Harly endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human melanoma and sarcoma treated by intravascular high-dose tumour necrosis factor alpha (rTNFα)

Authors

  • N. Renard,

    1. Department of Pathologic Anatomy, Jules Bordet Institute, University of Brussels, Brussels, Belgium
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  • D. Liénard,

    1. Laboratory of Oncology and Experimental Surgery (LOCE), Jules Bordet Institute, University of Brussels, Brussels, Belgium
    2. Centre Pluridisciplinaire d'Oncologie (CPO), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
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  • L. Lespagnard,

    1. Department of Pathologic Anatomy, Jules Bordet Institute, University of Brussels, Brussels, Belgium
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  • A. Eggermont,

    1. Dr. Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands
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  • R. Heimann,

    1. Department of Pathologic Anatomy, Jules Bordet Institute, University of Brussels, Brussels, Belgium
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  • F. Lejeune

    Corresponding author
    1. Laboratory of Oncology and Experimental Surgery (LOCE), Jules Bordet Institute, University of Brussels, Brussels, Belgium
    2. Centre Pluridisciplinaire d'Oncologie (CPO), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
    • Centre Pluridisciplinaire d'Oncologie (CPO), Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 46, Ch4011 Lausanne, Switzerland
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Abstract

Twenty-seven patients treated with high-dose rTNFα, IFNγ and melphalan by isolated limb perfusion were histologically documented. There were 20 cases of melanoma-in-transit metastases and 7 cases of high-grade soft-tissue sarcoma. Biopsies were taken before IFN7, after IFNγ, before TNFα and between 2 hr and 60 days after the TNFα perfusion. Immunohistochemistry was performed for adhesion molecules ICAM-I, ELAM-I (E selectin), VCAM-I and PECAM. During the first hours after beginning perfusion, the endothelial cells of the tumour capillaries appeared swollen. Significant tumour necrosis was already observed 3 hours after the perfusion in melanoma cases. The overall predominant feature was coagulative necrosis associated or not with haemorrhagic necrosis. TNFα induced increased expression of ELAM-I and VCAM-I adhesion molecules on intratumoral endothelial cells. The activated tumour vessels were progressively destroyed. Significant intra-vascular recruitment of polymorphonuclear cells (PMNs) was observed 3 hr after starting TNFα; it was followed by diapedesis and tumour colonization 3 days later. T lymphocytes and macrophages were detected during the first 7 days and B lymphocytes during the second week. Melanoma in transit metastases treated with alkylating agent alone did not show significant necrosis and did not express high levels of adhesion molecules (ELAM-1, VCAM-I) nor infiltration by PMN.

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