Uveal melanoma among Finnish children and young adults Rana’a T. Al-Jamal, MD, and Tero Kivel€a, MD, FEBO PURPOSE METHODS
RESULTS
CONCLUSIONS
To characterize uveal melanoma (UM) among children and young adults in a high-risk region for this cancer. The medical records of consecutive patients \25 years of age with UM treated from 1962 to 2009 were retrospectively reviewed. The following data were collected: sex, tumor location and size, tumor node metastasis (TNM) stage, vision, and survival. We compared data with five previous series reporting 70 matching patients and combined them for metaanalysis of survival. Of 1,185 UM patients, 18 were eligible. UM frequency in patients \25 years of age was 1.3%; in those #20 years of age, 0.6%. Median follow-up time was longer than in the previous series combined (11.6 vs 5.4 years). Females outnumbered males 2:1. Median tumor thickness was higher in our series (8 vs 5 mm) and increased with age. Median tumor diameter was similar to previous series (12 mm). Of our patients, 83% were stage II; 17%, stage III. In previous series, 26% were stage I; 64%, stage II; and 10%, stage III. Survival was 76% at 5 and 10 years, compared to 98% in previous series. By meta-analysis, mortality increased with stage, age . 17 years, female sex, and if the ciliary body was involved. Tumor stage was higher than in other regions. Age .17 years, female sex, and tumor stage adversely influenced survival among patients \25 years of age with UM. ( J AAPOS 2014;18:61-66)
U
veal melanoma (UM) is currently the second most common primary intraocular malignancy after retinoblastoma worldwide1 and the second most common type of primary malignant melanoma in humans.2 It is relatively rare, with an estimated incidence of 2-8 cases per million in whites, depending on latitude.3,4 UM is generally slow growing and gives rise to hematogeneous metastases, mainly in the liver,5 in over 50% of patients during the 3 decades following primary treatment.6 The incidence of UM increases after 45 years of age7; it is generally a disease of the elderly, with a median age at diagnosis of 62 years, but it may also be diagnosed at any age from birth8-10 to puberty. However, the majority of affected young patients are postpubescent.11-15 In one study, among 8,967 referred UM patients, 122 (1.4%) were #20 years of age.16 Characteristics of UM among children and young adults have not been precisely defined, except that the proportion Author affiliations: Ocular Oncology Service, Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland Supported by grants from the Finnish Eye Foundation, Evald and Hilda Nissi Foundation, and the Sigrid Juselius Foundation, and the HUCH Research Funds (TYH 2012106 and TYH 2013316). Submitted April 18, 2013. Revision accepted November 1, 2013. Correspondence: Rana’a T. Al-Jamal, MD, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL 220, FI-00029 HUS, Helsinki, Finland (email: [email protected]). Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.11.006
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with iris melanoma is higher and the rate of metastasis perhaps lower than in older patients.11,13,15,17-23 In a recent study evaluating clinical features and life prognosis of UM based on age at presentation, 21% of 106 patients #20 years old had iris melanoma, compared to 4% in adults aged 21-60 years and 2% in adults .60 years.24 Young and mid-range adults also showed a smaller tumor basal diameter and a lower metastasis and mortality rate. Known risk factors for development of UM are congenital ocular and oculodermal melanocytosis, neurofibromatosis type I, and the familial atypical mole-melanoma syndrome,25 but it is uncertain whether these factors play any significant role in children and young adults who develop UM. Of the many small retrospective cohorts of UM in children and young adults, none has been from northern Europe, where the risk for UM is the highest in the world, with an incidence of 6.1 to 8.6 cases per million.4 The purpose of this study was to compare data from a Finnish cohort of patients with choroidal and ciliary body melanoma who were \25 years of age with previous case series from areas of mostly lower risk for UM (2.0 to 4.1 per million).4,20 We also performed a meta-analysis of survival by combining our series with previous ones.
Patients and Methods The medical records of consecutive patients\25 years of age diagnosed with a choroidal or ciliary body melanoma at the Ocular Oncology Service, Helsinki University Central Hospital, between 1962 and 2009 were retrospectively reviewed. This age range was considered the best average match for previous series, which
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included patients up to 20-30 years of age, and allowed comparison of younger and older age subgroups. Patients with melanomas involving the iris were excluded. This study conformed to local laws and adhered to the principles of the Declaration of Helsinki. Clinical data extracted from records included age, sex, intraocular pressure (IOP), and visual acuity at diagnosis and at last visit, congenital ocular melanocytosis or other predisposing factors, tumor location, thickness, largest basal diameter, and primary treatment. Tumor thickness was earlier measured from enucleation specimens and later with ultrasound. Survival status and cause of death were acquired from Statistics Finland. The tumors were staged according to the 7th edition of the tumor, node, metastasis (TNM) system of the American Joint Committee on Cancer.26 Patients were divided in two groups (Table 1) based on the treatment type: surgical (1968-2002) or irradiated (1978-2006). We compared our results to previous series collected from studies (excepting isolated case reports) reporting case-wise data on UM among pediatric patients and young adults and performed a meta-analysis on the aggregate data.11-15 We identified five previously reported series with 70 patients matching our series (Table 1). The data extracted included age, sex, visual acuity at diagnosis and at final visit, presence of predisposing factors, tumor location, thickness, largest basal diameter, primary treatment, and survival status. All iris melanomas and patients .24 years were excluded. We also staged these tumors, whenever possible, according to the TNM system.27 All analyses were performed with Stata 11.0 statistical software (Stata, College Station, TX) with a P value of \ 0.05 considered statistically significant. All tests were two-tailed. The median and range are given as descriptive statistics. Pearson’s c2 and nonparametric test for trend28 were used to compare unordered and singly ordered contingency tables, respectively, and Mann-WhitneyWilcoxon-test to compare continuous variables between groups. Overall survival was calculated as the time from the date of diagnosis of primary tumor to death. Survival was analyzed with the Kaplan-Meier product-limit method and log-rank test. Patients judged to have died from causes other than UM were censored. Because only 1 patient died of unrelated causes, a separate competing risk analysis was not performed. The small number of 7 melanoma deaths did not allow for multivariate analysis.
