Presenting Symptoms Are Associated with Uveal Melanoma-Related Death
Authors: Maria Fili, Stefan Seregard, Gustav Stålhammar
Journal: Ophthalmology (2020)

Posterior uveal melanoma is the most common primary malignant intraocular tumor in adults, with fatal metastatic disease developing within 10 years of primary tumor treatment in more than 25% of patients.1Shields C.L. Furuta M. Thangappan A. et al.Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes.Arch Ophthalmol. 2009; 127: 989-998Crossref PubMed Scopus (366) Google Scholar, 2Stalhammar G. Forty-year prognosis after plaque brachytherapy of uveal melanoma.Sci Rep. 2020; 10: 11297Crossref PubMed Scopus (15) Google Scholar, 3Kujala E. Mäkitie T. Kivelä T. Very long-term prognosis of patients with malignant uveal melanoma.Invest Ophthalmol Vis Sci. 2003; 44: 4651-4659Crossref PubMed Scopus (667) Google Scholar Presenting symptoms include blurred vision, photopsia, floaters, visual field defects, pain, and metamorphopsia.4Krantz B.A. Dave N. Komatsubara K.M. et al.Uveal melanoma: epidemiology, etiology, and treatment of primary disease.Clin Ophthalmol. 2017; 11: 279-289Crossref PubMed Scopus (160) Google Scholar,5Damato E.M. Damato B.E. Detection and time to treatment of uveal melanoma in the United Kingdom: an evaluation of 2,384 patients.Ophthalmology. 2012; 119: 1582-1589Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar We investigated their prognostic significance and report our findings herein. The study adhered to the tenets of the Declaration of Helsinki, and approval was obtained from the regional ethical review board in Stockholm, which also waived the informed consent as this is a retrospective chart review that did not affect the treatment or follow-up of patients and did not require new collection of sensitive data. All patients treated with plaque brachytherapy for malignant melanoma originating in the choroid or ciliary body between January 1, 1980, and December 31, 2009, were included (n = 1449). Retrospective data were retrieved from our treatment directory according to a previously described methodology.2Stalhammar G. Forty-year prognosis after plaque brachytherapy of uveal melanoma.Sci Rep. 2020; 10: 11297Crossref PubMed Scopus (15) Google Scholar At the first visit, the patient was asked to describe his or her symptoms and their duration. The ophthalmologist classified and recorded them as 1 or several of (1) blurred vision (decreased visual acuity); (2) shadow in the visual field; (3) photopsia, floaters, or both; (4) metamorphopsia; (5) ocular pain; or (6) other, including photophobia, diplopia, and reduced perception of color. Of the 1449 included patients, 649 (45%) were women and 800 (55%) were men. The mean apical tumor thickness was 5.7 mm (standard deviation [SD], 2.9 mm), with a mean largest basal diameter of 10.9 mm (SD, 4.0 mm). Median follow-up was 17.5 years (SD, 7.1 years; Table S1, available at www.aaojournal.org). Five hundred fifty-nine patients (39%) presented with blurred vision, 277 (16%) with a shadow in the visual field; 176 (12%) with photopsia, floaters, or both; 29 (2%) with metamorphopsia; 17 (1%) with ocular pain; and 34 (2%) with other symptoms. The mean symptom duration before diagnosis was 4 months (SD, 5 months). Four hundred patients (28%) had no symptoms. One thousand two hundred fifty-three patients (86%) reported only 1 symptom, whereas 196 patients (14%) reported 2 symptoms or more. In 245 of 391 patients (63 %) with recorded retinal detachment (RD) status, an RD was observed. All 245 of the RDs (100%) were exudative. Blurred vision correlated with male gender (φ = 0.11; P < 0.001). Patients with blurred vision were older (64 years of age vs. 62 years of age; P = 0.02, Student t test), showed worse visual acuity (20/300 vs. 20/120; P < 0.001), and had tumors with greater apical thickness (7.8 mm vs. 7.3 mm; P < 0.001) closer to the macula (2.7 mm vs. 3.9 mm; P < 0.001). However, their tumors had similar diameters (13.0 mm vs. 12.7 mm; P = 0.51) and similar distances to the optic disc (3.2 mm vs. 3.8 mm; P = 0.09). Blurred vision did not correlate with RD (φ = 0.06; P = 0.90). A shadow in the visual field did not correlate with gender (φ = 0.01; P = 0.59). Patients with a shadow were older (64 years of age vs. 62 years of age; P = 0.04) and had tumors with greater apical thickness (6.3 mm vs. 5.6 mm; P = 0.002) with larger diameters (11.5 mm vs. 10.8 mm; P = 0.007) at equal distance to the optic disc (3.6 mm vs. 3.9 mm; P = 0.30) and the macula (3.6 mm vs. 3.4 mm; P = 0.39), but