Curr Oncol Rep (2014) 16:399 DOI 10.1007/s11912-014-0399-8
NEURO-ONCOLOGY (MR GILBERT, SECTION EDITOR)
Imaging Mimics of Primary Malignant Tumors of the Central Nervous System (CNS) Mark Daniel Anderson & Rivka R. Colen & Ivo W. Tremont-Lukats
# Springer Science+Business Media New York 2014
Abstract Imaging has become a central part of the evaluation of lesions of the central nervous system. Despite patterns of the appearances of several types of central nervous system malignancies and improving resolution of imaging techniques, there are other processes that can display similar characteristics. Time and again, vascular, inflammatory, and vascular lesions will mimic a neoplastic process, requiring tissue diagnosis. With the introduction of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging in the evaluation of the brain tumor, there has been improvement in determining whether a lesion is neoplastic, and further advances may lead to noninvasive pathological and molecular diagnoses. Keywords Oncology . Neuro-oncology . Central nervous system (CNS) . Imaging . Imaging techniques . Primary malignant tumors
Introduction Accurate and timely diagnosis is imperative to maximize treatment benefit while balancing the adverse effects of
This article is part of the Topical Collection on Neuro-oncology M. D. Anderson (*) Department of Neurology, University of Mississippi Medical Center, Jackson, MS, USA e-mail: [email protected] R. R. Colen Department of Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA I. W. Tremont-Lukats Department of Neuro-Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
treatment (treatment effects) in patients with a CNS malignancy. Studies report that the correlation of radiographic and pathological diagnosis is often inaccurate, precluding empiric treatment in most cases [1, 2]. A good understanding of the underlying pathologic diagnosis is essential to evaluating any changes that follow treatment. There are situations that present diagnostic and therapeutic dilemmas, such as space occupying lesions that are not malignant and that could be managed conservatively, as well as malignancies that do not present as space occupying lesions or that may have an atypical appearance (Tables 1 and 2). These cases may lead to delay in diagnosis and treatment or worse, an incorrect management with disastrous consequences. Clues in the clinical evaluation with a detailed history and physical exam can help determine the right diagnosis. A careful review of infectious, inflammatory, and vascular risk factors as well as other systemic abnormalities can provide helpful hints to a non-neoplastic process. While neuroimaging also can provide non-invasive clues using standard magnetic resonance imaging (MRI) sequences, these diagnostic dilemmas still occur frequently. Positron emission tomography (PET) imaging and advanced MRI sequences are tools that can assist in clarifying diagnoses non-invasively [3••, 4•, 5•]. Disorders that can mimic a neoplasm typically include vascular changes, reactive gliosis, infection, vascular malformations, and inflammatory processes. Additionally, the histologic grade of a malignancy can be difficult to predict by neuroimaging only, as some low- and high-grade lesions often appear similar on standard imaging [6]. The Importance of Tissue Diagnosis Published experience shows that while most presumed neoplastic diagnoses are correct, diagnosis is often different after biopsy. In a series of 300 stereotactic biopsies, the diagnostic yield was 91.7 % [1]. In 29/30 cases (96.7 %), a craniotomy
399, Page 2 of 8
Curr Oncol Rep (2014) 16:399
Table 1 Brain tumor representative cases Patient
Clinical data
Imaging impression
Pathologic diagnosis
A B
34 y.o. M with headaches, with new right insular, non-enhancing lesion 33 y.o. M with double vision, new left occipital lobe enhancing lesion
Low-grade glioma High-grade glioma
Astrocytoma, WHO grade II Glioblastoma
following the stereotactic biopsy accurately confirmed the results [1]. In this study, a change in treatment was necessary in 81 patients, because of a change in tumor type or grade, a change from tumor to non-neoplastic process and vice versa, and a shift from treatment-related changes to tumor and vice versa [1]. Another series of 635 patients also confirmed the safety and diagnostic accuracy of tissue diagnosis [7•]. Typical Characteristics of Gliomas Intracranial tumors are best evaluated on MRI. Low-grade gliomas are typically T1-hypointense, non-contrast enhancing (non-enhancing), T2/FLAIR-hyperintense lesions with little or no surrounding edema (Fig. 1A). High-grade gliomas are heterogeneously enhancing lesions with surrounding vasogenic edema (Fig. 1B). However, low-grade oligodendrogliomas can occasionally appear as contrastenhancing lesions [6]. Additionally, most anaplastic astrocytomas do not strongly enhance (up to 50 %) and even 9 % of glioblastomas do not enhance, leading to misleading radiographic impressions [8]. Vascular Mimics Stroke Evolution of intracranial ischemia and vascular lesions can occasionally mimic an intracranial lesion. Most often, the diagnosis of cerebral ischemia is straightforward due to a characteristic clinical history and typical radiologic findings that conform to a vascular distribution. Although computed tomography (CT) and MRI are important in the imaging assessment of stroke, non-contrast CT is the most widely used
study, initially due to its availability and speed allowing for quick evaluation of intracranial hemorrhage [9]. However, the appearance of brain tumors on CT is not specific, and often can be confused with stroke [10]. Although accuracy of diagnosis is better in the MRI era, imaging features of ischemic lesions in different phases of evolution and an atypical clinical history, such as the slow development of neurological symptoms, can lead to misdiagnosis. Subacute infarcts could have irregular contrast enhancement and can appear as “ring-enhancing” lesions. Further, larger infarctions will often develop significant mass effect, mimicking high-grade gliomas [11–14]. In contrast, small tumors may lack the characteristic mass effect and can be mistaken for small infarcts [15]. Understanding cerebral arterial distribution is fundamental in ruling out stroke. Additional diffusion-weighted imaging (DWI) in MRI is helpful to recognize early stroke, but is less helpful in subacute or chronic infarction because restricted diffusion may be absent or very subtle [16]. However, the evolution in time of MRI changes for stroke and tumor is quite different, requiring repeat testing over 4–6 weeks. Recent studies also indicate that advanced MRI techniques may play an additional role in distinguishing an ischemic infarct from a neoplasm [17]. MR spectroscopy reveals a unique pattern of change to distinguish ischemic lesions from high-grade neoplasms, but less frequently lowgrade lesion, when analyzing the choline, creatinine, and Nacetylaspartate peaks [17]. Measurements of cerebral blood flow (CBF), mean transit time (MTT), and relative cerebral blood volume (rCBV) with perfusion imaging can also help discriminate between neoplastic and benign lesions, although the clinical use of perfusion in acute stroke is to identify the area of ischemic, yet viable and not fully infarcted tissue surrounding the core of an infarct [18].
Table 2 Brain tumor mimics Patient Clinical data
Imaging impression
C D
Disease progression and abscess Recurrent Glioblastoma and abscess Disease progression Textilloma
E F
62 y.o. M with a history of GBM, with new enhancing lesions 61 y.o. F with a history of GBM, with new enhancement at the site of prior disease 44 y.o. F with headaches, right temporal enhancing lesion 66 y.o. M with new aphasia, left temporal minimally enhancing lesion
Primary brain tumor Glioma, indeterminate grade
Pathologic diagnosis
Sarcoid Progressive multifocal leukoencephalopathy
Curr Oncol Rep (2014) 16:399
Page 3 of 8, 399
Fig. 1 Images from representative cases. Patient A – MR axial sequences with T2 Flair (a), T1 post-contrast (b), MR perfusion (c-d) and MR spectroscopy (e-f) revealing a T2 hyperintense lesion with no enhance, change in perfusion or spectral signal, consistent with low-grade glioma.