Results The total number of cases in the meta-analysis of survival, which included our data and previous data, was 88 patients with choroidal or ciliary body melanoma (e-Supplement 1, available at jaapos.org). Of our registry of 1,185 white patients with a choroidal and ciliary body melanoma from May 1962 to December 2009, 18 (1.5%) met the inclusion criteria. During the 10-year period starting in January 2000 and ending in December 2009 our service was a national referral center that managed more than 95% of Finnish patients with uveal melanoma. During this period, an essentially population-based cohort of 534 patients was diagnosed, and 7 patients (1.3%; 95% CI, 0.5-2.6) fulfilled our inclusion criteria. Of these, 3 cases (0.6%; 95% CI, 0.1-1.6) were #20 years of age.
Volume 18 Number 1 / February 2014 The surgical group consisted of 8 mostly earlier patients (44%), including 6 females, who were treated by primary enucleation (6) or local tumor resection (Table 1, e-Supplement 1). Two melanomas extended to the ciliary body but none had extraocular extension. All were stage II. Five patients had visual acuity of $20/40. No recurrences developed locally. The 2 patients who underwent local resection retained visual acuity of 20/200 and counting fingers in the treated eye. Four patients have died, all female, 3 of metastases and 1 of intoxication (confirmed by autopsy). The irradiated group consisted of 10 patients (56%) treated by brachytherapy. In this group, 7 patients were female (Table 1, e-Supplement 1). One patient who was pregnant received iodine brachytherapy after consulting the National Radiation Authority and gave birth to a healthy baby 6 months after treatment. The tumors were confined to the choroid in all but 3 patients. Three patients had visual acuity of $20/40. Seven were stage II; 3, stage III. One patient retained reading vision and 9 became legally blind from adverse events (Table 1, Figure 1). One patient developed a vertical local recurrence (secondary enucleation), and another experienced sequential marginal recurrences (secondary irradiation and transpupillary thermotherapy). Three patients have died of metastases, all female. None of our 18 patients had a lesion predisposing to uveal melanoma. The median age of 20 years (range, 13-24 years) in our series was higher than the median of 18 years (range, 7-23 years) in the five previous series (P 5 0.016; Table 1, e-Supplement 1, e-Supplement 2A, available at jaapos.org). However, the median age of our patients #20 years was the same as in the previous series (18 years). Female patients predominated, as in the combined previous reports (72% vs 61%; P 5 0.37) except for one study14 in which males outnumbered females (33%). Males were significantly less often affected than females overall (29 vs 50; P 5 0.024, binomial test). The median tumor thickness was higher in our study than in previous series (8 mm vs 5 mm; P 5 0.024; Table 1, e-supplements 1 and 2B), whereas the median largest basal diameter was comparable with the previous series (12 mm vs 12 mm; P 5 0.47, Table 1, e-Supplement 1 and e-Supplement 2C). The median thickness was smaller in those who were #20 years of age as compared to older patients (7 vs 9.5 mm). Ciliary body involvement was comparable in frequency with previous series (28% vs 21%; P 5 0.56; Table 1). By the TNM classification, our tumors fell in the following categories: T2, 56%; T3, 33%; and T4, 11%; whereas in previous series T1, not seen in our series, accounted for 28%; T2, for 38%; T3, for 32%; and T4, for 2% (P 5 0.073; Table 1, e-Supplement 1). TNM stage in our series was stage II in 83% and stage III in 17%. By contrast, in the previous series stage I accounted for 26%; stage II, for 64%; and stage III, for 10% (P\0.073; Table 1). Whereas 56% of our patients underwent brachytherapy, only 37% of patients reported in the previous series were treated by irradiation (P 5 0.16; Table 1, e-Supplement 1).
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Table 1. Patient and tumor characteristics of young patients with choroidal and ciliary body melanoma in the present series and five matched previous series Present series by group Characteristics Sex, n (%) Male Female Median age, years (range) Median tumor thickness, mm (range) Median tumor size LBD, mm (range) Ciliary body involvement, n (%) Yes No TNM category, n (%) T1a T1b T2a T2b T3a T3b T4a T4b TNM stage, n (%) I IIA IIB IIIA IIIB Initial visual acuity, n (%) 20/20 20/25-20/40 20/50-20/200 CF-LP NLP Treatment type, n (%) Iodine plaque Ruthenium plaque Enucleation Local resection Proton beam Other Treatment complications, n (%) Cataract Glaucoma Maculopathy Optic neuropathy Local recurrence, n (%) Median follow-up time, years (range) Final visual acuity, n (%) 20/20 20/25-20/40 20/50-20/200 CF-LP NLP Survival status, n (%) Alive Dead of metastasis Female Male Dead of other causes
Surgery (n 5 8)
Brachytherapy (n 5 10)
Series combined for meta-analysis Present (n 5 18)
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P value 0.37a
2 (25) 6 (75) 19 (13-23) 7 (4-11) 12 (9-16.5)
3 (30) 7 (70) 20.5 (13-24) 8.5 (4.4-9.7) 13.25 (11-21)
5 (28) 13 (72) 20 (13-24) 8 (4-13) 12 (9-21)
24 (39) 37 (61) 18 (7-23) 5 (1-10.5) 12 (5-20)
2 (25) 6 (75)
3 (30) 7 (70)
5 (28) 13 (72)
15 (21) 55 (79)
4 (50) 2 (25) 2 (25) -
4 (40) 3 (30) 1 (10) 2 (20)
8 (44) 2 (11) 5 (28) 1 (6) 2 (11)
13 (26) 1 (2) 15 (30) 4 (8) 12 (24) 4 (8) 1 (2)
4 (50) 4 (50) -
4 (40) 3 (30) 1 (10) 2 (20)
8 (44) 7 (39) 1 (6) 2 (11)
13 (26) 16 (32) 15 (32) 4 (8) 1 (2)
1 (12.5) 4 (50) 1 (12.5) 1 (12.5) 1 (12.5)
1 (10) 2 (20) 5 (50) 2 (20) -
2 (11) 6 (33) 6 (33) 3 (17) 1 (6)
N/A N/A N/A N/A N/A
6 (75) 2 (25) -
8 (80) 2 (20) -
8 (45) 2 (11) 6 (33) 2 (11) -
N/Ad N/Ad 43 (96) 2 (4) 17 (68) 8 (32)
13.7 (4-37)
