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Advanced MRI assessment of non-enhancing peritumoral signal abnormality in brain lesions

  • Author Footnotes
    1 Carmelo Torres 2, 23007 Jaén, Spain.
    Teodoro Martín-Noguerol
    Correspondence
    Corresponding author at: MRI Section, Radiology Department, HT Medica, Carmelo Torres 2, 23007 Jaén. Spain.
    Footnotes
    1 Carmelo Torres 2, 23007 Jaén, Spain.
    Affiliations
    MRI Unit, Radiology Department, HT Medica, Jaén, Spain
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  • Author Footnotes
    2 399 S 34th St #21, Philadelphia, PA 19104, USA.
    Suyash Mohan
    Footnotes
    2 399 S 34th St #21, Philadelphia, PA 19104, USA.
    Affiliations
    Division of Neuroradiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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  • Author Footnotes
    3 Rúa de Salamanca, 5, 36211 Vigo, Pontevedra, Spain.
    Eloísa Santos-Armentia
    Footnotes
    3 Rúa de Salamanca, 5, 36211 Vigo, Pontevedra, Spain.
    Affiliations
    Radiology Department, Povisa Hospital, Vigo, Pontevedra, Spain
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  • Author Footnotes
    4 Labeaga Auzoa, 48960 Galdakao, Bizkaia, Spain.
    Alberto Cabrera-Zubizarreta
    Footnotes
    4 Labeaga Auzoa, 48960 Galdakao, Bizkaia, Spain.
    Affiliations
    OSATEK MR Unit Hospital of Galdakao, Galdakao-Usansolo. Spain
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  • Author Footnotes
    1 Carmelo Torres 2, 23007 Jaén, Spain.
    Antonio Luna
    Footnotes
    1 Carmelo Torres 2, 23007 Jaén, Spain.
    Affiliations
    MRI Unit, Radiology Department, HT Medica, Jaén, Spain
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  • Author Footnotes
    1 Carmelo Torres 2, 23007 Jaén, Spain.
    2 399 S 34th St #21, Philadelphia, PA 19104, USA.
    3 Rúa de Salamanca, 5, 36211 Vigo, Pontevedra, Spain.
    4 Labeaga Auzoa, 48960 Galdakao, Bizkaia, Spain.
Published:August 06, 2021DOI:https://doi.org/10.1016/j.ejrad.2021.109900

      Highlights

      • Non-enhancing peritumoral areas help to differentiate between brain lesions.
      • Advanced MRI sequences allow to evaluate non-enhancing peritumoral areas.
      • Most of these advanced MRI sequences can be integrated into routine MRI protocols.

      Abstract

      Evaluation of Central Nervous System (CNS) focal lesions has been classically made focusing on the assessment solid or enhancing component. However, the assessment of solitary peripherally enhancing lesions where the differential diagnosis includes High-Grade Gliomas (HGG) and metastasis, is usually challenging. Several studies have tried to address the characteristics of peritumoral non-enhancing areas, for better characterization of these lesions. Peritumoral hyperintense T2/FLAIR signal abnormality predominantly contains infiltrating tumor cells in HGG whereas CNS metastasis induce pure vasogenic edema. In addition, the accurate determination of the real extension of HGG is critical for treatment selection and outcome. Conventional MRI sequences are limited in distinguishing infiltrating neoplasm from vasogenic edema. Advanced MRI sequences like Diffusion Weighted Imaging (DWI), Diffusion Tensor Imaging (DTI), Perfusion Weighted Imaging (PWI) and MR spectroscopy (MRS) have all been utilized for this aim with acceptable results. Other advanced MRI approaches, less explored for this task such as Arterial Spin Labelling (ASL), Diffusion Kurtosis Imaging (DKI), T2 relaxometry or Amide Proton Transfer (APT) are also showning promising results in this scenario. In this article, we will discuss the physiopathological basis of peritumoral T2/FLAIR signal abnormality and review potential applications of advanced MRI sequences for its evaluation.

      Keywords

      1. Introduction

      MRI has demonstrated high sensitivity, specificity and accuracy for detecting and characterizing central nervous system (CNS) lesions [
      • Langen K.J.
      • Galldiks N.
      • Hattingen E.
      • Shah N.J.
      Advances in neuro-oncology imaging.
      ]. The introduction of advanced MRI sequences such as Diffusion Weighted imaging (DWI), gadolinium-based Perfusion Weighted Imaging (PWI) and MR Spectroscopy (MRS) offer complementary information to conventional MRI sequences, allowing neuroradiologists to identify physiopathological characteristics of CNS lesions [
      • Leung D.
      • Han X.
      • Mikkelsen T.
      • Nabors L.B.
      Role of MRI in primary brain tumor evaluation.
      ]. Based on the cellularity, presence of angiogenesis and changes in the metabolite profile of CNS lesions, respectively, differential diagnosis can be narrowed, improving overall diagnostic accuracy and even providing prognostic information about the patient outcome [
      • Jain R.
      • Poisson L.M.
      • Gutman D.
      • Scarpace L.
      • Hwang S.N.
      • Holder C.A.
      • Wintermark M.
      • Rao A.
      • Colen R.R.
      • Kirby J.
      • Freymann J.
      • Jaffe C.C.
      • Mikkelsen T.
      • Flanders A.
      Outcome prediction in patients with glioblastoma by using imaging, clinical, and genomic biomarkers: Focus on the nonenhancing component of the tumor.
      ]. However, there are still some clinical scenarios where conventional or even advanced MRI sequences are not enough to achieve sufficient accuracy for precise lesion characterization [
      • Chiavazza C.
      • Pellerino A.
      • Ferrio F.
      • Cistaro A.
      • Soffietti R.
      • Rudà R.
      Primary CNS Lymphomas: Challenges in Diagnosis and Monitoring.
      ]. These scenarios include the differential diagnosis between solitary enhancing brain lesions, as is the case of high-grade gliomas (HGG) versus CNS metastases [
      • Liao W.
      • Liu Y.
      • Wang X.
      • Jiang X.
      • Tang B.
      • Fang J.
      • Chen C.
      • Hu Z.
      Differentiation of primary central nervous system lymphoma and high-grade glioma with dynamic susceptibility contrast-enhanced perfusion magnetic resonance imaging.
      ,
      • Hartmann M.
      • Heiland S.
      • Harting I.
      • Tronnier V.M.
      • Sommer C.
      • Ludwig R.
      • Sartor K.
      Distinguishing of primary cerebral lymphoma from high-grade glioma with perfusion-weighted magnetic resonance imaging.
      ]. Most of the efforts have been classically focused on the evaluation of the enhancing or solid component of the lesion of interest, addressing physiopathological differences between the different types of lesions [
      • Kickingereder P.
      • Wiestler B.
      • Sahm F.
      • Heiland S.
      • Roethke M.
      • Schlemmer H.-P.
      • Wick W.
      • Bendszus M.
      • Radbruch A.
      Primary Central Nervous System Lymphoma and Atypical Glioblastoma: Multiparametric Differentiation by Using Diffusion- Perfusion-, and Susceptibility-weighted MR Imaging.
      ,
      • Lin X.
      • Lee M.
      • Buck O.
      • Woo K.M.
      • Zhang Z.
      • Hatzoglou V.
      • Omuro A.
      • Arevalo-Perez J.
      • Thomas A.A.
      • Huse J.
      • Peck K.
      • Holodny A.I.
      • Young R.J.
      Diagnostic accuracy of T1-weighted dynamic contrast-enhanced-MRI and DWI-ADC for differentiation of glioblastoma and primary CNS lymphoma.
      ,
      • Suh C.H.
      • Kim H.S.
      • Jung S.C.
      • Kim S.J.
      Diffusion-weighted imaging and diffusion tensor imaging for differentiating high-grade glioma from solitary brain metastasis: A systematic review and meta-analysis.
      ]. Unfortunately, in many cases is not possible to differentiate between these types of CNS lesions just based on contrast enhancement pattern [
      • Schiff D.
      Single brain metastasis.
      ]. Based on morphological MRI criteria, only an accuracy 68%, sensitivity 84%, and specificity 45% has been reported for the differential diagnosis between metastasis and HGG [
      • Maurer M.H.
      • Synowitz M.
      • Badakshi H.
      • Lohkamp L.N.
      • Wüstefeld J.
      • Schäfer M.L.
      • Wiener E.
      Glioblastoma multiforme versus solitary supratentorial brain metastasis: Differentiation based on morphology and magnetic resonance signal characteristics.
      ].
      For this reason, some authors have proposed not only to evaluate the enhancing areas but also to assess the characteristics of the non-enhancing peripheral area of the lesions, in order to increase diagnostic accuracy based on the histopathological differences of these surrounding areas [
      • Blanchet L.
      • Krooshof P.W.T.
      • Postma G.J.
      • Idema A.J.
      • Goraj B.
      • Heerschap A.
      • Buydens L.M.C.
      Discrimination between metastasis and glioblastoma multiforme based on morphometric analysis of MR images.
      ,
      • Fink K.
      • Fink J.
      Imaging of brain metastases.
      ]. In this line, the assessment of peritumoral CNS regions have raised interest. They are usually identified as hypertintense on T2-weighted imaging (WI) and Fluid-Attenuated Inversion Recovery (FLAIR) and hypointense on T1-WI (without enhancement after gadolinium administration) and may represent a wide range of different histopathological conditions such as vasogenic edema, peritumoral infiltration, micro-necrosis, inflammation or gliosis [
      • Villanueva-Meyer J.E.
      • Mabray M.C.
      • Cha S.
      Current clinical brain tumor imaging.
      ]. Depending on the nature of CNS lesions, this peritumoral area may predominantly contains malignant tumor infiltration cells, as occurs in HGG, resulting in the underestimation of tumor burden. This item has a direct impact on patient outcome, for example regarding incomplete surgical resection [
      • Haj A.
      • Doenitz C.
      • Schebesch K.M.
      • Ehrensberger D.
      • Hau P.
      • Putnik K.
      • Riemenschneider M.J.
      • Wendl C.
      • Gerken M.
      • Pukrop T.
      • Brawanski A.
      • Proescholdt M.A.
      Extent of resection in newly diagnosed glioblastoma: Impact of a specialized neuro-oncology care center.
      ]. In fact, there is an increasing focus on aggressive therapies targeting the non-enhancing peritumoral area which will enable better patient outcomes [
      • Lasocki A.
      • Gaillard F.
      Non-Contrast-Enhancing Tumor: A New Frontier in Glioblastoma Research.
      ]. Advanced MRI sequences such as DWI, PWI or MRS have been proposed for this aim but they show an incomplete accuracy for a proper evaluation of peritumoral edema [
      • Lee E.J.
      • Ahn K.J.
      • Lee E.K.
      • Lee Y.S.
      • Kim D.B.
      Potential role of advanced MRI techniques for the peritumoural region in differentiating glioblastoma multiforme and solitary metastatic lesions.
      ]. New advanced MRI sequences such as Diffusion Tensor Imaging (DTI), Diffusional Kurtosis Imaging (DKI), T2 mapping, Arterial Spin Labelling (ASL) or Amide Proton Transfer (APT) may also play a potential role for this challenging task [
      • Wang S.
      • Kim S.
      • Chawla S.
      • Wolf R.L.
      • Knipp D.E.
      • Vossough A.
      • O’Rourke D.M.
      • Judy K.D.
      • Poptani H.
      • Melhem E.R.
      Differentiation between glioblastomas, solitary brain metastases, and primary cerebral lymphomas using diffusion tensor and dynamic susceptibility contrast-enhanced MR imaging.
      ,
      • Lin L.
      • Xue Y.
      • Duan Q.
      • Sun B.
      • Lin H.
      • Huang X.
      • Chen X.
      The role of cerebral blood flow gradient in peritumoral edema for differentiation of glioblastomas from solitary metastatic lesions.
      ,
      • Lu S.
      • Ahn D.
      • Johnson G.
      • Cha S.
      Peritumoral diffusion tensor imaging of high-grade gliomas and metastatic brain tumors.
      ]. DTI or ASL are nowadays available in most MRI systems and have been included as part of routine protocols for CNS lesions evaluations. The introduction of other sequnces such as DKI, T2 mapping or APT into clinical practice is more recent and there is scarce experience not only for primary tumor assessment but also for non-enhancing peritumoral area. However, the new physiopathological information provided by these advanced sequences may help to improve the evaluation of non-enhancing peritumoral area.
      In this manuscript, we will review the physiopathological basis of the non-enhancing peritumoral areas. In addition, we will also summarize, from an educational point of view, the physical basis of these advanced MRI sequences focusing on how they can better assist neuroradiologists in the evaluation of these non-enhancing peritumoral areas.

