Delayed diffuse leukoencephalopathy is a well-known complication of standard fractionated external beam radiation therapy to the brain. Single fraction, high dose, focused radiation therapy such as Gamma Knife radiosurgery is being increasingly used for the treatment of metastatic cancer to the brain to avoid such diffuse injury. However, adverse radiation effects (ARE) on MRimaging are now also being reported in up to half of metastatic lesions treated with radiosurgery and are thought to also represent delayed leukoencephalopathy. While radiosurgery-induced leukoencephalopathy is known to be clinically different than that following fractionated radiation, the pathological differences are not well characterized. 

     We retrospectively reviewed the radiographic and histopathological findings in cases of surgically resected ARE to understand radiosurgery-induced leukoencephalopathy. Novel findings are reported.

     All 10 patients had metastatic tumors to the brain.

     We examined the histopathological tissue of 10 patients whose brain metastases had been previously treated with Gamma Knife radiosurgery. In all of these patients, surgical management of a symptomatic regrowing lesion was subsequently required. Given the surgical accessibility of these lesions, all were removed en bloc at Yale New Haven Hospital between January 1, 2009 and June 30, 2010. All specimens showed no evidence of tumor recurrence upon thorough review of their histopathology. The clinical and magnetic resonance imaging data for each of the 10 patients were then reviewed.

     The patients in this study all presented with progressively growing contrast-enhancing lesions on follow-up magnetic resonance imaging 8 to 17 months after Gamma Knife treatment, which prompted surgical resection of the affected area. Neuropathologic examination revealed absence of residual or recurrent tumor, but marked leukencephalopathic changes, including demyelination, coagulation necrosis and vascular sclerosis. In addition, abundant inflammatory cells were noted throughout the parenchyma, which were mostly CD3+ T lymphocytes. Unexpectedly, small and medium-sized vessels also showed a marked transmural T cell infiltrate indicative of active vasculitis.

     The main limitation was the sample size.

     In this study involving 10 patients who received Gamma Knife stereotactic radiosurgical treatment for brain metastases, we provide evidence that radiation-induced leukoencephalopathy may present as a rapidly advancing process that grows to extend beyond the original high-dose radiation field.  

     We hypothesize that a vasculitic process in association with radiation leukoencephalopathy may facilitate the progressive nature of the condition.