Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression

C G Colpaert, P B Vermeulen, I Benoy, A Soubry, F van Roy, P van Beest, G Goovaerts, L Y Dirix, P van Dam, S B Fox, A L Harris, E A van Marck, C G Colpaert, P B Vermeulen, I Benoy, A Soubry, F van Roy, P van Beest, G Goovaerts, L Y Dirix, P van Dam, S B Fox, A L Harris, E A van Marck

Abstract

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Improved understanding of the mechanisms responsible for the differences between IBC and non-IBC might provide novel therapeutic targets. We studied 35 consecutive patients with IBC, biopsied prior to the initiation of chemotherapy. Angiogenesis was evaluated by Chalkley counting and by assessment of endothelial cell proliferation (ECP) and vessel maturity. The presence of fibrin, expression of the hypoxia marker carbonic anhydrase IX (CA IX) and epithelialcadherin (E-cadherin) expression were immunohistochemically detected. The same parameters were obtained in a group of 104 non-IBC patients. Vascular density, assessed by Chalkley counting (P<0.0001), and ECP (P=0.01) were significantly higher in IBC than in non-IBC. Abundant stromal fibrin deposition was observed in 26% of IBC and in only 8% of non-IBC (P=0.02). Expression of CA IX was significantly less frequent in IBC than in non-IBC with early metastasis (P=0.047). There was a significant positive correlation between the expression of CA IX and ECP in IBC (r=0.4, P=0.03), implying that the angiogenesis is partly hypoxia driven. However, the higher ECP in IBC and the less frequent expression of CA IX in IBC vs non-IBC points at a role for other factors than hypoxia in stimulating angiogenesis. Strong, homogeneous E-cadherin expression was found at cell-cell contacts in all but two IBC cases, both in lymphovascular tumour emboli and in infiltrating tumour cells, challenging our current understanding of the metastatic process. Both the intense angiogenesis and the strong E-cadherin expression may contribute to the highly metastatic phenotype of IBC.

Figures

Figure 1
Figure 1
Highly vascularised area in IBC, showing tortuous and dilated vessels and vascular permeation (arrow) of tumour cells (CD 34 immunohistochemical stain). Scale bar=40 μm.
Figure 2
Figure 2
Mature vessels (thick arrows) lined by endothelial (brown) and mural cells (red) and immature vessels lined by endothelium only (thin arrows) and containing tumour emboli (CD34-α-smooth muscle actin immunohistochemical doublestain). Scale bar=30 μm.
Figure 3
Figure 3
Immunohistochemical doublestain to demonstrate proliferating (brown nucleus) and nonproliferating (blue nucleus) endothelial cells (PCNA-CD34 immunohistochemical doublestain). Scale bar=18 μm.
Figure 4
Figure 4
Intravascular tumour embolus, with hypoxic cells in the centre showing membranous immunoreactivity for the hypoxia marker carbonic anhydrase IX (CA IX immunohistochemical stain). Scale bar=70 μm.
Figure 5
Figure 5
Abundant fibrin deposition in the stroma surrounding a vessel (T2G1 immunohistochemical stain). Scale bar=36 μm.
Figure 6
Figure 6
E-cadherin expression in infiltrating carcinoma cells (thin arrow), in the lymphovascular tumour emboli (thick arrow) and in a normal mammary duct (asterisk). All tumour cells show homogeneous membranous immunoreactivity at cell–cell contacts. (E-cadherin immunohistochemical stain). Scale bar=60 μm.

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