      2. Physiopathology of Non-Enhancing Peritumoral Signal Abnormality (NEPSA)

      Several studies have demonstrated that there are histopathological differences within the non-contrast enhancing tumor and peritumoral area between various CNS lesions [
      • Lemée J.M.
      • Clavreul A.
      • Aubry M.
      • Com E.
      • de Tayrac M.
      • Eliat P.A.
      • Henry C.
      • Rousseau A.
      • Mosser J.
      • Menei P.
      Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis.
      ]. This peritumoral area, usually identified as high signal intensity regions on fluid sensitive MRI sequences (T2WI and FLAIR), represents the manifestation of local changes in vessels and membrane permeability [
      • Lemèe J.M.
      • Clavreul A.
      • Menei P.
      Intratumoral heterogeneity in glioblastoma: Don’t forget the peritumoral brain zone.
      ]. In some cases, peritumoral area contains a combination of infiltrating tumor, gliosis, and vasogenic edema. In the case of HGG, it is well recognized that malignant cells spread beyond the apparent limits of the enhancing tumor, so there is biological activity within the NEPSA (Fig. 1). This issue is one of the factors responsible for tumor recurrence or tumoral spread beyond apparent margins even after complete surgical resection [
      • Grabowski M.M.
      • Recinos P.F.
      • Nowacki A.S.
      • Schroeder J.L.
      • Angelov L.
      • Barnett G.H.
      • Vogelbaum M.A.
      Residual tumor volume versus extent of resection: Predictors of survival after surgery for glioblastoma.
      ,
      • Yan J.L.
      • Van Der Hoorn A.
      • Larkin T.J.
      • Boonzaier N.R.
      • Matys T.
      • Price S.J.
      Extent of resection of peritumoral diffusion tensor imaging-detected abnormality as a predictor of survival in adult glioblastoma patients.
      ] and may explain local recurrence or progression after aggressive multi-modal therapy [
      • van der Sanden B.
      • Ratel D.
      • Berger F.
      • Wion D.
      Glioma recurrence following surgery: Peritumoral or perilesional?.
      ]. Besides, it is not uncommon that primary central nervous system lymphomas (PCNSL) may also show tumoral infiltration in their NEPSA [
      • Lai R.
      • Rosenblum M.K.
      • DeAngelis L.M.
      Primary CNS lymphoma: A whole-brain disease?.
      ].
      Figure thumbnail gr1
      Fig. 1Example of non-enhancing peritumoral area of signal abnormality. 50 year-old male with left frontal HGG with heterogeneous enhancement on (a) axial Gradient Echo (GE) T1WI after gadolinium administration (white arrow). There is a large hyperintense area on (b) axial FLAIR image (black arrow) surrounding the enhancing lesion that does not show enhancement on postcotrast GE T1WI image (black arrow). This non-enhancing peritumoral area (NEPSA) usually surrounds primary or secondary CNS lesions.
      On the other hand, the NEPSA associated to other CNS lesions such as non-invasive meningiomas, metastasis or abcessess is due to pure reactive vasogenic edema [
      • Gawlitza M.
      • Fiedler E.
      • Schob S.
      • Hoffmann K.T.
      • Surov A.
      Peritumoral Brain Edema in Meningiomas Depends on Aquaporin-4 Expression and Not on Tumor Grade, Tumor Volume, Cell Count, or Ki-67 Labeling Index.
      ,
      • Wang P.
      • Ni R.Y.
      • Chen M.N.
      • Mou K.J.
      • Mao Q.
      • Liu Y.H.
      Expression of aquaporin-4 in human supratentorial meningiomas with peritumoral brain edema and correlation of VEGF with edema formation.
      ]. This kind of edema is constituted by extracellular water and in is, in theory, free from malignant cells infiltration. Several authors have proposed to discriminate between HGG and solitary ring-enhancing lesions in the basis of NEPSA [
      • Toh C.-H.
      • Wong A.-M.-C.
      • Wei K.-C.
      • Ng S.-H.
      • Wong H.-F.
      • Wan Y.-L.
      Peritumoral edema of meningiomas and metastatic brain tumors: differences in diffusion characteristics evaluated with diffusion-tensor MR imaging.
      ,
      • Sternberg E.J.
      • Lipton M.L.
      • Burns J.
      Utility of diffusion tensor imaging in evaluation of the peritumoral region in patients with primary and metastatic brain tumors.
      ,
      • Kamimura K.
      • Nakajo M.
      • Yoneyama T.
      • Fukukura Y.
      • Hirano H.
      • Goto Y.
      • Sasaki M.
      • Akamine Y.
      • Keupp J.
      • Yoshiura T.
      Histogram analysis of amide proton transfer–weighted imaging: comparison of glioblastoma and solitary brain metastasis in enhancing tumors and peritumoral regions.
      ,
      • Chernov M.F.
      • Kubo O.
      • Hayashi M.
      • Izawa M.
      • Maruyama T.
      • Usukura M.
      • Ono Y.
      • Hori T.
      • Takakura K.
      Proton MRS of the peritumoral brain.
      ]. Moreover, accurate presurgical identification of malignant infiltration of NEPSA is crucial for establish resection margins [
      • Eidel O.
      • Burth S.
      • Neumann J.O.
      • Kieslich P.J.
      • Sahm F.
      • Jungk C.
      • Kickingereder P.
      • Bickelhaupt S.
      • Mundiyanapurath S.
      • Bäumer P.
      • Wick W.
      • Schlemmer H.P.
      • Kiening K.
      • Unterberg A.
      • Bendszus M.
      • Radbruch A.
      Tumor infiltration in enhancing and non-enhancing parts of glioblastoma: A correlation with histopathology.
      ,
      • Li Y.M.
      • Suki D.
      • Hess K.
      • Sawaya R.
      The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection?.
      ]. Treated lesions, either benign or malignant, may also show NEPSA that may reflect residual infiltrative neoplasm, tumor progression or post-chemoradiotherapy related changes [
      • Prasanna P.
      • Patel J.
      • Partovi S.
      • Madabhushi A.
      • Tiwari P.
      Radiomic features from the peritumoral brain parenchyma on treatment-naïve multi-parametric MR imaging predict long versus short-term survival in glioblastoma multiforme: Preliminary findings.
      ].
      So…what is NEPSA? As explained before, several radiological findings could fit into the definition of NEPSA: vasogenic edema, gliosis, neoplastic infiltration or even post-therapeutic changes. Each of which have a different origin and histopathological basis. However, for practical propose, we are going to club all of them under the acronym NEPSA, considering two main types of NEPSA: infiltrative NEPSA, where there is malignant tumor cell infiltration within the interstitium but no enhancement due to preservation of blood–brain barrier (infiltrating edema) and non-infiltrative NEPSA, theoretically only composed of vasogenic edema (pure edema). Infiltrating NEPSA shows not only an increase of extracellular water, but also the presence of infiltrative neoplastic cells and neoangiogenesis as in a HGG (Fig. 2). Both scenarios can be evaluated using advanced MRI sequences that allow extraction of phsyiopathological information about neoangiogenesis, membranes preservation, white matter (WM) integrity or cell proliferation, providing indirect signs and parametric data of tumoral infiltration in vivo, that may help to differentiate between both types of NEPSA.
      Figure thumbnail gr2
      Fig. 2Scheme of enhancing brain lesions (white arrows) surrounded by non-enhancing peritumoral areas (black arrowheads) and normal brain parenchyma (asterisks). (a) At Infiltrative NEPSA, there are tumoral cells within intersitium despite no enhancement due to preservation of BBB (infiltrated edema). (b) At Non-infiltrative NEPSA, peritumoral areas is theoretically only composed by water molecules (pure edema).
      The analysis of NEPSA is particularly relevant in the case of HGG. In the pretreatment setting, several studies have demonstrated that the presence of extensive peritumoral edema on conventional MRI studies is a predictor of poor clinical outcomes [
      • Wu C.X.
      • Lin G.S.
      • Lin Z.X.
      • Zhang J.D.
      • Chen L.
      • Liu S.Y.
      • Tang W.L.
      • Qiu X.X.
      • Zhou C.F.
      Peritumoral edema on magnetic resonance imaging predicts a poor clinical outcome in malignant glioma.
      ,
      • Mangiola A.
      • Lama G.
      • Giannitelli C.
      • De Bonis P.
      • Anile C.
      • Lauriola L.
      • La Torre G.
      • Sabatino G.
      • Maira G.
      • Jhanwar-Uniyal M.
      • Sica G.
      Stem cell marker nestin and c-Jun NH2-terminal kinases in tumor and peritumor areas of glioblastoma multiforme: Possible prognostic implications.
      ]. In treated HGG, temozolamide induces increased vascular permeability and triggers intense inflammatory response at the tumor bed. These physiological events lead to the appearance of new/increasing contrast-enhancement with worsening of T2-FLAIR signal abnormality within the treatment field, also known as pseudoprogression or treatment effects [
      • Walker A.J.
      • Ruzevick J.
      • Malayeri A.A.
      • Rigamonti D.
      • Lim M.
      • Redmond K.J.
      • Kleinberg L.
      Postradiation imaging changes in the CNS: How can we differentiate between treatment effect and disease progression?.
      ]. Nowadays this point has become more relevant, especially with new biological and immune-mediated therapies. Antiangiogenic drugs such as bevacizumab or cediranib reduce the enhancing component of HGG (leading to a phenomenon called ‘pseudoresponse’) showing apparent increases in NEPSA, but with the persistence or increase in biologically active tumor [
      • Hygino Da Cruz L.C.
      • Rodriguez I.
      • Domingues R.C.
      • Gasparetto E.L.
      • Sorensen A.G.
      Pseudoprogression and pseudoresponse: Imaging challenges in the assessment of posttreatment glioma.
      ]. In the same line, areas of enhancement after Gadolinium-based contrast agents (GBCAs) administration may be identified at NEPSA following radiotherapy due to the breakdown of brain blood barrier (BBB), reflecting radionecrosis without associated increase of angiogenesis [
      • Thust S.C.
      • van den Bent M.J.
      • Smits M.
      Pseudoprogression of brain tumors.
      ]. Despite this paper is mostly focused in the evaluation of non-treated CNS lesions, the advanced MRI sequences described may also help to evaluated peritumoral non-enhancing areas linked to treated CNS lesions. At this point is crucial to know the histology of the treated lesion as well as the different therapies applied in order to achieve a better understanding of the physiopathological behaviour of NEPSA depending on the MRI sequence acquired.

