Diffusion-weighted imaging and diffusion tensor imaging as adjuncts to conventional MRI for the diagnosis and management of peripheral nerve sheath tumors: current perspectives and future directions
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Peripheral nerve sheath tumors (PNSTs) account for ~ 5% of soft tissue neoplasms and are responsible for a wide spectrum of morbidities ranging from localized neuropathy to fulminant metastatic spread and death. MR imaging represents the gold standard for identification of these neoplasms, however, current anatomic MR imaging markers do not reliably detect or differentiate benign and malignant lesions, and therefore, biopsy or excision is required for definitive diagnosis. Diffusion-weighted MR imaging (DWI) serves as a useful tool in the evaluation and management of PNSTs by providing functional information regarding the degree of diffusion, while diffusion tensor imaging (DTI) aids in determining the directional information of predominant diffusion and has been shown to be particularly useful for pre-operative planning of these tumors by delineating healthy and pathologic fascicles. The article focuses on these important neurogenic lesions, highlighting the current utility of diffusion MR imaging and future directions including computerized radiomic analysis.
• Anatomic MRI is moderately accurate in differentiating benign from malignant PNST.
• Diffusion tensor imaging facilitates pre-operative planning of PNSTs by depicting neuropathy and tractography.
• Radiomics will likely augment current observer-based diagnostic criteria for PNSTs.
KeywordsPeripheral nerves Nerve sheath neoplasms Diagnostic techniques, neurological Diffusion magnetic resonance imaging Diffusion tensor imaging
Benign peripheral nerve sheath tumor
Contrast-enhanced T1W image with fat suppression
- F18 FDG-PET
Fluorine-18 fluorodeoxyglucose positron emission tomography
Fat-saturated proton density weighted
Intravoxel incoherent motion
Maximum intensity projection
Malignant peripheral nerve sheath tumor
Neurofibromatosis type I
Neurofibromatosis type II
Peripheral nerve sheath tumor
Reversed fast imaging in steady-state free precession
Nerve sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging
Spectral attenuated inversion recovery
Short TI inversion recovery
Turbo spin echo
PNSTs are soft tissue neoplasms of Schwann cell and/or perineurial cell origin. They are responsible for a wide spectrum of morbidities ranging from localized symptoms such as pain and motor/sensory impairment to fulminant metastatic spread and death, depending on the local invasive behavior and malignant transformative potential of the lesion . Early diagnosis and treatment of these lesions is essential for the prevention of serious sequelae . MRI currently represents the gold standard for the initial identification and evaluation of PNSTs and other soft tissue neoplasms [3, 4].
Imaging features of PNSTs and their clinical correlates. BPNSTs such as neurofibromas, schwannomas, and perineuriomas may be differentiated with moderate efficacy using conventional MR imaging features. Use of FDG-PET imaging and diffusion-weighted MR imaging may augment the diagnostic accuracy of MRI in classifying these tumors. Likewise, BPNSTs may be differentiated from MPNSTs using conventional MRI, FDG-PET, diffusion-weighted MRI, and accompanying clinical features.
