this article reviews the magnetic resonance imaging ( mri ) techniques available for use in the diagnosis and management of patients with cerebral metastases .
particular attention is paid to advanced imaging methodologies from which quantitative parameters can be derived , the role of these imaging biomarkers in distinguishing metastases from primary central nervous system ( cns ) tumours and tumour mimics , and metrics that may be of value in predicting the origin of the primary tumour .
autopsy studies have reported an incidence of cerebral metastases of up to 25% in patients with systemic cancer . with advancements in the management of patients with systemic malignancy , there has been a decline in patients dying from uncontrolled systemic disease .
cancer patients are surviving longer and whilst their systemic disease is controlled with newer medications , an increase in cns dissemination has been reported .
cerebral metastases are a leading cause of mortality in patients with metastatic malignancy and the median survival for those patients receiving whole brain radiotherapy ( wbrt ) is 7 months
. surgical resection of solitary metastases has been shown to convey a survival advantage in patients with systemically controlled disease in a small number of studies , but this is diminished in the presence of small , additional , non - resectable metastases .
in addition , stereotactic radiosurgery ( srs ) is increasingly being utilized in the treatment of multiple ( up to 4 ) small ( less than 3  cm maximum diameter ) metastases , although the advantages of this technique over wbrt for the treatment of more than 2 lesions remains controversial .
it is therefore imperative that imaging provides accurate diagnosis , identification , size information and localization of all intracranial lesions in patients with presumed cerebral metastatic disease in order to optimize their management .
the differential diagnosis of the solitary enhancing cerebral mass , of which metastatic disease is one of the leading causes , can be a major diagnostic challenge in neuroradiology .
whilst multiplicity favours the diagnosis of metastatic disease , differentiation from multifocal glioblastoma multiforme ( gbm ) and tumour mimics such as infection or tumefactive demyelination can be difficult .
distinction between these entities and metastatic disease is important with regard to both immediate patient management , and the need for additional imaging in patients with no known malignancy to identify a primary site and treat appropriately .
classically , cerebral metastases are seen on either computed tomography ( ct ) scanning or mri as lesions occurring at the cortical interface at the grey and white matter junction , most commonly located within the cerebral hemispheres followed by the cerebellum .
lesions can vary from radiologically silent microscopic deposits to masses measuring several centimetres in diameter .
contrast enhancement is frequently seen and can be intense , punctate , nodular or ring enhancing .
haemorrhage can also be a feature , and occurs more frequently in certain underlying primary pathologies ( see below ) .
the degree of peri - tumoural oedema varies from virtually none to ( more commonly ) extensive surrounding oedema .
mri exhibits superior sensitivity to ct for small lesion identification , particularly in the posterior fossa , and double / triple dose contrast , delayed imaging and the use of magnetization transfer to suppress background signal from non - enhancing tissues can further improve the sensitivity of lesion detection .
in addition , certain imaging characteristics such as high attenuation on non - contrast ct and low t2 signal intensity as seen in mucinous metastases ( fig .
1 ) or high signal on non - contrast t1 imaging of melanoma metastases ( fig .
the utilization of alternative conventional sequences such as contrast - enhanced multi - shot echo planar fluid attenuated inversion recovery ( flair ) and pre- and post - contrast inversion recovery t1-weighted sequences instead of conventional t1 spin echo sequences have failed to demonstrate benefit in improving lesion conspicuity .
phenotypic descriptors such as non - enhancing cortical flair signal abnormality adjacent to the mass lesion have been described more frequently in glioma but this feature is also seen in some cases of cerebral metastases . 

figure 1imaging appearances of a solitary mucinous metastases from a colonic carcinoma primary on ( a ) non - contrast ct ( hyper - attenuating lesion ) ; ( b ) t2-weighted imaging ( markedly hypointense ) ; ( c ) t1-weighted pre - contrast imaging ( isointense ) ; ( d ) post - gadolinium contrast t1-weighted imaging ( rim enhancement ) . 
 figure 2imaging characteristics of melanoma metastases .