9 (90) 5 (50) 3 (50) 2 (20) 6.1 (0.6-28)
9 (50) 5 (28) 3 (17) 2 (11) 11.6 (0.6-37)
N/A N/A N/A N/A N/A 5.4 (0.4-25)
1 (12.5) 1 (12.5) 6 (75)
1 (10) 5 (50) 4 (40)
1 (5) 1 (5) 6 (34) 10 (56)
N/A N/A N/A N/A N/A
4 (50) 3 (38) 3 (50) 0 (0) 1 (12)
7 (70) 3 (30) 3 (43) 0 (0) -
11 (61) 6 (33) 6 (46) 0 (0) 1 (6)
69 (99) 1 (1) 1 (1) 0 (0) 0 (0)
CF, counting fingers; LBD, linear basal diameter; LP, light perception; TNM, tumor node metastasis. Two-tailed c2 test. b Two-tailed Mann-Whitney-Wilcoxon-test. c Two-tailed nonparametric test for trend. d Three patients were managed with brachytherapy, isotope unspecified (included here under “other”). a
Previous (n 5 70)
0.016b 0.024b 0.47b 0.56a 0.073c
0.073c
0.039b
\0.0001a
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Volume 18 Number 1 / February 2014 Median follow-up time was longer in our study than in previous series (11.6 years [range, 0.6-37 years] vs 5.4 years [range, 0.4-25 years]; P 5 0.039; Table 1, e-Supplement 2D). Survival in our series was 76% at 5 and 10 years (95% CI, 49-90), and 68% at 15 years (95% CI, 39-86; Figure 2A). It was lower in our study compared to the five previous series combined, corresponding to 98% survival at 15 years (Figure 2A; P 5 0.007, log-rank test). Combining both series in meta-analysis, mortality was nil if age was \18 years as compared to 20% at 15 years’ follow-up for those aged 18-20 years, and 42% in the 21-24 years age group (Figure 2B; P 5 0.019, log-rank test for trend). Mortality was not associated with tumor thickness (Figure 2C; P 5 0.87) or with tumor largest basal diameter (Figure 2D; P 5 0.25). Mortality was also higher if the ciliary body was involved (Figure 2E; P 5 0.019, log-rank test). Mortality at 5 years was 0% for stage I tumors, 8% (95% CI, 3-22) for stage II, and 50% (95% CI, 15-94) for stage III (Figure 2F; P 5 0.030 log-rank test for trend).
Discussion
FIG 1. A, Fundus photograph at diagnosis of an 18-year-old young woman with a choroidal melanoma (case 11, e-Supplement 1) B, Fundus of the same patient after treatment with iodine brachytherapy, tumor regressed from 6.0 to 1.5 mm in thickness, vision CF from radiation maculopathy, patient died of metastases at 3 years 9 months. C, Fundus photograph at diagnosis of a 20-year-old woman with a choroidal melanoma (case 13, e-Supplement 1) D, Fundus of the same patient after treatment twice with ruthenium brachytherapy and transpupillary thermotherapy for sequential marginal recurrences, vision CF from direct tumor involvement, patient is alive at 16 years 7 months. E, Fundus photograph of a 21-year-old woman with a choroidal melanoma (case 14, e-Supplement 1) F, Fundus of the same patient after treatment with iodine brachytherapy, vision HM from chronic exudative retinal detachment, patient died of metastases at 3 years 1 month. G, Fundus photograph at diagnosis of a 24-yearold woman with a choroidal melanoma photographed using a wideangle camera (case 18, e-Supplement 1), tumor extended from the iris (inset) to the optic nerve H, Fundus photograph of the same patient after treatment with two combined iodine plaques, vision HM from radiation maculopathy, anterior part of the tumor has also regressed (inset), patient is alive at 7 years and 2 months.
Previous series of UM among young individuals reporting case wise data have typically included both iris as well as choroidal and ciliary body melanomas.24 Only Vavvas and colleagues,12 who reported 17 patients \20 years of age, excluded iris melanomas. We did not include iris melanomas in our study because they have a more favorable prognosis24; our meta-analysis likewise included only choroidal and ciliary body melanomas. The frequency of choroidal and ciliary body melanomas in our dataset was 1.3% overall (no iris melanomas, upper age limit 24 years) and 0.6% in patients #20 years of age, which is roughly comparable with three previous estimates ranging from 0.4% to 0.8% (excluding iris melanomas) for this age limit, although Leonard and colleagues13 reported a frequency of 1.3% (Table 1). The latter figure is the same as the 1.3% to 1.4% frequency in a recent larger single-center series.16,24 This variation is influenced to an unknown extent by referral pattern; our estimate is population based. All our patients were $13 years of age, and none had a predisposing factor. In the five previous series analyzed, 2 of 33 patients (9 and 11 years old),11 3 of 9 patients (7-10 years old),15 and 1 of 17 patients (11 years old)12 were younger than those in our study. In the large referral series, 98 of 122 patients (80%) were $13 years of age.16 Although case reports exist of even younger patients,29,16 one can conclude that children who develop UM are typically $11 years of age and extremely rarely \7 years. The median age of our patients who were #20 years of age was the same as in comparable reports from lower risk areas for UM. Five patients in previous series had a predisposing factor (ocular melanocytosis).15 Females predominated in our study, and two-thirds of the patients overall also were females. In the referralbased single-center series reported by Kaliki and colleagues,16 however, female preponderance was not
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FIG 2. Kaplan-Meier survival curves representing survival among children and young adults with primary choroidal and ciliary body in our series and in five matched previous series (ticks indicate censored observations). Survival was lower in our series as compared the five previous reports (A). Combining both series in meta-analysis mortality increased with age (B), but was not associated with tumor thickness (C) or largest basal diameter (D). Mortality was higher if the ciliary body was involved (E) and it increased with tumor stage (F).