had slightly better visual acuity (20/100 vs. 20/125; P < 0.001). A shadow in the visual field correlated with RD (φ = 0.11; P = 0.03). Photopsia, floaters, or both correlated with female gender (φ = –0.10; P < 0.001). Patients with photopsia, floaters, or both were younger (59 years vs. 62 years; P = 0.04) and had tumors that were more distant to the macula (4.0 mm vs. 3.3 mm; P = 0.05), but had similar visual acuity (20/166 vs. 20/200; P = 0.47) and had tumors with similar apical thickness (5.5 mm vs. 5.8 mm; P = 0.09), similar diameters (11.0 mm vs. 10.9 mm; P = 0.80), and similar distances to the optic disc (4.2 mm vs. 3.8 mm; P = 0.19). Photopsia, floaters, or both did not correlate with RD (φ = 0.06; P = 0.90). Pain did not correlate with gender (φ = –0.04; P = 0.10). Patients with ocular pain were older (71 years of age vs. 63 years of age; P = 0.02) and showed worse visual acuity (20/125 vs. 20/63; P = 0.03), but had tumors with similar apical thickness (4.9 mm vs. 5.7 mm; P = 0.275), diameter (11.3 mm vs. 10.9 mm; P = 0.69), and distance to the optic disc (5.3 mm vs. 3.8 mm; P = 0.36) and the macula (5.0 mm vs. 3.4 mm; P = 0.37). None had extrascleral growth. The 277 patients who presented with a shadow in the visual field had significantly shorter disease-specific survival (P = 0.004, log-rank test; Fig 1A ). The 559 and 176 patients who demonstrated blurred vision and photopsia, floaters, or both did not have shorter disease-specific survival (P = 0.52 and P = 0.49, respectively; Fig 1B, C). Similarly, the small groups of patients with metamorphopsia (P = 0.54), ocular pain (P = 0.16), and other symptoms (P = 0.41) did not have shorter disease-specific survival. In a multivariate Cox regression model with all symptoms and American Joint Committee on Cancer T category 1 through 4 as covariates, a shadow in the visual field (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1–2.1; P = 0.02) and T category (HR, 2.0; 95% CI, 1.8–2.3; P < 0.001) were independent predictors of uveal melanoma-related mortality, but none of the other symptoms were (Table S2, available at www.aaojournal.org). A shadow in the visual field also was an independent predictor of uveal melanoma-related mortality when adjusting for tumor diameter (HR, 1.3; 95% CI, 1.0–1.6; P = 0.03), apical thickness (HR, 1.3; 95% CI, 1.0–1.6; P = 0.02), distance to the optic disc (HR, 1.5; 95% CI, 1.1–1.9; P = 0.006), distance to the macula (HR, 1.5; 95%, CI 1.1–1.9; P = 0.006), T category (HR, 1.3; 95% CI, 1.0–1.6; P = 0.03), and American Joint Committee on Cancer stage (HR, 1.3; 95% CI, 1.0–1.6; P = 0.03). Blurred vision (P > 0.47), photopsia, floaters, or both (P > 0.17), metamorphopsia (P > 0.61), ocular pain (P > 0.07), and other symptoms (P > 0.33) were not independent predictors of uveal melanoma-related mortality when adjusting for any one of these factors. When adjusting for all of tumor T category, stage, and distance to the macula, a shadow in the visual field retained its prognostic significance (HR, 1.3; 95% CI, 1.0–1.7; P = 0.04). Limitations of this study include the difficulty in differentiating between symptoms. Some patients who reported a shadow may have experienced what others would describe as blurry vision, and so forth. Patients' descriptions of symptoms were not confirmed by additional testing, including perimetry. In conclusion, a shadow in the visual field as a presenting symptom of uveal melanoma, experienced by 1 in 6 of 1449 patients, correlated with exudative RD and was a consistent predictor of uveal melanoma-related mortality regardless of other simultaneous symptoms, tumor size, location, local extent, and stage. Future studies should investigate other established prognostic factors such as tumor vascularity and cytogenetic and gene expression characteristics in relationship to the experience of a shadow to reveal the causality of its association with a poor prognosis.6Onken M.D. Worley L.A. Char D.H. et al.Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.Ophthalmology. 2012; 119: 1596-1603Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar,7Stålhammar G. See T.R.O. Phillips S.S. Grossniklaus H.E. Density of PAS positive patterns in uveal melanoma: correlation with vasculogenic mimicry, gene expression class, BAP-1 expression, macrophage infiltration, and risk for metastasis.Mol Vis. 2019; 25: 502-516PubMed Google Scholar Other presenting symptoms had no prognostic relevance. Download .pdf (.31 MB) Help with pdf files Table S1 Download .pdf (.22 MB) Help with pdf files Table S2