Patient B - MR axial sequences with T2 Flair (a), T1 post-contrast (b), MR perfusion (c-f) and MR spectroscopy (g-h) revealing a T2 hyperintense lesion with enhancement, increased perfusion, and very elevated Cho/Cr ration suggestive of a high-grade glioma
Acute Nonischemic Encephalopathy Syndromes
impaired autoregulation of blood flow and cerebral hyperperfusion as the cause for PRES. Findings on MRI are usually best seen with T2-weighted and FLAIR sequences, showing vasogenic edema in a parietal and occipital lobe distribution that is bilateral. However, broader experience with this syndrome has documented numerous exceptions, with abnormalities in anterior and unilateral distributions, brainstem, as well as cases with focal enhancement or DWI
Reversible posterior leucoencephalopathy syndrome (RPLS), or posterior reversible encephalopathy syndrome (PRES), is the radiographic manifestation of a syndrome characterized by hypertensive encephalopathy, headaches, seizures, and visual disturbances. Although the precise mechanism is unknown, most relate hypertension with
399, Page 4 of 8
changes [19•]. Therefore, atypical RPLS/PRES can mimic a primary CNS tumor [13]. Inflammatory Mimics Demyelinating Disease Inflammatory disorders may produce lesions that resemble a CNS neoplasm. In demyelinating diseases, such as multiple sclerosis, the typical radiological features include multiple white matter lesions with lack of mass effect or edema. However, clinical history can be inconclusive and some white matter lesions can have mass effect [11, 13, 20]. Other demyelinating diseases such as acute disseminated encephalomyelitis (ADEM) or neuromyelitis optica (NMO) can rarely present with these “tumefactive” lesions as well. As these white matter lesions have a predilection for the corpus callosum, their distribution can mimic a butterfly-patterned glioblastoma [11]. In the presence of a solitary lesion, discerning between a demyelinating lesion and a brain tumor can be difficult, and may lead to delay in appropriate therapy or prolonged hospitalization until the definitive diagnosis [13]. Textiloma
Curr Oncol Rep (2014) 16:399
headache, mental status changes or neurological deficit. Radiographic diagnosis can be difficult due to the variability of imaging characteristics, including multifocal contrast enhancing lesions, intracerebral hemorrhage, or isolated contrast enhancing lesions with mass effect [11, 25, 26•]. Additionally in primary CNS vasculopathy, there is often no systemic abnormality, making the diagnosis difficult to reach. Virchow-Robin perivascular spaces that are enlarged and simultaneously enhancing may be specific for a vasculitic process [27]. However, systemic diseases should be investigated, as developing CNS manifestations in patients with Sjogren syndrome can be confused initially as a glioma [28]. Granulomatous Disease Sarcoidosis is a multisystem granulomatous disorder, characterized by bilateral hilar adenopathy, pulmonary infiltration, that involves neurologic complications in 5 % of patients [29]. Usually this involves the meninges, cranial nerves, and spinal cord, but rarely can involve isolated intraparenchymal mass lesions mimicking a tumor (Fig. 2E) [30]. In some patients, we can exclude malignancy but cannot pinpoint the exact diagnosis because the patient does not meet all the diagnostic criteria for the suspected disease.
A significant foreign-body reaction to hemostatic agents such as gelatin foam, oxidized cellulose, and microfibrillar collagen (Gelfoam®, Surgicel®, and Avitene®), may produce a granulomatous reactive lesion termed textiloma (also known as gossypibomas, gauzomas, and muslinomas) [21•, 22]. Textilomas are often symptomatically or radiologically apparent, and the clinical course as well as the imaging findings can resemble a neoplasm or tumor progression [21•]. Fortunately, the morphologic features of the hemostatic agents often permit precise identification on histological evaluation. Some unique pathological features are characteristic of microfibrillar collagen (Avitene®) textilomas, including a robust allergic response with prominent eosinophilia infiltrate and foci of degeneration, surrounded by hypercellular cuffs that mimic the histologic appearance of necrosis, with pseudopalisading seen in high-grade gliomas [22]. In the differential diagnosis of a mass lesion arising after prior intracranial surgery, a textiloma should be considered. Advanced MR techniques have been rarely applied in these cases with mixed results; one report using MR spectroscopy (MRS) and perfusion MR confirmed a benign lesion, whereas another case using the same techniques was convincing for recurrent glioblastoma (Fig. 2D) [23•, 24].
Infectious Mimics
Vasculitis
Viral
Vascular inflammation in the CNS, including primary angiitis of the CNS (PACNS), can present with subacute progressive
Some neurotropic viral infections may present with confounding clinical or imaging findings. In progressive multifocal
Bacterial/Fungal A bacterial or fungal brain abscess and intra-axial tumors with necrosis often have similar patterns of ring enhancement and perilesional edema, thus making distinction difficult on postcontrast T1 and FLAIR images. However, other standard MRI sequences can provide some clues to the correct diagnosis. Often the enhancing capsule of the bacterial abscess is hypointense on T2 images, which is not usually the case for tumors [31•]. DWI sequences can be helpful in that intracranial abscesses typically have a strong signal of water restriction in the central area of necrosis, whereas most high-grade gliomas have a very weak or no signal. In both cases, the apparent diffusion coefficient (ADC) values are usually reduced (Fig. 2C) [31•]. Advanced MR imaging evaluating perfusion and MRS are also important tools to differentiate necrotic neoplasm from abscess, because an abscess can have decreased cerebral blood volume (CBV) in the wall and can have a unique spectral pattern [31•, 32•]. However, variability in the imaging appearance of lesions resulting from CNS infections may make biopsy necessary for diagnosis [33•, 34•, 35].
Curr Oncol Rep (2014) 16:399
Page 5 of 8, 399
Fig. 2 Imaging of Cases. Patient C – MR axial sequences with T1 post contrast (a), T2 weighted imaging (b), DWI (c), and ADC maps (d) showing a T2 hyperintense lesion with enhancement in the left frontal lobe consistent with disease progression and in the right frontal lobe, the pattern suggests abscess. Patient D – MR axial sequences with T2 Flair (a), T1 post-contrast (b), MR perfusion (c-f) and MR spectroscopy (g-h) revealing a T2 hyperintense lesion with enhancement, increased perfusion, and elevated Cho/Cr ratio suggestive of a recurrent high-grade glioma, though pathology revealed textiloma. Patient E - MR axial sequences with T2 Flair (a), T1 post-contrast (b) revealing a T2
hyperintense lesion with nodular enhancement causing entrapment of the right lateral ventricle, concerning for malignancy, pathology revealed non-caseating granuloma consistent with neurosarcoidosis. Patient F MR axial sequences with T2 Flair (a), T1 post-contrast (b), and MR spectroscopy (c-d) revealing a T2 hyperintense lesion with some enhancement and an elevated Cho/Cr ratio suggestive of a malignancy, pathology revealed significant macrophage infiltration with inclusions that stained for the JC Virus, consistent with progressive multifocal leukoencephalopathy (PML)
leucoencephalopathy (PML), patients present with subacute weakness, hemianopia or quadrantanopsia, and cognitive abnormalities [11, 36]. Typically, MRI reveals multifocal, large lesions in the subcortical white matter without mass effect; these are usually seen in the parietal lobes bilaterally, but can also be seen in the occipital lobe, corpus callosum, or thalamus. PML does not usually enhance in the setting of immune suppression, but PML lesions can develop areas of enhancement in the setting of the immune reconstitution inflammatory syndrome (IRIS). However, atypical lesions with mass effect and necrosis have been previously described (Fig. 2F) [37]. In the presence of a primary brain tumor, confounding imaging findings may delay diagnosis. Immunohistochemistry for the JC viral capsid protein can be performed for histological confirmation [36, 38•]. Neurosyphilis, “the great mimicker” may have a variety of CNS manifestations due to its tendency to resemble other diseases and make the differential diagnosis difficult. The standard MRI appearance of a syphilitic gumma
in the CNS can imitate gliomas, although MR perfusion or spectroscopy can provide additional information to distinguish this process from a neoplasm [39, 40•]. Advanced Imaging in the CNS Several studies have confirmed that MRS, perfusion MR (dynamic susceptibility contrast (DSC), dynamic contrastenhanced (DCE), and arterial spin labeling (ASL)), diffusion-weighted MR, diffusion tensor imaging (DTI), and PET/CT may increase sensitivity and specificity for the diagnosis of various cerebral lesions [4•, 5•, 17, 41]. These can also be valuable as imaging biomarkers to evaluate treatment response [42, 43••, 44, 45••]. For instance, in DWI the ADC value is mainly determined by cellularity. This allows for higher sensitivity and specificity when differentiating lesions with low ADC (epidermoid cysts, abscess, metastasis, highgrade gliomas, or lymphoma) from lesions with high ADC,