( a ) t2 ; ( b ) pre - contrast t1 ; ( c ) post - contrast t1 .
imaging appearances of a solitary mucinous metastases from a colonic carcinoma primary on ( a ) non - contrast ct ( hyper - attenuating lesion ) ; ( b ) t2-weighted imaging ( markedly hypointense ) ; ( c ) t1-weighted pre - contrast imaging ( isointense ) ; ( d ) post - gadolinium contrast t1-weighted imaging ( rim enhancement ) .
( a ) t2 ; ( b ) pre - contrast t1 ; ( c ) post - contrast t1 . the relative volume of signal hyperintensity on flair or t2-weighted imaging to the enhancing lesion volume is frequently cited as a good discriminator of malignant glioma and cerebral metastases in radiology textbooks
. a greater degree of peri - lesional signal change , commonly referred to as oedema although the underlying content in glioma is more complex , is reportedly indicative of metastatic disease rather than glioma .
a small ( n  =  29 ) ct - based study from 1989 reported differences in the mean ratio of oedema volume to tumour volume between metastases ( 3.1 ) and primary lesions ( 1.4 ) .
a more recent mri study of 26 metastases and 22 high - grade gliomas ( hgg ) evaluated the peri - tumoural oedema to tumour area ratio , and found significant differences between hgg ( 0.69    0.41 ) and metastases ( 2.41    1.63 ) , p  <  0.001 .
more evidence actually supports the use of advanced imaging metrics in the peri - lesional oedema to discriminate these 2 entities as detailed below , reflecting the underlying pathological differences in the origin of this signal change .
dynamic contrast - enhanced ( dce ) imaging techniques have been developed that allow for a number of parameters to be estimated that are thought to reflect the microvascular environment .
detailed descriptions of these methodologies are beyond the scope of this review and interested readers are directed to a number of excellent review articles on the subject of perfusion and permeability imaging in neuro - oncology . in brief , a bolus of contrast agent is injected intravenously and tracked with a series of dynamic images .
baseline longitudinal relaxivity ( t1 ) is measured , and changes in t1-weighted signal intensity are converted to changes in contrast agent concentration .
contrast agent concentration time courses are generated , and post - processing of the data with application of pharmacokinetic modelling techniques allows for the calculation of a number of parameters , the most widely used of which is k ( contrast volume transfer coefficient , in effect the amount of contrast passing from the intravascular space to the extravascular , extracellular space ) reflecting both local blood flow and capillary permeability . for dynamic susceptibility contrast techniques ( dsc - mri ) , the contrast agent bolus is tracked using fast t2- or t2 * -weighted acquisitions .
models of differing complexity can be used but the fundamental goal is to derive estimates of cerebral blood volume ( cbv ) and cerebral blood flow ( cbf ) . in distinguishing primary from metastatic cerebral tumours ,
the only parameter reported to have value in robustly separating the 2 entities is cbv .
a number of studies have reported higher cbv values in the solid tumour component of hggs than in metastases .
furthermore , in the examination of the peri - tumoural so - called oedematous region ( peri - lesional t2/flair signal hyperintensity seen adjacent to enhancing or clearly solid tumour mass ) , hggs are reported to demonstrate higher cbv values than metastases ( fig .
3 ) . this may reflect differences in the underlying mechanisms of the so - called peri - tumoural oedema , which in primary intrinsic tumour may contain infiltrating angiogenic tumour cells in addition to vasogenic oedema , and in metastatic disease is more likely to reflect pure vasogenic oedema . 

figure 3perfusion imaging in ( a ) solitary cerebral metastasis and ( b ) gbm ( axial imaging on the left and sagittal reformats on the right ) .
bottom row : cbv maps . magnified images of cbv maps and corresponding t2-weighted images .
