Pathology & Oncology Research

, Volume 25, Issue 1, pp 255–262 | Cite as

The Results of Stricter Inclusion Criteria in an Immunomagnetic Detection Study of Micrometastatic Cells in Bone Marrow of Uveal Melanoma Patients - Relevance for Dormancy

  • Nils EideEmail author
  • Ragnar S. Faye
  • Hanne K. Høifødt
  • Leiv Sandvik
  • Geir A. Qvale
  • Rowan Faber
  • Peter Jebsen
  • Gunnar Kvalheim
  • Øystein Fodstad
Original Article


Approximately 50% of uveal melanoma patients develop metastases. We want to evaluate the effect of stricter criteria on our data from our previous study correlating survival and bone marrow (BM) micrometastasis results using our immunomagnetic separation (IMS) method. Mononuclear cell fractions (MNC) isolated from BM were examined for tumour cells and the patients were classified as BM positive (BM+) or BM negative (BM-). The study originally included 328 consecutive patients with uveal melanoma from 1997 to 2006. The cohort was limited to 217 patients when we introduced cyto- or histopathological verification of melanoma cells in the patient as a main new criterion for inclusion. Tumour cells were found in BM-samples in 38.7% (95% CI, 32–45) at enrolment. Until the latest work-up 43.8% (95% CI, 38–50) of patients had developed melanoma metastases. After a minimum follow-up time of 8.5 years, 60.4% (95% CI, 54–66) of patients had died. The causes were: melanoma metastases 69.5%, another type of cancer 5.4% and non-cancerous causes 19.5%. Overall median survival was shorter for the BM- patients (11.3 years) (95% CI, 10–12) compared to the BM+ (16.5 years) (95% CI, 12–14), p = 0.04, log rank test. All-cause mortality and specific melanoma mortality estimated after 12 year follow-up showed a highly significant difference comparing BM- and BM+, p = 0.010 and p = 0,017, respectively. IMS yields a high fraction of BM+ samples due to micrometastasis at diagnosis and these cells appear to have a positive prognostic impact strengthening our previous report. The late recurrences support the concept of tumour dormancy.


Micrometastasis in bone marrow Uveal melanoma Exclusion criteria Immunomagnetic detection Survival Tumour dormancy 


