Abstract
Primary cancers of the eye are rare. These include uveal melanoma, a tumor that preferentially affects the choroid of light-eyed, fair-skinned Europeans, and the pediatric retinal neoplasm retinoblastoma, which is slightly more common worldwide. Uveal melanoma kills about half of affected patients. Most succumb to hepatic metastases, which are unresponsive to current therapy. Factors indicative of poor prognosis include tumor size, ciliary body involvement, epithelioid cells, extraocular extension, lymphocytic and melanophagic infiltration, mitotic activity, vascular mimicry patterns, and most importantly, the detection of monosomy 3 and class 2 gene expression profile in tumor cells using special tests. Most retinoblastomas are caused by sporadic somatic mutations in the RB1 gene, but about one-third arise in infants with germline mutations. The latter tend to develop earlier, are often bilateral and are transmissible to offspring as an autosomal dominant trait. Retinoblastoma displays varying degrees of differentiation including Homer Wright and Flexner–Wintersteiner rosettes and photoreceptor differentiation (fleurettes). Rosettes are more common in eyes enucleated from very young infants. Tumors composed entirely of fleurettes (retinoma/retinocytoma) are thought to be retinoblastoma precursors, and like retinoblastoma, harbor mutations in both copies of the RB1 gene. Retinoblastoma is a major cancer treatment success story in developed countries where most deaths are caused by secondary tumors in germline mutation carriers. High-risk histopathological features that are an indication for adjuvant chemotherapy include massive uveal invasion and retrolaminar optic nerve invasion. Eye-sparing therapies including brachyradiotherapy and systemic and intra-arterial chemotherapy have reduced the number of eyes with retinoblastoma requiring enucleation in recent years.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Nelson CC, Hertzberg BS, Klintworth GK . A histopathologic study of 716 unselected eyes in patients with cancer at the time of death. Am J Ophthalmol 1983; 95: 788–793.
Kivelä T . The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Brit J Ophthalmol 2009; 93: 1129–1131.
Hu DN, Yu GP, McCormick SA, Schneider S, Finger PT . Population-based incidence of uveal melanoma in various races and ethnic groups. Am J Ophthalmol 2005; 140: 612–617.
Lists of Ethnic Groups. http://en.wikipedia.org/wiki/Lists_of_ethnic_groups.
Shah CP, Weis E, Lajous M, Shields JA, Shields CL . Intermittent and chronic ultraviolet light exposure and uveal melanoma: a meta-analysis. Ophthalmology 2005; 112: 1599–1607.
Schmidt-Pokrzywniak A, Jöckel KH, Bornfeld N, Sauerwein W, Stang A . Positive interaction between light iris color and ultraviolet radiation in relation to the risk of uveal melanoma: a case-control study. Ophthalmology 2009; 116: 340–348.
Shields CL, Furuta M, Thangappan A, Nagori S, Mashayekhi A, Lally DR et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol 2009; 127: 989–998.
Albert DM, Diener-West M, Robinson NL, Grossniklaus HE, Green WR . Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol 1998; 125: 745–766.
Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci 2008; 49: 5230–5234.
Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457: 599–602.
Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363: 2191–2199.
Zuidervaart W, van der Velden PA, Hurks MH, van Nieuwpoort FA, Out-Luiting CJ, Singh AD et al. Gene expression profiling identifies tumour markers potentially playing a role in uveal melanoma development. Br J Cancer 2003; 89: 1914–1919.
Tschentscher F, Hüsing J, Hölter T, Kruse E, Dresen IG, Jöckel KH et al. Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Res 2003; 63: 2578–2584.
Onken MD, Worley LA, Ehlers JP, Harbour JW . Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res 2004; 64: 7205–7209.
Chang SH, Worley LA, Onken MD, Harbour JW . Prognostic biomarkers in uveal melanoma: evidence for a stem cell-like phenotype associated with metastasis. Melanoma Res 2008; 18: 191–200.
Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jöckel KH, Becher R et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996; 347: 1222–1225.
Sisley K, Rennie IG, Parsons MA, Jacques R, Hammond DW, Bell SM et al. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer 1997; 19: 22–28.
White VA, Chambers JD, Courtright PD, Chang WY, Horsman DE . Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer 1998; 83: 354–359.
Damato B, Dopierala JA, Coupland SE . Genotypic profiling of 452 choroidal melanomas with multiplex ligation-dependent probe amplification. Clin Cancer Res 2010; 16: 6083–6092.