399, Page 6 of 8
arachnoid cysts or necrotic and low-grade gliomas [41, 46]. Generally, ADC may be useful in predicting tumor grade, although tumor heterogeneity limits the predictive power. DTI is related to DWI, but requires further data to calculate the vector (tensor) of the direction and magnitude of water diffusion. Another value derived from the diffusion tensor is the anisotropy, which described how water diffusion is delayed in one direction and enabled in the other, allowing the imaging of the myelin sheaths of major white matter tracts [47]. Some but not all recent studies have suggested that DTI can aid in the distinction of vasogenic edema surrounding metastases and meningioma from non-enhancing tumor infiltration in glioma [48]. MRS, an in-vivo measurement of the relative concentration of metabolites, may provide biochemical information that is helpful in distinguishing neoplasms from other pathologies in the brain as well as in the prediction of tumor grade [4•]. The typical MRS patterns of high-grade glioma are wellestablished as a high choline-to-creatinine ratio (>2) and low or absent N-acetyl aspartate (NAA) peaks, with occasional lipid and lactate peaks. Low-grade glioma can have a myoinositol peak. 2-hydroxyglutarate, a byproduct of tumorspecific IDH mutations in gliomas, can now be detected with a recently described MRS protocol, which is both diagnostic and prognostic in gliomas [3••]. The MRS of multifocal enhancing lesions in one report revealed minimal elevation of the choline peak, but also marked elevation of the glutamate and glutamine peaks, suggestive of inflammation instead of tumor [49]. Infarcts typically have lower choline and higher N-acetylaspartate signals with higher NAA/Cho and lower Cho/Cr ratios [17]. The MRS patterns in patients with gliosis, neuro-Behçet, CNS Lupus, or CNS infections are also distinct compared with that of a glioma [17, 31•, 32•, 50, 51]. MRI perfusion imaging defines cerebral blood volume (CBV) and flow, helping to determine vascularity or hypoxia of a lesion. For instance, these techniques can aid in distinction of intracranial abscess from cystic glioma by demonstrating an rCBV lower than or equal to the surrounding white matter in abscess [41]. CBV is also the main parameter useful for distinguishing primary brain tumors from metastases, as CBV values in the solid tumor component of gliomas and tissue surrounding the enhancement are higher than in metastases [46, 52••]. Additionally, the rCBV in a neoplastic lesion is much higher than in ischemic lesions, although low-grade lesions are more difficult to distinguish from non-neoplastic processes due to lower rCBV [17]. The evaluation of dynamic contrast sequences help estimate the permeability of the blood-brain barrier (BBB). This can differentiate between microvessels within tumors of extra-axial and nonglial origin (meningioma, choroid plexus papilloma, metastases, lymphoma) that are not part of the BBB, from glioma microvessels that form a BBB that is impaired but not absent [52••]. One study showed that perfusion imaging revealing a considerable
Curr Oncol Rep (2014) 16:399
reduction in blood volume and flow with corresponding vasogenic edema in the affected region could be pathognomonic for hypertensive encephalopathy [53]. It is also possible to determine tumor grade in known or suspected astrocytoma, as there is a well-documented strong correlation between the maximum rCBV measured in a tumor and the histologic tumor grade [46, 54]. Permeability measures are slightly less predictive of tumor grade because there are physiologic processes that may increase capillary permeability. The use of positron emission tomography to evaluate and diagnose intracranial lesions has also become valuable as functional molecular imaging becomes more widely available. Traditional 2- 18F-fluoro-2-deoxy-D-glucose (FDG)-PET has been available since the 1980s, but given the heightened background update of the tracer in normal brain, there was limited utility in the evaluation of brain tumors [43••]. However, the introduction of the radiolabeled amino acids 11 C-methionine and 18F-fluoroethyltyrosine has improved our ability to find better targets for brain tumor imaging, in discriminating neoplasm from a non-neoplastic process, as well in determining tumor grade [5•, 43••, 45••]. Other tracers, 18 F-fluorthymidine (FLT), 1 8 F-fluorocholine, 1 8 Ffluoromisonidazole (FMISO) have been shown to measure proliferation rate, membrane metabolism, and oxygen metabolism, important mechanisms that are altered in tumors [43••]. However, studies evaluating the differential accuracy between PET techniques and their relative value in comparison to MRI are limited and preliminary at best.
Conclusion While the ability to directly examine tissue continues to provide the most accurate data informing diagnosis, prognosis, and treatment decisions, novel imaging technology continues to provide better methods to the noninvasive evaluation of intracranial tumors. In cases in which pathology may provide inaccurate information, such as with sampling error, imaging may help with diagnostic and treatment decisions. Methods to directly image tumor-specific metabolism are in development, such as 2-HG spectroscopy, that not only inform diagnosis but also prognosis, and may even direct future treatment. When considering observation of a lesion that appears nonneoplastic, a short-interval follow-up is the best strategy. Compliance with Ethics Guidelines Conflict of Interest Mark Daniel Anderson, Rivka Colen, and Ivo W. Tremont-Lukats declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Curr Oncol Rep (2014) 16:399
Page 7 of 8, 399
References 18.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Kim JE, Kim DG, Paek SH, Jung HW. Stereotactic biopsy for intracranial lesions: reliability and its impact on the planning of treatment. Acta Neurochir (Wien). 2003;145(7):547–54. discussion 554-545. 2. Lunsford LD, Martinez AJ. Stereotactic exploration of the brain in the era of computed tomography. Surg Neurol. 1984;22(3):222–30. 3.•• Choi C, Ganji SK, DeBerardinis RJ, et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med. 2012;18(4):624–9. An imaging technique to establish a diagnosis of an IDH mutated glioma with imaging alone is described, an important step in metabolic imaging. 4.• Rao PJ, Jyoti R, Mews PJ, Desmond P, Khurana VG. Preoperative magnetic resonance spectroscopy improves diagnostic accuracy in a series of neurosurgical dilemmas. Br J Neurosurg. 2013. A practical application of MR Spectroscopy in certain diagnostic intracranial dilemmas presenting to neurosurgeons. 5.• Rapp M, Heinzel A, Galldiks N, et al. Diagnostic performance of 18F-FET PET in newly diagnosed cerebral lesions suggestive of glioma. J Nucl Med. 2013;54(2):229–35. Evaluation of 18F-FET PET, which shows potential use in detecting glioma. 6. White ML, Zhang Y, Kirby P, Ryken TC. Can tumor contrast enhancement be used as a criterion for differentiating tumor grades of oligodendrogliomas? AJNR Am J Neuroradiol. 2005;26(4): 784–90. 7.• Reithmeier T, William O, Doostkam S, et al. Intraindividual comparison of histopathological diagnosis obtained by stereotactic serial biopsy to open surgical resection specimen in patients with intracranial tumours. Clin Neurol Neurosurg. 13 2013. Evaluation of accuracy of stereotactic biopsy in regards to tumor heterogeniety. 8. Scott JN, Brasher PM, Sevick RJ, Rewcastle NB, Forsyth PA. How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology. 2002;59(6):947–9. 9. Liu X, Almast J, Ekholm S. Lesions masquerading as acute stroke. J Magn Reson Imaging. 2013;37(1):15–34. 10. Morgenstern LB, Frankowski RF. Brain tumor masquerading as stroke. J Neurooncol. 1999;44(1):47–52. 11. Cunliffe CH, Fischer I, Monoky D, et al. Intracranial lesions mimicking neoplasms. Arch Pathol Lab Med. 2009;133(1): 101–23. 12. Haug V, Linder-Lucht M, Zieger B, Korinthenberg R, Mall V, Mader I. Unilateral venous thalamic infarction in a child mimicking a thalamic tumor. J Child Neurol. 2009;24(1):105–9. 13. Wurm G, Parsaei B, Silye R, Fellner FA. Distinct supratentorial lesions mimicking cerebral gliomas. Acta Neurochir (Wien). 2004;146(1):19–26. discussion 26. 14. Yaldizli O, Kastrup O, Wanke I, Maschke M. Basal ganglia infarction mimicking glioblastoma. Eur J Med Res. 2005;10(9):400–1. 15. Okamoto K, Ito J, Furusawa T, Sakai K, Watanabe M, Tokiguchi S. Small cortical infarcts mimicking metastatic tumors. Clin Imaging. 1998;22(5):333–8. 16. Omuro AM, Leite CC, Mokhtari K, Delattre JY. Pitfalls in the diagnosis of brain tumours. Lancet Neurol. 2006;5(11): 937–48. 17. Hourani R, Brant LJ, Rizk T, Weingart JD, Barker PB, Horska A. Can proton MR spectroscopic and perfusion imaging differentiate
19.•
20.
21.•
22.
23.•
24.
25.
26.•
27.
28.
29. 30.