MR imaging appearance
SUVmax (F18 FDG-PET)
DWI and DTI
Split fat sign
Often infiltration of the parent nerve
Low (< 2–3)
Low diffusion restriction
ADC > 1.3 × 10-3 mm/s2
FA of parent nerve—reduced
Tracts—partial disruption of tracts
Mild to moderate motor-sensory symptoms
Can be either isolated or associated with NF1
Split fat sign
Cystic changes, calcification, hemorrhage (ancient schwannoma)
Eccentric to parent nerve
One or two fascicular involvement in most cases
Multi-fascicular involvement in segmental or plexiform schwanomatosis
Low (< 2–3)
High SUV can be seen in schwannomatosis but malignancy is exceedingly rare
Low diffusion restriction
ADC > 1.3–1.5 × 10-3 mm/s2
FA of parent nerve—reduced
Tracts—nearly normal or partial disruption of tracts
Mild to moderate motor-sensory symptoms
Can be either isolated or associated with NF2 or schwannomatosis
Homogeneous and uniform fascicular enlargement and hyperintensity (honeycomb pattern)
Lower limbs most common
Can be associated with port wine stain (can mimic Klippel-Trènaunay-Weber
Low (< 2–3)
Moderate diffusion restriction
ADC > 1.1 × 10-3 mm/s2
FA of parent nerve—reduced
Tracts—nearly normal and/or thickened
Mild to moderate motor symptoms
Isolated, not associated with a neurocutaneous syndrome
Irregular or round shape
Generally > 5 cm
Heterogeneous or peripheral enhancement
High (> 3–4)
High diffusion restriction
ADC < 1.1 × 10-3 mm/s2
FA of parent nerve—reduced
Tracts—partial high-grade or complete disruption of tracts
New-onset pain or focal neurological deficit
Either isolated or associated with NF1
Confirmation of a neurogenic lesion limits the differential to spontaneously arising BPNSTs and MPNSTs, as well as PNSTs arising in the setting of a neurocutaneous syndrome such as neurofibromatosis types I (NF1) and II (NF2) or schwannomatosis . Apart from size and invasiveness of the lesion, there are no reliable anatomic MRI features that help distinguish BPNSTs from MPNSTs and thus, MRI features do not preclude the necessity of biopsy for definitive diagnosis of MPNSTs . Fluorine-18 fluorodeoxyglucose positron emission tomography (F18 FDG-PET) has been proposed to improve the diagnostic yield of BPNST versus MPNST; however, it is expensive, encompasses radiation, and both false positive and false negatives are not uncommon . Therefore, its utility remains limited.
Diagnostic limitations of conventional MRI and F18 FDG-PET imaging have prompted investigation of MR diffusion contrast (i.e., DWI and DTI) that relies on characterizing the behavior of water molecules during diffusion-driven random displacement . While DWI has been shown to provide information about tumor cellularity and necrosis , DTI is well suited for the evaluation of nerve microstructure by providing functional information about the direction and degree of diffusion as well as data about nerve orientation and integrity [17, 18]. DTI with fiber tractography appears particularly promising for the characterization of PNSTs. This article provides insights into the current perspectives of conventional MRI, DWI, and DTI in the diagnosis and management of such lesions. Future directions are also highlighted, including potential use of artificial intelligence approaches (radiomics) in the foreseeable future.
Conventional MRI techniques and MR neurography
Conventional MRI techniques involve the use of 2-dimensional (2D) T1-weighted (T1W) and T2-weighted (T2W) imaging, fat-suppressed T2W (fsT2W) imaging, and contrast-enhanced T1W image with fat suppression (CE-T1W) sequences for anatomic identification and lesion characterization . The peri-lesional anatomy is best seen on T1W and tumor conspicuity is best seen on T2W imaging . Multi-planar imaging reconstructions allow interrogation of the long axis of the nerve as well as the tumor, and CE-T1W interrogates tumor vascularity as well as cystic or hemorrhagic changes [21, 22]. Limitations of conventional MRI for PNST diagnosis include non-specific signal alterations on T1W and T2W images and variable contrast enhancement [21, 22]. Because the presence of fat within and around nerve structures significantly obscures pathologic signal intensity on T2W imaging, use of either frequency-selective fat saturation or short TI inversion recovery (STIR) sequences has become commonplace . STIR improves the contrast-to-noise ratio (CNR) of soft tissue tumors by providing homogeneous fat signal suppression; however, it is more susceptible to degradation by motion and blood flow artifacts and usually results in lower signal-to-noise ratio (SNR) .
