann M, Biegner T, Munz A, Teriete P, Kraut W, Reinert S (2014) Association of cancer metabolism-related proteins with oral carcinogenesis—indications for chemoprevention and metabolic sensitizing of oral squamous cell carcinoma? J Transl Med 12:208. doi:10.1186/1479-5876-12-208

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Grimm M, Kraut W, Hoefert S, Krimmel M, Biegner T, Teriete P, Cetindis M, Polligkeit J, Kluba S, Munz A, Reinert S (2015) Evaluation of a biomarker based blood test for monitoring surgical resection of oral squamous cell carcinomas. Clin Oral Invest. doi:10.1007/s00784-015-1518-0

    Google Scholar 

  10. 10.

    Grimm M, Krimmel M, Hoefert S, Kraut W, Calgeer B, Biegner T, Teriete P, Munz A, Reinert S (2015) Monitoring a ‘metabolic shift’ after surgical resection of oral squamous cell carcinomas by serum lactate dehydrogenase. J Oral Pathol Med Off Publ Int Assoc Oral Pathologists Am Acad Oral Pathol. doi:10.1111/jop.12374

    Google Scholar 

  11. 11.

    Project TIN-HsLPF (1993) A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329(14):987–994. doi:10.1056/NEJM199309303291402

    Article  Google Scholar 

  12. 12.

    Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Spatz A, Grob JJ, Malvehy J, Newton-Bishop J, Stratigos A, Pehamberger H, Eggermont AM, European Dermatology F, European Association of D-O, European Organization of R, Treatment of C (2012) Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline–Update 2012. Eur J Cancer 48(15):2375–2390. doi:10.1016/j.ejca.2012.06.013

    Article  PubMed  Google Scholar 

  13. 13.

    Grimm M, Schmitt S, Teriete P, Biegner T, Stenzl A, Hennenlotter J, Muhs HJ, Munz A, Nadtotschi T, Konig K, Sanger J, Feyen O, Hofmann H, Reinert S, Coy JF (2013) A biomarker based detection and characterization of carcinomas exploiting two fundamental biophysical mechanisms in mammalian cells. BMC Cancer 13(1):569. doi:10.1186/1471-2407-13-569

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Feyen O, Coy JF, Prasad V, Schierl R, Saenger J, Baum RP (2012) EDIM-TKTL1 blood test: a noninvasive method to detect upregulated glucose metabolism in patients with malignancies. Future Oncol 8(10):1349–1359. doi:10.2217/fon.12.98

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Parihar A, Eubank TD, Doseff AI (2010) Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death. J Innate Immu 2(3):204–215. doi:10.1159/000296507

    Article  Google Scholar 

  16. 16.

    Soland TM, Brusevold IJ (2013) Prognostic molecular markers in cancer - quo vadis? Histopathology 63(3):297–308. doi:10.1111/his.12184

    Article  PubMed  Google Scholar 

  17. 17.

    Powers RH, Dean DE (2009) Evaluation of potential lactate/lactate dehydrogenase interference with an enzymatic alcohol analysis. J Anal Toxicol 33(8):561–563

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Jansen N, Coy JF (2013) Diagnostic use of epitope detection in monocytes blood test for early detection of colon cancer metastasis. Future Oncol 9(4):605–609. doi:10.2217/fon.13.8

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Grimm M, Lazariotou M (2012) Clinical relevance of a new pre-treatment laboratory prognostic index in patients with oral squamous cell carcinoma. Med Oncol 29(3):1435–1447. doi:10.1007/s12032-011-0045-3

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Grimm M, Cetindis M, Lehmann M, Biegner T, Munz A, Teriete P, Reinert S (2015) Apoptosis resistance-related ABCB5 and DNaseX (Apo10) expression in oral carcinogenesis. Acta Odontol Scand 73(5):336–342. doi:10.3109/00016357.2014.961029

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Khurana P, Tyagi N, Salahuddin A, Tyagi SP (1990) Serum lactate dehydrogenase isoenzymes in breast tumours. Indian J Pathol Microbiol 33(4):355–359

    CAS  PubMed  Google Scholar 

  22. 22.

    Cantor JR, Sabatini DM (2012) Cancer cell metabolism: one hallmark, many faces. Cancer Discov 2(10):881–898. doi:10.1158/2159-8290.CD-12-0345

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Grimm M, Munz A, Teriete P, Nadtotschi T, Reinert S (2014) GLUT-1/TKTL1 coexpression predicts poor outcome in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 117(6):743–753. doi:10.1016/j.oooo.2014.02.007

    Article  PubMed  Google Scholar 

  25. 25.

    Kostakoglu L, Fardanesh R, Posner M, Som P, Rao S, Park E, Doucette J, Stein EG, Gupta V, Misiukiewicz K, Genden E (2013) Early detection of recurrent disease by FDG-PET/CT leads to management changes in patients with squamous cell cancer of the head and neck. Oncologist 18(10):1108–1117. doi:10.1634/theoncologist.2013-0068

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Suenaga Y, Kitajima K, Ishihara T, Sasaki R, Otsuki N, Nibu KI, Minamikawa T, Kiyota N, Sugimura K (2015) FDG-PET/contrast-enhanced CT as a post-treatment tool in head and neck squamous cell carcinoma: comparison with FDG-PET/non-contrast-enhanced CT and contrast-enhanced CT. European Radiol. doi:10.1007/s00330-015-3902-1

    Google Scholar 

  27. 27.