31.•
32.•
33.•
34.•
between neoplastic and nonneoplastic brain lesions in adults? AJNR Am J Neuroradiol. 2008;29(2):366–72. Cha S, Knopp EA, Johnson G, Wetzel SG, Litt AW, Zagzag D. Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging. Radiology. 2002;223(1):11–29. Stevens CJ, Heran MK. The many faces of posterior reversible encephalopathy syndrome. Br J Radiol. 2012;85(1020):1566–75. Recognition that posterior reversible encephalopathy syndrome can many different presentations and appearances on imaging. Capello E, Roccatagliata L, Pagano F, Mancardi GL. Tumor-like multiple sclerosis (MS) lesions: neuropathological clues. Neurol Sci. 2001;22 Suppl 2:S113–6. Anderson MD, Raghunathan A, Gilbert MR. Textiloma resembling anaplastic progression of an isocitrate dehydrogenase 1 (IDH1) mutant, low grade glioma. J Neurooncol. 2013;111(3):377–9. Report of a case of textiloma being confused for tumor progression. Ribalta T, McCutcheon IE, Neto AG, et al. Textiloma (gossypiboma) mimicking recurrent intracranial tumor. Arch Pathol Lab Med. 2004;128(7):749–58. Garciarena P, Anderson MD, Hamilton J, et al. Textiloma mimicking recurrent glioblastoma: a case report. J Clin Oncol. 2013;31(suppl; abstr e13044). Case report of a textiloma being confused for tumor progression. Jang SW, Kim SJ, Kim SM, et al. MR spectroscopy and perfusion MR imaging findings of intracranial foreign body granuloma: a case report. Korean J Radiol. 2010;11(3):359–63. Nabika S, Kiya K, Satoh H, et al. Primary angiitis of the central nervous system mimicking dissemination from brainstem neoplasm: a case report. Surg Neurol. 2008;70(2):182–5. discussion 185. You G, Yan W, Zhang W, Li S, Li G, Jiang T. Isolated angiitis of the central nervous system with tumor-like lesion, mimicking brain malignant glioma: a case report and review of the literature. World J Surg Oncol. 2011;9:97. Reports of angiitis mimicking a tumor. Campi A, Benndorf G, Filippi M, Reganati P, Martinelli V, Terreni MR. Primary angiitis of the central nervous system: serial MRI of brain and spinal cord. Neuroradiology. 2001;43(8):599–607. Koh MS, Goh KY, Chen C, Howe HS. Cerebral infarct mimicking glioma in Sjogren’s syndrome. Hong Kong Med J. 2002;8(4): 292–4. Stern BJ, Krumholz A, Johns C, Scott P, Nissim J. Sarcoidosis and its neurological manifestations. Arch Neurol. 1985;42(9):909–17. Christoforidis GA, Spickler EM, Recio MV, Mehta BM. MR of CNS sarcoidosis: correlation of imaging features to clinical symptoms and response to treatment. AJNR Am J Neuroradiol. 1999;20(4):655–69. Auffray-Calvier E, Toulgoat F, Daumas-Duport B, Lintia Gaultier A, Desal H. Infectious and metabolic brain imaging. Diagn Interv Imaging. 2012;93(12):911–34. Application of MRI techniques to brain abscess, herpes encephalitis, Creutzfeldt-Jacob disease, posterior reversible encephalopathy, and central pontine myelinolysis. Hsu SH, Chou MC, Ko CW, et al. Proton MR spectroscopy in patients with pyogenic brain abscess: MR spectroscopic imaging versus single-voxel spectroscopy. Eur J Radiol. 2013;82(8):1299– 307. Application of advanced imaging techniques in abscess. Erdem M, Namiduru M, Karaoglan I, Kecik VB, Aydin A, Tanriverdi M. Unusual presentation of neurobrucellosis: a solitary intracranial mass lesion mimicking a cerebral tumor : a case of encephalitis caused by Brucella melitensis. J Infect Chemother. 2012;18(5):767–70. Case report of an infection process mimicking a brain tumor. Peng J, Ouyang Y, Fang WD, et al. Differentiation of intracranial tuberculomas and high grade gliomas using proton MR spectroscopy and diffusion MR imaging. Eur J Radiol. 2012;81(12):4057–63.
399, Page 8 of 8 Application of advanced imaging techniques to distinguish tuberculosis and glioma. 35. Suslu HT, Bozbuga M, Bayindir C. Cerebral tuberculoma mimicking high grade glial tumor. Turk Neurosurg. 2011;21(3): 427–9. 36. Gallia GL, DelValle L, Laine C, Curtis M, Khalili K. Concomitant progressive multifocal leucoencephalopathy and primary central nervous system lymphoma expressing JC virus oncogenic protein, large T antigen. Mol Pathol. 2001;54(5):354–9. 37. Thurnher MM, Thurnher SA, Muhlbauer B, et al. Progressive multifocal leukoencephalopathy in AIDS: initial and follow-up CT and MRI. Neuroradiology. 1997;39(9):611–8. 38.• Wu J, Langford LA, Schellingerhout D, et al. Progressive multifocal leukoencephalopathy in a patient with glioblastoma. J Neurooncol. 2011;103(3):791–6. Case report of an infectious process mimicking tumor progression. 39. Herrold JM. A syphilitic cerebral gumma manifesting as a brainstem mass lesion that responded to corticosteroid monotherapy. Mayo Clin Proc. 1994;69(10):960–1. 40.• Ventura N, Cannelas R, Bizzo B, Gasparetto EL. Intracranial syphilitic gumma mimicking a brain stem glioma. AJNR Am J Neuroradiol. 2012;33(7):E110–1. Case report of an infectious process mimicking a tumor. 41. Young GS. Advanced MRI of adult brain tumors. Neurol Clin. 2007;25(4):947–73. viii. 42. Chenevert TL, Stegman LD, Taylor JM, et al. Diffusion magnetic resonance imaging: an early surrogate marker of therapeutic efficacy in brain tumors. J Natl Cancer Inst. 2000;92(24):2029–36. 43.•• la Fougere C, Suchorska B, Bartenstein P, Kreth FW, Tonn JC. Molecular imaging of gliomas with PET: opportunities and limitations. Neuro Oncol. 2011;13(8):806–19. Application of PET imaging techniques to management of gliomas; this describes the method of PET acquisition as well as the tracers used to image biological processes in gliomas. 44. Mardor Y, Roth Y, Ochershvilli A, et al. Pretreatment prediction of brain tumors’ response to radiation therapy using high b-value diffusion-weighted MRI. Neoplasia. 2004;6(2):136–42.
Curr Oncol Rep (2014) 16:399 45.•• Nihashi T, Dahabreh IJ, Terasawa T. PET in the clinical management of glioma: evidence map. AJR Am J Roentgenol. 2013;200(6):W654–60. This is a meta-analysis that constructs a map of clinical evidence on the use of PET in glioma and helps to identify research gaps. 46. Rollin N, Guyotat J, Streichenberger N, Honnorat J, Tran Minh VA, Cotton F. Clinical relevance of diffusion and perfusion magnetic resonance imaging in assessing intra-axial brain tumors. Neuroradiology. 2006;48(3):150–9. 47. Inoue T, Ogasawara K, Beppu T, Ogawa A, Kabasawa H. Diffusion tensor imaging for preoperative evaluation of tumor grade in gliomas. Clin Neurol Neurosurg. 2005;107(3):174–80. 48. Provenzale JM, McGraw P, Mhatre P, Guo AC, Delong D. Peritumoral brain regions in gliomas and meningiomas: investigation with isotropic diffusion-weighted MR imaging and diffusiontensor MR imaging. Radiology. 2004;232(2):451–60. 49. Panchal NJ, Niku S, Imbesi SG. Lymphocytic vasculitis mimicking aggressive multifocal cerebral neoplasm: mr imaging and MR spectroscopic appearance. AJNR Am J Neuroradiol. 2005;26(3): 642–5. 50. Park KS, Ko HJ, Yoon CH, et al. Magnetic resonance imaging and proton magnetic resonance spectroscopy in neuro-Behcet's disease. Clin Exp Rheumatol. 2004;22(5):561–7. 51. Peterson PL, Axford JS, Isenberg D. Imaging in CNS lupus. Best Pract Res Clin Rheumatol. 2005;19(5):727–39. 52.•• Mills SJ, Thompson G, Jackson A. Advanced magnetic resonance imaging biomarkers of cerebral metastases. Cancer Imaging. 2012;12:245–52. A discussion of imaging biomarkers in brain metastases. 53. Sundgren PC, Edvardsson B, Holtas S. Serial investigation of perfusion disturbances and vasogenic oedema in hypertensive encephalopathy by diffusion and perfusion weighted imaging. Neuroradiology. 2002;44(4):299–304. 54. Chaskis C, Stadnik T, Michotte A, Van Rompaey K, D'Haens J. Prognostic value of perfusion-weighted imaging in brain glioma: a prospective study. Acta Neurochir (Wien). 2006;148(3):277–85. discussion 285.