      3. Advanced MRI sequences for assessment of NEPSA

      Advanced MRI provides a wide range of sequences that allow neuroradiologists to evaluate NEPSA from a physiopathological point of view. These approaches have been mostly applied for the assessment of solid or enhancing component of CNS lesions, but scarcely used for NEPSA evaluation [
      • Lin L.
      • Xue Y.
      • Duan Q.
      • Sun B.
      • Lin H.
      • Huang X.
      • Chen X.
      The role of cerebral blood flow gradient in peritumoral edema for differentiation of glioblastomas from solitary metastatic lesions.
      ]. Table 1 summarizes the main characteristics of these advanced MRI sequences. Other approaches, based on artificial intelligence (AI) algorithms are also being evaluated with promising results [
      • Leung D.
      • Han X.
      • Mikkelsen T.
      • Nabors L.B.
      Role of MRI in primary brain tumor evaluation.
      ,
      • Prasanna P.
      • Patel J.
      • Partovi S.
      • Madabhushi A.
      • Tiwari P.
      Radiomic features from the peritumoral brain parenchyma on treatment-naïve multi-parametric MR imaging predict long versus short-term survival in glioblastoma multiforme: Preliminary findings.
      ], the discussion of which is out of scope of the current review.
      Table 1Advanced techniques for non-enhancing peritumoral areas evaluation.
      TechniqueTargetParametersClinical applicabilityAcquisition time
      DWIExtracellular spaceADC++++
      DTIWhite matter integrityFA, MD, AD, RD+++++
      DKI (Kurtosis)Water linked to membranesMK++++
      SpectroscopyTumor metabolismCho, Cr, NAA…++++++
      ASLIntravascular blood FlowCBF++++
      T2* DSCCapillary networkCBV, CBF, MTT,++++
      T1 permeabilityCapillary network and interstitiumKtrans, Kep, Ve, Vp+++++
      T2 mappingWater bounded to proteinsT2 relaxation time of water++++
      APTAmide protonMTR asymmetry+++
      DWI (Diffusion Weighted Imaging), DTI (Diffusion Tensor Imaging), DKI (Diffusion Kurtosis Imaging), ASL (Arterial Spin Labelling), DSC (Dynamic Susceptibility Contrast), APT (Amide Proton Transfer), ADC (Apparent Diffusion Coefficient), FA (Fractional Anisotropy), MD (Mean Diffusivity), AD (Axial Diffusivity), RD (Radial Diffusivity), MK (Mean Kurtosis), CBV (Cerebral Blood Volume), CBF (Cerebral Blood Flow), MTT (Mean Transit Time), Ktrans (volume transfer constant), Kep (reflux rate), Ve (fractional extracellular fluid space volume), Vp (fractional plasma volume), MTR (Magnetization Transfer Ratio) Simbols range from less clinical applicability/short acquisition time (+) to high clinical applicability/long acquisition time (+++).

      3.1 Diffusion Weighted Imaging

      DWI is able to assess the movement of water molecules, mainly in the extracellular space, limited by biological membranes, without using exogenous contrast agents. DWI is commonly used in clinical practice for assessment of acute ischemia, inflammatory diseases, and CNS tumors [
      • Martín Noguerol T.
      • Martínez Barbero J.P.
      RM-Difusión avanzada y biomarcadores en el sistema nervioso central: un nuevo enfoque.
      ,
      • Huisman T.A.G.M.
      Diffusion-weighted imaging: basic concepts and application in cerebral stroke and head trauma.
      ]. Apparent Coefficient Diffusion (ADC) values allow radiologists to quantify the degree of restriction of water molecules within normal brain tissue and CNS lesions. Using a simplistic approach, lesions with high signal intensity on high b value DWI and corresponding low ADC values are considered hypercellular lesions, meanwhile lesions with low signal intensity on high b value DWI and low ADC values are considered hypocellular lesions, usually related to cysts or presence of necrosis [
      • de Figueiredo E.H.M.S.G
      • Borgonovi A.F.N.G.
      • Doring T.M.
      Basic concepts of MR imaging, diffusion MR imaging, and diffusion tensor imaging.
      ].
      DWI can be also used for the evaluation of freedom of water molecules movement within the NEPSA of CNS lesions. This NEPSA usually shows high ADC values, in some cases linked to T2-shine through effect, which means that there is also high signal intensity on high b value due to the long T2 value of NEPSA [

      K. Kono, Y. Inoue, K. Nakayama, M. Shakudo, M. Morino, K. Ohata, K. Wakasa, R. Yamada, The role of diffusion-weighted imaging in patients with brain tumors, 2001. 10.18535/jmscr/v6i2.95.

