The Clinical Utility of Neuron-Specific Enolase (NSE) Serum Levels as a Biomarker for Merkel Cell Carcinoma (MCC)



No adequate biomarker for Merkel cell carcinoma (MCC) has been identified. Serum neuron-specific enolase (NSE) has been tested and is commonly used as a biomarker for several other small cell malignancies. However, the role of NSE in MCC is still unclear. The purpose of this study was to investigate the role of NSE as a biomarker in MCC.


A prospective cohort of MCC patients was analyzed using Kaplan–Meier curves with log-rank test, ROC curves, Cox regression, and mixed models. A separate evaluation was performed for patients treated with immunotherapy.


Eighty-four patients were included [47 males, median age 71 years, stages I & II, III, and IV MCC in respectively 39 (46%), 42 (50%), and 4 (3%) patients at time of diagnosis] with 565 NSE samples (median 15; interquartile range 12.6–22 ng/ml). Baseline NSE had no association with prognosis. NSE correlated with extent of disease (P = 0.01) and increased with 15 ng/ml per class (no tumor load, localized MCC, regional or distant metastases, respectively). NSE was able to detect progression (AUC 0.89). A NSE of 18.2 ng/ml was considered the most optimal level for clinical use (sensitivity 91%, specificity 78%, PPV 48%, NPV 98%). During immunotherapy (N = 23; 248 NSE values), all complete responders (N = 10) had a normalized NSE (< 18.2 ng/ml), all partial responders (N = 5) had a decreasing NSE. In nonresponders (N = 8), all NSE levels remained elevated.


NSE could be a valuable biomarker in MCC. NSE correlates with extent of disease; it is able to rule out progression and distinguishes responders from nonresponders during immunotherapy.

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

Fig. 1
Fig. 2


  1. 1.

    Youlden DR, Soyer HP, Youl PH, et al. Incidence and survival for Merkel cell carcinoma in Queensland, Australia, 1993–2010. JAMA Dermatol. 2014;150:864–72.

    Article  Google Scholar 

  2. 2.

    Reichgelt BA, Visser O. Epidemiology and survival of Merkel cell carcinoma in the Netherlands. A population-based study of 808 cases in 1993–2007. Eur J Cancer. 2011;47:579–85.

    CAS  Article  Google Scholar 

  3. 3.

    Harms KL, Healy MA, Nghiem P, et al. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC Staging System. Ann Surg Oncol. 2016;23:3564–71.

  4. 4.

    Harms PW, Harms KL, Moore PS, et al. International Workshop on Merkel Cell Carcinoma Research (IWMCC) Working Group. The biology and treatment of Merkel cell carcinoma: current understanding and research priorities. Nat Rev Clin Oncol. 2018;15(12):763–76.

  5. 5.

    Becker JC, Stang A, Hausen AZ, et al. Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC. Cancer Immunol Immunother. 2018;67:341–51.

    CAS  Article  Google Scholar 

  6. 6.

    Fields RC, Busam KJ, Chou JF, et al. Five hundred patients with Merkel cell carcinoma evaluated at a single institution. Ann Surg. 2011;254:465–75.

    Article  Google Scholar 

  7. 7.

    van Veenendaal LM, van Akkooi ACJ, Verhoef C, et al. Merkel cell carcinoma: clinical outcome and prognostic factors in 351 patients. J Surg Oncol. 2018;117:1768–75.

    Article  Google Scholar 

  8. 8.

    Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients undergoing sentinel lymph node biopsy for merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol. 2011;18:2529–37.

    Article  Google Scholar 

  9. 9.

    Poulsen MG, Rischin D, Porter I, et al. Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin? Int J Radiat Oncol Biol Phys. 2006;64:114–9.

    Article  Google Scholar 

  10. 10.

    Tai PT, Yu E, Winquist E, et al. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol. 2000;18:2493–9.

    CAS  Article  Google Scholar 

  11. 11.

    Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374–85.

    CAS  Article  Google Scholar 

  12. 12.

    Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. New Engl J Med. 2016; 374: 2542–52.

    CAS  Article  Google Scholar 

  13. 13.

    Kaufman HL, Russell JS, Hamid O, et al. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥ 1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer. 2018;6:7.

    Article  Google Scholar 

  14. 14.

    Schadendorf D, Lebbé C, zur Hausen A, et al. Merkel cell carcinoma: epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer. 2017;71:53–69.

    Article  Google Scholar 

  15. 15.

    Harmsma M, Schutte B, Ramaekers FC. Serum markers in small cell lung cancer: opportunities for improvement. Biochim Biophys Acta. 2013;1836:255–72.

    CAS  PubMed  Google Scholar 

  16. 16.

    Burghuber OC, Worofka B, Schernthaner G, et al. Serum neuron-specific enolase is a useful tumor marker for small cell lung cancer. Cancer. 1990;65:1386–90.

    CAS  Article  Google Scholar 

  17. 17.