NEURO-ONCOLOGY (MR GILBERT, SECTION EDITOR)
Imaging Mimics of Primary Malignant Tumors of the Central Nervous System (CNS) Mark Daniel Anderson & Rivka R. Colen & Ivo W. Tremont-Lukats
# Springer Science+Business Media New York 2014
Abstract Imaging has become a central part of the evaluation of lesions of the central nervous system. Despite patterns of the appearances of several types of central nervous system malignancies and improving resolution of imaging techniques, there are other processes that can display similar characteristics. Time and again, vascular, inflammatory, and vascular lesions will mimic a neoplastic process, requiring tissue diagnosis. With the introduction of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging in the evaluation of the brain tumor, there has been improvement in determining whether a lesion is neoplastic, and further advances may lead to noninvasive pathological and molecular diagnoses. Keywords Oncology . Neuro-oncology . Central nervous system (CNS) . Imaging . Imaging techniques . Primary malignant tumors
Introduction Accurate and timely diagnosis is imperative to maximize treatment benefit while balancing the adverse effects of
This article is part of the Topical Collection on Neuro-oncology M. D. Anderson (*) Department of Neurology, University of Mississippi Medical Center, Jackson, MS, USA e-mail: [email protected] R. R. Colen Department of Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA I. W. Tremont-Lukats Department of Neuro-Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
treatment (treatment effects) in patients with a CNS malignancy. Studies report that the correlation of radiographic and pathological diagnosis is often inaccurate, precluding empiric treatment in most cases [1, 2]. A good understanding of the underlying pathologic diagnosis is essential to evaluating any changes that follow treatment. There are situations that present diagnostic and therapeutic dilemmas, such as space occupying lesions that are not malignant and that could be managed conservatively, as well as malignancies that do not present as space occupying lesions or that may have an atypical appearance (Tables 1 and 2). These cases may lead to delay in diagnosis and treatment or worse, an incorrect management with disastrous consequences. Clues in the clinical evaluation with a detailed history and physical exam can help determine the right diagnosis. A careful review of infectious, inflammatory, and vascular risk factors as well as other systemic abnormalities can provide helpful hints to a non-neoplastic process. While neuroimaging also can provide non-invasive clues using standard magnetic resonance imaging (MRI) sequences, these diagnostic dilemmas still occur frequently. Positron emission tomography (PET) imaging and advanced MRI sequences are tools that can assist in clarifying diagnoses non-invasively [3••, 4•, 5•]. Disorders that can mimic a neoplasm typically include vascular changes, reactive gliosis, infection, vascular malformations, and inflammatory processes. Additionally, the histologic grade of a malignancy can be difficult to predict by neuroimaging only, as some low- and high-grade lesions often appear similar on standard imaging [6]. The Importance of Tissue Diagnosis Published experience shows that while most presumed neoplastic diagnoses are correct, diagnosis is often different after biopsy. In a series of 300 stereotactic biopsies, the diagnostic yield was 91.7 % [1]. In 29/30 cases (96.7 %), a craniotomy
399, Page 2 of 8
Curr Oncol Rep (2014) 16:399
Table 1 Brain tumor representative cases Patient
Clinical data
Imaging impression
Pathologic diagnosis
A B
34 y.o. M with headaches, with new right insular, non-enhancing lesion 33 y.o. M with double vision, new left occipital lobe enhancing lesion
Low-grade glioma High-grade glioma
Astrocytoma, WHO grade II Glioblastoma
following the stereotactic biopsy accurately confirmed the results [1]. In this study, a change in treatment was necessary in 81 patients, because of a change in tumor type or grade, a change from tumor to non-neoplastic process and vice versa, and a shift from treatment-related changes to tumor and vice versa [1]. Another series of 635 patients also confirmed the safety and diagnostic accuracy of tissue diagnosis [7•]. Typical Characteristics of Gliomas Intracranial tumors are best evaluated on MRI. Low-grade gliomas are typically T1-hypointense, non-contrast enhancing (non-enhancing), T2/FLAIR-hyperintense lesions with little or no surrounding edema (Fig. 1A). High-grade gliomas are heterogeneously enhancing lesions with surrounding vasogenic edema (Fig. 1B). However, low-grade oligodendrogliomas can occasionally appear as contrastenhancing lesions [6]. Additionally, most anaplastic astrocytomas do not strongly enhance (up to 50 %) and even 9 % of glioblastomas do not enhance, leading to misleading radiographic impressions [8]. Vascular Mimics Stroke Evolution of intracranial ischemia and vascular lesions can occasionally mimic an intracranial lesion. Most often, the diagnosis of cerebral ischemia is straightforward due to a characteristic clinical history and typical radiologic findings that conform to a vascular distribution. Although computed tomography (CT) and MRI are important in the imaging assessment of stroke, non-contrast CT is the most widely used
study, initially due to its availability and speed allowing for quick evaluation of intracranial hemorrhage [9]. However, the appearance of brain tumors on CT is not specific, and often can be confused with stroke [10]. Although accuracy of diagnosis is better in the MRI era, imaging features of ischemic lesions in different phases of evolution and an atypical clinical history, such as the slow development of neurological symptoms, can lead to misdiagnosis. Subacute infarcts could have irregular contrast enhancement and can appear as “ring-enhancing” lesions. Further, larger infarctions will often develop significant mass effect, mimicking high-grade gliomas [11–14]. In contrast, small tumors may lack the characteristic mass effect and can be mistaken for small infarcts [15]. Understanding cerebral arterial distribution is fundamental in ruling out stroke. Additional diffusion-weighted imaging (DWI) in MRI is helpful to recognize early stroke, but is less helpful in subacute or chronic infarction because restricted diffusion may be absent or very subtle [16]. However, the evolution in time of MRI changes for stroke and tumor is quite different, requiring repeat testing over 4–6 weeks. Recent studies also indicate that advanced MRI techniques may play an additional role in distinguishing an ischemic infarct from a neoplasm [17]. MR spectroscopy reveals a unique pattern of change to distinguish ischemic lesions from high-grade neoplasms, but less frequently lowgrade lesion, when analyzing the choline, creatinine, and Nacetylaspartate peaks [17]. Measurements of cerebral blood flow (CBF), mean transit time (MTT), and relative cerebral blood volume (rCBV) with perfusion imaging can also help discriminate between neoplastic and benign lesions, although the clinical use of perfusion in acute stroke is to identify the area of ischemic, yet viable and not fully infarcted tissue surrounding the core of an infarct [18].
Table 2 Brain tumor mimics Patient Clinical data
Imaging impression
C D
Disease progression and abscess Recurrent Glioblastoma and abscess Disease progression Textilloma
E F
62 y.o. M with a history of GBM, with new enhancing lesions 61 y.o. F with a history of GBM, with new enhancement at the site of prior disease 44 y.o. F with headaches, right temporal enhancing lesion 66 y.o. M with new aphasia, left temporal minimally enhancing lesion
Primary brain tumor Glioma, indeterminate grade
Pathologic diagnosis
Sarcoid Progressive multifocal leukoencephalopathy
Curr Oncol Rep (2014) 16:399
Page 3 of 8, 399
Fig. 1 Images from representative cases. Patient A – MR axial sequences with T2 Flair (a), T1 post-contrast (b), MR perfusion (c-d) and MR spectroscopy (e-f) revealing a T2 hyperintense lesion with no enhance, change in perfusion or spectral signal, consistent with low-grade glioma.