      ]. However, despite these high ADC values, subtle differences may be found between infiltrating and non-infiltrating NEPSA. The presence of neoplastic cells within infiltrative NEPSA, mixed with areas of vasogenic edema, will place biological barriers that hinder the free movement of water molecules hence demonstrating lower ADC values than pure vasogenic edema [
      • Lee E.J.
      • Ahn K.J.
      • Lee E.K.
      • Lee Y.S.
      • Kim D.B.
      Potential role of advanced MRI techniques for the peritumoural region in differentiating glioblastoma multiforme and solitary metastatic lesions.
      ]. The absence of neoplastic cells within the non-infiltrative NEPSA vasogenic edema enables more degrees of freedom of movement of water molecules, hence demonstrating higher ADC values than infiltrating NEPSA (Movie 1) [
      • Lee E.J.
      • Ahn K.J.
      • Lee E.K.
      • Lee Y.S.
      • Kim D.B.
      Potential role of advanced MRI techniques for the peritumoural region in differentiating glioblastoma multiforme and solitary metastatic lesions.
      ].
      The use of exponential DWI (e-DWI) maps, which are based on a correction of T2 shine-through effect, has been proposed to distinguish between infiltrative NEPSA, that shows intermediate signal intensity on e-DWI maps, and non-infiltrative NEPSA which shows decreased signal intensity on e-DWI maps [
      • Lee E.J.
      • Ahn K.J.
      • Lee E.K.
      • Lee Y.S.
      • Kim D.B.
      Potential role of advanced MRI techniques for the peritumoural region in differentiating glioblastoma multiforme and solitary metastatic lesions.
      ]. In the differentiation between HGG and metastasis, several studies have suggested a cutoff value of 1.302 × 10−3 mm2/s for the minimum peritumoral ADC value with a sensitivity and specificity of 82.9% and 78.9%, respectively (Fig. 3) [
      • Lee E.J.
      • TerBrugge K.
      • Mikulis D.
      • Choi D.S.
      • Bae J.M.
      • Lee S.K.
      • Moon S.Y.
      Diagnostic value of peritumoral minimum apparent diffusion coefficient for differentiation of glioblastoma multiforme from solitary metastatic lesions.
      ,
      • Rahman R.
      • Hamdan A.
      • Zweifler R.
      • Jiang H.
      • Norden A.D.
      • Reardon D.A.
      • Mukundan S.
      • Wen P.Y.
      • Huang R.Y.
      Histogram analysis of apparent diffusion coefficient within enhancing and nonenhancing tumor volumes in recurrent glioblastoma patients treated with bevacizumab.
      ]. Moreover, a positive ADC gradient has been found within infiltrating HGG-NEPSA which indicates a higher number of malignant cells close to the enhancing edge of the solid tumor than in areas located farther away from it [
      • Ko C.C.
      • Tai M.H.
      • Li C.F.
      • Chen T.Y.
      • Chen J.H.
      • Shu G.
      • Kuo Y.T.
      • Lee Y.C.
      Differentiation between glioblastoma multiforme and primary cerebral lymphoma: Additional benefits of quantitative diffusion- Weighted MR imaging.
      ,
      • Lemercier P.
      • Maya S.P.
      • Patrie J.T.
      • Flors L.
      • Leiva-Salinas C.
      Gradient of apparent diffusion coefficient values in peritumoral edema helps in differentiation of glioblastoma from solitary metastatic lesions.
      ]. DWI has also been tested for discrimination between HGG and PCNSL based not only on the enhancing lesion but also on the features of their respective NEPSA showing significantly lower ADC values in HGG than in PCNSL [
      • Ko C.C.
      • Tai M.H.
      • Li C.F.
      • Chen T.Y.
      • Chen J.H.
      • Shu G.
      • Kuo Y.T.
      • Lee Y.C.
      Differentiation between glioblastoma multiforme and primary cerebral lymphoma: Additional benefits of quantitative diffusion- Weighted MR imaging.
      ].
      Figure thumbnail gr3
      Fig. 3Usefulness of DWI for assessment of NEPSA. (a) 65 year-old female with breast cancer and left hemiparesis. Axial FLAIR and axial postcontrast GE T1WI show a right precentral frontal lesion with intense enhancement (black arrows) and large NEPSA (white arrows). No significant restriction of water diffusion is identified within NEPSA at DWI b 1000 s/mm2, showing high ADC values (2.5 × 10−3 mm2/s). Metastasis was confirmed after biopsy. (b) 75 year-old male with recurrent headache. Left periatrial lesion is identified at axial FLAIR with peripheral enhancement on axial postcontrast GE T1WI (black arrows). Lesion shows areas of peripheral restriction of water diffusion at DWI b 1000 s/mm2 with areas of high signal intensity on DWI and low ADC values (1.3 × 10−3 mm2/s) within NEPSA (white arrows) at corpus callosum splenium. HGG was confirmed after biopsy.
      Concerning the prognostic value of DWI applied to NEPSA, a recently published study suggests the use of ADC values at distal peritumoral edema before treatment as a potential biomarker for determining the progression-free survival in patients with glioblastoma [
      • Durand-Muñoz C.
      • Flores-Alvarez E.
      • Moreno-Jimenez S.
      • Roldan-Valadez E.
      Pre-operative apparent diffusion coefficient values and tumour region volumes as prognostic biomarkers in glioblastoma: correlation and progression-free survival analyses.
      ]. Along the same line, other authors have proposed the use of ADC histogram analysis for stratifying patients that have undergone bevacizumab therapy to assess progression-free survival and overall survival in patients with recurrent glioblastoma [
      • Rahman R.
      • Hamdan A.
      • Zweifler R.
      • Jiang H.
      • Norden A.D.
      • Reardon D.A.
      • Mukundan S.
      • Wen P.Y.
      • Huang R.Y.
      Histogram analysis of apparent diffusion coefficient within enhancing and nonenhancing tumor volumes in recurrent glioblastoma patients treated with bevacizumab.
      ].
      The influence of the movement of water molecules within the capillary network conditions an overestimation of ADC values. This influence of vascular component became more evident at HGG whereas the expression of vascular endothelial growth factors (VEGFR) induces neoangiogenesis [
      • Grau S.J.
      • Trillsch F.
      • Herms J.
      • Thon N.
      • Nelson P.J.
      • Tonn J.C.
      • Goldbrunner R.
      Expression of VEGFR3 in glioma endothelium correlates with tumor grade.
      ]. For this aim, new advanced DWI models have been developed in an attempt to adjust signal intensity decay to the real histopathology of brain tumors. IVIM-DWI model considers the existence of two compartments within biological tissues: the extracellular space and the intravascular space [
      • Le Bihan D.
      • Breton E.
      • Lallemand D.
      • Grenier P.
      • Cabanis E.
      • Laval-Jeantet M.
      MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders.
      ]. Movement of water molecules within intravascular space can be also evaluated by DWI as it follows a random distribution in a similar manner than movement at extracellular space. The final goal of this approach is to discriminate the influence of the capillary network water movement to the whole bulk of water molecules within a certain voxel of brain tissue [
      • Catanese A.
      • Malacario F.
      • Cirillo L.
      • Toni F.
      • Zenesini C.
      • Casolino D.
      • Bacci A.
      • Agati R.
      Application of intravoxel incoherent motion (IVIM) magnetic resonance imaging in the evaluation of primitive brain tumours.
      ]. This manner, hypervascular infiltrating areas within NEPSA can be theoretically differentiate from hypovascular ones without needed of GBCAs administration. Despite several studies have demonstrated the usefulness of IVIM model for primary CNS lesions assessment, scarce authors have addressed their potential role for NEPSA evaluation [
      • Shim W.H.
      • Kim H.S.
      • Choi C.G.
      • Kim S.J.
      Comparison of apparent diffusion coefficient and intravoxel incoherent motion for differentiating among glioblastoma, metastasis, and lymphoma focusing on diffusion-related parameter.
      ,
      • Puig J.
      • Sánchez-González J.
      • Blasco G.
      • Daunis-I-Estadella P.
      • Federau C.
      • Alberich-Bayarri Á.
      Intravoxel Incoherent Motion Metrics as Potential Biomarkers for Survival in Glioblastoma.
      ].

      3.2 Diffusion Tensor Imaging

      DTI is based on the acquisition of motion probing gradients in multiple directions generating a matrix (tensor) which allows determining the presence of a dominant direction of movement of water molecules within tissues. The existence of biological barriers such as microtubules, axons and myelin within WM tracts leads to presence of an anisotropic (dominant) water diffusion that is accurately assessed using DTI sequences [
      • de Figueiredo E.H.M.S.G
      • Borgonovi A.F.N.G.
      • Doring T.M.
      Basic concepts of MR imaging, diffusion MR imaging, and diffusion tensor imaging.
      ]. DTI has been classically applied for CNS tumor evaluation, especially for the assessment of tumor infiltration, disruption or displacement of WM tracts for surgical planning, as well as for prognostication and survival prediction [
      • Mohan S.
      • Wang S.
      • Coban G.
      • Kural F.
      • Chawla S.
      • O’Rourke D.M.
      • Poptani H.
      Detection of occult neoplastic infiltration in the corpus callosum and prediction of overall survival in patients with glioblastoma using diffusion tensor imaging.
      ]. There are two main parameters derived from DTI: fractional anisotropy (FA) and mean diffusivity (MD). FA is considered an index of fiber integrity, very sensitive to loss of WM organization. MD evaluates the movement of water molecules in the extracellular space using the directional information provided by the main three eigenvalues [
      • Martín Noguerol T.
      • Martínez Barbero J.P.
      RM-Difusión avanzada y biomarcadores en el sistema nervioso central: un nuevo enfoque.
      ]. Several studies have evaluated the role of DTI for assessment of NEPSA trying to discriminate between HGG and metastasis. A significant increase of MD values has been identified at non-infiltrative NEPSA compared with infiltrative NEPSA due to the greater amount of free water present in the former (Movie 2) [
      • Lu S.
      • Ahn D.
      • Johnson G.
      • Cha S.
      Peritumoral diffusion tensor imaging of high-grade gliomas and metastatic brain tumors.
      ,
      • Byrnes T.J.D.
      • Barrick T.R.
      • Bell B.A.
      • Clark C.A.
      Diffusion tensor imaging discriminates between glioblastoma and cerebral metastases in vivo.
      ].
      Most studies have demonstrated a decrease of FA values at NEPSA compared with apparent normal WM, regardless their origin [
      • Sternberg E.J.
      • Lipton M.L.
      • Burns J.
      Utility of diffusion tensor imaging in evaluation of the peritumoral region in patients with primary and metastatic brain tumors.
      ]. However, discrepancies have been reported in the use of FA for discriminating between HGG-NEPSA and metastasis-NEPSA. Some authors point that HGG-NEPSA shows lower FA values than metastasis-NEPSA due to increased water content and tumor infiltration that causes loss of normal WM anisotropy [
      • Sternberg E.J.
      • Lipton M.L.
      • Burns J.
      Utility of diffusion tensor imaging in evaluation of the peritumoral region in patients with primary and metastatic brain tumors.
      ]. Other authors support the hypothesis that the presence of neoplastic cells/infiltrative tumor within NEPSA, mixed with vasogenic edema, may lead to a certain degree of organization of WM edema, leading to a less pronounced decrease of FA values compared with pure vasogenic edema (Fig. 4) [
      • Holly K.S.
      • Barker B.J.
      • Murcia D.
      • Bennett R.
      • Kalakoti P.
      • Ledbetter C.
      • Gonzalez-Toledo E.
      • Nanda A.
      • Sun H.
      High-grade Gliomas Exhibit Higher Peritumoral Fractional Anisotropy and Lower Mean Diffusivity than Intracranial Metastases.
      ,
      • Jiang R.
      • Du F.-Z.
      • He C.
      • Gu M.
      • Ke Z.-W.
      • Li J.-H.
      The value of diffusion tensor imaging in differentiating high-grade gliomas from brain metastases: a systematic review and meta-analysis.
      ]. Moreover, significantly lower FA values are identified at the peritumoral area within PCNSL compared with HGG [
      • Wang S.
      • Kim S.
      • Chawla S.
      • Wolf R.L.
      • Knipp D.E.
      • Vossough A.
      • O’Rourke D.M.
      • Judy K.D.
      • Poptani H.
      • Melhem E.R.
      Differentiation between glioblastomas, solitary brain metastases, and primary cerebral lymphomas using diffusion tensor and dynamic susceptibility contrast-enhanced MR imaging.
      ]. Changes in FA values at HGG-NEPSA have also been described as a potential marker of tumor progression through WM tracts dissemination showing lower FA values at NEPSA in recurrent tumors compared with treatment effects [
      • Sternberg E.J.
      • Lipton M.L.
      • Burns J.
      Utility of diffusion tensor imaging in evaluation of the peritumoral region in patients with primary and metastatic brain tumors.
      ,
      • Sundgren P.C.
      • Fan X.
      • Weybright P.
      • Welsh R.C.
      • Carlos R.C.
      • Petrou M.
      • McKeever P.E.
      • Chenevert T.L.
      Differentiation of recurrent brain tumor versus radiation injury using diffusion tensor imaging in patients with new contrast-enhancing lesions.
      ].
      Figure thumbnail gr4
      Fig. 4Usefulness of DTI for assessment of NEPSA. (a) 75 year-old male with recurrent headache (same patient than b). Left periatrial lesion is identified at axial FLAIR (black arrows) with peripheral enhancement on axial postcontrast GE T1WI sequence (black arrows). DTI study was performed identifying moderate decrease of FA values (0.35) and slight increase of MD values (1.34 × 10−3 mm2/s) within NEPSA (white arrows) at posterior arm of left internal capsule. HCG was confirmed after biopsy. (b) 41 year-old female with right hemiparesis. At least two intraaxial lesion with ring enhancement are identified at left frontal lobe (black arrows) on both axial FLAIR and axial postcontrast GE T1WI sequences. These lesions are accompanied by moderate NEPSA (white arrow). Evaluation by means of DTI of this NEPSA showed very low FA values (0.1) and markedly increase of MD values (2.8 × 10−3 mm2/s) (white arrows). CNS metastasis of breast cancer was confirmed after biopsy.
      Radial Diffusivity (RD) and Axial Diffusivity (AD) are also parameters derived from DTI acquisitions which have been tested for evaluation of NEPSA. RD reflects the movement of water molecules in the short axis of WM tracts. AD equals to the major eigenvector and represents the movement of water molecules along the long axis of WM tracts [
      • Wheeler-Kingshott C.A.M.
      • Cercignani M.
      About “axial” and “radial” diffusivities.
      ]. Both, RD and AD seem to be less influenced by edema than MD or FA. Some studies have demonstrated an increase of RD values due to myelin damage and showing the regression coefficient of RD to AD as a potential tool for detecting HGG-NEPSA, discriminating it from pure vasogenic edema [
      • Min Z.G.
      • Niu C.
      • Rana N.
      • Ji H.M.
      • Zhang M.
      Differentiation of pure vasogenic edema and tumor-infiltrated edema in patients with peritumoral edema by analyzing the relationship of axial and radial diffusivities on 3.0T MRI.
      ,
      • Wang S.
      • Zhou J.
      Diffusion tensor magnetic resonance imaging of rat glioma models: A correlation study of MR imaging and histology.
      ].

