Vasculogenic mimicry is associated with poor survival in patients with mesothelial sarcomas and alveolar rhabdomyosarcomas.

Increased vasculogenesis must occur for tumors to develop and be maintained. Normally, vascular networks are composed of tube structures lined with endothelial cells. However, the vascular networks that form around some highly aggressive cancers possess a distinct tubular structure, resulting from a process called vasculogenic mimicry (VM) that does not have endothelial cells. In these tubes, the tumor cells function as endothelial cells. VM has been found in several different types of cancers such as melanoma, breast cancer, prostate cancer, and ovarian cancer. We hypothesized that it also plays a role in the development and metastasis of sarcomas, which are typically aggressive tumors. We used immunohistochemical analyses and electron microscopy to identify VM channels in 81 synovial sarcomas (SSs), 37 mesothelial sarcomas (MSs), 69 alveolar rhabdomyosarcomas (ARs), and 190 melanomas, which were used as a comparison group. The presence of red blood cells in the vessels was also used as a criterion for VM. Because VM is generally believed to be associated with aggressive cancers, we tested whether the presence of VM channel correlated with patient survival. We detected VM channels in 11 of 81 SSs (13.6%), 10 of 37 MSs (27.0%), 13 of 69 ARs (18.8%), and 10 of 190 melanomas (5.3%). The VM channels were not distributed uniformly in the tumor tissues but appeared in patches. In addition, VM channels were most frequently observed in the boundary regions between the tumor and adjacent normal tissues. The tumor cells around the VM tubes frequently stained positive for collagen IV and CD31 and were also PAS-positive. In contrast, tumors that lack VM channels generally also lack these markers. Our studies of the correlation of VM with patient survival also showed that VM correlated with shorter survival in patients with MS (P=0.03), AR (P=0.03), and melanoma (P=0.04), but not with SS (P=0.76). Our studies demonstrated that VM channels are a clinically important phenotype in sarcomas and melanomas. Our findings also suggested that a subpopulation of tumor cells possess features of both endothelial cells that line the vessels and mesenchymal cells that secrete the extracellular matrix required for the vascular infrastructure.

Angiogenesis is an independent prognostic factor in malignant mesothelioma.

Angiogenesis is essential for tumour growth beyond 1 to 2 mm in diameter. The clinical relevance of angiogenesis, as assessed by microvessel density (MVD), is unclear in malignant mesothelioma (MM). Immunohistochemistry was performed on 104 archival, paraffin-embedded, surgically resected MM samples with an anti-CD34 monoclonal antibody, using the Streptavidin-biotin complex immunoperoxidase technique. 93 cases were suitable for microvessel quantification. MVD was obtained from 3 intratumoural hotspots, using a Chalkley eyepiece graticule at x 250 power. MVD was correlated with survival by Kaplan-Meier and log-rank analysis. A stepwise, multivariate Cox model was used to compare MVD with known prognostic factors and the EORTC and CALGB prognostic scoring systems. Overall median survival from the date of diagnosis was 5.0 months. Increasing MVD was a poor prognostic factor in univariate analysis (P = 0.02). Independent indicators of poor prognosis in multivariate analysis were non-epithelial cell type (P = 0.002), performance status > 0 (P = 0.003) and increasing MVD (P = 0.01). In multivariate Cox analysis, MVD contributed independently to the EORTC (P = 0.006), but not to the CALGB (P = 0.1), prognostic groups. Angiogenesis, as assessed by MVD, is a poor prognostic factor in MM, independent of other clinicopathological variables and the EORTC prognostic scoring system. Further work is required to assess the prognostic importance of angiogenic regulatory factors in this disease.

Basic fibroblast growth factor in mesothelioma pleural effusions: correlation with patient survival and angiogenesis.

The expression of angiogenic factors may represent useful markers for diagnosis and prediction of disease outcome. Basic fibroblast growth factor (b-FGF) is a potent angiogenic factor which promotes in vitro growth of endothelial cells and in vivo vessel formation. We investigated the expression of b-FGF in patients affected with malignant and non-malignant pleural diseases and presenting clinically with non-specific signs and symptoms. We also studied the relationships between the expression of b-FGF in patients with malignant pleural mesothelioma (MM) and tumour aggressiveness, assessed as tumour vessel density (TVD), or patient survival. Basic-FGF was measured by immunoassay in the serum and pleural effusions (PE) of 37 patients. Of these, MM was diagnosed in 15/37 patients while the remaining patients had either peripheral lung adenocarcinoma (PLA) or benign inflammatory pleural disease (BPD). The mean b-FGF level measured 8.5+/-6.1 pg/ml in the PE of the malignant group (MM + PLA) and 23.9+/-19.8 in the PE of the non-malignant group (BPD) (p=0.001). The mean b-FGF level was significantly lower in the PE of MM patients (6.9+/-5.2 pg/ml) compared to BPD patients (p=0.004). Linear regression analysis showed a significant inverse correlation (r=-0.59; p=0.041) between b-FGF levels found in MM PE and patient survival. A noteworthy relationship between high serum b-FGF levels and reduced survival was also observed (r=-0.57; p=0.052). Interestingly, both serum (r=0.48; p=0.114) and PE (r=0.26; p=0.413) b-FGF levels in MM patients correlated poorly with TVD. Our data indicate that b-FGF is significantly more expressed in non-malignant compared to malignant PE, this difference being particularly evident between MM and BPD. Our results also suggest that high b-FGF levels correlate with poor MM patient survival through mechanisms which may be independent of b-FGF angiogenic potential.