Patient B - MR axial sequences with T2 Flair (a), T1 post-contrast (b), MR perfusion (c-f) and MR spectroscopy (g-h) revealing a T2 hyperintense lesion with enhancement, increased perfusion, and very elevated Cho/Cr ration suggestive of a high-grade glioma
Acute Nonischemic Encephalopathy Syndromes
impaired autoregulation of blood flow and cerebral hyperperfusion as the cause for PRES. Findings on MRI are usually best seen with T2-weighted and FLAIR sequences, showing vasogenic edema in a parietal and occipital lobe distribution that is bilateral. However, broader experience with this syndrome has documented numerous exceptions, with abnormalities in anterior and unilateral distributions, brainstem, as well as cases with focal enhancement or DWI
Reversible posterior leucoencephalopathy syndrome (RPLS), or posterior reversible encephalopathy syndrome (PRES), is the radiographic manifestation of a syndrome characterized by hypertensive encephalopathy, headaches, seizures, and visual disturbances. Although the precise mechanism is unknown, most relate hypertension with
399, Page 4 of 8
changes [19•]. Therefore, atypical RPLS/PRES can mimic a primary CNS tumor [13]. Inflammatory Mimics Demyelinating Disease Inflammatory disorders may produce lesions that resemble a CNS neoplasm. In demyelinating diseases, such as multiple sclerosis, the typical radiological features include multiple white matter lesions with lack of mass effect or edema. However, clinical history can be inconclusive and some white matter lesions can have mass effect [11, 13, 20]. Other demyelinating diseases such as acute disseminated encephalomyelitis (ADEM) or neuromyelitis optica (NMO) can rarely present with these “tumefactive” lesions as well. As these white matter lesions have a predilection for the corpus callosum, their distribution can mimic a butterfly-patterned glioblastoma [11]. In the presence of a solitary lesion, discerning between a demyelinating lesion and a brain tumor can be difficult, and may lead to delay in appropriate therapy or prolonged hospitalization until the definitive diagnosis [13]. Textiloma
Curr Oncol Rep (2014) 16:399
headache, mental status changes or neurological deficit. Radiographic diagnosis can be difficult due to the variability of imaging characteristics, including multifocal contrast enhancing lesions, intracerebral hemorrhage, or isolated contrast enhancing lesions with mass effect [11, 25, 26•]. Additionally in primary CNS vasculopathy, there is often no systemic abnormality, making the diagnosis difficult to reach. Virchow-Robin perivascular spaces that are enlarged and simultaneously enhancing may be specific for a vasculitic process [27]. However, systemic diseases should be investigated, as developing CNS manifestations in patients with Sjogren syndrome can be confused initially as a glioma [28]. Granulomatous Disease Sarcoidosis is a multisystem granulomatous disorder, characterized by bilateral hilar adenopathy, pulmonary infiltration, that involves neurologic complications in 5 % of patients [29]. Usually this involves the meninges, cranial nerves, and spinal cord, but rarely can involve isolated intraparenchymal mass lesions mimicking a tumor (Fig. 2E) [30]. In some patients, we can exclude malignancy but cannot pinpoint the exact diagnosis because the patient does not meet all the diagnostic criteria for the suspected disease.
A significant foreign-body reaction to hemostatic agents such as gelatin foam, oxidized cellulose, and microfibrillar collagen (Gelfoam®, Surgicel®, and Avitene®), may produce a granulomatous reactive lesion termed textiloma (also known as gossypibomas, gauzomas, and muslinomas) [21•, 22]. Textilomas are often symptomatically or radiologically apparent, and the clinical course as well as the imaging findings can resemble a neoplasm or tumor progression [21•]. Fortunately, the morphologic features of the hemostatic agents often permit precise identification on histological evaluation. Some unique pathological features are characteristic of microfibrillar collagen (Avitene®) textilomas, including a robust allergic response with prominent eosinophilia infiltrate and foci of degeneration, surrounded by hypercellular cuffs that mimic the histologic appearance of necrosis, with pseudopalisading seen in high-grade gliomas [22]. In the differential diagnosis of a mass lesion arising after prior intracranial surgery, a textiloma should be considered. Advanced MR techniques have been rarely applied in these cases with mixed results; one report using MR spectroscopy (MRS) and perfusion MR confirmed a benign lesion, whereas another case using the same techniques was convincing for recurrent glioblastoma (Fig. 2D) [23•, 24].
Infectious Mimics
Vasculitis
Viral
Vascular inflammation in the CNS, including primary angiitis of the CNS (PACNS), can present with subacute progressive
Some neurotropic viral infections may present with confounding clinical or imaging findings. In progressive multifocal
Bacterial/Fungal A bacterial or fungal brain abscess and intra-axial tumors with necrosis often have similar patterns of ring enhancement and perilesional edema, thus making distinction difficult on postcontrast T1 and FLAIR images. However, other standard MRI sequences can provide some clues to the correct diagnosis. Often the enhancing capsule of the bacterial abscess is hypointense on T2 images, which is not usually the case for tumors [31•]. DWI sequences can be helpful in that intracranial abscesses typically have a strong signal of water restriction in the central area of necrosis, whereas most high-grade gliomas have a very weak or no signal. In both cases, the apparent diffusion coefficient (ADC) values are usually reduced (Fig. 2C) [31•]. Advanced MR imaging evaluating perfusion and MRS are also important tools to differentiate necrotic neoplasm from abscess, because an abscess can have decreased cerebral blood volume (CBV) in the wall and can have a unique spectral pattern [31•, 32•]. However, variability in the imaging appearance of lesions resulting from CNS infections may make biopsy necessary for diagnosis [33•, 34•, 35].
Curr Oncol Rep (2014) 16:399
Page 5 of 8, 399
Fig. 2 Imaging of Cases. Patient C – MR axial sequences with T1 post contrast (a), T2 weighted imaging (b), DWI (c), and ADC maps (d) showing a T2 hyperintense lesion with enhancement in the left frontal lobe consistent with disease progression and in the right frontal lobe, the pattern suggests abscess. Patient D – MR axial sequences with T2 Flair (a), T1 post-contrast (b), MR perfusion (c-f) and MR spectroscopy (g-h) revealing a T2 hyperintense lesion with enhancement, increased perfusion, and elevated Cho/Cr ratio suggestive of a recurrent high-grade glioma, though pathology revealed textiloma. Patient E - MR axial sequences with T2 Flair (a), T1 post-contrast (b) revealing a T2
hyperintense lesion with nodular enhancement causing entrapment of the right lateral ventricle, concerning for malignancy, pathology revealed non-caseating granuloma consistent with neurosarcoidosis. Patient F MR axial sequences with T2 Flair (a), T1 post-contrast (b), and MR spectroscopy (c-d) revealing a T2 hyperintense lesion with some enhancement and an elevated Cho/Cr ratio suggestive of a malignancy, pathology revealed significant macrophage infiltration with inclusions that stained for the JC Virus, consistent with progressive multifocal leukoencephalopathy (PML)
leucoencephalopathy (PML), patients present with subacute weakness, hemianopia or quadrantanopsia, and cognitive abnormalities [11, 36]. Typically, MRI reveals multifocal, large lesions in the subcortical white matter without mass effect; these are usually seen in the parietal lobes bilaterally, but can also be seen in the occipital lobe, corpus callosum, or thalamus. PML does not usually enhance in the setting of immune suppression, but PML lesions can develop areas of enhancement in the setting of the immune reconstitution inflammatory syndrome (IRIS). However, atypical lesions with mass effect and necrosis have been previously described (Fig. 2F) [37]. In the presence of a primary brain tumor, confounding imaging findings may delay diagnosis. Immunohistochemistry for the JC viral capsid protein can be performed for histological confirmation [36, 38•]. Neurosyphilis, “the great mimicker” may have a variety of CNS manifestations due to its tendency to resemble other diseases and make the differential diagnosis difficult. The standard MRI appearance of a syphilitic gumma
in the CNS can imitate gliomas, although MR perfusion or spectroscopy can provide additional information to distinguish this process from a neoplasm [39, 40•]. Advanced Imaging in the CNS Several studies have confirmed that MRS, perfusion MR (dynamic susceptibility contrast (DSC), dynamic contrastenhanced (DCE), and arterial spin labeling (ASL)), diffusion-weighted MR, diffusion tensor imaging (DTI), and PET/CT may increase sensitivity and specificity for the diagnosis of various cerebral lesions [4•, 5•, 17, 41]. These can also be valuable as imaging biomarkers to evaluate treatment response [42, 43••, 44, 45••]. For instance, in DWI the ADC value is mainly determined by cellularity. This allows for higher sensitivity and specificity when differentiating lesions with low ADC (epidermoid cysts, abscess, metastasis, highgrade gliomas, or lymphoma) from lesions with high ADC,
