Introduction
Uveal melanoma (UM) is a malignant tumor of the eye involving the iris, choroid or ciliary body (collectively referred to as the uvea). It is the most common intraocular tumor, with an incidence of 5–6 cases per 1,000,000 individuals (1). There is a reported incidence of 4–6 cases per 1,000,000 individuals annually in the US and Europe (2). UM spreads through the blood and exhibits a high degree of malignancy.
Angiogenesis is a prognostic factor that has been extensively investigated in patients with UM (3). It involves the formation of new blood vessels from the endothelium of the existing vasculature. When a new tumor reaches a size of 1–2 mm, its further growth requires the formation of new blood vessels, which may lead to the development of metastases (4). As one of the most important biological markers, vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and permeability factor that is potently angiogenic in vivo (5). VEGF induces the proliferation, differentiation and migration of vascular endothelial cells. VEGF is also required for haematopoiesis in malignant tumors, which favors primary tumor growth and metastasis (6).
Targeting constitutive VEGF and/or its receptors has been an attractive approach for cancer therapy. However, the most widely investigated clinicopathological characteristics associated with VEGF refer to variables including tumor size, largest tumor diameter (LTD), depth of invasion, lymph node status and vascular invasion. Although implicated in the pathogenesis of UM, the results on the correlation between VEGF and these factors have been conflicting and inconclusive (7–10).
It has not been elucidated whether the differences in these studies were due to the limited size of the samples or genuine heterogeneity. Therefore, in order to gain a full insight into the clinicopathological characteristics of VEGF expression in patients with UM, we enrolled data from studies of medical centers. The clinicopathological significance of our present analysis may enable a better understanding of the natural history of UM. In addition, the use of VEGF may be converted from candidate to the routine clinical setting as a predictor of the outcome of individual patients.
Discussion
Since the VEGF was identified, there has been an increasing number of studies on the association between VEGF and cancer research. It was demonstrated that VEGF expression is strongly positive in a variety of human malignant tumors in the mRNA and/or the protein level (11). Pigment and blood vessels are abundant in uveal tissue. Tumor cells are mainly transferred through the blood; therefore, angiogenesis is crucial for the development of the tumor. However, currently available studies on VEGF expression in UM are sparse and the results obtained are inconsistent. Kvanta et al (5) reported that VEGF mRNA and protein expression were strongly positive in retinoblastoma, although there was no VEGF expression in UM. Stitt et al (12) investigated the expression of VEGF mRNA, VEGF protein and its receptor in retinoblastoma or UM and reported a strongly positive VEGF expression in the tumor; the VEGF expression rate was higher compared to that in the uninvolved normal retina, choroid and iris. Sheidow et al (13) reported that 37% (16/43) of the patients with choroidal melanoma developed distant metastases within the 10-year follow-up, but did not confirm the association of VEGF expression with distant metastasis, although the expression of VEGF in the choroidal melanoma cells was strongly positive (94% positivity rate).
To the best of our knowledge, this is the first comprehensive and detailed meta-analysis assessing the association between the expression of VEGF in UM and clinicopathological characteristics. The stratification of the baseline patient characteristics, including gender, age, cell type, LTD, tumor size and scleral invasion, our results demonstrated that VEGF expression is of clinicopathological value in UM, which may increase the predictive accuracy of prognosis in UM patients.
Our results demonstrated that high VEGF expression, as detected by immunohistochemistry, was confirmed in patients with UM according to evidence-based medicine. Notably, in the subgroup meta-analysis, we also observed that VEGF overexpression was correlated with a patient age of <50 years (P=0.008), which may explain its prognostic effect to some extent. Similar findings were also reported by other studies on age (14). However, further studies are required to assess the association of VEGF expression with age. We also observed that VEGF expression was significantly higher in mixed-cell and epithelioid-cell tumors and lower in spindle-cell tumors.
The association between tumor size and VEGF expression was not clearly determined. Our meta-analysis indicated that the VEGF expression was increased in large-sized tumors and decreased in small- and medium-sized tumors. We also demonstrated that VEGF expression was significantly higher in patients with scleral invasion. A collaborative ocular melanoma study in the USA investigated 1,091 enucleation specimens and reported a scleral invasion rate of 55% (15). The data mentioned previously questions the feasibility and safety of the implementation of local tumor resection and may explain the high recurrence rate following tumor resection in patients with UM (16). Those findings may also explain the increased formation of tumor microvasculature with the increasing degree and local infiltration of UM.
High VEGF expression induces the formation of a rich vascular network and nutritious environment, which is an active process that requires degradation of the extracellular matrix and increase in vascular permeability of blood and lymphatic vessels, favoring the progression of tumor cells into the blood and lymphatic vascular space (17). This may offer an explanation for the observed strong statistical association of VEGF overexpression with tumor invasion and metastasis (18).
The present study had several limitations. Firstly, although we did not detect significant publication bias among the studies, apart for erythrocyte sedimentation rate (ESR), it is uncertain whether the cases are comparably representative. Furthermore, the studies were observational and, therefore, more prone to biases compared with prospective randomized controlled studies. We detected publication bias for ESR (P=0.2) and there may be missing information which may reflect a negative or a more conservative association of ESR with DR4. More samples are required to validate the reliability of our conclusions.
In conclusion, our meta-analysis demonstrated that VEGF may be a marker that may enable earlier identification of high-risk patients and guide clinical decision-making regarding therapy and outcome. The evaluation of serum levels of VEGF expression may therefore play an important role in selecting melanoma patients for antiangiogenic therapy (19).
However, our conclusion should be interpreted with caution, since this analysis would be ideally performed on series of patient data. Further investigation into this subset of patients from other studies should assess the generalization of results prior to the implementation of VEGF in the routine clinical management of UM patients. Future prospective studies investigating the association of VEGF expression with survival or response to antiangiogenic therapy are required. The assessment of these angiogenic markers may be better standardised in future studies.