Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in advanced soft-tissue sarcomas: Histopathological considerations

Background: Hyperthermic isolated limb perfusion with tumor necrosis factor -alpha and melphalan was used as induction treatment in locally advanced ex tremity soft-tissue sarcomas for limb sparing surgery. The typical histopat hological changes that occur in these tumoral masses are described in a ser ies of 30 patients. Methods: Fresh tumor specimens of 27 high grade extensive soft-tissue sarco mas and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks after hyperthermic isolated limb perfusion with tumor necrosis facto r-alpha plus melphalan. The specimens were studied for surgical margins, ex tent and type of tumor necrosis, lymph node involvement, perineural and vas cular invasion, and the effects on adjacent normal tissues such as nerves, muscles, and blood vessels. Results: The typical histological changes were central cystic hemorrhagic n ecrosis with pericystic extensive fibrosis. Some nonspecific changes were n oted in the soft tissues around the mass. In eight cases, more than 90% nec rosis was found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%-90% in 4 of 17 cases). In five cases, less than 60% necrosis was noted. The best responses (>90% necrosis) were observed in distally located tumors. The responsive types were malignant fibrous histiocytoma, followed by myxoid liposarcoma and synovial sarcoma. Desmoid tumors showed less nec rosis than high grade sarcomas. Vascular invasion was observed in two cases and intralesional venous thrombosis in one case. No perineural invasion or lymph nodes involvement were observed. The soft tissues adjacent to the tu mor bed did not show major morphological changes. No correlation was found between the histological changes and each of the following: the anatomical (upper vs. lower limb) or compartmental location of the tumor; whether the tumor was primary or recurrent; and the types of previous treatment (system ic chemotherapy or radiotherapy) and tumor size. Conclusions: This is the first serial histological description of the effec ts of tumor necrosis factor-alpha and melphalan administered via hypertherm ic isolated limb perfusion on the tumoral masses of limb soft-tissue sarcom as. The small number of specimens and, especially, the variability of tumor s preclude definite conclusions. Larger numbers and more homogeneity are ne eded in future studies.