  1. 1.
    Bergman L, Seregard S, Nilsson B, Ringborg U, Lundell G, Ragnarsson-Olding B (2002) Incidence of uveal melanoma in Sweden from 1960 to 1998. Invest Ophthalmol Vis Sci 43(8):2579–2583Google Scholar
  2. 2.
    Jensen OA (1982) Malignant melanomas of the human uvea: 25-year follow-up of cases in Denmark, 1943--1952. Acta Ophthalmol 60(2):161–182CrossRefGoogle Scholar
  3. 3.
    Kujala E, Makitie T, Kivela T (2003) Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 44(11):4651–4659CrossRefGoogle Scholar
  4. 4.
    Singh AD (2001) Uveal melanoma: implications of tumor doubling time. Ophthalmology 108(5):829–831CrossRefGoogle Scholar
  5. 5.
    Eyles J, Puaux A-L, Wang X, Toh B, Prakash C, Hong M, Tan TG, Zheng L, Ong LC, Jin Y, Kato M, Prévost-Blondel A, Chow P, Yang H, Abastado J-P (2010) Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest 120(6):2030–2039. CrossRefGoogle Scholar
  6. 6.
    Eide N, Faye RS, Hoifodt HK, Overgaard R, Jebsen P, Kvalheim G, Fodstad O (2009) Immunomagnetic detection of micrometastatic cells in bone marrow in uveal melanoma patients. Acta Ophthalmol 87(8):830–836. CrossRefGoogle Scholar
  7. 7.
    Eide N, Faye RS, Høifødt HK, Sandstad B, Qvale G, Faber R, Jebsen P, Kvalheim G, Fodstad Ø (2015) Immunomagnetic detection of micrometastatic cells in bone marrow of uveal melanoma patients: a paradox. Acta Ophthalmol 93(1):59–66. CrossRefGoogle Scholar
  8. 8.
    Coupland SE, Sidiki S, Clark BJ, McClaren K, Kyle P, Lee WR (1996) Metastatic choroidal melanoma to the contralateral orbit 40 years after enucleation. Arch Ophthalmol 114(6):751–756. CrossRefGoogle Scholar
  9. 9.
    Mooy CM, Luyten GP, de Jong PT, Luider TM, Stijnen T, van de Ham F, van Vroonhoven CC, Bosman FT (1995) Immunohistochemical and prognostic analysis of apoptosis and proliferation in uveal melanoma. Am J Pathol 147 (4):1097–1104Google Scholar
  10. 10.
    Pantel K, Cote RJ, Fodstad O (1999) Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst 91(13):1113–1124CrossRefGoogle Scholar
  11. 11.
    Borthwick NJ, Thombs J, Polak M, Gabriel FG, Hungerford JL, Damato B, Rennie IG, Jager MJ, Cree IA (2011) The biology of micrometastases from uveal melanoma. J Clin Pathol 64(8):666–671. CrossRefGoogle Scholar
  12. 12.
    Bronkhorst IHG, Jager MJ (2013) Inflammation in uveal melanoma. Eye 27(2):217–223. CrossRefGoogle Scholar
  13. 13.
    Ma J, Usui Y, Takeuchi M, Okunuki Y, Kezuka T, Zhang L, Mizota A, Goto H (2010) Human uveal melanoma cells inhibit the immunostimulatory function of dendritic cells. Exp Eye Res 91(4):491–499. CrossRefGoogle Scholar
  14. 14.
    Suesskind D, Ulmer A, Schiebel U, Fierlbeck G, Spitzer B, Spitzer MS, Bartz-Schmidt KU, Grisanti S (2011) Circulating melanoma cells in peripheral blood of patients with uveal melanoma before and after different therapies and association with prognostic parameters: a pilot study. Acta Ophthalmol 89(1):17–24. CrossRefGoogle Scholar
  15. 15.
    Torres V, Triozzi P, Eng C, Tubbs R, Schoenfiled L, Crabb JW, Saunthararajah Y, Singh AD (2011) Circulating tumor cells in uveal melanoma. Future Oncol 7(1):101–109. CrossRefGoogle Scholar
  16. 16.
    Edge SB, Compton CC (2010) The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17(6):1471–1474. CrossRefGoogle Scholar
  17. 17.
    Khan S, Finger PT, Yu GP, Razzaq L, Jager MJ, de Keizer RJ, Sandkull P, Seregard S, Gologorsky D, Schefler AC, Murray TG, Kivela T, Giuliari GP, McGowan H, Simpson ER, Corriveau C, Coupland SE, Damato BE (2012) Clinical and pathologic characteristics of biopsy-proven iris melanoma: a multicenter international study. Arch Ophthalmol 130(1):57–64. CrossRefGoogle Scholar
  18. 18.
    Li Y, Madigan MC, Lai K, Conway RM, Billson FA, Crouch R, Allen BJ (2003) Human uveal melanoma expresses NG2 immunoreactivity. Br J Ophthalmol 87(5):629–632CrossRefGoogle Scholar
  19. 19.
    Char DH, Miller T (1995) Accuracy of presumed uveal melanoma diagnosis before alternative therapy. Br J Ophthalmol 79(7):692–696CrossRefGoogle Scholar
  20. 20.
    Damato B (2010) Does ocular treatment of uveal melanoma influence survival? Br J Cancer 103(3):285–290Google Scholar
  21. 21.
    Finger PT, Kurli M, Reddy S, Tena LB, Pavlick AC (2005) Whole body PET/CT for initial staging of choroidal melanoma. Br J Ophthalmol 89(10):1270–1274. CrossRefGoogle Scholar