      3.3 Diffusion Kurtosis Imaging

      DKI is one of the latest advanced mathematical models of analysis of diffusion signal intensity decay incorporated into the assessment of CNS lesions. DKI considers a non-gaussian distribution of water molecules movement within tissues, conversely to classical Gaussian distribution of DWI, due to their interaction with membranes [
      • Steven A.J.
      • Zhuo J.
      • Melhem E.R.
      Diffusion kurtosis imaging: An emerging technique for evaluating the microstructural environment of the brain.
      ]. Mean Kurtosis (MK) has been related to tissular complexity, with histologically complex lesions showing higher MK values compared to less complex lesions [
      • Pang H.
      • Ren Y.
      • Dang X.
      • Feng X.
      • Yao Z.
      • Wu J.
      • Yao C.
      • Di N.
      • Ghinda D.C.
      • Zhang Y.
      Diffusional kurtosis imaging for differentiating between high-grade glioma and primary central nervous system lymphoma.
      ]. The presence of mitosis, membrane receptors, ligands, necrosis, angiogenesis and glial cells, all cause an increase in tissues complexity [
      • Steven A.J.
      • Zhuo J.
      • Melhem E.R.
      Diffusion kurtosis imaging: An emerging technique for evaluating the microstructural environment of the brain.
      ]. For DKI analysis, it is mandatory to acquire DWI with very high b-values (greater than to 1,500 s/mm2) to assess this very slow interaction of water molecules with cell membranes [
      • Jensen J.H.
      • Helpern J.A.
      MRI quantification of non-Gaussian water diffusion by kurtosis analysis.
      ].
      DKI has been lately applied to NEPSA assessment showing even higher accuracy than DWI or DTI for discriminating between infiltrative and non-infiltrative NEPSA [
      • Tan Y.
      • Wang X.C.
      • Zhang H.
      • Wang J.
      • Qin J.B.
      • Wu X.F.
      • Zhang L.
      • Wang L.
      Differentiation of high-grade-astrocytomas from solitary-brain-metastases: Comparing diffusion kurtosis imaging and diffusion tensor imaging.
      ] Infiltrative NEPSA has a complex composition due to the presence of neoplastic cells, mitosis, gliosis, edema, and even vessels, so it shows higher MK values than non-infiltrative NEPSA. On the other hand, non-infiltrative NEPSA, with the presence of theoretically only vasogenic edema within WM, is less complex than infiltrative NEPSA showing lower MK values than infiltrative NEPSA (Movie 3) [
      • Turkin A.M.
      • Pogosbekyan E.L.
      • Tonoyan A.C.
      • Shults E.I.
      • Maximov I.I.
      • Dolgushin M.B.
      • Khachanova N.V.
      • Fadeeva L.M.
      • Melnikova-Pitskhelauri T.V.
      • Pitskhelauri D.I.
      • Pronin I.N.
      • Kornienko V.N.
      Diffusion Kurtosis Imaging in the Assessment of Peritumoral Brain Edema in Glioblastomas and Brain Metastases.
      ]. As we referred before, NEPSA usually shows some element of T2-shine through effects. For this aim, the use of high b values for DKI may also allow to discriminate between infiltrative (with real restriction of water diffusion) and non-infiltrative NEPSA (with predominance of T2-shine through effects) from a qualitative standpoint [
      • Turkin A.M.
      • Pogosbekyan E.L.
      • Tonoyan A.C.
      • Shults E.I.
      • Maximov I.I.
      • Dolgushin M.B.
      • Khachanova N.V.
      • Fadeeva L.M.
      • Melnikova-Pitskhelauri T.V.
      • Pitskhelauri D.I.
      • Pronin I.N.
      • Kornienko V.N.
      Diffusion Kurtosis Imaging in the Assessment of Peritumoral Brain Edema in Glioblastomas and Brain Metastases.
      ]. MK values are higher within HGG-NEPSA than in metastasis-NEPSA or meningioma-NEPSA (Fig. 5) [
      • Tan Y.
      • Wang X.C.
      • Zhang H.
      • Wang J.
      • Qin J.B.
      • Wu X.F.
      • Zhang L.
      • Wang L.
      Differentiation of high-grade-astrocytomas from solitary-brain-metastases: Comparing diffusion kurtosis imaging and diffusion tensor imaging.
      ]. Theoretically, du to the angiocentric infiltration of PCNSL and the histological features of their cells, PCNSL-NEPSA is expected to show evan higher MK values than HGG-NEPSA. Nevertheless, further studies are needed to explore this scenario.
      Figure thumbnail gr5
      Fig. 5Usefulness of DKI for assessment of NEPSA. (a) 61 year-old female with seizures underwent MRI. A large left temporal extraaxial lesion is identified at axial FLAIR and postcontrast GE T1WI consistent with non-invasive meningioma (white arrow) with small NEPSA (black arrow) at its periphery. DKI is performed obtaining a MK value of 0.6 within NEPSA, suggesting simple vasogenic edema. (b) 48 year-old male with seizures shows a large right frontoparietal lesion (white arrow) with peripheral ring like enhancement and moderate NEPSA (black arrow) associated. DKI analysis shows MK values at NEPSA of 0.72 (black arrow) suggesting complex (infiltrated) edema. HGG was confirmed after biopsy.