( a ) the peri - lesional non - enhancing tissue surrounding the metastasis exhibits a very low relative cbv ( white arrowhead ) and represents vasogenic oedema ; ( b ) the peri - lesional non - enhancing tissue surrounding the gbm has a slightly higher relative cerebral blood volume ( white arrow ) and represents infiltrating glioma . perfusion imaging in ( a ) solitary cerebral metastasis and ( b ) gbm ( axial imaging on the left and sagittal reformats on the right ) . top row : t2-weighted imaging .
bottom row : cbv maps . magnified images of cbv maps and corresponding t2-weighted images .
( a ) the peri - lesional non - enhancing tissue surrounding the metastasis exhibits a very low relative cbv ( white arrowhead ) and represents vasogenic oedema ; ( b ) the peri - lesional non - enhancing tissue surrounding the gbm has a slightly higher relative cerebral blood volume ( white arrow ) and represents infiltrating glioma .
diffusion - weighted imaging and tractography diffusion - weighted imaging ( dwi ) allows quantification of the movement of free water molecules occurring secondarily to random thermal motion .
the apparent diffusion coefficient ( adc ) is a measure of the degree of random motion of water molecules due to thermal energy .
the term apparent is used to convey that it is not truly the free diffusion of water that is being observed . on visual inspection of diffusion imaging and adc maps , there is considerable evidence suggesting that this is of value in distinguishing necrotic tumours ( both primary hggs and metastases ) from abscesses , with restricted diffusion seen in the core of abscesses .
however , it should be noted that the distinction is not clear cut and restricted diffusion has been reported in cerebral metastases of certain histological types ( both small and non - small - cell lung , breast , colon and testicular carcinoma ) ( fig .
the literature regarding the usefulness of measurement of adc values and related metrics in distinguishing hgg from cerebral metastases is controversial .
some groups have reported higher values of adc and adc ratios in the solid tumour or peri - tumoural tissue in cerebral metastases than in hgg , while others have reported lower values in either tumour or peri - lesional tissue and some have reported no significant difference in adc values between hgg and metastatic disease .
these conflicting results may be a reflection of the wide variation in different imaging acquisitions , post - processing analysis techniques and scanners used .
in addition , all studies have had relatively small recruitment numbers , few containing more than 20 patients with cerebral metastases and none containing a single metastatic histological tissue type , thus making the data rather heterogeneous and limiting its interpretation and applicability . 
 figure 4restricted diffusion in cerebral metastases .
( a ) t2-weighted imaging ; ( b ) post - contrast t1-weighted imaging ; ( c ) dwi ; ( d ) adc map .
there is restricted diffusion within the medial aspect of the tumour which demonstrates restriction in the more solid , t2 hypointense , non - enhancing component . restricted diffusion in cerebral metastases .
( a ) t2-weighted imaging ; ( b ) post - contrast t1-weighted imaging ; ( c ) dwi ; ( d ) adc map .
there is restricted diffusion within the medial aspect of the tumour which demonstrates restriction in the more solid , t2 hypointense , non - enhancing component .
the use of diffusion tensor imaging ( dti ) allows assessment of different , more detailed , diffusion - based parameters such as mean diffusivity ( md ) and fractional anisotropy ( fa ) .
md from dti takes into account the orientation of the diffusion ellipsoid in each voxel , while adc from dwi represents diffusion in the orthogonal measurement directions as applied to every voxel .
confusion can arise from the often interchangeable use of md and adc . like studies evaluating the role of adc in cerebral metastases ,
the literature regarding md and fa measures is also controversial . in a study comparing 16 gbms with 12 metastases , measures of md in both tumoural and peri - tumoural tissue was found to be significantly different between metastases and gbm , with low md values in the solid tumour in metastatic disease ( 0.98    0.188 ) compared with gbm ( 1.22    0.284 ) , and high md values in the peri - tumoural tissue of metastases ( 1.41    0.097 ) versus gbm ( 1.25    0.201 ) .
