Background
Malignant melanoma (MM) is the most aggressive skin cancer and the most common skin disorder in Caucasians characterized by aggressive and progressive disease states, leading to major cancer-related morbidity and mortality, with an estimated global incidence of about 200,000 new cases per year and 50,000 cancer-related deaths in 2018 [
1‐
3]. The incidence of MM has been rapidly increasing over the last 10 years in the Asian and Mediterranean population and in Singapore is diagnosed as the seventh and the eighth most common cancer among men and women, respectively [
3‐
6]. Nevertheless, the Asian population has a notably lower risk of MM than Caucasians due to ethnic differences, anatomic distribution, histologic subtypes, and stage at diagnosis [
6,
7]. Interestingly, Ultraviolet (UV) radiation, race, lifestyle, and genetic differences are the most important reasons for the high mortality rate of melanoma which can be decreased via early-stage detection and prevention [
8‐
13]. Dermoscopy and intrinsic molecular subtyping of melanoma have been widely accepted as accurate diagnostic methods with more than 50% accuracy compared with the clinical diagnosis in patients with MM [
14,
15].
Recent investigations identified a new non-angiogenesis-dependent pathway entitled vasculogenic mimicry (VM), which refers to a vessel-like structure formed by extremely aggressive tumor cells that imitate endothelial cells [
16,
17]. VM has been considered as a cancer hallmark that can independently facilitate tumor neovascularization by the formation of fluid-conducting and vascular endothelial cells [
18‐
20]. VM could dedifferentiate into numerous cellular phenotypes and obtain endothelial-like features, resulting in the formation of the de novo matrix-rich vascular-like network, such as plasma and red blood cells [
21,
22]. The co-generation of endothelial cells, channels, laminar structures, and heparin sulfate proteoglycans are the main pathophysiological characteristics of VM in human melanoma patients [
23‐
25]. Aggressive VM+ tumor cells are characterized by a higher expression of the basement membrane extracellular matrix (ECM) components laminin5γ2 and metalloproteinases (MMPs)-1, − 2, − 9, and − 14 [
21,
22,
26]. In highly aggressive melanoma cells downregulation of vascular endothelial cadherin and upregulation of ECM components promotes the perfusion of the VM pathway [
19,
21]. Ultimately, the VM+ melanoma cells are associated with more aggressive and metastatic tumor biology.
Accumulating evidence suggests that VM is associated with poor prognosis in various malignant human tumors, including breast [
27], colorectal [
28], prostate [
29], hepatocellular carcinoma [
30], lung [
29], ovarian [
31], gastric [
32], and bladder cancers [
33]. Despite numerous experimental studies, the prognostic value of VM status for survival in MM patients is still controversial and inconclusive. Understanding the role of VM in MM pathogenesis may help to develop effective treatments for tumor invasion and to overcome drug resistance in MM [
34].
Hence, we conducted a quantitative systematic review along with a comprehensive meta-analysis investigation based on eligible studies to resolve inconsistent and often ambiguous findings. Furthermore, we identified the prognostic accuracy of VM status in cancer patients to predict other clinical pathological feature outcomes of MM.
Discussion
To the best of our knowledge, this is the first meta-analysis study to identify the prognostic value of VM status in advanced melanoma patients. Our results indicate that 38% of MM patients with VM+ have a poor prognosis (P = 0.35, 95% CI: 0.27–0.42, p < 0.001). Moreover, a significant association was identified in the pathologic features of the VM+ melanoma samples by race, sample size, and VM detection methods, which adversely influenced cancer survival. In the current study, the AUC of SROC was 0.63, indicating the high accuracy of VM status as a biomarker for MM. In addition, our pooled results provided convincing evidence for a significant positive relationship between VM and small sample size.
Accumulating evidence indicates that VM is a new model of tumor microcirculation in highly aggressive malignant tumor cells [
16,
17]. Recently, in vivo and in vitro studies have shown that twist-related protein 1 (Twist1), neurogenic locus notch homolog protein 4 (Notch4), hypoxia inducible factor (HIF)-1a, EPH receptor A2 (EphA2), matrix metalloproteinase (MMP)-1, 2, − 9, − 14, and vascular endothelial (VE)-cadherin are potential therapeutic targets and prognostic indicators in VM+ tumor samples [
22,
56]. Moreover, these studies suggested that VM+ tumor samples are resistant to common antiangiogenic drugs, such as apatinib, bevacizumab, and sunitinib [
23,
34,
57]. The high ratio of neovascularization in VM+ tumors promotes angiogenesis, metastasis, and tumor growth along with extensive hypoxia and necrosis. It also induces recruitment of various pro-angiogenic factors, such as bone marrow-derived CD45
+ myeloid cells, pericyte progenitor cells, and mature F4/80
+ tumor-associated macrophages [
58,
59]. Varying locations and heterogenic morphology of MM tumors display a close relationship with VM formation, which represents a noteworthy challenge for dermatologists [
16,
60].