      3.4 MR Spectroscopy

      MRS can characterize “in vivo” the presence of specific metabolites and chemical composition of various CNS lesions in a non invasively manner [
      • Ishimaru H.
      • Morikawa M.
      • Iwanaga S.
      • Kaminogo M.
      • Ochi M.
      • Hayashi K.
      Differentiation between high-grade glioma and metastatic brain tumor using single-voxel proton MR spectroscopy.
      ]. MRS is used for increasing specificity in the characterization of focal lesions with uncertain diagnosis, histological grading or in assessment of post-treatment follow-up of oncological lesions [
      • Hellström J.
      • Romanos Zapata R.
      • Libard S.
      • Wikström J.
      • Ortiz-Nieto F.
      • Alafuzoff I.
      • Raininko R.
      The value of magnetic resonance spectroscopy as a supplement to MRI of the brain in a clinical setting.
      ]. The ratios between main metabolites derived from MRS acquisitions, like Choline (Cho), Creatine (Cr) or N-Acetyl Aspartate (NAA), help radiologist to differentiate between benign and malignant lesions, including approximation to tumoral grade. There are two main approaches for MRS acquisition: Single voxel and Multi-voxel. MRS voxel of interest (VOI) is usually placed on the enhancing solid component of the lesions. The use of color-coded metabolite maps or ratios provided by multi-voxel MRS may help to identify the extent of malignant tumors beyond enhancing margins [
      • Delorme S.
      • Weber M.A.
      Applications of MRS in the evaluation of focal malignant brain lesions.
      ]. Thus, both, solid enhancing tumor component and NEPSA, can be accurately assessed in the same plane using a single multivoxel MRS acquisition [
      • Caivano R.
      • Lotumolo A.
      • Rabasco P.
      • Zandolino A.
      • D’antuono F.
      • Villonio A.
      • Lancellotti M.I.
      • Macarini L.
      • Cammarota A.
      3 Tesla magnetic resonance spectroscopy: Cerebral gliomas vs. metastatic brain tumors. Our experience and review of the literature.
      ]. Infiltrating NEPSA may show higher Cho/NAA and Cho/Cr ratios than apparent normal surrounding parenchyma due to the presence of malignant neoplastic cells [
      • Server A.
      • Josefsen R.
      • Kulle B.
      • Mæhlen J.
      • Schellhorn T.
      • Gadmar Ø.
      • Kumar T.
      • Haakonsen M.
      • Langberg C.W.
      • Nakstad P.H.
      Proton magnetic resonance spectroscopy in the distinction of high-grade cerebral gliomas from single metastatic brain tumors.
      ]. Non-infiltrating NEPSA, because of the lack of malignant cells, shows lower Cho/NAA or Cho/Cr ratios than in NEPSA related to gliomas (Movie 4) [
      • Min Z.G.
      • Niu C.
      • Rana N.
      • Ji H.M.
      • Zhang M.
      Diffusion tensor imaging and proton magnetic resonance spectroscopy in brain tumor correlation between structure and metabolism.
      ,
      • Chiang I.C.
      • Kuo Y.T.
      • Lu C.Y.
      • Yeung K.W.
      • Lin W.C.
      • Sheu F.O.
      • Liu G.C.
      Distinction between high-grade gliomas and solitary metastases using peritumoral 3-T magnetic resonance spectroscopy, diffusion, and perfusion imagings.
      ]. Using ROC analysis, a cutoff value of 1.24 in the Cho/Cr ratio of peritumoral edema has shown high sensitivity (100%) and specificity (88.9%) in the differentiation between HGG and metastasis. Also, for Cho/NAA ratio, a threshold value of 1.11 provided a sensitivity of 100% and a specificity of 91.1% (Fig. 6) [
      • Server A.
      • Josefsen R.
      • Kulle B.
      • Mæhlen J.
      • Schellhorn T.
      • Gadmar Ø.
      • Kumar T.
      • Haakonsen M.
      • Langberg C.W.
      • Nakstad P.H.
      Proton magnetic resonance spectroscopy in the distinction of high-grade cerebral gliomas from single metastatic brain tumors.
      ]. A recent study has evaluated the role of MRS in postoperative NEPSA for determining the risk of early recurrence of glioblastoma based on higher Cho/NAA ratios compared with contralateral normal brain [
      • Cui Y.
      • Zeng W.
      • Jiang H.
      • Ren X.
      • Lin S.
      • Fan Y.
      • Liu Y.
      • Zhao J.
      Higher Cho/NAA Ratio in Postoperative Peritumoral Edema Zone Is Associated With Earlier Recurrence of Glioblastoma.
      ]. In this study, patients with high Cho/NAA ratios show poor prognosis and earlier recurrence rates. Other metabolites such as lactate and glutamate have also been evaluated for NEPSA assessment. The increase of lactate, which represents anaerobic metabolism, has been found in NEPSA linked to gliomas in an almost consistent manner [
      • Chernov M.F.
      • Kubo O.
      • Hayashi M.
      • Izawa M.
      • Maruyama T.
      • Usukura M.
      • Ono Y.
      • Hori T.
      • Takakura K.
      Proton MRS of the peritumoral brain.
      ,
      • Ricci R.
      • Bacci A.
      • Tugnoli V.
      • Battaglia S.
      • Maffei M.
      • Agati R.
      • Leonardi M.
      Metabolic findings on 3T 1H-MR spectroscopy in peritumoral brain edema.
      ].
      Figure thumbnail gr6
      Fig. 6Usefulness of MRS for assessment of NEPSA. (a) 59 yearl-o female with breast cancer. A large intraaxial lesion is identified with peripheral enhancement in left parietal region. Multi-voxel MRS is performed without relevant findings within voxels located at NEPSA (black arrows) which suggests pure vasogenic edema due to brain metastasis. (b) 68 year-old male with HGG. A large intraaxial lesion is identified with peripheral enhancement in left parietal region. Multi-voxel MRS is performed showing areas of increase of Cho and Cho/Cr ratios at NEPSA (black arrows), which suggests tumoral infiltration.

      3.5 T2* Dynamic Susceptibility Contrast and T1 Dynamic Contrast Enhancement

      Both approaches, T2*-based Dynamic Susceptibility Contrast (DSC) and T1-based Dynamic Contrast Enhancement (DCE) are the two more commonly types of PWI techniques used in clinical practice. PWI allows to evaluate the capillary network and angiogenesis of CNS lesions using contrast-enhanced dynamic sequences [
      • Essig M.
      • Nguyen T.B.
      • Shiroishi M.S.
      • Saake M.
      • Provenzale J.M.
      • Enterline D.S.
      • Anzalone N.
      • Dörfler A.
      • Rovira Á.
      • Wintermark M.
      • Law M.
      Perfusion MRI: The five most frequently asked clinical questions.
      ]. There is a wide range of parameters derived from PWI studies depending on the sequences used, each one with a specific biological meaning. The common parameters used in the field of tumor imaging are Cerebral Blood Volume (CBV) and Cerebral Blood Flow (CBF) from DSC acquisitions and Ktrans (volume transfer constant), Vp (plasma volume) and Kep (rate constant) from DCE. PWI sequences have been classically focused on the evaluation of the solid enhancing component of CNS tumors, however, PWI is also able to assess the behavior of NEPSA [
      • Chiang I.C.
      • Kuo Y.T.
      • Lu C.Y.
      • Yeung K.W.
      • Lin W.C.
      • Sheu F.O.
      • Liu G.C.
      Distinction between high-grade gliomas and solitary metastases using peritumoral 3-T magnetic resonance spectroscopy, diffusion, and perfusion imagings.
      ,
      • Law M.
      • Cha S.
      • Knopp E.A.
      • Johnson G.
      • Arnett J.
      • Litt A.W.
      High-grade gliomas and solitary metastases: Differentiation by using perfusion and proton spectroscopic MR imaging.
      ].
      Color-coded parametric maps, as well as the measurement of region of interest (ROI) and semi-quantitative or quantitative assessment, help to identify the extent of malignant tumor infiltration beyond the enhancing margins [
      • Cha S.
      • Lupo J.M.
      • Chen M.H.
      • Lamborn K.R.
      • McDermott M.W.
      • Berger M.S.
      • Nelson S.J.
      • Dillon W.P.
      Differentiation of glioblastoma multiforme and single brain metastasis by peak height and percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging.
      ]. Some studies have proposed the use of PWI sequences for discriminating between infiltrating and non-infiltrating NEPSA [
      • Wang S.
      • Kim S.
      • Chawla S.
      • Wolf R.L.
      • Knipp D.E.
      • Vossough A.
      • O’Rourke D.M.
      • Judy K.D.
      • Poptani H.
      • Melhem E.R.
      Differentiation between glioblastomas, solitary brain metastases, and primary cerebral lymphomas using diffusion tensor and dynamic susceptibility contrast-enhanced MR imaging.
      ,
      • Ma J.H.
      • Kim H.S.
      • Rim N.J.
      • Kim S.H.
      • Cho K.G.
      Differentiation among glioblastoma multiforme, solitary metastatic tumor, and lymphoma using whole-tumor histogram analysis of the normalized cerebral blood volume in enhancing and perienhancing lesions.
      ,
      • Wang D.
      • Wang M.L.
      • Li Y.H.
      Quantitative MRI study of the permeability of peritumoral brain edema in lung cancer patients with brain metastases.
      ]. The presence of malignant cells within infiltrating NEPSA is usually linked to the expression of endothelial and vascular growth factors that induce angiogenesis, thus, PWI would theoretically identify areas with increased values of CBV, CBF, Ktrans or Kep values [
      • Tsougos I.
      • Svolos P.
      • Kousi E.
      • Fountas K.
      • Theodorou K.
      • Fezoulidis I.
      • Kapsalaki E.
      Differentiation of glioblastoma multiforme from metastatic brain tumor using proton magnetic resonance spectroscopy, diffusion and perfusion metrics at 3 T.
      ]. In contrast, non-infiltrating NEPSA, where only pure vasogenic edema is present, is less likely to show pathological increases in CBV values suggestive of neo-angiogenesis (Movie 5). The maximum value of CBV has been proposed for differentiating between HGG, PCNSL and solitary metastasis. HGG-NEPSA has shown the highest CBV values followed by PCNSL-NEPSA and metastasis-NEPSA [
      • Ma J.H.
      • Kim H.S.
      • Rim N.J.
      • Kim S.H.
      • Cho K.G.
      Differentiation among glioblastoma multiforme, solitary metastatic tumor, and lymphoma using whole-tumor histogram analysis of the normalized cerebral blood volume in enhancing and perienhancing lesions.
      ].Moreover, permeability studies have demonstrated a positive correlation between Ktrans values and edema index (a ratio between NEPSA volume and tumoral volume) in metastatic lesions from a lung primary, located at gray-withe matter junction, as well as, with VEGF expression in the original primary tumor (Fig. 7) [
      • Wang D.
      • Wang M.L.
      • Li Y.H.
      Quantitative MRI study of the permeability of peritumoral brain edema in lung cancer patients with brain metastases.
      ]. Relative CBV (rCBV) is higher in HGG-NEPSA, related to the presence of tumor angiogenesis, than in metastasis-NEPSA, representing pure vasogenic edema, and a maximum rCBV cutoff value of 0.94 has been proposed to discriminate between both entities [
      • Wang S.
      • Kim S.
      • Chawla S.
      • Wolf R.L.
      • Knipp D.E.
      • Vossough A.
      • O’Rourke D.M.
      • Judy K.D.
      • Poptani H.
      • Melhem E.R.
      Differentiation between glioblastomas, solitary brain metastases, and primary cerebral lymphomas using diffusion tensor and dynamic susceptibility contrast-enhanced MR imaging.
      ,
      • Neska-Matuszewska M.
      • Bladowska J.
      • Sąsiadek M.
      • Zimny A.
      Differentiation of glioblastoma multiforme, metastases and primary central nervous system lymphomas using multiparametric perfusion and diffusion MR imaging of a tumor core and a peritumoral zone—Searching for a practical approach.
      ]. Further studies are needed to confirm if data regarding neoangiogenesis at NEPSA identified with PWI techniques can be extrapolated to information about capillary network obtained with IVIM model [
      • Bisdas S.
      • Braun C.
      • Skardelly M.
      • Schittenhelm J.
      • Teo T.H.
      • Thng C.H.
      • Klose U.
      • Koh T.S.
      Correlative assessment of tumor microcirculation using contrast-enhanced perfusion MRI and intravoxel incoherent motion diffusion-weighted MRI: Is there a link between them?.
      ].
      Figure thumbnail gr7
      Fig. 7Usefulness of PWI for assessment of NEPSA. (a) 65 year-oold female with breast cancer. Right frontoparietal lesion is identified at axial FLAIR and postcontrast GE T1WI with intense enhancement (white arrows) and presence of NEPSA (black arrows). No increase of CBV values is identified at NEPSA (black arrow) (purple curve) compared with contralateral WM (orange curve). Findings consistent with CNS metastasis. (b) 54 year-old male with left occipital HGG identified at axial FLAIR and postcontrast GE T1WI (white arrow) and extensive NEPSA (black arrows). ROI at NEPSA (black arrow) shows a slight increase of CBV and CBF values (yellow curve) at temporal WM, suggesting presence of neoangiogenesis outside the enhancing component of the tumor.