this study also reported differences in the fa values of the peri - tumoural region , but not the solid tumour between the 2 malignancy types with metastases having significantly lower fa values ( 0.159    0.02 ) than gbm ( 0.188    0.045 ) . in comparison ,
a similar study that included 10 gbms and 6 metastases reported no significant difference between enhancing tumoural or peri - tumoural tissue md or fa values , although the md value of the cystic component was reported to be significantly lower in the metastatic group than the gbm group ; however there was considerable overlap between the 2 entities .
a larger study by wang et al . of 63 patients with ring - enhancing lesions ( 38 gbms and 25 metastases ) examined more detailed features of the diffusion tensor shape , namely linear and planar coefficients ( cl and cp , respectively ) , in addition to measures of fa and adc in the tumour core , enhancing rim , immediate peri - tumoural region and distant peri - tumoural region .
they reported significantly higher values of both fa and cp for all tissue regions and elevated cl in all but the distant peri - tumoural region in gbm tumours compared with cerebral metastases .
no significant difference in adc measures was found between gbm or metastases but the model from this study that best predicted tumour type with a sensitivity of 92% and specificity of 100% included adc , fa and cp measures .
other scalar measures of directional diffusion that can be derived include p ( pure isotropic diffusion ) , q ( pure anisotropic diffusion ) and l ( the total magnitude of the diffusion tensor ) . in a comparative study of the value of these measures in distinguishing gbm from metastases ,
the only parameter found to have a significantly lower value in the cerebral metastases compared with gbm was the measure q in the peri - tumoural region .
there is also evidence for the utility of dwi or dti in discriminating solitary , cystic metastases from cerebral abscesses .
since abscesses often exhibit significantly lower central adc , they can be confused with mucinous adenocarcinomas .
have recently suggested that a combination of central adc with rim fa helps to distinguish those neoplastic cysts with low central adc from abscesses .
proton magnetic resonance spectroscopy ( mrs ) allows tissue metabolites to be assessed non - invasively .
the 2 main techniques use single voxel ( e.g. press , steam ) or multivoxel chemical shift imaging ( csi ) techniques .
a number of studies using csi have shown some potential in differentiating gbm from cerebral metastases , wherein examination of the peri - tumoural region has been reported to show a lower choline ( cho)/creatine ( cr ) ratio in cerebral metastases than that seen in gbms . in a study of 53 hggs and 20 metastases ,
server et al . reported 100% sensitivity , 88.9% specificity , a positive predictive value ( ppv ) of 80% and a negative predictive value ( npv ) of 100% using a cut - off value of 1.24 for the peri - tumoural cho / cr ratio to discriminate between hgg and metastases .
similarly , this group also reported the value of examining the peri - tumoural cho / naa ratio and , using a cut - off value of 1.11 , found 100% sensitivity , 91.1% specificity , 83.3% ppv , and 100% npv in discriminating hgg from cerebral metastases . a recent report in 2 cases of mucinous adenocarcinoma
has described the presence of a metabolite peak that mimics naa and may reduce the specificity of mrs in this tumour type . the use of short echo time proton spectroscopy allows lipid and macromolecule signals to be observed
opstad et al . studied the value of short echo time mrs in comparing lipid and macromolecule signals in cerebral metastases ( n  =  34 ) and gbm ( n  =  25 ) and reported significantly higher values in metastases than gbm , although there was considerable overlap between the 2 groups .
in an attempt to address the multicenter applicability of single voxel spectroscopy for assisting differential diagnosis of brain tumours , garca - gmez et al . assessed spectra from several sites in over 300 intracranial lesions with histological diagnosis .
they reported around 90% accuracy in pairwise discriminant analysis for differentiation between meningiomas , low - grade gliomas , gbm and metastases .
unfortunately , the discrimination of gbm from metastasis was less accurate at 78% , and they recommend a combined approach in further work .
the value of mrs in non - invasive discrimination of source tissue in cerebral metastases has been studied by 2 groups .
reported increased mobile lipid content and elevated lip / ncr in cerebral metastases arising from a colorectal primary when compared with metastases from histologically distinct primary tumours .