399, Page 6 of 8
arachnoid cysts or necrotic and low-grade gliomas [41, 46]. Generally, ADC may be useful in predicting tumor grade, although tumor heterogeneity limits the predictive power. DTI is related to DWI, but requires further data to calculate the vector (tensor) of the direction and magnitude of water diffusion. Another value derived from the diffusion tensor is the anisotropy, which described how water diffusion is delayed in one direction and enabled in the other, allowing the imaging of the myelin sheaths of major white matter tracts [47]. Some but not all recent studies have suggested that DTI can aid in the distinction of vasogenic edema surrounding metastases and meningioma from non-enhancing tumor infiltration in glioma [48]. MRS, an in-vivo measurement of the relative concentration of metabolites, may provide biochemical information that is helpful in distinguishing neoplasms from other pathologies in the brain as well as in the prediction of tumor grade [4•]. The typical MRS patterns of high-grade glioma are wellestablished as a high choline-to-creatinine ratio (>2) and low or absent N-acetyl aspartate (NAA) peaks, with occasional lipid and lactate peaks. Low-grade glioma can have a myoinositol peak. 2-hydroxyglutarate, a byproduct of tumorspecific IDH mutations in gliomas, can now be detected with a recently described MRS protocol, which is both diagnostic and prognostic in gliomas [3••]. The MRS of multifocal enhancing lesions in one report revealed minimal elevation of the choline peak, but also marked elevation of the glutamate and glutamine peaks, suggestive of inflammation instead of tumor [49]. Infarcts typically have lower choline and higher N-acetylaspartate signals with higher NAA/Cho and lower Cho/Cr ratios [17]. The MRS patterns in patients with gliosis, neuro-Behçet, CNS Lupus, or CNS infections are also distinct compared with that of a glioma [17, 31•, 32•, 50, 51]. MRI perfusion imaging defines cerebral blood volume (CBV) and flow, helping to determine vascularity or hypoxia of a lesion. For instance, these techniques can aid in distinction of intracranial abscess from cystic glioma by demonstrating an rCBV lower than or equal to the surrounding white matter in abscess [41]. CBV is also the main parameter useful for distinguishing primary brain tumors from metastases, as CBV values in the solid tumor component of gliomas and tissue surrounding the enhancement are higher than in metastases [46, 52••]. Additionally, the rCBV in a neoplastic lesion is much higher than in ischemic lesions, although low-grade lesions are more difficult to distinguish from non-neoplastic processes due to lower rCBV [17]. The evaluation of dynamic contrast sequences help estimate the permeability of the blood-brain barrier (BBB). This can differentiate between microvessels within tumors of extra-axial and nonglial origin (meningioma, choroid plexus papilloma, metastases, lymphoma) that are not part of the BBB, from glioma microvessels that form a BBB that is impaired but not absent [52••]. One study showed that perfusion imaging revealing a considerable
Curr Oncol Rep (2014) 16:399
reduction in blood volume and flow with corresponding vasogenic edema in the affected region could be pathognomonic for hypertensive encephalopathy [53]. It is also possible to determine tumor grade in known or suspected astrocytoma, as there is a well-documented strong correlation between the maximum rCBV measured in a tumor and the histologic tumor grade [46, 54]. Permeability measures are slightly less predictive of tumor grade because there are physiologic processes that may increase capillary permeability. The use of positron emission tomography to evaluate and diagnose intracranial lesions has also become valuable as functional molecular imaging becomes more widely available. Traditional 2- 18F-fluoro-2-deoxy-D-glucose (FDG)-PET has been available since the 1980s, but given the heightened background update of the tracer in normal brain, there was limited utility in the evaluation of brain tumors [43••]. However, the introduction of the radiolabeled amino acids 11 C-methionine and 18F-fluoroethyltyrosine has improved our ability to find better targets for brain tumor imaging, in discriminating neoplasm from a non-neoplastic process, as well in determining tumor grade [5•, 43••, 45••]. Other tracers, 18 F-fluorthymidine (FLT), 1 8 F-fluorocholine, 1 8 Ffluoromisonidazole (FMISO) have been shown to measure proliferation rate, membrane metabolism, and oxygen metabolism, important mechanisms that are altered in tumors [43••]. However, studies evaluating the differential accuracy between PET techniques and their relative value in comparison to MRI are limited and preliminary at best.
Conclusion While the ability to directly examine tissue continues to provide the most accurate data informing diagnosis, prognosis, and treatment decisions, novel imaging technology continues to provide better methods to the noninvasive evaluation of intracranial tumors. In cases in which pathology may provide inaccurate information, such as with sampling error, imaging may help with diagnostic and treatment decisions. Methods to directly image tumor-specific metabolism are in development, such as 2-HG spectroscopy, that not only inform diagnosis but also prognosis, and may even direct future treatment. When considering observation of a lesion that appears nonneoplastic, a short-interval follow-up is the best strategy. Compliance with Ethics Guidelines Conflict of Interest Mark Daniel Anderson, Rivka Colen, and Ivo W. Tremont-Lukats declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Curr Oncol Rep (2014) 16:399
Page 7 of 8, 399
References 18.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Kim JE, Kim DG, Paek SH, Jung HW. Stereotactic biopsy for intracranial lesions: reliability and its impact on the planning of treatment. Acta Neurochir (Wien). 2003;145(7):547–54. discussion 554-545. 2. Lunsford LD, Martinez AJ. Stereotactic exploration of the brain in the era of computed tomography. Surg Neurol. 1984;22(3):222–30. 3.•• Choi C, Ganji SK, DeBerardinis RJ, et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med. 2012;18(4):624–9. An imaging technique to establish a diagnosis of an IDH mutated glioma with imaging alone is described, an important step in metabolic imaging. 4.• Rao PJ, Jyoti R, Mews PJ, Desmond P, Khurana VG. Preoperative magnetic resonance spectroscopy improves diagnostic accuracy in a series of neurosurgical dilemmas. Br J Neurosurg. 2013. A practical application of MR Spectroscopy in certain diagnostic intracranial dilemmas presenting to neurosurgeons. 5.• Rapp M, Heinzel A, Galldiks N, et al. Diagnostic performance of 18F-FET PET in newly diagnosed cerebral lesions suggestive of glioma. J Nucl Med. 2013;54(2):229–35. Evaluation of 18F-FET PET, which shows potential use in detecting glioma. 6. White ML, Zhang Y, Kirby P, Ryken TC. Can tumor contrast enhancement be used as a criterion for differentiating tumor grades of oligodendrogliomas? AJNR Am J Neuroradiol. 2005;26(4): 784–90. 7.• Reithmeier T, William O, Doostkam S, et al. Intraindividual comparison of histopathological diagnosis obtained by stereotactic serial biopsy to open surgical resection specimen in patients with intracranial tumours. Clin Neurol Neurosurg. 13 2013. Evaluation of accuracy of stereotactic biopsy in regards to tumor heterogeniety. 8. Scott JN, Brasher PM, Sevick RJ, Rewcastle NB, Forsyth PA. How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology. 2002;59(6):947–9. 9. Liu X, Almast J, Ekholm S. Lesions masquerading as acute stroke. J Magn Reson Imaging. 2013;37(1):15–34. 10. Morgenstern LB, Frankowski RF. Brain tumor masquerading as stroke. J Neurooncol. 1999;44(1):47–52. 11. Cunliffe CH, Fischer I, Monoky D, et al. Intracranial lesions mimicking neoplasms. Arch Pathol Lab Med. 2009;133(1): 101–23. 12. Haug V, Linder-Lucht M, Zieger B, Korinthenberg R, Mall V, Mader I. Unilateral venous thalamic infarction in a child mimicking a thalamic tumor. J Child Neurol. 2009;24(1):105–9. 13. Wurm G, Parsaei B, Silye R, Fellner FA. Distinct supratentorial lesions mimicking cerebral gliomas. Acta Neurochir (Wien). 2004;146(1):19–26. discussion 26. 14. Yaldizli O, Kastrup O, Wanke I, Maschke M. Basal ganglia infarction mimicking glioblastoma. Eur J Med Res. 2005;10(9):400–1. 15. Okamoto K, Ito J, Furusawa T, Sakai K, Watanabe M, Tokiguchi S. Small cortical infarcts mimicking metastatic tumors. Clin Imaging. 1998;22(5):333–8. 16. Omuro AM, Leite CC, Mokhtari K, Delattre JY. Pitfalls in the diagnosis of brain tumours. Lancet Neurol. 2006;5(11): 937–48. 17. Hourani R, Brant LJ, Rizk T, Weingart JD, Barker PB, Horska A. Can proton MR spectroscopic and perfusion imaging differentiate
19.•
20.
21.•
22.
23.•
24.
25.
26.•
27.
28.
29. 30.
