Uveal melanoma natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Overview

If left untreated, 50% of patients with uveal melanoma may progress to develop metastasis. Common complications of uveal melanoma include glaucoma, vision loss, and metastasis. Prognosis is generally good for patients with iris melanoma, and the 10 year-survival for iris melanoma is approximately 95 percent and for ciliochoroidal tumors is 77 percent respectively.[1]

Natural History

The clinical course is unpredictable and metastatic disease can develop very late after a long disease-free interval. Uveal melanoma metastasizes haematogenously, predominantly to the liver.[2] Less than 4% of patients with uveal melanoma have detectable metastatic disease, at the time of diagnosis. However in further course about half of patients will develop metastases. When metastatic disease appears it unavoidably leads to death because of lack of effective systemic treatment.[1]

Complications

Complications of eye melanoma include the following:[3]

Eye melanoma can spread outside of the eye and to distant areas of the body, including the liver, lungs and bones.

Complications of therapy of uveal melanoma

Prognosis

Poor prognostic factors for systemic disease include the follwing:

The mortality rate for small (< 2 - 3 mm apical height), medium (3 - 8 mm apical height) and large (> 8 mm apical height) melanoma is 16%, 32% and 53% in 5 years, respectively.[10]
  • Choroidal nevi are considered benign if there diameter and thickness are approximately ≤5 mm and ≤ 1 mm respectively. The mortality risk from such a lesion is essentially zero.[11]
  • Ciliary body involvement[12]
  • Presence of orange pigment overlying the tumor[5]
  • Extrascleral extension[13][14][15][16]
  • Histological and cytological factors associated with higher risk of metastasis includes the following:
    • Presence and extent of cells with epitheliod morphology
    • Presence of looping extracellular matrix patterns
    • Increased infiltration of immune cells[17]
    • Staining with several immunohistochemical markers[18]
  • Cell type
Cell type is the most commonly used predictor of outcome following enucleation, with spindle-A cell melanomas carrying the best prognosis and epithelioid cell melanomas carrying the least favorable prognosis. Nevertheless, most tumors have an admixture of cell types, and there is no clear consensus regarding the proportion of epithelioid cells that constitutes designation of a tumor as mixed or epithelioid.
  • Several additional microscopic features can affect the prognosis of intraocular melanoma, including:[19]
    • Mitotic activity.
    • Lymphocytic infiltration.
    • Fibrovascular loops
    • Extraocular extension, recurrence, and metastasis are associated with an extremely poor prognosis, and long-term survival cannot be expected. Systemic metastases may be wide spread, with the liver > lung > bone > kidney > brain being a common sites for tumor deposits.
    • Uveal melanoma disseminates hematogenously, with a high propensity for liver, which is the most common (93%) site of metastasizing, followed by lung (24%) and bones (16%). It can also metastasize in brain and skin, or any other site in the body. The majority of patients with metastatic disease have metastases in multiple sites of body. Patients without liver metastases or with liver being not the first site of metastases have better prognosis.
    • Patients with iris melanoma have better prognosis. In patients with iris melanoma at 5 and 10 years of follow up metastases were found in 4.1%, and 6.9%, respectively, compared to 15% and 25%, respectively, for choroidal melanomas. Ciliary body melanoma carries worse prognosis with metastases found at 5 and 10 years follow up in 19% and 33%, respectively.
    • Uveal melanoma does not spread to regional lymph nodes, due to lack of lymphatic drainage in uvea except in rare cases of direct invasion of conjunctiva and then through conjunctival lymphatics to regional lymph nodes. Five-year survival rates for uveal melanoma ranges from 69% to 81.6% and ten-year survival rates from 57% to 62%. After detection of metastases 80% of patients die within 1 year, and 92% within 2 year. Long term survivals are rare in patients with uveal melanoma, and mean survival is only few months.[1]
  • The 5-year mortality rate associated with metastasis from ciliary body or choroidal melanoma is approximately 30%, compared with a rate of 2% to 3% for iris melanomas.
  • Overall survival depends on tumour size, extraocular spread, and metastases. Even small (<10 mm diameter, <3 mm thickness) tumors still carry a 10-15% 5-year mortality.
  • The 10 year-survival for iris melanoma is approximately 95 percent and for ciliochoroidal tumors is 77 percent respectively.
  • The most important genetic alteration associated with poor prognosis in uveal melanoma is inactivation of BAP1, which most often occurs through mutation of one allele and subsequent loss of an entire copy of chromosome 3 (monosomy 3 ) to unmask the mutant copy.[20] Because of this function in inactivation of BAP1, monosomy 3 correlates strongly with metastatic spread.[21]
  • Where BAP1 mutation status is not available, gains on chromosomes 6 and 8 can be used to refine the predictive value of the monosomy 3 screen, with gain of 6p indicating a better prognosis and gain of 8q indicating a worse prognosis in disomy 3 tumors.[22]
  • In rare instances, monosomy 3 tumors may duplicate the BAP1-mutant copy of the chromosome to return to a disomic state referred to as isodisomy. Thus, isodisomy 3 is prognostically equivalent to monosomy 3, and both can be detected by tests for chromosome 3 loss of heterozygosity.[23]
  • Monosomy 3, along with other chromosomal gains, losses, amplifications, and LOH, can be detected in fresh or paraffin embedded samples by virtual karyotyping.
  • The most accurate prognostic factor is molecular classification by gene expression profiling of uveal melanomas. This analysis has been used to identify two subclasses of uveal melanomas:[24] [25]
    • Class 1 tumors that have a very low risk of metastasis.
    • Class 2 tumors that have a very high risk of metastasis.
Gene expression profiling outperforms all of the above-mentioned factors at predicting metastatic spread of the primary tumor, including monosomy 3.[26][27][28]
The tumor node metastasis (TNM) staging system of the American Joint Committee on Cancer takes into account the key factors involved which are known to be of prognostic significance.[29][7]
  • The prognosis is usually poor when local control is not achieved with the initial treatment.[30] [31]
Detection of circulating tumor cells at the time of diagnosis is an independent risk factor for relapse and shortened survival in patients at high-risk based upon clinical parameters.[32][33]
  • The prognosis for any patient with recurring or relapsing disease is poor, regardless of cell type or stage.