in addition , huang et al . compared non - small - cell lung carcinoma ( nsclc ) cerebral metastases ( n  =  40 ) with those from breast ( n  =  17 ) and melanoma ( n  =  9 ) using csi mrs , reporting the cho / cr ratio to be significantly lower in nsclc metastases than in either breast or melanoma metastases .
mrs can be performed ex vivo on biopsy samples for metabolic classification of tumours , and there is evidence for clinically useful differential characterization of cerebral metastases . while this is invasive , it provides evidence for the potential use of new metabolic and spectroscopic imaging techniques in vivo .
as with many advanced mri techniques , where optimization of acquisition and analysis requires further work , there is often diagnostic overlap within a particular imaging parameter .
evidence suggests that the ability to distinguish primary hggs from solitary cerebral metastases is improved when a multi - parametric imaging approach is taken .
law et al . reported significant differences in both rcbv and cho / cr in the peri - tumoural region of gbm and metastases and advocated that these imaging parameters could be used together to try and distinguish between the 2 tumour types .
similarly , bulakbasi et al . found both adc values and mrs values were separately useful in differentiating cerebral tumours , but when combined there was added value in predicting tumour type .
the combined use of perfusion - weighted imaging ( pwi ) and mrs has also shown value in differentiating cerebral metastases originating from primary lung carcinoma from lesions originating from either breast carcinoma or melanoma .
wang et al . used a combination of dti and dsc to distinguish gbm , solitary metastases and primary cerebral lymphoma ( pcl ) .
they concluded that the best discriminative combination for distinguishing gbm from the other tumour types involved fa from the enhancing rim and rcbv from the peri - tumoural region .
this finding is in keeping with the histopathological findings in gbm with pseudopallisading cellular rim , and angiogenesis occurring adjacent to microinvasive disease in the surrounding oedema .
again , the multiparametric approach has been used for the discrimination of infectious from cystic neoplastic lesions . in a relatively small study ,
the lower central adc was again found in infectious lesions , while the presence of amino acids on mrs was also indicative of infection .
in addition , the blood volume in the rim of the neoplastic lesions was found to be higher .
the evidence regarding the use of advanced imaging techniques in cerebral metastatic disease is largely controversial with a variety of conflicting results regarding the different advanced imaging modalities .
the majority of studies have focused on discriminating hgg from solitary cerebral metastases , with fewer studies attempting to differentiate metastatic lesions according to histological subtype , and therefore inform further imaging . at best
, the majority of evidence suggests that quantitative metrics derived from pwi , dwi , dti or mrs of the peri - tumoural tissue may provide a supplementary means of discriminating hgg from cerebral metastases , and the use of a multimodality approach combining parameters derived from each of the advanced imaging techniques is likely to improve both the diagnostic sensitivity and specificity .
unfortunately , most of the current studies are limited with regard to their small patient numbers ( few have more than 30 patients for a given tumour type ) and the heterogeneous collection of histological types of cerebral metastases that are frequently grouped together . a large multi - centre trial is required to evaluate the usefulness of these combined advanced mr parameters in discriminating both gbm from cerebral metastases , and metastases of different histological subtype . in order to achieve diagnostic currency in the setting of busy clinical scanners ,
a selection of optimized advanced mr techniques requiring limited post - processing is desirable . a combination of short echo time mrs
, dti and dsc imaging is a likely combination , with attention paid to both the enhancing tumour itself and the peri - tumoural tissue .
the limitations in the receiver operating characteristics of these approaches mean that the expert input of a suitably experienced radiologist with a complete clinical picture will still be crucial in each case .
 abstractthere are a number of magnetic resonance imaging techniques available for use in the diagnosis and management of patients with cerebral metastases . 
 this article reviews these techniques , in particular , the advanced imaging methodologies from which quantitative parameters can be derived , the role of these imaging biomarkers have in distinguishing metastases from primary central nervous system tumours and tumour mimics , and metrics that may be of value in predicting the origin of the primary tumour . 