statistically significant (53 vs 69; P 5 0.17, binomial test). Unlike the case with older age groups,6 this sex imbalance cannot be explained by more frequent competing causes of death. Our meta-analysis series was large enough to confirm that the difference was unlikely due to chance. Tumor thickness in our study was significantly larger by 2.5 mm, or 50%, compared to the five previous series, but the median largest basal diameter did not differ, reflected in the fact that none of our melanomas staged into size category T1a (small, stage I), which otherwise comprised 22% of patients in the five previous series combined. This stage difference might relate to the fact that our patients came
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from a high-incidence area for UM, a hypothesis that must be tested by a prospective collaborative multinational study. The proportions of tumors that represented size categories T3 (large) and T4 (very large) were, however, comparable in our cohort and the five previous series. Survival was significantly shorter in our series compared to the previous series (76% vs 98% at 5 and 10 years, and 68% vs 98% at 15 years). The median follow-up time in our study was twice as long as in the previous series combined (11.6 vs 5.8 years), which explains only part of the survival difference because half of this difference already became evident during the first 5 years. Kaliki and
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colleagues16 reported a survival rate among 92 patients with ciliary body or choroidal melanoma who were #20 years of age of 92% at 5 years, 92% at 10 years, and 84% at 15 years.16 These rates were intermediate between our series and the five previous series and higher than among mid-range adults matched for tumor and demographic characters (86%, 66%, and 66%).16 These statistics, however, were not adjusted for the higher risk of death from other causes in older age groups.6 Meta-analysis of 88 patients revealed that mortality was higher for age .17 years, if ciliary body was involved, and if TNM stage was higher. Tumor thickness was not statistically associated with survival: those with thickest tumors had the best survival rate. Moreover, all patients who died of metastasis in our series and in the previous five series were females.24 In the recent referral based series including iris melanomas, 6 of 122 patients died of metastasis (one had an iris melanoma), and 3 of them were males.16 Altogether, of 13 young patients with metastasis, at least 10 were females.16 In a recent matched series of 92 ciliary body and choroidal melanomas, age was also found to be a risk factor for metastasis in patients #20 of age.16 In conclusion, we found that the percentage of young patients with UM was not higher nor the age of diagnosis in this group of patients earlier in northern Europe, a high-incidence region for UM, compared with previous reports predominantly from lower-risk areas. However, the tumors in our series were on average of more advanced TNM stage at the time of diagnosis, contributing to higher mortality estimates. Our meta-analysis suggests that children and adolescents \17 years of age with a choroidal melanoma are likely to have an excellent life prognosis, especially if they are boys, but the life prognosis may be guarded in the 18-24 years age group, especially in females and if the ciliary body is involved. Further collaboration through a controlled prospective population-based, multinational study is needed to confirm these hypotheses.
Literature Search PubMed was searched using the following keywords: uveal, choroidal OR ciliary body; melanoma; young, child, children, OR adolescent(s), and corresponding ages.
Acknowledgments The authors gratefully acknowledge Dr. Mamunur Rashid for his assistance. References 1. Kivel€a T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol 2009;93:1129-31. 2. Singh AD, Rennie IG, Kivel€a T, Seregard S, Grossniklaus H. The Zimmerman-McLean-Foster hypothesis: 25 years later. Br J Ophthalmol 2004;88:962-7.
Volume 18 Number 1 / February 2014 3. Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology 2003;110:956-61. 4. Virgili G, Gatta G, Ciccolallo L, et al., EUROCARE Working Group. Incidence of uveal melanoma in Europe. Ophthalmology 2007;114:2309-15. 5. Eskelin S, Summanen P, Pyrh€ onen S, Prause JU, Kivel€a T. Screening for metastatic uveal melanoma revisited. Cancer 1999;85:1151-9. 6. Kujala E, M€akitie T, Kivel€a T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 2003;44: 4651-9. 7. Bergman L, Seregard S, Nilsson B, Ringborg U, Lundell G, Ragnarsson-Olding B. Incidence of uveal melanoma in Sweden from 1960 to 1998. Invest Ophthalmol Vis Sci 2002;43:2579-83. 8. Broadway D, Lang S, Harper J, et al. Congenital malignant melanoma of the eye. Cancer 1991;67:2642-52. 9. Greer CH. Congenital melanoma of the anterior uvea. Arch Ophthalmol 1966;76:77-8. 10. Reese AB. Congenital melanomas. Am J Ophthalmol 1974;77:789-808. 11. Shields CL, Shields JA, Milite J, De Potter P, Sabbagh R, Menduke H. Uveal melanoma in teenagers and children: a report of 40 cases. Ophthalmology 1991;98:1662-6. 12. Vavvas D, Kim I, Lane AM, Chaglassian A, Mukai S, Gragoudas E. Posterior uveal melanoma in young patients treated with proton beam therapy. Retina 2010;30:1267-71. 13. Leonard BC, Shields JA, McDonald PR. Malignant melanomas of the uveal tract in children and young adults. Can J Ophthalmol 1975;10: 441-9. 14. Pogrzebielski A, Orlowska-Heitzman J, Romanowska-Dixon B. Uveal melanoma in young patients. Graefes Arch Clin Exp Ophthalmol 2006;244:1646-9. 15. Verdaguer J. Prepuberal and puberal melanomas in ophthalmology. Am J Ophthalmol 1965;60:1002-11. 16. Kaliki S, Shields CL, Mashayekhi A, Ganesh A, Furuta M, Shields JA. Influence of age on prognosis of young patients with uveal melanoma: a matched retrospective cohort study. Eur J Immunol 2013;43: 208-16. 17. Barr CC, McLean IW, Zimmerman LE. Uveal melanoma in children and adolescents. Arch Ophthalmol 1981;99:2133-6. 18. Greven CM, Stanton C, Yeatts RP, Shields CL. Diffuse iris melanoma in a young patient. Arch Ophthalmol 1997;115:682-3. 19. Jensen OA. Malignant melanomas of the human uvea: 25-year followup of cases in Denmark, 1943-1952. Acta Ophthalmol (Copenh) 1982; 60:161-82. 20. Singh AD, Shields CL, Shields JA, Sato T. Uveal melanoma in young patients. Arch Ophthalmol 2000;118:918-23. 21. Cury D, Lucic H, Irvine A Jr. Prepubertal intraocular malignant melanoma. Am J Ophthalmol 1959;47:202-6. 22. Ellsworth RM. Juvenile melanoma of the uvea. Trans Am Acad Ophthalmol Otolaryngol 1960;64:148-9. 23. Gailloud C, Zografos L, Bercher L, Uffer S, Egger E. Uveal melanomas in patients less than 20 years of age [in French]. Klin Monatsbl Augenheilkd 1992;200:428-30. 24. Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina 2012;32:1363-72. 25. Singh AD, Wang MX, Donoso LA, Shields CL, De Potter P, Shields JA. Genetic aspects of uveal melanoma: a brief review. Semin Oncol 1996;23:768-72. 26. Malignant melanoma of the uvea. In: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010:547-59. 27. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours. 6th ed. New York, NY: Wiley-Liss; 2002:218-21. 28. Altman DG. Practical Statistics for Medical Research. London: Chapman & Hall; 1991. 29. Grabowska A, Abelarias J, Peralta J, et al. Uveal melanoma in a 19-month-old child. J AAPOS 2011;15:606-8.