Our results clearly show that VM has a negative effect on the overall survival of MM patients with a risk ratio of 0.35 (95% CI: 0.27–0.42,
p < 0.001). Furthermore, our findings from sub-analyses underlined the status of VM formation in MM patients. Our results reveal a strong association between VM+ and sample size, between VM+ and race, as well as between VM+ and detection method of VM (
p < 0.001). Our findings suggest that VM status can be a significantly accurate prognostic biomarker when diagnosed by CD31−/PAS+ staining, with a relatively accurate diagnostic value for VM detection (75% sensitivity and 70% specificity). Also, the results of subgroup analyses implied a better diagnosis of VM in small sample sizes compared to that in samples containing greater than 100 cases (P: 0.31, 95% CI: 0.23–0.41;
p < 0.001), with a pooled sensitivity of 85% and specificity of 78%. Interestingly, our results propose VM status as a more promising, accurate biomarker and target for MM diagnosis and therapeutics in Asian patients than in Caucasian patients, with a pooled sensitivity of 91% and specificity of 70.5% vs. Lifestyle factors such as UV radiation exposure and nutrition are synergistically contributing to the prevalence of MM [
61,
62]. Compared to Caucasians, Asian MM patients are diagnosed at older ages; hence, in Asia we face a large population of old MM patients [
4,
12]. But considering that our study was limited to a small sample size of cases in the Caucasian group (475 cases), more large-sized studies among the Caucasian MM population should be performed to obtain a comprehensive result [
61]. It is known that VM+ tumor sample profiling is more accurate in the Asian population than in the Caucasian population [
62]. The meta-analysis showed that the CD31−/PAS+ staining is a more accurate detection method for VM+ tumor samples than CD34−/PAS+ and PAS+ staining. Meanwhile, this meta-analysis suggests that postoperative detection with CD34- and/or CD31- of VM+ tumor samples in MM would be useful in finding critical therapy targets as well as for making better follow-up plans. Thus, we estimated OS in the meta-analysis, taking into account that the great majority of the studies do not report this information [
62].
Several published meta-analyses have attempted to evaluate the dissimilarity of tumor VM relevant to the prognosis of cancers [
27,
28,
30,
42,
63]. For example,
Cao et al. suggested that VM+ cancer patients have a poor 5-year overall survival rate compared to VM- cancer patients, particularly in metastatic diseases of sarcomas and lung, colon, liver, and melanoma cancers [
19]. In contrast,
Shen et al. addressed the tumor VM formation as an unfavorable prognostic indicator in breast cancer patients (
P = 0.23, 95% CI: 0.08–0.38,
p = 0.003) [
64]. In line with our results,
Yang et al. showed that tumor VM is significantly associated with cancer differentiation, lymph node metastasis and distant metastasis, (
P = 2.16; 95% CI: 1.98–2.38;
p < 0.001) [
65]. With such foreground and assumptions, this current study allows us to reach a better understanding of the clinical role of VM formation in MM patients using statistical approaches. Conversely, the correlation between VM and survival of cancer patients remain controversial or inconclusive.
We would like to point out that there are some limitations in the current work: First, we only included papers published in English, while papers published in other languages, notably Chinese and Russian, were excluded, which certainly could cause selection bias. Also, we did not consider the sensitivity analysis when reflecting on the significant difference among individual articles. Importantly, in most selected studies, the common detection methods were IHC techniques. The different primary antibodies using a wide range of antibody dilutions might also affect the IHC sensitivity. Furthermore, the small sample size, short follow-up times, and lack of homogeneous distribution of the population (no studies dealing with the African continent) might also affect the precision of the estimates. However, the publication bias results showed that these limitations were not important enough to influence the analysis of late-stage and fatal complications. Future clinical studies with larger sample sizes, standardized protocols, and more homogeneous populations would be required to fully understand the prognostics potential of VM status of tumors in melanoma patients.
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