Shields CL, Ganguly A, Materin MA, Teixeira L, Mashayekhi A, Swanson LA et al. Chromosome 3 analysis of uveal melanoma using fine-needle aspiration biopsy at the time of plaque radiotherapy in 140 consecutive cases: The Deborah Iverson, MD, Lectureship. Arch Ophthalmol 2007; 125: 1017–1024.
Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330: 1410–1413.
Onken MD, Worley LA, Tuscan MD, Harbour JW . An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 2010; 12: 461–468.
Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012; 119: 1596–1603.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti AM (eds).. American Joint Commission on Cancer. Cancer Staging Manual 7th Edition Springer: New York, 2010.
McLean IW, Foster WD, Zimmerman LE . Uveal melanoma: location, size, cell type, and enucleation as risk factors in metastasis. Hum Pathol 1982; 13: 123–132.
Callender G . Malignant melanotic tumors of the eye: A study of histologic types in 111 cases. Trans Am Acad Ophthalmol Otolaryngol 1931; 36: 131–142.
McLean IW, Foster WD, Zimmerman LE, Gamel JW . Modifications of Callender’s classification of uveal melanoma at the Armed Forces Institute of Pathology. Am J Ophthalmol 1983; 96: 502–509.
Gamel JW, McLean IW . Quantitative analysis of the Callender classification of uveal melanoma cells. Arch Ophthalmol 1977; 95: 686–691.
Diener-West M, Earle JD, Fine SL, Hawkins BS, Moy CS, Reynolds SM et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: III. Initial mortality findings. COMS Report No. 18. Arch Ophthalmol 2001; 119: 969–982.
Schmittel A, Bechrakis NE, Martus P, Mutlu D, Scheibenbogen C, Bornfeld N et al. Independent prognostic factors for distant metastases and survival in patients with primary uveal melanoma. Eur J Cancer 2004; 40: 2389–2395.
McLean IW, Ainbinder DJ, Gamel JW, McCurdy JB . Choroidal-ciliary body melanoma. A multivariate survival analysis of tumor location. Ophthalmology 1995; 102: 1060–1064.
Al-Jamal RT, Kivela T . KI-67 immunopositivity in choroidal and ciliary body melanoma with respect to nucleolar diameter and other prognostic factors. Curr Eye Res 2006; 31: 57–67.
de la Cruz PO, Specht CS, McLean IW . Lymphocytic infiltration in uveal malignant melanoma. Cancer 1990; 65: 112–115.
Whelchel JC, Farah SE, McLean IW, Burnier MN . Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci 1993; 34: 2603–2606.
Mäkitie T, Summanen P, Tarkkanen A, Kivelä T . Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 2001; 42: 1414–1421.
Folberg R, Rummelt V, Parys-Van Ginderdeuren R, Woolson RF, Pe’er J, Gruman LM et al. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 1993; 100: 1389–1398.
Makitie T, Summanen P, Tarkkanen A, Kivela T . Microvascular loops and networks as prognostic indicators in choroidal and ciliary body melanomas. J Natl Cancer Inst 1999; 91: 359–367.
Coupland SE, Campbell I, Damato B . Routes of extraocular extension of uveal melanoma: Risk factors and influence on survival probability. Ophthalmology 2008; 115: 1778–1785.
Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD et al. 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 2005; 123: 1639–1643.
Eskelin S, Pyrhonen S, Summanen P, Hahka-Kemppinen M, Kivelä T . Tumor doubling times in metastatic malignant melanoma of the uvea: Tumor progression before and after treatment. Ophthalmology 2000; 107: 1443–1449.
Augsburger JJ, Corrêa ZM, Shaikh AH . Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol 2009; 148: 119–127.
Shields CL, Shields JA, Shah P . Retinoblastoma in older children. Ophthalmology 1991; 98: 395–399.
Dryja TP, Cavenee W, White R, Rapaport JM, Petersen R, Albert DM et al. Homozygosity of chromosome 13 in retinoblastoma. N Engl J Med 1984; 310: 550–553.
Albert DM, Dryja TP . Recent studies of the retinoblastoma gene. What it means to the ophthalmologist. Arch Ophthalmol 1988; 106: 181–182.
Brantley MA, Harbour JW . The molecular biology of retinoblastoma. Ocul Immunol Inflamm 2001; 9: 1–8.