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RESULTS
CONCLUSIONS
To characterize uveal melanoma (UM) among children and young adults in a high-risk region for this cancer. The medical records of consecutive patients \25 years of age with UM treated from 1962 to 2009 were retrospectively reviewed. The following data were collected: sex, tumor location and size, tumor node metastasis (TNM) stage, vision, and survival. We compared data with five previous series reporting 70 matching patients and combined them for metaanalysis of survival. Of 1,185 UM patients, 18 were eligible. UM frequency in patients \25 years of age was 1.3%; in those #20 years of age, 0.6%. Median follow-up time was longer than in the previous series combined (11.6 vs 5.4 years). Females outnumbered males 2:1. Median tumor thickness was higher in our series (8 vs 5 mm) and increased with age. Median tumor diameter was similar to previous series (12 mm). Of our patients, 83% were stage II; 17%, stage III. In previous series, 26% were stage I; 64%, stage II; and 10%, stage III. Survival was 76% at 5 and 10 years, compared to 98% in previous series. By meta-analysis, mortality increased with stage, age . 17 years, female sex, and if the ciliary body was involved. Tumor stage was higher than in other regions. Age .17 years, female sex, and tumor stage adversely influenced survival among patients \25 years of age with UM. ( J AAPOS 2014;18:61-66)
U
veal melanoma (UM) is currently the second most common primary intraocular malignancy after retinoblastoma worldwide1 and the second most common type of primary malignant melanoma in humans.2 It is relatively rare, with an estimated incidence of 2-8 cases per million in whites, depending on latitude.3,4 UM is generally slow growing and gives rise to hematogeneous metastases, mainly in the liver,5 in over 50% of patients during the 3 decades following primary treatment.6 The incidence of UM increases after 45 years of age7; it is generally a disease of the elderly, with a median age at diagnosis of 62 years, but it may also be diagnosed at any age from birth8-10 to puberty. However, the majority of affected young patients are postpubescent.11-15 In one study, among 8,967 referred UM patients, 122 (1.4%) were #20 years of age.16 Characteristics of UM among children and young adults have not been precisely defined, except that the proportion Author affiliations: Ocular Oncology Service, Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland Supported by grants from the Finnish Eye Foundation, Evald and Hilda Nissi Foundation, and the Sigrid Juselius Foundation, and the HUCH Research Funds (TYH 2012106 and TYH 2013316). Submitted April 18, 2013. Revision accepted November 1, 2013. Correspondence: Rana’a T. Al-Jamal, MD, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL 220, FI-00029 HUS, Helsinki, Finland (email: [email protected]). Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.11.006
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with iris melanoma is higher and the rate of metastasis perhaps lower than in older patients.11,13,15,17-23 In a recent study evaluating clinical features and life prognosis of UM based on age at presentation, 21% of 106 patients #20 years old had iris melanoma, compared to 4% in adults aged 21-60 years and 2% in adults .60 years.24 Young and mid-range adults also showed a smaller tumor basal diameter and a lower metastasis and mortality rate. Known risk factors for development of UM are congenital ocular and oculodermal melanocytosis, neurofibromatosis type I, and the familial atypical mole-melanoma syndrome,25 but it is uncertain whether these factors play any significant role in children and young adults who develop UM. Of the many small retrospective cohorts of UM in children and young adults, none has been from northern Europe, where the risk for UM is the highest in the world, with an incidence of 6.1 to 8.6 cases per million.4 The purpose of this study was to compare data from a Finnish cohort of patients with choroidal and ciliary body melanoma who were \25 years of age with previous case series from areas of mostly lower risk for UM (2.0 to 4.1 per million).4,20 We also performed a meta-analysis of survival by combining our series with previous ones.
Patients and Methods The medical records of consecutive patients\25 years of age diagnosed with a choroidal or ciliary body melanoma at the Ocular Oncology Service, Helsinki University Central Hospital, between 1962 and 2009 were retrospectively reviewed. This age range was considered the best average match for previous series, which
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included patients up to 20-30 years of age, and allowed comparison of younger and older age subgroups. Patients with melanomas involving the iris were excluded. This study conformed to local laws and adhered to the principles of the Declaration of Helsinki. Clinical data extracted from records included age, sex, intraocular pressure (IOP), and visual acuity at diagnosis and at last visit, congenital ocular melanocytosis or other predisposing factors, tumor location, thickness, largest basal diameter, and primary treatment. Tumor thickness was earlier measured from enucleation specimens and later with ultrasound. Survival status and cause of death were acquired from Statistics Finland. The tumors were staged according to the 7th edition of the tumor, node, metastasis (TNM) system of the American Joint Committee on Cancer.26 Patients were divided in two groups (Table 1) based on the treatment type: surgical (1968-2002) or irradiated (1978-2006). We compared our results to previous series collected from studies (excepting isolated case reports) reporting case-wise data on UM among pediatric patients and young adults and performed a meta-analysis on the aggregate data.11-15 We identified five previously reported series with 70 patients matching our series (Table 1). The data extracted included age, sex, visual acuity at diagnosis and at final visit, presence of predisposing factors, tumor location, thickness, largest basal diameter, primary treatment, and survival status. All iris melanomas and patients .24 years were excluded. We also staged these tumors, whenever possible, according to the TNM system.27 All analyses were performed with Stata 11.0 statistical software (Stata, College Station, TX) with a P value of \ 0.05 considered statistically significant. All tests were two-tailed. The median and range are given as descriptive statistics. Pearson’s c2 and nonparametric test for trend28 were used to compare unordered and singly ordered contingency tables, respectively, and Mann-WhitneyWilcoxon-test to compare continuous variables between groups. Overall survival was calculated as the time from the date of diagnosis of primary tumor to death. Survival was analyzed with the Kaplan-Meier product-limit method and log-rank test. Patients judged to have died from causes other than UM were censored. Because only 1 patient died of unrelated causes, a separate competing risk analysis was not performed. The small number of 7 melanoma deaths did not allow for multivariate analysis.