    Fizazi K, Cojean I, Pignon JP, et al. Normal serum neuron specific enolase (NSE) value after the first cycle of chemotherapy: an early predictor of complete response and survival in patients with small cell lung carcinoma. Cancer. 1998;82:1049–55.

    CAS  Article  Google Scholar 

  18. 18.

    van Adrichem RC, Kamp K, Vandamme T, et al. Serum neuron-specific enolase level is an independent predictor of overall survival in patients with gastroenteropancreatic neuroendocrine tumors. Ann Oncol. 2016;27:746–7.

    Article  Google Scholar 

  19. 19.

    Riley RD, Heney D, Jones DR, et al. A systematic review of molecular and biological tumor markers in neuroblastoma. Clin Cancer Res. 2004;10:4–12.

    CAS  Article  Google Scholar 

  20. 20.

    Plowman PN. Serum marker for Merkel cell tumour. Clin Radiol. 1989;40:542.

    CAS  Article  Google Scholar 

  21. 21.

    Gaiser MR, Daily K, Hoffmann J, et al. Evaluating blood levels of neuron specific enolase, chromogranin A, and circulating tumor cells as Merkel cell carcinoma biomarkers. Oncotarget. 2015;6:26472–82.

    Article  Google Scholar 

  22. 22.

    Nobels FRE, Kwekkeboom DJ, Coopmans W, et al. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the α-subunit of glycoprotein hormones. J Clin Endocrinol Metab. 1997;82:2622–8.

    CAS  PubMed  Google Scholar 

  23. 23.

    Giannone L, Johnson DH, Grosh WW, et al. Serum neuron-specific enolase in metastatic Merkel cell tumors. Med Pediatr Oncol. 1985;13:357–62.

    CAS  Article  Google Scholar 

  24. 24.

    Isgrò MA, Bottoni P, Scatena R. Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects. Adv Exp Med Biol. 2015;867:125–43.

  25. 25.

    Kaiser E, Kuzmits R, Pregant P, et al. Clinical biochemistry of neuron-specific enolase. Clin Chim Acta. 1989;183:13–31.

    CAS  Article  Google Scholar 

  26. 26.

    Kirkham N, Isaacson P. Merkel cell carcinoma: a report of three cases with neurone-specific enolase activity. Histopathology 1983;7:251–9.

    CAS  Article  Google Scholar 

  27. 27.

    Gould VE, Moll R, Moll I, et al. Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab Invest. 1985;52:334–53.

    CAS  PubMed  Google Scholar 

  28. 28.

    Gu J, Polak JM, Van Noorden S, et al. Immunostaining of neuron-specific enolase as a diagnostic tool for Merkel cell tumors. Cancer. 1983;52:1039–43.

    CAS  Article  Google Scholar 

  29. 29.

    Obuchowski NA. Nonparametric analysis of clustered ROC curve data. Biometrics. 1997;53:567–78.

    CAS  Article  Google Scholar 

  30. 30.

    Paulson KG, Lewis CW, Redman MW, et al. Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: a prospective validation study. Cancer. 2017;123:1464–74.

    CAS  Article  Google Scholar 

  31. 31.

    Riethdorf S, Hildebrandt L, Heinzerling L, et al. Detection and characterization of circulating tumor cells in patients with Merkel cell carcinoma. Clin Chem. 2019;65:462–72.

    CAS  Article  Google Scholar 

  32. 32.

    Wang H, Peng R, Wang J, et al. Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage. Clin Epigenetics. 2018;10:59.

    Article  Google Scholar 

  33. 33.

    Xie H, Lee L, Caramuta S, et al. MicroRNA expression patterns related to merkel cell polyomavirus infection in human merkel cell carcinoma. J Invest Dermatol. 2014;134(2):507–17.

    CAS  Article  Google Scholar 

  34. 34.

    Konstatinell A, Coucheron DH, Sveinbjørnsson B, et al. MicroRNAs as potential biomarkers in Merkel cell carcinoma. Int J Mol Sci. 2018;19(7):e1873.

    Article  Google Scholar 

  35. 35.

    Erovic I, Erovic BM. Merkel cell carcinoma: the past, the present, and the future. J Skin Cancer. 2013;2013:929364.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Alexander C. J. van Akkooi MD, PhD.

Ethics declarations


Alexander van Akkooi: Advisory board/Consultancy: Amgen, Bristol-Myers, Novartis, MSD-Merck, Merck-Pfizer, 4SC: all paid to institute, not related to submitted work. Research grant: Amgen, Bristol-Myers Squibb, Novartis: all paid to institute, not related to submitted work. All other authors have declared no conflicts of interest related to our study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplement 1: KM survival curves (TIFF 2702 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

van Veenendaal, L.M., Bertolli, E., Korse, C.M. et al. The Clinical Utility of Neuron-Specific Enolase (NSE) Serum Levels as a Biomarker for Merkel Cell Carcinoma (MCC). Ann Surg Oncol (2020).

Download citation