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result of this adaptive PTEN loss, brain metastatic tumor Depending on clinical symptoms and neuroradiological
cells released more chemokine CC chemokine ligand 2, features, one single spinal tap or up to three spinal taps can
leading to recruitment of IBA1-expressing myeloid cells be considered. If, for example, clinical symptoms strongly
and further enhancement of the growth and maintenance of suggest an underlying meningeomatosis, a single lumbar
brain metastases. [23] puncture might not be enough to detect atypical cells in
the CSF, so serial lumbar punctures might be necessary.
Infiltrating inflammatory host cells, including tumor- Diagnostic workup of the CSF includes analyses of
infiltrating lymphocytes or myeloid cells, are a third opening pressure, protein, glucose, and lactate levels as
key component shaping the tumor microenvironment well as cytology and immunocytology.
and correlating with patients’ survival times in several
extracranial malignancies. These cells significantly Standard MRI exams include T1-weighted images with
[24]
change their functional characteristics under the influence or without contrast enhancement, T2-weighted imaging,
of high-grade glioma, indicating that they might and FLAIR sequences. Differential diagnosis of brain
[25]
also play a role for supporting CNS metastatic growth. metastases includes malignant gliomas and lymphomas
Clinicopathological correlations of associated lymphocytic or nonneoplastic conditions, such as abscess, infections,
infiltrates indicate a beneficial outcome for CNS immune demyelinating diseases, and vascular lesions. Recently,
response. Two functional phenotypes of tumor- the Response Assessment in Neuro-Oncology Brain
[26]
associated macrophages have been proposed: the M1 and Metastases (RANO-BM) working group has proposed
the M2 phenotype. While M1 is characterized by tumor- criteria for a harmonization of the assessment of CNS
suppressive functions, the M2 may have more tumor- metastases. This might contribute to a standardization
[32]
promoting functions, including suppression of immune of techniques and assessment tools, particularly important
responses and promotion of adaptive immune response and in the era of targeted compounds. It is not yet entirely
migration/invasion. However, recent studies suggest that clear to what extent and how novel targeted therapies (e.g.
[25]
this dichotomy does not completely reflect the situation in immunotherapies and kinase inhibitors) will alter imaging
brain tumors. [27] characteristics. The recently published recommendations
of the RANO-BM working group provide a guideline to
In recent years, high-throughput technologies have evolved differentiate imaging alterations during immunotherapies
significantly. Thus, molecular tumor profiling (e.g. by Next- in brain tumors. Innovative and advanced neuroimaging
[33]
generation sequencing, panel sequencing) for identifying techniques will certainly gain even more importance.
molecular targets is in principle feasible in the short term. Examples include the addition of diffusion-weighted MRI
Data on the molecular characteristics of CNS metastases (DW-MRI), perfusion MRI, proton magnetic resonance
have only recently been acquired. This might be due to spectroscopy (MRS), and various amino acid tracers in
the fact that CNS metastatic tissues are only available positron emission tomography (PET). These techniques
from patients who are eligible for neurosurgical resection. might be especially relevant to meet the challenges of
Because craniotomies are not indicated in all patients disease monitoring (e.g. the discrimination of radiation
with CNS metastases (see below), a systematic analysis necrosis from recurrent tumor might be challenging on MRI
of the molecular differences between CNS metastases and since both conditions present with contrast enhancement
matched primary tumors or between CNS metastases and on T1-weighted MR images, and the pattern of abnormal
extracranial metastases remains challenging. Molecular enhancement closely mimics that of a recurrent brain
profiling of matched CNS and extracranial metastases in metastasis). In fact, small studies with perfusion MRI
[34]
smaller series of melanoma patients showed that CNS using CBV analysis showed the potential to differentiate
metastases distinguished themselves through specific between radiation necrosis and tumor recurrence with good
molecular differences in the activation of the PI3K/mTOR/ sensitivity and specificity. Nuclear medicine techniques
[35]
Akt or HER2 or kirsten rat sarcoma (KRAS) pathway. [28-31] might contribute to answering this critical question. While
These studies highlight, for example, the potential of an fludeoxyglucose (FDG) tracer was not sensitive enough
adding PI3K inhibitors or mTOR inhibitors as adjunct to differentiate vital brain metastases from unspecific non-
targeted therapy in the treatment of CNS metastases. tumor changes related to therapy, the amino-acid PET
[36]
tracer 11 C-methionine showed higher tumor-to-lesion
TREATMENT STRATEGIES NEED A uptake ratios in patients with recurrent metastases/glioma
PROFOUND INTERDISCIPLINARY after radiation treatment than in patients with radiation
DIAGNOSTIC WORKUP necrosis. Furthermore, the combination of two amino
[37]
acid tracers (FET and MET) identified treatment-related
In addition to the staging of extracranial disease, a thorough changes with high sensitivity and specificity. [38]
neurological workup including neurological examination,
neurocognitive assessments, neuroimaging, and a spinal The blood-brain-barrier is often mentioned as a challenge
tap is in principle indicated in all patients with established for diagnosis and therapy. In a very interesting preclinical
malignant disease and suspected brain metastases. study using mouse models of small metastatic breast

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 20, 2016 ¦ 165