Results The total number of cases in the meta-analysis of survival, which included our data and previous data, was 88 patients with choroidal or ciliary body melanoma (e-Supplement 1, available at jaapos.org). Of our registry of 1,185 white patients with a choroidal and ciliary body melanoma from May 1962 to December 2009, 18 (1.5%) met the inclusion criteria. During the 10-year period starting in January 2000 and ending in December 2009 our service was a national referral center that managed more than 95% of Finnish patients with uveal melanoma. During this period, an essentially population-based cohort of 534 patients was diagnosed, and 7 patients (1.3%; 95% CI, 0.5-2.6) fulfilled our inclusion criteria. Of these, 3 cases (0.6%; 95% CI, 0.1-1.6) were #20 years of age.
Volume 18 Number 1 / February 2014 The surgical group consisted of 8 mostly earlier patients (44%), including 6 females, who were treated by primary enucleation (6) or local tumor resection (Table 1, e-Supplement 1). Two melanomas extended to the ciliary body but none had extraocular extension. All were stage II. Five patients had visual acuity of $20/40. No recurrences developed locally. The 2 patients who underwent local resection retained visual acuity of 20/200 and counting fingers in the treated eye. Four patients have died, all female, 3 of metastases and 1 of intoxication (confirmed by autopsy). The irradiated group consisted of 10 patients (56%) treated by brachytherapy. In this group, 7 patients were female (Table 1, e-Supplement 1). One patient who was pregnant received iodine brachytherapy after consulting the National Radiation Authority and gave birth to a healthy baby 6 months after treatment. The tumors were confined to the choroid in all but 3 patients. Three patients had visual acuity of $20/40. Seven were stage II; 3, stage III. One patient retained reading vision and 9 became legally blind from adverse events (Table 1, Figure 1). One patient developed a vertical local recurrence (secondary enucleation), and another experienced sequential marginal recurrences (secondary irradiation and transpupillary thermotherapy). Three patients have died of metastases, all female. None of our 18 patients had a lesion predisposing to uveal melanoma. The median age of 20 years (range, 13-24 years) in our series was higher than the median of 18 years (range, 7-23 years) in the five previous series (P 5 0.016; Table 1, e-Supplement 1, e-Supplement 2A, available at jaapos.org). However, the median age of our patients #20 years was the same as in the previous series (18 years). Female patients predominated, as in the combined previous reports (72% vs 61%; P 5 0.37) except for one study14 in which males outnumbered females (33%). Males were significantly less often affected than females overall (29 vs 50; P 5 0.024, binomial test). The median tumor thickness was higher in our study than in previous series (8 mm vs 5 mm; P 5 0.024; Table 1, e-supplements 1 and 2B), whereas the median largest basal diameter was comparable with the previous series (12 mm vs 12 mm; P 5 0.47, Table 1, e-Supplement 1 and e-Supplement 2C). The median thickness was smaller in those who were #20 years of age as compared to older patients (7 vs 9.5 mm). Ciliary body involvement was comparable in frequency with previous series (28% vs 21%; P 5 0.56; Table 1). By the TNM classification, our tumors fell in the following categories: T2, 56%; T3, 33%; and T4, 11%; whereas in previous series T1, not seen in our series, accounted for 28%; T2, for 38%; T3, for 32%; and T4, for 2% (P 5 0.073; Table 1, e-Supplement 1). TNM stage in our series was stage II in 83% and stage III in 17%. By contrast, in the previous series stage I accounted for 26%; stage II, for 64%; and stage III, for 10% (P\0.073; Table 1). Whereas 56% of our patients underwent brachytherapy, only 37% of patients reported in the previous series were treated by irradiation (P 5 0.16; Table 1, e-Supplement 1).
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Table 1. Patient and tumor characteristics of young patients with choroidal and ciliary body melanoma in the present series and five matched previous series Present series by group Characteristics Sex, n (%) Male Female Median age, years (range) Median tumor thickness, mm (range) Median tumor size LBD, mm (range) Ciliary body involvement, n (%) Yes No TNM category, n (%) T1a T1b T2a T2b T3a T3b T4a T4b TNM stage, n (%) I IIA IIB IIIA IIIB Initial visual acuity, n (%) 20/20 20/25-20/40 20/50-20/200 CF-LP NLP Treatment type, n (%) Iodine plaque Ruthenium plaque Enucleation Local resection Proton beam Other Treatment complications, n (%) Cataract Glaucoma Maculopathy Optic neuropathy Local recurrence, n (%) Median follow-up time, years (range) Final visual acuity, n (%) 20/20 20/25-20/40 20/50-20/200 CF-LP NLP Survival status, n (%) Alive Dead of metastasis Female Male Dead of other causes
Surgery (n 5 8)
Brachytherapy (n 5 10)
Series combined for meta-analysis Present (n 5 18)
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P value 0.37a
2 (25) 6 (75) 19 (13-23) 7 (4-11) 12 (9-16.5)
3 (30) 7 (70) 20.5 (13-24) 8.5 (4.4-9.7) 13.25 (11-21)
5 (28) 13 (72) 20 (13-24) 8 (4-13) 12 (9-21)
24 (39) 37 (61) 18 (7-23) 5 (1-10.5) 12 (5-20)
2 (25) 6 (75)
3 (30) 7 (70)
5 (28) 13 (72)
15 (21) 55 (79)
4 (50) 2 (25) 2 (25) -
4 (40) 3 (30) 1 (10) 2 (20)
8 (44) 2 (11) 5 (28) 1 (6) 2 (11)
13 (26) 1 (2) 15 (30) 4 (8) 12 (24) 4 (8) 1 (2)
4 (50) 4 (50) -
4 (40) 3 (30) 1 (10) 2 (20)
8 (44) 7 (39) 1 (6) 2 (11)
13 (26) 16 (32) 15 (32) 4 (8) 1 (2)
1 (12.5) 4 (50) 1 (12.5) 1 (12.5) 1 (12.5)
1 (10) 2 (20) 5 (50) 2 (20) -
2 (11) 6 (33) 6 (33) 3 (17) 1 (6)
N/A N/A N/A N/A N/A
6 (75) 2 (25) -
8 (80) 2 (20) -
8 (45) 2 (11) 6 (33) 2 (11) -
N/Ad N/Ad 43 (96) 2 (4) 17 (68) 8 (32)
13.7 (4-37)