Simultaneous application of 2D methods with 3-dimensional (3D) non-selective MR neurography (MRN) sequences such as T2W spectral attenuated inversion recovery (SPAIR) and other variable turbo spin echo (TSE) sequences using variable flip angle evolutions allow better lesion localization and multi-planar isotropic tissue characterization than the 2D methods alone . The MRN techniques continue to evolve with multiple nerve-selective techniques now available on both 1.5 Tesla (T) and 3T platforms. These include 3D DW reversed fast imaging in steady-state free precession (PSIF), 3D T2W TSE Dixon, and nerve sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI), which provide excellent nerve tissue CNR and fascicular details with effective vascular signal and background fat suppression . Using these techniques, anatomic detail of the tumor and nerve can be generated at the fascicular level with sub-millimeter resolution, aiding in pre-operative planning of PNSTs. MRN techniques can also be employed to identify post-operative tumor recurrence, which presents as a focal, irregular, nodular, hyperintense nerve enlargement or mass in the operated tumor bed with enhancement on CE-T1W .
Key MRI characteristics of PNSTs
Diffusion-weighted MR imaging
An increasingly diverse array of diffusion-weighted MR imaging techniques has allowed invaluable diagnostic advances in the field of neuroimaging over the past two decades. The common theoretical framework for these techniques is built upon the physical principles of free molecular diffusion, described as the Brownian motion. In contrast, biological tissues are complex media which impose bounded domains that interfere with free diffusion, the most significant of which is the cell membrane .
In DWI, displacement along the axis of the diffusion gradient is visualized as attenuation of MR signal intensity. The opposite phenomenon is observed among highly cellular tissues, such as tumors, where there is greater restriction of free diffusion along the axis of the diffusion gradient, and consequently, high signal intensity.
Due to differences in the way manufacturers implement calculation of ADC, and inherent differences in water diffusion in human tissue compared to laboratory models used for ADC estimation, this technique suffers from certain limitations . Although the ADC can provide valuable quantitative data concerning tissue diffusivity, it is sensitive to the effects of micro-capillary perfusion, also known as pseudodiffusivity . Using multi-b value diffusion-weighted MR imaging, it is possible to differentiate the effects of diffusion and pseudodiffusion by interrogating parameters of intravoxel incoherent motion (IVIM) . Because of their ability to characterize the effects of capillary perfusion, IVIM surrogate imaging markers have been explored as a possible alternative to contrast enhancement for characterizing lesion vascularity in some tumors . However, the application of these markers in the setting of PNSTs remains unexplored.
DWI does not provide directional information in the setting of anisotropic diffusion. DTI overcomes this limitation by sampling diffusion across six or more gradient directions, thereby allowing visualization of anisotropic diffusion across multiple axes simultaneously [34, 35]. Mean diffusivity [MD] is thought to be more useful than ADC in the domain of PNSTs due to larger number of directions in diffusion encoding . The degree of anisotropy of a tissue is easily obtained through the calculation of fractional anisotropy [FA]. FA is indexed from 0 to 1, with FA = 0 representing free isotropic diffusion and FA = 1 representing complete anisotropy. The FA of pathologic nerves is usually lower than that which is seen in healthy contralateral nerves, possibly reflecting myelin loss and/or axonal degeneration of involved nerve segments .
Fiber tractography can be used to accurately delineate healthy and pathologic fascicles in most PNSTs, as well as in the setting of other PNS pathologies [17, 36]. Tract disruption is often more severe in MPNSTs than BPNSTs, with BPNSTs usually exhibiting a near normal appearance and partial rather than complete tract disruption [17, 18]. The treatment goal for most PNSTs is gross total resection with neural preservation; however, there is often considerable difficulty in the intra-operative delineation of healthy and pathologic nerve tissues . Pre-operative visualization of the fascicular course and integrity using fiber tractography is therefore likely to be of great value for surgical planning and subsequent preservation of existing nerve function following tumor resection. In a preliminary study by Schmidt M et al , there was good correlation of pre-operative fascicular visualization and intra-operative anatomy. The authors did not attempt correlation of DTI measurements of different areas of neural topography with intra-operative electrophysiology to define fascicular involvement and function, which can be a subject of future research using this novel technique. In median nerves, the optimization of reconstruction parameters for fiber tractography on echo planar imaging is best achieved at a b value of 1200 s/mm2, with a maximum angulation tolerance of 10 degrees and minimum FA threshold of 0.2 . Reproducibility of tractography, anisotropy, and diffusivity, however, remains a challenge even in healthy subjects without disease, when the peripheral nerve (lumbosacral nerve roots) DTI is obtained after an interval, as recently shown by Haakma W et al . Nevertheless, DTI tractography remains a work in progress, with a recent study showing improved tractography and less image distortion using single-shot spin echo sequences as compared to echo planar imaging in the domain of lumbar nerve root evaluation .