      3.6 Arterial Spin Labelling

      In the last decades, ASL sequences have been used for assessment of CNS lesion vasculature without the need of administration of exogenous contrast agents. For this aim, blood is tagged, usually at the level of cervical internal carotid arteries and vertebral arteries, by the application of a saturation radiofrequency pulse that inverts all the water spins of blood. This tagged blood travels to CNS and is delivered following capillary network to the brain lesions [
      • Grade M.
      • Hernandez Tamames J.A.
      • Pizzini F.B.
      • Achten E.
      • Golay X.
      • Smits M.
      A neuroradiologist’s guide to arterial spin labeling MRI in clinical practice.
      ]. Those lesions with high vascularization will show a higher concentration of these spins, identifying high signal intensity within these areas [
      • Huang Y.C.
      • Liu H.L.
      • Der Lee J.
      • Yang J.T.
      • Weng H.H.
      • Lee M.
      • Yeh M.Y.
      • Tsai Y.H.
      Comparison of Arterial Spin Labeling and Dynamic Susceptibility Contrast Perfusion MRI in Patients with Acute Stroke.
      ]. In addition, ASL is able to provide quantitative measurements of CBV, in a similar fashion to contrast-enhanced PWI.
      The use of the patient’s own blood as an inner tracer to evaluate angiogenesis supposes an added value for of ASL approach over conventional contrast-enhanced PWI, because tagged blood has demonstrated greater diffusibility into the capillary network than GBCAs with relative insensitivity to permeability [
      • Huang Y.C.
      • Liu H.L.
      • Der Lee J.
      • Yang J.T.
      • Weng H.H.
      • Lee M.
      • Yeh M.Y.
      • Tsai Y.H.
      Comparison of Arterial Spin Labeling and Dynamic Susceptibility Contrast Perfusion MRI in Patients with Acute Stroke.
      ]. Also, now it is recommended to limit the use of GBCA as much as possible due to the possibility of systemic nephrogenic fibrosis in patient́s with advanced renal insufficiency or brain deposition in patient́s submitted to repetitive contrast-enhanced MRI studies [
      • Lancelot E.
      • Raynaud J.S.
      • Desché P.
      Current and Future MR Contrast Agents: Seeking a Better Chemical Stability and Relaxivity for Optimal Safety and Efficacy.
      ].
      ASL has been explored for differentiation between infiltrative and non-infiltrative NEPSA [
      • Sunwoo L.
      • Yun T.J.
      • You S.H.
      • Yoo R.E.
      • Kang K.M.
      • Choi S.H.
      • Kim J.H.
      • Sohn C.H.
      • Park S.W.
      • Jung C.
      • Park C.K.
      Differentiation of glioblastoma from brain metastasis: Qualitative and quantitative analysis using arterial spin labeling MR imaging.
      ]. As we referred before with PWI, VEGF expressed by malignant cells within infiltrating NEPSA induces angiogenesis, thus, ASL would identify areas of increase CBF within these regions. Non-infiltrating NEPSA, in which only vasogenic edema or gliosis is present, is less likely to show pathological increases in CBF values with ASL acquisitions (Movie 6). In this manner, CBF derived from ASL shows higher values in HGG-NEPSA than in metastasis-NEPSA [
      • Sunwoo L.
      • Yun T.J.
      • You S.H.
      • Yoo R.E.
      • Kang K.M.
      • Choi S.H.
      • Kim J.H.
      • Sohn C.H.
      • Park S.W.
      • Jung C.
      • Park C.K.
      Differentiation of glioblastoma from brain metastasis: Qualitative and quantitative analysis using arterial spin labeling MR imaging.
      ]. A cutoff value of 1.92 mL/100 g has been proposed to discriminate between NEPSA in these lesions with high sensitivity (92.86%) and specificity (100%), on the basis of the CBF gradient between the nearest and the most distant peritumoral area from the enhancing tumor (Fig. 8) [
      • Lin L.
      • Xue Y.
      • Duan Q.
      • Sun B.
      • Lin H.
      • Huang X.
      • Chen X.
      The role of cerebral blood flow gradient in peritumoral edema for differentiation of glioblastomas from solitary metastatic lesions.
      ]. Quantitative analysis of CBF obtained with ASL has shown a significant increase of CBF in HGG compared with metastasis with AUC of 0.835 [
      • Sunwoo L.
      • Yun T.J.
      • You S.H.
      • Yoo R.E.
      • Kang K.M.
      • Choi S.H.
      • Kim J.H.
      • Sohn C.H.
      • Park S.W.
      • Jung C.
      • Park C.K.
      Differentiation of glioblastoma from brain metastasis: Qualitative and quantitative analysis using arterial spin labeling MR imaging.
      ]. In addition, CBF derived from ASL has been found to have higher values in HGG-NEPSA (2.6 mL/100 g) compared with PCNSL-NEPSA (1.4 mL/100 g) [
      • Yamashita K.
      • Yoshiura T.
      • Hiwatashi A.
      • Togao O.
      • Yoshimoto K.
      • Suzuki S.O.
      • Abe K.
      • Kikuchi K.
      • Maruoka Y.
      • Mizoguchi M.
      • Iwaki T.
      • Honda H.
      Differentiating primary CNS lymphoma from glioblastoma multiforme: Assessment using arterial spin labeling, diffusion-weighted imaging, and 18F-fluorodeoxyglucose positron emission tomography.
      ].
      Figure thumbnail gr8
      Fig. 8Usefulness of ASL for assessment of NEPSA. (a) 54 year-old female with seizures shows left temporal lesion with nodular enhancement on coronal postcontrast GE T1WI (black arrow) with extensive NEPSA better depicted at coronal FLAIR (white arrow). PCASL acquisition fused with coronal g postcontrast GE T1WI shows high CBF at primary tumor and NEPSA (black arrow). HGG was confirmed after biopsy. (b) 65 year-old male with colorectal cancer shows a small enhancing lesion at left cerebellum (black arrow) with intense uptake at axial postcontrast GE T1WI and moderate NEPSA at axial FLAIR (white arrow). Axial PCASL acquisition fused with postcontrast GE T1WI shows high CBF (black arrow) at lesion. However, a ROI placed at NEPSA (white arrow) shows neglible increase of CBF values (10 mL/100 g/min). CNS metastasis was confirmed after biopsy.

      3.7 T2 mapping

      T2 mapping (T2 relaxometry) techniques have been scarcely applied for CNS tumor assessment. With this technique, subtle differences in the T2 relaxation times of water molecules, bonded and not bonded to macromolecules and/or membranes, can be detected and quantified. In this manner, water molecules bonded to macromolecules will show shorter T2 relaxation than free water molecules [
      • Margaret Cheng H.-L.
      • Stikov N.
      • Ghugre N.R.
      • Wright G.A.
      Practical medical applications of quantitative MR relaxometry.
      ]. T2 mapping is based on the acquisition of T2-weighted Turbo/Fast Spin Echo (FSE) or Gradient-Echo (GE) sequences with different TEs to assess the decay of T2 signal intensity. This approach is more precise than visual estimation of NEPSA with conventional T2-WI sequences [
      • Sichtermann T.
      • Furtmann J.K.
      • Dekeyzer S.
      • Gilmour G.
      • Oros-Peusquens A.M.
      • Bach J.P.
      • Wiesmann M.
      • Shah N.J.
      • Nikoubashman O.
      Increased Water Content in Periventricular Caps in Patients without Acute Hydrocephalus.
      ]. Another valid approach to evaluate T2 relaxation times is based on synthetic MRI multi-echo quantitative scans that provide information about proton density, longitudinal relaxation rate (R1) and transverse relaxation rate (R2) [
      • Blystad I.
      • Marcel Warntjes J.B.
      • Smedby O.
      • Lundberg P.
      • Larsson E.M.
      • Tisell A.
      Quantitative MRI for analysis of peritumoral edema in malignant gliomas.
      ].
      It is well known that NEPSA shows higher signal intensity on conventional T2-WI than apparent normal WM. Infiltrating NEPSA shows an increase of water content, however, these water molecules interact not only with WM tracts and myelin, but also with membranes and proteins of malignant cells, a circumstance that will reduce the T2 relaxation time of these areas (Movie 7) [
      • Blystad I.
      • Marcel Warntjes J.B.
      • Smedby O.
      • Lundberg P.
      • Larsson E.M.
      • Tisell A.
      Quantitative MRI for analysis of peritumoral edema in malignant gliomas.
      ]. This phenomenon has been demonstrated in HGG, differentiating non enhancing tumor from edema on the basis of T2 relaxation times using a dual-echo TSE approach [
      • Ellingson B.M.
      • Lai A.
      • Nguyen H.N.
      • Nghiemphu P.L.
      • Pope W.B.
      • Cloughesy T.F.
      Quantification of Nonenhancing tumor burden in Gliomas using effective T2 maps derived from dual-echo turbo spin-echo MRI.
      ]. Non enhancing tumor will show T2 values between 125 and 250 msec and edema between 250 and 500 msec. In fact, a gradient in relaxation times has been described in the HGG-NEPSA, showing shorter relaxation times in the nearest NEPSA to contrast-enhanced solid component of the tumor compared to the more distant one (Fig. 9) [
      • Blystad I.
      • Marcel Warntjes J.B.
      • Smedby O.
      • Lundberg P.
      • Larsson E.M.
      • Tisell A.
      Quantitative MRI for analysis of peritumoral edema in malignant gliomas.
      ].
      Figure thumbnail gr9
      Fig. 9Usefulness of T2-mapping for assessment of NEPSA. (a) 48 year-old male with seizures shows a large right frontoparietal lesion with peripheral enhancement on postcontrast GE T1WI (white arrow) and moderate NEPSA at FLAIR (black arrow). T2 mapping shows low T2 relaxation times (138 ms) at NEPSA (black arrow) consistent with edema infiltration (same patient than b). (b) 60 year-old female with breast cancer and ataxia. Left cerebellar lesion is identified (white arrow) at both FLAIR and postcontrast GE T1WI, with important NEPSA (white arrow). T2 mapping shows high relaxation time values (242 ms) at NEPSA (black arrow) suggesting pure vasogenic edema. Breast cancer metastasis was confirmed after biopsy.
      Conversely, non-infiltrating NEPSA, related to metastasis or non-invasive meningiomas, may only show an increase of water molecules that interact with myelin, so T2 relaxation times are expected to be longer than in infiltrating NEPSA [
      • Oh J.
      • Cha S.
      • Aiken A.H.
      • Han E.T.
      • Crane J.C.
      • Stainsby J.A.
      • Wright G.A.
      • Dillon W.P.
      • Nelson S.J.
      Quantitative apparent diffusion coefficients and T2 relaxation times in characterizing contrast enhancing brain tumors and regions of peritumoral edema.
      ]. With regard to treatment response assessment, significant decreases on T2 relaxation time values in the peritumoral regions have been found in patients with recurrent glioblastoma after anti-VEGF treatment [
      • Ellingson B.M.
      • Cloughesy T.F.
      • Lai A.
      • Nghiemphu P.L.
      • Lalezari S.
      • Zaw T.
      • Motevalibashinaeini K.
      • Mischel P.S.
      • Pope W.B.
      Quantification of edema reduction using differential quantitative T2 (DQT2) relaxometry mapping in recurrent glioblastoma treated with bevacizumab.
      ].