9 (90) 5 (50) 3 (50) 2 (20) 6.1 (0.6-28)
9 (50) 5 (28) 3 (17) 2 (11) 11.6 (0.6-37)
N/A N/A N/A N/A N/A 5.4 (0.4-25)
1 (12.5) 1 (12.5) 6 (75)
1 (10) 5 (50) 4 (40)
1 (5) 1 (5) 6 (34) 10 (56)
N/A N/A N/A N/A N/A
4 (50) 3 (38) 3 (50) 0 (0) 1 (12)
7 (70) 3 (30) 3 (43) 0 (0) -
11 (61) 6 (33) 6 (46) 0 (0) 1 (6)
69 (99) 1 (1) 1 (1) 0 (0) 0 (0)
CF, counting fingers; LBD, linear basal diameter; LP, light perception; TNM, tumor node metastasis. Two-tailed c2 test. b Two-tailed Mann-Whitney-Wilcoxon-test. c Two-tailed nonparametric test for trend. d Three patients were managed with brachytherapy, isotope unspecified (included here under “other”). a
Previous (n 5 70)
0.016b 0.024b 0.47b 0.56a 0.073c
0.073c
0.039b
\0.0001a
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Volume 18 Number 1 / February 2014 Median follow-up time was longer in our study than in previous series (11.6 years [range, 0.6-37 years] vs 5.4 years [range, 0.4-25 years]; P 5 0.039; Table 1, e-Supplement 2D). Survival in our series was 76% at 5 and 10 years (95% CI, 49-90), and 68% at 15 years (95% CI, 39-86; Figure 2A). It was lower in our study compared to the five previous series combined, corresponding to 98% survival at 15 years (Figure 2A; P 5 0.007, log-rank test). Combining both series in meta-analysis, mortality was nil if age was \18 years as compared to 20% at 15 years’ follow-up for those aged 18-20 years, and 42% in the 21-24 years age group (Figure 2B; P 5 0.019, log-rank test for trend). Mortality was not associated with tumor thickness (Figure 2C; P 5 0.87) or with tumor largest basal diameter (Figure 2D; P 5 0.25). Mortality was also higher if the ciliary body was involved (Figure 2E; P 5 0.019, log-rank test). Mortality at 5 years was 0% for stage I tumors, 8% (95% CI, 3-22) for stage II, and 50% (95% CI, 15-94) for stage III (Figure 2F; P 5 0.030 log-rank test for trend).
Discussion
FIG 1. A, Fundus photograph at diagnosis of an 18-year-old young woman with a choroidal melanoma (case 11, e-Supplement 1) B, Fundus of the same patient after treatment with iodine brachytherapy, tumor regressed from 6.0 to 1.5 mm in thickness, vision CF from radiation maculopathy, patient died of metastases at 3 years 9 months. C, Fundus photograph at diagnosis of a 20-year-old woman with a choroidal melanoma (case 13, e-Supplement 1) D, Fundus of the same patient after treatment twice with ruthenium brachytherapy and transpupillary thermotherapy for sequential marginal recurrences, vision CF from direct tumor involvement, patient is alive at 16 years 7 months. E, Fundus photograph of a 21-year-old woman with a choroidal melanoma (case 14, e-Supplement 1) F, Fundus of the same patient after treatment with iodine brachytherapy, vision HM from chronic exudative retinal detachment, patient died of metastases at 3 years 1 month. G, Fundus photograph at diagnosis of a 24-yearold woman with a choroidal melanoma photographed using a wideangle camera (case 18, e-Supplement 1), tumor extended from the iris (inset) to the optic nerve H, Fundus photograph of the same patient after treatment with two combined iodine plaques, vision HM from radiation maculopathy, anterior part of the tumor has also regressed (inset), patient is alive at 7 years and 2 months.
Previous series of UM among young individuals reporting case wise data have typically included both iris as well as choroidal and ciliary body melanomas.24 Only Vavvas and colleagues,12 who reported 17 patients \20 years of age, excluded iris melanomas. We did not include iris melanomas in our study because they have a more favorable prognosis24; our meta-analysis likewise included only choroidal and ciliary body melanomas. The frequency of choroidal and ciliary body melanomas in our dataset was 1.3% overall (no iris melanomas, upper age limit 24 years) and 0.6% in patients #20 years of age, which is roughly comparable with three previous estimates ranging from 0.4% to 0.8% (excluding iris melanomas) for this age limit, although Leonard and colleagues13 reported a frequency of 1.3% (Table 1). The latter figure is the same as the 1.3% to 1.4% frequency in a recent larger single-center series.16,24 This variation is influenced to an unknown extent by referral pattern; our estimate is population based. All our patients were $13 years of age, and none had a predisposing factor. In the five previous series analyzed, 2 of 33 patients (9 and 11 years old),11 3 of 9 patients (7-10 years old),15 and 1 of 17 patients (11 years old)12 were younger than those in our study. In the large referral series, 98 of 122 patients (80%) were $13 years of age.16 Although case reports exist of even younger patients,29,16 one can conclude that children who develop UM are typically $11 years of age and extremely rarely \7 years. The median age of our patients who were #20 years of age was the same as in comparable reports from lower risk areas for UM. Five patients in previous series had a predisposing factor (ocular melanocytosis).15 Females predominated in our study, and two-thirds of the patients overall also were females. In the referralbased single-center series reported by Kaliki and colleagues,16 however, female preponderance was not
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FIG 2. Kaplan-Meier survival curves representing survival among children and young adults with primary choroidal and ciliary body in our series and in five matched previous series (ticks indicate censored observations). Survival was lower in our series as compared the five previous reports (A). Combining both series in meta-analysis mortality increased with age (B), but was not associated with tumor thickness (C) or largest basal diameter (D). Mortality was higher if the ciliary body was involved (E) and it increased with tumor stage (F).
