Obesity paradox in uveal melanoma: high body mass index is associated with low metastatic risk.

BACKGROUND: Metabolic factors and obesity may influence the development and progression of cancer. In this study, we examine their association with the risk of developing metastases of uveal melanoma. METHODS: Data on metabolic factors, medications, serum leptin levels, tumour leptin receptor RNA expression and clinical outcomes were examined in three cohorts. HRs for metastasis and cumulative incidences of melanoma-related mortality were calculated, and the levels of tumour leptin receptor expression were compared with prognostic factors including BAP1 mutation, and tumour cell morphology. RESULTS: Of 581 patients in the main cohort, 116 (20%) were obese and 7 (1 %) had metastatic disease at presentation. In univariate Cox regressions, tumour diameter, diabetes type II and use of insulin were associated with metastases, but patients with obesity had a lower risk. The beneficial prognostic implication of obesity was retained in multivariate regressions. In competing risk analyses, the incidence of melanoma-related mortality was significantly lower for patients with obesity. Serum leptin levels≥median were associated with a reduced risk for metastasis, independent of patient sex and cancer stage in a separate cohort (n=80). Similarly, in a third cohort (n=80), tumours with BAP1 mutation and epithelioid cells had higher leptin receptor RNA expression levels, which have a negative correlation with serum leptin levels. CONCLUSION: Obesity and elevated serum leptin levels are associated with a lower risk for developing metastases and dying from uveal melanoma.

Multiorgan Involvement of Dormant Uveal Melanoma Micrometastases in Postmortem Tissue From Patients Without Coexisting Macrometastases.

OBJECTIVES: Almost half of all patients diagnosed with uveal melanoma will die of metastatic disease. This has been attributed to early seeding of micrometastases. We investigate the presence, density, organ involvement, and characteristics of micrometastases of uveal melanoma in tissue obtained at autopsy of patients with and without coexisting macrometastases. METHODS: Patients diagnosed with primary uveal melanoma at a national referral center between 1960 and 2020 (n = 4,282) were cross-referenced with autopsy registers at nearby hospitals. Eleven patients were included. Formalin-fixed, paraffin-embedded tissue samples obtained during autopsy were examined with routine histology, immunohistochemistry, and immunomagnetic separation. RESULTS: Micrometastases were detected in 5 of 5 patients with and in 5 of 6 patients without coexisting macrometastases. Micrometastases were identified in several sites, including lungs, kidneys, myocardium, and bone marrow. Their highest density per mm2 of tissue was seen in the liver. Of 11 examined patients, 2 had at least 1 BAP-1-positive metastasis. All micrometastases had immune cell infiltrates and no or very low proliferative activity. CONCLUSIONS: We demonstrate multiorgan involvement of apparently dormant micrometastases in patients with uveal melanoma. This suggests that micrometastases are present in nearly all patients diagnosed with primary uveal melanoma, regardless of coexisting macrometastases.

A prognostic classification system for uveal melanoma based on a combination of patient age and sex, the American Joint Committee on Cancer and the Cancer Genome Atlas models.

PURPOSE: To revisit the independent importance of ciliary body involvement (CBI), monosomy 3 (M3), tumour size, histological and clinical factors in uveal melanoma (UM) and to devise a new prognostic classification based on a combination of the American Joint Committee on Cancer (AJCC) and the Cancer Genome Atlas (TCGA) models. METHODS: Two cohorts with a total of 1796 patients were included. Clinicopathological factors were compared between patients with and without CBI and M3. Development of the prognostic classification was performed in a training cohort and was then tested in two independent validation cohorts. RESULTS: Tumours with CBI were more common in women, had greater apical thickness, greater basal tumour diameter, greater rates of vasculogenic mimicry and greater rates of M3, were more often asymptomatic at diagnosis and had poorer 5- and 10-year globe conservation rates (p < 0.023). In multivariate logistic regression, patient age at diagnosis, tumour diameter and CBI were independent predictors of M3 (p < 0.001). In multivariate Cox regression, male sex, age at diagnosis, tumour diameter, M3 and CBI were independent predictors of metastasis. The proposed prognostic classification combined patient age, sex, CBI, extraocular extension, M3, 8q (optional) and tumour size, and demonstrated greater prognostic acumen than both AJCC 4 T categories and TCGA groups A to D in validation cohorts. CONCLUSIONS: Tumour size does not confound the prognostic implication of CBI, M3, male sex and age at diagnosis in UM. These factors were included in a new prognostic classification that outperforms AJCC T category and TCGA groups.

Trends in Uveal Melanoma Presentation and Survival During Five Decades: A Nationwide Survey of 3898 Swedish Patients.