Abramson DH . Second nonocular cancers in retinoblastoma: a unified hypothesis. The Franceschetti Lecture. Ophthalmic Genet 1999; 20: 193–204.
Meadows AT, Leahey AM . More about second cancers after retinoblastoma. J Natl Cancer Inst 2008; 100: 1743–1745.
Dimaras H, Khetan V, Halliday W, Orlic M, Prigoda NL, Piovesan B et al. Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet 2008; 15 (17): 1363–1372.
Gallie BL, Rushlow DE, Yee JY, Kennett P, Boutros NL, Prigoda-Lee W et al. A new disease: retinoblastoma with no detectable RB1 mutations driven by MYCN. Abstract. XVth Biannual Meeting. International Society of Ocular Oncology: Buenos Aires, Nov 14 2011.
Shields JA, Shields CL, Eagle RC, Blair CJ . Spontaneous pseudohypopyon secondary to diffuse infiltrating retinoblastoma. Arch Ophthalmol 1988; 106: 1301–1302.
Shields JA, Shields CL, Suvarnamani C, Schroeder RP, DePotter P . Retinoblastoma manifesting as orbital cellulitis. Am J Ophthalmol 1991; 112: 442–449.
Burnier MN, McLean IW, Zimmerman LE, Rosenberg SH . Retinoblastoma. The relationship of proliferating cells to blood vessels. Invest Ophthalmol Vis Sci 1990; 31: 2037–2040.
Ts’o MO, Fine BS, Zimmerman LE . The Flexner-Wintersteiner rosettes in retinoblastoma. Arch Pathol 1969; 88: 664–671.
Ts'o MO, Zimmerman LE, Fine BS . The nature of retinoblastoma. I. Photoreceptor differentiation: a clinical and histopathologic study. Am J Ophthalmol 1970; 69: 339–349.
Ts’o MO, Fine BS, Zimmerman LE . The nature of retinoblastoma. II. Photoreceptor differentiation: an electron microscopic study. Am J Ophthalmol 1970; 69: 350–359.
Eagle RC . High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med 2009; 133: 1203–1209.
Sastre X, Chantada GL, Doz F, Wilson MW, de Davila MT, Rodriguez-Galindo C et al. Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med 2009; 133: 1199–1202.
Chévez- Barrios P . Pathology of high-risk retinoblastoma. In Ramasubrahmanian A, Shields CL, (eds). Retinoblastoma. Jaypee: New Delhi, pp 223–230.
Shields CL, Shields JA, De Potter P, Minelli S, Hernandez C, Brady LW et al. Plaque radiotherapy in the management of retinoblastoma. Use as a primary and secondary treatment [see comments]. Ophthalmology 1993; 100: 216–224.
Shields CL, Mashayekhi A, Cater J, Shelil A, Meadows AT, Shields JA et al. Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol 2004; 138: 329–337.
Kaliki S, Shields CL, Shah SU, Eagle RC, Shields JA, Leahey A . Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Arch Ophthalmol 2011; 129 (11): 1422–1427.
Eagle RC, Shields CL, Bianciotto C, Jabbour P, Shields JA . Histopathologic observations after intra-arterial chemotherapy for retinoblastoma. Arch Ophthalmol 2011; 129: 1416–1421.
Munier FL, Gaillard MC, Balmer A, Soliman S, Podilsky G, Moulin AP et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 2012; 96: 1078–1083.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no conflict of interest.
Rights and permissions
About this article
Cite this article
Eagle, R. The pathology of ocular cancer. Eye 27, 128–136 (2013). https://doi.org/10.1038/eye.2012.237
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/eye.2012.237
Keywords
This article is cited by
-
Systemic adjuvant chemotherapy for advanced malignant ocular medulloepithelioma
Eye (2023)
-
Natural killer cells and pigment epithelial-derived factor control the infiltrative and nodular growth of hepatic metastases in an Orthotopic murine model of ocular melanoma
BMC Cancer (2019)
-
Prognostic relevance of ATM protein in uveal melanoma and its association with clinicopathological factors
International Journal of Clinical Oncology (2019)
-
Exploration of potential key pathways and genes in multiple ocular cancers through bioinformatics analysis
Graefe's Archive for Clinical and Experimental Ophthalmology (2019)
-
In vitro characterization of CD133lo cancer stem cells in Retinoblastoma Y79 cell line
BMC Cancer (2017)