statistically significant (53 vs 69; P 5 0.17, binomial test). Unlike the case with older age groups,6 this sex imbalance cannot be explained by more frequent competing causes of death. Our meta-analysis series was large enough to confirm that the difference was unlikely due to chance. Tumor thickness in our study was significantly larger by 2.5 mm, or 50%, compared to the five previous series, but the median largest basal diameter did not differ, reflected in the fact that none of our melanomas staged into size category T1a (small, stage I), which otherwise comprised 22% of patients in the five previous series combined. This stage difference might relate to the fact that our patients came
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from a high-incidence area for UM, a hypothesis that must be tested by a prospective collaborative multinational study. The proportions of tumors that represented size categories T3 (large) and T4 (very large) were, however, comparable in our cohort and the five previous series. Survival was significantly shorter in our series compared to the previous series (76% vs 98% at 5 and 10 years, and 68% vs 98% at 15 years). The median follow-up time in our study was twice as long as in the previous series combined (11.6 vs 5.8 years), which explains only part of the survival difference because half of this difference already became evident during the first 5 years. Kaliki and
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colleagues16 reported a survival rate among 92 patients with ciliary body or choroidal melanoma who were #20 years of age of 92% at 5 years, 92% at 10 years, and 84% at 15 years.16 These rates were intermediate between our series and the five previous series and higher than among mid-range adults matched for tumor and demographic characters (86%, 66%, and 66%).16 These statistics, however, were not adjusted for the higher risk of death from other causes in older age groups.6 Meta-analysis of 88 patients revealed that mortality was higher for age .17 years, if ciliary body was involved, and if TNM stage was higher. Tumor thickness was not statistically associated with survival: those with thickest tumors had the best survival rate. Moreover, all patients who died of metastasis in our series and in the previous five series were females.24 In the recent referral based series including iris melanomas, 6 of 122 patients died of metastasis (one had an iris melanoma), and 3 of them were males.16 Altogether, of 13 young patients with metastasis, at least 10 were females.16 In a recent matched series of 92 ciliary body and choroidal melanomas, age was also found to be a risk factor for metastasis in patients #20 of age.16 In conclusion, we found that the percentage of young patients with UM was not higher nor the age of diagnosis in this group of patients earlier in northern Europe, a high-incidence region for UM, compared with previous reports predominantly from lower-risk areas. However, the tumors in our series were on average of more advanced TNM stage at the time of diagnosis, contributing to higher mortality estimates. Our meta-analysis suggests that children and adolescents \17 years of age with a choroidal melanoma are likely to have an excellent life prognosis, especially if they are boys, but the life prognosis may be guarded in the 18-24 years age group, especially in females and if the ciliary body is involved. Further collaboration through a controlled prospective population-based, multinational study is needed to confirm these hypotheses.
Literature Search PubMed was searched using the following keywords: uveal, choroidal OR ciliary body; melanoma; young, child, children, OR adolescent(s), and corresponding ages.
Acknowledgments The authors gratefully acknowledge Dr. Mamunur Rashid for his assistance. References 1. Kivel€a T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol 2009;93:1129-31. 2. Singh AD, Rennie IG, Kivel€a T, Seregard S, Grossniklaus H. The Zimmerman-McLean-Foster hypothesis: 25 years later. Br J Ophthalmol 2004;88:962-7.
Volume 18 Number 1 / February 2014 3. Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology 2003;110:956-61. 4. Virgili G, Gatta G, Ciccolallo L, et al., EUROCARE Working Group. Incidence of uveal melanoma in Europe. Ophthalmology 2007;114:2309-15. 5. Eskelin S, Summanen P, Pyrh€ onen S, Prause JU, Kivel€a T. Screening for metastatic uveal melanoma revisited. Cancer 1999;85:1151-9. 6. Kujala E, M€akitie T, Kivel€a T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 2003;44: 4651-9. 7. Bergman L, Seregard S, Nilsson B, Ringborg U, Lundell G, Ragnarsson-Olding B. Incidence of uveal melanoma in Sweden from 1960 to 1998. Invest Ophthalmol Vis Sci 2002;43:2579-83. 8. Broadway D, Lang S, Harper J, et al. Congenital malignant melanoma of the eye. Cancer 1991;67:2642-52. 9. Greer CH. Congenital melanoma of the anterior uvea. Arch Ophthalmol 1966;76:77-8. 10. Reese AB. Congenital melanomas. Am J Ophthalmol 1974;77:789-808. 11. Shields CL, Shields JA, Milite J, De Potter P, Sabbagh R, Menduke H. Uveal melanoma in teenagers and children: a report of 40 cases. Ophthalmology 1991;98:1662-6. 12. Vavvas D, Kim I, Lane AM, Chaglassian A, Mukai S, Gragoudas E. Posterior uveal melanoma in young patients treated with proton beam therapy. Retina 2010;30:1267-71. 13. Leonard BC, Shields JA, McDonald PR. Malignant melanomas of the uveal tract in children and young adults. Can J Ophthalmol 1975;10: 441-9. 14. Pogrzebielski A, Orlowska-Heitzman J, Romanowska-Dixon B. Uveal melanoma in young patients. Graefes Arch Clin Exp Ophthalmol 2006;244:1646-9. 15. Verdaguer J. Prepuberal and puberal melanomas in ophthalmology. Am J Ophthalmol 1965;60:1002-11. 16. Kaliki S, Shields CL, Mashayekhi A, Ganesh A, Furuta M, Shields JA. Influence of age on prognosis of young patients with uveal melanoma: a matched retrospective cohort study. Eur J Immunol 2013;43: 208-16. 17. Barr CC, McLean IW, Zimmerman LE. Uveal melanoma in children and adolescents. Arch Ophthalmol 1981;99:2133-6. 18. Greven CM, Stanton C, Yeatts RP, Shields CL. Diffuse iris melanoma in a young patient. Arch Ophthalmol 1997;115:682-3. 19. Jensen OA. Malignant melanomas of the human uvea: 25-year followup of cases in Denmark, 1943-1952. Acta Ophthalmol (Copenh) 1982; 60:161-82. 20. Singh AD, Shields CL, Shields JA, Sato T. Uveal melanoma in young patients. Arch Ophthalmol 2000;118:918-23. 21. Cury D, Lucic H, Irvine A Jr. Prepubertal intraocular malignant melanoma. Am J Ophthalmol 1959;47:202-6. 22. Ellsworth RM. Juvenile melanoma of the uvea. Trans Am Acad Ophthalmol Otolaryngol 1960;64:148-9. 23. Gailloud C, Zografos L, Bercher L, Uffer S, Egger E. Uveal melanomas in patients less than 20 years of age [in French]. Klin Monatsbl Augenheilkd 1992;200:428-30. 24. Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina 2012;32:1363-72. 25. Singh AD, Wang MX, Donoso LA, Shields CL, De Potter P, Shields JA. Genetic aspects of uveal melanoma: a brief review. Semin Oncol 1996;23:768-72. 26. Malignant melanoma of the uvea. In: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010:547-59. 27. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours. 6th ed. New York, NY: Wiley-Liss; 2002:218-21. 28. Altman DG. Practical Statistics for Medical Research. London: Chapman & Hall; 1991. 29. Grabowska A, Abelarias J, Peralta J, et al. Uveal melanoma in a 19-month-old child. J AAPOS 2011;15:606-8.
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