Vasculogenic mimicry correlates to presenting symptoms and mortality in uveal melanoma

Abstract

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.

Sex‐based differences in early and late uveal melanoma‐related mortality

“…For example, gene expression class, BAP1, SF3B1, EIF1AX, and chromosome 3 status, presence or absence of vasculogenic mimicry, and tumor cell type are all important prognostic factors that were not accounted for herein. [44][45][46][47][48][49] Mutations in SF3B1 have been associated with late onset of metastases at a median of 8 years after diagnosis but no sex predilection has been observed in previous studies. [50][51][52] The reader should be aware that the worse survival for women in the second decade after UM diagnosis and beyond is not necessarily caused by increased presence of a poor prognostic factor in the women surviving ≥10 years.…”

“…Other than the potential dissimilarity in hormonal and reproductive factors, it is fully possible that there were differences in other established predictors. For example, gene expression class, BAP1, SF3B1, EIF1AX , and chromosome 3 status, presence or absence of vasculogenic mimicry, and tumor cell type are all important prognostic factors that were not accounted for herein 44–49 . Mutations in SF3B1 have been associated with late onset of metastases at a median of 8 years after diagnosis but no sex predilection has been observed in previous studies 50–52 .…”

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

“…We have previously shown that patients presenting with a shadow in the visual field have significantly shorter disease‐specific survival, regardless of other symptoms, tumour size, location, local extent and stage (Fili et al, 2020 ). In turn, tumours from UM patients that report a visual field shadow are more likely to display vasculogenic mimicry and greater density of PAS positive patterns, which may underpin the association between this symptom and poor prognosis (Sabazade et al, 2021a , 2021b ).…”

“…One exception is a large study by Kujala et al ( 2013 ), who found that tumour diameter, tumour thickness, CBI and extraocular extension were all independent predictors of melanoma‐related mortality in multivariate Cox regression (Kujala et al, 2013 ). In contrast to iris melanomas who have no better prognosis than choroidal melanomas when adjusting for tumour diameter and thickness, this should make it unlikely that increased tumour size is the real reason for the prognostic implication of CBI (Johansson et al, 2020 ; Sabazade et al, 2021a , 2021b ). The American Joint Committee on Cancer (AJCC) classification of UM consequently assigns tumours with CBI a subcategory with shorter metastasis‐free survival (Kujala et al, 2013 ; Kujala & Kivela, 2005 ; Simpson et al, 2015 ).…”

N-myc downstream–regulated gene 1 can promote vasculogenic mimicry and angiogenesis in urothelial carcinoma

“…In order to assess the VM area, the CD31/PAS stained slides were scanned by low power to identify areas which are positive for VM, and then five images at high-power field (×400) were captured. The VM area was recorded in these five high-power fields (400×) using open-access ImageJ and then averaged [ 22 ].…”