References

  1. ↑ 1.0 1.1 1.2 Jovanovic P, Mihajlovic M, Djordjevic-Jocic J, Vlajkovic S, Cekic S, Stefanovic V (2013). "Ocular melanoma: an overview of the current status". Int J Clin Exp Pathol. 6 (7): 1230–44. PMC 3693189. PMID 23826405.
  2. ↑ Wöll E, Bedikian A, Legha SS (1999). "Uveal melanoma: natural history and treatment options for metastatic disease". Melanoma Res. 9 (6): 575–81. PMID 10661768.
  3. ↑ Singh, Arun D., and Bertil Damato. Clinical ophthalmic oncology : uveal tumors. Heidelberg: Springer, 2014. Print.
  4. ↑ Augsburger JJ, Gamel JW (1990). "Clinical prognostic factors in patients with posterior uveal malignant melanoma". Cancer. 66 (7): 1596–600. PMID 2208011.
  5. ↑ 5.0 5.1 Gragoudas E, Li W, Goitein M, Lane AM, Munzenrider JE, Egan KM (2002). "Evidence-based estimates of outcome in patients irradiated for intraocular melanoma". Arch Ophthalmol. 120 (12): 1665–71. PMID 12470140.
  6. ↑ Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD; et al. (2005). "Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26". Arch Ophthalmol. 123 (12): 1639–43. doi:10.1001/archopht.123.12.1639. PMID 16344433.
  7. ↑ 7.0 7.1 Shields CL, Kaliki S, Furuta M, Fulco E, Alarcon C, Shields JA (2013). "American Joint Committee on Cancer classification of posterior uveal melanoma (tumor size category) predicts prognosis in 7731 patients". Ophthalmology. 120 (10): 2066–71. doi:10.1016/j.ophtha.2013.03.012. PMID 23664467.
  8. ↑ Kujala E, Damato B, Coupland SE, Desjardins L, Bechrakis NE, Grange JD; et al. (2013). "Staging of ciliary body and choroidal melanomas based on anatomic extent". J Clin Oncol. 31 (22): 2825–31. doi:10.1200/JCO.2012.45.2771. PMID 23816968.
  9. ↑ AJCC Ophthalmic Oncology Task Force (2015). "International Validation of the American Joint Committee on Cancer's 7th Edition Classification of Uveal Melanoma". JAMA Ophthalmol. 133 (4): 376–83. doi:10.1001/jamaophthalmol.2014.5395. PMID 25555246.
  10. ↑ van, J.G.M.; Koopmans, A.E.; Verdijk, R.M.; Naus, N.C.; de, A.; Kilic, E. (2013). "Diagnosis, Histopathologic and Genetic Classification of Uveal Melanoma". doi:10.5772/53631.
  11. ↑ Augsburger JJ (1993). "Is observation really appropriate for small choroidal melanomas". Trans Am Ophthalmol Soc. 91: 147–68, discussion 169-75. PMC 1298464. PMID 8140689.
  12. ↑ Li W, Gragoudas ES, Egan KM (2000). "Metastatic melanoma death rates by anatomic site after proton beam irradiation for uveal melanoma". Arch Ophthalmol. 118 (8): 1066–70. PMID 10922199.
  13. ↑ Gragoudas ES, Seddon JM, Egan KM, Polivogianis L, Hsieh CC, Goitein M; et al. (1986). "Prognostic factors for metastasis following proton beam irradiation of uveal melanomas". Ophthalmology. 93 (5): 675–80. PMID 3014416.
  14. ↑ Schmittel A, Bechrakis NE, Martus P, Mutlu D, Scheibenbogen C, Bornfeld N; et al. (2004). "Independent prognostic factors for distant metastases and survival in patients with primary uveal melanoma". Eur J Cancer. 40 (16): 2389–95. doi:10.1016/j.ejca.2004.06.028. PMID 15519510.
  15. ↑ Kleineidam M, Guthoff R, Bentzen SM (1993). "Rates of local control, metastasis, and overall survival in patients with posterior uveal melanomas treated with ruthenium-106 plaques". Radiother Oncol. 28 (2): 148–56. PMID 8248556.
  16. ↑ Affeldt JC, Minckler DS, Azen SP, Yeh L (1980). "Prognosis in uveal melanoma with extrascleral extension". Arch Ophthalmol. 98 (11): 1975–9. PMID 7436829.
  17. ↑ Robbins, Stanley L., Vinay Kumar, and Ramzi S. Cotran. Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Saunders/Elsevier, 2010. Print.
  18. ↑ Pardo M, Dwek RA, Zitzmann N (2007). "Proteomics in uveal melanoma research: opportunities and challenges in biomarker discovery". Expert Rev Proteomics. 4 (2): 273–86. doi:10.1586/14789450.4.2.273. PMID 17425462.