31.•
32.•
33.•
34.•
between neoplastic and nonneoplastic brain lesions in adults? AJNR Am J Neuroradiol. 2008;29(2):366–72. Cha S, Knopp EA, Johnson G, Wetzel SG, Litt AW, Zagzag D. Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging. Radiology. 2002;223(1):11–29. Stevens CJ, Heran MK. The many faces of posterior reversible encephalopathy syndrome. Br J Radiol. 2012;85(1020):1566–75. Recognition that posterior reversible encephalopathy syndrome can many different presentations and appearances on imaging. Capello E, Roccatagliata L, Pagano F, Mancardi GL. Tumor-like multiple sclerosis (MS) lesions: neuropathological clues. Neurol Sci. 2001;22 Suppl 2:S113–6. Anderson MD, Raghunathan A, Gilbert MR. Textiloma resembling anaplastic progression of an isocitrate dehydrogenase 1 (IDH1) mutant, low grade glioma. J Neurooncol. 2013;111(3):377–9. Report of a case of textiloma being confused for tumor progression. Ribalta T, McCutcheon IE, Neto AG, et al. Textiloma (gossypiboma) mimicking recurrent intracranial tumor. Arch Pathol Lab Med. 2004;128(7):749–58. Garciarena P, Anderson MD, Hamilton J, et al. Textiloma mimicking recurrent glioblastoma: a case report. J Clin Oncol. 2013;31(suppl; abstr e13044). Case report of a textiloma being confused for tumor progression. Jang SW, Kim SJ, Kim SM, et al. MR spectroscopy and perfusion MR imaging findings of intracranial foreign body granuloma: a case report. Korean J Radiol. 2010;11(3):359–63. Nabika S, Kiya K, Satoh H, et al. Primary angiitis of the central nervous system mimicking dissemination from brainstem neoplasm: a case report. Surg Neurol. 2008;70(2):182–5. discussion 185. You G, Yan W, Zhang W, Li S, Li G, Jiang T. Isolated angiitis of the central nervous system with tumor-like lesion, mimicking brain malignant glioma: a case report and review of the literature. World J Surg Oncol. 2011;9:97. Reports of angiitis mimicking a tumor. Campi A, Benndorf G, Filippi M, Reganati P, Martinelli V, Terreni MR. Primary angiitis of the central nervous system: serial MRI of brain and spinal cord. Neuroradiology. 2001;43(8):599–607. Koh MS, Goh KY, Chen C, Howe HS. Cerebral infarct mimicking glioma in Sjogren’s syndrome. Hong Kong Med J. 2002;8(4): 292–4. Stern BJ, Krumholz A, Johns C, Scott P, Nissim J. Sarcoidosis and its neurological manifestations. Arch Neurol. 1985;42(9):909–17. Christoforidis GA, Spickler EM, Recio MV, Mehta BM. MR of CNS sarcoidosis: correlation of imaging features to clinical symptoms and response to treatment. AJNR Am J Neuroradiol. 1999;20(4):655–69. Auffray-Calvier E, Toulgoat F, Daumas-Duport B, Lintia Gaultier A, Desal H. Infectious and metabolic brain imaging. Diagn Interv Imaging. 2012;93(12):911–34. Application of MRI techniques to brain abscess, herpes encephalitis, Creutzfeldt-Jacob disease, posterior reversible encephalopathy, and central pontine myelinolysis. Hsu SH, Chou MC, Ko CW, et al. Proton MR spectroscopy in patients with pyogenic brain abscess: MR spectroscopic imaging versus single-voxel spectroscopy. Eur J Radiol. 2013;82(8):1299– 307. Application of advanced imaging techniques in abscess. Erdem M, Namiduru M, Karaoglan I, Kecik VB, Aydin A, Tanriverdi M. Unusual presentation of neurobrucellosis: a solitary intracranial mass lesion mimicking a cerebral tumor : a case of encephalitis caused by Brucella melitensis. J Infect Chemother. 2012;18(5):767–70. Case report of an infection process mimicking a brain tumor. Peng J, Ouyang Y, Fang WD, et al. Differentiation of intracranial tuberculomas and high grade gliomas using proton MR spectroscopy and diffusion MR imaging. Eur J Radiol. 2012;81(12):4057–63.
399, Page 8 of 8 Application of advanced imaging techniques to distinguish tuberculosis and glioma. 35. Suslu HT, Bozbuga M, Bayindir C. Cerebral tuberculoma mimicking high grade glial tumor. Turk Neurosurg. 2011;21(3): 427–9. 36. Gallia GL, DelValle L, Laine C, Curtis M, Khalili K. Concomitant progressive multifocal leucoencephalopathy and primary central nervous system lymphoma expressing JC virus oncogenic protein, large T antigen. Mol Pathol. 2001;54(5):354–9. 37. Thurnher MM, Thurnher SA, Muhlbauer B, et al. Progressive multifocal leukoencephalopathy in AIDS: initial and follow-up CT and MRI. Neuroradiology. 1997;39(9):611–8. 38.• Wu J, Langford LA, Schellingerhout D, et al. Progressive multifocal leukoencephalopathy in a patient with glioblastoma. J Neurooncol. 2011;103(3):791–6. Case report of an infectious process mimicking tumor progression. 39. Herrold JM. A syphilitic cerebral gumma manifesting as a brainstem mass lesion that responded to corticosteroid monotherapy. Mayo Clin Proc. 1994;69(10):960–1. 40.• Ventura N, Cannelas R, Bizzo B, Gasparetto EL. Intracranial syphilitic gumma mimicking a brain stem glioma. AJNR Am J Neuroradiol. 2012;33(7):E110–1. Case report of an infectious process mimicking a tumor. 41. Young GS. Advanced MRI of adult brain tumors. Neurol Clin. 2007;25(4):947–73. viii. 42. Chenevert TL, Stegman LD, Taylor JM, et al. Diffusion magnetic resonance imaging: an early surrogate marker of therapeutic efficacy in brain tumors. J Natl Cancer Inst. 2000;92(24):2029–36. 43.•• la Fougere C, Suchorska B, Bartenstein P, Kreth FW, Tonn JC. Molecular imaging of gliomas with PET: opportunities and limitations. Neuro Oncol. 2011;13(8):806–19. Application of PET imaging techniques to management of gliomas; this describes the method of PET acquisition as well as the tracers used to image biological processes in gliomas. 44. Mardor Y, Roth Y, Ochershvilli A, et al. Pretreatment prediction of brain tumors’ response to radiation therapy using high b-value diffusion-weighted MRI. Neoplasia. 2004;6(2):136–42.
Curr Oncol Rep (2014) 16:399 45.•• Nihashi T, Dahabreh IJ, Terasawa T. PET in the clinical management of glioma: evidence map. AJR Am J Roentgenol. 2013;200(6):W654–60. This is a meta-analysis that constructs a map of clinical evidence on the use of PET in glioma and helps to identify research gaps. 46. Rollin N, Guyotat J, Streichenberger N, Honnorat J, Tran Minh VA, Cotton F. Clinical relevance of diffusion and perfusion magnetic resonance imaging in assessing intra-axial brain tumors. Neuroradiology. 2006;48(3):150–9. 47. Inoue T, Ogasawara K, Beppu T, Ogawa A, Kabasawa H. Diffusion tensor imaging for preoperative evaluation of tumor grade in gliomas. Clin Neurol Neurosurg. 2005;107(3):174–80. 48. Provenzale JM, McGraw P, Mhatre P, Guo AC, Delong D. Peritumoral brain regions in gliomas and meningiomas: investigation with isotropic diffusion-weighted MR imaging and diffusiontensor MR imaging. Radiology. 2004;232(2):451–60. 49. Panchal NJ, Niku S, Imbesi SG. Lymphocytic vasculitis mimicking aggressive multifocal cerebral neoplasm: mr imaging and MR spectroscopic appearance. AJNR Am J Neuroradiol. 2005;26(3): 642–5. 50. Park KS, Ko HJ, Yoon CH, et al. Magnetic resonance imaging and proton magnetic resonance spectroscopy in neuro-Behcet's disease. Clin Exp Rheumatol. 2004;22(5):561–7. 51. Peterson PL, Axford JS, Isenberg D. Imaging in CNS lupus. Best Pract Res Clin Rheumatol. 2005;19(5):727–39. 52.•• Mills SJ, Thompson G, Jackson A. Advanced magnetic resonance imaging biomarkers of cerebral metastases. Cancer Imaging. 2012;12:245–52. A discussion of imaging biomarkers in brain metastases. 53. Sundgren PC, Edvardsson B, Holtas S. Serial investigation of perfusion disturbances and vasogenic oedema in hypertensive encephalopathy by diffusion and perfusion weighted imaging. Neuroradiology. 2002;44(4):299–304. 54. Chaskis C, Stadnik T, Michotte A, Van Rompaey K, D'Haens J. Prognostic value of perfusion-weighted imaging in brain glioma: a prospective study. Acta Neurochir (Wien). 2006;148(3):277–85. discussion 285.