Background: In contrast to most other cancers, uveal melanoma (UM) is characterized by an absence of major improvements in patient survival during the last several decades. In this study, we examine changes in incidence rates, patient age and tumor size at diagnosis, treatment practices and survival for patients diagnosed in Sweden during the period 1960-2010. Methods: All patients diagnosed with posterior UM between January 1st, 1960, and December 31st, 2009, in Sweden, were included (n = 3898). Trends in incidence, primary treatment modality, patient age and tumor size were analyzed. Disease-specific survival was plotted in Kaplan-Meier curves and the cumulative incidence of UM-related mortality was evaluated in competing risk analysis. Results: Crude (6.5-11.6 cases/million/year) and age-standardized incidence rates (5.6-9.6 cases/million/year) varied between individual years during the study period, but both had a stable linear trend overall (p ≥ 0.12). Gradually, plaque brachytherapy with ruthenium-106 replaced enucleation as the most common primary treatment. The mean patient age at diagnosis increased from 59.8 years in 1960 to 66.0 in 2009. Conversely, the mean tumor size became gradually smaller during the period. In linear regression, the basal diameter and tumor apical thickness decreased with a slope coefficient of -0.03 mm (p = 0.012) and -0.05 mm (p = 1.2 × 10-5) per year after 1960, respectively. Patients diagnosed after 1990 had significantly better disease-specific survival than patients diagnosed before 1990 (p = 2.0 × 10-17). Similarly, the cumulative incidence of UM-related mortality was highest for patients diagnosed 1960-1969 and 1970-1979, with slightly lower incidences for patients diagnosed 1980-1989 and even lower for those diagnosed after 1990 (p = 7.1 × 10-13). The incidence of mortality from other causes than UM did not differ between periods (p = 0.16). Conclusion: In the period from 1960-2010, crude and age-standardized incidence rates of UM have remained stable in Sweden. Several other aspects have changed: Plaque brachytherapy with ruthenium-106 has replaced enucleation as the most common primary treatment modality; patients have become older and their tumors smaller at the time of diagnosis; and their survival has improved. This might indicate a beneficial survival effect of earlier diagnosis and treatment, but the potential influence from lead-time bias should be taken into consideration.

Vasculogenic mimicry correlates to presenting symptoms and mortality in uveal melanoma.

PURPOSE: Fluid-conducting extracellular matrix patterns known as vasculogenic mimicry (VM) have been associated with poor prognosis in uveal melanoma and other cancers. We investigate the correlations between VM, presenting symptoms, mortality, and the area density of periodic acid-Schiff positive histological patterns (PAS density). METHODS: Sixty-nine patients that underwent enucleation for uveal melanoma between 2000 and 2007 were included. Clinicopathological parameters presenting symptoms and outcomes were collected. Histological tumor sections were evaluated for VM and PAS density was quantified with digital image analysis. RESULTS: Thirty-four patients (49%) presented with blurred vision. 18 (26%) with a shadow in the visual field, 7 (10%) with photopsia and/or floaters, and 2 (3%) with metamorphopsia. Nine patients (13%) had no symptoms at all. Median follow-up was 16.7 years (SD 2.6). A shadow in the visual field, but no other symptom, was positively correlated with the presence of VM (φ 0.70, p < 0.001) and greater PAS density (p < 0.001). In multivariate regression, retinal detachment (RD), presence of VM, and PAS density ≥ median were independent predictors of a shadow, but not tumor distance to the macula, tumor apical thickness, tumor diameter, or ciliary body engagement. The presence of VM was associated with significantly shorter cumulative disease-specific survival (Wilcoxon p = 0.04), but not PAS density ≥ median, presenting symptoms or RD (p > 0.28). CONCLUSION: Tumors from uveal melanoma patients that report a visual field shadow are likely to display VM and greater PAS density, likely explaining the previously reported association between this symptom and poor prognosis.

No differences in the long-term prognosis of iris and choroidal melanomas when adjusting for tumor thickness and diameter.

OBJECTIVE: To assess the long-term prognosis for patients with iris melanomas and compare it with the prognosis for small choroidal melanomas. DESIGN: Retrospective observational case series. METHODS: All patients treated for iris melanomas at a single referral institution between January 1st 1986 and January 1st 2016 were included. Patients treated for small choroidal melanomas during the same period were included for comparison. The cumulative incidence of melanoma-related mortality was calculated. Patient and tumor characteristics and size-adjusted hazard ratio (HR) for melanoma-related mortality were compared between iris and small choroidal melanomas. RESULTS: Forty-five iris melanomas and 268 small choroidal melanomas were included. Twenty-four iris melanomas (53%) had been treated with local resection, 12 (27%) with Ruthenium-106 brachytherapy, 7 (16%) with enucleation and 2 (4%) with proton beam irradiation. Twenty-one (68%), 7 (16%) and 2 (4%) of the iris melanomas were of the spindle, mixed and epithelioid cell types, respectively. Twenty-three patients had deceased before the end of follow-up. Median follow-up for the 22 survivors was 13.3 years (SD 9.4). Patients with iris melanomas were more often asymptomatic at presentation and had a trend towards significantly lower age (59 versus 63 years, Student's T-tests p = 0.057). Further, iris melanomas had significantly smaller basal diameter (5.8 versus 8.0 mm, p < 0.0001) and tumor volume (79 mm3 versus 93 mm mm3, p < 0.0001) but greater thickness (3.0 versus 2.5 mm, p < 0.0001). The cumulative incidence of iris melanoma-related mortality was 5% at 5 years after diagnosis, and 8% at 10, 15 and 20 years. The incidence was not significantly different to small choroidal melanomas (Wilcoxon p = 0.46). In multivariate Cox regression with tumor diameter and thickness as covariates, patients with choroidal melanomas did not have increased HR for melanoma-related mortality (HR 2.2, 95% CI 0.5-9.6, p = 0.29). Similarly, there were no significant survival differences in matched subgroups (Wilcoxon p = 0.82). CONCLUSIONS: There are no survival differences between iris and choroidal melanomas when adjusting for tumor size. The reason for the relatively favorable prognosis of iris melanomas compared to melanomas of the choroid and ciliary body is likely that they are diagnosed at a smaller size.