  19. ↑ Uveal melanoma. National Cancer Institute(2015) http://www.cancer.gov/types/eye/hp/intraocular-melanoma-treatment-pdq#link/_304_toc Accessed on October 23, 2015
  20. ↑ Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA; et al. (2010). "Frequent mutation of BAP1 in metastasizing uveal melanomas". Science. 330 (6009): 1410–3. doi:10.1126/science.1194472. PMC 3087380. PMID 21051595.
  21. ↑ Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jöckel KH, Becher R (1996). "Prognostic implications of monosomy 3 in uveal melanoma". Lancet. 347 (9010): 1222–5. PMID 8622452.
  22. ↑ Damato B, Dopierala J, Klaasen A, van Dijk M, Sibbring J, Coupland SE (2009). "Multiplex ligation-dependent probe amplification of uveal melanoma: correlation with metastatic death". Invest Ophthalmol Vis Sci. 50 (7): 3048–55. doi:10.1167/iovs.08-3165. PMID 19182252.
  23. ↑ Onken MD, Worley LA, Person E, Char DH, Bowcock AM, Harbour JW (2007). "Loss of heterozygosity of chromosome 3 detected with single nucleotide polymorphisms is superior to monosomy 3 for predicting metastasis in uveal melanoma". Clin Cancer Res. 13 (10): 2923–7. doi:10.1158/1078-0432.CCR-06-2383. PMID 17504992.
  24. ↑ Tschentscher F, Hüsing J, Hölter T, Kruse E, Dresen IG, Jöckel KH; et al. (2003). "Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities". Cancer Res. 63 (10): 2578–84. PMID 12750282.
  25. ↑ Onken MD, Worley LA, Ehlers JP, Harbour JW (2004). "Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death". Cancer Res. 64 (20): 7205–9. doi:10.1158/0008-5472.CAN-04-1750. PMID 15492234.
  26. ↑ Petrausch U, Martus P, Tönnies H, Bechrakis NE, Lenze D, Wansel S; et al. (2008). "Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases". Eye (Lond). 22 (8): 997–1007. doi:10.1038/sj.eye.6702779. PMID 17384575.
  27. ↑ van Gils W, Lodder EM, Mensink HW, Kiliç E, Naus NC, Brüggenwirth HT; et al. (2008). "Gene expression profiling in uveal melanoma: two regions on 3p related to prognosis". Invest Ophthalmol Vis Sci. 49 (10): 4254–62. doi:10.1167/iovs.08-2033. PMID 18552379.
  28. ↑ Worley LA, Onken MD, Person E, Robirds D, Branson J, Char DH; et al. (2007). "Transcriptomic versus chromosomal prognostic markers and clinical outcome in uveal melanoma". Clin Cancer Res. 13 (5): 1466–71. doi:10.1158/1078-0432.CCR-06-2401. PMID 17332290.
  29. ↑ Shields, CarolL; Mellen, PhoebeL; Morton, SpenserJ (2013). "American joint committee on cancer staging of uveal melanoma". Oman Journal of Ophthalmology. 6 (2): 116. doi:10.4103/0974-620X.116652. ISSN 0974-620X.
  30. ↑ Egger E, Zografos L, Schalenbourg A, Beati D, Böhringer T, Chamot L; et al. (2003). "Eye retention after proton beam radiotherapy for uveal melanoma". Int J Radiat Oncol Biol Phys. 55 (4): 867–80. PMID 12605964.
  31. ↑ Egan KM, Ryan LM, Gragoudas ES (1998). "Survival implications of enucleation after definitive radiotherapy for choroidal melanoma: an example of regression on time-dependent covariates". Arch Ophthalmol. 116 (3): 366–70. PMID 9514491.
  32. ↑ Schuster R, Bechrakis NE, Stroux A, Busse A, Schmittel A, Scheibenbogen C; et al. (2007). "Circulating tumor cells as prognostic factor for distant metastases and survival in patients with primary uveal melanoma". Clin Cancer Res. 13 (4): 1171–8. doi:10.1158/1078-0432.CCR-06-2329. PMID 17317826.
  33. ↑ Boldin I, Langmann G, Richtig E, Schwantzer G, Ardjomand N, Wegscheider B; et al. (2005). "Five-year results of prognostic value of tyrosinase in peripheral blood of uveal melanoma patients". Melanoma Res. 15 (6): 503–7. PMID 16314735.

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