  22. 22.
    Faye RS, Aamdal S, Hoifodt HK, Jacobsen E, Holstad L, Skovlund E, Fodstad O (2004) Immunomagnetic detection and clinical significance of micrometastatic tumor cells in malignant melanoma patients. Clin Cancer Res 10(12 Pt 1):4134–4139. CrossRefGoogle Scholar
  23. 23.
    Eide N, Hoifodt HK, Nesland JM, Faye RS, Qvale GA, Faber RT, Jebsen P, Kvalheim G, Fodstad O (2013) Disseminated tumour cells in bone marrow of patients with uveal melanoma. Acta Ophthalmol 91(4):343–348. CrossRefGoogle Scholar
  24. 24.
    Ulmer A, Schmidt-Kittler O, Fischer J, Ellwanger U, Rassner G, Riethmuller G, Fierlbeck G, Klein CA (2004) Immunomagnetic enrichment, genomic characterization, and prognostic impact of circulating melanoma cells. Clin Cancer Res 10(2):531–537CrossRefGoogle Scholar
  25. 25.
    Tura A, Luke J, Merz H, Reinsberg M, Luke M, Jager MJ, Grisanti S (2014) Identification of circulating melanoma cells in uveal melanoma patients by dual-marker immunoenrichment. Invest Ophthalmol Vis Sci 55(7):4395–4404. CrossRefGoogle Scholar
  26. 26.
    Freeman JB, Gray ES, Millward M, Pearce R, Ziman M (2012) Evaluation of a multi-marker immunomagnetic enrichment assay for the quantification of circulating melanoma cells. J Transl Med 10:192. CrossRefGoogle Scholar
  27. 27.
    Cools-Lartigue JJ, McCauley CS, Marshall JC, Di Cesare S, Gregoire F, Antecka E, Logan P, Burnier MN (2008) Immunomagnetic isolation and in vitro expansion of human uveal melanoma cell lines. Mol Vis 14:50–55Google Scholar
  28. 28.
    Callejo SA, Antecka E, Blanco PL, Edelstein C, Burnier MN Jr (2006) Identification of circulating malignant cells and its correlation with prognostic factors and treatment in uveal melanoma. A prospective longitudinal study. Eye 21(6):752–759CrossRefGoogle Scholar
  29. 29.
    Tura A, Merz H, Reinsberg M, Luke M, Jager MJ, Grisanti S, Luke J (2016) Analysis of monosomy-3 in immunomagnetically isolated circulating melanoma cells in uveal melanoma patients. Pigment Cell Melanoma Res 29(5):583–589. CrossRefGoogle Scholar
  30. 30.
    Demicheli R, Fornili M, Biganzoli E (2014) Bimodal mortality dynamics for uveal melanoma: a cue for metastasis development traits? BMC Cancer 14:392–392. CrossRefGoogle Scholar
  31. 31.
    Zimmerman LE, McLean IW, Foster WD (1978) Does enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells. Br J Ophthalmol 62:420–425CrossRefGoogle Scholar
  32. 32.
    Packard RBS (1980) Pattern of mortality in choroidal malignant melanoma. Br J Ophthalmol 64:565–575CrossRefGoogle Scholar
  33. 33.
    Eide MB, Liestol K, Lingjaerde OC, Hystad ME, Kresse SH, Meza-Zepeda L, Myklebost O, Troen G, Aamot HV, Holte H, Smeland EB, Delabie J (2010) Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallel evolution of tumor cell clones. Blood 116(9):1489–1497. CrossRefGoogle Scholar
  34. 34.
    Marshall JC, Nantel A, Blanco P, Ash J, Cruess SR, Burnier MN Jr (2007) Transcriptional profiling of human uveal melanoma from cell lines to intraocular tumors to metastasis. Clin Exp Metastasis 24(5):353–362. CrossRefGoogle Scholar
  35. 35.
    Mackie RM, Reid R, Junor B (2003) Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med 348:567–568CrossRefGoogle Scholar
  36. 36.
    Kolandjian NA, Wei C, Patel SP, Richard JL, Dett T, Papadopoulos NE, Bedikian AY (2013) Delayed systemic recurrence of uveal melanoma. Am J Clin Oncol 36(5):443–449. CrossRefGoogle Scholar
  37. 37.
    Burg MA, Grako KA, Stallcup WB (1998) Expression of the NG2 proteoglycan enhances the growth and metastatic properties of melanoma cells. J Cell Physiol 177(2):299–312.<299:aid-jcp12>;2-5 CrossRefGoogle Scholar
  38. 38.
    Eide N, Garred O, Beiske K, Fodstad O (2016) Bilateral uveal melanomas with different gene expression detected with 7 years interval. Acta Ophthalmol 94(1):99–102. CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  1. 1.Department of OphthalmologyOslo University Hospital HFOsloNorway
  2. 2.Department of DermatologyOslo University Hospital HFOsloNorway
  3. 3.Department of Tumor BiologyOslo University Hospital HF and University of OsloOsloNorway
  4. 4.Department of StatisticsOslo University Hospital HFOsloNorway
  5. 5.Division of PathologyOslo University Hospital HFOsloNorway
  6. 6.Department of OncologyOslo University Hospital HFOsloNorway

Personalised recommendations