      3.8 Amide Proton Transfer

      APT may be considered as a newcomer among advanced MRI sequences for CNS lesions evaluation [
      • Jones C.K.
      • Schlosser M.J.
      • Van Zijl P.C.M.
      • Pomper M.G.
      • Golay X.
      • Zhou J.
      Amide proton transfer imaging of human brain tumors at 3T.
      ]. Amide is an endogenous peptide from a protein present in HGG. APT is a free contrast technique based on the Chemical Exchange Saturation Transfer (CEST) principle [
      • Jiang S.
      • Yu H.
      • Wang X.
      • Lu S.
      • Li Y.
      • Feng L.
      • Zhang Y.
      • Heo H.Y.
      • Lee D.H.
      • Zhou J.
      • Wen Z.
      Molecular MRI differentiation between primary central nervous system lymphomas and high-grade gliomas using endogenous protein-based amide proton transfer MR imaging at 3 Tesla.
      ]. The contrast between healthy and malignant tissue is generated by applying a specific saturation radiofrequency pulse that nulls the signal from amide protons [
      • Zhou J.
      • Blakeley J.O.
      • Hua J.
      • Kim M.
      • Laterra J.
      • Pomper M.G.
      • Van Zijl P.C.M.
      Practical data acquisition method for human brain tumor amide proton transfer (APT) imaging.
      ]. Chemical exchange of these nulled protons to free water conditions decreases their signal [
      • Zhou J.
      • Blakeley J.O.
      • Hua J.
      • Kim M.
      • Laterra J.
      • Pomper M.G.
      • Van Zijl P.C.M.
      Practical data acquisition method for human brain tumor amide proton transfer (APT) imaging.
      ]. Up to date, scientific papers evaluating the usefulness of APT at CNS have focused in the grading of CNS tumors and in the follow-up evaluation of treated lesions, particularly in differentiating tumor progression from post-treatment changes, as a valid alternative to DWI and PWI [
      • Zhou J.
      • Blakeley J.O.
      • Hua J.
      • Kim M.
      • Laterra J.
      • Pomper M.G.
      • Van Zijl P.C.M.
      Practical data acquisition method for human brain tumor amide proton transfer (APT) imaging.
      ,
      • Zhou J.
      • Tryggestad E.
      • Wen Z.
      • Lal B.
      • Zhou T.
      • Grossman R.
      • Wang S.
      • Yan K.
      • Fu D.X.
      • Ford E.
      • Tyler B.
      • Blakeley J.
      • Laterra J.
      • Van Zijl P.C.M.
      Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides.
      ]. APT has been also used in the differential diagnosis between PCNSL and HGG [
      • Jiang S.
      • Yu H.
      • Wang X.
      • Lu S.
      • Li Y.
      • Feng L.
      • Zhang Y.
      • Heo H.Y.
      • Lee D.H.
      • Zhou J.
      • Wen Z.
      Molecular MRI differentiation between primary central nervous system lymphomas and high-grade gliomas using endogenous protein-based amide proton transfer MR imaging at 3 Tesla.
      ].
      Theoretically, infiltrating NEPSA may show increased APT values due to the presence of amide protons within malignant cells located inside the tumoral edema. Conversely, non-infiltrating NEPSA will show no signal from amide protons due to the absence of malignant cells (Movie 8). Thus, APT will be able to discriminate between NEPSA linked to solitary brain metastasis and that related to HGG. Controversial results have been found when APT has been applied to this task, probably due to obscuring infiltrating limits between tumors from pure edema in cases of HGG and APT signal normalization [
      • Kamimura K.
      • Nakajo M.
      • Yoneyama T.
      • Fukukura Y.
      • Hirano H.
      • Goto Y.
      • Sasaki M.
      • Akamine Y.
      • Keupp J.
      • Yoshiura T.
      Histogram analysis of amide proton transfer–weighted imaging: comparison of glioblastoma and solitary brain metastasis in enhancing tumors and peritumoral regions.
      ]. However, some authors found significant differences with lower absolute and relative APT values at metastatic-NEPSA compared with HGG-NEPSA with an AUC of 0.95 and an accuracy of 85.2% for discriminating between both entities [
      • Yu H.
      • Lou H.
      • Zou T.
      • Wang X.
      • Jiang S.
      • Huang Z.
      • Du Y.
      • Jiang C.
      • Ma L.
      • Zhu J.
      • He W.
      • Rui Q.
      • Zhou J.
      • Wen Z.
      Applying protein-based amide proton transfer MR imaging to distinguish solitary brain metastases from glioblastoma.
      ]. In fact, in the same study, no significant differences were found between the tumor core of metastasis and HGG, so hypothetically APT will be more helpful for discriminating between both lesions in basis of their NEPSA than the tumoral core (Fig. 10) [
      • Yu H.
      • Lou H.
      • Zou T.
      • Wang X.
      • Jiang S.
      • Huang Z.
      • Du Y.
      • Jiang C.
      • Ma L.
      • Zhu J.
      • He W.
      • Rui Q.
      • Zhou J.
      • Wen Z.
      Applying protein-based amide proton transfer MR imaging to distinguish solitary brain metastases from glioblastoma.
      ]. APT values have been used for differentiating between PCSNL and HGG not only from their enhancing component but also at NEPSA. Significant lower APT values (p < 0.01) for PCNSL-NEPSA have been found compared with those at HGG-NEPSA [
      • Jiang S.
      • Yu H.
      • Wang X.
      • Lu S.
      • Li Y.
      • Feng L.
      • Zhang Y.
      • Heo H.Y.
      • Lee D.H.
      • Zhou J.
      • Wen Z.
      Molecular MRI differentiation between primary central nervous system lymphomas and high-grade gliomas using endogenous protein-based amide proton transfer MR imaging at 3 Tesla.
      ]. However, further studies are needed to determine if APT imaging is also able to detect changes within NEPSA in treated patients that help to distinguish between tumor progression and treatment effects.
      Figure thumbnail gr10
      Fig. 10Usefulness of APT for assessment of NEPSA. (a) 51 year-old male with lung cancer shows right frontal lesion with peripheral enhancement in axial postcontrast GE T1WI (white arrow). Lesion shows associated moderate NEPSA better identified at FLAIR (black arrow). APT study reveals high APT values at lesion and higher APT values at NEPSA (black arrow) (0.9) compared with contralateral frontal lobe (0.5). HGG was confirmed after biopsy. (b) 51 year-old male with lung cancer shows a right parietal lesion with peripheral enhancement in postcontrast GE T1WI (white arrow). Lesion shows moderate NEPSA better identified at FLAIR (black arrow). APT study reveals high APT values within lesion and lower APT values (0.1) at NEPSA (black arrow) compared with contralateral parietal lobe (0.3). Metastasis was confirmed after biopsy.

      4. Conclusions

      The use of the advanced MRI sequences described above may help to facilitate the differential between infiltrating and non-infiltrating NEPSA. Radiologists should be familiarized with the physical basis and biological significance of each one of these sequences. The main goal of these techniques is to help in differentiating between non-infiltrative NEPSA, usually linked to brain metastasis or non-invasive meningiomas, and infiltrative-NEPSA linked to HGG. However, in the common radiological practice, not all of these sequences are usually acquired. Moreover, some of them, such as T2 mapping, APT or DKI are not available in all MRI systems nowadays and their accuracy and feasibility need for further studies for being incorporate to routine protocols. A reasonable application of these advanced sequences is recommended for evaluating not only NEPSA but also the solid component of CNS lesions, in which these sequnces have demonstrated widely their usefulness. MRI sequences such as DWI, PWI, MRS or even DTI are nowadays part of routine MRI protcols for CNS lesions characterization together with morphological criteria. For this reason the assessment of ADC, CBV, Cho/NAA or FA, not only at solid component of the lesions but also at their respective NEPSA should be assessed when these sequences are evaluated.

      CRediT authorship contribution statement

      Teodoro Martín-Noguerol: Conceptualization, Methodology, Writing – original draft, Visualization, Supervision. Suyash Mohan: Conceptualization, Methodology, Writing – original draft, Visualization, Supervision. Eloísa Santos-Armentia: Conceptualization, Methodology, Writing – review & editing, Visualization, Supervision. Alberto Cabrera-Zubizarreta: Conceptualization, Methodology, Writing – review & editing, Visualization, Supervision. Antonio Luna: Conceptualization, Methodology, Writing – review & editing, Visualization, Supervision.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:
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