Until now, the rarity of extraneural metastases has not had a clear explanation. The most current hypotheses are because (1) there is an absence of lymphatic vessels in the central nervous system (CNS); (2) the intracranial perivascular spaces do not communicate with the extracranial fluid space; (3) connections between the subarachnoid space and extracranial lymphatic vessels are rare; (4) intracerebral veins walls are thin and they probably collapse from compression before a tumor penetrates them; (5) meningeal tumors grow on the dura mater but remain only on the surface; and (6) dural veins are protected by a dense connective tissue [5].

An additional hypothesis regarding the pathogenesis of the brain metastases has suggested that the metastatic potential of the GBM might be correlated with particular molecular features, such as P53 gene mutations and differential clonal selection [6]. In fact, some metastases arise from genetically altered subclones of the primary tumor. Several biological and molecular studies have shown an overexpression of insulin growth factor and a decrease of DNA-PK (a DNA-dependent protein kinase involved in DNA repair mechanisms) genetic expression. The first probably plays a role in tumor progression; the second contributes to the malignant transformation of the glioma. One study suggested that distant dissemination is the consequence of direct infiltration of tumor cells into extracranial blood vessels [6].

A review of 128 patients affected by GBM with extra-CNS metastases found 19 patients who had liver metastases (14.8 %) [7]. The total numbers of patients reported in the literature as affected by hepatic metastases from brain primary tumors are reported in Table 16.3.