Focal Hyperthermia Produces Progressive Tumor Necrosis Independent of the Initial Thermal Effects

Focal hyperthermia, produced using laser, radio frequency, and microwave, is used to treat liver tumors. The exact mechanisms of tissue destruction using focal hyperthermia are, however, unknown. Clinical and experimental studies suggest a progression of injury after cessation of the initial heat stimulus. This study investigates the mechanisms and time sequence of progressive tissue necrosis induced using focal hyperthermia in a murine model of colorectal liver metastases. Focal hyperthermia produced using a neodymium-yttrium aluminum garnet (Nd-YAG) laser source was applied to the normal liver and colorectal cancer liver metastases in inbred male CBA strain mice. The extent of direct lethal thermal injury was assessed histochemically using vital stain for nicotinamide adenine dinucleotide (NADH) diaphorase immediately after laser application. Tissue injury at subsequent time points was assessed using both NADH diaphorase staining and routine histology to determine the temporal relationship between tissue necrosis and time. Thermal injury occurring immediately after the application of 100 joules of energy was greater in the tumor tissue than in the normal liver (mean [standard error of the mean (SEM)]), measuring 23.5 (3.4) and 16.3 (2.6) mm3, respectively (P = 0.046), despite similar tissue temperature profiles. There was a significant increase in tissue necrosis after initial injury that was greater in the normal liver than in the tumor tissue. In the normal liver, the peak volume of necrosis was 137.4 (9.8) mm3 and occurred at 3 days, whereas in the tumor tissue the peak was 49.0 (3.5) mm3 at 4.5 days (P < 0.001). Focal hyperthermia produces tissue necrosis that occurs in two phases. The first phase is caused by the direct lethal thermal injury followed by a second phase involving a progression of necrosis beyond the initial thermal effects. The normal liver and the tumor tissue responded differently to focal hyperthermia. In the tumor tissue, the direct injury is more pronounced, whereas the progression of injury is more rapid and extensive in the normal liver.