    Yeh CY, Lin CL, Chang MC, Chen HM, Kok SH, Chang SH, Kuo YS, Hahn LJ, Chan CP, Lee JJ, Jeng JH (2015) Differences in oral habit and lymphocyte subpopulation affect malignant transformation of patients with oral precancer. J Formos Med Assoc Taiwan yi zhi. doi:10.1016/j.jfma.2015.07.017

    Google Scholar 

  28. 28.

    Lee JJ, Lin CL, Chen TH, Kok SH, Chang MC, Jeng JH (2010) Changes in peripheral blood lymphocyte phenotypes distribution in patients with oral cancer/oral leukoplakia in Taiwan. Int J Oral Maxillofac Surg 39(8):806–814. doi:10.1016/j.ijom.2010.04.045

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Millrud CR, Mansson Kvarnhammar A, Uddman R, Bjornsson S, Riesbeck K, Cardell LO (2012) The activation pattern of blood leukocytes in head and neck squamous cell carcinoma is correlated to survival. PLoS one 7(12):e51120. doi:10.1371/journal.pone.0051120

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Tabata T, Hazama S, Yoshino S, Oka M (1999) Th2 subset dominance among peripheral blood T lymphocytes in patients with digestive cancers. Am J Surg 177(3):203–208

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Young M (2014) Immunological phenotypes of premalignant oral lesions and the immune shifts with the development of head and neck cancer. Austin J Otolaryngol 1(2):7

    Google Scholar 

  32. 32.

    Ma Y, Zhang Z, Tang L, Xu YC, Xie ZM, Gu XF, Wang HX (2012) Cytokine-induced killer cells in the treatment of patients with solid carcinomas: a systematic review and pooled analysis. Cytotherapy 14(4):483–493. doi:10.3109/14653249.2011.649185

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Grimm M, Feyen O, Hofmann H, Teriete P, Biegner T, Munz A, Reinert S (2015) Immunophenotyping of patients with oral squamous cell carcinoma in peripheral blood and associated tumor tissue. Tumour Biol J Int Soc Oncodevelopmental Biol Med. doi:10.1007/s13277-015-4224-2

    Google Scholar 

  34. 34.

    Omar E (2015) Future imaging alternatives: the clinical non-invasive modalities in diagnosis of oral squamous cell carcinoma (OSCC). Open Dentist J 9:311–318. doi:10.2174/1874210601509010311

    CAS  Article  Google Scholar 

  35. 35.

    Omar E (2015) Current concepts and future of noninvasive procedures for diagnosing oral squamous cell carcinoma–a systematic review. Head Face Med 11:6. doi:10.1186/s13005-015-0063-z

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Weigum SE, Floriano PN, Redding SW, Yeh CK, Westbrook SD, McGuff HS, Lin A, Miller FR, Villarreal F, Rowan SD, Vigneswaran N, Williams MD, McDevitt JT (2010) Nano-bio-chip sensor platform for examination of oral exfoliative cytology. Cancer Prev Res 3(4):518–528. doi:10.1158/1940-6207.CAPR-09-0139

    CAS  Article  Google Scholar 

  37. 37.

    Ebenezar J, Ganesan S, Aruna P, Muralinaidu R, Renganathan K, Saraswathy TR (2012) Noninvasive fluorescence excitation spectroscopy for the diagnosis of oral neoplasia in vivo. J Biomed Opt 17(9):97007–97001. doi:10.1117/1.JBO.17.9.097007

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank biovis’ Diagnostik MVZ especially Melanie Hügen and Martina Thümmler for the technical support.

Authors’ contributions

MG, SH, and MK performed follow-up of the patient and were major contributors in conducting, writing, and revising the manuscript. TB and MG evaluated the immunohistology and immunohistochemistry slides. OF performed the flow cytometric analysis. PT and SR conceived the study and drafted the manuscript. All authors read and approved the final manuscript.

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Corresponding author

Correspondence to Martin Grimm.

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Consent

Written informed consent to participate was obtained prospectively from the patient (Ethics Committee Tuebingen, Germany, approval number: 562-2013BO2).

Competing interests

OF is an employee and shareholder of Zyagnum AG, Frankfurt am Main, Germany, and declares a potential conflict of interest due to the possible utilization of Apo10 and TKTL1 for diagnostic and/or therapeutic purposes. The authors have no other affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Cite this article

Grimm, M., Hoefert, S., Krimmel, M. et al. Monitoring carcinogenesis in a case of oral squamous cell carcinoma using a panel of new metabolic blood biomarkers as liquid biopsies. Oral Maxillofac Surg 20, 295–302 (2016). https://doi.org/10.1007/s10006-016-0549-2

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Keywords

  • Biomarkers
  • monitoring
  • Transketolase-like-1
  • Lactate dehydrogenase
  • Squamous cell carcinoma antigen
  • Cytokeratin fraction 21-1
  • Epitope detection in monocytes (EDIM) technology
  • Oral squamous cell carcinoma