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Page 4 of 16 Enrique et al. J Cancer Metastasis Treat 2019;5:54 I http://dx.doi.org/10.20517/2394-4722.2019.20

an inflamed cerebral microenvironment that is appropriate for their development and growth, which is
known as their niche .
[16]

Tumor cells can evade growth-suppressing factors and inhibitors of cell proliferation through mechanisms
that include resistance to apoptosis, overexpression of Bcl-2 and Bcl-xL, and the inhibition of proapoptotic
pathways Bax and Bim . Tumor cells can be dedifferentiated, migrate to a distant site, survive apoptosis,
[12]
disseminate, and redifferentiate. The activation of cells in the adjacent stroma by paracrine signaling with
pro-tumor factors maintains the growth of the tumor, intensifying genomic instability and epigenetic
dysregulation [11,13] .

Tumor cells adhere to the endothelium of recipient tissue and act as macrophages, creating pseudopods
and penetrating cell-to-cell junctions, subsequently gaining access to normal tissue parenchyma to activate
angiogenesis and develop new vessels for its nutrition, in this way promoting the growth of secondary
injuries . Circulating cells attract platelets due to the proteins they express on their surface, which protects
[17]
them from the immune system. Likewise, metastatic cells activate mechanisms to escape immunity by
reducing the expression of TAP1, which decreases the effects of T-cell-mediated death .
[18]

DIAGNOSIS
Although clinical manifestations of a history of malignant disease with central nervous system metastasis
potential may obviously occur, it will not always be possible to obtain histological confirmation of these
lesions [Figure 3]. In such cases, complementary image studies may play an important role in determining
the best management for these patients.

Image studies
Magnetic resonance imaging (MRI) is the tool of choice when brain metastasis is suspected, due to its high
sensitivity and specificity, which support its high capacity to detect smaller lesions than those that appear
in computed tomography (CT) with or without contrast; it is also associated with fewer bone artifacts in
posterior fossa. However, if MRI cannot be used, CT is still a valid option .
[19]
CT will show isodense lesions in contrast with brain parenchyma, which will intensify with the application
of intravenous contrast medium. When lesions appear hyperdense, one may suspect secondary bleeding,
especially in histologies associated with high spontaneous bleeding risk (including choriocarcinoma,
melanoma, and renal carcinoma); there are also other findings that are secondary to lesions and that can be
easily visualized, such as hydrocephaly, ring-enhancing cerebral lesions, and brain herniation [19,20] .

The sensitivity and specificity of CT scans are 92% and 99%, respectively, and they are considerably higher
in tumors that have a high incidence of central nervous system metastasis, such as non-small-cell lung
cancer . MRI exhibits an ability to detect lesions smaller than 1 cm, up to 70% more sensitive than CT, and
[21]
this increases in cases of multiple metastases . MRI has other beneficial characteristics, for example, in
[19]
the use of distinct sequences such as T1, T2, FLAIR, diffusion, and perfusion, which can be used along with
spectroscopy to increase sensibility and specificity .
[22]
The majority of metastatic lesions are hypointense in T1 sequence images, which can be an indication of
hemorrhage and necrosis. In T2 weighted images, the majority of lesions appear hyperintense [Figure 4].
Bleeding appears as acutely hypointense and becomes hyperintense as chronicity develops, while vasogenic
edema appears hyperintense. The use of contrast significantly increases its sensitivity and specificity for the
detection of brain metastases relative to simple MRI .
[23]