DTI seems promising in the domain of PNST diagnosis, pre-operative planning, and characterization. Augmentation of diagnostic accuracy has been shown in peripheral neuropathy . However, no large efforts have yet been undertaken to classify peripheral nerve tumors based on parameters of diffusivity, or to corroborate these markers using histology, electrophysiology, and intravenous contrast perfusion imaging. Scientific studies are relatively lacking in demonstrating the utility of these techniques in correlation of nerve function with the size or type of tumor. While newer methods of exploiting DWI and DTI are available including multi-shot DTI, kurtosis, and histogram analysis, more research is needed to demonstrate their efficacy . Limitations in DTI mapping, such as an inability to resolve more than a single fiber orientation, may soon be overcome by employment of techniques like q-ball imaging, which provide enhanced angular resolution in lesions with tortuously coursing fascicles and multiple fiber directions [43, 44]. New MRN methods such as SHINKEI quant or 3D T2W TSE Dixon quant are becoming available for T2 mapping during nerve-selective neurography, and may be useful to distinguish different tumor types quantitatively .
Beyond the realm of MR technologies, the advent of artificial intelligence-directed radiomics and high-throughput image mining promises to reveal new imaging signatures that will augment or, perhaps, supersede current diagnostic models in oncology . Radiomics refers to the automated quantification of a radiographic phenotype. It uses computerized approaches for generation of a convolutional neural network, initial machine learning followed by validation and evaluation of test data sets. Many quantitative measures, also known as radiomic measures, such as intensity, shape, texture, wavelet, and LOG features, are extracted by the machine from the image data sets. Using deep learning methods and multi-order statistics to one or more MRI sequences in isolation and/or combination, many diagnostic, predictive, or prognostic imaging markers can be derived. In our recent evaluation of benign versus malignant soft tissue musculoskeletal tumors using simple T2W imaging, 85–90% accuracy was achieved using radiomics for multiple geometric and textural pathologic features (work under review). We also compared the accuracy of radiomic analysis to the accuracy of expert radiologists, and the former exceeded reader diagnostic capability. Computational approaches such as these are expected to improve diagnostic confidence among radiologists and can uncover quantitative imaging characteristics that fail to be appreciated by the naked eye. If one could differentiate schwannoma from neurofibroma, the automated approach of radiomics could substantially aid pre-surgical planning and assist in patient management and prognostication.
To summarize, diffusion imaging augments the moderate diagnostic utility of conventional MR imaging. As newer functional MR technologies and software approaches become increasingly familiar and available, it is likely that their utility will continue to expand outward beyond applications in the central nervous system to improve the diagnosis and management of PNSTs.
The authors state that this work has not received any funding.
Compliance with ethical standards
The scientific guarantor of this publication is Avneesh Chhabra, MD.
Conflict of interest
The authors of this manuscript declare relationships with the following companies: AC receives royalties from Jaypee and Wolters. AC also serves as consultant with ICON Medical.
The remaining authors declare that they have no conflicts of interest.
Statistics and biometry
No complex statistical methods were necessary for this paper.
For this type of study, formal consent is not required.
Institutional Review Board approval was obtained.
Study subjects or cohorts overlap
One study subject has been previously reported in AJNR News Digest, May–June 2017, but the images submitted herein are different from those submitted in that digest.
• Performed at one institution
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